Science, Faculty of
Chemistry, Department of
DSpace
UBCV
Bolduc, Trevor G.
Doctor of Philosophy - PhD
University of British Columbia
The development of mild, selective, efficient, and economical chemical transformations is a foundation of modern synthetic organic chemistry. These chemical processes may be utilized in the syntheses of pharmaceutical compounds, facilitating improved approaches to complex targets. Novel reagents are often created and studied during the development of these more effective protocols. This dissertation explores several synthetic applications of sulfuryl fluoride and thionyl fluoride as reagents in useful chemical processes. Little is known about the synthetic applications of thionyl fluoride, and the work presented herein includes some of the first investigations of this chemical as a reagent in synthetic organic chemistry. Chapter 2 describes the sulfuryl fluoride-mediated transformation of thiols to the corresponding 1,1-dihydrofluoroalkyl sulfide. The primary themes of the work outlined in this chapter include investigations into the chemoselectivity of the title reaction for thiols over other nucleophilic moieties, as well as an expansion of the scope of 1,1-dihydrofluoroalcohols. In Chapter 3, the kinetics of the one-pot sulfuryl fluoride-mediated activation and nucleophilic acyl substitution of carboxylic acids are explored using quantitative 1H and 19F nuclear magnetic resonance spectroscopy. The addition of a tetrabutylammonium halide salt additive as much as doubles the rate of formation of the intermediate acyl fluoride, yet there is no effect on the rate of consumption of this intermediate by the nucleophilic coupling partner. Contributions made to the substrate scope are further outlined in this chapter. Chapter 4 details a comprehensive study of several new synthetic applications of thionyl fluoride in the context of carboxylic acid activation. One-pot, column-free nucleophilic acyl substitutions and one-pot, mild reductions are described in this work. Activated esters, amides, and alcohols are all accessible via the corresponding acyl fluoride intermediate. Chapter 5 explores an expedited one-pot, thionyl-fluoride mediated conversion of sulfinic acids to the corresponding sulfonimidoyl fluoride, utilizing bench-stable and accessible reagents. Sulfonimidoyl fluorides bear both synthetic and pharmaceutical relevance as they enable direct access to other highly desirable sulfur(VI) motifs. This work serves as an advancement over comparable literature protocols as no unstable intermediates need be isolated, and the reaction is conducted in a single reaction vessel.
INVESTIGATIONS OF ONE-POT SYNTHETIC TRANSFORMATIONS MEDIATED BY SULFURYL FLUORIDE AND THIONYL FLUORIDE by Trevor G. Bolduc B.Sc. (Honours), University of Victoria, 2018 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) September 2023 © Trevor G. Bolduc, 2023 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Investigations of One-Pot Synthetic Transformations Mediated by Sulfuryl Fluoride and Thionyl Fluoride submitted by Trevor G. Bolduc in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry Examining Committee: Glenn M. Sammis, Professor, Chemistry, UBC Supervisor Laurel L. Schafer, Professor, Chemistry, UBC Supervisory Committee Member Gregory R. Dake, Associate Professor, Chemistry, UBC University Examiner Allan K. Bertram, Professor, Chemistry, UBC University Examiner Additional Supervisory Committee Members: Jason E. Hein, Associate Professor, Chemistry, UBC Supervisory Committee Member Parisa Mehrkhodavandi, Professor, Chemistry, UBC Supervisory Committee Member iii Abstract The development of mild, selective, efficient, and economical chemical transformations is a foundation of modern synthetic organic chemistry. These chemical processes may be utilized in the syntheses of pharmaceutical compounds, facilitating improved approaches to complex targets. Novel reagents are often created and studied during the development of these more effective protocols. This dissertation explores several synthetic applications of sulfuryl fluoride and thionyl fluoride as reagents in useful chemical processes. Little is known about the synthetic applications of thionyl fluoride, and the work presented herein includes some of the first investigations of this chemical as a reagent in synthetic organic chemistry. Chapter 2 describes the sulfuryl fluoride-mediated transformation of thiols to the corresponding 1,1-dihydrofluoroalkyl sulfide. The primary themes of the work outlined in this chapter include investigations into the chemoselectivity of the title reaction for thiols over other nucleophilic moieties, as well as an expansion of the scope of 1,1-dihydrofluoroalcohols. In Chapter 3, the kinetics of the one-pot sulfuryl fluoride-mediated activation and nucleophilic acyl substitution of carboxylic acids are explored using quantitative 1H and 19F nuclear magnetic resonance spectroscopy. The addition of a tetrabutylammonium halide salt additive as much as doubles the rate of formation of the intermediate acyl fluoride, yet there is no effect on the rate of consumption of this intermediate by the nucleophilic coupling partner. Contributions made to the substrate scope are further outlined in this chapter. Chapter 4 details a comprehensive study of several new synthetic applications of thionyl fluoride in the context of carboxylic acid activation. One-pot, column-free nucleophilic acyl iv substitutions and one-pot, mild reductions are described in this work. Activated esters, amides, and alcohols are all accessible via the corresponding acyl fluoride intermediate. Chapter 5 explores an expedited one-pot, thionyl-fluoride mediated conversion of sulfinic acids to the corresponding sulfonimidoyl fluoride, utilizing bench-stable and accessible reagents. Sulfonimidoyl fluorides bear both synthetic and pharmaceutical relevance as they enable direct access to other highly desirable sulfur(VI) motifs. This work serves as an advancement over comparable literature protocols as no unstable intermediates need be isolated, and the reaction is conducted in a single reaction vessel. v Lay Summary The development of new reactions is a cornerstone of modern synthetic organic chemistry. New protocols are developed to more readily access chemical motifs that bear pharmaceutical, industrial, or synthetic relevance. Some of the major limitations to a given reaction are the conditions or chemical agents required to facilitate the process, which may lead to undesirable outcomes. The study and development of new reagents and protocols is therefore crucial to enable more control over chemical reactivity. This thesis describes the investigations made into the synthetic applications of two gaseous sulfur-fluorine agents. These two chemicals were used to synthesize and study fluorinated chemical motifs that are otherwise difficult-to-access with other reported protocols. The reactions outlined herein are facile to perform, make use of commercially available starting materials, and can be conducted using mild reagents and conditions. The design of straightforward one-pot reactions is a central theme to this work. vi Preface Chapter 2 is based on research performed in the Sammis group with my colleagues Dr. Paul J. Foth, Frances Gu, Sahil S. Kanani, and Prof. Glenn M. Sammis. This work was published as a communication in 2019: Foth, P. J.; Gu, F.; Bolduc, T. G.; Kanani, S. S.; Sammis, G. M. Chem. Sci. 2019, 10, 10331–10335. The reaction development and optimization were performed by Foth with assistance from Gu. All experiments pertaining to the substrate scope of this work that are presented in this chapter were performed by me, including syntheses, characterization, and experimental work. Substrates that I did not study have been omitted and were instead studied by Foth, Gu, and Kanani. I contributed to the writing and revision of the associated manuscript. Chapter 3 is based on research performed in the Sammis group with my colleagues Dr. Paul J. Foth, Hao Yu, and Prof. Glenn M. Sammis, in collaboration with Prof. Jason E. Hein and Dr. Thomas C. Malig of the Hein group at the University of British Columbia. This work was published as a communication in 2020: Foth, P. J.; Malig, T. C.; Yu, H.; Bolduc, T. G.; Hein, J. E.; Sammis, G. M. Org. Lett. 2022, 22 (16), 6682–6686. The reaction development and optimization were performed by Foth. The ReactIR experiments were performed by Malig. All quantitative 19F NMR spectroscopy experiments were designed and performed by me. All experiments pertaining to the substrate scope or competition experiments of this work that are presented in this chapter were performed by me, including syntheses, characterization, and experimental work. Substrates that I did not study have been omitted and were instead studied by Foth and Yu. I contributed to the writing and revision of the associated manuscript. Chapter 4 is based on research performed in the Sammis group with my colleagues Dr. Chia Wei Lee, William P. Chappell, and Prof. Glenn M. Sammis. This work was published as a vii communication in 2022: Bolduc, T. G.; Lee, C.; Chappell, W. P., Sammis, G. M. J. Org. Chem. 2022, 87 (11), 7308–7318. The reaction development, optimization, and substrate scope of the peptide couplings were performed by Dr. Chia Wei Lee. The reaction development, optimization, and substrate scope of the thioester coupling were performed by William P. Chappell—a Ph.D. student in the Sammis group—under my supervision. All experiments pertaining to the reaction development, optimization, and substrate scope of activated esters, activated amides, and alcohols in this work that are presented in this chapter were performed by me, including syntheses, characterization, and experimental work. I wrote the associated manuscript and supporting information, with consultation and revisions from Lee, Chappell, and Prof. Sammis. Chapter 5 is based on research performed in the Sammis group with my colleagues Brodie J. Thomson, Carlota Bahri, William Yang, Kathleen T. Downey, and Prof. Glenn M. Sammis. A manuscript describing this work is in preparation. Initial experiments investigating possible routes to sulfonimidoyl fluorides were performed by Downey and myself. The separate reaction development, optimization, and substrate scope of sulfinyl fluorides was performed by Brodie J. Thomson and is omitted from this chapter. The one-pot reaction development and optimization for the synthesis of sulfonimidoyl fluorides from sulfinic acids was performed by me. The design of the substrate scope of sulfonimidoyl fluorides was performed by me. All experiments pertaining to the substrate scope development were performed by Bahri and Yang—two undergraduate students—under my supervision, as well as by me, including syntheses, characterization, and experimental work. Sulfonimidoyl fluorides synthesized by Bahri or Yang are indicated as such in the main body of text and in Scheme 5.21 in Chapter 5. I will write the associated manuscript with consultation and revisions from Thomson and Prof. Sammis. viii Table of Contents Abstract ......................................................................................................................................... iii Lay Summary .................................................................................................................................v Preface ........................................................................................................................................... vi Table of Contents ....................................................................................................................... viii List of Tables .............................................................................................................................. xvi List of Figures ............................................................................................................................ xvii List of Schemes ........................................................................................................................... xix List of Symbols ......................................................................................................................... xxix List of Abbreviations .................................................................................................................xxx Acknowledgements ................................................................................................................ xxxvi Dedication ............................................................................................................................. xxxviii Chapter 1: Introduction ................................................................................................................1 1.1 Synthetic organic chemistry and chemical methodology ............................................... 1 1.2 Fluorine incorporation in organic molecules .................................................................. 2 1.3 Synthetic fluorination reagents ....................................................................................... 5 1.3.1 Traditional synthetic fluorination reagents ................................................................. 5 1.3.2 Gaseous fluorination reagents ..................................................................................... 6 1.3.2.1 Sulfuryl fluoride (SO2F2) .................................................................................... 6 1.3.2.2 Thionyl Fluoride (SOF2) ................................................................................... 12 1.4 Personal contributions ................................................................................................... 17 Chapter 2: Sulfuryl Fluoride-Mediated 1,1-Dihydrofluoroalkylation of Thiols ....................21 ix 2.1 1,1-Dihydrofluoroalkylated thiols: applications, properties, and existing synthetic approaches................................................................................................................................. 21 2.1.1 Applications and properties of 1,1-dihydrofluoroalkylated thiols ............................ 21 2.1.2 Existing synthetic approaches to the synthesis of 1,1-dihydrofluoroalkylated thiols22 2.1.3 Literature precedent: the sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of amines ………………………………………………………………………………………31 2.1.4 Sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of thiols: initial work (Foth, Gu, Kanani) ........................................................................................................................... 32 2.2 Results and discussion .................................................................................................. 35 2.2.1 Competition studies of the sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of thiols ………………………………………………………………………………………35 2.2.2 Substrate scope of the sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of thiols ………………………………………………………………………………………39 2.3 Conclusions ................................................................................................................... 47 2.4 Experimental information ............................................................................................. 48 2.4.1 General methods ....................................................................................................... 48 2.4.2 General procedure for the determination of NMR spectroscopy yields ................... 49 2.4.3 Sulfuryl fluoride safety ............................................................................................. 49 2.4.4 2,2,2-Trifluoroethylation of thiols ............................................................................ 50 2.4.4.1 General procedure for the one-pot 2,2,2-trifluoroethylation of thiols .............. 50 2.4.4.2 General procedure for the one-pot sequential 2,2,2-trifluoroethylation of thiols …………………………………………………………………………………51 x 2.4.4.3 General isolation and purification of the one-pot and one-pot sequential 2,2,2-trifluoroethylation of thiols ............................................................................................... 51 2.4.5 2,2,3,3,3-Pentafluoropropylation of thiols ................................................................ 52 2.4.5.1 General procedure for the one-pot 2,2,3,3,3-pentafluoropropylation of thiols . 52 2.4.5.2 General procedure for the one-pot sequential 2,2,3,3,3-pentafluoropropylation of thiols …………………………………………………………………………………53 2.4.5.3 General isolation and purification of the one-pot and one-pot sequential 2,2,3,3,3-pentafluoropropylation of thiols ........................................................................ 53 2.4.6 Workup and purification for compound 2.10g ......................................................... 54 2.4.7 Workup and purification for compound 2.10h ......................................................... 54 2.4.8 2,2,2-Trifluoroethylation competition study between benzyl mercaptan (2.7e) and pyrrolidine (2.48) .................................................................................................................. 55 2.4.9 2,2,2-Trifluoroethylation of piperidine (2.50) .......................................................... 56 2.4.10 2,2,2-Trifluoroethylation of glutathione (2.52) with 2,2,2-trifluoroethyl triflate (2.53) ……………………………………………………………………………………57 2.4.11 Characterization data of 2.10d, 2.10e, 2.10g, 2.10h, 2.10k, 2.10l, , 2.11d, 2.11e, 2.11i, 2.11j, 2.29a, and 2.29b ................................................................................................ 58 Chapter 3: Mechanistic Studies of the Sulfuryl Fluoride-Mediated Generation and One-Pot Nucleophilic Acyl Substitution of Acyl Fluorides .....................................................................64 3.1 Acyl fluorides: applications, properties, and existing synthetic approaches ................ 64 3.1.1 Applications and properties of acyl fluorides ........................................................... 64 3.1.2 Existing synthetic approaches to the synthesis of acyl fluorides .............................. 69 xi 3.1.3 Literature precedent: the sulfuryl fluoride-mediated synthesis of acyl fluorides, and the one-pot synthesis of esters and amides from carboxylic acids ....................................... 77 3.2 Results and discussion .................................................................................................. 80 3.2.1 Mechanistic analyses of the sulfuryl fluoride-mediated generation and one-pot nucleophilic acyl substitution of acyl fluorides using NMR spectroscopy........................... 80 3.2.2 Substrate scope of the sulfuryl fluoride-mediated generation and one-pot nucleophilic acyl substitution of acyl fluorides ......................................................................................... 92 3.3 Conclusions ................................................................................................................... 98 3.4 Experimental information ............................................................................................. 99 3.4.1 General methods ....................................................................................................... 99 3.4.2 General procedure for the quantitative determination of NMR spectroscopy yields ……………………………………………………………………………………..100 3.4.3 General procedure for the one-pot synthesis and nucleophilic acyl substitution of acyl fluorides .............................................................................................................................. 100 3.4.4 Procedure for the synthesis and isolation of acyl fluorides 3.1g and 3.1h.............. 102 3.4.5 Quantitative NMR spectroscopy data for the one-pot synthesis and nucleophilic acyl substitution of acyl fluorides ............................................................................................... 103 3.4.6 Characterization data of compounds 3.1g–h, 3.48f–j, and 3.58–3.60 .................... 103 Chapter 4: Thionyl Fluoride-Mediated One-Pot Esterifications, Amidations, and Reductions of Carboxylic Acids via Acyl Fluorides ....................................................................................108 4.1 Acyl fluorides, activated esters, and amides: applications, properties, and existing synthetic approaches ............................................................................................................... 108 4.1.1 Acyl fluorides.......................................................................................................... 108 xii 4.1.2 N-Hydroxyphthalimidyl esters and N-hydroxysuccinimidyl esters ........................ 110 4.1.3 Weinreb and morpholine amides ............................................................................ 113 4.2 Reductions of carboxylic acids to primary alcohols ................................................... 116 4.2.1 Direct reductions of carboxylic acids ..................................................................... 116 4.2.2 Reductions of carboxylic acid derivatives .............................................................. 122 4.2.3 Literature precedent: the cyanuric fluoride-mediated two-step reduction of carboxylic acids via isolated acyl fluoride intermediates and sulfuryl fluoride-mediated one-pot reductions ............................................................................................................................ 123 4.3 Project goals: one-pot, thionyl fluoride mediated esterifications, amidations, and reductions of carboxylic acids ................................................................................................ 125 4.4 Results and discussion ................................................................................................ 126 4.4.1 Attempted synthesis of N-hydroxyphthalimidyl and N-hydroxysuccinimidyl esters utilizing thionyl fluoride ..................................................................................................... 126 4.4.2 Substrate scope of the thionyl fluoride-mediated one-pot and column-free esterifications and amidations of carboxylic acids via acyl fluorides ................................. 130 4.4.3 Attempted one-pot SOF2-mediated reductions of carboxylic acids via non-isolated acyl fluoride intermediates .................................................................................................. 142 4.4.4 Substrate scope of the thionyl fluoride-mediated one-pot reduction of carboxylic acids via acyl fluorides ................................................................................................................. 145 4.5 Conclusions ................................................................................................................. 153 4.6 Experimental information ........................................................................................... 155 4.6.1 General methods ..................................................................................................... 155 4.6.2 Procedure for the generation of thionyl fluoride (SOF2) ........................................ 156 xiii 4.6.3 General procedure for the synthesis of activated esters (4.7 and 4.8) .................... 157 4.6.4 General procedure for the synthesis of non-activated esters (4.5c and 4.5d) ......... 158 4.6.5 General procedure for the synthesis of Weinreb (4.15) and morpholine (4.16) amides ……………………………………………………………………………………..159 4.6.6 General procedure for the synthesis of alcohols (4.6) ............................................ 160 4.6.7 Characterization data of 4.3p, 4.3q, 4.5c, 4.5d, 4.6c, 4.6e, 4.6f, 4.6i–z, 4.6aa, 4.6ab, 4.7e–q, 4.8e–q, 4.15a, 4.15b, 4.16a, and 4.16b ................................................................... 161 Chapter 5: Thionyl Fluoride-Mediated One-Pot Conversions of S(IV)-Sulfinic Acids to S(VI)-Sulfonimidoyl Fluorides ..................................................................................................190 5.1 Sulfonimidoyl fluorides: applications, properties, and existing synthetic approaches 190 5.1.1 Properties of sulfonimidoyl fluorides ..................................................................... 190 5.1.2 Applications of sulfonimidoyl fluorides ................................................................. 193 5.1.3 Existing synthetic approaches to the synthesis of sulfonimidoyl fluorides ............ 198 5.2 Results and discussion ................................................................................................ 205 5.2.1 Summary of approaches taken towards the synthesis of sulfonimidoyl fluorides .. 205 5.2.2 Initial approaches to the synthesis of sulfonimidoyl fluoride: N-methylimidazolium sulfinyl fluoride hexafluorophosphate (MISF) ................................................................... 206 5.2.3 The attempted synthesis of sulfonimidoyl fluorides via an iminosulfur oxydifluoride intermediate......................................................................................................................... 211 5.2.4 The attempted synthesis of sulfonimidoyl fluoride precursors via ((arylsulfonyl)oxy)carbamates ............................................................................................ 212 5.2.5 A new approach: the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides from sulfinic acids............................................................................................................... 213 xiv 5.2.6 Attempted one-pot synthesis of 4-methyl-N-tosylbenzenesulfonimidoyl fluoride from 4-methylbenzenesulfinic acid ............................................................................................. 215 5.2.7 Substrate scope of sulfinic acids for the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides ....................................................................................................... 224 5.3 Conclusions ................................................................................................................. 229 5.4 Experimental information ........................................................................................... 230 5.4.1 General methods ..................................................................................................... 230 5.4.2 Procedure for the generation of thionyl fluoride (SOF2) ........................................ 230 5.4.3 Procedure for the reduction of sulfonyl chlorides to sulfinic acids ........................ 231 5.4.4 General procedure for the SOF2-mediated conversion of S(IV)-sulfinic acids to S(VI)-sulfonimidoyl fluorides 5.1d–t ............................................................................................ 232 5.4.5 Characterization data of compounds 5.1d–5.1t....................................................... 233 Chapter 6: Conclusion ...............................................................................................................245 6.1 Chapter 2: conclusions and future work ..................................................................... 245 6.2 Chapter 3: conclusions and future work ..................................................................... 246 6.3 Chapter 4: conclusions and future work ..................................................................... 248 6.4 Chapter 5: conclusions and future work ..................................................................... 249 6.5 Potential future directions of thionyl fluoride as a synthetic reagent ......................... 253 6.6 Summary of Conclusions ............................................................................................ 255 References ...................................................................................................................................256 Appendices ..................................................................................................................................276 Appendix A Selected Spectra for Chapter 2 ........................................................................... 276 Appendix B Selected Spectra for Chapter 3 ........................................................................... 290 xv Appendix C Selected Spectra for Chapter 4 ........................................................................... 298 Appendix D Selected Spectra for Chapter 5 ........................................................................... 350 xvi List of Tables Table 4.1. Base optimization of the SOF2-mediated one-pot synthesis of activated esters. ....... 128 Table 4.2. Time and temperature optimization of the SOF2-mediated one-pot synthesis of activated esters. .......................................................................................................................................... 129 Table 4.3. Optimization of the SOF2-mediated general esterification of 3,3-diphenylpropionic acid...................................................................................................................................................... 138 Table 4.4. Reductant and time investigations of the one-pot SOF2-mediated reduction of carboxylic acids. ........................................................................................................................................... 145 Table 5.1. Initial attempts to synthesize 5.56 from MISF and chloramine T. ............................ 208 Table 5.2. Initial attempts to synthesize 5.56 from SOCl2 and chloramine T. ........................... 209 Table 5.3. Initial attempts to synthesize iminosulfur oxydifluorides from SOF2 and chloramine T...................................................................................................................................................... 212 Table 5.4. Base optimization of the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides...................................................................................................................................................... 217 Table 5.5. Optimization of chloramine T for the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides. ..................................................................................................................................... 220 Table 5.6. Optimization of volume of toluene for the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides. .............................................................................................................. 221 Table 5.7. Reaction temperature optimization for the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides. .............................................................................................................. 222 Table 5.8. Examination of the effects of moisture on the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides. .............................................................................................................. 223 xvii List of Figures Figure 1.1. Representative examples of common fluorinated motifs in FDA-approved pharmaceutical compounds. ............................................................................................................ 2 Figure 1.2. Representative examples of traditional and common fluorination reagents. ............... 6 Figure 2.1. Chemical structure of 1,1-dihydrofluoroalkyl thiols. ................................................. 21 Figure 2.2. Chemical structures of some representative pharmaceutically and agrochemically relevant compounds with the 1,1-dihydrolfuoroalkyl motif. ........................................................ 22 Figure 2.3. General reaction setup for the 2,2,2-trifluoroethylation of thiols. .............................. 50 Figure 3.1. The reactivity trend of acyl halides correlates to the pKa of the conjugate acid of their leaving groups. .............................................................................................................................. 64 Figure 3.2. Common reagents used for the synthesis of acyl fluorides. ....................................... 70 Figure 3.3. Common sulfur-based reagents used for the synthesis of acyl fluorides. .................. 72 Figure 3.4. The effects of tetrabutylammonium halide additives on the rate of (a) the formation of 3-phenylpropanoyl fluoride (3.1f) from 3-phenylpropionic acid (3.17f), and (b) formation of 3.48f with N-hydroxysuccinimide (3.49). .............................................................................................. 82 Figure 3.5. The effects of tetrabutylammonium chloride on the rate of (a) the formation of 3-phenylpropanoyl fluoride (3.1f) from 3-phenylpropionic acid (3.17f), and (b) formation of 3.51 with aniline (3.50). ........................................................................................................................ 84 Figure 3.6. The effects of tetrabutylammonium chloride on the rate of formation of (a) benzoyl fluoride (3.1c), (b) 4-methoxybenzoyl fluoride (3.1a), and (c) 3-fluorobenzoyl fluoride (3.1g), as well as formation of (d) 3.48c, (e) 3.48a, and (f) 3.48g with N-hydroxysuccinimide (3.49). ...... 87 xviii Figure 3.7. 24-Hour experiment studying the effects of tetrabutylammonium chloride on the rate of (a) formation of 4-methoxybenzoyl fluoride (3.1a), and (b) formation of 3.48a with N-hydroxysuccinimide (3.49). .......................................................................................................... 89 Figure 3.8. Diagram of the reaction setup for the SO2F2-mediated synthesis and coupling of acyl fluorides. ..................................................................................................................................... 100 Figure 4.1. N-Hydroxyphthalimidyl and N-hydroxysuccinimidyl esters, along with their respective leaving groups (shown as the conjugate acids). .......................................................................... 110 Figure 4.2. Schematic of SOF2 generation apparatus. ................................................................ 156 Figure 5.1. The chemical structures of sulfonimidoyl fluorides and chlorides, as well as other sulfur(IV) and sulfur(VI) compounds. ........................................................................................ 190 Figure 5.2. Envisioned approach for the rapid synthesis of sulfonimidoyl fluorides directly from SOF2, by way of a sulfur(VI) iminosulfur oxydifluoride intermediate. ..................................... 211 Figure 5.3. Sulfonimidoyl fluoride substrates under development in the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides from sulfinic acids. ........................................................... 229 xix List of Schemes Scheme 1.1. Illustrated representation of methodology in synthetic organic chemistry, depicted as a generic chemical modification of a given class of substrate compounds with an optimized set of reaction conditions. ......................................................................................................................... 1 Scheme 1.2. The relative reactivity of acyl fluorides versus acyl chlorides in the presence of various nucleophiles (a) and their respective reactivities in peptide coupling processes (b). ........ 4 Scheme 1.3. The relative reactivity of sulfonyl fluorides versus sulfonyl chlorides in the presence of organolithium nucleophiles (a), and the respective reactivities of the mono-aza equivalents (b).......................................................................................................................................................... 5 Scheme 1.4. Some representative syntheses of sulfuryl fluoride by (a) Moissan, (b) the Dow Chemical Company, and (c) De Borggraeve. ................................................................................. 7 Scheme 1.5. (a) Firth’s and (b) Sharpless’ syntheses of polysulfate polymers and copolymers. ... 8 Scheme 1.6. Sharpless’ syntheses of (a) sulfamoyl fluorides, and (b) aryl fluorosulfates, as well as (c) representative examples of some synthetic applications of aryl fluorosulfates, accessed from SO2F2............................................................................................................................................... 9 Scheme 1.7. Representative examples of the synthetic applications of SO2F2 towards alcohol activation. ...................................................................................................................................... 11 Scheme 1.8. Representative examples of the synthetic applications of SO2F2 towards the activation of non-alcohol functional groups. ................................................................................................. 12 Scheme 1.9. (a) Meslans’ and (b) Coffman’s syntheses of thionyl fluoride with nucleophilic fluorine sources. ............................................................................................................................ 12 Scheme 1.10. Shreeve’s use of SOF2 in the fluorination of various compounds. ........................ 13 xx Scheme 1.11. Sammis’ (a) column-free SOF2-mediated one-pot peptide coupling of amino acids via acyl fluorides, and (b) SO2F2-mediated one-pot coupling of carboxylic acids via acyl fluorides........................................................................................................................................................ 15 Scheme 1.12. Sammis’ room temperature ex situ synthesis of SOF2 under neat conditions. ....... 15 Scheme 1.13. Relative reactivity of SOF2 versus SO2F2 with stereochemically defined carboxylic acid substrates, and the effects of the reactive intermediates formed in situ on the overall reaction........................................................................................................................................................ 17 Scheme 1.14. Sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of thiols (Chapter 2). ..... 18 Scheme 1.15. Mechanistic studies of the sulfuryl fluoride-mediated generation and one-pot nucleophilic acyl substitution of acyl fluorides (Chapter 3). ........................................................ 18 Scheme 1.16. Thionyl fluoride-mediated one-pot esterifications, amidations, and reductions of carboxylic acids via acyl fluorides (Chapter 4). ........................................................................... 19 Scheme 1.17. Thionyl fluoride-mediated one-pot conversions of S(IV)-sulfinic acids to S(VI)-sulfonimidoyl fluorides (Chapter 5).............................................................................................. 20 Scheme 2.1. General SN2-based approaches to the synthesis of 1,1-dihydrofluoroalkyl sulfides with thiol nucleophiles. ................................................................................................................. 22 Scheme 2.2. Representative SN2 approaches to 1,1-dihydrofluoroalkyl thiols. ........................... 24 Scheme 2.3. Zhang’s cascade trifluoroethylation-cyclization of isothiocyanates. ....................... 25 Scheme 2.4. Lukin’s radical approach to 1-chloro-1-hydrofluoroalkyl thiols. ............................. 25 Scheme 2.5. Weng’s copper-catalyzed approach to 1,1-dihydrofluoroalkyl thiols. ..................... 26 Scheme 2.6. Gouverneur’s copper-catalyzed approaches to 1,1-dihydrofluoroalkyl thiols and 1-aryl-1-hydrofluoroalkyl thiols. ...................................................................................................... 27 xxi Scheme 2.7. Titanyuk’s and Menczinger’s copper-catalyzed approaches to 1,1-dihydrofluoroalkyl thiols. ............................................................................................................................................. 28 Scheme 2.8. Phosphorous-induced reductive approaches to 1,1-dihydrofluoroalkyl thiols. ........ 29 Scheme 2.9. Johannes’ photoredox catalysis approach to a 1,1-dihydrofluoroalkyl thiol. .......... 29 Scheme 2.10. Pan’s hemin-catalyzed approach to 1,1-dihydrofluoroalkyl thiols. ....................... 30 Scheme 2.11. 1,1-Dihydrofluoroalkylation of amines, mediated by sulfuryl fluoride. ................ 31 Scheme 2.12. Shreeve’s utility of 2,2,2-trifluoroethyl fluorosulfate in the presence of methanethiol........................................................................................................................................................ 32 Scheme 2.13. (a) Foth’s initial attempt at the 1,1-dihydrofluoroalkylation of thiols, utilizing the 2018 Sammis protocol for amines, and (b) the associated mechanism. ....................................... 33 Scheme 2.14. Effects of base on SO2F2-mediated reactions with 1,1-dihydrofluoroalcohols. ..... 34 Scheme 2.15. (a) The final optimized protocol for the 1,1-dihydrofluoroalkylation of thiols, and (b) the associated mechanism. ...................................................................................................... 34 Scheme 2.16. Intermolecular competition experiment between benzyl mercaptan and pyrrolidine........................................................................................................................................................ 36 Scheme 2.17. 1,1-Dihydrofluoroalkylation of piperidine with bis(2,2,2-trifluoroethyl)sulfate. .. 37 Scheme 2.18. 1,1-Dihydrofluoroalkylation of glutathione with 2,2,2-trifluoroethyl triflate. ....... 38 Scheme 2.19. The 2,2,2-trifluoroethylation of thiol substrates with multiple reactive functional groups. ........................................................................................................................................... 40 Scheme 2.20. The 2,2,2-pentafluoropropylation of alkyl and aryl thiol substrates. ..................... 42 Scheme 2.21. Contribution to the substrate scope of the 2,2,2-trifluoroethylation of aliphatic and aryl thiols. ..................................................................................................................................... 44 Scheme 2.22. Unsuccessful 2,2,2-trifluoroethylations and/or isolations of thiol substrates. ....... 46 xxii Scheme 3.1. (a) Epimerization of acyl chlorides versus acyl fluorides, and (b,c,d) modes of epimerization of amino acyl chlorides. ......................................................................................... 66 Scheme 3.2. Representative examples of synthetic applications of acyl fluorides in substitution reactions. ....................................................................................................................................... 67 Scheme 3.3. Sanford’s approach to aryl and heteroaryl fluorides, utilizing acyl fluorides as a fluoride source. ............................................................................................................................. 67 Scheme 3.4. Representative examples of synthetic applications of acyl fluorides in transition metal-catalyzed transformations. .................................................................................................. 69 Scheme 3.5. Representative approaches to the synthesis of acyl fluorides using (a) cyanuric fluoride, (b) Ishikawa’s reagent, and (c) TFFH. ........................................................................... 71 Scheme 3.6. Representative approaches to the synthesis of acyl fluorides utilizing sulfur-based reagents. ........................................................................................................................................ 74 Scheme 3.7. Representative approaches to acyl fluoride synthesis utilizing palladium-catalyzed (a, b) fluorocarbonylation and (c) acyl exchange. ............................................................................. 75 Scheme 3.8. Baker’s cobalt-catalyzed approach to acyl fluoride synthesis. ................................ 76 Scheme 3.9. Representative approaches to acyl fluoride synthesis utilizing phosphorous reagents........................................................................................................................................................ 76 Scheme 3.10. Qin’s SO2F2-mediated one-pot syntheses of amides and esters from carboxylic acids........................................................................................................................................................ 78 Scheme 3.11. The optimized protocol for the SO2F2-mediated synthesis of acyl fluorides, accelerated with TBAB, and their one-pot application to nucleophilic acyl substitutions. .......... 79 Scheme 3.12. Proposed mechanistic rationale for the observed rate acceleration in the SO2F2-mediated synthesis of acyl fluorides. ............................................................................................ 90 xxiii Scheme 3.13. Mechanism of the one-pot SO2F2-mediated synthesis of acyl fluorides. ............... 91 Scheme 3.14. Substrate scope of the one-pot SO2F2-mediated coupling of carboxylic acids (3.17) with N-hydroxysuccinimide (3.49). .............................................................................................. 94 Scheme 3.15. Substrate scope of the one-pot SO2F2-mediated coupling of carboxylic acids (3.17) with various nucleophiles. ............................................................................................................ 96 Scheme 3.16. Attempted syntheses of acyl fluorides (3.1) and failed one-pot esterifications. .... 97 Scheme 4.1. Lee’s one-pot column-free SOF2-mediated peptide coupling of amino acids via acyl fluoride intermediates. ................................................................................................................ 109 Scheme 4.2. Envisioned one-pot SOF2-mediated transformations of carboxylic acids via acyl fluoride intermediates. ................................................................................................................ 109 Scheme 4.3. Applications of N-hydroxyphthalimidyl and N-hydroxysuccinimidyl esters in peptide synthesis. ..................................................................................................................................... 111 Scheme 4.4. A representative example of a DCC-mediated condensation of an amino acid and N-hydroxysuccinimide. ................................................................................................................... 112 Scheme 4.5. Mechanism of the competitive Lossen rearrangement in one-pot peptide couplings of N-hydroxysuccinimidyl esters. ................................................................................................... 112 Scheme 4.6. Weinreb and morpholine amides form stable tetrahedral intermediates that persist until workup, preventing over-addition of nucleophiles. ............................................................ 113 Scheme 4.7. Representative examples of the synthetic applications of Weinreb and morpholine amides. ........................................................................................................................................ 114 Scheme 4.8. Representative synthetic routes to generate Weinreb and morpholine amides. ..... 115 Scheme 4.9. Representative examples of direct carboxylic acid reduction using (a) LAH, (b) Red-Al, and (c) BH3·THF................................................................................................................... 117 xxiv Scheme 4.10. Representative examples of direct carboxylic acid reduction using (a) NaBH4 and TiCl4, (b) NaBH4 and I2, and (c) SmI2 and H2O/THF as alternative reagents to LAH and borane complexes. .................................................................................................................................. 118 Scheme 4.11. Representative examples of direct carboxylic acid reduction via transition metal-catalyzed hydrogenations with (a) ruthenium, (b) cobalt, and (c) palladium-rhenium catalysts.119 Scheme 4.12. Representative examples of direct carboxylic acid reduction via transition metal-catalyzed hydrosilations. ............................................................................................................. 121 Scheme 4.13. Representative examples of reductions of carboxylic acid derivatives using mild reductants. ................................................................................................................................... 123 Scheme 4.14. Kokotos and Noula’s two-step approach to carboxylic acid reductions via isolated acyl fluoride intermeidtaes. ......................................................................................................... 124 Scheme 4.15. Yu’s one-pot SO2F2-mediated reduction of carboxylic acids to the corresponding alcohol (unpublished work). ....................................................................................................... 124 Scheme 4.16. Presumed formation of acyl fluoride and acyl pyridinium species during the reaction...................................................................................................................................................... 128 Scheme 4.17. Substrate scope of the SOF2-mediated one-pot esterification of aromatic carboxylic acids via acyl fluoride intermediates. .......................................................................................... 132 Scheme 4.18. Substrate scope of the SOF2-mediated one-pot esterification of aliphatic carboxylic acids via acyl fluoride intermediates. .......................................................................................... 134 Scheme 4.19. Unsuccessful carboxylic acid substrates in the SOF2-mediated one-pot esterification of carboxylic acids via acyl fluoride intermediates. ................................................................... 135 Scheme 4.20. Unsuccessful attempts of the SOF2-mediated one-pot esterification of carboxylic acids via acyl fluoride intermediates, using non-activated nucleophiles. ................................... 137 xxv Scheme 4.21. Scope of non-activated esters in the SOF2-mediated one-pot esterification of carboxylic acids via acyl fluoride intermediates. ........................................................................ 140 Scheme 4.22. Scope of Weinreb and morpholine amides in the SOF2-mediated one-pot amidation of carboxylic acids via acyl fluoride intermediates. ................................................................... 141 Scheme 4.23. (a) Initial attempted one-pot SOF2-mediated reduction of 3,3-diphenylpropionic acid to 3,3-diphenylpropanol, and (b) hypothesized competitive reduction of the acyl pyridinium intermediate................................................................................................................................. 144 Scheme 4.24. Substrate scope of the one-pot SOF2-mediated reduction of aliphatic carboxylic acids. ........................................................................................................................................... 146 Scheme 4.25. Substrate scope of the one-pot SOF2-mediated reduction of aromatic carboxylic acids. ........................................................................................................................................... 148 Scheme 4.26. Examples of failed substrates or substrates that were impossible to fully isolate and purify. .......................................................................................................................................... 150 Scheme 5.1. (a) Reactivity differences between sulfonimidoyl fluorides and chlorides with strong carbon nucleophiles, and (b) their similarities to the reactivity of sulfonyl fluorides and chlorides...................................................................................................................................................... 191 Scheme 5.2. The two commonly accepted mechanisms of nucleophilic attack on an electrophilic sulfur centre. ............................................................................................................................... 191 Scheme 5.3. Investigations into the hydrolytic stability of sulfonimidoyl fluorides and chlorides under neutral and basic conditions by Jeanguenat et al. ............................................................. 193 Scheme 5.4. Representative examples of the application of sulfonimidoyl fluorides to the synthesis of (a) sulfonimidamides and 18O-labelled sulfonamides and (b) stereochemically pure sulfonimidamides. ....................................................................................................................... 194 xxvi Scheme 5.5. Representative examples of the application of sulfonimidoyl fluorides to the synthesis of sulfoximines............................................................................................................................ 196 Scheme 5.6. Representative examples of the application of sulfonimidoyl fluorides to the synthesis of (a) sulfonimidate esters and (b) polysulfonimidates. .............................................................. 197 Scheme 5.7. Representative examples of the application of SulfoxFluor to the (a) deoxyfluorination and (b) deoxyazidation of alcohols. .............................................................. 198 Scheme 5.8. The first synthesis of sulfonimidoyl fluorides via halogen exchange of sulfonimidoyl chlorides by Johnson et al. .......................................................................................................... 199 Scheme 5.9. Traditional approaches to the synthesis of sulfonimidoyl fluorides and their utility towards the synthesis of trifluoromethyl sulfonimidamides. ...................................................... 200 Scheme 5.10. The synthesis of sulfonimidoyl fluorides using (a) SOF4, (b) ArSOF3, and (c) N-protected sulfinylamines. ............................................................................................................ 201 Scheme 5.11. Synthesis of sulfonimidoyl fluorides through SuFEx of sulfur(VI) imidazoles. . 202 Scheme 5.12. Original synthesis of SulfoxFluor by Hu et al. .................................................... 203 Scheme 5.13. Representative syntheses of sulfonimidoyl fluorides with an electrophilic fluorine source. ......................................................................................................................................... 204 Scheme 5.14. Proposed thematic approaches to the synthesis of sulfonimidoyl fluorides via nucleophilic substitution and oxidative addition processes. ....................................................... 206 Scheme 5.15. Envisioned approach for the rapid synthesis of sulfonimidoyl fluorides from MISF, by way of a sulfur(VI) sulfonimidamide-type intermediate (5.56)............................................. 207 Scheme 5.16. Attempted synthesis of a sulfonimidoyl fluoride precursor from MISF and an N-tosyloxy carbamate analogue. ..................................................................................................... 213 xxvii Scheme 5.17. Thomson’s SOF2-mediated conversion of sulfinic acids to the corresponding sulfinyl fluoride. ....................................................................................................................................... 214 Scheme 5.18. (a) A newly envisioned approach to the rapid synthesis of sulfonimidoyl fluorides, by way of a sulfinyl fluoride intermediate, and (b) the proposed mechanism of oxidative addition by chloramine T (5.47). .............................................................................................................. 215 Scheme 5.19. Potential disproportionation of sulfur(IV) sulfinyl fluorides into sulfur(VI) sulfonyl fluorides and sulfur(II) sulfenyl halides. ..................................................................................... 217 Scheme 5.20. Proposed mechanistic rationale for the negative impact of excess pyridine on the formation of sulfinyl fluorides (5.54) and sulfonimidoyl fluorides (5.1). .................................. 219 Scheme 5.21. Sulfinic acid substrate scope for the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides from sulfinic acids. ............................................................................... 226 Scheme 6.1. Summary of the one-pot sulfuryl fluoride (SO2F2)- and thionyl fluoride (SOF2)-mediated reactions developed and investigated in this thesis. .................................................... 245 Scheme 6.2. Summary of the contributions made to the SO2F2-mediated 1,1-dihydrofluoroalkylation of thiols described in Chapter 2. .......................................................... 246 Scheme 6.3. Summary of the contributions made to the SO2F2-mediated carboxylic acid activations and nucleophilic acyl substitutions described in Chapter 3. ..................................... 247 Scheme 6.4. Summary of the contributions made to the SOF2-mediated carboxylic acid activations and nucleophilic acyl substitutions/reductions described in Chapter 4. ..................................... 248 Scheme 6.5. Summary of the contributions made to the SOF2-mediated one-pot synthesis of sulfonimidoyl fluorides described in Chapter 5. ......................................................................... 250 Scheme 6.6. Proposed additional sulfonimidoyl fluorides to be synthesized using the SOF2-mediated protocol........................................................................................................................ 252 xxviii Scheme 6.7. Proposed representative scope of alkyl azides as nitrene sources in the SOF2-mediated synthesis of sulfonimidoyl fluorides. .......................................................................................... 252 Scheme 6.8. (a) The proposed telescopic approach to the synthesis of other sulfur(VI) motifs directly from the sulfinic acid, utilizing the sulfonimidoyl fluoride as a reactive intermediate, and (b) the proposed direct-displacement mechanism. ...................................................................... 253 Scheme 6.9. (a) The proposed SOF2-mediated Pummerer-type rearrangement of sulfoxides, and (b) the SOCl2-mediadted approach by Hisashi et al. .................................................................. 254 Scheme 6.10. Thionyl chloride-mediated reduction of sulfoxides to sulfides and the proposed corresponding process with thionyl fluoride............................................................................... 255 xxix List of Symbols 13C carbon-13 °C degrees Celsius cm–1 wavenumber δ chemical shift Đ dispersity 19F fluorine-19 1H hydrogen-1 (proton) [H] reductant Rf polyfluoroalkyl or perfluoroalkyl χP Pauling electronegativity xxx List of Abbreviations acac acetylacetonate Ac acetyl anh. anhydrous Ar aryl Boc tert-butyloxycarbonyl BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate br broad Bn benzyl BPA bisphenol A Bz benzoyl Cbz benzyloxycarbonyl CDI 1,1’-carbonyldiimidazole COD 1,5-cyclooctadiene Cp cyclopentadienyl CPME cyclopentyl methyl ether cr crown Cy cyclohexyl d deuterated d doublet DAST (diethylamino)sulfur trifluoride xxxi DBU 1,8-diazabicyclo(5.4.0)undec-7-ene DCC N,N'-dicyclohexylcarbodiimide DCE 1,2-dichloroethane DCPE 1,2-bis(dicyclohexylphosphino)ethane dd doublet of doublets ddd doublet of doublets of doublets dddd doublet of doublets of doublets of doublets ddt doublet of doublets of triplets DIBAL-H diisobutylaluminium hydride DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMT 4,4′-dimethoxytrityl dppb 1,4-bis(diphenylphosphino)butane dt doublet of triplets ee enantiomeric excess EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EI electron ionization equiv equivalents Et ethyl Et3N triethylamine xxxii EtOAc ethyl acetate FDA Food and Drug Administration Fmoc fluorenylmethoxycarbonyl G gauge GC gas chromatography h hour; hextet/sextet hept heptet HOBt N-hydroxybenzotriazole HSAB hard-soft acid-base HRMS high-resolution mass spectrometry Hz hertz iPr isopropyl I.D. interior diameter J J-coupling (spin-spin coupling) kDa kilodalton KHMDS potassium hexamethyldisilazane LAH lithium aluminum hydride LDA lithium diisopropylamide LRMS low-resolution mass spectrometry m multiplet M molar Me methyl MeCN acetonitrile xxxiii MHz megahertz min minute MISF N-methylimidazolium sulfinyl fluoride hexafluorophosphate MnPS number-average molar mass of polysulfonimidates m.p. melting point MS mass spectrometry NAS nucleophilic acyl substitution NCS N-chlorosuccinimide N.D. not detected NFSI N-fluorobenzenesulfonimide NMM N-methylmorpholine NMR nuclear magnetic resonance Ns 4-nitrophenylsulfonyl O.D. outer diameter p pentet pKa acid dissociation constant phen 1,10-phenanthroline PFP 2,2,3,3,3-pentafluoropropanol Ph phenyl Phth phthalimidyl PMHS polymethylhydrosiloxane PPE personal protective equipment ppm parts per million xxxiv psig pounds per square in gauge PTFE polytetrafluoroethylene pyr pyridine q quartet R generic functional group Red-Al sodium bis(2-methoxyethoxy)aluminum hydride Rf retention factor rt room temperature s singlet SDI N,N-sulfonyldiimidazole SN2 bimolecular nucleophilic substitution SNAr nucleophilic aromatic substitution SPPS solid-phase peptide synthesis Succ succinimidyl SuFEx sulfur(VI)-fluoride exchange t triplet T temperature TBA+ tetrabutylammonium TBAB tetrabutylammonium bromide TBAC tetrabutylammonium chloride TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide TBAX tetrabutylammonium halide xxxv TCICA trichloroisocyanuric acid td triplet of doublets Tf trifluoromethanesulfonyl TFA trifluoroacetic acid TFE 2,2,2-trifluoroethanol TFFH tetramethylfluoroformamidinium hexafluorophosphate TLC thin-layer chromatography TMA+ tetramethylammonium TMAF tetramethylammonium fluoride TMDS tetramethyldisiloxane TOF time of flight Ts toluenesulfonyl Tr trityl TRPV1 transient receptor potential vanilloid 1 tt triplet of triplets UV ultraviolet XtalFluor-E® (diethylamino)difluorosulfonium tetrafluoroborate xxxvi Acknowledgements There are so many people who have supported me throughout my time at UBC, and it is such a pleasure to acknowledge those wonderful individuals here. Firstly, to Prof. Glenn M. Sammis. You have supported me in my desire to teach from the moment we met, and I cannot thank you enough for the opportunities you have provided me towards pursuing my passion. You have been a wonderful supervisor, and I have learned so much from being a part of your group. Thank you for everything. Thank you to my committee for your support: Prof. Laurel L. Schafer, Prof. Gregory R. Dake, Prof. Allan K. Bertram, and Prof. Jean-Philip Lumb, as well as Prof. Jason E. Hein, Prof. Parisa Mehrkhodavandi. Special thanks to Profs. Schafer, Hein, and Lumb for reviewing this dissertation and providing feedback. To the Sammis group: Wei, Max, Paul, Kayi, Cayo, Brodie, Joey, Will, Korey, Taniya, Hao, Alina, Katy, Bill, and Carlota—thank you all! Each of you has helped to shape me and I have learned so much from working with each of you. Special thanks to Brodie, Joey, Will, Korey, Taniya, Bill, and Carlota for a fantastic end to my time at UBC, and for making the group such a fun place to be! Alina, thank you for being wonderfully weird with me and jamming to musicals in the lab—you are a wonderful friend! Thank you as well to Katherine—our honorary Sammis group member and fellow skydiver—for being such a lovely friend to me these past few years. You are all amazing friends and colleagues, and it has been so much better here because of you. To my fantastic friends outside of the lab: Tina, Andrew, Maddie, August, Micah, Cam, Max, Sabrina, Jesse, Chelsea, Felino, Natasha AJ, Emily, Angela, Darrel, Raylen, and Breanna. Thank you for everything! You are all amazing, and I am so lucky to have each of you in my life. xxxvii To these incredible educators in the department: Emma, Laura, Justin, Lourdes, Ben, Jose, Montse, Jay, Richard, Greg, and Jackie. Thank you for such a fantastic time in my role as lab director for the Chem 203 labs. It was an amazing experience and I learned so much about myself and the students we teach. You all were incredibly supportive, and it was a pleasure working alongside and learning from each of you. Special thanks to Lourdes for being the most incredible lab tech (and saving the day!), to Justin for being the best office buddy (thank you for making me laugh!), and to Emma and Laura (hey friendos!) for being such amazing role models and friends. Of course, I would be remiss to forget the invaluable staff who have supported myself and my work in my time in the department. Thank you to Sheri, Ken, Sabrina, Sunny, Nicky, Adana, Yun, Jenny, Ben (again!), Maria, Paul, and all the others who keep the department running and do so much thankless work for us all. My gratitude as well to NSERC and UBC for funding my work. To my wonderful family: Mom, Dad, Jason, and Cameron. You have all been there for me from the moment I started the first grade, right to now. Thank you for loving me, for supporting me, and for being my family. C'est un plaisir d’être votre fils et frère. Je vous aime. And finally, to you, Owen T. Quindipan. Thank you from the bottom of my heart for all who you are and all that you have done for us these past few years. This ride was so much the better because of you. You are my favourite person, and you are my best friend. Your love and support mean more to me than I can ever say, and I hope that I have been even half as good a partner to you as you have been to me. As I leave behind this chapter of my life, I am so excited to step into the next with you by my side. I hope it has cats and dogs! xxxviii Dedication And to Owen. Thank you for singing with me. I do believe I have been changed for the better. 1 Chapter 1: Introduction 1.1 Synthetic organic chemistry and chemical methodology Chemistry is traditionally segregated into five main subdisciplines: analytical chemistry, biochemistry, inorganic chemistry, physical chemistry, and organic chemistry. Organic chemistry is the study of the synthesis, properties, reactivity, and applications of carbon-based molecules. Synthetic organic chemistry can in turn be divided into three major areas of research and study: total synthesis, medicinal chemistry, and methodology. Methodology, or methods development, is the branch of synthetic organic chemistry that emphasizes the development and optimization of new synthetic protocols designed to carry out a particular molecular transformation across a wide-reaching scope of compounds (Scheme 1.1). Scheme 1.1. Illustrated representation of methodology in synthetic organic chemistry, depicted as a generic chemical modification of a given class of substrate compounds with an optimized set of reaction conditions. Factors that are important in methods development include: (1) chemoselectivity, the selective reactivity of one chemical functional group over other potential candidates; (2) efficiency and efficacy, the goal of achieving the greatest product yield in the most rapid and economical manner; (3) scope, the applicability of the protocol to a wide array of molecular compounds containing the target functional group; and (4) novelty, the advancement of the field through the 2 development of procedures that advance the scientific community’s understanding of synthetic organic chemistry, including synthesizing chemical motifs that are otherwise inaccessible. The work described in this thesis focuses primarily on synthetic methodology. 1.2 Fluorine incorporation in organic molecules Fluorine-containing molecules serve a variety of important purposes in organic chemistry. This is exemplified by the prevalence of fluorine incorporation in industrially relevant compounds. For example, more than 20% of all drugs contain at least one fluorine atom, and more than 50% of the top-grossing drugs are fluorinated as well.1–3 The incorporation of fluorine in organic molecules can modulate the pharmacokinetic profiles and properties of pharmaceutically relevant compounds, including their acidity, lipophilicity, conformational stability, and membrane permeability. A variety of fluorinated motifs are commonly found in marketed drug molecules, including aryl- (1.1), heteroaryl- (1.2), and alkyl fluoride (1.3); trifluoromethyl (1.4); and 1,1-dihydrofluoroalkyl ether (1.5) and -thiol (1.6) moieties (Figure 1.1).4 The agrochemical industry also makes use of fluorine-containing molecules, whose stability can be modified through the incorporation of one or more fluorine atoms. Figure 1.1. Representative examples of common fluorinated motifs in FDA-approved pharmaceutical compounds.4 Synthetically, fluorine serves a variety of purposes. Carbon-fluorine (C–F) bonds can be utilized to modulate the reactivity of a substrate molecule, potentially enabling selective reactivity under mild conditions. The C–F bond is the strongest carbon–atom covalent bond, with a bond 3 dissociation energy of 105.4 kcal/mol; in comparison, the carbon-chlorine (C–Cl) bond is significantly weaker at 78.5 kcal/mol.5 The great strength of the C–F bond can be explained in large part by the electronegativity of fluorine. The C–F bond is highly polarized as fluorine is the most electronegative element on the periodic table (χ = 4.0), leading to a significant degree of ionic character in the polar-covalent bond. This ionic character leads to bond shortening (i.e. 1.35 Å for C–F versus 1.77 Å for C–Cl), and an overall stronger bond. The significant degree of ionic character present in the polar-covalent C–F bond can be used to explain the fact that fluoride is a poor leaving group in nucleophilic substitution reactions; the pseudo-electrostatic stabilization between the carbon atom and the highly electronegative fluorine is sufficiently strong to disfavour direct displacement. The C–F bond is also stabilized more so than the C–Cl bond due to more effective orbital overlap between carbon and fluorine, versus carbon and chlorine; this is due to the differing principal quantum numbers between carbon and chlorine lending to significantly different sized atomic orbitals. As a representative example of the unique synthetic utility of the C–F bond, acyl fluorides (1.7) are known to be less electrophilic than the corresponding acyl chlorides (1.8) in nucleophilic acyl substitution (NAS) processes (Scheme 1.2a).6 As a result of their more moderate reactivity, acyl fluorides can be used to great effect as acylating agents in a variety of one-pot solution-phase peptide couplings; the tempered electrophilicity of the acyl halide leads to fewer undesirable side-processes, including stereochemical inversion or epimerization of alpha carbon stereocentres in amino acyl halide substrates (1.9, Scheme 1.2b). The reduced reactivity of the acyl fluoride is attributed to the stronger C–F bond versus the C–Cl bond in acyl chlorides. 4 aAssuming no acid or base catalyst was utilized. Scheme 1.2. The relative reactivity of acyl fluorides versus acyl chlorides in the presence of various nucleophiles (a) and their respective reactivities in peptide coupling processes (b).6 Sulfur-fluorine (S–F) bonds also find use in a number of important synthetic applications. For example, the S–F bond (82.0 kcal/mol) in sulfur (VI) sulfonyl fluorides (1.10) is stronger than the corresponding sulfur-chlorine (S–Cl) bond (60.9 kcal/mol) in the analogous sulfonyl chlorides (1.11). As a result, the reactivity profiles of these two electrophilic motifs differs greatly in the presence of organolithium nucleophiles; sulfonyl fluorides undergo nucleophilic attack at the sulfur(VI) centre with displacement of fluoride to yield sulfones (1.12), whereas sulfonyl chlorides experience competitive sulfur(VI)-to-sulfur(IV) reductive attack at chlorine to yield sulfinic acids (1.13, Scheme 1.3a).7 The respective mono-aza analogues—sulfonimidoyl fluorides (1.14) and sulfonimidoyl chlorides (1.15), respectively—display similar substitution/reduction reactivity trends (Scheme 1.3b). 5 Scheme 1.3. The relative reactivity of sulfonyl fluorides versus sulfonyl chlorides in the presence of organolithium nucleophiles (a), and the respective reactivities of the mono-aza equivalents (b). 1.3 Synthetic fluorination reagents 1.3.1 Traditional synthetic fluorination reagents Fluorine incorporation into organic compounds is a focal point in modern chemical research. A number of nucleophilic, electrophilic, and radical fluorination reagents have been developed to install fluorine atoms or fluorinated motifs in substrate molecules.1 Fluorine gas (F2) is the simplest tool—chemically—for fluorine incorporation. However, F2 is extremely hazardous and difficult to utilize as a reagent. Originally isolated by Henri Moissan in 1886, F2 is a highly toxic and corrosive substance that reacts with a variety of compounds. This over-active reactivity makes handling the gas a challenge, and a variety of other traditional fluorination reagents have thus been developed to replace F2. Some representative examples of common or traditionally utilized electrophilic fluorinating agents include hypofluorites (1.16), xenon difluoride (XeF2, 1.17), N-fluorobenzenesulfonimide (NFSI, 1.18), Selectfluor (1.19), and (diethylamino)difluorosulfonium 6 tetrafluoroborate (XtalFluor-E®, 1.20, Figure 1.2), although many more exist. Each of 1.17, 1.18, and 1.19 have also been used as radical fluorination agents.1,8,9 Some common examples of nucleophilic sources of fluoride include cyanuric fluoride (1.21) and (diethylamino)sulfur trifluoride (DAST, 1.22). Hypofluorites are very reactive and—like fluorine gas—have largely been supplanted by other fluorination reagents, including XtalFluor-E®, in modern chemistry. The XtalFluor® reagents also serve as a safer alternative to DAST, although the latter is still utilized. Figure 1.2. Representative examples of traditional and common fluorination reagents. 1.3.2 Gaseous fluorination reagents 1.3.2.1 Sulfuryl fluoride (SO2F2) Sulfuryl fluoride (SO2F2, 1.23) was originally synthesized by Moissan and Lebeau in 1901 from the reaction of F2 and sulfur dioxide (SO2) gases in a specialized reactor (Scheme 1.4a).10 The gases were heated with a platinum wire, accelerating what would otherwise be a slow and potentially explosive process. Several industrial-scale processes have since been reported,11–14 including a 1963 patent for the synthesis of SO2F2 (trademarked as Vikane®) by the Dow Chemical Company (Scheme 1.4b).15 Sulfuryl fluoride was afforded from the reaction between SO2, chlorine gas (Cl2), and excess hydrofluoric acid (HF) over an activated charcoal catalyst. However, these methods to produce SO2F2 are limited to industrial settings and are unsuitable in research 7 laboratory settings. Of the smaller-scale processes developed throughout the 20th century, most are not easily adopted.16,17 In 2017, De Borggraeve et al. described a more straightforward and generally applicable approach to the ex situ generation of sulfuryl fluoride from bench-stable N,N-sulfonyldiimidazole (SDI, 1.24) and potassium fluoride (KF) under acidic conditions (Scheme 1.4c).18 The De Borggraeve approach further obviates the need for industry-sourced compressed gas cylinders of SO2F2. Scheme 1.4. Some representative syntheses of sulfuryl fluoride by (a) Moissan,10 (b) the Dow Chemical Company,15 and (c) De Borggraeve.18 SO2F2 is a colourless, odorless gas with properties more like sulfur hexafluoride (SF6) than its chlorinated analogue, sulfuryl chloride (SO2Cl2).7 Whereas anhydrous SO2F2 is thermally stable to 400 °C and does not readily generate fluorine radicals under photolytic conditions, SO2Cl2 decomposes at 100 °C and easily generates chlorine radicals. SO2F2 is a nucleophilic source of fluorine that reacts exclusively at the sulfur(VI) centre in the presence of strong nucleophiles—i.e. organolithium reagents—in turn producing nucleophilic fluoride. Conversely, SO2Cl2 is prone to competitive reductive dehalogenation via nucleophilic attack on chlorine under similar conditions, similar to sulfonyl chlorides (vide supra). Sulfuryl fluoride will hydrolyze slowly in aqueous media, and this can be accelerated under basic conditions, yielding fluoride (F–) and fluorosulfate (FSO3–) anions.19 8 Sulfuryl fluoride was utilized successfully by Firth in 1972 for the synthesis of aromatic polysulfates (Scheme 1.5a).20 In treating bisphenol A (BPA, 1.25) with SO2F2, the corresponding difluorosulfate-containing products (1.26) were successfully generated and subsequently mixed with the disodium salt of bisphenol A (1.25a) to yield aromatic polysulfates (1.27). The reaction was successful with SO2F2, whereas SO2Cl2 led to a number of undesirable side-reactions including aryl chlorination. Polysulfate generation using the intermediate bischlorosulfates from SO2Cl2 consistently yielded only low-molecular weight chlorinated sulfate esters. Harsh reaction conditions were necessary to enable formation of the bisfluorosulfate intermediates, with the reaction of BPA and SO2F2 heated in a pressurized autoclave at 120 °C for 19 hours. Scheme 1.5. (a) Firth’s20 and (b) Sharpless’21 syntheses of polysulfate polymers and copolymers. In 2014, Sharpless et al. developed a milder variant of Firth’s SO2F2-mediated protocol, utilizing mildly basic reaction conditions to enable room temperature conversion of 1.28 to 1.29, and subsequently to 1.30 with 1.28a (Scheme 1.5b).21 The mild conditions reported by Sharpless 9 et al. were attributed to the unique thermodynamic and kinetic properties of the S(VI)–F bond of the fluorosulfates in the presence of nucleophilic agents, and the class of reactivity came to be known as sulfur(VI)-fluoride exchange (SuFEx) chemistry.7 SuFEx reactions are those that benefit from “click-like” conditions, wherein the S(VI) electrophilic centre undergoes facile S(VI)–F substitution by a nucleophile under a specific set of conditions. Generally, the S(VI)–F bond is otherwise stable and resistant to decomposition in typical acidic or basic media. The protocol by Sharpless et al. was extended to the synthesis of sulfamoyl fluorides (1.31) from amines (1.32, Scheme 1.6a) and aryl fluorosulfates (1.33) from aryl alcohols (1.34, Scheme 1.6b).7 Briefly, aryl fluorosulfates (1.35) are utilized synthetically as triflate surrogates in robust cross-coupling processes, including Suzuki-Miyaura (1.36) and Buchwald-Hartwig couplings (1.37), as well as carbonylations (1.38, Scheme 1.6c).19 Scheme 1.6. Sharpless’ syntheses of (a) sulfamoyl fluorides, and (b) aryl fluorosulfates,7 as well as (c) representative examples of some synthetic applications of aryl fluorosulfates, accessed from SO2F2.19 10 More than thirty SO2F2-mediated processes have been developed since the advancements made by Sharpless et al. in 2014. Key contributors to the field include—but are not limited to—the Sharpless, Qin, Ding, Sanford, and Sammis research groups. SO2F2-mediated reactions can be broadly divided between alcohol activation and the activation of other functional groups. Through functional group activation with SO2F2, a variety of transformations can be conducted, including substitution, redox, and coupling processes. Some representative advancements utilizing SO2F2 for alcohol activation include: (1) the deoxyfluorination of phenolic derivatives (1.34) to 1.1 (Scheme 1.7a);22 (2) the deoxyfluorination (1.39, Scheme 1.7b)23 and nucleophilic substitution (1.40, Scheme 1.7c)24,25 of aliphatic alcohols (1.41); (3) the 1,1-dihydrofluoroalkylation of amines (1.32) to afford 1.42 (Scheme 1.7d);26 (4) the oxidation of alcohols (1.41) to aldehydes and ketones (1.43)27 or alkynes (1.44, Scheme 1.7e);28 and (5) the oxidation of primary alcohols (1.45) to nitriles (1.46, Scheme 1.7f).29 11 Scheme 1.7. Representative examples of the synthetic applications of SO2F2 towards alcohol activation.22–29 SO2F2 has been utilized for the activation and transformation of functional groups besides alcohols as well. Some representative examples of the SO2F2-mediated activation of other functional groups include: (1) the conversion of carboxylic acids (1.47) to amides (1.48)30 and 12 esters (1.49, Scheme 1.8a);31 and (2) the deoxyfluorination of benzaldehydes or α-ketoesters (1.50) to afford 1.51 (Scheme 1.8b).32 Scheme 1.8. Representative examples of the synthetic applications of SO2F2 towards the activation of non-alcohol functional groups.30–32 1.3.2.2 Thionyl Fluoride (SOF2) Thionyl fluoride (SOF2, 1.52) is a colourless and gaseous sulfur(IV) compound, and was not extensively studied as a synthetic reagent for fluorination applications until early 2022.33,34 Thionyl fluoride was first isolated in 1896 by Meslans (Scheme 1.9a), who reported that it underwent hydrolysis with water to produce sulfurous and hydrofluoric acids.35 A number of alternative syntheses of thionyl fluoride were reported throughout the 20th century, including one by Tullock and Coffman in 1960, who described their conversion of thionyl chloride to thionyl fluoride in the presence of sodium fluoride (NaF, Scheme 1.9b).36 Scheme 1.9. (a) Meslans’35 and (b) Coffman’s36 syntheses of thionyl fluoride with nucleophilic fluorine sources. 13 The synthetic applications of SOF2 were not studied further until 1985 when Shreeve et al. investigated its utility to C–H, N–H, and P–H bond functionalization (Scheme 1.10).33 Shreeve reported that the C–H and P–H bonds of 1.53 and 1.54—respectively—underwent fluorination by SOF2 to yield the corresponding C–F (1.55) and P–F species (1.56, Scheme 1.10a and b, respectively), and that phosphines (1.57) and phosphites (1.58) underwent oxidative fluorination to yield 1.59 (Scheme 1.10c) and 1.60 (Scheme 1.10d), respectively. Conversely, nitrogenous nucleophiles (1.61) instead underwent nucleophilic substitution (SN2) with SOF2 to yield 1.62 (Scheme 1.10e). It was proposed that the thermodynamic stability of the C–F and P–F product bonds favoured carbon and phosphorous fluorination, whereas the weaker N–F bond did not. This lack of thermodynamic drive for amines disfavoured the subsequent displacement of the sulfinyl fluoride moiety by fluoride. Scheme 1.10. Shreeve’s use of SOF2 in the fluorination of various compounds.33 14 Only seven reports detailed explorations into the synthetic applications of thionyl fluoride between 1985 and 2022.37–43 However, no comprehensive study of the synthetic utility of SOF2 as a reagent for organic chemistry existed prior to the work of Sammis et al. in early 2022, wherein a one-pot column-free peptide coupling protocol was described (Scheme 1.11a).34 As with the analogous SO2F2-mediated reaction between carboxylic acids (1.47) and nucleophilic reagents to afford 1.63 (Scheme 1.11b),44 the SOF2-mediated protocol proceeded via an acyl fluoride intermediate (1.7). The SOF2-mediated process generated dipeptides with only negligible racemization of the α-carbon of the electrophilic partner, and was sequentially applied to the synthesis of penta- and decapeptides. This peptide coupling was the first example of an in-depth SOF2-mediated methodology study, with the experimental work exploring carboxylic acid substrates. A new ex situ approach to the synthesis of SOF2 was described as part of the peptide coupling protocol by Sammis et al. as well (Scheme 1.12).34 Through the neat reaction of thionyl chloride and potassium bifluoride (KHF2), gaseous SOF2 was evolved and collected as a solution-phase reagent in a selected solvent. The SOF2 was generated alongside other acidic gases, including HF and HCl. The SOF2 was therefore passed through a column of imidazole prior to collection in the solvent, consuming any undesirable acidic vapors. It was observed that the solution-phase SOF2 was bench-stable for several weeks after generation. 15 Scheme 1.11. Sammis’ (a) column-free SOF2-mediated one-pot peptide coupling of amino acids via acyl fluorides,34 and (b) SO2F2-mediated one-pot coupling of carboxylic acids via acyl fluorides.44 Scheme 1.12. Sammis’ room temperature ex situ synthesis of SOF2 under neat conditions.34 The crucial difference between SOF2- and SO2F2-mediated approaches to acyl fluoride synthesis is the reactive intermediate formed in situ from the carboxylic acid (1.64, Scheme 1.13). For SO2F2-mediated protocols, a S(VI) acyl fluorosulfate (1.65) is generated from carboxylate attack on SO2F2,44 whereas the analogous S(IV) acyl fluorosulfite (1.66) is produced from carboxylate attack on SOF2.34,45 Sulfuryl fluoride is less reactive than thionyl fluoride in the context of carboxylic acid activation—as well as general substitution processes—as S(VI) compounds are generally slower to react with nucleophiles than S(IV) species.6 One reason for this is that the sulfur centre of SO2F2 is more sterically encumbered than of SOF2, limiting access to nucleophilic attack. Additionally, SO2F2 can be depicted in a resonance form with a formal charge of 2+ on sulfur, whereas the analogous charge-separated form of SOF2 has only a 1+ formal charge on sulfur. Therefore, SO2F2 is a “harder” electrophile than SOF2 according to hard-soft acid-base theory, which would in turn render it a poorer electrophile than SOF2 in the presence of “softer” carboxylic acid nucleophiles. Orbital hybridization arguments could also be considered 16 when comparing the relative reactivity of SO2F2 versus SOF2. However, SO2F2 is sp3-hybridized at the central sulfur46 and SOF2 is as well. Therefore, the relative orbital energies of SO2F2 and SOF2 cannot be properly predicted on hybridization arguments alone. Both 1.65 and 1.66 may be converted to the corresponding acyl fluoride (1.67) in the presence of nucleophilic fluoride (F–). However, acyl fluorosulfites (1.66) pose a distinct synthetic advantage over acyl fluorosulfates (1.65) in peptide couplings: 1.66 are less electrophilic at the carbonyl carbon than 1.65. The difference in electrophilicity can be attributed to the inductively withdrawing character of the fluorosulfite versus the fluorosulfate moieties. Fluorosulfites are functionalized with one less oxygen atom than fluorosulfates, making them less inductively withdrawing upon the adjacent carbonyl. The greater inductively withdrawing nature of the fluorosulfates increases the electrophilicity of the acyl fluorosulfate functional group (1.65). This difference in carbonyl electrophilicity prevents in situ racemization of the carbon centre alpha to the carbonyl in 1.66, thereby allowing for epimerization-free peptide couplings. For this reason, SOF2 can be utilized effectively in peptide coupling reactions. Conversely, the carbonyl carbon of acyl fluorosulfates (1.65) are more electrophilic and readily undergo epimerization to 1.68 through the corresponding enolate (1.69) or ketene, undermining the synthetic application of SO2F2-mediated peptide couplings. 17 Scheme 1.13. Relative reactivity of SOF2 versus SO2F2 with stereochemically defined carboxylic acid substrates, and the effects of the reactive intermediates formed in situ on the overall reaction. 1.4 Personal contributions The work outlined in this thesis describes my efforts towards the development of one-pot reactions mediated by either sulfuryl fluoride, or thionyl fluoride. The primary target motifs synthesized through the use of these reagents include: (1) 1,1-dihydrofluoroalkyl sulfides (Chapter 2); (2) acyl fluorides, esters, amides, and primary alcohols (Chapters 3 and 4); and (3) sulfonimidoyl fluorides (Chapter 5). Chapter 2 describes the use of SO2F2 in a one-pot 1,1-dihydrofluoroalkylation of thiol nucleophiles (1.70) with 1,1-dihdyrofluoroalcohols (1.71) to afford 1.72 (Scheme 1.14). The chemoselectivity of the reaction was studied using free amine and thiol nucleophiles in direct competition, with the reaction universally favouring thiol alkylation over amine alkylation. The source of the chemoselectivity in the reaction was attributed to the reactive bis(1,1-dihydrofluoroalkyl)sulfate intermediate formed in situ. Contributions were made to the substrate 18 scope of this reaction, placing an emphasis on (1) examining the chemoselectivity of the reaction across several substrates, and (2) expanding the scope of 1,1-dihydrofluoroalcohols to include 2,2,3,3,3-pentafluoropropanol. Scheme 1.14. Sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of thiols (Chapter 2). Chapter 3 details a one-pot SO2F2-mediated synthesis of amides (1.48) and esters (1.49) from carboxylic acid substrates (1.47), proceeding via an acyl fluoride intermediate (1.7, Scheme 1.15). The contributions made to this work focused on elucidating the effects of tetrabutylammonium halide salt additives on the reaction rates using quantitative 19F NMR spectroscopy. The addition of these salt additives led to rate enhancements of up to 100% in forming the acyl fluoride intermediates, yet they had no observable effect upon the rate of nucleophilic acyl substitution by amine or alcohol nucleophiles. The reaction mechanism was determined in part from the work outlined herein, with the rate acceleration attributed to the formation of reactive acyl halide intermediates that thermodynamically favoured the formation of the target acyl fluorides. A number of esters, amides, and thioesters were subsequently synthesized as part of the substrate scope of this one-pot reaction. Scheme 1.15. Mechanistic studies of the sulfuryl fluoride-mediated generation and one-pot nucleophilic acyl substitution of acyl fluorides (Chapter 3). 19 Chapter 4 outlines the development, optimization, and results of a series of one-pot SOF2-mediated esterification, amidation, and reduction protocols (Scheme 1.16). This work greatly expands our understanding of the applicability of SOF2 to carboxylic acid substrates, enabling rapid and column-free access to synthetically relevant activated amides (1.48) and esters (1.49) in up to 99% isolated yields from commercially available and bench-stable reagents (1.47). The protocol was initially designed to facilitate production of activated esters, although non-activated esters were recovered in quantitative yields as well. The protocol was expanded to include Weinreb and morpholine amide syntheses, enabling facile access to these synthetically advantageous chemical motifs. The acyl fluoride intermediates generated through this SOF2-mediated protocol were then exploited for the one-pot reduction of carboxylic acids to the corresponding primary alcohols (1.45), using mild reducing agents. The reduction serves as the first published example of a one-pot reduction of carboxylic acids that proceeds via an acyl fluoride intermediate. Substrate scopes of each of the esterifications, amidations, and reductions are included. Scheme 1.16. Thionyl fluoride-mediated one-pot esterifications, amidations, and reductions of carboxylic acids via acyl fluorides (Chapter 4). Chapter 5 represents the culmination of the work presented in this thesis, describing the first example of a one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides (1.14) from accessible starting materials (Scheme 1.17). This work also serves as the first in-depth analysis of the synthetic applications of SOF2 to a class of substrates other than carboxylic acids. Sulfonimidoyl fluorides are a synthetically useful sulfur(IV) motif that are bench-stable for 20 extended periods of time and can be treated with a variety of nucleophilic reagents to access other synthetically and pharmaceutically relevant sulfur(VI) derivatives. Furthermore, sulfonimidoyl fluorides have been investigated for use as tyrosine-specific covalent warheads, indicating that they may also be utilized in pharmaceutical applications. This chapter describes the diverse approaches taken to access sulfonimidoyl fluorides from a number of starting materials, as well as the route ultimately pursued with SOF2 and sulfinic acids (1.13). The reaction of sulfinic acids with SOF2 enables up-to-quantitative deoxyfluorination to yield a sulfinyl fluoride intermediate (1.73), which subsequently undergoes oxidative addition by nitrenes such as chloramine T (1.74) to afford the target sulfonimidoyl fluoride. The reaction optimization and substrate scope of sulfinic acid substrates are discussed. This work serves as an advancement over comparable literature protocols in that it enables rapid access to lab-scale quantities of sulfonimidoyl fluorides, and may therefore be applicable to medicinal chemistry applications where the rapid development of a compound library is desirable. No niche or unstable reagents or isolated intermediates are required by this method. The future directions of this work are detailed in Chapter 6. Scheme 1.17. Thionyl fluoride-mediated one-pot conversions of S(IV)-sulfinic acids to S(VI)-sulfonimidoyl fluorides (Chapter 5). 21 Chapter 2: Sulfuryl Fluoride-Mediated 1,1-Dihydrofluoroalkylation of Thiols 2.1 1,1-Dihydrofluoroalkylated thiols: applications, properties, and existing synthetic approaches 2.1.1 Applications and properties of 1,1-dihydrofluoroalkylated thiols As detailed in Chapter 1, the incorporation of fluorine into an organic molecule can impart significant effects on its chemical and pharmacological properties. Fluoroalkyl thiol motifs—also referred to as fluoroalkyl sulfides—are often used to modulate a pharmaceutically relevant compound’s lipophilicity, membrane permeability, and acidity.47 1,1-Dihydrofluoroalkyl sulfides (2.1, Figure 2.1) are of particular interest as they confer greater pharmacological activity than other fluoroalkylated thiols, such as trifluoromethyl sulfide. Drug compounds with 1,1-dihydrofluoroalkyl motifs are also typically more stable and resistant to metabolic oxidation, thereby improving oral bioavailability and potency.4 1,1-Dihydrofluoroalkyl sulfides are, therefore, among the most prevalent fluorinated heteroatom chemotypes in pharmaceuticals and agrochemicals.4,48 Representative examples include (a) the potent oral diuretic and antihypertensive agent, Polythiazide (2.2), (b) Cefazaflur antibiotic derivative 2.3, (c) a TRPV1 antagonist with analgesic properties (2.4), (d) patented insecticide Ia-135 (2.5), and (e) insecticide C.1-4 (2.6, Figure 2.2). Figure 2.1. Chemical structure of 1,1-dihydrofluoroalkyl thiols. 22 Figure 2.2. Chemical structures of some representative pharmaceutically and agrochemically relevant compounds with the 1,1-dihydrolfuoroalkyl motif.48 2.1.2 Existing synthetic approaches to the synthesis of 1,1-dihydrofluoroalkylated thiols A host of synthetic approaches have been developed to access 1,1-dihydrofluoroalkyl thiols given their pharmaceutical relevance. Broadly, these include direct bimolecular nucleophilic substitution (SN2) processes (Scheme 2.1), copper- or iron-catalyzed reactions, reductive methods, and photoredox catalysis (vide infra). SN2-based reactions and copper-catalyzed processes account for the majority of synthetic methods currently available. Scheme 2.1. General SN2-based approaches to the synthesis of 1,1-dihydrofluoroalkyl sulfides with thiol nucleophiles. 23 SN2-type processes typically proceed by thiol (2.7) or thiolate (2.8) displacement of an activated 1,1-dihydrofluoroalkyl electrophile (2.9) to yield the corresponding 1,1-dihydrofluoroalkyl sulfide (i.e. 2.10 and 2.11). An early demonstration of this approach was reported by Ishikawa and coworkers in 1977, wherein they treated sodium thiolates (2.8) with 2,2,2-trifluoroethyl p-toluenesulfonate (2.12) under basic conditions to yield the corresponding 1,1-dihydrofluoroalkylated products (2.10a and 2.10b) in 73% and 80% yields, respectively (Scheme 2.2a).49 In 1984, Shreeve et al. described an early example of the diverse reactivity of a 1,1-dihydrofluoroalkyl fluorosulfate (2.13), 2,2,2-tifluoroethyl fluorosulfate (2.13a), in the presence of various alcohol, amine, and thiol (2.7) nucleophiles.50 Treatment of 2.13a with alcohols or amines and triethylamine (Et3N) resulted in sulfur-fluorine bond cleavage and substitution, affording the corresponding sulfate- or sulfamate ester, respectively. However, treatment of 2,2,2-trifluoroethyl fluorosulfate (2.13a) with methanethiol (2.7c) in triethylamine produced none of the expected thiosulfate, and instead produced 2.10c in 31% yield (Scheme 2.2b). This result indicated preferential thiolate attack at the alpha carbon instead of at the sulfur centre; dimethyldisulfane (14%) and unreacted fluorosulfate 2.13a (47%) were recovered, alongside SO2 and a 2,2,2-trifluoroethanol-triethylamine adduct. In 1986, Umemoto and Gotoh reported a 2,2,2-trifluoroethylation of 1-dodecanethiol (2.7d) with their hypervalent iodine reagent, (2,2,2-trifluoroethyl)phenyliodinium triflate (2.14), generating 2.10d in 80% yield (Scheme 2.2c).51 The protocol tolerated an array of amine and alcohol nucleophiles, yet only this single instance of thiol alkylation was explored. In 1987, Langler and Morrison described their treatment of benzyl mercaptan (2.7e) with mesylate 2.15 in isopropanol to produce 2.10e in 57% yield (Scheme 2.2d).52 During the course of their experiments, Langler and Morrison observed that the same reaction conducted in methanol produced a mixture of benzyl methyl sulfide (27%) and 24 2.10e (12%). They claimed a competitive reaction pathway was responsible for this result, wherein the solvent attacks the sulfur centre of 2.15 first, followed by methylation of benzyl mercaptan (2.7e); smaller solvent molecules such as methanol are capable of nucleophilic attack via this competitive pathway whereas larger solvent molecules including isopropanol cannot due to their greater steric bulk. Scheme 2.2. Representative SN2 approaches to 1,1-dihydrofluoroalkyl thiols.49–52 Umemoto’s hypervalent iodine reagents are effective for the 1,1-dihydrofluoroalkylation of heteroatom and carbon nucleophiles under mild reaction conditions. One such modern example applying (2,2,2-trifluoroethyl)phenyliodinium triflate (2.14) was described by Zhang et al. in 2018, with their transition metal-free cascade trifluoroethylation-cyclization of isothiocyanates (2.17, Scheme 2.3).53 Zhang’s protocol enabled rapid access to both trifluoroethylthiol 25 phenanthridines (2.18) and isoquinolines (2.19), and was largely tolerant of a variety of functionalized arenes, particularly those with electron-donating groups. Several other SN2-based approaches to 1,1-dihydrofluoroalkyl sulfides have been described.54–56 Scheme 2.3. Zhang’s cascade trifluoroethylation-cyclization of isothiocyanates.53 Alternative methods for the installation of structurally similar fluoroalkyl sulfide motifs have also been reported. This includes work by Lukin et al., who utilized 1-bromo-1-chloro-2,2,2-trifluoroethane (2.20) for the synthesis of 1-chloro-1-hydrofluoroalkylated thiols (2.21, Scheme 2.4).57 Lukin hypothesized that their reaction proceeded by a radical mechanism instead of the SN2 pathway. In 2015, Chen and Tang performed a mechanistic analysis of this process and reported that the reaction most likely proceeded via a radical nucleophilic substitution (SRN1) mechanism with a unimolecular rate law.58 Scheme 2.4. Lukin’s radical approach to 1-chloro-1-hydrofluoroalkyl thiols.57 26 Since 2016, several reports have described copper-catalyzed approaches to 1,1-dihydrofluoroalkyl sulfide synthesis. Weng et al. demonstrated that aryl bromides or iodides 2.22 could be coupled with elemental sulfur and 2,2,2-trifluoroethyl iodide (2.23) in the presence of copper(I) iodide and NaBH4 (Scheme 2.5).59 Their air- and moisture-free approach was used to synthesize 35 1,1-dihydrofluoroalkyl sulfides (2.24) in excellent yields of 60—99%, with only a single example of a lower yield (36%). This method was equally tolerant of aryl halides with either strongly withdrawing or donating groups and was suitable for gram-scale production. However, few heteroaryl halide substrates were examined, and no vinyl or alkyl halides were utilized. Scheme 2.5. Weng’s copper-catalyzed approach to 1,1-dihydrofluoroalkyl thiols.59 Gouverneur et al. described a copper-catalyzed sulfur-hydrogen insertion reaction between alkyl or aryl thiols 2.7 and 2,2,2-trifluoro-1-diazoethane (2.25, Scheme 2.6a).60 This protocol was well-suited to aryl thiol substrates containing both electron-donating and electron-withdrawing substituents. Only a single alkyl substrate—benzyl mercaptan—was reported. With minimal modification, they further expanded their reaction to accommodate 1-aryl-2,2,2-trifluoro-1-diazoethanes 2.26, enabling the formation of 2.27 as a racemic mixture (Scheme 2.6b). The modified reaction was also tolerant of a variety of alkyl and aryl functional groups on the diazoalkane, although strongly electron-donating and -withdrawing groups (–OMe and –NO2, respectively) in the para position of the arene were incompatible. 27 Scheme 2.6. Gouverneur’s copper-catalyzed approaches to 1,1-dihydrofluoroalkyl thiols and 1-aryl-1-hydrofluoroalkyl thiols.60 Additional copper-catalyzed processes have been described, including a copper-catalyzed coupling using aryl boronic acids.61 Titanyuk et al.62 employed a similar strategy to Gouverneur utilizing N-(2-trifluorophenylsulfonyl)hydrazone (2.28) as a 2,2,2-trifluorodiazoethane surrogate (Scheme 2.7a). The reaction was tolerant only of electron-deficient heteroaryl thiols. In 2020, Menczinger and coworkers reported a Goldberg-Ullmann coupling utilizing aryl and heteroaryl iodides 2.23 and derivatives of 2.29 (i.e. 2,2,2-trifluoroethylthioacetate, 2.29a) in benzylamine (Scheme 2.7b).48 They described a modest substrate scope that indicated the conditions were tolerant of electron-rich aryl iodides as well as electron-withdrawing aryl substituents including trifluoromethyl (–CF3) and nitro (–NO2) groups. Substituents bearing a meta- or para-substituted arene suffered from yield loss during chromatographic purification. 28 Scheme 2.7. Titanyuk’s and Menczinger’s copper-catalyzed approaches to 1,1-dihydrofluoroalkyl thiols.48,62 Several reductive approaches to 1,1-dihydrofluoroalkyl thiols have also been reported. In 2016, Yi et al. described a phosphorous-induced reductive fluoroalkylthiolation of indole and pyrrole derivatives (2.30) to the corresponding thioalkylated product (2.31) with electrophilic CF3CH2SO2Cl (2.32, Scheme 2.8a).63 Their report primarily focused on trifluoromethylated products, though they nonetheless included four examples of indole 2,2,2-trifluoroethylthiolation. Yi et al. explored a different approach in their 2018 report, with the 2,2,2-trifluoroethylthiolation of indoles and other heterocycles (2.33), as well as activated arenes (2.34). They utilized the nucleophilic sulfur(IV) reagent, NaSO2CH2CF3 (2.35) as the thioalkylation agent (Scheme 2.8b).47 The reaction was primarily tolerant of electron-rich heterocycles and arenes, with heterocyclic products (2.36) generally formed in greater yield than arenes (2.37). 29 Scheme 2.8. Phosphorous-induced reductive approaches to 1,1-dihydrofluoroalkyl thiols.47,63 Photoredox catalysis has also been utilized for the formation of 1,1-dihydrofluoroalkyl thiols. In 2016, Johannes et al. described a synthesis of 2.10b from p-iodotoluene (2.22b) and 2,2,2-trifluoromethanethiol (2.38) using iridium-mediated photoredox nickel catalysis for the cross-coupling of thiols and aryl iodides (Scheme 2.9).64 Scheme 2.9. Johannes’ photoredox catalysis approach to a 1,1-dihydrofluoroalkyl thiol.64 Iron-catalyzed trifluoroethylations of sulfides have also been described. One such example was reported by Pan et al. in 2020, who utilized hemin-catalysis for a halide-intercepted [2,3]-sigmatropic rearrangement (Scheme 2.10).65 Various allyl aryl sulfides 2.39 were treated with 2,2,2-trifluorodiazoethane (2.25) to generate a variety 1,1-dihydrofluoroalkylated products 2.10 in good yields. While both electron-rich and -poor aryl systems were well-tolerated, only a single example of an alkyl allyl substrate was described. Shortly thereafter, Pan et al. published another 30 report of a hemin-mediated cyclopropanation reaction, wherein they demonstrated a similar rearrangement process on a single vinylic sulfide substrate.66 Scheme 2.10. Pan’s hemin-catalyzed approach to 1,1-dihydrofluoroalkyl thiols.65 Several other reports describe additional approaches to the synthesis of 1,1-dihydrofluoroalkyl sulfides. These include a patent disclosing a handful of examples of SN2-based 1,1-dihydrofluoroalkylated thiol products,67 and a 2,2,2-trifluoroethylthiolation of substituted indoles using 2,2,2-trifluoroethyl iodide (2.23).68 Despite the array of processes available, efficiently accessing 1,1-dihydrofluoroalkyl thiol motifs remains a challenge, particularly for 2,2,2-trifluoroethyl sulfides. These challenges are largely due to the limits imposed by the approaches undertaken thus far. SN2 processes typically necessitate a suitably activated leaving group in the 1,1-dihydrofluoroalkyl-based electrophile, including halides and triflates, and several copper-catalyzed approaches require diazoalkane coupling partners. However, many of the longer chain 1,1-dihydrofluoroalkyl electrophiles and diazoalkanes are often not commercially available. Furthermore, many of the aforementioned protocols suffer from low yields, limited substrate scope, high reaction temperatures, or poor selectivity in the presence of multiple candidate nucleophiles. Such factors limit the applicability of these protocols in late-stage thioalkylation processes. As 1,1-dihydrofluoroalkyl sulfide motifs are a common motif in many pharmaceutical and insecticidal compounds (vide supra), mild methods that permit their late-stage incorporation are highly advantageous. Given that many of these 1,1,-dihydrofluoroalkyl-containing motifs are 31 commercially available as the alcohol (i.e. 2,2,3,3,3-pentafluoropropanol), utilizing the alcohol as the alkylation source would be ideal. This chapter describes (1) my investigations into the chemoselectivity of a sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of thiols using competition experiments, (2) my efforts to expand the reaction substrate scope to include 2,2,3,3,3-pentafluoropropylated sulfides, and (3) my contributions to the general 2,2,2-trifluoroethylation substrate scope.69 2.1.3 Literature precedent: the sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of amines In 2018, Sammis et al. described a novel approach to the 1,1-dihydrofluoroalkylation of amines, mediated by sulfuryl fluoride (SO2F2, 2.40, Chapter 1).26 1,1-Dihydrofluoroalcohols (2.41) were treated with SO2F2 under mildly basic conditions at 40 °C to furnish the corresponding fluorosulfates (2.13, Scheme 2.11). These fluorosulfates were then treated with an amine nucleophile (2.42), facilitating the desired 1,1-dihydrofluoroalkylation, producing 2.43 through the expulsion of the fluorosulfate anion (FSO3–) via an SN2 mechanism. Scheme 2.11. 1,1-Dihydrofluoroalkylation of amines, mediated by sulfuryl fluoride.26 The Sammis group then explored whether a similar sulfuryl fluoride-mediated approach could be pursued for the 1,1-dihydrofluoroalkylation of thiols. Precedence for this route was reported in 1984 by Shreeve et al. (vide supra), who demonstrated that 2,2,2-trifluoroethyl fluorosulfate (2.13a) would react with methanethiol (2.7c) in the presence of triethylamine (Et3N) 32 to produce a mixture of products, including methyl 2,2,2-trifluoroethyl sulfide (2.10c) and dimethyldisulfane (2.44) in 31% and 14% yields, respectively (Scheme 2.12).50 The latter is produced from a competitive side reaction wherein methanethiol attacks at the sulfur centre of 2.13a versus the alpha carbon, followed by extrusion of SO2 gas. Scheme 2.12. Shreeve’s utility of 2,2,2-trifluoroethyl fluorosulfate in the presence of methanethiol.50 2.1.4 Sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of thiols: initial work (Foth, Gu, Kanani) The initial design of this project took inspiration from Sammis’ 2018 report on the 1,1-dihydrofluoroalkylation of amines. The major goals of the project were to: (1) identify a set of conditions suitable for the 2,2,2-trifluoroethylation of thiols, mediated by sulfuryl fluoride; (2) assess the chemoselectivity of the reaction conditions for thiol nucleophiles relative to alcohols and amines, and re-optimize as necessary; (3) explore the substrate scope of the optimized protocol; and (4) expand the substrate scope to include longer-chain 2,2,3,3,3-pentafluoropropyl 33 sulfides. Initial exploration and optimization of the 1,1-dihydrofluoroalkylation of thiols was conducted by Dr. Paul Foth, a former Ph.D. student in the Sammis group.70 Utilizing benzyl mercaptan (2.7e) in place of the amine nucleophile under the optimized conditions outlined in Sammis’ 2018 report, Foth observed a similarly low-yielding result to that of Shreeve, having synthesized the target 2,2,2-trifluoroethylated sulfide (2.10e) in only 12% yield by 19F NMR spectroscopy (Scheme 2.13). Scheme 2.13. (a) Foth’s initial attempt at the 1,1-dihydrofluoroalkylation of thiols, utilizing the 2018 Sammis protocol for amines, and (b) the associated mechanism. Foth determined that the cause of the low-yielding reaction was the competitive side-reactivity that fluorosulfates (2.13) experience, due to the electrophilic sulfur centre as described above. With the assistance of Frances Gu and Sahil Kanani, Foth observed that 2.10e formed in greater yield (86%, by 19F NMR spectroscopy) when stronger bases than N,N-diisopropylethylamine (DIPEA, 2.45) were utilized, particularly 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU, 2.46). It was determined that the use of bases such as 2.45 favoured formation of fluorosulfate 2.13, whereas stronger bases such as 2.46 led to the formation of bis(1,1-dihydrofluororalkyl) sulfates (2.47, Scheme 2.14). The steric bulk of the base was assumed to have less of an effect than its strength, as sterically encumbered bases such as potassium hexamethyldisilazide (KHMDS) yielded comparable results to DBU.69 34 Scheme 2.14. Effects of base on SO2F2-mediated reactions with 1,1-dihydrofluoroalcohols. Foth concluded that the stronger DBU base thermodynamically favoured the formation of a greater quantity of nucleophilic alkoxide in situ, in turn leading to preferential formation of 2.47a. Given that little was known about the reactivity of such bis-sulfate species and that 2.47a led to greater yield of 2.10e, Foth sought to explore the applicability of bis(1,1-dihydrofluoroalkyl) sulfates for the 1,1-dihydrofluoroalkylation of thiols. His efforts ultimately led to the final optimized one-pot protocol (Scheme 2.15). Scheme 2.15. (a) The final optimized protocol for the 1,1-dihydrofluoroalkylation of thiols, and (b) the associated mechanism. It was at this point that I joined the project. My focus of the project was to (1) quantitatively assess the chemoselectivity of the reaction with regards to thiol and amine nucleophiles in direct competition, (2) demonstrate the synthetic application of this chemoselectivity with representative 35 substrates containing multiple nucleophilic functional groups, (3) further develop the substrate scope of this 2,2,2-trifluoroethylation protocol utilizing alkyl and aryl thiol substrates, and (4) apply the synthetic approach to the 2,2,3,3,3-pentafluoropropylation of thiols, with re-optimization as necessary. 2.2 Results and discussion 2.2.1 Competition studies of the sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of thiols My initial investigations of SO2F2-mediated 1,1-dihydrofluoroalkylations of thiols focused on quantitatively assessing the chemoselectivity of the optimized protocol for thiol nucleophiles over amines. An experiment was designed wherein a suitably potent thiol nucleophile would be placed in direct competition with a comparably potent amine nucleophile, and the reaction monitored by quantitative 19F NMR spectroscopy. For this study, benzyl mercaptan (2.7e) was selected as a representative thiol nucleophile as it had been utilized previously by Foth in the reaction optimization. To draw meaningful conclusions from the competition experiment, the amine nucleophile would ideally be as nucleophilic as possible so as to compete with the thiol under the reaction conditions. Pyrrolidine (2.48) was selected as a representative amine nucleophile as it is more nucleophilic than many other common primary and secondary amine nucleophiles, including piperidine, diethylamine, morpholine, and benzylamine.71 It was evident from the initial reaction optimization that the bis-sulfate intermediate (2.47) was better suited than the corresponding fluorosulfate (2.13) for the 1,1-dihydrofluoroalkylation of thiols versus amines. To test the chemoselectivity of 2.47 for the 1,1-dihydrofluoroalkylation of thiols in lieu of amines, it was crucial that the two nucleophiles be added to a preformed solution 36 of 2.47 with no 2.13 present. The experiment was conducted per the standard optimized procedure, albeit without any nucleophile present during initial formation of the bis-sulfate intermediate (2.47a, Scheme 2.16). In the presence of 1.0 equivalent of 2.47a, quantitative 19F NMR spectroscopic data indicated that benzyl mercaptan (2.7e) underwent preferential 1,1-dihydrofluoroalkylation to deliver 2.10e, with only trace alkylated amine 2.49 observed. This result supported the theory that 2.47a was responsible for the near-exclusive chemoselectivity of the reaction, and it suggested that the reaction could be effectively performed in the presence of unprotected nucleophilic moieties. The carbon centre of 2.47a can be classified as a “hard” electrophile according to hard-soft acid-base (HSAB) theory. Similarly, amines such as 2.48 would be classified as “hard” nucleophiles, while thiols such as 2.7e would be “soft” nucleophiles. By HSAB theory, 2.47a should have reacted preferentially with 2.48. The result of 2.7e outcompeting 2.48 with 2.47a empirically supports the conclusion that bis-sulfates are chemoselective alkylation agents for thiols rather than amines, in spite of HSAB theory. The reaction was run on a 0.35 mmol scale each of thiol (2.7e) and amine (2.48), following the sequential one-pot protocol. 19F NMR spectroscopic yields are indicated in parentheses. PhCF3 (30 μL) was added as an internal standard. Scheme 2.16. Intermolecular competition experiment between benzyl mercaptan and pyrrolidine. In a complementary process, the 1,1-dihydrofluoroalkylation was conducted in the presence of piperidine (2.50) and no thiol nucleophile (Scheme 2.17). The purpose of this 37 experiment was to test whether or not the thiol 1,1-dihydrofluoroalkylation protocol was poorly suited to amine alkylation, even in the absence of a thiol nucleophile. The greater nucleophilicity of pyrrolidine over piperidine is not significant,71 and the latter was considered sufficiently nucleophilic for the purposes of the reaction. Without any competing thiol nucleophile present, only 11% of the N-alkylated amine (2.51) was measured by 19F NMR spectroscopy after stirring for one hour. This result further indicated that 2.47a was poorly suited to amine 1,1-dihydrofluoroalkylations. Presumably, more alkylated amine was measured in this experiment (11%) than in the competition reaction between 2.7e and 2.48 (<3%) as there was no thiol nucleophile present in the former to preferentially outcompete piperidine in attacking 2.47a. The reaction was run on a 1.0 mmol scale of amine (2.50), following the sequential one-pot protocol. The 19F NMR spectroscopic yield of 2.51 is indicated in parentheses. PhCF3 (100 μL) was added as an internal standard. Scheme 2.17. 1,1-Dihydrofluoroalkylation of piperidine with bis(2,2,2-trifluoroethyl)sulfate. Foth and I then conducted parallel 2,2,2-trifluoroethylation experiments using glutathione (2.52) to compare the synthetic utility of bis-sulfates (2.47) against commercially available alternatives such as 2,2,2-trifluoroethyl triflate (2.53) in 1,1-dihydrofluoroalkylations. Glutathione was selected as a representative substrate for these studies on account of its free thiol and amine moieties, as well as the two unprotected carboxylic acid groups. Foth’s complementary experiment with glutathione and 2.47a using the SO2F2-mediated protocol produced 2.54 in 92% yield by 19F NMR spectroscopy and an isolated yield of 59% of the pure product. 38 In my experiment, glutathione (2.52) was treated with 2,2,2-trifluoroethyl triflate (2.53, Scheme 2.18). Treating 2.52 with either 1.1 or 1.5 equivalents of 2.53 afforded the corresponding S-alkylated product (2.54) in 66% and 50% yield (–67.57 ppm, t, J = 10.1 Hz), respectively, along with the formation of by-products bearing a 2,2,2-trifluoroethyl motif (Scheme 2.18). These by-products were formed in <3% yield by 19F NMR spectroscopy with 1.1 equivalents of 2.53 and approximately 10% yield with 1.5 equivalents of 2.53. Based on the 19F NMR spectroscopic chemical shifts of these by-products (–67.26 ppm, t, J = 10.0 Hz; –67.45 ppm, t, J = 9.8 Hz) and the Sammis group’s previous work with 1,1-dihydrofluoroalkylations of amines, it was determined that these by-products were likely a mixture of N- and S-alkylated species.26 These results indicated that while 2.53 was efficient in generating 2.54 in good yield after only five minutes, such speed came at the cost of amine/thiol selectivity with the concomitant production of multiple by-products. The limited chemoselectivity of 2.53 was apparent in comparison to the SO2F2-mediated 1,1-dihydrofluoroalkylation reaction by Foth. Foth’s excellent 19F NMR spectroscopic yield of 92% using 2.47a compares favourably to the lower yields observed in my reactions with 2.53, suggesting bis-sulfates (2.47) pose a synthetic advantage and impart greater chemoselectivity in these reactions. The reaction was run on a 0.3 mmol scale of glutathione (2.52). 19F NMR spectroscopic yields of 2.54 are indicated in parentheses. PhCF3 (30 μL) was added as an internal standard. Scheme 2.18. 1,1-Dihydrofluoroalkylation of glutathione with 2,2,2-trifluoroethyl triflate. 39 2.2.2 Substrate scope of the sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of thiols The initial work towards the substrate scope of this project sought to expand upon the findings of the competition studies (vide supra), namely through the study of substrates with multiple potentially reactive functional groups. Therefore, the hydrochloride salt of L-cysteine ethyl ester (2.7g) was selected as a first representative substrate, as it has both free thiol and amino groups under suitably basic conditions. As 2.7g is also an amino acid derivative, its successful chemoselective 1,1-dihydrofluoroalkylation could demonstrate potential applicability of this SO2F2-mediated protocol to peptide modification. Treatment of 2.7g with SO2F2 and 2,2,2-trifluoroethanol (2.41a) resulted in exclusive thioalkylation, generating ethyl S-(2,2,2-trifluoroethyl)-L-cysteinate (2.10g) in quantitative yield by 19F NMR spectroscopy (Scheme 2.19). Initial attempts to isolate 2.10g proved difficult, and only low isolated yields could be recovered. It was hypothesized that the ethyl ester moiety may be undergoing hydrolysis during the mildly acidic or basic workup steps. Therefore, the isolation protocol was modified to more neutral conditions for this substrate (Chapter 2.4.6). Moderate yield increases were observed as a result, although the isolated yields were still unsatisfactory. The free amine moiety of 2.10g may have interacted too strongly with the acidic silica of the column during purification, leading to product loss. This issue was circumvented by preemptively acidifying the product and generating the hydrochloride salt of 2.10g with 2 M HCl in diethyl ether. Doing so also greatly reduced the volatility of the product, an issue plaguing the isolation of many 1,1-dihydrofluoroalkyl sulfides synthesized during this project. Subsequent isolation and neutralization of the product with potassium carbonate, followed by a facile filtration through a short column of basic alumina yielded target compound 2.10g in 65% yield. 40 Reactions were run on a 1.0 mmol scale of thiol (2.7) following the standard one-pot protocol. Isolated yields are reported with 19F NMR spectroscopic yields indicated in parentheses. PhCF3 (100 μL) was added as an internal standard. Scheme 2.19. The 2,2,2-trifluoroethylation of thiol substrates with multiple reactive functional groups. The effective synthesis of 2.10g indicated that esters were tolerated under the reaction conditions and that they were not susceptible to nucleophilic acyl substitution by the large quantity of nucleophilic thiolate produced in the reaction. To confirm this assumption, methyl 2-mercaptoacetate (2.7h) was subjected to the standard 2,2,2-trifluoroethylation protocol, undergoing successful 1,1-dihydrofluoroalkylation according to quantitative 19F NMR spectroscopic analysis (2.10h, 79%). There was no observed thioester nucleophilic acyl substitution by-product detected by 1H NMR spectroscopy, indicating that thiol 1,1-dihydrofluoroalkylation was the preferred pathway. However, the isolation of 2.10h was negatively impacted by its volatility, significantly reducing the isolated yield (31%). One of the primary objectives for this project was to apply the 1,1-dihydrofluoroalkylation protocol to the synthesis of 2,2,3,3,3-pentafluoropropyl sulfides (vide supra). Four representative thiol substrates (2.7e, 2.7d, 2.7i, and 2.7j) were selected to study the pentafluoropropylation. Benzyl mercaptan (2.7e) was chosen so as to better align the scope of the pentafluoropropylation with the project’s trifluoroethylation scope, particularly as benzyl mercaptan was utilized in the 41 original protocol optimization. 1-Decanethiol (2.7d) was selected as a representative long-chain alkyl substrate as it is markedly less volatile—and therefore less odorous—than other shorter chain thiols, minimizing its stench hazard. 6-Mercaptohexan-1-ol (2.7i) was chosen for two reasons: (1) the successful alkylation of this alkyl thiol substrate would complement the data from 1-decanethiol, and (2) the terminal hydroxyl group is a potential competitive nucleophile in the reaction, potentially enabling further study of the chemoselectivity of the protocol. Finally, 4-aminothiophenol (2.7j) was chosen as a representative aryl substrate, with the free amine serving as a potentially competitive nucleophile. The free amine in 2.7j would again serve to study the protocol’s chemoselectivity for thiol nucleophiles over amines. In the initial experiments with benzyl mercaptan, 2.11e was synthesized in only 44% isolated yield (Scheme 2.20). It was further noted that the product was measured in only 67% yield by 19F NMR spectroscopy, which was considerably lower than expected. Benzyl mercaptan was known to undergo quantitative 2,2,2-trifluoroethylation, according to comparable experiments with 2,2,2-trifluoroethanol in Foth’s optimization. It had previously been observed that the thiol nucleophile could compete with the 1,1-dihydrofluoroalcohol and react directly with SO2F2 to instead produce disulfide-type products. This competition was inferred to be the issue limiting the success of this reaction. Since 2,2,3,3,3-pentafluoropropanol (2.41b) is a weaker nucleophile than 2,2,2-trifluoroethanol (2.41a), it would not be unreasonable to assume that this reduction in nucleophilicity is pronounced enough that benzyl mercaptan can successfully out-compete the 1,1-dihydrofluoroalcohol (2.41) in the pentafluoropropylations. In repeating the reaction, the benzyl mercaptan nucleophile was added only after having already sparged SO2F2 through the solution of DMF, 2,2,2-pentafluoropropanol, and DBU. This sequential addition effectively maximized bis-sulfate 2.47b formation without competitive reactivity between SO2F2 and benzyl mercaptan. This 42 one-pot sequential approach proved effective, increasing the 19F NMR spectroscopic yield of 2.11e to 98%. Unfortunately, the volatility of the product complicated purification, and only an isolated yield of 50% was obtained. Reactions were run on a 1.0 mmol scale of thiol (2.7) following the standard one-pot protocol. Isolated yields are reported, with 19F NMR spectroscopic yields indicated in parentheses. PhCF3 (100 μL) was added as an internal standard. aReactions were run according to the sequential one-pot protocol, with the thiol nucleophile added 5 minutes after the generation of SO2F2 (Section 2.4). Scheme 2.20. The 2,2,2-pentafluoropropylation of alkyl and aryl thiol substrates. 1-Decanethiol (2.7d) was an effective nucleophile in the pentafluoropropylation, with 2.11d isolated in 61% yield and with a notably greater 19F NMR spectroscopic yield (92%) than in the case of the 2,2,2-trifluoroethylation (2.10d, 77%, vide infra). As with 2.11e, the comparably low isolated yield was attributed to the intrinsic volatility of the product. 6-Mercaptohexan-1-ol (2.7i) was next assessed in the standard one-pot reaction. Quantitative yields of 2.11i were observed by 19F NMR spectroscopy, despite the potential for nucleophilic competition from the alcohol. This reaction demonstrated that the favourable chemoselectivity of the 2,2,2-trifluoroethylation extended to 2,2,3,3,3-pentafluoropropylations as well, reinforcing the understanding that the unique reactivity of the bis-sulfate intermediate (2.47) was responsible. 43 Finally, the pentafluoropropylation was tested with a single aryl thiol substrate, 4-aminothiophenol (2.7j). No aminoalkylation was detected by either 1H or 19F NMR spectroscopy, and the desired product 2.11j was observed in 85% 19F NMR spectroscopic yield. As the isolated yield was only 51%, it was worth testing whether the one-pot sequential approach would offer greater product yield. Indeed, the one-pot sequential protocol furnished 2.11j in 95% 19F NMR spectroscopic yield, as well as a superior isolated yield of 71%. This result further exemplified the chemoselectivity of the 2,2,3,3,3-pentafluoropropylation. The final work contributed towards this project was to the substrate scope of the 2,2,2-trifluoroethylation. Four substrates were investigated, specifically benzyl mercaptan (2.7e), 1-decanethiol (2.7d), 4-chlorothiophenol (2.7k), and 3-chlorothiophenol (2.7l). Benzyl mercaptan (2.7e) was selected so as to procure complementary isolation data to Foth’s original optimization, and to make comparisons to the 2,2,3,3,3-pentafluoropropylation experiment conducted previously (vide supra). 1-Decanethiol (2.7d) was also selected in order to make similar comparisons to the 2,2,3,3,3-pentafluoropropylation experiment (vide supra), and to investigate the applicability of the 2,2,2-trifluoroethylation protocol to aliphatic thiols. Aryl thiols 2.7k and 2.7l were selected primarily to study the amenability of the alkylation method to aryl thiols. These two aryl chloride substrates would also be useful in assessing the effects of aryl halide substitution patterns on the outcome of the reaction. Benzyl mercaptan (2.7e) proved amenable to the 2,2,2-trifluoroethylation, producing 2.10e in 90% yield by 19F NMR spectroscopy and in a moderate isolated yield of 58% (Scheme 2.21). This result is nearly identical to that of the analogous sequential-addition 2,2,3,3,3-pentafluoropropylation (98% yield by 19F NMR spectroscopy, 50% isolated), yet is far superior to the single-addition pentafluoropropylation conditions (67% yield by 19F NMR spectroscopy, 44% 44 isolated), indicating that 2,2,2-trifluoroethanol (2.41a) can successfully out-compete benzyl mercaptan in the nucleophilic attack on SO2F2 under single-addition conditions. Reactions were run on a 1.0 mmol scale of thiol (2.7) following the standard one-pot protocol. Isolated yields are reported, with 19F NMR spectroscopic yields indicated in parentheses. PhCF3 (100 μL) was added as an internal standard. Scheme 2.21. Contribution to the substrate scope of the 2,2,2-trifluoroethylation of aliphatic and aryl thiols. 1-Decanethiol (2.7d) yielded slightly poorer results in the trifluoroethylation than benzyl mercaptan, with a 77% 19F NMR spectroscopic yield of 2.10d and an isolated yield of 67%. The 19F NMR spectroscopic yield for the pentafluoropropylation was significantly greater at 92%, although the isolated yield was similarly only 61%. This data indicates that the formation of bis(2,2,2-trifluoroethyl)sulfate (2.47a) did not go to completion in this experiment, unlike in the case of the pentafluoropropylation. The 2,2,2-trifluoroethylation could potentially be improved in the future by way of a sequential addition, ideally to maximize the formation of 2.47a prior to addition of 2.7d. The site of chlorination in 4-chlorothiophenol (2.7k) versus 3-chlorothiophenol (2.7l) had no impact on the degree of formation of the 2,2,2-trifluoroethylated products, which were recorded in 99% and 98% 19F NMR spectroscopic yields, respectively. These near-quantitative examples demonstrate the potential superiority of the 2,2,2-trifluoroethylation with respect to aryl thiols over 45 alkyl thiol substrates. As was the case for the other 1,1-dihydrofluoroalkyl sulfides, both 2.10k and 2.10l were isolated in significantly lower yields—57% and 72%, respectively—on account of their inherent volatility. During the course of these experiments, 2,2,2-trifluoroethylations were attempted on a small group of substrates that ultimately either failed to undergo alkylation or proved impossible to isolate in pure form. These substrates were potassium thioacetate (2.55a), potassium benzothioate (2.55b), and 2-amino-4-chlorobenzenethiol (2.7m). Treatment of potassium thioacetate (2.55a) with 2,2,2-trifluoroethanol (2.41a) under the sequential-addition reaction conditions successfully generated the corresponding thioester (2.29a) in quantitative yield by 19F NMR spectroscopy (Scheme 2.22). A 2018 report by Menczinger et al. indicates that the 19F NMR spectroscopic chemical shift of 2.29a is –67.05 ppm (t, J = 9.9 Hz),72 which aligned with my observations of –67.3 ppm (t, J = 9.7 Hz). A trivial quantity—present in a ratio of less than 1:20, relative to 2.29a—of 2,2,2-trifluoroethanethiol (2.38) was detected at –68.93 ppm (t, J = 10.7 Hz). Isolation and purification of 2.29a was challenging as it has a known boiling point of 115 °C and could evaporate if placed under reduced pressure. The thioester moiety could also be hydrolyzed by an acidic or basic workup; the potential hydrolysis was less concerning as the protocol described by Menczinger et al. required either sodium metal or sodium methoxide in refluxing conditions to facilitate this process. Nonetheless, neutral conditions were utilized during workup to avoid this potential side-reaction. Despite successfully isolating the product thioester as an impure mixture in hexanes along with residual 2,2,2-trifluoroethanol (2.41a) and trace 2,2,2-trifluoroethanethiol (2.38), purification via distillation was unsuccessful, with only low-yielding mixtures of 2.29a, 2.41a, and 2.38 recovered. 46 Reactions were run on a 1.0 mmol scale of thiol (2.7) or 2.55, following the sequential one-pot protocol, with the thiol nucleophile added 5 minutes after the generation of SO2F2 (Section 2.4). 19F NMR spectroscopic yields indicated in parentheses. PhCF3 (100 μL) was added as an internal standard. aThe reaction was stirred for 60 minutes. Scheme 2.22. Unsuccessful 2,2,2-trifluoroethylations and/or isolations of thiol substrates. The experiments with potassium benzothioate (2.55b) suffered from similar complications as those with potassium thioacetate (2.55a). Treatment of 2.55b with 2,2,2-trifluoroethanol (2.41a) under the sequential-addition reaction conditions also generated the corresponding thioester (2.29b) in quantitative yield by 19F NMR spectroscopy (–67.7 ppm, t, J = 9.7 Hz), with trivial 2,2,2-trifluoroethanethiol (2.38) present once more (–68.97 ppm, t, J = 10.8 Hz). Product thioester 2.29b was isolated as a crude mixture with 2,2,2-trifluoroethanol (2.41a) in diethyl ether, although separation by distillation was unsuccessful. Attempted concentration under reduced pressure to remove the ether and 2.41b instead removed 2.29b. Repeated attempts to alkylate the thiol moiety of 2-amino-4-chlorobenzenethiol (2.7m) were unsuccessful, with no 5-chloro-2-((2,2,2-trifluoroethyl)thio)aniline (2.10m) detected by quantitative 19F NMR spectroscopy even after stirring for 60 minutes at 40 °C. No S- or N-alkylated products were observed by 19F NMR spectroscopy. 1H NMR spectroscopic data of the reaction mixture indicated that none of 2.7m had reacted with 2.41a or SO2F2. The reason for this result is not known; however, it was hypothesized that the amino group ortho to the nucleophilic thiol may have interfered in the reaction in some 47 manner, potentially through undesirable weak intramolecular hydrogen-bonding to the thiolate, reducing the latter’s nucleophilic character and impeding the reaction.73 The para-substituted chlorine substituent was not expected to have led to this result on account of 2.7k having previously undergone successful 2,2,2-trifluoroethylation to yield 2.10k. 2.3 Conclusions The chemoselectivity of this SO2F2-mediated 1,1-dihydrofluoroalkylation protocol has been studied in detail through the competition study with benzyl mercaptan and pyrrolidine, as well as the experiments with piperidine and glutathione.69 This work indicates that thiols will selectively undergo alkylation even in the presence of an equimolar equivalent of competitive amine nucleophile, on account of the bis(1,1-dihydrofluoroalkyl)sulfate intermediate. The ten alkylated thiols contributed to the substrate scope of this project further survey this chemoselectivity, with thiols favoured in all cases over potentially competitive free amine and alcohol nucleophiles. Through the experiments with the hydrochloride salt of L-cysteine ethyl ester, it was determined that the 1,1-dihydrofluoroalkylation reaction has potential applicability to selective peptide modification, and that the protocol effectively tolerates ester functionality. This work surveyed chemoselective thiol 2,2,3,3,3-pentafluoropropylations and both single-addition and sequential-addition approaches were effectively applied to the alkylation of four thiol substrates. The results showed that single-addition conditions could be utilized in some cases, but that the sequential addition of the thiol nucleophile was superior when utilizing longer-chain 1,1-dihydrofluoroalcohols. Doing so permits uninhibited generation of the key bis(1,1-dihydrofluoroalkyl)sulfate intermediate. 48 Finally, the contributions to the general 2,2,2-trifluoroethylation scope provided meaningful comparison data between the trifluoroethylation and pentafluoropropylation protocols, proving that both could be effectively applied to the same substrates to yield similar results. Despite failed isolations, the 2,2,2-trifluoroethylation was also applied to a pair of low molecular weight thiol substrates. This work demonstrates the applicability of this protocol to both aliphatic and aryl thiol substrates, and that this protocol may have synthetic applications in late-stage 1,1-dihydrofluoroalkylations of pharmaceutically and industrially relevant compounds. 2.4 Experimental information 2.4.1 General methods All reactions were conducted in either two 4 mL (0.3 mmol scale) or two 20 mL (1.0 mmol scale) borosilicate scintillation vials, equipped with screw caps and PTFE/Silicon septa, purchased from ChemGlass Life Sciences LLC. These vials were connected through the equipped septa via BD IntramedicTM polyethylene tubing (I.D. 1.57 mm, O.D. 2.08 mm). N,N-Dimethylformamide (DMF) was dried over 4 Å molecular sieves. Flash column chromatography was completed using F60 silica: 230-400 mesh (40-63 μm) silica. TLC analyses were conducted on Merck Kieselgel 60 F254 aluminum-backed plates and visualized by UV fluorescence (254 nm) followed by one of the following stains: KMnO4, ninhydrin, p-anisaldehyde, or bromocresol green. All 19F and 1H NMR spectroscopic data collected on a Bruker AV300 NMR spectrometer, equipped with an autosampler. All spectra were collected at room temperature. 49 2.4.2 General procedure for the determination of NMR spectroscopy yields To the reaction mixture containing substrate (1.0 mmol) was added PhCF3 (100 μL, 0.8 mmol) immediately after removing the polyethylene tubing and needle. An aliquot was removed by syringe and diluted in CDCl3 for NMR spectroscopic analysis. All 19F NMR spectroscopy yields were calculated using PhCF3 as an internal standard (19F NMR spectroscopy: 282 MHz, Chloroform-d, δ –63.72 ppm). Four scans and a relaxation delay of 40 seconds were used. A sample calculation for the determination of 19F yield is as follows: ((𝑖𝑛𝑡𝑒𝑔𝑟𝑎𝑡𝑖𝑜𝑛 𝑣𝑎𝑙𝑢𝑒 𝑜𝑓 𝑝𝑟𝑜𝑑𝑢𝑐𝑡𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑛𝑢𝑐𝑙𝑒𝑖 𝑖𝑛 𝑝𝑟𝑜𝑑𝑢𝑐𝑡)(𝑖𝑛𝑡𝑒𝑔𝑟𝑎𝑡𝑖𝑜𝑛 𝑣𝑎𝑙𝑢𝑒 𝑜𝑓 𝑖𝑛𝑡𝑒𝑟𝑛𝑎𝑙 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑛𝑢𝑐𝑙𝑒𝑖 𝑖𝑛 𝑖𝑛𝑡𝑒𝑟𝑛𝑎𝑙 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑)) ((𝑚𝑎𝑠𝑠 𝑖𝑛𝑡𝑒𝑟𝑛𝑎𝑙 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 (𝑔)𝑀𝑊 𝑖𝑛𝑡𝑒𝑟𝑛𝑎𝑙 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 (𝑔𝑚𝑜𝑙))(𝑚𝑎𝑠𝑠 𝑠𝑢𝑏𝑠𝑡𝑟𝑎𝑡𝑒 (𝑔)𝑀𝑊 𝑠𝑢𝑏𝑠𝑡𝑟𝑎𝑡𝑒 (𝑔𝑚𝑜𝑙))) x 100% ((3.293 F nuclei)(3.003 F nuclei)) ((0.1202 𝑔 𝑡𝑟𝑖𝑓𝑙𝑢𝑜𝑟𝑜𝑡𝑜𝑙𝑢𝑒𝑛𝑒146.11 𝑔𝑚𝑜𝑙 𝑡𝑟𝑖𝑓𝑙𝑢𝑜𝑟𝑜𝑡𝑜𝑙𝑢𝑒𝑛𝑒)(0.124 𝑔 benzyl mercaptan124.21 𝑔𝑚𝑜𝑙 𝑏𝑒𝑛𝑧𝑦𝑙 𝑚𝑒𝑟𝑐𝑎𝑝𝑡𝑎𝑛)) x 100% = 90.3% All 1H NMR spectroscopy yields were calculated using 1,3,5-trimethoxybenzene as an internal standard (1H NMR spectroscopy: 300 MHz, Chloroform-d, δ 6.10 and 3.80 ppm). 12 scans and a relaxation delay of 35 seconds were used. Quantitative 1H NMR spectroscopy yields were calculated by a similar method to 19F NMR spectroscopy. 2.4.3 Sulfuryl fluoride safety Sulfuryl fluoride is a toxic gas and potential source of hydrofluoric acid (HF). All work should be conducted in a fully operational fumehood. 50 2.4.4 2,2,2-Trifluoroethylation of thiols 2.4.4.1 General procedure for the one-pot 2,2,2-trifluoroethylation of thiols The setup for the 2,2,2-trifluoroethylation procedure is shown. The same setup can be used for the 2,2,3,3,3pentafluoropropylation procedure, as well as the one-pot sequential modifications. Stir plates and heating sources are omitted for clarity. Figure 2.3. General reaction setup for the 2,2,2-trifluoroethylation of thiols. Two 20 mL vials (Vial A and Vial B) equipped with magnetic stir bars were capped with PTFE/silicone septa and connected by approximately 15–20 cm of polyethylene tubing. To Vial A were added N,N-sulfonyldiimidazole (SDI, 2.9 mmol, 2.9 equiv.) and KF (7.8 mmol, 7.8 equiv.). To Vial B was added thiol substrate (2.7, 1.0 mmol, 1.0 equiv.), if it were a solid. The system was purged of air using N2 gas via Vial B, with the cap of Vial A loosened. To Vial B were added dry N,N-dimethylformamide (DMF, 1.47 mL, 19.0 equiv.), 2,2,2-trifluoroethanol (2.41a, TFE, 1.47 mL, 20.6 equiv.), and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU, 0.88 mL, 5.9 equiv.). Thiol substrate (2.7, 1.0 mmol, 1.0 equiv.) was added to Vial B, if it were a liquid. Vial B was heated to 40 °C and the polyethylene tubing was fully submerged into the Vial B solution. Both Vials A and B were set to stir at a rapid rate. 51 To Vial A was added trifluoroacetic acid (TFA, 1.6 mL, 20.9 equiv.) in one portion, initiating the reaction. Energetic SO2F2 (2.40) bubbling was observed in Vial B for 2–3 minutes, with the bubbling decreasing in vigour as the reaction progressed. Additional SO2F2 was bubbled through the Vial B solution for approximately 1 minute by inserting an open needle into the septum of Vial B. Upon cessation of bubbling in Vial B, the needle and polyethylene tubing were removed from Vial B, which was allowed to stir at 40 °C for 20 minutes from initial TFA addition. To Vial B was added PhCF3 internal standard (100 μL, 0.8 mmol, 0.8 equiv), as required. The acidic contents of Vial A were quenched with aqueous NaOH (1 or 2 M). Isolation and purification were completed as outlined in Section 2.4.4.3. 2.4.4.2 General procedure for the one-pot sequential 2,2,2-trifluoroethylation of thiols The one-pot sequential 2,2,2-trifluoroethylation of thiols was conducted in the same manner as the one-pot method (Section 2.4.4.1), with the following changes: the thiol substrate (2.7, 1.0 mmol, 1.0 equiv.) was added to Vial B five minutes after SO2F2 bubbling, either by syringe (for liquid substrates) or by briefly opening Vial B (for solid substrates). To Vial B was then added PhCF3 (100 μL, 0.8 mmol, 0.8 equiv) in the manner described previously. The reaction was stirred at 40 °C for 20 minutes from substrate addition. Isolation and purification were completed as outlined in Section 2.4.4.3. 2.4.4.3 General isolation and purification of the one-pot and one-pot sequential 2,2,2-trifluoroethylation of thiols The reaction mixture was diluted in aqueous HCl (1 M or 3 M, 10 mL) over ice and extracted with ethyl acetate, diethyl ether, hexanes, or pentane (3–5 x 10 mL) as appropriate. The combined organic fractions were washed with aqueous HCl (1 M, 2 x 10 mL), then either aqueous 52 NaOH (1 M, 2 x 10 mL) or saturated aqueous NaHCO3 (2 x 10 mL), followed by H2O (3 x 10 mL) and brine (2 x 10 mL). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography. Fractions containing the desired material were concentrated in vacuo. 2.4.5 2,2,3,3,3-Pentafluoropropylation of thiols 2.4.5.1 General procedure for the one-pot 2,2,3,3,3-pentafluoropropylation of thiols Two 20 mL vials (Vial A and Vial B) equipped with magnetic stir bars were capped with PTFE/silicone septa and connected by approximately 15–20 cm of polyethylene tubing. To Vial A were added N,N-sulfonyldiimidazole (SDI, 2.9 mmol, 2.9 equiv.) and KF (7.8 mmol, 7.8 equiv.). To Vial B was added thiol substrate (2.7, 1.0 mmol, 1.0 equiv.), if it were a solid. The system was purged of air using N2 gas via Vial B, with the cap of Vial A loosened. To Vial B, were added dry N,N-dimethylformamide (DMF, 1.94 mL, 25.1 equiv.), 2,2,3,3,3-pentafluoropropanol (2.41b, PFP, 1.0 mL, 10.0 equiv.), and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU, 0.88 mL, 5.9 equiv.). Thiol substrate (2.7, 1.0 mmol, 1.0 equiv.) was added, if it were a liquid. Vial B was heated to 40 °C and the polyethylene tubing was fully submerged into the Vial B solution. Both Vials A and B were set to stir at a rapid rate. To Vial A was added trifluoroacetic acid (TFA, 1.6 mL, 20.9 equiv.) in one portion, initiating the reaction. Energetic SO2F2 (2.40) bubbling was observed in Vial B for 2–3 minutes, with the bubbling decreasing in vigour as the reaction progressed. Additional SO2F2 was bubbled 53 through the Vial B solution for approximately 1 minute by inserting an open needle into the septum of Vial B. Upon cessation of bubbling in Vial B, the needle and polyethylene tubing were removed from Vial B, which was allowed to stir at 40 °C for 20 minutes from initial TFA addition. To Vial B was added PhCF3 internal standard (100 μL, 0.8 mmol, 0.8 equiv), as required. The acidic contents of Vial A were quenched with aqueous NaOH (1 or 2 M). Isolation and purification were completed as outlined in Section 2.4.5.3. 2.4.5.2 General procedure for the one-pot sequential 2,2,3,3,3-pentafluoropropylation of thiols The one-pot sequential 2,2,3,3,3-pentafluoropropylation of thiols was conducted in the same manner as the one-pot method (Section 2.4.5.1), with the following changes: the thiol substrate (2.7, 1.0 mmol, 1.0 equiv.) was added to Vial B five minutes after SO2F2 bubbling, either by syringe (liquid substrate) or by briefly opening Vial B (solid substrate). To Vial B was then added PhCF3 (100 μL, 0.8 mmol, 0.8 equiv) in the manner described previously. The reaction was stirred at 40 °C for 20 minutes from substrate addition. Isolation and purification were completed as outlined in Section 2.4.5.3. 2.4.5.3 General isolation and purification of the one-pot and one-pot sequential 2,2,3,3,3-pentafluoropropylation of thiols The reaction mixture was diluted in aqueous HCl (1 M or 3 M, 10 mL) over ice and extracted with ethyl acetate, diethyl ether, hexanes, or pentane (3–5 x 10 mL) as appropriate. The combined organic fractions were washed with one of: (a) aqueous HCl (1 M or 3 M, 2 x 10 mL) over ice, followed by aqueous NaOH (1 M, 2 x 10 mL); or (b) aqueous NaOH (1 M, 2 x 10 mL); 54 or (c) saturated aqueous NaHCO3 (2 x 10 mL). The combined organic fractions were washed with H2O (3 x 10 mL) and brine (2 x 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography. Fractions containing the desired material were concentrated in vacuo. 2.4.6 Workup and purification for compound 2.10g The reaction mixture was diluted in H2O (20 mL) and the product was extracted with ethyl acetate (5 x 10 mL). The combined organic fractions were washed with H2O (5 x 10 mL), and brine (1 x 10 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The crude material was diluted in a minimum of diethyl ether, to which HCl dissolved in diethyl ether (2.0 M, 2.0 mL, 4.0 equiv.) was added. The solution was purged with argon gas for 2 minutes, concentrated in vacuo, and the solid washed with diethyl ether, yielding the hydrochloride salt of 2.10g. The salt of 2.10g was added to a solution of K2CO3 (0.42 g) in ethanol (10 mL) and stirred at room temperature for 10 minutes. Reaction completion was determined by TLC. The solution was filtered through 3 cm of basic alumina and concentrated in vacuo, yielding the desired product. 2.4.7 Workup and purification for compound 2.10h The reaction mixture was diluted in aqueous HCl (3 M, 10 mL) with ice and washed with hexanes (3 x 10 mL). The aqueous phase was basified with aqueous saturated NaHCO3, and the product was extracted with diethyl ether or ethyl acetate (3 x 10 mL). The combined organic fractions were sequentially washed with aqueous NaOH (1 M, 4 x 20 mL), H2O (3 x 15 mL), and brine (2 x 15 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude material 55 was purified by silica gel flash column chromatography. Fractions containing 2.10h were concentrated in vacuo. 2.4.8 2,2,2-Trifluoroethylation competition study between benzyl mercaptan (2.7e) and pyrrolidine (2.48) Two 4 mL vials (Vial A and Vial B) equipped with magnetic stir bars were capped with PTFE/silicone septa and connected by approximately 15–20 cm of polyethylene tubing. Vial A was charged with SDI (0.87 mmol, 2.9 equiv.) and anhydrous KF (2.34 mmol, 7.8 equiv.), then the system was placed under a N2 atmosphere. To Vial B were added dry DMF (0.80 mL), 2,2,2-trifluoroethanol (2.41a, 1.1 mmol, 3.7 equiv.) and DBU (0.26 mL, 1.8 mmol, 5.9 equiv.). The polyethylene tube in Vial B was immersed into the solution and to Vial A was added TFA (0.48 mL, 6.3 mmol, 21 equiv.) in one portion. in one portion, initiating the reaction. Energetic SO2F2 (2.40) bubbling was observed in Vial B for 2–3 minutes, with the bubbling decreasing in vigour 56 as the reaction progressed. Additional SO2F2 was bubbled through the Vial B solution for approximately 1 minute by inserting an open needle into the septum of Vial B. Upon cessation of bubbling in Vial B, the needle and polyethylene tubing were removed from Vial B, which was allowed to stir at 40 °C for 20 minutes from initial TFA addition. To Vial B was added PhCF3 internal standard (30 μL, 0.24 mmol, 0.24 equiv), and the quantity of 2.47a was assessed by quantitative 19F NMR spectroscopy. The acidic contents of Vial A were quenched with aqueous NaOH (1 or 2 M). To the reaction was added a pre-mixed solution of benzyl mercaptan (2.7e, 1.0 equiv, relative to 2.47a) and pyrrolidine (2.48, 1.0 equiv, relative to 2.47a) in DMF (0.10 mL). The reaction was stirred at ambient temperature and the quantity of products formed was determined by quantitative 19F NMR spectroscopy. 2.4.9 2,2,2-Trifluoroethylation of piperidine (2.50) The reaction was performed as described in Section 2.4.4.2 using piperidine (2.50, 1.0 mmol, 1.0 equiv.) in lieu of the thiol substrate. The 2,2,2-trifluoroethylated amine (2.51) was measured in 11% yield by quantitative 19F NMR spectroscopy. 57 2.4.10 2,2,2-Trifluoroethylation of glutathione (2.52) with 2,2,2-trifluoroethyl triflate (2.53) To a 4 mL vial equipped with a magnetic stir bar were added glutathione (2.52, 97 mg, 0.3 mmol, 1 equiv), DBU (0.22 mL, 1.5 mmol, 5 equiv), and DMF (1 mL) at room temperature. To this solution was added trifluoroethyl triflate (2.53, 76.8 mg, 0.33 mmol, 1.1 equiv), and the reaction was stirred at room temperature. α,α,α-Trifluorotoluene (37.6 mg) was added as an internal standard and the reaction mixture was sampled after five minutes. 19F NMR spectroscopy indicated S-alkylation occurred in 66% yield, alongside the formation of unidentified by-products. 19F NMR: (282 MHz, Chloroform-d) δ -67.1 (t, J = 10.1 Hz). In a parallel experiment trifluoroethyl triflate (2.49, 101 mg, 0.45 mmol, 1.5 equiv) was added; 19F NMR spectroscopy indicated S-alkylation occurred in 66% yield, alongside the formation of unidentified by-products. 19F NMR: (282 MHz, Chloroform-d) δ -67.1 (t, J = 10.1 Hz). 58 2.4.11 Characterization data of 2.10d, 2.10e, 2.10g, 2.10h, 2.10k, 2.10l, , 2.11d, 2.11e, 2.11i, 2.11j, 2.29a, and 2.29b Compound 2.10d Following the general 2,2,2-trifluoroethylation procedure with 2,2,2-trifluoroethanol (2.41a), 2.9g was isolated in 67% yield as a colourless oil. 1H NMR: (300 MHz, Chloroform-d) δ 3.06 (q, J = 10.0 Hz, 2H), 2.66 (t, J = 7.3 Hz, 2H), 1.65 – 1.51 (m, 2H), 1.42 – 1.18 (m, 14H), 0.93 – 0.83 (m, 3H). 19F NMR: (282 MHz, Chloroform-d) δ -66.8 (t, J = 9.9 Hz). Compound 2.10e Following the general 2,2,2-trifluoroethylation procedure with 2,2,2-trifluoroethanol (2.41a), 2.10e was isolated in 58% yield as a colourless oil. 1H NMR: (300 MHz, Chloroform-d) δ 7.71 – 7.24 (m, 5H), 3.84 (s, 2H), 2.89 (q, J = 10.0 Hz, 2H). 13C NMR: (75 MHz, Chloroform-d) δ 136.6, 129.3, 128.9, 127.7, 126.3 (q, J = 276.5 Hz), 36.6, 32.6 (q, J = 32.6 Hz). 19F NMR: (282 MHz, Chloroform-d) δ -66.2 (t, J = 9.9 Hz). 59 Compound 2.10g Following the general 2,2,2-trifluoroethylation procedure with 2,2,2-trifluoroethanol (2.41a) and the workup described in Section 2.4.6, 2.10g was isolated in 65% yield as a pale-yellow oil. 1H NMR: (300 MHz, Chloroform-d) δ 4.21 (q, J = 7.3 Hz, 2H), 3.68 (dd, J = 7.2, 4.8 Hz, 1H), 3.19 (q, J = 9.9 Hz, 2H), 3.09 – 2.87 (m, 2H), 1.74 (s, 2H), 1.29 (t, J = 7.1 Hz, 3H). 19F NMR: (282 MHz, Chloroform-d) δ -67.0 (t, J = 9.8 Hz). 13C NMR: (75 MHz, Chloroform-d) δ 173.7, 125.9 (q, J = 276.3 Hz), 61.6, 54.7, 37.9, 35.0 (q, J = 32.8 Hz), 14.3. Compound 2.10h Following the general 2,2,2-trifluoroethylation procedure with 2,2,2-trifluoroethanol (2.41a), 2.10h was isolated in 31% yield as a colourless oil. 1H NMR: (300 MHz, Chloroform-d) δ 3.75 (s, 3H), 3.36 (s, 2H), 3.25 (q, J = 9.8 Hz, 2H). 13C NMR: (101 MHz, Chloroform-d) δ 170.0, 125.9 (q, J = 276.4 Hz), 52.7, 34.0 (q, J = 33.0 Hz), 33.5. 19F NMR: (282 MHz, Chloroform-d) δ -66.9 (t, J = 9.8 Hz). 60 Compound 2.10k Following the general 2,2,2-trifluoroethylation procedure with 2,2,2-trifluoroethanol (2.41a), 2.10k was isolated in 57% yield as a colourless oil. 1H NMR: (300 MHz, Chloroform-d) δ 7.48 – 7.38 (m, 2H), 7.36 – 7.25 (m, 2H), 3.41 (q, J = 9.6 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 134.6, 133.5, 132.2, 129.6, 125.4 (q, J = 277.6 Hz), 38.4 (q, J = 32.9 Hz). 19F NMR: (282 MHz, Chloroform-d) δ -66.7 (t, J = 9.4 Hz). Compound 2.10l Following the general 2,2,2-trifluoroethylation procedure with 2,2,2-trifluoroethanol (2.41a), 2.10l was isolated in 72% yield as a colourless oil. 1H NMR: (300 MHz, Chloroform-d) δ 7.50 (dt, J = 1.9, 1.0 Hz, 1H), 7.39 (ddd, J = 5.6, 3.1, 1.8 Hz, 1H), 7.34 – 7.25 (m, 2H), 3.48 (q, J = 9.6 Hz, 2H). 13C NMR: (75 MHz, Chloroform-d) δ 135.7, 135.0, 131.3, 130.4, 129.6, 128.3, 125.3 (q, J = 276.4 Hz), 37.9 (q, J = 33.0 Hz). 19F NMR: (282 MHz, Chloroform-d) δ -66.7 (t, J = 9.7 Hz). 61 Compound 2.11d Following the general 2,2,3,3,3-pentafluoropropylation procedure with 2,2,3,3,3-pentafluoropropanol (2.41b), 2.11d was isolated in 61% yield as a colourless oil. 1H NMR: (300 MHz, Chloroform-d) δ 3.06 (t, J = 17.0 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H), 1.65 – 1.50 (m, 2H), 1.44 – 1.18 (m, 14H), 0.92 – 0.83 (m, 3H). 19F NMR: (282 MHz, Chloroform-d) δ -84.9, -117.4 (t, J = 17.1 Hz). Compound 2.11e Following the general 2,2,3,3,3-pentafluoropropylation procedure with 2,2,3,3,3-pentafluoropropanol (2.41b), 2.11e was isolated in 44% yield as a colourless oil. Following the sequential 2,2,3,3,3-pentafluoropropylation procedure with 2,2,3,3,3-pentafluoropropanol (2.41b), 2.11e was isolated in 50% yield as a colourless oil. 1H NMR: (300 MHz, Chloroform-d) δ 7.34 (qd, J = 7.0, 3.5 Hz, 5H), 3.86 (s, 2H), 2.90 (ddd, J = 17.6, 16.7, 1.0 Hz, 2H). 19F NMR: (282 MHz, Chloroform-d) δ -85.0, -116.9 (t, J = 17.2 Hz). Compound 2.11i Following the general 2,2,3,3,3-pentafluoropropylation procedure with 2,2,3,3,3-pentafluoropropanol (2.41b), 2.11i was isolated in 68% yield as a colourless oil. 62 1H NMR: (300 MHz, Chloroform-d) δ 3.64 (t, J = 6.5 Hz, 2H), 3.05 (t, J = 17.1 Hz, 2H), 2.68 (t, J = 7.3 Hz, 2H), 1.70 – 1.51 (m, 4H), 1.49 – 1.31 (m, 5H). 19F NMR: (282 MHz, Chloroform-d) δ -84.9, -117.4 (t, J = 17.1 Hz). Compound 2.11j Following the general 2,2,3,3,3-pentafluoropropylation procedure with 2,2,3,3,3-pentafluoropropanol (2.41b), 2.11j was isolated in 51% yield as a yellow oil. Following the sequential 2,2,3,3,3-pentafluoropropylation procedure with 2,2,3,3,3-pentafluoropropanol (2.41b), 2.11j was isolated in 71% yield as a yellow oil. 1H NMR: (300 MHz, Chloroform-d) δ 7.40 – 7.31 (m, 2H), 6.66 – 6.57 (m, 2H), 3.80 (s, 2H), 3.28 (tt, J = 17.3, 0.9 Hz, 2H). 13C NMR: (75 MHz, Chloroform-d) δ 147.4, 135.9, 121.1, 115.7, 38.1 (t, J = 23.5 Hz). 19F NMR: (282 MHz, Chloroform-d) δ -84.9, -117.4 (t, J = 17.0 Hz). Compound 2.29a Following the general 2,2,2-trifluoroethylation procedure with 2,2,2-trifluoroethanol (2.41a), 2.29a was recorded in 99% yield by quantitative 19F NMR. Isolation and purification of this compound failed. 19F NMR: (282 MHz, Chloroform-d) δ -67.3 (t, J = 9.4 Hz). 63 Compound 2.29b Following the general 2,2,2-trifluoroethylation procedure with 2,2,2-trifluoroethanol (2.41a), 2.29b was recorded in 99% yield by quantitative 19F NMR. Isolation and purification of this compound failed. 19F NMR: (282 MHz, Chloroform-d) δ -67.7 (t, J = 9.4 Hz). 64 Chapter 3: Mechanistic Studies of the Sulfuryl Fluoride-Mediated Generation and One-Pot Nucleophilic Acyl Substitution of Acyl Fluorides 3.1 Acyl fluorides: applications, properties, and existing synthetic approaches 3.1.1 Applications and properties of acyl fluorides Acyl fluorides (3.1) are synthetically versatile motifs with reactivity that is unique from that of other acyl halides (i.e. 3.2, and 3.3). Acyl fluorides undergo nucleophilic acyl substitution (NAS) reactions more similarly to activated esters (i.e. 3.4) than to acyl chlorides (3.3).6,74 This reactivity trends well with acid dissociation constant (pKa) values for the conjugate acid of the halide or halide surrogate leaving group (Figure 3.1). Figure 3.1. The reactivity trend of acyl halides correlates to the pKa of the conjugate acid of their leaving groups. While acyl fluorides are less reactive than acyl chlorides, they nonetheless are amenable to nucleophilic acyl substitution reactions. Acyl fluorides can be treated with amines and alkoxides to produce the corresponding amide or ester, respectively. The differences in reactivity of acyl fluorides versus their chloride analogues is evident upon treatment of the former with neutral alcohols or water; acyl fluorides are typically inert with respect to these nucleophiles, whereas acyl 65 chlorides readily undergo facile substitution or hydrolysis to the ester or acid, respectively.6,75–78 Given their stability in neutral aqueous media, acyl fluorides have also been studied as electrophilic tags for selective bioconjugation.79–81 Stereochemically defined acyl fluorides (3.5) are also less prone to epimerization of the carbon alpha to the carbonyl during the synthesis of molecules such as amino acids (Scheme 3.1a).6,77,82,83 As a result, 3.5 are an attractive alternative to the analogous acyl chlorides (3.6) in peptide couplings for the production of NAS-based products (3.7 and 3.8), although 3.6 still find use. The epimerization of stereochemically defined acyl chlorides is usually achieved in one of three ways: (1) direct deprotonation of an α-proton of 3.9, leading to an enolate intermediate (3.10, Scheme 3.1b); (2) ketene (3.11) formation by way of deprotonation of an α-proton, possibly via an enolate intermediate (3.10, Scheme 3.1c); or (3) intramolecular cyclization to form an oxazolone intermediate (3.12) in the case of acylated N-protected amino acids (Scheme 3.1d). The oxazolone is produced by deprotonation of 3.13 to yield 3.14. Cyclization of 3.14, followed by collapse of tetrahedral intermediate 3.15 and subsequent enolization of 3.12, yields enolate 3.16. All three mechanistic routes lead to epimerization of the α-carbon. Acyl fluorides are less-prone to these epimerization processes on account of the greater covalent bond strength of the C–F over the C–Cl bond. 66 Scheme 3.1. (a) Epimerization of acyl chlorides versus acyl fluorides, and (b,c,d) modes of epimerization of amino acyl chlorides.6,82,83 The tempered reactivity of acyl fluorides compared to the analogous acyl chlorides has resulted in their use in a variety of synthetic applications. Acyl fluorides are generally sourced from the corresponding carboxylic acid (3.17), and are used predominantly for nucleophilic acyl substitution reactions; these include the formation of amides (3.18)84,85 and Weinreb amides.84,86 Acyl fluorides are also applied to peptide couplings, including the work of Georg et al. with their use of Deoxo-Fluor® (3.19, Scheme 3.2a).87 Similarly, acyl fluorides find use as acylating tools for the aminoacylation of nucleosides (3.20) to produce 3.21, as demonstrated by Oliver and Oyelere in 1996 (Scheme 3.2b).88 67 Scheme 3.2. Representative examples of synthetic applications of acyl fluorides in substitution reactions.84,86,88 In a different approach, Sanford et al. utilized 4-methoxybenzoyl fluoride (3.1a) as a fluoride source in the presence of N-heterocyclic carbenes (3.22) for their nucleophilic aromatic substitution (SNAr) of chloro- and nitroarenes (3.23) to produce aryl and heteroaryl fluorides (3.24, Scheme 3.3).89 Electron-rich acyl fluorides were far superior to electron-deficient ones, including 4-trifluoromethylbenzoyl fluoride. Scheme 3.3. Sanford’s approach to aryl and heteroaryl fluorides, utilizing acyl fluorides as a fluoride source.89 Acyl fluorides are also well-documented in transition metal-mediated transformations. For example, Rovis and Zhang reported a cross-coupling of alkyl, aryl, and vinyl acyl fluorides (3.1) with aryl- and alkyl zinc species to produce ketones (3.25), mediated by commercially available Ni(COD)2 (Scheme 3.4a).90 The protocol was primarily applied to electron-rich acyl fluorides, 68 with no electron-deficient acyl fluoride substrates included in the original scope. Another nickel-catalyzed protocol was developed in 2018 by Sanford et al., who described a base-free decarbonylative Suzuki-Miyaura cross-coupling of aryl acids (3.17) and aryl boronic acids (3.26) to produce 3.27 via the intermediate acyl fluoride (Scheme 3.4b).91 Sanford’s protocol was tolerant of both electron-rich and -deficient aryl acyl fluorides and was utilized for the cross-coupling and derivatization of seven bioactive molecules. Acyl fluorides have also been used in palladium-catalyzed transformations. One such example was developed in 1989 by Himmler and Braden, wherein they treated 3-trifluoromethylbenzoyl fluoride (3.1b) with H2/CO to afford a mixture of the corresponding aldehyde (3.28) and decarbonylated arene (3.29, Scheme 3.4c).92 A more recent publication from Sakai et al. described reductive methods with triethylsilane (Et3SiH) for the synthesis of aldehydes (3.30) and alkanes (3.31), the latter of which also proceeded via palladium-catalyzed decarbonylation (Scheme 3.4d).93 Acyl fluorides (3.1) can also be utilized for the synthesis of trifluoromethyl arenes (3.32) in the presence of triethyl(trifluoromethyl)silane, as shown by Schoenebeck and Keaveney in 2018 (Scheme 3.4e).94 69 Scheme 3.4. Representative examples of synthetic applications of acyl fluorides in transition metal-catalyzed transformations.90–94 3.1.2 Existing synthetic approaches to the synthesis of acyl fluorides A variety of reagents can be used to access acyl fluorides, predominantly from the corresponding carboxylic acid.75 Some classic examples include cyanuric fluoride (3.33),95 Ishikawa’s reagent (3.34),96 and aminium salts such as tetramethylfluoroformamidinium hexafluorophosphate (3.35, TFFH, Figure 3.3).97 70 Figure 3.2. Common reagents used for the synthesis of acyl fluorides.95–97 An early example of the use of cyanuric fluoride (3.33) was reported by Olah et al. in 1973, wherein treatment of carboxylic acids (3.17) with 3.33 furnished the corresponding acyl fluoride (3.1, Scheme 3.5a).95 One benefit of this approach was that it only required 0.33 equivalents of 3.33, improving overall atom economy. Ishikawa et al. later developed a reagent (3.34) that could carry out a similar process, with 3.34 formed in situ from hexafluoropropylene and diethylamine (Scheme 3.5b).96 One advantage of Ishikawa’s reagent (3.34) is that it is more stable than Yarovenko’s reagent, an adduct of chlorotrifluoroethylene and diethylamine.75 Similarly to cyanuric fluoride, aminium salts such as TFFH (3.35) are a common tool in peptide synthesis, as acyl fluorides can be synthesized in situ and/or isolated under mild reaction conditions. As a representative example, Carpino et al. utilized 3.35 in the presence of Fmoc amino acids (3.17) for acyl fluoride formation and one-pot peptide couplings (Scheme 3.5c).97 Carpino’s approach could also successfully be applied to solid-phase peptide synthesis (SPPS). 71 Scheme 3.5. Representative approaches to the synthesis of acyl fluorides using (a) cyanuric fluoride,95 (b) Ishikawa’s reagent,96 and (c) TFFH.97 There also exist a plethora of sulfur-based reagents that can be used for the syntheses of acyl fluorides, including sulfur tetrafluoride (SF4, 3.36),98 (diethylamino)sulfur trifluoride (DAST, 3.37),99 Deoxo-Fluor® (3.19),100 XtalFluor-E and -M (3.38 and 3.39, respectively),101,102 phenylsulfur trifluoride (3.40),103 reduced sulfur hexafluoride reagents (3.41),104 tetramethylammonium trifluoromethylthiolate (3.42),105 and benzene-1,3-disulfonyl fluoride (3.43).106 72 Figure 3.3. Common sulfur-based reagents used for the synthesis of acyl fluorides.99–106 Sulfur tetrafluoride (SF4, 3.36) is used for the conversion of carboxylic acids to the corresponding trifluoromethyl group (–CF3) via an acyl fluoride intermediate at higher temperatures (i.e. >100 °C).98 While SF4 can also be utilized for the synthesis of acyl fluorides using strictly controlled reaction temperatures, mixtures of several fluorinated products may form under the reaction conditions. Therefore, it is usually reserved for acid-to-trifluoromethyl conversions. Sulfur-based reagents like DAST (3.37) have been utilized extensively for acyl fluoride synthesis as well. This includes the early work of Markovskij, who treated a variety of alcohols, aldehydes, and acids with 3.37, including benzoic acid (3.17c) and 4-nitrobenzoic acid (3.17d, Scheme 3.6a).99 Deoxo-Fluor® (3.19) has been described as a slightly more thermally stable deoxyfluorination alternative to DAST, and is well-suited for the synthesis of acyl fluorides from acids (Scheme 3.6b).100 However, one of the major concerns with DAST and Deoxo-Fluor® is their risk of explosion upon mild heating.107 The XtalFluor-E® (3.38) and -M® (3.39) reagents are notably more stable than DAST and Deoxo-Fluro®, and are considered suitable alternative fluorinating agents.102 Additionally, the XtalFluor® reagents do not react violently with water to 73 generate free HF, unlike DAST and Deoxo-Fluro®.101 The XtalFluor® reagents have also been utilized for the conversion of carboxylic acids to the corresponding acyl fluorides (Scheme 3.6c).101,102 Umemoto et al. further describe a single example of acyl fluoride synthesis—benzoyl fluoride (3.1c)—using phenylsulfur trifluoride (3.40), a fluorinating agent generated in situ from phenylsulfur chlorotetrafluoride (3.44) and a suitable reducing agent (Scheme 3.6d).103 In 2017, Reuping et al. developed a novel approach to acyl fluoride formation, utilizing a 2,2′-bipyridine derivative in the presence of SF6 for the in situ formation of 3.41, and subsequent generation of 4-phenylbenzoyl fluoride (3.1e, Scheme 3.6e).104 That same year, Schoenebeck et al. utilized tetramethylammonium trifluoromethylthiolate (3.42) for the synthesis of acyl fluorides, generating a diverse substrate scope including three pharmaceutical derivatives (Scheme 3.6f).105 Their method proved advantageous in that only a simple filtration was required to purify the acyl fluoride products. Moses et al. reported an amidation protocol mediated by benzene-1,3-disulfonyl fluoride (3.43) that proceeded via acyl fluoride intermediates (Scheme 3.6g).106 This protocol proved effective for amide synthesis and is just one of many examples of the synthetic utility of acyl fluorides. 74 Scheme 3.6. Representative approaches to the synthesis of acyl fluorides utilizing sulfur-based reagents.99–106 There are also a number of transition metal catalyzed approaches to acyl fluoride synthesis, including palladium and cobalt catalysis. For example, there are several reports of palladium-catalyzed fluorocarbonylation of alkyl, aryl, and vinyl halides (3.45, Scheme 3.7a).108,109 One such method described by Manabe et al. utilizes N-formylsaccharin (3.46) as a carbon monoxide source in their one-pot amide, ester, and thioester coupling protocol (Scheme 3.7b).110 The reaction proceeds by way of an acyl fluoride intermediate, which they could also successfully isolate. Early in 2020, Sakai et al. reported a unique route to acyl fluoride synthesis, namely their palladium-75 catalyzed reversible acyl exchange protocol which utilized benzoyl fluoride (3.1c) as the acylating reagent (Scheme 3.7c).111 The reaction is a potentially powerful acylation method, although the reversible nature results in only middling yields even with an excess of anhydride substrate (3.47). Scheme 3.7. Representative approaches to acyl fluoride synthesis utilizing palladium-catalyzed (a, b) fluorocarbonylation and (c) acyl exchange.108–111 In 2015, Baker et al. reported a method to access acyl fluorides from the corresponding acyl chloride (3.3) by way of an in situ-generated cobalt(III) catalyst.112 The authors went on to expand their protocol to encompass a small substrate scope in 2017 (Scheme 3.8).113 The method was primarily applied to aryl acyl chloride substrates, displaying tolerance towards both electron-rich and -deficient arenes, as well as aryl halides. However, the acyl fluoride products were only analyzed by NMR spectroscopy, and no isolation protocol was described. 76 Scheme 3.8. Baker’s cobalt-catalyzed approach to acyl fluoride synthesis.113 In addition to the methods and reagents previously described, a variety of other options exist for the synthesis of acyl fluorides. Phosphorous reagents such as triphenylphosphine can be utilized in the presence of both electrophilic and nucleophilic fluorine sources to transform carboxylic acids (3.17) to the corresponding acyl fluoride (3.1), as described by Jang (Scheme 3.9a),114 and Prakash (Scheme 3.9b).85 Prakash’s protocol was also used in one-pot amidations, further exemplifying the robustness of the technique for the facile synthesis of important chemical motifs. Tang et al. also utilized a similar system of PPh3 and SelectfluorTM for one-pot esterifications and amidations of carboxylic acids (Scheme 3.9c).115 Tang’s protocol focused on and proceeded by way of isolable acid anhydride intermediates, although acyl fluorides were synthesized unexpectedly in lieu of the anhydrides in four substrates. Scheme 3.9. Representative approaches to acyl fluoride synthesis utilizing phosphorous reagents.85,114,115 77 Other approaches to the synthesis of acyl fluorides include: (1) the coupling of carboxylic acids and HF·pyridine with N,N’-dicyclohexylcarbodiimide (DCC);116 (2) the fluorination of acids by uranium hexafluoride (UF6);117 (3) the oxidative fluorination or fluorination of primary alcohols, acids, or acyl chlorides with bromine trifluoride (BrF3);118–120 (4) the oxidative fluorination of aldehydes with 4-trifluoromethylphenyl(difluoro)-λ3-bromane ((4-CF3)PhBrF2);121 and (5) the photocatalytic radical fluorination of unactivated C—H bonds using N-fluorobenzenesulfonimide (NFSI) and tungsten photocatalysts.122,123 Additionally, since the publication of the manuscript this chapter focuses on,44 the Sammis group has utilized thionyl fluoride (SOF2) for the synthesis of acyl fluorides;34,45 the details of this work are described in Chapter 4. While there are numerous methods to access acyl fluorides, the majority utilize some form of nucleophilic acyl substitution of an activated carboxylic acid. Many of the protocols require harsh reaction conditions or reagents (i.e. cyanuric fluoride, DAST, HF·pyridine, etc.), are limited in scope, or are low-yielding. Additionally, many of the aforementioned processes require obscure or difficult-to-acquire reagents that are air- or water-sensitive, limiting their applicability. 3.1.3 Literature precedent: the sulfuryl fluoride-mediated synthesis of acyl fluorides, and the one-pot synthesis of esters and amides from carboxylic acids Following the success of the sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of thiols (Chapter 2), the Sammis group sought to explore additional synthetic applications of sulfuryl fluoride. Specifically, we were interested in exploring reactions of carboxylic acids and sulfuryl fluoride, potentially to form an acyl fluoride intermediate which could subsequently be applied to the one-pot synthesis of amides and peptides. A 2009 patent from Ishii et al. describes the sulfuryl 78 fluoride-mediated syntheses of a pair of acyl fluorides from the corresponding carboxylic acids in a stainless-steel reactor at –78 °C, over 12 hours.124 The equipment and reaction conditions used by Ishii et al. were poorly suited to an overall one-pot coupling protocol, and we hypothesized that a SO2F2-mediated coupling protocol could be conducted more efficiently with standard lab equipment under better optimized reaction conditions. Concurrent to initial investigations in the Sammis group, Qin et al. published their findings on their one-pot synthesis of amides (3.18, Scheme 3.10a)30 and esters (3.48, Scheme 3.10b)31 from the corresponding carboxylic acid (3.17) in 2019. The Qin methodology afforded a variety of amides and esters and was tolerant of electron-rich and -poor acid electrophiles and amine nucleophiles. Qin also applied the amidation protocol to one-pot peptide couplings. While they were high-yielding, the reaction conditions led to epimerization of the stereocentre alpha to the carbonyl of the acid substrate (3.17), limiting the applicability of the protocol to peptide couplings. It was suggested that the reactions proceeded via either an acyl fluorosulfate or an acyl fluoride intermediate, but no mechanistic studies were performed. Scheme 3.10. Qin’s SO2F2-mediated one-pot syntheses of amides and esters from carboxylic acids.30,31 The absence of any mechanistic analysis into Qin’s amidation and esterification reactions was worth exploring further. A major reason for this was that Qin’s methodology—while promising—bore significant limitations that needed addressing. The reactions were generally 79 conducted over the course of five or more hours, which is slower than similar carboxylic acid coupling processes that can be completed in as little as 15 minutes (vide supra and Chapter 4). Greater insight into the underlying reaction mechanism was crucial, as such an understanding would make it more straightforward to improve the reaction conditions and perform the protocol more efficiently. A better understanding of the mechanism would further provide rationale for the observed epimerization in Qin’s peptide couplings and may help the development of a method that would prevent loss of stereochemical configuration. Prior to the Qin publication, Dr. Paul Foth had conducted an initial reaction development and optimization.70 Under his optimized conditions, Foth noted that additives such as pyridine, DABCO, and tetrabutylammonium bromide (TBAB) or chloride (TBAC) resulted in improvements to the reaction efficiency and conversion of 3-phenylpropionic acid (3.17f) to the corresponding carboxylic acid derivative (3.5), via what he confirmed to be an acyl fluoride intermediate (3.1f, Scheme 3.11). This was especially true for TBAB and TBAC, additives which resulted in acyl fluoride 19F NMR spectroscopic reaction yields exceeding 90% in as little as 30 minutes. The exact role of the tetrabutylammonium halide (TBAX) salts in the reaction was unknown, particularly in whether or not their presence accelerated the acyl fluoride formation step (Scheme 3.11, Step 1), the nucleophilic acyl substitution step (Scheme 3.11, Step 2), or both. Scheme 3.11. The optimized protocol for the SO2F2-mediated synthesis of acyl fluorides, accelerated with TBAB, and their one-pot application to nucleophilic acyl substitutions.44 80 This chapter describes my efforts towards determining the mechanism and role of tetrabutylammonium halide salt additives in the SO2F2-mediated one-pot synthesis of amides and esters, as well as my conclusions from these experiments. My contributions towards the development of the substrate scope of activated esters, amides, and thioesters are described as well.44 3.2 Results and discussion 3.2.1 Mechanistic analyses of the sulfuryl fluoride-mediated generation and one-pot nucleophilic acyl substitution of acyl fluorides using NMR spectroscopy My primary goals for this project were to: (1) study the SO2F2-mediated reaction using quantitative 19F NMR spectroscopy to determine the mechanism; (2) quantify the effects of different additives on the rate of reactivity to identify a set of conditions that accelerate the reaction and make it more synthetically competitive with literature protocols; (3) investigate the effects of additives on the reaction rate with multiple carboxylic acid substrates to assess the degree of rate modulation; and (4) contribute to the substrate scope of this project and synthesize synthetically relevant carboxylic acid derivatives. The initial studies on the optimized reaction began with an analysis of the conversion of 3-phenylpropionic acid (3.17f) to 3-phenylpropanoyl fluoride (3.1f), with and without TBAX salt additives. 3-Phenylpropionic acid was selected as a representative substrate for the initial reaction analyses to better align these experiments to the optimization work done previously using this acid substrate. Additionally, 3-phenylpropionic acid does not have any strongly electron-donating or -withdrawing groups or undesirable steric bulk near the reactive site that could otherwise enhance or inhibit the reaction; therefore, data obtained from this substrate acid would more accurately 81 reflect the efficacy of the reaction conditions with TBAX additives, rather than its own intrinsic properties. The absence of any TBAX salt additive led to a slower reaction, with 3.1f afforded in 93% yield after two hours (Figure 3.4a). The addition of tetrabutylammonium chloride, bromide, and iodide (TBAI) led to increases in the rate of formation of 3.1f, with equivalent yields achieved in half the time (one hour). This was particularly evident with TBAC, with 3.1f measured in 66% yield by 19F NMR spectroscopy after just five minutes, whereas TBAB and TBAI additives led to 54% and 50% yields, respectively, and only 34% was measured without any TBAX additive. This initial study suggested that the addition of TBAC doubled the rate of formation of the acyl fluoride intermediate in the reaction. Each reaction was only performed once; however, as the main purpose of these analyses was to investigate the overall impact of TBAX additives in the reaction, the general trend observed in the data was more important than a single data point. This approach was taken for all the quantitative 19F NMR spectroscopic analyses conducted as part of the rate investigations in this chapter. 82 a) b) Օ = TBAI; ● = TBAB; □ = TBAC; ▲ = no TBAX (control). The reaction was run on a 0.3 mmol scale of 3.17 according to the optimized protocol. Aliquots were sampled and diluted in CDCl3 at the indicated timepoints for quantitative 19F and 1H NMR spectroscopic analyses to quantify the yield of 3.1f and 3.48f, respectively. PhCF3 (30 μL) and 1,3,5-trimethoxybenzene (55 mg) were added as internal standards. The reactions were performed once; see Section 3.4.1 for additional information. Figure 3.4. The effects of tetrabutylammonium halide additives on the rate of (a) the formation of 3-phenylpropanoyl fluoride (3.1f) from 3-phenylpropionic acid (3.17f), and (b) formation of 3.48f with N-hydroxysuccinimide (3.49). With this first data set indicating TBAC and other TBAX salts doubled the rate of acyl fluoride formation in the first step of the reaction, the second nucleophilic acyl substitution step was investigated. The purpose of these reactions was to determine whether the presence of a TBAX additive had any effect on rate of consumption of 3.1f in the second nucleophilic acyl substitution step. Each of the four reaction mixtures—containing one of TBAI, TBAB, TBAC, or no additive—were subsequently treated with N-hydroxysuccinimide (3.49). Since 3.49 has a pKa of 6.0,125 it was expected to be sufficiently acidic under the reaction conditions with DIPEA (pKa ~ 11) to undergo quantitative deprotonation. The conjugate base of 3.49 is a potent nucleophile, and therefore would likely react efficiently with the acyl fluoride intermediate. Indeed, 3.1f underwent nucleophilic acyl substitution with 3.49 extremely rapidly, reaching a 1H NMR spectroscopic yield 305070900 20 40 60 80 100 12019F NMR percent yield (%)time (min)60801000 20 40 601H NMR percent yield (%)time (min)83 of approximately 80% of activated ester 3.48f in as little as five minutes with or without a TBAX salt additive (Figure 3.4b). The measured 1H NMR spectroscopic yield of 3.48f did not decrease over the course of the following 55 minutes. These results indicated that the second step of the SO2F2-mediated protocol was independent of the TBAX additives, and that these additives only accelerated the rate of formation of 3.1f. A series of similar experiments to those of Figure 3.4 were then performed to determine if a different nucleophile—aniline (3.50)—would yield similar results to N-hydroxysuccinimide (3.49). Aniline was expected to be a weaker nucleophile than N-hydroxysuccinimide as the nucleophilic nitrogen lone pair of aniline is delocalized into the adjacent π-system of the phenyl ring through resonance. A weaker nucleophile would presumably consume the acyl fluoride intermediate (3.1f) less readily, permitting greater analysis of the rate of consumption of 3.1f with and without TBAX additives. Since the previous experiments had demonstrated that TBAC was superior to both TBAB and TBAI in accelerating the rate of formation of 3.1f, only TBAC was selected for the remainder of the experiments. Once again, the presence of TBAC as an additive accelerated the first step of the reaction, generating 3.1f in 94% 19F NMR spectroscopic yield after one hour (Figure 3.5a). Conversely, the absence of TBAC produced 3.1f in only 75% yield after one hour. Just as before, the yield of 3.1f after five minutes was doubled from 32% to 70% with the addition of TBAC. Despite its weaker nucleophilicity relative to 3.49, aniline (3.50) underwent nucleophilic acyl substitution with 3.1f to produce 3.51, albeit in low yield (Figure 3.5b). The production of 3.51 appeared to reach a maximum yield more quickly with TBAC in this experiment, yet the maximum measured yield was lower with the additive. The data collected for Figure 3.5b was subject to error as the integrated signal of 3.51 in the 1H NMR spectrum was weak, relative to both the internal standard 84 and the baseline. Furthermore, as this experiment was not replicated, the data were considered solely in terms of general trend instead of absolute values. 19F NMR spectroscopic data indicated that the acyl fluoride intermediate was not fully consumed by aniline. Despite the low yield, these results suggested that either the TBAX additive had little-to-no effect on the rate of NAS in the second step of the reaction, or that the rate of acceleration was irrelevant as the second step was already efficient. a) b) Օ = TBAC; ● = no TBAC (control). The reaction was run on a 0.3 mmol scale of 3.17 according to the optimized protocol. Aliquots were sampled and diluted in CDCl3 at the indicated timepoints for quantitative 19F and 1H NMR spectroscopic analyses to quantify the yield of 3.1f and 3.51, respectively. PhCF3 (30 μL) and 1,3,5-trimethoxybenzene (55 mg) were added as internal standards. The reactions were performed once; see Section 3.4.1 for additional information. Figure 3.5. The effects of tetrabutylammonium chloride on the rate of (a) the formation of 3-phenylpropanoyl fluoride (3.1f) from 3-phenylpropionic acid (3.17f), and (b) formation of 3.51 with aniline (3.50). The following experiments were designed to assess whether the observed rate acceleration in the acyl fluoride formation step was exclusively dependent upon the TBAX salt, or if it was substrate-dependent. For these studies, benzoic acid (3.17c), 4-methoxybenzoic acid (3.17a), and 3-fluorobenzoic acid (3.17g) were selected as representative test substrates. These aryl carboxylic acid substrates were chosen for two key purposes: (1) to provide insight into the reaction with non-0204060801000 20 40 60 80 100 12019F NMR percent yield (%)time (min)020400 10 20 30 40 50 601H NMR percent yield (%)time (min)85 aliphatic acids, and (2) to assess the impact of electronically diverse aryl substituents on the outcome of the reaction. Benzoic acid (3.17c) would serve as a representative “simple” aryl acid, as it is devoid of any aryl substituents. 4-Methoxybenzoic acid (3.17a) would provide insight into the effects of electron-donating aryl substituents on the course of the reaction, and 3-fluorobenzoic acid (3.17g) would yield representative data on the effects of inductively electron-withdrawing groups. Additionally, the fluorine substituent of 3.17g would enable reaction monitoring through quantitative 19F NMR spectroscopy. Benzoic acid (3.17c) reacted similarly to 3-phenylpropionic acid (3.17f) under the reaction conditions for both steps, with and without the TBAC additive present. In the first step, benzoyl fluoride (3.1c) was generated in 36% 19F NMR spectroscopic yield after five minutes with TBAC, but in only 17% yield without (Figure 3.17a). The yield of 3.1c had increased to 87% after one hour in the presence of TBAC, versus 70% without. The second nucleophilic acyl substitution step with N-hydroxysuccinimide (3.49) indicated that the maximum consumption of 3.1c by 3.49 to produce 3.48c occurred within five minutes (Figure 3.17d), consistent with previous findings. Experiments with 4-methoxybenzoic acid (3.17a) yielded similar results, producing the corresponding acyl fluoride (3.1a) in 32% 19F NMR spectroscopic yield after five minutes with TBAC present, versus 7% without (Figure 3.17b). At the one-hour timepoint, 3.1a had been generated in 64% yield with TBAC and 36% without. The reaction appeared to not reach a maximum yield after stirring for four hours, even with TBAC, suggesting that 3.17a may require a longer reaction time to fully convert to 3.1a. However, the synthetic advantage of the TBAC additive was evident, as the 19F NMR spectroscopic yield of 3.1a was only 63% after four hours without TBAC, versus 87% with the additive. As observed with benzoic acid, the N-86 hydroxysuccinimidyl ester of 4-methoxybenzoic acid (3.48a) was generated independently of TBAC and reached a maximum 1H NMR spectroscopic yield within five minutes (Figure 3.17e). The experiment with 3-fluorobenzoic acid (3.17g) yielded slightly differing data than had been observed until this point in the project. While the final quantity of 3-fluorobenzoyl fluoride (3.1g) produced was greater (73%) with TBAC than without (60%) after four hours, the degree of rate acceleration was not doubled early on in the experiment (Figure 3.17c), as had been the case for previous carboxylic acid substrates. After stirring for five minutes, 3.1g was produced in 17% 19F NMR spectroscopic yield without TBAC, and 14% with the additive. Despite the significantly weaker effect TBAC had on the formation of 3.1g than for previous substrates, the results nonetheless indicated a clear—if small—increase in the production of the acyl fluoride. The reason for this deviation from previous experiments is not known, although the inductively withdrawing nature of the meta fluorine substituent may have slowed the nucleophilic attack by the conjugate base of 3.17g on SO2F2 to form the initial acyl fluorosulfate intermediate. As had been the case for 3.17c and 3.17a, the aryl fluoride substituent had no effect on the rate of nucleophilic acyl substitution in the second step with 3.49; ester 3.48g reached a maximum yield after five minutes, with and without TBAC (Figure 3.6f). As with previous experiments, these reactions were performed only once. The data is still considered reliable based upon the overall trends observed and the consistent manner in which the rate acceleration was observed between substrate acids in the presence of TBAC. 87 a) d) b) e) c) f) Օ = TBAC; ● = no TBAC (control). The reaction was run on a 0.3 mmol scale of 3.17 according to the optimized protocol. Aliquots were sampled and diluted in CDCl3 at the indicated timepoints for quantitative 19F and 1H NMR spectroscopic analyses to quantify the yields of 3.1 and 3.48, respectively. PhCF3 (30 μL) and 1,3,5-trimethoxybenzene (55 mg) were added as internal standards. The reactions were performed once; see Section 3.4.1 for additional information. Figure 3.6. The effects of tetrabutylammonium chloride on the rate of formation of (a) benzoyl fluoride (3.1c), (b) 4-methoxybenzoyl fluoride (3.1a), and (c) 3-fluorobenzoyl fluoride (3.1g), as well as formation of (d) 3.48c, (e) 3.48a, and (f) 3.48g with N-hydroxysuccinimide (3.49). The experiments conducted thus far had yet to determine whether or not the TBAX additive had an effect on the maximum potential yield of the acyl fluoride in the first step of the reaction. 0204060801000 60 120 180 24019F NMR percent yield (%)time (min)5060700 10 20 301H NMR percent yield (%)time (min)0204060800 60 120 180 24019F NMR percent yield (%)time (min)40506070800 10 20 301H NMR percent yield (%)time (min)0204060800 60 120 180 24019F NMR percent yield (%)time (min)4050600 10 20 301H NMR percent yield (%)time (min)88 It was expected that the reactions would produce the same quantity of acyl fluoride regardless of if a TBAX additive was included, provided the reactions were left to stir for a sufficient period of time (i.e. up to 24 hours). To test this hypothesis, a model substrate that was known to be slow to produce the acyl fluoride was required. 4-Methoxybenzoic acid (3.17a) was selected to fill this role in lieu of 3-phenylpropionic acid (3.17f), as the former had not reached completion after four hours of stirring with or without TBAC (Figure 3.6b) and was much slower to react than the other acid substrates tested thus far. The reactions were conducted in parallel over the course of 24 hours—with and without TBAC—and aliquots were sampled at suitable timepoints for quantitative 19F NMR spectroscopic analyses. In the presence of TBAC, 4-methoxybenzoyl fluoride (3.1a) was produced in quantitative yield within in six hours (Figure 3.7a), whereas it took at least twice as long (twelve hours) without the additive. This data demonstrated two key points: (1) the SO2F2-mediated generation of acyl fluorides could be performed with or without a TBAX additive and the same yields could be achieved either way, and (2) the rate of acyl fluoride formation could be doubled with the addition of TBAC. As expected from previous experiments with this substrate, the subsequent nucleophilic acyl substitution of 4-methoxybenzoyl fluoride (3.1a) by N-hydroxysuccinimide (3.49) was once again independent of TBAC, with equivalent yields reached within 15 minutes (Figure 3.7b). These experiments proved that TBAC could meaningfully accelerate the reaction of 3.17a with SO2F2, leading to an overall more useful protocol. 89 a) b) Օ = TBAC; ● = no TBAC (control). The reaction was run on a 0.3 mmol scale of 3.17 according to the optimized protocol. Aliquots were sampled and diluted in CDCl3 at the indicated timepoints for quantitative 19F and 1H NMR spectroscopic analyses to quantify the yields of 3.1a and 3.48a, respectively. PhCF3 (30 μL) and 1,3,5-trimethoxybenzene (55 mg) were added as internal standards. The reactions were performed once; see Section 3.4.1 for additional information. Figure 3.7. 24-Hour experiment studying the effects of tetrabutylammonium chloride on the rate of (a) formation of 4-methoxybenzoyl fluoride (3.1a), and (b) formation of 3.48a with N-hydroxysuccinimide (3.49). Since the reaction studies using 19F NMR spectroscopy indicated that the addition of TBAX accelerated only the first step of the overall protocol to form the acyl fluoride (3.1), it was hypothesized that the salt provided an alternative route to access 3.1 (Scheme 3.12). It was expected that carboxylic acid 3.17 would first undergo a thermodynamically favoured deprotonation by DIPEA to produce nucleophilic carboxylate 3.52, which would subsequently attack SO2F2 to generate acyl fluorosulfate 3.53 and one equivalent of fluoride (F–).30 From there, two potential pathways were envisioned to generate acyl fluoride 3.1: either the liberated fluoride could directly attack the carbonyl carbon of 3.53 in a single nucleophilic acyl substitution (pathway A), or the halide (X–) from TBAX could first perform a similar substitution to produce corresponding acyl halide 3.54 (pathway B), which would then undergo a second substitution by 0204060801000 240 480 720 960 1200 144019F NMR percent yield (%)time (min)4050600 10 20 301H NMR percent yield (%)time (min)90 fluoride to generate the target acyl fluoride (3.1, pathway C). In both cases, each nucleophilic acyl substitution would reasonably be expected to proceed via a discreet tetrahedral intermediate, although it should be noted that there are a small number of reports of direct nucleophilic acyl substitution of other acyl motifs in the literature.126 It is possible that the cation (tetrabutylammonium, TBA+) may have had some effect on the efficacy of this reaction. Were that to be the case, the use of alternative cations (i.e. Na+, K+, or tetramethylammonium (TMA+)) would be expected to change the rate of acyl fluoride formation. If the observed rate acceleration can be solely attributed to the anion, then changing the cationic partner should have no measurable effect. Scheme 3.12. Proposed mechanistic rationale for the observed rate acceleration in the SO2F2-mediated synthesis of acyl fluorides. It was predicted that pathways B and C provided the following rationale for the observed rate acceleration: first, fluoride (F–) is not as powerful a nucleophile as chloride (Cl–), bromide (Br–), or iodide (I–), so a preliminary halide attack on 3.53 could conceivably out-compete fluoride; second, the resultant acyl halide (3.54) is also less stable and therefore more reactive than the corresponding acyl fluoride (3.1), thus thermodynamically favouring the second nucleophilic acyl substitution by fluoride in pathway C to produce 3.1. Dr. Thomas Malig from the Hein group at The University of British Columbia joined the project to conduct complementary in situ reaction analyses using ReactIR and COmplex PAthway SImulator (COPASI) software.127 With my findings using quantitative 19F NMR spectroscopy and 91 Malig’s in situ reaction analyses revealing the identities of the reactive intermediates, we collaboratively elucidated the reaction mechanism (Scheme 3.13). As expected, the mechanism of the reaction operates first through nucleophilic attack by the conjugate base of carboxylic acid 3.17 on sulfuryl fluoride, producing acyl fluorosulfate 3.53. Intermediate 3.53 can then undergo one of several processes: it can react at the carbonyl with a second equivalent of carboxylate 3.52 to produce anhydride 3.47 (pathway A); 3.53 may undergo nucleophilic acyl substitution by fluoride to directly produce acyl fluoride 3.1 (pathway B); or, as had been predicted, 3.53 may instead undergo nucleophilic acyl substitution by a halide from TBAX (Cl–, Br–, or I–) to produce corresponding acyl halide 3.54 (pathway C). Should either pathway (A) or (C) occur, intermediates 3.47 or 3.54 may both undergo a second nucleophilic acyl substitution by fluoride to produce acyl fluoride 3.1. Both 3.47 and 3.54 were determined by Malig to be in equilibrium with one another (pathway D). The effects of the cation on this reaction were studied independently by Foth. Scheme 3.13. Mechanism of the one-pot SO2F2-mediated synthesis of acyl fluorides.44,127 92 3.2.2 Substrate scope of the sulfuryl fluoride-mediated generation and one-pot nucleophilic acyl substitution of acyl fluorides The next goal of the project was to explore the substrate scope of this new synthetic methodology. My contributions to this scope focused initially on exploring the suitability of five carboxylic acid substrates to the reaction conditions, specifically 3-phenylpropionic acid (3.17f), 3-fluorobenzoic acid (3.17g), 3-cyanobenzoic acid (3.17h), isonicotinic acid (3.17i), and nicotinic acid (3.17j). With the exception of 3.17f, these acid substrates were selected to partially survey the reaction suitability to electron-deficient arenes and the applicability to heterocyclic substrates. Furthermore, 3.17f and 3.17g had both been utilized as representative substrates during the initial quantitative 19F NMR spectroscopic analyses (vide supra), so their inclusion in the substrate scope was logical for the purposes of making direct comparisons. For similar reasons, since N-hydroxysuccinimide (3.49) had been used as the representative nucleophile for these 19F NMR spectroscopic analyses, it was utilized for this substrate scope as well. The mechanistic studies had shown that TBAB was slightly inferior to TBAC as an accelerant; however, TBAB was utilized in the optimized protocol on account of its greater ease of handling and reduced hygroscopicity. The rest of the acid scope was developed by Foth and Hao Yu, a former undergraduate student in the Sammis group. Working initially with 3-phenylpropionic acid (3.17f), the corresponding acyl fluoride (3.1f) was generated in quantitative yield under the reaction conditions with SO2F2 (Scheme 3.14). This yield was consistent with that which had been observed previously (Figure 3.4). Treatment of 3.17f with 3.49 furnished the corresponding ester (3.48f), which was subsequently isolated in 85% yield. The acyl fluoride intermediate was fully consumed in the second step with the nucleophile, suggesting that the slight reduction in final yield could be attributed to the isolation 93 and purification of this ester compound. 3-Fluorobenzoic acid (3.17g) yielded similar results to those observed previously (Figure 3.17), with 3.1g measured in 75% yield by 19F NMR spectroscopy. The corresponding ester product (3.48g) was isolated in 55% yield, which was approximately 20% lower than had been previously measured using quantitative 1H NMR spectroscopy. This reduction in yield of the product was therefore attributed to the isolation and purification of the compound, rather than the reaction with 3.49. 3-Cyanobenzoic acid (3.17h) proved less well-suited to the reaction, having generated the corresponding acyl fluoride (3.1h) in only 34% yield after one hour. The corresponding N-hydroxysuccinimidyl ester (3.48h) was isolated in 32% yield, indicating that the poor yield was due to the limited formation of the acyl fluoride, rather than the second step with 3.49. The low 19F NMR spectroscopy yields of 3.1g and 3.1h could be accounted for by the electron-withdrawing meta fluorine and cyano substituents, which could have impeded the initial nucleophilic attack by the carboxylates on SO2F2, thereby limiting the formation of the crucial acyl fluorosulfate intermediate (3.53). 94 Reactions were run according to the optimized protocol on a 1.0 mmol scale of 3.17. Isolated yields shown, with 19F NMR spectroscopic yields of the acyl fluoride (3.1) indicated in parentheses. PhCF3 (100 μL) was added as an internal standard. Scheme 3.14. Substrate scope of the one-pot SO2F2-mediated coupling of carboxylic acids (3.17) with N-hydroxysuccinimide (3.49). Isonicotinic acid (3.17i) and nicotinic acid (3.17j) were each esterified utilizing N-hydroxysuccinimide (3.49) in low-to-moderate isolated yields of 29% and 51%, respectively. The corresponding 19F NMR spectroscopic yields of the acyl fluoride intermediates (36% and 73%, respectively) were lower than had been the case for 3.1f, indicating that these substrates were less well-suited to the acyl fluoride-formation reaction, particularly 3.17i. As with 3.1g and 3.1h, the lower 19F NMR spectroscopic yields of 3.1i and 3.1j could be attributed to the inductively-withdrawing nature of the heteroaryl moieties of these substrates, which could have impeded their initial nucleophilic reaction with SO2F2. With all four aryl/heteroaryl acid substrates undergoing acyl fluoride formation in inferior yield (<75%) compared to 3-phenylpropionic acid (99%) over the one-hour duration of these experiments, it appeared that the SO2F2-mediated protocol was potentially more applicable to aliphatic acid substrates. The exact reason for this is not known; however, the electron-deficient 95 aryl/heteroaryl moieties were assumed to be the cause of the lower 19F NMR spectroscopic yields of acyl fluoride intermediates. The hypothesis that the protocol is better suited to aliphatic acids is partially reinforced by the previous mechanistic studies, wherein none of the aryl acids underwent quantitative conversion to the corresponding acyl fluoride within one hour. Benzoic acid (3.17c) had required up to two hours (Figure 3.6a) and 4-methoxybenzoic acid (3.17a) needed up to six hours (Figure 3.7) to generate the corresponding acyl fluorides in quantitative yield with TBAC. Neither 3.1c nor 3.1a are electron-deficient aryl acyl fluorides, particularly the latter which is electron-donating via resonance of the methoxy group. It was assumed that the carbonyl carbon of acyl fluorosulfate 3.53 may be less reactive to subsequent nucleophilic acyl substitution reactions than other analogues on account of the electron-donating character of the adjacent arene, limiting the formation of acyl fluoride 3.1. Increased acyl fluoride yields could be achieved for aryl and heteroaryl acids by allowing them to stir for a longer duration. This was described by Foth in the manuscript associated with this project for 3.1i and 3.1j, wherein increased 19F NMR spectroscopic yields of 52% and 86% were observed, respectively, when the reactions were stirred for two hours.44 Next, the scope of nucleophiles suitable for this one-pot coupling protocol were assessed. The majority of this work was conducted by Foth and Yu, however, I contributed three substrates to this analysis. One of either 3-phenylpropionic acid (3.17f) or 3,3-diphenylpropionic acid (3.17k) were treated with one of N-hydroxyphthalimide (3.55), N-methoxymethanamine hydrochloride (3.56), or 1-decanethiol (3.57) in these experiments. 3,3-Diphenylpropionic acid was included in this scope to test the applicability of the protocol to a second aliphatic acid substrate. Treatment of 3.17k with SO2F2 under the reaction conditions furnished the corresponding acyl fluoride (3.1k) in 92% yield by 19F NMR spectroscopy (Scheme 3.15), reinforcing the hypothesis that the reaction 96 was well-suited to aliphatic acids. The subsequent addition of 3.55 produced the corresponding ester (3.58), which was isolated in 71% yield. Reactions were run according to the optimized protocol on a 1.0 mmol scale of 3.17. Isolated yields shown, with 19F NMR spectroscopic yields of the acyl fluoride (3.1) indicated in parentheses. PhCF3 (100 μL) was added as an internal standard. Scheme 3.15. Substrate scope of the one-pot SO2F2-mediated coupling of carboxylic acids (3.17) with various nucleophiles. 3-Phenylpropionic acid (3.17f) was selected as the electrophilic coupling partner for the following two experiments, so as to make comparisons to the earlier results in synthesizing the corresponding N-hydroxysuccinimidyl ester (3.48f). As before, 3-phenylpropanoyl fluoride (3.1f) was generated in at least 95% yield for both reactions. Treatment of either reaction mixture with N,O-dimethylhydroxylamine hydrochloride (3.56) or 1-decanethiol (3.57) produced the corresponding Weinreb amide (3.59) or thioester (3.60) in 80% or 70% isolated yield, respectively. This was close to the isolated yield of 3.48f (85%), demonstrating the synthetic versatility of this SO2F2-mediated coupling protocol for commonly used nucleophiles. Compounds 3.49, 3.55, and 3.56 were selected as representative nucleophiles for these couplings as the resulting esters or amides are synthetically useful motifs for a variety of subsequent synthetic transformations and bioconjugation applications. An in-depth discussion of the synthetic utility of N-hydroxysuccinimidyl and N-hydroxyphthalimidyl esters, as well as Weinreb amides, is provided in Chapter 4. 97 The synthesis and isolation of a pair of acyl fluorides was pursued as well. Treatment of 3.17g with SO2F2 under the reaction conditions furnished the corresponding acyl fluoride (3.1g) in 83% 19F NMR spectroscopic yield, a similar result as had been observed before (Scheme 3.16). The attempted isolation of this compound was unsuccessful and only a mixture of carboxylic acid 3.17g, PhCF3, and diethyl ether were observed after mild basic workup and filtration through a short pad of silica. Presumably, the volatility of 3.1g and/or its instability to silica gel was the major source of the low isolated yield.44 The reaction of 3.17h with SO2F2 under the optimized conditions produced 3.1h in only 35% yield by 19F NMR spectroscopy, which was also consistent with previous results. The isolation of this acyl fluoride proceeded more smoothly than for 3.1g, with 3.1h isolated in 33% yield. This yield was corrected to account for the small quantity of hexanes that was present in the sample after purification as the volatility of the acyl fluoride prevented the complete removal of the solvent. Reactions were run according to the optimized protocol on a 1.0 mmol scale of 3.17. Isolated yields shown, with 19F NMR spectroscopic yields of the acyl fluoride (3.1) indicated in parentheses. PhCF3 (100 μL) was added as an internal standard. aThe reaction was terminated after acyl fluoride formation, with no nucleophile added. bThe isolated yield has been corrected for residual hexanes. Scheme 3.16. Attempted syntheses of acyl fluorides (3.1) and failed one-pot esterifications. 98 The esterification of abietic acid (3.17l) with N-hydroxysuccinimide (3.49) to produce 3.48l was attempted. This acid was selected to test whether the acyl fluoride generation and overall one-pot esterification protocol could be applied to the functionalization of natural compounds. Treatment of 3.17l with SO2F2 and under the reaction conditions failed to furnish any measurable quantity of the corresponding acyl fluoride (3.1l) by 19F NMR spectroscopy. Samples aliquoted after 1–3 hours showed no indication of acyl fluoride formation. The dosing of a second portion of SO2F2 into the reaction mixture had no effect, with no acyl fluoride detected after 4.5 hours of stirring from the original start time. It was determined by 1H NMR spectroscopy after conducting the reaction that the abietic acid reagent had decomposed during storage, leading to the poor result. This substrate was not pursued further. 3.3 Conclusions The addition of TBAX compounds—particularly TBAC—have a major impact on the rate of formation of the crucial acyl fluoride intermediates in these SO2F2-mediated reactions with carboxylic acids.44 These experiments indicate that TBAC is capable of as much as doubling the rate of acyl fluoride generation, while having no impact on the subsequent consumption of these intermediates by a given nucleophile. The addition or absence of TBAX additives in the reaction mixture has no effect on the maximum possible yield of the acyl fluoride intermediate, which will be the same if given enough time to react. A significant reduction in reaction time for 4-methoxybenzoic acid to form the corresponding acyl fluoride was observed in the presence of TBAC, with quantitative yield reached in six hours versus twelve without the additive. This exemplifies the significant synthetic impact of the TBAX additives in accelerating these reactions. 99 The rate acceleration is attributed to the thermodynamically favourable formation of a separate acyl halide (Cl–, Br–, I–) intermediate from the corresponding acyl fluorosulfate. This acyl halide can undergo a subsequent substitution by fluoride to generate the more thermodynamically stable acyl fluoride. This understanding of the reaction mechanism grants greater insight into SO2F2-mediated protocols with carboxylic acid substrates. A small survey of the substrate scope of the overall SO2F2-mediated one-pot nucleophilic acyl substitution was examined, with six representative carboxylic acid substrates and four representative nucleophiles. The findings indicated that aliphatic acids were better suited to the protocol, consistently producing the corresponding acyl fluoride in near-quantitative yields. Conversely, aryl and heteroaryl acids generally reacted more slowly, generating lower yields of the acyl fluorides. These acyl fluoride yields could be increased by stirring the reactions for a longer duration. The differing acyl fluorides yields has been attributed to the electronics of the aryl and heteroaryl motifs negatively impacting the favourability of intermediate acyl fluorosulfate formation or consumption. The reactions were treated with suitable nucleophiles to produce the corresponding activated ester, Weinreb amide, or thioester. This work in conjunction with Malig’s contributions represents the first example of an in-depth mechanistic analysis of a SO2F2-mediated reaction with carboxylic acid substrates. 3.4 Experimental information 3.4.1 General methods These reactions were carried out using the same equipment and reaction setups described previously in Section 2.4.1. 100 All 19F and 1H NMR spectroscopic data collected on a Bruker AV300 NMR spectrometer, equipped with an autosampler. All spectra were collected at room temperature. The quantitative NMR spectroscopy analyses of the rates of acyl fluoride formation and consumption were only performed once for each substrate. These experiments were not performed in triplicate as the complementary ReactIR experiments had already been conducted by Malig; these NMR spectroscopy experiments were carried out to ensure consistency between the in situ ReactIR data and the solution-phase behaviour of the reaction mixture. 3.4.2 General procedure for the quantitative determination of NMR spectroscopy yields Quantitative NMR spectroscopy analyses were conducted in the same manner as described previously in Section 2.4.2. 3.4.3 General procedure for the one-pot synthesis and nucleophilic acyl substitution of acyl fluorides Stir plates and heating sources are omitted for clarity. Figure 3.8. Diagram of the reaction setup for the SO2F2-mediated synthesis and coupling of acyl fluorides. 101 Two 20 mL vials (Vial A and Vial B) equipped with magnetic stir bars were capped with PTFE/silicone septa and connected by approximately 15–20 cm of polyethylene tubing (Figure 3.8). To Vial A were added N,N’-sulfonyldiimidazole (SDI, 5.7 mmol, 5.7 equiv.) and KF (7.8 mmol, 7.8 equiv.). To Vial B were added carboxylic acid substrate (3.17, 1.0 mmol, 1.0 equiv.) and TBAB (1.0 mmol, 1.0 equiv.). The system was purged of air using N2 gas via Vial B, with the cap of Vial A loosened. To Vial B, was added dry acetonitrile (MeCN, 10 mL, 191.5 equiv.) and N,N-diisopropylethylamine (DIPEA, 0.53 mL, 3.0 equiv.). Additional DIPEA (1.0 equiv.) was added for reactions utilizing hydrochloride salt nucleophiles. Vial B was heated to 40 °C and the polyethylene tubing was fully submerged into the Vial B solution. Both Vials A and B were set to stir at a rapid rate. To Vial A was added trifluoroacetic acid (TFA, 3.3 mL, 43.6 equiv.) in one portion, initiating the reaction. Energetic SO2F2 bubbling was observed in Vial B for 2–3 minutes, with the bubbling decreasing in vigour as the reaction progressed. Additional SO2F2 was bubbled through the Vial B solution for approximately 1 minute by inserting an open needle into the septum of Vial B. Upon cessation of bubbling in Vial B, the needle and polyethylene tubing were removed from Vial B, which was allowed to stir at 40 °C for 30 minutes from initial TFA addition. To Vial B was added PhCF3 internal standard (100 μL, 0.8 mmol, 0.8 equiv), as required. The acidic contents of Vial A were quenched with aqueous NaOH (1 or 2 M). After 30 minutes, the reaction mixture in Vial B was degassed of any unreacted SO2F2 with a balloon of argon for 2 minutes. To Vial B was added nucleophile (1.2 mmol, 1.2 equiv), and 102 1,3,5-trimethoxybenzene internal standard (1.0 mmol, 1.0 equiv.) as required. The reaction was left to stir for one hour at room temperature. The reaction mixture was diluted in EtOAc (25 mL) and washed successively with saturated NH4Cl (2 x 10 mL), H2O (2 x 10 mL), and brine (2 x 10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography. Fractions containing the desired material were concentrated in vacuo. 3.4.4 Procedure for the synthesis and isolation of acyl fluorides 3.1g and 3.1h These acyl fluorides were synthesized according to the protocol outlined in Section 3.4.3, with the following changes: following quantification of the acyl fluoride (3.1) by quantitative 19F NMR spectroscopy, the reaction was removed from heat and no nucleophile was added. For 3.1g, the reaction mixture was partitioned between diethyl ether (20 mL), and aq. NaHCO3 (50 mL, 5%). The aqueous phase was extracted with diethyl ether (2 x 20 mL), and the organic fractions were collected, washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude acyl fluoride was passed through a short column of silica gel using 20% diethyl ether in petroleum ether, and the filtrate concentrated in vacuo. The target acyl fluoride was unsuccessfully isolated by this protocol. For 3.1h, the reaction mixture was concentrated in vacuo and passed through a short column of silica gel using 50% DCM in hexanes. The filtrate was concentrated in vacuo and passed through a second short plug of silica gel using 50% DCM in hexanes. The filtrate was concentrated in vacuo to yield 3.1h as a white solid (50 mg, 33%). The isolated yield has been corrected to reflect the minor quantity of hexanes present. 103 3.4.5 Quantitative NMR spectroscopy data for the one-pot synthesis and nucleophilic acyl substitution of acyl fluorides All reactions for quantitative 19F or 1H NMR spectroscopic analyses were performed on a 0.3 mmol scale of carboxylic acid substrate (3.17) according to the general procedure (Section 3.4.3). TBAC was used in lieu of TBAB for these studies, except where indicated otherwise (Section 3.2.1). Reactions were sampled for NMR spectroscopic analyses at the indicated time points. PhCF3 (30 μL) was used as an internal standard for quantitative 19F NMR spectroscopic analyses, and 1,3,5-trimethoxybenzene (55 mg) was used as an internal standard for quantitative 1H NMR spectroscopic analyses. 3.4.6 Characterization data of compounds 3.1g–h, 3.48f–j, and 3.58–3.60 Compound 3.1g Following the general one-pot acyl fluoride generation procedure with SO2F2, 3.1g was synthesized but not isolated on account of its volatility and instability. 1H NMR: (300 MHz, Chloroform-d) δ 7.91 (dt, J = 7.7, 1.3 Hz, 1H), 7.84 – 7.73 (m, 1H), 7.56 – 7.42 (m, 1H), 7.38 – 7.26 (m, 1H). 19F NMR: (282 MHz, Chloroform-d) δ -112.4 (td, J = 8.9, 5.7 Hz). 104 Compound 3.1h Following the general one-pot acyl fluoride generation procedure with SO2F2, 3.1h was isolated in 33% yield as a white solid. 1H NMR: (300 MHz, Chloroform-d) δ 8.37 – 8.23 (m, 2H), 7.99 (dt, J = 7.8, 1.4 Hz, 1H), 7.71 (td, J = 7.9, 1.3 Hz, 1H). 19F NMR: (282 MHz, Chloroform-d) δ 19.0. Compound 3.48f Following the general one-pot nucleophilic acyl substitution procedure with N-hydroxysuccinimide (3.49), 3.48f was isolated in 85% yield as a white solid. 1H NMR: (300 MHz, Chloroform-d) δ 7.36 – 7.28 (m, 2H), 7.24 (dd, J = 7.6, 5.0 Hz, 3H), 3.11 – 3.01 (m, 2H), 2.98 – 2.88 (m, 2H), 2.84 (s, 4H). Compound 3.48g Following the general one-pot nucleophilic acyl substitution procedure with N-hydroxysuccinimide (3.49), 3.48g was isolated in 55% yield as an off-white solid. 105 1H NMR: (300 MHz, Chloroform-d) δ 7.95 (dt, J = 7.7, 1.3 Hz, 1H), 7.82 (dt, J = 8.8, 2.1 Hz, 1H), 7.51 (td, J = 8.0, 5.4 Hz, 1H), 7.39 (tdd, J = 8.3, 2.7, 1.1 Hz, 1H), 2.92 (s, 4H). This spectrum contains residual solvent signals from ethyl acetate and hexanes. The isolated yield has been corrected to reflect this. 19F NMR: (282 MHz, Chloroform-d) δ -111.2 (td, J = 8.4, 5.5 Hz). Compound 3.48h Following the general one-pot nucleophilic acyl substitution procedure with N-hydroxysuccinimide (3.49), 3.48h was isolated in 32% yield as a white solid. 1H NMR: (300 MHz, Chloroform-d) δ 8.43 (t, J = 1.7 Hz, 1H), 8.36 (dt, J = 8.0, 1.5 Hz, 1H), 7.97 (dt, J = 7.8, 1.4 Hz, 1H), 7.68 (t, J = 7.9 Hz, 1H), 2.93 (s, 4H). Compound 3.48i Following the general one-pot nucleophilic acyl substitution procedure with N-hydroxysuccinimide (3.49), 3.48i was isolated in 29% yield as a white solid. 1H NMR: (300 MHz, Chloroform-d) δ 8.93 – 8.84 (m, 1H), 8.00 – 7.92 (m, 1H), 2.93 (s, 2H). 13C NMR: (75 MHz, Chloroform-d) δ 168.8, 160.9, 151.0, 132.9, 123.4, 25.8. 106 Compound 3.48j Following the general one-pot nucleophilic acyl substitution procedure with N-hydroxysuccinimide (3.49), 3.48j was isolated in 51% yield as a white solid. 1H NMR: (300 MHz, Chloroform-d) δ 9.34 (dd, J = 2.2, 0.9 Hz, 1H), 8.90 (dd, J = 4.9, 1.7 Hz, 1H), 8.41 (dt, J = 8.0, 2.0 Hz, 1H), 7.49 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 2.93 (s, 4H). This spectrum contains residual solvent signals from ethyl acetate and hexanes. The isolated yield has been corrected to reflect this. Compound 3.58 Following the general one-pot nucleophilic acyl substitution procedure with N-hydroxyphthalimide (3.55), 3.58 was isolated in 71% yield as a white solid. 1H NMR: (300 MHz, Chloroform-d) δ 7.85 (dd, J = 5.5, 3.1 Hz, 2H), 7.76 (dd, J = 5.5, 3.1 Hz, 2H), 7.40 – 7.18 (m, 10H), 4.65 (t, J = 7.9 Hz, 1H), 3.42 (d, J = 7.9 Hz, 2H). 107 Compound 3.59 Following the general one-pot nucleophilic acyl substitution procedure with N,O-dimethylhydroxylamine hydrochloride (3.56), 3.59 was isolated in 80% yield as a clear, light yellow oil. 1H NMR: (300 MHz, Chloroform-d) δ 7.35 – 7.14 (m, 5H), 3.60 (s, 3H), 3.18 (s, 3H), 2.96 (dd, J = 9.0, 6.7 Hz, 2H), 2.74 (dd, J = 9.0, 6.8 Hz, 2H). 13C NMR: (75 MHz, Chloroform-d) δ 173.8, 141.4, 128.5, 126.2, 61.3, 33.9, 32.3, 30.8. Compound 3.60 Following the general one-pot nucleophilic acyl substitution procedure with 1-decanethiol (3.57), 3.60 was isolated in 70% yield as a colourless oil. 1H NMR: (300 MHz, Chloroform-d) δ 7.35 – 7.24 (m, 2H), 7.25 – 7.17 (m, 3H), 3.03 – 2.95 (m, 2H), 2.92 – 2.82 (m, 4H), 1.63 – 1.49 (m, 2H), 1.41 – 1.22 (m, 14H), 0.94 – 0.84 (m, 3H). 13C NMR: (75 MHz, Chloroform-d) δ 198.9, 140.3, 128.6, 128.5, 126.4, 45.7, 32.0, 31.6, 29.7, 29.6, 29.4, 29.3, 29.1, 29.0, 22.8, 14.3. 108 Chapter 4: Thionyl Fluoride-Mediated One-Pot Esterifications, Amidations, and Reductions of Carboxylic Acids via Acyl Fluorides 4.1 Acyl fluorides, activated esters, and amides: applications, properties, and existing synthetic approaches 4.1.1 Acyl fluorides Acyl fluorides are key reactive intermediates in one-pot SO2F2-mediated couplings of carboxylic acids and alcohol, amine, and thiol nucleophiles (Chapter 3).44 Shortly after the Sammis group’s investigations into SO2F2-mediated couplings, Dr. Chia Wei Lee—a former Ph.D. student in the Sammis group—began exploring the synthetic potential of thionyl fluoride (SOF2, 4.1). Lee’s work led to the development of a synthetically robust one-pot, column-free SOF2-mediated peptide coupling of carboxylic acids (4.2, Scheme 4.1), which also proceeded via an acyl fluoride intermediate (4.3) to yield the corresponding amide (4.4, Chapter 1).34 The SOF2-mediated protocol benefited from several synthetic advantages over the analogous SO2F2-mediated reaction: (1) the reaction to form the acyl fluoride proceeded much more rapidly (30 minutes versus one hour) without any additives, (2) the peptide product could be isolated after extractive workup and without the need for flash column chromatography, and (3) almost no epimerization of the alpha carbon stereocentre from the carboxylic acid substrate was observed (i.e. >98:2 dr). This last point is particularly significant as SO2F2-mediated peptide couplings are known to suffer from substrate racemization, limiting their synthetic applicability.30 109 Scheme 4.1. Lee’s one-pot column-free SOF2-mediated peptide coupling of amino acids via acyl fluoride intermediates.34 Little was known about the synthetic applications of SOF2 prior to Lee’s work. Lee’s investigation focused exclusively on peptide couplings and did not examine alternative synthetic uses of SOF2, particularly other reactions that could make use of an acyl fluoride intermediate. The primary goal of the work presented in this chapter was to explore additional one-pot SOF2-mediated transformations of carboxylic acids through exploitation of the corresponding acyl fluoride intermediate (4.3, Scheme 4.2). In particular, one-pot syntheses of activated and non-activated esters (4.5) and synthetically valuable amides (4.4) were a major focal point of this work. The development of a one-pot reduction of carboxylic acids to the corresponding primary alcohol (4.6) under mild conditions was also investigated, and served as the first study of the applications of SOF2 in a redox process for acid substrates. Scheme 4.2. Envisioned one-pot SOF2-mediated transformations of carboxylic acids via acyl fluoride intermediates. 110 4.1.2 N-Hydroxyphthalimidyl esters and N-hydroxysuccinimidyl esters Activated esters such as N-hydroxyphthalimidyl esters (4.7) and N-hydroxysuccinimidyl esters (4.8) are composed of an acyl moiety and some oxygen-containing leaving group whose conjugate acid is significantly more acidic (i.e. pKa << 16) than a standard alcohol (pKa ~ 16, Scheme 2.3. Zhang’s cascade trifluoroethylation-cyclization of isothiocyanates.). The greater acidity of the conjugate acid of the leaving group thermodynamically favours nucleophilic acyl substitution processes, thus “activating” the ester towards nucleophilic attack. Given that N-hydroxyphthalimide (4.9) and N-hydroxysuccinimide (4.10) have pKa values of 6.3 and 6.0, respectively,128,129 the corresponding esters are susceptible to nucleophilic acyl substitutions under mild reaction conditions. Figure 4.1. N-Hydroxyphthalimidyl and N-hydroxysuccinimidyl esters, along with their respective leaving groups (shown as the conjugate acids). Activated esters such as 4.7 and 4.9 are common acylating agents utilized in peptide syntheses. In 1961, Nefkens and Tesser reported dipeptide couplings with amino acid ester hydrochloride salts (4.11·HCl) and N-hydroxyphthalimidyl esters (4.7a).130 The authors observed that quantitative peptide coupling could be achieved in seconds at 0 °C, furnishing two dipeptides. The protocol benefited from facile purification, with residual 4.9 removed with an aqueous sodium bicarbonate wash. Nefkens et al. subsequently applied their work to the synthesis of seven dipeptides (4.12) with no observed epimerization (Scheme 4.3a).131 Shortly after, Anderson et al. 111 demonstrated the utility of N-hydroxysuccinimidyl esters 4.8a for the synthesis of dipeptides (4.12) in a communication in 1963132 and a full paper in 1964 (Scheme 4.3b).133 Scheme 4.3. Applications of N-hydroxyphthalimidyl and N-hydroxysuccinimidyl esters in peptide synthesis.131,133 An attractive feature of N-hydroxysuccinimidyl and N-hydroxyphthalimidyl esters are their resilience to α-epimerization, which is particularly important in peptide couplings.134 As discussed in Chapter 3, other common acylating agents, such as acyl chlorides, are less suited to many peptide coupling reactions because they are prone to epimerization of the stereochemically defined α-carbon stereocentre. Practically, N-hydroxysuccinimidyl esters are generally considered superior to N-hydroxyphthalimidyl esters in peptide couplings as they are more water soluble.132,133 Activated esters 4.7 and 4.8 are traditionally synthesized from the corresponding carboxylic acid (4.2b, Scheme 4.4). A coupling agent, such as N,N’-dicyclohexylcarbodiimide (DCC, 4.14) is required for carboxylic acid activation, and the reaction is typically complete after standing overnight at 0 °C; purification of the product (4.8b) can generally be completed through filtration of the urea by-product and recrystallization.130,133 While robust, this approach for N-112 hydroxysuccinimidyl esters is susceptible to a competitive Lossen rearrangement to form the corresponding β-alanine derivative (4.14), diminishing its applicability to one-pot peptide couplings (Scheme 4.5).134 Scheme 4.4. A representative example of a DCC-mediated condensation of an amino acid and N-hydroxysuccinimide.133 Cy = cyclohexyl; Succ = succinimidyl. Scheme 4.5. Mechanism of the competitive Lossen rearrangement in one-pot peptide couplings of N-hydroxysuccinimidyl esters.134 113 4.1.3 Weinreb and morpholine amides Weinreb (4.15) and morpholine amides (4.16) are both versatile reactive motifs for synthetic applications. Both amide functional groups are capable of metal-chelation, enabling reactivity that other amides are incapable of undergoing (Scheme 4.6),135,136 including acylation processes with potent nucleophiles—such as organomagnesium or organolithium reagents—for the synthesis of ketones (4.17) via a single nucleophilic acyl substitution. The formation of a stable tetrahedral intermediate (4.18 and 4.19) that persists until reaction workup prevents an undesired second nucleophilic attack and subsequent tertiary alcohol formation. Weinreb and morpholine amides have thus been utilized for the synthesis of symmetric and unsymmetric ketones,137,138 as well as α-amino aryl ketones.139 Scheme 4.6. Weinreb and morpholine amides form stable tetrahedral intermediates that persist until workup, preventing over-addition of nucleophiles.135–139 Weinreb amides have also been reported in other synthetic applications beyond acylations. Davies et al. described the use of chiral Weinreb amide equivalents (4.20) for diastereoselective enolate alkylations (Scheme 4.7a).140 The bulky tert-butyl group of the Weinreb amide in conjunction with the N-1-(10-naphthyl)ethyl group forced the enolate intermediate to adopt a conformation in which syn-alkylation was favoured to form 4.21. Weinreb amides (4.22) have also been utilized for the transformation of 4.23 into aldehydes (4.24), as reported by Hisler et al., who 114 demonstrated their use in Wittig reactions (Scheme 4.7b).141 The Weinreb amides served as a formylation agent, generating the corresponding aldehydes in good yield under mild conditions. Weinreb amides (4.25) can be reduced to the corresponding aldehyde (4.26) with powerful reducing agents, such as lithium aluminum hydride (LiAlH4) or diisobutylaluminium hydride (DIBAL-H); these methods have been utilized in numerous total synthesis applications. As a representative example, these include a LAH reduction that was used as part of a route to the synthesis of (–)-hemiasterlin by Andersen and Piers et al. (Scheme 4.7c).142 Morpholine amides (4.16) are considered viable synthetic alternatives to Weinreb amides.143 They have been used in the synthesis of ketones,136,144 N-protected α-amino aldehydes through reduction with LiAlH4,145 and acyl silanes (4.27, Scheme 4.7d).146 Scheme 4.7. Representative examples of the synthetic applications of Weinreb and morpholine amides.140–142,146 115 The synthesis of Weinreb amides has been reviewed extensively,135 and will not be described in detail here. However, a brief selection of representative reagents and methods to access this motif is included for context. Weinreb amides (4.15) are most often synthesized from the corresponding carboxylic acid (4.2) in the presence of an activating agent, along with the Weinreb amine hydrochloride salt, N,O-dimethylhydroxylamine hydrochloride (4.28, Scheme 4.8). These agents include DCC,142,147 hydroxybenzotriazole (HOBt) and DCC,148 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),149 HOBt and EDCI,150 1,1’-carbonyldiimidazole (CDI),151 and N-methoxy-N-methylcarbamoylimidazolium iodide.152 Scheme 4.8. Representative synthetic routes to generate Weinreb and morpholine amides.142,147–152 Weinreb amides (4.15) also can be generated from the corresponding acyl halide (4.29), including acyl chlorides153,154 and fluorides (Scheme 4.8).84,86,155 Esters, amides, and oxazolidones (4.30) are also viable substrates for Weinreb amide synthesis in the presence of 4.28 and a suitable Lewis acid such as AlMe3,156,157AlMe2Cl,150,158 or DIBAL-H.159 Aldehydes (4.31) are suitable precursors for Weinreb amide synthesis as well; the transformation is enabled via conversion to the cyanohydrin with sodium cyanide, followed by oxidation to an acyl cyanide intermediate.160,161 Lastly, palladium-catalyzed aminocarbonylations of aryl halides have been described as alternative 116 routes to access these valuable motifs.162 Morpholine amides can be synthesized through many similar processes as Weinreb amides. 4.2 Reductions of carboxylic acids to primary alcohols 4.2.1 Direct reductions of carboxylic acids The reduction of carboxylic acids (4.2) to the corresponding primary alcohol (4.6) is a prevalent reaction in synthetic organic chemistry. A number of reports describe facile methods and conditions for these reductions, most of which make use of aluminum- or boron-hydride reagents. These include reagents such as lithium aluminum hydride (LiAlH4 or LAH, Scheme 4.9a),163–165 sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al, Scheme 4.9b),166 and borane complexes including BH3·THF (Scheme 4.9c).167 LAH reductions are not selective for carboxylic acids and reduce numerous other functional groups, including aldehydes, ketones, anhydrides, esters, acyl halides, amides, nitriles, nitro groups, azides, disulfides, sulfones, thioesters, and alkyl and aryl halides, to name just a few.165 Additionally, LAH reductions are almost exclusively conducted in ethereal solvents, which can lead to solubility issues of the substrate acid. This issue can sometimes be circumvented with the use of THF at greater temperatures.164 In spite of the lack of chemoselectivity, LAH reductions continue to be a robust and staple synthetic protocol for the reduction of carboxylic acids lacking other competitive functional groups. 117 Scheme 4.9. Representative examples of direct carboxylic acid reduction using (a) LAH, (b) Red-Al, and (c) BH3·THF.163,166,167 Since the advent of LAH reductions in the 1940s, milder reducing conditions have been developed to offer greater chemoselectivity. For example, BH3·THF reduces carboxylic acids to the alcohol in yields comparable to LAH, yet borane complexes exhibit significantly greater chemoselectivity and tolerate ketones, esters, nitriles, nitro groups, and alkyl and aryl halides.167 The difference in reactivity between basic LAH and borane towards carboxylic acid reductions is attributed to the Lewis acidity of the latter. However, olefins display comparable reactivity to acids in the presence of borane complexes (i.e. hydroboration), somewhat limiting their applicability. Beyond borane complexes, other conditions have been reported for direct acid reduction under mild conditions, including NaBH4 in the presence of a Lewis acid (Scheme 4.10a),168,169 NaBH4 and I2 (Scheme 4.10b),170,171 and SmI2 in H2O/THF (Scheme 4.10c).172 Depending on the choice of Lewis acid in combination with NaBH4, mixed hydride reducing agents generated in situ are capable of the reduction of carboxylic acids, esters, acyl halides, amides, oximes, imines, nitriles, nitro groups, and sulfoxides, leading to generally non-selective conditions.168,169 Conversely, Periasamy and Kanth demonstrated that reductions with NaBH4 and I2 are selective for carboxylic acids over esters, as well as olefins, a notable advantage over borane complexes.170 118 The greater chemoselectivity was attributed to the in situ oxidation of the intermediate RCO2BH3Na by I2 to the reactive RCO2BH2 species, which normally could only be accessed with borane. A subsequent report by Periasamy the following year described how simply increasing the temperature of the reaction from 0 °C or ambient temperature to 70 °C led to ester, amide, and nitrile reduction by this system.171 Olefins underwent hydroboration-type processes when the reaction is carried out at room temperature, although this process sometimes competed with some acid reductions. Reductions of carboxylic acids using the SmI2 and H2O/THF system are robust, with high-yielding reductions possible in as little as one minute. However, the reaction also suffers from selectivity issues and will competitively reduce aryl halides, ketones, esters, nitriles, and amides, as well as some olefins. Scheme 4.10. Representative examples of direct carboxylic acid reduction using (a) NaBH4 and TiCl4, (b) NaBH4 and I2, and (c) SmI2 and H2O/THF as alternative reagents to LAH and borane complexes.168,170,172 Transition metal-catalyzed hydrogenations of carboxylic acids have also been described. These include ruthenium (Scheme 4.11a),173–175 cobalt (Scheme 4.11b),176 and platinum-rhenium catalysis (Scheme 4.11c),177 much of which has been explored in the past decade. An advantage of transition metal-catalyzed hydrogenations over LAH and other “basic” reductants is their superior atom economy, as the latter generally require greater than stoichiometric quantities of the 119 reductant, leading to significantly more waste. However, hydrogenations often necessitate harsh reaction conditions, including temperatures in excess of 150 °C and high-pressure conditions of >60 bar to enable reactivity. One challenge in transition metal-catalyzed hydrogenations is the inherent risk of catalyst deactivation by the free carboxylic acid.177 Additionally, there is the potential for side-reactions to occur, including esterification, olefin reduction, or dearomatization of arene-containing substrates.175,177 Scheme 4.11. Representative examples of direct carboxylic acid reduction via transition metal-catalyzed hydrogenations with (a) ruthenium,174 (b) cobalt,176 and (c) palladium-rhenium catalysts.177 Transition metal-catalyzed hydrosilations offer the benefit of less harsh reaction conditions than their hydrogenation counterparts. In 2002, Nagashima et al. reported a ruthenium-catalyzed hydrosilation protocol suited for esters, amides, and carboxylic acids (Scheme 4.12a).178 Only three acids were analyzed under the protocol, none of which contained chemical functionality prone to undesirable side-reactivity. In 2014, Nolan et al. described a more versatile ruthenium-catalyzed approach that examined a variety of acid substrates with more diverse functionality (Scheme 4.12b).179 Nolan’s hydrosilation protocol was effective for the reduction of carboxylic acids in the presence of ketones, esters, amides, and nitriles, and alkenes, displaying a degree of 120 chemoselectivity that had not been demonstrated before. Iron-catalyzed hydrosilations have also been reported, with Darcel et al. demonstrating the tunable reactivity of their photocatalytic protocol for the selective reduction of acids to either alcohols, or aldehydes (Scheme 4.12c).180 Their protocol proved robust, although their report lacked any studies exploring the potential chemoselectivity of the reaction in the presence of other carbonyl functional groups. As another representative example, Sakai et al. reported an indium-catalyzed hydrosilation of carboxylic acids (Scheme 4.12d).181 Other than the inclusion of a few substrates containing nitro groups and alkenes, little evidence was presented to assess the possible chemoselectivity offered by the protocol, a recurring issue amongst hydrosilations reports prior the work of Nolan et al. 121 COD = cycloocta-1,5-diene. Scheme 4.12. Representative examples of direct carboxylic acid reduction via transition metal-catalyzed hydrosilations.178–181 A thematic problem plaguing direct carboxylic acid reduction is the combination of low reactivity of the acid and unfavourably high reactivity of the reducing agent leading to indiscriminate reductive processes. The poor chemoselectivity offered by more powerful reducing agents such as LAH and Red-Al—as well as more selective borane complexes—can mitigate their utility in late-stage synthetic processes. As a result, new methods and reagents continue to be developed to enable facile carboxylic acid reduction with greater chemoselectivity. 122 4.2.2 Reductions of carboxylic acid derivatives Many of the aforementioned methods (vide supra) are too harsh and/or utilize too powerful reducing agents to apply to late-stage organic synthesis without causing nonselective reduction of multiple functional groups. Therefore, a variety of one-pot processes have been developed to address this obstacle by making use of more reactive carboxylic acid derivative intermediates (i.e. esters or acyl halides), thereby permitting the use of milder—and therefore, more selective—reducing agents. Commonly employed carboxylic acid derivatives include activated esters such as benzotriazoles (4.32, Scheme 4.13a),182–185 boronate esters (4.33, Scheme 4.13b),186,187 mixed anhydrides (4.34, Scheme 4.13c),188,189 and acyl chlorides (4.35, Scheme 4.13d),190,191 as well as a number of additional motifs.185 An advantage to these approaches is that the more reactive carboxylic acid derivative may be formed in situ, making way for an overall one-pot reductive process of commercially available acids with mild reductants like NaBH4. 123 Scheme 4.13. Representative examples of reductions of carboxylic acid derivatives using mild reductants.183,186,188,190 4.2.3 Literature precedent: the cyanuric fluoride-mediated two-step reduction of carboxylic acids via isolated acyl fluoride intermediates and sulfuryl fluoride-mediated one-pot reductions In 1996, Kokotos and Noula reported that acyl fluorides (4.3) were suitable synthetic intermediates for reductions of carboxylic acids to the corresponding primary alcohol (4.6, Scheme 4.14).192 Their protocol made use of cyanuric fluoride (4.36) as an efficient deoxyfluorinating agent for the synthesis and isolation of intermediate acyl fluorides, prior to their reduction with 124 NaBH4. The reaction was tolerant of olefins, esters, lactones, and amino acid derivatives. However, the protocol was not a true one-pot synthetic approach to acid reduction, as it was necessary to isolate the acyl fluoride intermediates. Scheme 4.14. Kokotos and Noula’s two-step approach to carboxylic acid reductions via isolated acyl fluoride intermeidtaes.192 Hao Yu, a former undergraduate student in the Sammis group, developed a one-pot sulfuryl fluoride-mediated reduction of carboxylic acids (4.2) as part of his thesis work (Scheme 4.15).193 While this work remains unpublished, the synthetic protocol was robust and was successfully applied to the one-pot reduction of fifteen carboxylic acids in good yields. The protocol was well-suited to aliphatic acid substrates, as well as several aryl acids. Aryl acids bearing strongly electron-withdrawing groups (i.e. nitro groups) were tolerated by the reduction procedure, yet strongly electron-donating aryl substituents including methoxy groups were less so. Scheme 4.15. Yu’s one-pot SO2F2-mediated reduction of carboxylic acids to the corresponding alcohol (unpublished work).193 125 4.3 Project goals: one-pot, thionyl fluoride mediated esterifications, amidations, and reductions of carboxylic acids Lee’s SOF2-mediated peptide protocol notwithstanding, little was known about the potential breadth of SOF2-mediated NAS-based synthetic protocols. To address this hole in the literature, I investigated alternative synthetic applications of thionyl fluoride. My initial studies focused on nucleophilic acyl substitution reactions of carboxylic acid substrates mediated by thionyl fluoride, with a primary focus on the generation of synthetically useful activated esters and amides. There were no published examples of a mild one-pot reduction of carboxylic acids via an acyl fluoride intermediate prior to the work outlined in this chapter. This, compounded with the limited investigations into the synthetic utility of thionyl fluoride beyond applications in nucleophilic acyl substitutions,34,45 a one-pot SOF2-mediated carboxylic acid reduction via an acyl fluoride intermediate was envisioned. The more robust reactivity of SOF2 relative to SO2F2 in carboxylic acid activation was predicted to have a positive effect on the targeted reduction protocol, and lead to a more widely applicable method than the one originally explored by Yu. The investigations of the one-pot SOF2-mediated synthesis of activated esters and amides (vide infra) had already demonstrated the synthetic ease of acyl fluoride synthesis from carboxylic acids and SOF2, paving the way for an overall one-pot reduction via the acyl fluoride intermediate. This, combined with the fact that residual SOF2 can be removed from a reaction mixture by sparging the solution with inert gas, suggested that a straightforward one-pot, two-step approach may be possible. My goals for this project were to: (1) identify and optimize a set of reaction conditions suited to the one-pot SOF2-mediated synthesis of activated esters from carboxylic acids, (2) 126 explore the scope of acid substrates tolerated by the reaction protocol, (3) explore the scope of alcohol nucleophiles tolerated by the reaction protocol, beyond N-hydroxyphthalimide and N-hydroxysuccinimide, (4) expand the scope of nucleophiles to include amines such as N,O-dimethylhydroxylamine and morpholine for the synthesis of synthetically useful Weinreb and morpholine amides, respectively, and (5) extend the utility of the reaction to mild one-pot reductions of carboxylic acids to the corresponding primary alcohol. My primary goal for the reduction aspect of this project was to explore an additional, fundamental application of thionyl fluoride as a synthetic reagent in organic chemistry and devise an optimized reduction protocol. My secondary goal was to apply the resulting optimized reduction to a variety of carboxylic acid substrates to assess the reaction scope and functional group tolerance. This work represents the first example of thionyl fluoride’s utility as a synthetic reagent in a reductive process with carboxylic acids, and the first published example of a true one-pot reduction of carboxylic acids via acyl fluoride intermediates. My efforts towards reaction development, an analysis of the advantages and disadvantages of the title protocol relative to standard literature methods, and my conclusive findings from the project are detailed herein. 4.4 Results and discussion 4.4.1 Attempted synthesis of N-hydroxyphthalimidyl and N-hydroxysuccinimidyl esters utilizing thionyl fluoride Initial investigations into one-pot syntheses of activated esters began with 3-fluorobenzoic acid (4.2e) and N-hydroxyphthalimide (4.9). The goal of these experiments was to determine a set of reaction parameters that generated the largest quantity of acyl fluoride (4.3e) possible, and subsequently favoured the greatest conversion of 4.3e to the corresponding ester (4.7e). The 127 quantity of acyl fluoride produced and subsequently consumed were measured in these experiments using quantitative 19F NMR spectroscopy, with PhCF3 present as an internal standard. 3-Fluorobenzoic acid was selected as an initial model substrate as it is commercially available and known to undergo quantitative deoxyfluorination to the corresponding acyl fluoride in the presence of SOF2.34 The aryl fluoride moiety would also enable quantitative 19F NMR spectroscopic monitoring of the production of 4.7e. Bench-stable N-hydroxyphthalimide (4.9, pKa ~ 6.3)128 was selected as it has a comparable pKa to pyridinium (pKa ~ 5.23) and was, therefore, expected to undergo deprotonation by the amine base and subsequent esterification. Reaction optimization began with a base screen, utilizing conditions similar to those described by Lee (Table 4.1). In an attempt to favour acyl fluoride generation and to simplify the overall protocol, the two equivalents of base used in the overall reaction were added in a single portion during the first stage of acyl fluoride synthesis. Pyridine proved to be an effective base for the one-pot esterification of 4.2e, leading to quantitative formation and subsequent consumption of 4.3e, with concomitant quantitative formation of 4.7e by 19F NMR spectroscopy (entry 1). DIPEA proved less effective, generating both the acyl fluoride and subsequent ester in only 75% 19F NMR spectroscopic yield, each (entry 2). A similar result was observed with Et3N (65% and 84% of 4.3e and 4.7e, respectively; entry 3) and DBU (68% and 75% of 4.3e and 4.7e, respectively; entry 4). The measured quantity of acyl fluoride was less than the measured ester product with both Et3N and DBU, perhaps indicating that some other reactive intermediate was present in an equilibrium. Given that pyridine is known to act as a nucleophilic catalyst in nucleophilic acyl substitutions of acyl chlorides, it was hypothesized that the other reactive intermediate was an acyl pyridinium species (4.37, Scheme 4.16). These experiments indicated that pyridine was the clear choice of base in the overall reaction, in alignment with previous work.34 128 Table 4.1. Base optimization of the SOF2-mediated one-pot synthesis of activated esters.a entry base yield 4.3e (%)b yield 4.3e (%)c yield 4.7e (%)d 1 pyridine 95 N.D. 99 2 DIPEA 75 N.D. 75 3 Et3N 65 N.D. 84 4 DBU 68 N.D. 75 aReaction conditions: 4.2e (0.5 mmol), SOF2 in MeCN (1.2 equiv.), base (2.0 equiv.), 4.9 (1.0 equiv.). bDetermined by quantitative 19F NMR spectroscopy, utilizing PhCF3 (50 μL) as an internal standard. Aliquot sampled immediately after sparging with N2. cDetermined by quantitative 19F NMR spectroscopy, utilizing PhCF3 (50 μL) as an internal standard. Aliquot sampled 1 h after addition of N-hydroxyphthalimide (4.9). dDetermined by quantitative 19F NMR spectroscopy, utilizing C6F6 (20 μL) as an internal standard. Aliquot sampled 1 h after addition of N-hydroxyphthalimide (4.9). N.D. = not detected. Scheme 4.16. Presumed formation of acyl fluoride and acyl pyridinium species during the reaction. With quantitative yields of the ester accessible within one hour, the next question was whether the reaction could be conducted more rapidly without erosion of the yield (Table 4.2). When the reaction was conducted at room temperature, quantitative yields of 4.7e were measured by 19F NMR spectroscopy in as little as 15 minutes (entry 1), with no erosion detected in parallel experiments at 30 (entry 2) or 120 minutes (entry 3). When the temperature of the second step was elevated to 40 °C, identical 19F NMR spectroscopic yields of 4.7e were obtained. These results indicated that the second step of this esterification protocol could be conducted at both room and 129 slightly elevated temperatures to equal effect, and that the process could be completed in as little as 15 minutes. However, as some acyl fluorides were later determined to require up to one hour to react fully, a standard reaction time of one hour was used in all subsequent experiments. The slightly greater yields of 4.7e versus 4.3e prior to addition of 4.9 are within the margin of error associated with the quantitative 19F NMR spectroscopic experiments. Table 4.2. Time and temperature optimization of the SOF2-mediated one-pot synthesis of activated esters.a entry temperature (°C) time (min) yield 4.3e (%)b yield 4.3e (%)c yield 4.7e (%)d 1 rt 15 96 N.D. 99 2 rt 30 95 N.D. 99 3 rt 120 96 N.D. 99 4 40 15 96 N.D. 99 5 40 30 98 N.D. 99 6 40 120 97 N.D. 99 aReaction conditions: 4.2e (0.5 mmol), SOF2 in MeCN (1.2 equiv.), pyridine (2.0 equiv.), 4.9 (1.0 equiv.). bDetermined by quantitative 19F NMR spectroscopy, utilizing PhCF3 (50 μL) as an internal standard. Aliquot sampled immediately after sparging with N2. cDetermined by quantitative 19F NMR spectroscopy, utilizing PhCF3 (50 μL) as an internal standard. Aliquot sampled 1 h after addition of N-hydroxyphthalimide (4.9). dDetermined by quantitative 19F NMR spectroscopy, utilizing C6F6 (20 μL) as an internal standard. Aliquot sampled 1 h after addition of N-hydroxyphthalimide (4.9). rt = room temperature. N.D. = not detected. Having confirmed the success of the esterification by NMR spectroscopy, a mild extractive workup and series of aqueous washes were performed to isolate the crude product as a white solid. 1H, 19F, and 13C NMR spectroscopic data all confirmed that the crude product was indeed the activated ester (4.7e, 95%), with no solvents or other impurities detected. 130 The experiment was replicated, using N-hydroxysuccinimide (4.10, pKa ~6.0)129 in place of 4.9. This nucleophile was selected to compliment the data obtained with 4.9, as the corresponding N-hydroxysuccinimidyl ester (4.8e) is also a synthetically useful motif (vide supra). Furthermore, the diagnostic 1H NMR spectroscopy methylene singlet of approximately 2.8–2.9 ppm from the succinimidyl moiety194 could be used to help identify the product in the reaction mixture. The one-pot SOF2-mediated esterification of 4.2e with 4.10 proved equally successful, with 4.8e isolated in 90% yield without the need for column chromatography. With effective reaction and isolation conditions in hand, the full substrate scope of this SOF2-mediated esterification protocol was explored. 4.4.2 Substrate scope of the thionyl fluoride-mediated one-pot and column-free esterifications and amidations of carboxylic acids via acyl fluorides Having determined that 3-fluorobenzoic acid (4.2e) was a suitable substrate for the reaction with both 4.9 and 4.10, the para and ortho-substituted isomers—4.2f and 4.2g, respectively—were investigated next (Scheme 4.17). The reaction was equally well-suited for either fluorinated isomer, generating 4.7f, 4.8f, 4.7g, and 4.8g in excellent isolated yields of 87–97%. These six aryl fluoride substrates effectively demonstrated that the site of aryl substitution had little-to-no effect on the outcome of the reaction. To probe the tolerance of the reaction towards strongly electron-rich arenes, 4-methoxybenzoic acid (4.2h) was examined. The 19F NMR spectroscopic yield of the acyl fluoride intermediate (4.3h) was not quite as high as with the fluorinated derivatives (4.2e, 4.2f, and 4.2g), presumably due to the electron-rich arene reducing the electrophilicity of the acyl fluorosulfite intermediate. The subsequent nucleophilic acyl substitutions by 4.9 and 4.10 successfully generated 4.7h and 4.8h in 88% and 67% isolated yields, respectively. Overall, the 131 reaction protocol appeared well-suited to the esterification of electron-rich aryl acid substrates. The esterification was similarly applied to electron-deficient arenes bearing nitro groups, successfully producing 4.7i and 4.8i in 72% and 81% yields, respectively. 4-Nitrobenzoyl fluoride (4.3i) was measured in near-quantitative yields by 19F NMR spectroscopy for both reactions, suggesting that the isolation protocol may have been the source of the slightly reduced isolated yields for the two esters; 4.3i should have been more susceptible to nucleophilic substitution than 3-fluorobenzoyl fluoride (4.3e) on account of the electron-withdrawing nitro group. 4-Methylbenzoic acid (4.2j) was utilized next to test whether the reaction was suitable for aryl acids lacking any significantly electron-donating or -withdrawing substituents. Esters 4.7j and 4.8j were isolated in excellent yields of 93% each, demonstrating that para-substituted alkylarenes were suited to the protocol as well. 132 aReaction conditions: 4.2 (1.0 mmol), SOF2 in MeCN (1.2 equiv.), pyridine (2.0 equiv.), 4.9 or 4.10 (1.0 equiv.). 19F NMR spectroscopic yields determined using PhCF3 (100 μL) as an internal standard. Isolated yields are reported, with 19F NMR spectroscopic yields of the acyl fluoride intermediate (4.3) in parentheses. bThe reaction mixture was stirred for two hours after the addition of the nucleophile. Scheme 4.17. Substrate scope of the SOF2-mediated one-pot esterification of aromatic carboxylic acids via acyl fluoride intermediates. The efficacy of the reaction was next investigated with a variety of aliphatic carboxylic acid substrates (Scheme 4.18). Commercially available 3-phenylpropionic acid (4.2k) was selected to assess the suitability of the protocol to primary carboxylic acids. Corresponding esters 4.7k and 4.8k were isolated in near-quantitative yields, suggesting the reaction was tolerant of aliphatic acids. This assumption was further reinforced by the successful one-pot esterifications of 3,3-diphenylpropionic acid (4.2l), yielding 4.7l and 4.8l in near-quantitative yields. trans-Cinnamic 133 acid (4.2m) was equally suited to the esterification, with 4.7m and 4.8m isolated in 98% and 94% yield, respectively. No conjugate-addition side-product was observed by 1H NMR spectroscopy. Pivalic acid (4.2n) was utilized next to study the efficacy of the reaction with sterically encumbered acid substrates. The three α-methyl groups were expected to sterically limit access to the acyl carbonyl by fluoride and the alcohol nucleophiles, thus leading to significantly lower acyl fluoride and ester yields. Pivaloyl fluoride (4.3n) was only measured in 53—58% yield by quantitative 19F NMR spectroscopy; this suggested that the initial attack by the carboxylate on SOF2 and/or the attack by fluoride on the intermediate acyl fluorosulfite was impeded. However, the low 19F NMR spectroscopic yield of 4.3n proved inconsequential, as the corresponding activated esters 4.7n and 4.8n were successfully isolated in 84% and 64% yield, respectively. The significantly greater yields of isolated ester versus the comparatively lower 19F NMR spectroscopic yields of the acyl fluoride suggest that an alternate, non-fluorinated reactive intermediate may have been present in solution during the reaction to form the acyl fluoride. This intermediate could have been the symmetric anhydride, pivalic anhydride. To further assess the esterification protocol’s application to sterically encumbered acid substrates, 1-adamantyl carboxylic acid (4.2o) was investigated. The adamantyl functionality presented little issue in either step of the reaction, generating the acyl fluoride (4.3o) in near-quantitative yield by 19F NMR spectroscopy and the activated esters 4.7o and 4.8o in 98% and 93% yields, respectively. It may be that the more conformationally restricted methylene carbons beta to the carbonyl of 1-adamantyl carboxylic acid (4.2o) were less impactful on the reaction than the tert-butyl moiety of pivalic acid (4.2n). 134 aReaction conditions: 4.2 (1.0 mmol), SOF2 in MeCN (1.2 equiv.), pyridine (2.0 equiv.), 4.9 or 4.10 (1.0 equiv.). 19F NMR spectroscopic yields determined using PhCF3 (100 μL) as an internal standard. Isolated yields are reported, with 19F NMR spectroscopic yields of the acyl fluoride intermediate (4.3) in parentheses. bThe reaction mixture was stirred for two hours prior to addition of the nucleophile. cThe reaction mixture was stirred for two hours after the addition of the nucleophile. Scheme 4.18. Substrate scope of the SOF2-mediated one-pot esterification of aliphatic carboxylic acids via acyl fluoride intermediates. A handful of carboxylic acid substrates failed to undergo the desired esterifications (Scheme 4.19). The trityl moiety in 4.2p proved to be an issue for the synthesis of the corresponding acyl fluoride, generating 4.3p in only 10% yield by quantitative 19F NMR spectroscopy each time. Esterifications with 4.9 and 4.10 were nonetheless attempted, although neither activated ester was successfully isolated, presumably due to the large steric effects of the adjacent trityl group impeding nucleophilic attack by 4.9 and 4.10. This result was unsurprising, given the larger size of 4.9 and 4.10 compared to fluoride during the two nucleophilic acyl 135 substitution steps. 2,6-Dimethylbenzoic acid (4.2q) was next investigated to determine if two ortho substituents could be tolerated under the reaction conditions. The two ortho-substituted methyl groups were expected to inhibit one or both steps of the reaction. The corresponding acyl fluoride (4.3q) was measured in excellent yield (89—91%), indicating that the steric effects of the two methyl groups did not occlude nucleophilic attack by fluoride. However, the addition of 4.9 and 4.10 both failed to produce the corresponding esters (4.7q and 4.8q, respectively), indicating the steric effects of the two methyl groups were too great for larger nucleophiles. It is possible that smaller nucleophiles such as ethoxide or methoxide may be tolerated in the second step of the reaction with this substrate. aReaction conditions: 4.2 (1.0 mmol), SOF2 in MeCN (1.2 equiv.), pyridine (2.0 equiv.), 4.9, or 4.10 (1.0 equiv.). 19F NMR spectroscopic yields determined using PhCF3 (100 μL) as an internal standard. Isolated yields are reported, with 19F NMR spectroscopic yields of the acyl fluoride intermediate (4.3) in parentheses. Scheme 4.19. Unsuccessful carboxylic acid substrates in the SOF2-mediated one-pot esterification of carboxylic acids via acyl fluoride intermediates. To explore additional N-oxide nucleophiles, the reaction of 3-fluorobenzoic acid (4.2e) and 2-methylpyridine-1-oxide (4.38) was investigated (Scheme 4.20). The corresponding acyl fluoride (4.3e) was measured in 98% yield by quantitative 19F NMR spectroscopy, in agreement with previous reactions. However, even after stirring for one hour with 4.38, no erosion to the quantity 136 of 4.3e—nor production of 4.39—were detected by NMR spectroscopy, indicating that 4.38 was not a suitable nucleophile under the reaction conditions. Given that 3,3-diphenylpropionic acid (4.2l) was well-suited to the acyl fluoride-forming step of the reaction (Scheme 4.17, vide supra), it was selected as a representative substrate for the attempted syntheses of a handful of additional non-activated esters. Phenol (4.40, pKa ~10) was expected to be a suitable nucleophile under the reaction conditions, although the undesired pKa differences between it and pyridine necessitated a stronger base be used in the second step of the reaction. Therefore, two equivalents of Et3N were utilized with phenol. Only 5% of the intermediate acyl fluoride were detected by quantitative 19F NMR spectroscopy after stirring with 4.40 for one hour, indicating consumption of 4.3l. Unfortunately, isolation of 4.5a proved unsuccessful, potentially indicating that the intended product had not formed or that decomposition had occurred. In future experiments, analysis of the reaction mixture with mass spectrometry would be a suitable method to determine if the product had formed and then simply decomposed. A similar issue was encountered during the attempted synthesis of 4.5b with benzyl alcohol (4.6c); despite utilizing two equivalents of KHMDS in the second step and observing quantitative consumption of the acyl fluoride intermediate by 19F NMR spectroscopy, isolation of the product ester (4.5b) was unsuccessful. 137 aReaction conditions: 4.2 (1.0 mmol), SOF2 in MeCN (1.2 equiv.), pyridine (2.0 equiv.), 4.38, 4.40, or 4.6c (1.0 equiv.). 19F NMR spectroscopic yields determined using PhCF3 (100 μL) as an internal standard. Isolated yields are reported, with 19F NMR spectroscopic yields of the acyl fluoride intermediate (4.3) in parentheses. bPyridine (1.0 equiv.) was used in the first step, and Et3N (2.0 equiv.) was used in the second. cPyridine (1.0 equiv.) was used in the first step, and KHMDS (2.0 equiv., 1.0 M in THF) was used in the second. Scheme 4.20. Unsuccessful attempts of the SOF2-mediated one-pot esterification of carboxylic acids via acyl fluoride intermediates, using non-activated nucleophiles. Efforts were then made to expand the SOF2-mediated protocol to general esterifications with non-activated alcohol nucleophiles (i.e. methanol, ethanol, etc.). The initial failed esterification attempts with phenol and benzyl alcohol were not ideal and suggested that a new approach was required. To circumvent this obstacle, the reaction was attempted again using methanol in lieu of either phenol or benzyl alcohol. Since methanol is the smallest and simplest alcohol, it would serve as an ideal representative nucleophile for re-optimization of the protocol to general esterifications. To this end, the synthesis of methyl 3,3-diphenylpropanoate (4.5c) was attempted with commercially available sodium methoxide (Table 4.3). Utilizing two equivalents of sodium methoxide—one equivalent to consume the equivalent of pyridinium, and one equivalent to act as a nucleophile—resulted in moderate consumption of the acyl fluoride intermediate (4.3l, entry 1), although a significant amount remained. Following this, a pre-formed mixture of sodium methoxide in methanol (1.0 M) was generated from sodium metal and the alcohol. Using 2.5 equivalents of this alkoxide solution immediately led to quantitative 138 consumption of 4.3l, and quantitative formation and isolation of the methyl ester (4.5c, entry 2). A slight excess of basic methoxide was utilized in order to favour nucleophilic attack. This was an encouraging result and was explored further with additional alcohols. Similar results were obtained when solid sodium ethoxide was used directly (entry 3), with only partial consumption of the acyl fluoride observed. A pre-formed 1.0 M solution of sodium ethoxide in ethanol (2.5 equivalents) completely consumed the acyl fluoride, furnishing the corresponding ester (4.5d) in quantitative isolated yield (entry 4). Table 4.3. Optimization of the SOF2-mediated general esterification of 3,3-diphenylpropionic acid.a entry nucleophile (NuH) yield 4.3l (%)b yield 4.3l (%)c yield 4.5 (%)d 1 NaOMe (2 equiv.) 97 43 — 2e NaOMe/MeOH (2.5 equiv) 95 N.D. 99 3 NaOEt (2 equiv.) 99 33 — 4 NaOEt/EtOH (2.5 equiv) 95 N.D. 99 aReaction conditions: 4.2l (1.0 mmol), SOF2 in solvent (1.2 equiv.), pyridine (1.0 equiv.), and nucleophile. bDetermined by quantitative 19F NMR spectroscopy, utilizing PhCF3 as an internal standard. Aliquot sampled immediately after sparging with N2. cDetermined by quantitative 19F NMR spectroscopy, utilizing PhCF3 as an internal standard. Aliquot sampled 30 minutes after addition of nucleophile. dIsolated yield of ester. eA pre-formed 1.0 M solution of alkoxide in alcohol was prepared using sodium metal. N.D. = not detected. With newly-optimized conditions in hand, this synthetic approach was applied to the synthesis of a small array of non-activated esters (Scheme 4.21). Benzyl alcohol (4.6c) was re-examined for these experiments, and 2-phenylethanol (4.6f) was selected to further investigate the scope. NaH was used in place of sodium metal for these experiments as the latter does not react efficiently with alcohols larger than methanol or ethanol. Utilizing NaH and benzyl alcohol (4.6c), 139 a pre-formed solution of sodium phenylmethanolate in hexanes (2.5 equivalents, 0.5 M) was added to 3,3-diphenylpropanoyl fluoride. The reaction did not proceed to completion, with 3,3-diphenylpropanoyl fluoride (4.3l) measured in 50% yield by quantitative 19F NMR spectroscopy after stirring with the nucleophile for one hour. Even stirring the reaction for up to three hours resulted in 4.3l persisting in 35% 19F NMR spectroscopic yield. The attempted isolation of 4.5b resulted in a mixture of the final ester and the acyl fluoride intermediate. Since this was to be a column-free protocol, this substrate was not pursued further. A similar problem occurred in the attempted synthesis of phenethyl 3,3-diphenylpropanoate (4.5e). 3,3-Diphenylpropanoyl fluoride was treated with a pre-formed solution of sodium 2-phenylethan-1-olate in hexanes (2.5 equivalents, 0.5 M). Isolation also yielded a mixture of the acyl fluoride and ester product. The syntheses of 4.5b and 4.5e could be improved in future iterations with the addition of a larger excess of nucleophilic alkoxide. Doing so may better favour consumption of the acyl fluoride intermediate and streamline subsequent product isolation, at the cost of poorer atom economy. Alternatively, stirring the reaction for a longer duration or at elevated temperature may improve overall yield for these substrates. Despite the failed isolations of 4.5b and 4.5e, the successful quantitative isolations of 4.5c and 4.5d demonstrated that the SOF2-mediated esterification could be applied to the synthesis of non-activated esters. 140 aReaction conditions: 4.2l (1.0 mmol), SOF2 in MeCN (1.2 equiv.), pyridine (1.0 equiv.), nucleophile (2.5 equiv.). 19F NMR spectroscopic yields determined using PhCF3 (100 μL) as an internal standard. Isolated yields are reported, with 19F NMR spectroscopic yields of the acyl fluoride intermediate (4.3l) in parentheses. b2.5 equivalents of NaOMe in MeOH (1.0 M) were used in the second step. c2.5 equivalents of NaOEt in EtOH (1.0 M) were used in the second step. dBnOH, NaH, and THF (0.5 M) were used in the second step, equating to 2.5 equivalents of NaOBn. e2-Phenylethanol, NaH, and THF (0.5 M) were used in the second step, equating to 2.5 equivalents of NaOCH2CH2Ph. Scheme 4.21. Scope of non-activated esters in the SOF2-mediated one-pot esterification of carboxylic acids via acyl fluoride intermediates. As discussed previously (vide supra) Weinreb (4.15) and morpholine amides (4.16) are synthetically useful compounds, so mild and efficient methods towards their syntheses are highly desirable. Therefore, the SOF2-mediated one-pot synthesis of four of these amide motifs was attempted (Scheme 4.22). 3,3-Diphenylpropionic acid (4.2l) was selected as a representative aliphatic acid substrate as it consistently generated the corresponding acyl fluoride (4.3l) in quantitative yield under the reaction conditions. In the presence of the Weinreb amine hydrochloride salt (4.28) and one extra equivalent of pyridine, 4.15a was furnished in quantitative yield. The extra equivalent of pyridine was necessary to compensate for the equivalent of acid introduced by 4.28. In a complementary experiment, two of the three equivalents of pyridine were replaced with K2CO3, affording 4.15a in 95% yield. This demonstrated that other commercially available and easily handled bases could be used for the second step of the reaction. Similarly, morpholine amide 4.16a was synthesized in 93% isolated yield, albeit after stirring the reaction mixture at 40 °C in the second step. This heating was required to achieve 141 maximal yield, as 4.3l was detected in only 17% yield by quantitative 19F NMR spectroscopy after one hour when the reaction mixture was instead stirred at room temperature. It is presumed the steric bulk of morpholine led to this slight reduction in nucleophilicity—especially compared to the neutral form of 4.28, which likely benefits nucleophilically from the alpha effect.195 To further the new amidation protocol with aryl acid substrates, 3-fluorobenzoic acid (4.2e) was selected as it previously underwent quantitative conversion to the corresponding acyl fluoride under the esterification reaction conditions (vide supra). Treatment of 4.2e with 4.28 or morpholine (4.41) under the reaction conditions furnished Weinreb (4.15b) or morpholine (4.16b) amides in 80% and 94% isolated yields, respectively. aReaction conditions: 4.2 (1.0 mmol), SOF2 in MeCN (1.2 equiv.), pyridine (2.0 equiv.), 4.28 or 4.41 (1.0 equiv.). 19F NMR spectroscopic yields determined using PhCF3 (100 μL) as an internal standard. Isolated yields are reported, with 19F NMR spectroscopic yields of the acyl fluoride intermediate (4.3) in parentheses. b3.0 equiv. of pyridine were used, on account of the 1.0 equiv. of HCl from 4.28. c1.0 equiv. of pyridine was used in the first step, and 2.0 equiv. of K2CO3 were used in the second step. dThe second step of the reaction was conducted at 40 °C. Scheme 4.22. Scope of Weinreb and morpholine amides in the SOF2-mediated one-pot amidation of carboxylic acids via acyl fluoride intermediates. 142 4.4.3 Attempted one-pot SOF2-mediated reductions of carboxylic acids via non-isolated acyl fluoride intermediates Having explored nucleophilic acyl substitution-based applications of SOF2-mediated reactions of carboxylic acids, one-pot reductions were investigated next. Given that acyl fluorides had been reported as synthetic intermediates in acid-to-alcohol reductions with cyanuric fluoride192 and SO2F2,193 the one-pot SOF2-mediated reduction seemed plausible and would be the first published work of a one-pot reduction of carboxylic acids to the alcohol via an acyl fluoride intermediate. The reduction protocol was developed from the optimized SOF2-mediated esterification process (vide supra), with a few minor modifications: (1) pyridine, Et3N, and DIPEA were each known to be suitable bases for acyl fluoride formation, and the appropriate base was selected for each substrate; (2) MeCN and DCM were used on an as-needed basis to ensure dissolution of the acid substrate (3) following the formation of 4.3, a solution of NaBH4 in either DMF or DMA was added to complete the reduction. NaBH4 was selected as it is commercially available, more atom-economical than other common borohydride reductants, and known to readily reduce 4.3 to 4.6.192 DMA was selected in favour of DMF as it has been reported that NaBH4/DMF solutions of sufficient concentration may lead to violent runaway reactions at elevated temperatures.196 While the preliminary reduction experiments had been conducted on a 1.0 mmol scale in DMF with no violent or explosive outcomes, the solvent switch was made anyway to mitigate the potential safety hazards of the protocol. The difference in product yield when using DMF or DMA was negligible. The reduction protocol was initially tested on 3,3-diphenylpropionic acid (4.2l) as it had previously undergone quantitative conversion to the corresponding acyl fluoride (4.3l) with pyridine (Scheme 4.23a). However, pyridine was not used with this substrate as there were 143 concerns that the small quantity of intermediate acyl pyridinium (4.37) could potentially be reduced by the NaBH4 to the de-aromatized amide (4.42, Scheme 4.23b). A similar outcome had been observed by Yu in their SO2F2-mediated protocol,193 wherein an intermediate acyl 4-dimethylaminopyridine (DMAP) adduct was hypothesized to undergo competitive reduction and de-aromatization. To circumvent this potential side-reaction, DIPEA was used in lieu of pyridine, despite knowing that it was not as effective in generating 4.3l. Acyl fluoride 4.3l was measured in 87% yield by quantitative 19F NMR spectroscopy under the reaction conditions, with PhCF3 added as an internal standard. The addition of NaBH4/DMA led to full consumption of 4.3l by 19F NMR spectroscopy within one hour of stirring. The quantitative consumption of 4.3l was encouraging, and isolation was attempted to confirm 4.6l had formed. After an extractive workup and extensive purification process via column chromatography (vide infra), 4.6l was measured in 79% yield. During purification, at least five compounds were observed by thin-layer chromatography, with the product alcohol identified between at least two compounds with similar Rf values (0.14, 0.21, 0.28; 50% Et2O/hexanes). While the purification was difficult, the successful generation of 4.6l indicated that the SOF2-mediated reduction could be performed effectively in a single reaction vessel. The minimal difference between the 19F NMR spectroscopic yield of 4.3l (87%) versus the isolated yield of 4.6l (79%) suggested that the reduction effectively reduced most—if not all—of the acyl fluoride to the alcohol, and the yield reduction may be attributed to the isolation and purification protocol. 144 Scheme 4.23. (a) Initial attempted one-pot SOF2-mediated reduction of 3,3-diphenylpropionic acid to 3,3-diphenylpropanol, and (b) hypothesized competitive reduction of the acyl pyridinium intermediate. Having determined that the reduction protocol could be effectively employed, the choice of reductant and reaction time for the second step were briefly investigated. Treatment of 4.3l with n-Bu4BH4 fully consumed 4.3l by quantitative 19F NMR spectroscopy (Table 4.4, entry 1). A control experiment using NaBH4 yielded an identical result. This indicated that either NaBH4 or (n-Bu)4BH4 could be utilized in the reduction to equal effect. However, NaBH4 was used for future experiments due to its lower cost and superior atom economy. Two additional experiments were conducted to study the effects of conducting the reduction over different time periods. Terminating the reduction after 30 minutes (entry 2) or two hours (entry 3) had no effect on the degree of acyl fluoride consumption, with 4.3l fully consumed in each case. This indicated that the reduction could be conducted over a shorter period of time; however, a standard reaction time of one hour was used in future experiments to ensure that all substrates could fully react. 145 Table 4.4. Reductant and time investigations of the one-pot SOF2-mediated reduction of carboxylic acids.a entry [H] time (h) yield 4.3l pre-[H] (%)b yield 4.3l post-[H] (%)c 1 (n-Bu)4BH4 1 92 N.D. 2 NaBH4 0.5 94 N.D. 3 NaBH4 2 94 N.D. aReaction conditions: 4.2l (0.6 mmol), SOF2 in MeCN (1.2 equiv.), DIPEA (1.0 equiv.), reductant (6.0 equiv.). bDetermined by quantitative 19F NMR spectroscopy, utilizing PhCF3 (50 μL) as an internal standard; aliquot sampled immediately after sparging with N2. cDetermined by quantitative 19F NMR spectroscopy, utilizing PhCF3 (50 μL) as an internal standard; aliquot sampled at the indicted time after addition of reductant/DMA. N.D. = not detected. [H] = reductant. 4.4.4 Substrate scope of the thionyl fluoride-mediated one-pot reduction of carboxylic acids via acyl fluorides Initial investigations of the substrate scope focused on the reduction of aliphatic carboxylic acids (Scheme 3.16). DCM or MeCN were utilized as required in order to achieve full substrate dissolution, and pyridine or DIPEA were used as needed to afford maximum product yield. As with 4.2l, the one-pot reduction of 4.2k proceeded smoothly to afford 4.6k in 70% isolated yield. The reduction of 4.2r was slightly less effective, with 4.6r isolated in 56% yield. Given the structural similarity of 4.2r and 4.2k, it was assumed that the lower isolated yield of 4.6r was primarily a result of the extensive column chromatography required to purify these compounds. A similar result was observed for 4.6s, which was isolated in 53% yield. Triphenylacetic acid (4.2p) was next treated with SOF2 and DIPEA in an attempt to generate the corresponding acyl fluoride 146 (4.3p). This reaction was not expected to produce much—if any—acyl fluoride, given the poor yields observed previously for the analogous one-pot SOF2-mediated esterifications (vide supra). However, acyl fluoride 4.3p was observed in 66% yield by quantitative 19F NMR spectroscopy. This deviation from previous experiments is attributed to the use of DIPEA here versus pyridine during the esterifications. The subsequent reduction of 4.3p to 4.6p proceeded in excellent yield relative to the acyl fluoride intermediate (61% isolated). The results of this substrate indicate that the reduction may be successfully applied to carboxylic acids bearing sterically encumbered alpha carbon centres. Reactions were run according to the optimized protocol on a 1.0 mmol scale of 4.2. Isolated yields shown, with 19F NMR spectroscopic yields of the acyl fluoride (4.3) indicated in parentheses. PhCF3 (100 μL) was added as an internal standard. aDCM was used. bMeCN was used. cDIPEA was used. Scheme 4.24. Substrate scope of the one-pot SOF2-mediated reduction of aliphatic carboxylic acids. Following the successful reduction of aliphatic acids, the scope of aromatic acids was explored. Initial investigations began with 3-fluorobenzoic acid (4.2e), as it was known to react favourably with SOF2 to form the corresponding acyl fluoride (4.3e). The one-pot reduction of 4.2e afforded 4.6e in 53% isolated yield (Scheme 4.25). Three other halogenated aryl acids were then examined (4.2t, 4.2u, and 4.2v). The reduction of 4.2t proceeded smoothly to afford 4.6t in 64% isolated yield. The isolated yields of both 4.6e and 4.6t were likely reduced through the 147 isolation and purification steps, rather than the reaction itself. This assumption was based on the extensive purification required, and the fact that no acyl fluoride intermediate was detected by 19F NMR spectroscopy after stirring with NaBH4 for one hour, suggesting full consumption of the intermediate. Conversely, 4-iodobenzoyl fluoride (4.3u) was produced in 70% yield by 19F NMR spectroscopy and subsequently reduced to the corresponding alcohol (4.6u, 61%) with minimal yield loss. This indicated that the yield of 4.6u could potentially be improved further by using conditions (i.e. pyridine in lieu of DIPEA) that generate 4.3u in quantitative yield prior to reduction. Similarly, 2-iodobenzoic acid (4.2v) was successfully converted to the 2-iodobenzoyl fluoride (4.3v) in 84% yield, and subsequently reduced to 2-iodobenzyl alcohol (4.6v) in 80% isolated yield. As with the para-substituted isomer, the minimal difference in yield between 4.3v and the isolated alcohol (4.6v) suggest that conditions favouring quantitative formation of 4.3v could improve the overall yield of 4.6v. The reduction of 2,6-dimethylbenzoic acid (4.2q) was attempted next. From the esterifications attempted previously (vide supra), this acid was known to undergo deoxyfluorination to 4.3q, with subsequent esterifications failing due to disfavourable steric interactions between the acyl fluoride and the nucleophile. The reduction suffered no such effects, with the corresponding alcohol (4.6q) isolated in 48% yield. As with the other substrates examined thus far, this product required extensive purification via column chromatography, likely resulting in the significant yield loss observed. At least eight compounds were observed in the crude product mixture with thin-layer chromatography (Rf: 0–0.73; 80% Et2O/hexanes). The product alcohol either co-eluted or was measured between two other compounds in all eluent systems utilized (Rf: 0.43, 0.50, 0.56; 80% Et2O/hexanes). 148 Both 3-methylbenzyl alcohol (4.6w) and 4-methylbenzyl alcohol (4.6j) were successfully produced by this protocol, although only in low isolated yields of 33% and 21%, respectively. Both of these products partially co-eluted with an unidentifiable impurity from their respective columns, and the contaminated column fractions were discarded to favour pure product isolation over a larger, impure yield. The reduction of 4.2x proceeded much more smoothly, with the intermediate acyl fluoride (4.3x) generated in 90% yield by 19F NMR spectroscopy, and the alcohol (4.6x) isolated in 73% yield. Reactions were run according to the optimized protocol on a 1.0 mmol scale of 4.2. Isolated yields shown, with 19F NMR spectroscopic yields of the acyl fluoride (4.3) indicated in parentheses. PhCF3 (100 μL) was added as an internal standard. aMeCN was used. bDCM was used. cDIPEA was used. dPyridine was used. Scheme 4.25. Substrate scope of the one-pot SOF2-mediated reduction of aromatic carboxylic acids. Several additional carboxylic acids were investigated during the development of the substrate scope. Pivalic acid (4.2n) was selected to complement the observations made previously with triphenylacetic acid (4.2p, vide supra). Pivalic acid was expected to undergo only moderate conversion to the corresponding acyl fluoride (4.3n), given the findings of the SOF2-mediated 149 esterifications. However, treatment of 4.2n with SOF2 and pyridine in DCM instead generated 4.3n in 98% yield by quantitative 19F NMR spectroscopy (Scheme 4.26). The use of DCM in lieu of MeCN may have better solubilized the pivalic acid and led to the improved yield. Subsequent reduction of 4.3n with NaBH4 in DMA successfully generated target alcohol 4.6n, although attempts to purify the crude reaction mixture failed on account of significant co-elution with at least one other unidentifiable impurity. Adamantane-1-carboxylic acid (4.2o) was similarly selected to investigate the effects of sterically encumbered carboxylic acids. Following generation of the intermediate acyl fluoride (4.3o, 97%), the alcohol (4.6o) was afforded in an excellent yield of 97%. A small quantity of unidentifiable impurities co-eluted with the product during purification; however, this substrate nonetheless indicated that the reaction worked well, given the similarity between the yields of the intermediate acyl fluoride and slightly impure isolated product. The reduction of trans-cinnamic acid (4.2m) afforded trans-cinnamyl alcohol (4.6m) in a corrected isolated yield of 36%. The product was collected alongside approximately 4% of 3-phenyl-1-propanol (4.6k). 3-Phenyl-1-propanol was detected in less than 5% yield in subsequent column fractions. The preferential production of 4.6m over 4.6k suggests that this protocol can be utilized for the selective 1,2-reduction of α,β-unsaturated carboxylic acids. 150 Reactions were run according to the optimized protocol on a 1.0 mmol scale of 4.2. Isolated yields shown, with 19F NMR spectroscopic yields of the acyl fluoride (4.3) indicated in parentheses. PhCF3 (100 μL) was added as an internal standard. aThe product alcohol was observed in the crude isolate by 1H NMR spectroscopy, yet purification failed due to significant co-elution. bThe product alcohol was recovered after attempted purification via column chromatography, along with a minor quantity of unidentifiable impurities; the exact yield cannot be accurately determined due to the presence of these unidentifiable impurities. cThe product alcohol was recovered after attempted purification via column chromatography, along with a minor quantity (~4%) of 3-phenyl-1-propanol; the isolated yield has been corrected to reflect this. dThe product alcohol was recovered after attempted purification via column chromatography, along with a minor quantity of pyridine; the isolated yield has been corrected to reflect this. Scheme 4.26. Examples of failed substrates or substrates that were impossible to fully isolate and purify. Several additional aryl acids were also tested under the reaction conditions. 3-Cyanobenzoic acid (4.2y) underwent deoxyfluorination to produce 4.3y in 96% yield by 19F NMR spectroscopy. Subsequent reduction to the alcohol (4.6y) was successful per 1H NMR spectroscopic analyses of the crude isolated product, although purification attempts failed due to co-elution with unidentifiable impurities. There was no evidence of nitrile reduction in the 1H NMR spectrum of the crude isolated product. This was expected given that NaBH4 is generally considered too weak a reductant to react with cyano moieties. The reduction of 4-methoxybenzoic acid (4.2h) proceeded smoothly and afforded 4.6h in 62% isolated yield; trace pyridine co-eluted with 4.6h, and the isolated yield was corrected to reflect this. The successful reduction of 4.2h 151 indicated that the reduction protocol could be effectively applied to electron-rich aryl acids. The reduction of 4-nitrobenzoic acid (4.2i) was less effective, with the corresponding alcohol (4.6i) isolated after purification in a yield of less than 21%; several unidentifiable contaminants co-eluted with the product alcohol. Despite the low yield, the production of 4.6i suggested that electron-poor aryl acids may also be reduced through this one-pot reductive protocol, although to a lesser degree than electron-rich acids. 4-Acetoxybenzoic acid (4.2z) and 4-acetamidobenzoic acid (4.2aa) were both selected to examine if esters and amides would be tolerated under the reaction conditions with NaBH4. 4-Acetoxybenzyl alcohol (4.6z) was produced with no evidence of ester reduction, although purification of the crude product failed on account of co-elution with pyridine and some other unidentifiable impurities. Similarly, 4-acetamidobenzyl alcohol (4.6aa) was successfully generated with the amide moiety intact, yet purification attempts of the crude product were unsuccessful due to significant co-elution of one or more unidentifiable impurities. Despite the failed purifications of these two alcohols, their successful production and isolation as crude products suggested that esters and amides may be tolerated under the reaction conditions. Unsubstituted benzoic acid (4.2c) was successfully reduced to benzyl alcohol (4.6c) under the reaction conditions according to 1H NMR spectroscopic analyses of the crude product material, yet purification failed on account of unidentifiable impurities co-eluting with the product alcohol from the column. Lastly, thiophene-2-carboxylic acid (4.2ab) was investigated to provide some insight into whether or not reductions of heteroaryl acids were feasible by this method. The deoxyfluorination of 4.2ab produced 4.3ab in 65% yield by 19F NMR spectroscopy, in agreement with previous reports.34 The subsequent reduction successfully afforded 4.6ab, although the purification of the 152 crude product mixture also failed for this substrate due to the co-elution of impurities that could not be identified. Despite initial concerns that a competitive side-reduction of 4.37 may take place if pyridine were used as the base for the reaction (vide supra), at no point was the corresponding de-aromatized side-product (4.42) observed. This was the case for the syntheses of 4.6t, 4.6v, and 4.6x, each of which was produced successfully using pyridine as the base. A central issue plaguing this reductive protocol was the production of unidentifiable impurities that either co-eluted, or eluted from the column in close proximity to the product alcohol. Even after isolation and characterization of these impurities utilizing 1H, 19F, and 13C{1H} NMR spectroscopy as well as GCMS, none of these side-products could be accurately identified. One component of the reaction mixtures was potentially an amine base borohydride adduct of some form (e.g. pyridinium borohydride). Attempts to remove boron-containing by-products from the crude reaction mixture through oxidative workup were unsuccessful. Practically, the optimized chromatography conditions required (1) the use of an approximate ratio of 150:1 grams of silica gel to grams of crude product, (2) elution by gravity alone over the course of approximately three hours, and (3) a slowly increased gradient of 20–50% Et2O/hexanes, all in order to maximize the probability of isolating the pure product alcohol. Even these purification conditions were insufficient for several compounds, leading to several failed product isolations (Scheme 4.26). In the future, this protocol could be improved in the following ways: (1) pyridine should be utilized in lieu of DIPEA or Et3N in most—if not all—cases to maximize formation of the acyl fluoride intermediate, and by extension, the yield of the alcohol product; (2) automated chromatography should be used, specifically reverse-phase chromatography; (3) multiple 153 chromatographic purifications may be required for a given product mixture, rather than a single long column purification. 4.5 Conclusions This chapter describes the development of a widely applicable and versatile one-pot SOF2-mediated coupling protocol, as well as the first example of the applications of SOF2 to redox processes with carboxylic acid substrates.45 The esterification reaction is well-suited to both alkyl and aryl carboxylic acids of varying complexity. The conditions are tolerant of a variety of electron-donating and -withdrawing functional groups, and the reaction is primarily sensitive to steric bulk of the carboxylic acid. For sterically unencumbered acids, larger nucleophiles such as N-hydroxyphthalimide and N-hydroxysuccinimide react efficiently to form the corresponding activated ester. Sterically encumbered acids—such as pivalic acid—with sp3-hybridized tertiary-substituted alpha carbons appear to be suitable substrates in the overall reaction, although they may undergo partial condensation to form a mixture of both acyl fluoride and anhydride intermediates. Sterically encumbered acids—such as 2,6-dimethylbenzoic acid—with sp2-hybridized alpha carbons and ortho-aryl substituents can undergo conversion to the corresponding acyl fluoride in excellent yield, yet subsequent substitution by large nucleophiles appears to be disfavoured. The SOF2-mediated esterification was applied to the synthesis of non-activated esters, including methyl and ethyl esters. Preliminary results indicate the sodium alkoxide salt can be used as an effective nucleophile in these esterifications. Furthermore, the esterification protocol was repurposed for the synthesis of four synthetically versatile Weinreb and morpholine amides in excellent yield, demonstrating the synthetic versatility of the overall protocol. 154 In all cases, the product esters and amides were isolated exclusively by simple extractive workup, without the need for a dedicated purification step. Combined with the simple reaction protocol and mild conditions, this one-pot SOF2-mediated esterification/amidation can be used to rapidly synthesize a library of activated esters and amides from the corresponding carboxylic acid. The SOF2-mediated reduction protocol can be effectively applied to the synthesis of primary alcohols from the corresponding carboxylic acid. Both aliphatic and aryl acids were successfully reduced under the optimized reaction conditions. The protocol could be applied to acid substrates with sterically encumbered alpha carbon centres, as evidenced by the reductions of triphenylacetic acid and pivalic acid. α,β-Unsaturated carboxylic acids—such as trans-cinnamic acid—are tolerated under the reaction conditions, selectively yielding the 1,2-reduction product with comparatively minimal reduction of the alkene. Aryl acid substrates substituted with strongly electron-donating groups (i.e. –OMe) appeared more amenable to the reduction than those with strongly electron-withdrawing moieties (i.e. –NO2). The reaction conditions had no effect on cyano, ester, or amide functional groups. The SOF2-mediated reduction protocol displays some synthetic utility and applicability. The use of NaBH4 permits greater chemoselectivity than processes using stronger reductants like LAH, and the use of SOF2 in place of alternative fluorinating agents like cyanuric fluoride enables the overall one-pot protocol. Despite the extensive purification process required, this project succeeded in its two primary goals of exploring a new synthetic application of SOF2 and in developing the first published one-pot reduction of acids through acyl fluoride intermediates. Future improvements would primarily target the purification protocol, as this was determined to be the greatest source of yield loss in the protocol. These investigations provide greater insight into the reactivity and synthetic applicability of SOF2 in organic chemistry. 155 4.6 Experimental information 4.6.1 General methods All chemicals were from commercial sources: Sigma-Aldrich, AK Scientific, Alfa Aesar, TCI America, and Fluka. All solvents were purchased from commercial sources: Sigma-Aldrich, Fisher Scientific, OmniSolv, and Acros. All reactions were performed in disposable scintillation 20 mL (28 x 61 mm) glass vials, round-bottom flasks or Econo-Pac® chromatography columns. Screw caps and PTFE/Silicone septa (22 mm x 0.060”) were from ChemGlass Life Sciences. Polyethylene tubing (I.D. 1.67 mm) was from Becton Dickinson. Disposable 1 mL syringes (I.D 4.69 mm), 3 mL syringes (I.D. 9.65 mm), 5 mL syringes (I.D. 12.45 mm), 10 mL syringes (I.D. 15.90 mm), and 30 mL syringes (I.D. 22.90 mm) were from Norm-Ject and Henk-Ject. Disposable needles 16 G x 1 ½ (1.6 mm x 40 mm) and 21 G x 2 (0.8 mm x 5 mm) were from BD PrecisionGlideTM. Hypodermic Needles (22 G x 4”) were from Air-TiteTM. White sleeve stoppers (24 x 40 mm) were from VWR®, white sleeve stoppers (O.D. 14mm) were from Kimble®, and red Suba-Seal® septa were from ChemGlass. Thin-layer chromatography (TLC) was performed on Merck Silica gel 60 F254 TLC aluminum sheets and visualized with 254 nm light and KMnO4 followed by heating with a heat gun. Infrared (IR) spectral data were obtained using a Perkin Elmer Frontier FT-IR. The spectra are reported in cm−1. NMR spectral data were obtained on a Bruker Avance-300, Avance-III 300, 400inv, 400dir, or AV III HD 400 spectrometer. 1H, 13C, and 19F NMR spectroscopic chemical shifts are reported in parts per million (ppm) relative to the residual solvent peak (CDCl3: 1H: δ = 7.26 ppm, 13C: δ = 77.16 ppm). 19F NMR spectroscopic chemical shifts were referenced to CFCl3. NMR spectroscopic yields were determined by 19F NMR spectroscopy using 4 scans and a relaxation 156 time of 40 seconds to complete relaxation of all fluorine nuclei. α,α,α-Trifluorotoluene (PhCF3) was used as an internal standard. Multiplicities are reported as follows: singlet (s), doublet (d), triplet (t), quartet (q), pentet (p), multiplet (m), doublet of doublets (dd), doublet of triplets (dt) and triplet of doublets (td). Assignment of peaks was done based on the chemical shifts, multiplicities, and integrals of the peaks. Coupling constants (J) are reported in Hz. 4.6.2 Procedure for the generation of thionyl fluoride (SOF2) Stir plate is omitted for clarity. Figure 4.2. Schematic of SOF2 generation apparatus. To a 20 mL vial was added KHF2 (7.0 g, 90 mmol, 3.0 equiv). To a 100 mL round-bottom flask equipped with a stir bar was added MeCN or CH2Cl2 (60 mL). Both the vial and the flask were sealed with rubber septa, and the two vessels were connected via needle, polyethylene tubing, and a column of imidazole (27g), as shown in Figure 4.2. Note that the imidazole was packed tightly into the syringe body to form the column. To the 20 mL vial was added thionyl chloride (4.43, 2.2 mL, 30 mmol, 1.0 equiv) via a 5 mL syringe in a single portion. The syringe was not removed from the 20 mL vial. The generated gaseous thionyl fluoride passed through the imidazole column in order to quench any gaseous HCl, before dissolving in the rapidly stirring solvent in the 157 round-bottom flask. The gas generation was allowed to proceed for 30–60 min until either (1) the solvent began to flow backwards up the polyethylene tubing inserted into the round-bottom flask, or (2) the 5 mL syringe plunger began to be pushed out. At this point, an empty balloon was quickly inserted via needle through the septum of the round-bottom flask to release the pressure in the system and increase the concentration of dissolved thionyl fluoride. After either a cessation of bubbling, or near-consumption of the imidazole column (visualized by a front of green-black liquified imidazole), the polyethylene tubing was removed from the round-bottom flask. To a 1.0 mL aliquot of the resulting solution was added PhCF3 (10 μL) as an internal standard. The concentration of thionyl fluoride (4.1) in solution was quantified using quantitative 19F NMR spectroscopy. Typical SOF2 concentrations: 0.07–0.19 M (CH2Cl2); 0.10–0.29 M (MeCN). Note: gaseous thionyl fluoride is hazardous. Gas generation/reagent manipulation should only be conducted in a fully operational fumehood. In addition to standard PPE, face and/or reaction shields are recommended. In the event of a dermal exposure to SOF2-containing solutions, the affected area should be washed with water and calcium gluconate (2.5% gel) should be applied to the affected area by a person wearing protective gloves; the affected individual should seek medical attention. 4.6.3 General procedure for the synthesis of activated esters (4.7 and 4.8) To a 20 mL vial equipped with a stir bar were added sequentially carboxylic acid (4.2, 1.0 mmol, 1.0 equiv), SOF2 in MeCN (1.2 mmol, 1.2 equiv), and pyridine (2.0 mmol, 2.0 equiv). The vial was sealed, and the contents were stirred for 1 hour at room temperature. The solution was 158 completely purged of SOF2 with N2 gas for 10 minutes, and PhCF3 (100 μL) was added as an internal standard. An aliquot of the solution was sampled to quantify production of acyl fluoride intermediate. To the vial was added either N-hydroxyphthalimide (4.9) or N-hydroxysuccinimide (4.10, 1.0 mmol, 1.0 equiv), and the resulting solution was stirred for a further 1 hour at room temperature. An aliquot of the solution was sampled to quantify consumption of acyl fluoride intermediate. The solution was diluted in ethyl acetate (30 mL), and successively washed with H2O (2 x 20 mL) and brine (20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to yield the pure N-oxy ester product. No further purification was required. 4.6.4 General procedure for the synthesis of non-activated esters (4.5c and 4.5d) To a 20 mL vial equipped with a stir bar were added sequentially carboxylic acid (4.2, 1.0 mmol, 1.0 equiv), SOF2 in MeCN (1.2 mmol, 1.2 equiv), and pyridine (1.0 mmol, 1.0 equiv). The vial was sealed, and the contents were stirred for 1 hour at room temperature. The solution was completely purged of SOF2 with N2 gas for 10 minutes, and PhCF3 (100 μL) was added as an internal standard. An aliquot of the solution was sampled to quantify production of the acyl fluoride intermediate. To the vial was added preformed alkoxide nucleophile (2.5 mmol, 2.5 equiv) in the corresponding alcohol solvent, and the resulting solution was stirred for a further 1 hour at room temperature. An aliquot of the solution was sampled to quantify consumption of the acyl fluoride intermediate. The solution was diluted in 1 M aq. HCl (20 mL) and ethyl acetate (30 mL), and the resulting organic phase was successively washed with H2O (2 x 20 mL) and brine (20 mL). The 159 organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to yield the pure ester product. No further purification was required. The preformed alkoxide solution was generated by dissolving sodium metal in either methanol or ethanol. Neither solvent was distilled prior to use. 4.6.5 General procedure for the synthesis of Weinreb (4.15) and morpholine (4.16) amides To a 20 mL vial equipped with a stir bar were added sequentially carboxylic acid (4.2, 1.0 mmol, 1.0 equiv), SOF2 in MeCN (1.2 mmol, 1.2 equiv), and pyridine (1.0 mmol, 1.0 equiv). The vial was sealed, and the contents were stirred for 1 hour at room temperature. The solution was completely purged of SOF2 with N2 gas for 10 minutes, and PhCF3 (100 μL) was added as an internal standard. An aliquot of the solution was sampled to quantify production of acyl fluoride intermediate. To the vial was added amine or amine hydrochloride salt nucleophile (1.0 mmol, 1.0 equiv), and the resulting solution was stirred for a further 1 hour at room temperature. An aliquot of the solution was sampled to quantify consumption of acyl fluoride intermediate. The solution was diluted in 1 M aq. HCl (20 mL) and ethyl acetate (30 mL), and the resulting organic phase was successively washed with H2O (2 x 20 mL) and brine (20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to yield the pure amide product. No further purification was required. 160 4.6.6 General procedure for the synthesis of alcohols (4.6) To a 20 mL vial equipped with a stir bar were added sequentially carboxylic acid (4.2, 1.0 mmol, 1.0 equiv), SOF2 in MeCN or CH2Cl2 (1.2 mmol, 1.2 equiv), and DIPEA or pyridine (1.0 mmol, 1.0 equiv). The vial was sealed, and the contents were stirred for 1 hour at room temperature. The solution was completely purged of SOF2 with N2 gas for 10 minutes, and PhCF3 (100 μL) was added as an internal standard. An aliquot of the solution was sampled to quantify production of acyl fluoride intermediate. To the vial was added a solution of NaBH4 (6.0 mmol, 6.0 equiv) in DMA (6–7 mL) and the resulting solution was stirred for a further 1 hour at room temperature. The solution was diluted in 1 M aq. HCl (50 mL) over ice and extracted with diethyl ether (4 x 20 mL). The combined organic phases were successively washed with H2O (4 x 20 mL) and brine (20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to yield the crude alcohol product, which was then purified via column chromatography. 161 4.6.7 Characterization data of 4.3p, 4.3q, 4.5c, 4.5d, 4.6c, 4.6e, 4.6f, 4.6i–z, 4.6aa, 4.6ab, 4.7e–q, 4.8e–q, 4.15a, 4.15b, 4.16a, and 4.16b Compound 4.3p Following the general procedure using triphenylacetic acid and SOF2, (4.3p) was measured in 10% yield by quantitative 19F NMR spectroscopy. The acyl fluoride was not isolated. 19F NMR: (282 MHz, Chloroform-d) δ 45.3. Compound 4.3q Compound spectral data is in agreement with previously reported data.197 Following the general procedure using 2,6-dimethylbenzoic acid and SOF2, (4.3q) was measured in 91% yield by quantitative 19F NMR spectroscopy. The acyl fluoride was not isolated. 19F NMR: (282 MHz, Chloroform-d) δ 52.6 (dt, J = 6.7, 3.0 Hz). 162 Compound 4.5c Compound spectral data is in agreement with previously reported data.198,199 Following the general procedure using 3,3-diphenylpropionic acid and sodium methoxide, (4.5c) was obtained as a clear, colourless oil (239 mg, 99% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.33 – 7.09 (m, 10H), 4.56 (t, J = 8.0 Hz, 1H), 3.53 (s, 3H), 3.05 (d, J = 8.0 Hz, 2H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 172.2, 143.5, 128.6, 127.7, 126.6, 51.6, 47.0, 40.6. Compound 4.5d Compound spectral data is in agreement with previously reported data.200,201 Following the general procedure using 3,3-diphenylpropionic acid and sodium ethoxide, (4.5d) was obtained as a clear, colourless oil (252 mg, 99% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.31 – 7.09 (m, 10H), 4.54 (t, J = 8.1 Hz, 1H), 4.00 (q, J = 7.1 Hz, 2H), 3.03 (d, J = 8.1 Hz, 2H), 1.07 (t, J = 7.1 Hz, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 171.9, 143.6, 128.6, 127.8, 126.6, 60.5, 47.2, 40.9, 14.1. 163 Compound 4.6c Compound spectral data is in agreement with previously reported data.202 Following the general procedure using benzoic acid, crude 4.6c was obtained and analyzed by 1H NMR. Attempts to purify this alcohol were unsuccessful. The following data is included to support the claim that the product alcohol was generated by the one-pot SOF2-mediated reduction. 1H NMR: (300 MHz, Chloroform-d) δ 7.40 – 7.35 (m, 5H), 4.70 (d, J = 5.9 Hz, 2H). Compound 4.6e Compound spectral data is in agreement with previously reported data.203 Following the general procedure using 3-fluorobenzoic acid, (4.6e) was obtained as a clear, colourless oil (67 mg, 53% yield) after purification by column chromatography (20–60% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.30 (td, J = 7.9, 5.9 Hz, 1H), 7.13 – 7.03 (m, 2H), 7.01 – 6.92 (m, 1H), 4.65 (s, 2H), 2.36 (s, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 163.1 (d, J = 246.0 Hz), 143.6 (d, J = 7.0 Hz), 130.2 (d, J = 8.1 Hz), 122.3 (d, J = 3.0 Hz), 114.5 (d, J = 21.2 Hz), 113.8 (d, J = 21.7 Hz), 64.6 (d, J = 1.9 Hz). 19F NMR: (282 MHz, Chloroform-d) δ -113.5 (td, J = 9.2, 5.9 Hz). 164 Compound 4.6h Compound spectral data is in agreement with previously reported data.202 Following the general procedure using 4-methoxybenzoic acid, crude 4.6h was obtained and analyzed by 1H NMR spectroscopy. Attempts to purify this alcohol were marginally successful, with 4.6h isolated in 62% corrected yield; a minor quantity of pyridine co-eluted with the product. The following data is included to support the claim that the product alcohol was generated by the one-pot SOF2-mediated reduction. 1H NMR: (300 MHz, Chloroform-d) δ 7.33 – 7.24 (m, 2H), 6.94 – 6.83 (m, 2H), 4.60 (s, 2H), 3.81 (s, 3H). Compound 4.6i Compound spectral data is in agreement with previously reported data.202,204 Following the general procedure using 4-nitrobenzoic acid, crude 4.6i was obtained and analyzed by 1H NMR spectroscopy. Attempts to purify this alcohol were marginally successful; however, unidentifiable impurities co-eluted with the product (<21% yield). The following data is included to support the claim that the product alcohol was generated by the one-pot SOF2-mediated reduction. 1H NMR: (300 MHz, Chloroform-d) δ 8.26 – 8.17 (m, 2H), 7.53 (d, J = 8.5 Hz, 2H), 4.83 (s, 2H). 165 Compound 4.6j Compound spectral data is in agreement with previously reported data.203 Following the general procedure using 4-methylbenzoic acid, (4.6j) was obtained as a white solid (25 mg, 21% yield) after purification by column chromatography (20–50% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.25 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 4.62 (s, 2H), 2.36 (s, 3H), 1.98 (s, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 138.0, 137.5, 129.3, 127.2, 65.3, 21.3. Compound 4.6k Compound spectral data is in agreement with previously reported data.205 Following the general procedure using 3-phenylpropionic acid, (4.6k) was obtained as a clear, colourless oil (94 mg, 70% yield) after purification by column chromatography (5–50% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.35 – 7.25 (m, 2H), 7.25 – 7.14 (m, 3H), 3.68 (t, J = 6.4 Hz, 2H), 2.72 (dd, J = 8.7, 6.8 Hz, 2H), 1.98 – 1.83 (m, 2H), 1.42 (s, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 141.9, 128.6, 128.5, 126.0, 62.4, 34.4, 32.2. 166 Compound 4.6l Compound spectral data is in agreement with previously reported data.206 Following the general procedure using 3-phenylpropionic acid, (4.6l) was obtained as a clear, colourless oil (169 mg, 79% yield) after purification by column chromatography (20–50% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.36 – 7.22 (m, 8H), 7.22 – 7.15 (m, 2H), 4.14 (t, J = 7.9 Hz, 1H), 3.62 (t, J = 6.5 Hz, 2H), 2.33 (dt, J = 7.9, 6.5 Hz, 2H), 1.38 (s, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 144.6, 128.7, 128.0, 126.4, 61.2, 47.5, 38.3. Compound 4.6m Compound spectral data is in agreement with previously reported data.202 Following the general procedure using trans-cinnamic acid, crude 4.6m was obtained and analyzed by 1H NMR spectroscopy. Attempts to purify this alcohol were marginally successful, with 4.6m isolated in 36% corrected yield; 3-phenyl-1-propanol (4.6k, 4%) co-eluted with the product. The following data is included to support the claim that the product alcohol was generated by the one-pot SOF2-mediated reduction. 1H NMR: (300 MHz, Chloroform-d) δ 7.43 – 7.35 (m, 2H), 7.37 – 7.28 (m, 2H), 7.32 – 7.20 (m, 1H), 6.63 (dt, J = 15.9, 1.6 Hz, 1H), 6.37 (dt, J = 15.9, 5.7 Hz, 1H), 4.33 (dd, J = 5.8, 1.6 Hz, 2H). 167 Compound 4.6n Compound spectral data is in agreement with previously reported data.203 Following the general procedure using pivalic acid, crude 4.6n was obtained and analyzed by 1H NMR spectroscopy. Attempts to purify this alcohol were unsuccessful. The following data is included to support the claim that the product alcohol was generated by the one-pot SOF2-mediated reduction. 1H NMR: (300 MHz, Chloroform-d) δ 3.29 (s, 2H), 0.90 (s, 9H). Compound 4.6o Compound spectral data is in agreement with previously reported data.207 Following the general procedure using 1-adamantane carboxylic acid, crude 4.6o was obtained and analyzed by 1H NMR spectroscopy. Attempts to purify this alcohol were marginally successful; however, unidentifiable impurities co-eluted with the product (<97% yield). The following data is included to support the claim that the product alcohol was generated by the one-pot SOF2-mediated reduction. 1H NMR: (300 MHz, Chloroform-d) δ 3.20 (s, 2H), 1.99 (p, J = 3.2 Hz, 3H), 1.80 – 1.59 (m, 6H), 1.51 (d, J = 2.9 Hz, 6H). 168 Compound 4.6p Compound spectral data is in agreement with previously reported data.208 Following the general procedure using triphenylacetic acid, (4.6p) was obtained as a white solid (168 mg, 61% yield) after purification by column chromatography (20–45% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.37 – 7.14 (m, 15H), 4.65 (s, 2H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 145.3, 129.6, 128.4, 126.7, 70.5, 59.0. Compound 4.6q Compound spectral data is in agreement with previously reported data.209 Following the general procedure using 2, 6-dimethylbenzoic acid, (4.6q) was obtained as a white solid (66 mg, 48% yield) after purification by column chromatography (20–50% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.16 – 7.08 (m, 1H), 7.05 (d, J = 6.4 Hz, 2H), 4.75 (s, 2H), 2.44 (s, 6H), 1.38 (s, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 137.5, 136.7, 128.6, 128.2, 59.5, 19.6. 169 Compound 4.6r Compound spectral data is in agreement with previously reported data.210 Following the general procedure using 3-(2-bromophenyl)-propanoic acid, (4.6r) was obtained as a clear, colourless oil (121 mg, 56% yield) after purification by column chromatography (20–50% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.58 – 7.49 (m, 1H), 7.28 – 7.20 (m, 2H), 7.06 (ddd, J = 7.9, 5.2, 3.8 Hz, 1H), 3.71 (t, J = 6.4 Hz, 2H), 2.89 – 2.79 (m, 2H), 1.97 – 1.83 (m, 2H), 1.46 (s, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 141.2, 133.0, 130.6, 127.8, 127.6, 124.6, 62.3, 32.9, 32.5. Compound 4.6s Compound spectral data is in agreement with previously reported data.211 Following the general procedure using 2-(4-methylphenyl)-acetic acid, (4.6s) was obtained as a clear, colourless oil (72 mg, 53% yield) after purification by column chromatography (20–50% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.14 (s, 4H), 3.83 (t, J = 6.6 Hz, 2H), 2.84 (t, J = 6.6 Hz, 2H), 2.34 (s, 3H), 1.65 (s, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 136.1, 135.4, 129.4, 129.0, 63.9, 38.9, 21.1. 170 Compound 4.6t Compound spectral data is in agreement with previously reported data.212 Following the general procedure using 4-chlorobenzoic acid, (4.6t) was obtained as a clear, colourless oil (91 mg, 64% yield) after purification by column chromatography (50–70% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.37 – 7.27 (m, 4H), 4.67 (s, 2H), 1.65 (s, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 139.4, 133.5, 128.8, 128.4, 64.7. Compound 4.6u Compound spectral data is in agreement with previously reported data.213 Following the general procedure using 4-iodobenzoic acid, (4.6u) was obtained as a white solid (143 mg, 61% yield) after purification by column chromatography (20–50% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.69 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 4.65 (s, 2H), 1.66 (s, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 140.6, 137.7, 128.9, 93.1, 64.8. 171 Compound 4.6v Compound spectral data is in agreement with previously reported data.202 Following the general procedure using 2-iodobenzoic acid, (4.6v) was obtained as a white solid (188 mg, 80% yield) after purification by column chromatography (50–80% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.82 (dd, J = 7.9, 1.2 Hz, 1H), 7.46 (dd, J = 7.7, 1.8 Hz, 1H), 7.37 (td, J = 7.5, 1.2 Hz, 1H), 7.00 (td, J = 7.6, 1.8 Hz, 1H), 4.68 (s, 2H), 2.02 (s, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 142.7, 139.3, 129.5, 128.6, 128.6, 97.6, 69.5. Compound 4.6w Compound spectral data is in agreement with previously reported data.214 Following the general procedure using 3-methylbenzoic acid, (4.6w) was obtained as a clear, colourless oil (41 mg, 33% yield) after purification by column chromatography (20–50% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.26 (d, J = 14.9 Hz, 1H), 7.21 – 7.08 (m, 3H), 4.64 (s, 2H), 2.37 (s, 3H), 1.95 (s, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 140.9, 138.3, 128.6, 128.5, 127.9, 124.2, 65.4, 21.5. 172 Compound 4.6x Compound spectral data is in agreement with previously reported data.215 Following the general procedure using 4-phenylbenzoic acid, (4.6x) was obtained as a white solid (133 mg, 73% yield) after purification by column chromatography (50% Et2O in hexanes). 1H NMR: (300 MHz, Chloroform-d) δ 7.63 – 7.56 (m, 4H), 7.48 – 7.40 (m, 4H), 7.39 – 7.31 (m, 1H), 4.75 (s, 2H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 140.9, 140.5, 140.0, 128.9, 127.5, 127.4, 127.3, 127.1, 64.9. Compound 4.6y Compound spectral data is in agreement with previously reported data.204 Following the general procedure using 3-cyanobenzoic acid, crude 4.6y was obtained and analyzed by 1H NMR. Attempts to purify this alcohol were unsuccessful. The following data is included to support the claim that the product alcohol was generated by the one-pot SOF2-mediated reduction. 1H NMR: (300 MHz, Chloroform-d) δ 7.63 – 7.51 (m, 1H), 7.56 – 7.46 (m, 2H), 7.45 (t, J = 7.7 Hz, 1H), 4.74 (s, 2H). 173 Compound 4.6z Compound spectral data is in agreement with previously reported data.202 Following the general procedure using 4-acetoxybenzoic acid, crude 4.6z was obtained and analyzed by 1H NMR spectroscopy. Attempts to purify this alcohol were unsuccessful. The following data is included to support the claim that the product alcohol was generated by the one-pot SOF2-mediated reduction. 1H NMR: (300 MHz, Chloroform-d) δ 7.38 – 7.29 (m, 2H), 7.06 – 6.98 (m, 2H), 4.62 (s, 2H), 2.26 (s, 3H). Compound 4.6aa Compound spectral data is in agreement with previously reported data.216 Following the general procedure using 4-acetamidobenzoic acid, crude 4.6aa was obtained and analyzed by 1H NMR spectroscopy. Attempts to purify this alcohol were unsuccessful. The following data is included to support the claim that the product alcohol was generated by the one-pot SOF2-mediated reduction. 1H NMR: (300 MHz, Chloroform-d) δ 7.55 – 7.47 (m, 2H), 7.21 (d, J = 8.3 Hz, 2H), 5.08 (t, J = 5.7 Hz, 1H), 4.41 (d, J = 5.6 Hz, 2H), 2.28 (s, 3H). 174 Compound 4.6ab Compound spectral data is in agreement with previously reported data.217 Following the general procedure using thiophene-2-carboxylic acid, crude 4.6ab was obtained and analyzed by 1H NMR spectroscopy. Attempts to purify this alcohol were unsuccessful. The following data is included to support the claim that the product alcohol was generated by the one-pot SOF2-mediated reduction. 1H NMR: (300 MHz, Chloroform-d) δ 7.28 (dd, J = 5.0, 1.3 Hz, 1H), 7.06 – 6.93 (m, 2H), 4.84 (d, J = 0.8 Hz, 2H). Compound 4.7e Compound spectral data is in agreement with previously reported data.194 Following the general procedure using 3-fluorobenzoic acid and N-hydroxyphthalimide, (4.7e) was obtained as a white solid (270 mg, 95% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.01 (dt, J = 7.7, 1.3 Hz, 1H), 7.98 – 7.78 (m, 5H), 7.54 (td, J = 8.0, 5.5 Hz, 1H), 7.41 (tdd, J = 8.3, 2.7, 1.1 Hz, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 164.3, 162.0, 161.0, 135.0, 130.8 (d, J = 7.8 Hz), 129.1, 127.4 (d, J = 8.2 Hz), 126.6 (d, J = 3.3 Hz), 124.3, 122.3 (d, J = 21.0 Hz), 117.7 (d, J = 23.8 Hz). 19F NMR: (282 MHz, Chloroform-d) δ -111.2 (td, J = 8.6, 8.1, 5.4 Hz). IR (cm-1): 3103, 1774, 1732, 1589, 1480, 1463, 1266, 1178, 1136, 1019. 175 Compound 4.7f Compound spectral data is in agreement with previously reported data.218 Following the general procedure using 4-fluorobenzoic acid and N-hydroxyphthalimide, (4.7f) was obtained as a white solid (263 mg, 91% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.23 (dd, J = 8.9, 5.3 Hz, 2H), 7.93 (dd, J = 5.5, 3.1 Hz, 2H), 7.82 (dd, J = 5.5, 3.1 Hz, 2H), 7.22 (t, J = 8.6 Hz, 2H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 169.3, 167.0 (d, J = 257.7 Hz), 161.0, 133.5 (d, J = 9.7 Hz), 121.5 (d, J = 3.0 Hz), 116.4 (d, J = 22.3 Hz), 25.8. 19F NMR: (282 MHz, Chloroform-d) δ -101.7 (tt, J = 8.3, 5.3 Hz). IR (cm-1): 3105, 1801, 1771, 1732, 1602, 1507, 1468, 1231, 1188, 1134, 1030, 1007. Compound 4.7g Compound spectral data is in agreement with previously reported data.194,218 Following the general procedure using 2-fluorobenzoic acid and N-hydroxyphthalimide, (4.7g) was obtained as a white solid (271 mg, 97% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.15 (ddd, J = 8.3, 7.0, 1.8 Hz, 1H), 7.93 (dd, J = 5.5, 3.1 Hz, 2H), 7.82 (dd, J = 5.5, 3.1 Hz, 2H), 7.75 – 7.62 (m, 1H), 7.37 – 7.19 (m, 2H). 176 13C{1H} NMR: (75 MHz, Chloroform-d) δ 162.7 (d, J = 264.3 Hz), 162.0, 160.4 (d, J = 4.4 Hz), 136.9 (d, J = 9.3 Hz), 135.0, 132.9, 129.1, 124.6 (d, J = 3.9 Hz), 124.2, 117.6 (d, J = 21.6 Hz), 114.1 (d, J = 9.9 Hz). 19F NMR: (282 MHz, Chloroform-d) δ -105.1 (ddd, J = 11.4, 7.0, 4.9 Hz). IR (cm-1): 3103, 3046, 1805, 1777, 1731, 1610, 1490, 1455, 1374, 1226, 1190, 1140, 1023, 1002. Compound 4.7h Compound spectral data is in agreement with previously reported data.219 Following the general procedure using 4-methoxybenzoic acid and N-hydroxyphthalimide, (4.7h) was obtained as a white solid (246 mg, 88% yield). The reaction was stirred for 2 h after the addition of the nucleophile. 1H NMR: (300 MHz, Chloroform-d) δ 8.15 (d, J = 8.9 Hz, 2H), 7.92 (dd, J = 5.5, 3.1 Hz, 2H), 7.80 (dd, J = 5.5, 3.1 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 3.91 (s, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 165.0, 162.6, 162.4, 134.9, 133.1, 129.2, 124.1, 117.4, 114.4, 55.8. 177 Compound 4.7i Compound spectral data is in agreement with previously reported data.219 Following the general procedure using 4-nitrobenzoic acid and N-hydroxyphthalimide, (4.7i) was obtained as a white solid (225 mg, 72% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.39 (s, 4H), 7.95 (dd, J = 5.5, 3.1 Hz, 2H), 7.89 – 7.81 (m, 2H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 161.8, 161.4, 151.7, 135.2, 132.0, 130.9, 129.0, 124.4, 124.1. IR (cm-1): 3110, 1805, 1779, 1737, 1524, 1345, 1231, 1187, 1029, 1005. Compound 4.7j Compound spectral data is in agreement with previously reported data.220 Following the general procedure using 4-methylbenzoic acid and N-hydroxyphthalimide, (4.7j) was obtained as a white solid (260 mg, 93% yield). The reaction was stirred for 2 h after the addition of the nucleophile. 1H NMR: (300 MHz, Chloroform-d) δ 8.13 – 8.04 (m, 2H), 7.93 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 2.46 (s, 3H). 178 13C{1H} NMR: (75 MHz, Chloroform-d) δ 163.0, 162.3, 146.2, 134.9, 130.8, 129.7, 129.2, 124.1, 122.6, 22.1. IR (cm-1): 3034, 1757, 1736, 1607, 1463, 1350, 1251, 1180, 1119, 1026, 999. Compound 4.7k Compound spectral data is in agreement with previously reported data.44,221 Following the general procedure using 3-phenylpropionic acid and N-hydroxyphthalimide, (4.7k) was obtained as a white solid (287 mg, 97% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.90 (dd, J = 5.5, 3.1 Hz, 2H), 7.79 (dd, J = 5.5, 3.1 Hz, 2H), 7.39 – 7.30 (m, 2H), 7.26 (dd, J = 7.6, 1.1 Hz, 3H), 3.11 (ddd, J = 8.9, 7.0, 1.9 Hz, 2H), 2.99 (ddd, J = 8.7, 7.1, 1.9 Hz, 2H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 169.0, 162.0, 139.3, 134.9, 129.1, 128.9, 128.5, 126.9, 124.1, 32.9, 30.7. IR (cm-1): 2927, 1816, 1786, 1735, 1372, 1349, 1185, 1062. Compound 4.7l Compound spectral data is in agreement with previously reported data.44 Following the general procedure using 3,3-diphenylpropionic acid and N-hydroxyphthalimide, (4.7l) was obtained as a white solid (373 mg, 99% yield). 179 1H NMR: (300 MHz, Chloroform-d) δ 7.85 (dd, J = 5.5, 3.1 Hz, 2H), 7.76 (dd, J = 5.5, 3.1 Hz, 2H), 7.40 – 7.18 (m, 10H), 4.66 (t, J = 7.9 Hz, 1H), 3.42 (d, J = 7.9 Hz, 2H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 168.0, 161.8, 142.5, 134.8, 129.0, 128.9, 127.8, 127.1, 124.1, 46.8, 37.6. IR (cm-1): 1784, 1735, 1358, 1074, 964, 875, 749, 701. Compound 4.7m Compound spectral data is in agreement with previously reported data.222 Following the general procedure using trans-cinnamic acid and N-hydroxyphthalimide, (4.7m) was obtained as a white solid (288 mg, 98% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.97 (d, J = 16.0 Hz, 1H), 7.92 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.65 – 7.56 (m, 2H), 7.50 – 7.40 (m, 3H), 6.67 (d, J = 16.1 Hz, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 163.2, 162.2, 150.1, 134.9, 133.7, 131.7, 129.3, 129.2, 128.8, 124.2, 111.9. IR (cm-1): 1798, 1773, 1741, 1630, 1361, 1179, 1134, 1081. 180 Compound 4.7n Compound spectral data is in agreement with previously reported data.223 Following the general procedure using pivalic acid and N-hydroxyphthalimide, (4.7n) was obtained as a white solid (207 mg, 84% yield). The reaction was stirred for 2 h prior to the addition of the nucleophile. 1H NMR: (300 MHz, Chloroform-d) δ 7.92 – 7.83 (m, 2H), 7.82 – 7.73 (m, 2H), 1.43 (s, 9H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 174.5, 162.2, 134.8, 129.2, 124.0, 38.5, 27.2. IR (cm-1): 3099, 2987, 1784, 1740, 1708, 1463, 1370, 1185, 1175, 1132, 1060, 1022, 1012. Compound 4.7o Compound spectral data is in agreement with previously reported data.224 Following the general procedure using 1-adamantanecarboxylic acid and N-hydroxyphthalimide, (4.7o) was obtained as a white solid (320 mg, 98% yield). The reaction was stirred for 2 h after the addition of the nucleophile. 1H NMR: (300 MHz, Chloroform-d) δ 7.88 (dd, J = 5.5, 3.1 Hz, 2H), 7.77 (dd, J = 5.5, 3.1 Hz, 2H), 2.18 – 2.06 (m, 9H), 1.81 – 1.75 (m, 6H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 173.4, 162.3, 134.8, 129.3, 124.0, 40.7, 38.6, 36.4, 27.8. 181 IR (cm-1): 2927, 2911, 2852, 1805, 1774, 1746, 1466, 1450, 1362, 1348, 1184, 1170, 1128, 1008. Compound 4.8e Compound spectral data is in agreement with previously reported data.194 Following the general procedure using 3-fluorobenzoic acid and N-hydroxysuccinimide, (4.8e) was obtained as a white solid (213 mg, 90% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.95 (dt, J = 7.8, 1.3 Hz, 1H), 7.87 – 7.78 (m, 1H), 7.51 (td, J = 8.0, 5.4 Hz, 1H), 7.46 – 7.33 (m, 1H), 2.92 (s, 4H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 169.1, 164.3, 161.0 (d, J = 5.0 Hz), 130.8 (d, J = 7.8 Hz), 127.3 (d, J = 7.9 Hz), 126.6 (d, J = 3.2 Hz), 122.3 (d, J = 21.1 Hz), 117.6 (d, J = 23.7 Hz), 25.8. 19F NMR: (282 MHz, Chloroform-d) δ -110.8 (td, J = 8.5, 5.5 Hz). IR (cm-1): 3078, 2924, 1797, 1775, 1731, 1591, 1448, 1421, 1263, 1205, 1174, 1072. Compound 4.8f Compound spectral data is in agreement with previously reported data.220 Following the general procedure using 4-fluorobenzoic acid and N-hydroxysuccinimide, (4.8f) was obtained as a white solid (221 mg, 94% yield). 182 1H NMR: (300 MHz, Chloroform-d) δ 8.17 (dd, J = 8.9, 5.3 Hz, 2H), 7.20 (t, J = 8.6 Hz, 2H), 2.91 (s, 4H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 169.3, 167.0 (d, J = 257.8 Hz), 161.1, 133.5 (d, J = 9.8 Hz), 121.5 (d, J = 3.1 Hz), 116.5 (d, J = 22.4 Hz), 25.8. 19F NMR: (282 MHz, Chloroform-d) δ -101.6 (tt, J = 8.3, 5.3 Hz). IR (cm-1): 2989, 1792, 1771, 1723, 1603, 1508, 1378, 1236, 1210, 1160, 1074, 1000. Compound 4.8g Compound spectral data is in agreement with previously reported data.194,220 Following the general procedure using 2-fluorobenzoic acid and N-hydroxysuccinimide, (4.8g) was obtained as a white solid (208 mg, 87% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.14 – 8.02 (m, 1H), 7.73 – 7.60 (m, 1H), 7.35 – 7.16 (m, 2H), 2.91 (s, 4H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 169.2, 162.7 (d, J = 264.2 Hz), 159.4 (d, J = 4.2 Hz), 136.9 (d, J = 9.3 Hz), 132.8, 124.6 (d, J = 3.9 Hz), 117.5 (d, J = 21.7 Hz), 113.9 (d, J = 9.9 Hz), 25.8. 19F NMR: (282 MHz, Chloroform-d) δ -105.2 (ddd, J = 11.3, 6.8, 4.6 Hz). IR (cm-1): 2954, 1802, 1759, 1728, 1612, 1489, 1457, 1366, 1283, 1226, 1198, 1065, 1007. 183 Compound 4.8h Compound spectral data is in agreement with previously reported data.219 Following the general procedure using 4-methoxybenzoic acid and N-hydroxysuccinimide, (4.8h) was obtained as a white solid (168 mg, 67% yield). The reaction was stirred for 2 h after the addition of the nucleophile. 1H NMR: (300 MHz, Chloroform-d) δ 8.09 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 3.89 (s, 4H), 2.90 (s, 4H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 169.6, 165.1, 161.6, 133.0, 117.3, 114.4, 55.8, 25.8. Compound 4.8i Compound spectral data is in agreement with previously reported data.225 Following the general procedure using 4-nitrobenzoic acid and N-hydroxysuccinimide, (4.8i) was obtained as a white solid (218 mg, 81% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.41 – 8.29 (m, 4H), 2.94 (s, 4H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 168.9, 160.5, 151.7, 131.9, 130.7, 124.1, 25.8. IR (cm-1): 3118, 2992, 2945, 1787, 1770, 1734, 1608, 1528, 1349, 1235, 1193, 1065, 1002. 184 Compound 4.8j Compound spectral data is in agreement with previously reported data.226 Following the general procedure using 4-methylbenzoic acid and N-hydroxysuccinimide, (4.8j) was obtained as a white solid (212 mg, 93% yield). The reaction was stirred for 2 h after the addition of the nucleophile. 1H NMR: (300 MHz, Chloroform-d) δ 8.06 – 7.99 (m, 2H), 7.30 (d, J = 8.1 Hz, 2H), 2.90 (s, 4H), 2.44 (s, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 169.5, 162.0, 146.2, 130.8, 129.7, 122.4, 25.8, 22.0. IR (cm-1): 2952, 1760, 1727, 1608, 1427, 1259, 1239, 1195, 1181, 1066. Compound 4.8k Compound spectral data is in agreement with previously reported data.44,227 Following the general procedure using 3-phenylpropionic acid and N-hydroxysuccinimide, (4.8k) was obtained as a white solid (238 mg, 95% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.40 – 7.28 (m, 2H), 7.31 – 7.19 (m, 3H), 3.14 – 3.01 (m, 2H), 3.00 – 2.88 (m, 2H), 2.85 (s, 4H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 169.2, 168.1, 139.2, 128.8, 128.4, 126.8, 32.8, 30.6, 25.7. IR (cm-1): 2947, 1808, 1778, 1737, 1418,m 1377, 1204, 1076, 1064, 1046. 185 Compound 4.8l Compound spectral data is in agreement with previously reported data.44 Following the general procedure using 3,3-diphenylpropionic acid and N-hydroxysuccinimide, (4.8l) was obtained as a white solid (316 mg, 98% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.38 – 7.17 (m, 10H), 4.61 (t, J = 7.9 Hz, 1H), 3.36 (d, J = 7.9 Hz, 2H), 2.76 (s, 4H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 169.0, 167.1, 142.4, 128.9, 127.7, 127.1, 46.7, 37.5, 25.6. IR (cm-1): 2923, 1815, 1783, 1733, 1495, 1366, 1200, 1062. Compound 4.8m Compound spectral data is in agreement with previously reported data.228 Following the general procedure using trans-cinnamic acid and N-hydroxysuccinimide, (4.8m) was obtained as a white solid (232 mg, 94% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.93 (d, J = 16.1 Hz, 1H), 7.62 – 7.53 (m, 2H), 7.50 – 7.36 (m, 3H), 6.59 (d, J = 16.1 Hz, 1H), 2.88 (s, 4H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 169.3, 162.0, 150.1, 133.5, 131.6, 129.1, 128.7, 111.6, 25.7. IR (cm-1): 2944, 1755, 1725, 1626, 1368, 1268, 1205, 1184, 1070, 1048, 989. 186 Compound 4.8n Compound spectral data is in agreement with previously reported data.229 Following the general procedure using pivalic acid and N-hydroxysuccinimide, (4.8n) was obtained as a white solid (127 mg, 64% yield). The reaction was stirred for 2 h prior to the addition of the nucleophile. 1H NMR: (300 MHz, Chloroform-d) δ 2.82 (d, J = 1.8 Hz, 4H), 1.38 (s, 9H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 173.6, 169.3, 38.5, 27.1, 25.8. IR (cm-1): 2977, 1174, 1730, 1480, 1366, 1206, 1063, 1030, 997. Compound 4.8o Compound spectral data is in agreement with previously reported data.198 Following the general procedure using 1-adamantanecarboxylic acid and N-hydroxysuccinimide, (4.8o) was obtained as a white solid (259 mg, 93% yield). The reaction was stirred for 2 h after the addition of the nucleophile. 1H NMR: (300 MHz, Chloroform-d) δ 2.81 (d, J = 1.7 Hz, 4H), 2.07 (s, 9H), 1.75 (d, J = 2.4 Hz, 6H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 172.4, 169.4, 40.6, 38.5, 36.3, 27.7, 25.8. IR (cm-1): 2936, 2904, 2855, 1799, 1777, 1738, 1451, 1426, 1356, 1197, 1169, 1062, 1046, 1004. 187 Compound 4.15a Compound spectral data is in agreement with previously reported data.44 Following the general procedure using 3,3-diphenylpropionic acid and the Weinreb amine hydrochloride salt, (4.15a) was obtained as a clear, colourless oil (269 mg, 99% yield). Following a modified version of the general procedure using 3,3-diphenylpropionic acid and the Weinreb amine hydrochloride salt, (4.28) was obtained as a clear, colourless oil (258 mg, 95% yield). In this modified procedure, only 1 equivalent of pyridine was added in the first step of the reaction to form 3,3-diphenylpropanoyl fluoride. During the subsequent addition of the Weinreb amine hydrochloride salt, 2 equivalents of K2CO3 were added to replace the 2 equivalents of pyridine that would normally have been added under the unmodified general procedure. All other aspects of the procedure, including workup, were unchanged. 1H NMR: (300 MHz, Chloroform-d) δ 7.32 (d, J = 4.3 Hz, 8H), 7.22 (ddd, J = 8.6, 5.1, 3.8 Hz, 2H), 4.75 (t, J = 7.7 Hz, 1H), 3.59 (d, J = 0.8 Hz, 3H), 3.24 (d, J = 7.7 Hz, 2H), 3.14 (s, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 172.4, 144.2, 128.5, 127.9, 126.4, 61.3, 46.4, 37.9, 32.2. 188 Compound 4.15b Compound spectral data is in agreement with previously reported data.230 Following the general procedure using 3-fluorobenzoic acid and the Weinreb amine hydrochloride salt, (4.15b) was obtained as a clear, colourless oil (146.1 mg, 80% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.43 (dt, J = 7.7, 1.3 Hz, 1H), 7.34 (ddt, J = 10.1, 7.8, 3.8 Hz, 2H), 7.11 (tdd, J = 8.3, 2.7, 1.1 Hz, 1H), 3.51 (s, 3H), 3.31 (s, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 168.4 (d, J = 2.5 Hz), 162.1 (d, J = 246.6 Hz), 136.1 (d, J = 7.2 Hz), 129.7 (d, J = 7.9 Hz), 124.0 (d, J = 3.2 Hz), 117.6 (d, J = 21.1 Hz), 115.4 (d, J = 23.3 Hz), 61.2, 33.6. 19F NMR: (282 MHz, Chloroform-d) δ -112.8 (q, J = 8.3 Hz). Compound 4.16a Compound spectral data is in agreement with previously reported data.231 Following the general procedure using 3,3-diphenylpropionic acid and morpholine, (4.16a) was obtained as a white solid (274 mg, 93% yield). The second step of the reaction was carried out at 40 °C. 1H NMR: δ 7.33 – 7.12 (m, 10H), 4.65 (t, J = 7.6 Hz, 1H), 3.52 (s, 4H), 3.30 (s, 4H), 3.03 (d, J = 7.6 Hz, 2H). 189 13C{1H} NMR: (75 MHz, Chloroform-d) δ 170.1, 144.1, 128.7, 128.0, 126.7, 66.9, 66.5, 47.6, 46.4, 42.2, 38.7. Compound 4.16b Compound spectral data is in agreement with previously reported data.232 Following the general procedure using 3-fluorobenzoic acid and morpholine, (4.16b) was obtained as a clear, colourless oil (196 mg, 94% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.36 (ddd, J = 9.1, 7.6, 5.4 Hz, 1H), 7.19 – 7.02 (m, 3H), 3.67 (br s, 6H), 3.41 (br s, 2H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 168.9 (d, J = 2.5 Hz), 162.5 (d, J = 248.3 Hz), 137.4 (d, J = 6.9 Hz), 130.4 (d, J = 8.0 Hz), 122.7 (d, J = 3.2 Hz), 116.9 (d, J = 21.2 Hz), 114.4 (d, J = 22.9 Hz), 66.8, 48.1, 42.6. 19F NMR: (282 MHz, Chloroform-d) δ -111.5 (td, J = 8.7, 5.5 Hz). 190 Chapter 5: Thionyl Fluoride-Mediated One-Pot Conversions of S(IV)-Sulfinic Acids to S(VI)-Sulfonimidoyl Fluorides 5.1 Sulfonimidoyl fluorides: applications, properties, and existing synthetic approaches 5.1.1 Properties of sulfonimidoyl fluorides Sulfonimidoyl fluorides (5.1) are a sulfur(VI) motif with synthetically advantageous and unique properties. Unlike the corresponding sulfonimidoyl chlorides (5.2), 5.1 are a bench-stable class of compounds that are resistant to hydrolysis,7 and display enhanced thermodynamic and redox stability.233 Figure 5.1. The chemical structures of sulfonimidoyl fluorides and chlorides, as well as other sulfur(IV) and sulfur(VI) compounds. In the presence of strong carbon nucleophiles (i.e. organolithium or organomagnesium reagents), sulfonimidoyl fluorides react only at sulfur to yield the corresponding sulfoximine (5.3), whereas sulfonimidoyl chlorides are prone to undergoing reductive attack at the halide to yield the corresponding sulfinamide (5.4, Scheme 5.1a).7,234–236 The reason for this reactivity difference is the greater polarizability of the chlorine centre towards sulfur in 5.2 compared to the fluorine towards sulfur in 5.1; chlorine is more electropositive than fluorine as a result of this polarizability difference and by electronegativity arguments. The reactivity differences between sulfonimidoyl fluorides and chlorides in the presence of strong carbon nucleophiles mirrors that observed for 191 sulfonyl fluorides (5.5) and chlorides (5.6), yielding the corresponding sulfones (5.7) or sulfinate salts (5.8), respectively (Scheme 5.1b).237,238 Sulfonyl fluorides are known to undergo both addition-elimination as well as direct substitution mechanisms by a number of nucleophiles;6 a similar mode of reactivity can be claimed for sulfonimidoyl fluorides (Scheme 5.2). Scheme 5.1. (a) Reactivity differences between sulfonimidoyl fluorides and chlorides with strong carbon nucleophiles,234,235 and (b) their similarities to the reactivity of sulfonyl fluorides and chlorides.237 Scheme 5.2. The two commonly accepted mechanisms of nucleophilic attack on an electrophilic sulfur centre.6 192 Sulfonimidoyl fluorides (5.1) react similarly to sulfonyl fluorides (5.5) and can be used in similar biological applications. For example, 5.1 can be utilized as electrophilic targeted covalent binding partners—or electrophilic “warheads”—and have been studied as tyrosine-selective covalent probes.239 It was reported that the sulfonimidoyl fluoride derivatives that displayed greater reactivity towards N-acetyl tyrosine were also more hydrolytically stable than the analogous sulfonyl fluorides, indicating that motifs like 5.1 may be superior warheads compared to 5.5.240 Much of the greater binding affinity of 5.1 over 5.5 can be attributed to the nitrogen substituent in the former. Sulfonimidoyl fluorides may possess greater chemical versatility and binding potential at the sulfur centre than sulfonyl fluorides on account of the diverse electronic and steric characteristics imparted by the nitrogen substituent (e.g. N-acyl, N-alkyl, N-aryl).239 For example, electron-withdrawing substituents on nitrogen (i.e. N-acyl or N-sulfonyl) will increase the electrophilicity of the sulfur centre and promote SuFEx chemistry on a similar order to sulfonyl fluorides, whereas electron-donating groups (i.e. N-alkyl or N-aryl) decrease the electrophilicity of sulfur; this reduction in electrophilicity confers greater bench stability and resistance to hydrolysis under basic conditions in the latter group.7 The differences in hydrolytic stability of sulfonimidoyl halides were investigated by Jeanguenat et al. in 2012 with 5.2b and 5.1b (Scheme 5.3a).241 It was found that sulfonimidoyl chloride 5.2b hydrolyzed slowly to the corresponding sulfonamide (5.9) over several hours in deuterated chloroform or THF, but that instantaneous hydrolysis was achieved upon addition of water. The addition of Et3N to 5.2b resulted in near-instantaneous decomposition, and the addition of pyridine also led to degradation, albeit over the course of several days. Conversely, sulfonimidoyl fluoride 5.1b suffered no such hydrolysis whether in the presence of excess D2O or 193 Et3N over the course of 24 hours at room temperature or two hours at reflux (Scheme 5.3b). Decomposition was only observed after 24 hours at room temperature in the presence of DBU. Scheme 5.3. Investigations into the hydrolytic stability of sulfonimidoyl fluorides and chlorides under neutral and basic conditions by Jeanguenat et al.241 Sulfonimidoyl fluorides are geometrically tetrahedral at the sulfur centre and undergo configurational inversion processes with nucleophiles. Unlike the chlorinated analogues, sulfonimidoyl fluorides are configurationally stable and not prone to racemization of the sp3-hybrizided sulfur centre.234,242,243 This stability has been exploited in the stereospecific synthesis of other sulfur(VI) motifs, including sulfoximines (vide infra).244 5.1.2 Applications of sulfonimidoyl fluorides For the reasons described previously (vide supra), sulfonimidoyl fluorides are utilized as stable alternatives to sulfonimidoyl chlorides, and as mono-aza analogues of sulfonyl fluorides in organic syntheses. Synthetically, sulfonimidoyl fluorides are primarily used for the generation of other high-value sulfur(VI) compounds through SuFEx processes, including sulfonamides, sulfonimidamides, sulfoximines, and sulfonimidate esters. 194 Liu et al. described the syntheses of sulfonimidamides (5.10) and 18O-labelled primary sulfonamides (5.11) from the corresponding N-trityl sulfonimidoyl fluorides (5.12, Scheme 5.4a).233 Strongly acidic conditions (HBF4·Et2O) were necessary to facilitate hydrolysis of the sulfur–fluorine bond in 5.12, and it was hypothesized that the steric hinderance of the N-trityl moiety helped to further stabilize the sulfonimidoyl fluorides used in this report. Similarly, Bull et al. utilized stereochemically pure sulfonimidoyl fluorides (5.13)—sourced from the corresponding sulfinamide salts—for the stereospecific synthesis of enantiopure sulfonimidamides (5.14, Scheme 5.4b).245 Scheme 5.4. Representative examples of the application of sulfonimidoyl fluorides to the synthesis of (a) sulfonimidamides and 18O-labelled sulfonamides233 and (b) stereochemically pure sulfonimidamides.245 Sulfoximines (5.3) are rapidly gaining popularity in medicinal chemistry and the pharmaceutical industry, and are currently being incorporated in drug candidates at the drug-discovery and clinical trials stages of the drug development process.246 Therefore, facile methods for the synthesis of sulfoximines and fluorinated sulfoximines247 are also growing in significance. In 2011, Bolm et al. utilized sulfonimidoyl fluorides (5.1) as part of their syntheses of trifluoromethyl-substituted sulfoximines (5.15, Scheme 5.5a).248 It was noted that the reaction conditions failed for the synthesis of sulfoximines from the corresponding sulfonimidoyl chloride. 195 In 2018, Sharpless et al. reported a protocol for the synthesis of sulfonimidoyl fluorides from SOF4. These sulfonimidoyl fluorides (5.1) were then treated with the appropriate nucleophile to form the corresponding, sulfoximine (5.3), sulfonimidate (5.16, also referred to as sulfonimidate esters), or sulfonimidamide (5.10, Scheme 5.5b).242 DBU was utilized for the syntheses of the sulfonimidamides and sulfonimidates as it is a known nucleophilic promotor in SuFEx chemistry.249 The breadth of reactions conducted by Sharpless et al. effectively demonstrated the synthetic utility of sulfonimidoyl fluorides in organic chemistry. In 2022, Bull et al. described the syntheses of stereochemically defined sulfoximines (5.17) with configurational inversion from the corresponding sulfonimidoyl fluoride (5.13) and Grignard reagent (Scheme 5.5c).244 Sulfoximines (5.18) have also been generated from the corresponding sulfonimidoyl fluoride (5.19) and alkene (5.20) in a Lewis acid-mediated hydrosulfonimidoylation, as described by Jiang et al. (Scheme 5.5d).250 The protocol was tolerant of a variety of primary and secondary alkene coupling partners, yet 1,1-disubstituted alkenes were disfavoured. In a similar protocol by the same authors, alkynyl (5.21) or vinyl sulfoximines (5.22) were produced from the corresponding sulfonimidoyl fluoride (5.1) and alkyne (5.23, Scheme 5.5e).251 196 Scheme 5.5. Representative examples of the application of sulfonimidoyl fluorides to the synthesis of sulfoximines.242,244,248,250,251 Sulfonimidoyl fluorides have also been utilized in the synthesis of sulfonimidate esters. For example, Zuilhof et al. treated 5.1c with phenolic derivatives (5.24) and DBU to produce the corresponding sulfonimidate ester (5.25) through either a concerted SN2 or an addition-elimination mechanism (Scheme 5.6a).252 The reaction conditions were mild, generally producing the 197 sulfonimidate ester product in less than 30 minutes at room temperature. It was observed that 5.1c was resistant to racemization in the presence of phenolic nucleophiles (5.24) except when treated with DBU; this issue was circumvented through the use of sodium phenoxide nucleophiles, enabling the stereospecific generation of 5.25 where desired. Zuilhof et al. further described the treatment of chiral disulfonimidoyl fluorides (5.26) with aryl alcohol coupling partners (5.27) in SuFEx polymerization processes for the synthesis of both racemic and configurationally stable chiral polysulfonimidates (5.28) in 2022 (Scheme 5.6b).253 Scheme 5.6. Representative examples of the application of sulfonimidoyl fluorides to the synthesis of (a) sulfonimidate esters252 and (b) polysulfonimidates.253 In addition to their roles as electrophiles for SuFEx chemistry, sulfonimidoyl fluorides have also been used as fluoride sources in deoxyfluorination reactions. One such example comes from Hu et al., who utilized SulfoxFluor (5.1d) for the deoxyfluorination of alcohols (5.29), affording the corresponding alkyl fluorides (5.30, Scheme 5.7a).254,255 The protocol was effectively applied to an array of primary and secondary alcohols, leaving tertiary alcohols unaffected. It was proposed that the reaction proceed via a sulfonimidate ester, which would then undergo attack by fluoride 198 to afford the fluoroalkane product. A major point of this work was the author’s synthetic route to SulfoxFluor (5.1d), which they later optimized further to enable a more scalable synthesis of 5.1d.256 Hu et al. also utilized SulfoxFluor for the one-pot deoxyazidation of alcohols, yielding the corresponding organic azide (5.31, Scheme 5.7b).257 Scheme 5.7. Representative examples of the application of SulfoxFluor to the (a) deoxyfluorination254,255 and (b) deoxyazidation of alcohols.257 5.1.3 Existing synthetic approaches to the synthesis of sulfonimidoyl fluorides The first syntheses of sulfonimidoyl fluorides were reported by Johnson et al. in 1983; they were generated from either the corresponding sulfonimidoyl chloride (5.2) via direct halogen exchange using NaF, or from the corresponding sulfinamide (5.4) via a two-step oxidative chlorination-halogen exchange protocol with tert-butyl hypochlorite and KF or TBAF (Scheme 5.8).235 The protocols proved effective for the synthesis of 5.1, yet the strongly oxidizing conditions with tert-butyl hypochlorite limited the scope of sulfonimidoyl chlorides and sulfinamides to only phenyl or 1-napthyl substituents (R1). Additionally, each of these methods proceeded via an isolated sulfonimidoyl chloride, which are known to not be bench stable in the presence of water (vide supra) and must be synthesized on-demand. Successful halogen exchange has been reported with a variety of fluoride sources, including NaF, KF, TBAF, SbF3, and AgF.247 199 Scheme 5.8. The first synthesis of sulfonimidoyl fluorides via halogen exchange of sulfonimidoyl chlorides by Johnson et al.235 The generation of sulfonimidoyl fluorides traditionally requires two-to-four synthetic steps, with product isolation usually required after each step. Additionally, many routes are lengthened through the use of starting materials that require one or more steps to access. Many of the early routes to sulfonimidoyl fluorides proceeded via a halogen exchange of the corresponding isolated sulfonimidoyl chloride; this inherently limits the applications of these protocols as sulfonimidoyl chlorides are not bench-stable intermediates and will readily hydrolyze under neutral and basic conditions. Due to their instability, the sulfonimidoyl chlorides must be synthesized on-demand, contributing to the lengthy synthetic process. For example, Bolm et al. synthesized sulfonimidoyl fluorides as part of their route to trifluoromethyl-substituted sulfoximines in 2010 through the following two previously reported routes (Scheme 5.9): (a) conversion of thiols (5.32), disulfides, or sulfinic acids to the corresponding sulfinyl chloride (5.33), followed by oxidative addition with a nitrene source to the sulfonimidoyl chloride (5.34), and then halogen exchange to the target sulfonimidoyl fluoride (5.35), or (b) oxidative chlorination of sulfinamides (5.4) to the sulfonimidoyl chloride (5.34), followed by halogen exchange to yield 5.35.248 200 Scheme 5.9. Traditional approaches to the synthesis of sulfonimidoyl fluorides and their utility towards the synthesis of trifluoromethyl sulfonimidamides.235,248,258–260 These lengthy procedures have been largely supplanted by more modern advancements, most of which were developed within the last decade. For example, Oehlrich et al. developed a one-pot transformation of trifluoromethyl-sulfinamides (5.36) to the corresponding trifluoromethyl-sulfonimidamides (5.37, Scheme 5.9c).260 The protocol proceeded via a sulfonimidoyl fluoride (5.38) intermediate formed in situ from oxidative addition with N-chlorosuccinimide (NCS) and halogen exchange with TBAF. This route further demonstrated the synthetic advantage of sulfonimidoyl fluorides over sulfonimidoyl chlorides, the latter of which were unsuccessfully investigated in a similar application by Bolm et al.248 In 2018, Sharpless et al. described the application of SOF4 (5.39) to the synthesis of sulfonimidoyl fluorides (5.1) via iminosulfur oxydifluorides (5.40) and organolithium reagents (Scheme 5.10a).242 The protocol was applied to the synthesis of a wide array of sulfonimidoyl fluorides, which could then be treated with a variety of nucleophiles to afford other sulfur(VI) compounds (vide supra). However, the use of strongly basic and nucleophilic organolithium reagents inherently limits the substrate scope of this reaction. Furthermore, the synthesis of SOF4 201 is challenging and requires specialized laboratory equipment with corrosion-resistant components.261 In 2020, Cornella and Wang devised a route to sulfonimidoyl fluorides (5.41) from the corresponding aryl or heteroaryl sulfinyl trifluoride (5.42, Scheme 5.10b).262 The protocol successfully generated the sulfonimidoyl fluorides in good yield. However, the route required three steps and proceeded via a sulfenyl phthalimide (5.43) that itself required two separate steps to generate. The synthetic versatility offered by 5.43 to further access motifs including sulfonyl fluorides, tetrafluorosulfanyl chlorides, and the sulfinyl trifluorides is an attractive feature of this approach, yet such versatility comes at the expense of a significantly increased step-count. Liu et al. described a one-pot copper-mediated reaction of N-protected sulfinylamines (5.44) and aryl diazonium tetrafluoroborate salts (5.45) in 2021 (Scheme 5.10c).233 This robust protocol benefited from mild reaction conditions and was tolerant of a variety of functional groups, and the diazonium salt substrates were easily produced from the corresponding commercially available arylamine. Scheme 5.10. The synthesis of sulfonimidoyl fluorides using (a) SOF4,242 (b) ArSOF3,262 and (c) N-protected sulfinylamines.233 In 2022, Bolm et al. developed a one-pot acid-mediated imidazole-to-fluoride exchange protocol, utilizing sulfur(VI) imidazoles (5.46) and KHF2.263 The reaction was primarily optimized 202 for the synthesis of sulfonyl fluorides, although three sulfonimidoyl fluorides were also reported (Scheme 5.11). The substrates for this protocol were synthesized from the corresponding sulfonimidoyl chloride. Scheme 5.11. Synthesis of sulfonimidoyl fluorides through SuFEx of sulfur(VI) imidazoles.263 As described previously (vide supra) Hu et al. developed an efficient alcohol deoxyfluorination protocol using SulfoxFluor (5.1d) in 2019.254,255 Their synthesis of 5.1d required four distinct synthetic steps (Scheme 5.12), proceeding by way of: (1) reduction of sulfonyl chloride 5.6d to sulfinate salt 5.8d with Na2SO3 and NaHCO3, (2) chlorination of 5.8d with SOCl2 to afford sulfinyl chloride 5.33d, (3) oxidative addition of 5.33d with chloramine T (5.47) to produce sulfonimidoyl chloride 5.2d, and (4) halogen exchange of 5.2d with KF and 18crown-6 to yield 5.1d, according to the 2011 protocol by Bolm et al.248 The protocol suffered from a lengthy synthetic route to 5.1d, yet was nonetheless effectively applied to the synthesis of 5.1d on multi-gram scale (~30 g, 50% overall). The protocol was improved further for the synthesis of 5.1d on >150 g scale (67% overall).256 203 Scheme 5.12. Original synthesis of SulfoxFluor by Hu et al.254,255 Electrophilic fluorine sources have been utilized in the syntheses of sulfonimidoyl fluorides as well. Shermolovich et al. described the transformation of three cyclic sulfinamides (5.48) to the corresponding sulfonimidoyl fluorides (5.49) using SelectfluorTM in 2014 (Scheme 5.13a).264 A more comprehensive scope was explored in 2020 by Bull et al., who reported a SelectfluorTM-mediated protocol that converted enantiomerically pure sodium sulfinamide salts (5.50) to the corresponding enantioenriched sulfonimidoyl fluoride (5.13, Scheme 5.13b).245 As SelectfluorTM is an electrophilic fluorine source, there was no free fluoride present in solution to racemize any sulfonimidoyl fluorides produced in situ. However, this protocol suffered from a lengthy synthetic route, with three synthetic steps required to convert a sulfinamide into the corresponding sulfonimidoyl fluoride. As part of their route to chiral polysulfonimidates in 2022 (vide supra), Zuilhof et al. described the synthesis of chiral disulfonimidoyl fluorides (5.26) from the corresponding chiral disulfinamides (5.51) and SelectfluorTM (Scheme 5.13c).253 The protocol was 204 conducted under Bolm’s conditions and five chiral disulfonimidoyl fluorides were synthesized in good yield with excellent diastereoselectivity. Scheme 5.13. Representative syntheses of sulfonimidoyl fluorides with an electrophilic fluorine source.245,253,264 There are few published routes for the synthesis of sulfonimidoyl fluorides, and even recently developed methods are hampered by lengthy synthetic protocols or limited substrate scopes. I sought to address some of these issues by using SOF2 in a new approach to the synthesis of sulfonimidoyl fluorides. Investigations of the synthetic applicability of SOF2 thus far were primarily limited to carboxylic acid activation (Chapter 4), as well as a scattered handful of other processes reported in the late 20th century. An expedited synthesis of sulfonimidoyl fluorides mediated by SOF2 would serve as the first in-depth analysis of the sulfur(IV) gas in an application unrelated to carboxylic acid activation. My primary goals for this project were: (1) utilize SOF2 or an SOF2-sourced derivative for an overall one-pot reaction to synthesize sulfonimidoyl fluorides 205 from readily accessible starting materials, (2) optimize the one-pot coupling protocol, and (3) explore the substrate scope of the reaction. Future goals for this project are outlined in Chapter 6. 5.2 Results and discussion 5.2.1 Summary of approaches taken towards the synthesis of sulfonimidoyl fluorides Several approaches were investigated to rapidly synthesize sulfonimidoyl fluorides from accessible starting materials during the course of this project. Initially, attempts were made to synthesize N-methylimidazolium sulfonimidoyl fluoride-like precursors (5.52), which could hypothetically be converted to the desired sulfonimidoyl fluoride (5.1) with an appropriate nucleophile (Scheme 5.14a). Alternative routes through iminosulfur oxydifluoride intermediates (5.40, Scheme 5.14b) or a carboxybenzyl-protected activated sulfonimidamide derivative (5.53, Scheme 5.14c) were also pursued, both of which would proceed via nucleophilic substitution processes as well. Finally, a one-pot conversion of sulfinyl fluoride intermediates (5.54) to the corresponding sulfonimidoyl fluoride (5.1) was envisioned as an expedited route to the lab-scale synthesis of the target motif (Scheme 5.14d). This process would proceed via oxidative addition of a suitable nitrene or nitrene surrogate to the sulfur(IV) centre, and ultimately proved to be the most successful of the four approaches. The investigations of all four of these methods and the associated conclusions are presented herein. 206 Scheme 5.14. Proposed thematic approaches to the synthesis of sulfonimidoyl fluorides via nucleophilic substitution and oxidative addition processes. 5.2.2 Initial approaches to the synthesis of sulfonimidoyl fluoride: N-methylimidazolium sulfinyl fluoride hexafluorophosphate (MISF) Initial attempts to synthesize sulfonimidoyl fluorides focused primarily upon the synthesis of a highly electrophilic sulfonimidamide reagent using N-methylimidazolium sulfinyl fluoride hexafluorophosphate (MISF, 5.55). MISF was originally synthesized from SOF2 and N-methylimidazole by Kathleen Downey, a former undergraduate student in the Sammis group.265 It was hypothesized that sulfur(IV) MISF could potentially undergo an oxidative addition process with an appropriate nitrene source (i.e. chloramine T, 5.47) to yield the corresponding sulfur(VI) sulfonimidamide-type species (5.56, Scheme 5.15). With the imidazolium moiety present, the goal was to treat this intermediate in situ with an appropriate carbon nucleophile (Nu– or NuH) for the expedited synthesis of sulfonimidoyl fluorides (5.57). It was envisioned that this modular approach would benefit from a reduced step-count and the ability to install a variety of diverse nucleophiles in place of the imidazolium group. Anticipated challenges with this approach included: (1) potential rapid degradation of 5.56, and (2) selectivity issues for the imidazolium group in favour of the fluoride during the subsequent substitution with the carbon nucleophile. 207 Scheme 5.15. Envisioned approach for the rapid synthesis of sulfonimidoyl fluorides from MISF, by way of a sulfur(VI) sulfonimidamide-type intermediate (5.56). The reaction of MISF (5.55) with chloramine T (5.47) to produce 5.56 was attempted according to the conditions presented in Table 5.1 in a series of parallel experiments. In treating chloramine T with 1.0 equivalent of MISF in THF, a signal was observed at 100.1 ppm by quantitative 19F NMR spectroscopy (entry 1). Based upon comparisons to known sulfonimidoyl fluoride chemical shifts, it was presumed that this signal may have reflected the formation of 5.56 in 15% 19F NMR spectroscopic yield. Increasing the quantity of MISF relative to chloramine T to 2.0 equivalents led to a notable decrease in the observed 19F NMR spectroscopic yield of 5.56 (3%, entry 2). Further increasing the ratio of MISF to chloramine T resulted in no observable signals close to 100 ppm in the 19F NMR spectra (entries 3–5). This suggested that an excess of MISF relative to chloramine T may inhibit this reaction. In an attempt to rule out poor solubility of 5.56 in the reaction solvent, an experiment was performed using MeCN in lieu of THF (entry 6). The use of MeCN appeared to completely prevent the desired reaction, with no 5.56 detected by 19F NMR spectroscopy; this indicated that THF was better suited for the reaction than MeCN. 208 Table 5.1. Initial attempts to synthesize 5.56 from MISF and chloramine T.a entry equivalents 5.47 solvent 19F NMR δ (ppm) 19F NMR yield of 5.56 (%) 1 1.0 THF 100.1 15 2 2.0 THF 100.1 3 3 3.0 THF N.D. — 4 4.0 THF N.D. — 5 5.0 THF N.D. — 6 1.0 MeCN N.D. — aReactions conditions: 5.55 in solvent (X equiv.), chloramine T (5.47, 0.1 mmol, 1 equiv.). 19F NMR spectroscopic yields determined with PhCF3 (10 μL) utilized as an internal standard. N.D. = not detected. Taking a new approach, it was hypothesized that 5.56 could potentially be synthesized by way of a one-pot substitution reaction of SOCl2 with N-methylimidazole to yield intermediate 5.58 (Table 5.2). Intermediate 5.58 could then undergo oxidative addition with chloramine T (5.47) to give the penultimate intermediate (5.59), followed by halogen exchange to afford 5.56. This approach would make use of the chlorinated analogue of MISF. In a first attempt at synthesizing 5.56, N-methylimidazole (5.60) was treated with SOCl2 and KPF6 (entry 1). The resultant sulfur(IV) species (5.58a, Y = Cl) was detected by 1H NMR spectroscopy and subsequently treated with 5.47 to afford a mixture of compounds; the 1H NMR spectroscopic data for the penultimate intermediate indicated that the sulfur(VI) species may have successfully formed, although the evidence was not conclusive. It was also noted that chloramine T did not appear to fully dissolve in the MeCN. An attempted halogen exchange with KF and 18-crown-6 failed, with no S–F signals 209 observed by 19F NMR spectroscopy. It was hypothesized that the addition of KPF6 may have inhibited some aspect of the reaction, and the protocol was subsequently repeated without an additive (entry 2). However, the reaction between chloramine T and the sulfur(IV) intermediate (5.58a, Y = Cl) failed, so no halogen exchange procedure was performed. Table 5.2. Initial attempts to synthesize 5.56 from SOCl2 and chloramine T.a entry solvent additive fluoride source 19F NMR δ (ppm) 19F NMR yield of 5.56 (%) 1 MeCN KPF6 (4 equiv.) KF (2 equiv.) N.D. — 2 MeCN none N.A. — — 3 DMF none N.A. — — 4 DMA none KF (2 equiv.)c N.D. — 5b DMA none TBAF (2 equiv.)d 64.7 5 6b THF none KF (5 equiv.)c 67.8 5 7b THF DIPEA (1 equiv.) KF (5 equiv.)c 67.8 4 aReactions conditions: 5.60 (4 equiv.), SOCl2 (4 equiv.), additive, solvent (4 mL), chloramine T (5.47, 1.0 mmol, 1 equiv.), fluoride source, 18-crown-6 (6 equiv.). 19F NMR spectroscopic yields determined with PhCF3 (100 μL) utilized as an internal standard. b5.60 (2 equiv.), SOCl2 (1 equiv.), additive, solvent (4 mL) chloramine T (5.47, 0.5 mmol, 1 equiv.), fluoride source. c18-crown-6 (0.2 equiv.) was used. dNo 18-crown-6 was used. N.D. = not detected; N.A. = not applicable (the second step of the reaction failed, and no halogen exchange was attempted). 210 The limited solubility of chloramine T in MeCN was thought to be the root cause of this failure, so the reaction was repeated using DMF (entry 3) and DMA (entry 4) as solvents. In DMF, the sulfur(IV) intermediate (5.58a, Y = Cl) failed to react with chloramine T. In DMA, the signal integrations from the 1H NMR spectrum suggested that 1,1'-sulfinylbis(3-methyl-1H-imidazol-3-ium) (5.58b, Y = N-methylimidazole) may have formed instead of 5.58a (Y = Cl) after the first step of the reaction. Given that the chloride was to be exchanged with fluoride anyway, it was worth exploring the possible reactivity of this unexpected species further. Treatment of what was presumed to be 5.58b with chloramine T (5.47) appeared to yield the desired sulfur(VI) intermediate (5.59b, Y = N-methylimidazole); however, treatment with KF again failed to produce any product, per 19F NMR spectroscopic analyses. The loading of 18-crown-6 was significantly reduced for this and future experiments to better align with similar literature protocols,248 and the ratio of 5.60 to SOCl2 was increased to favour formation of 5.58. Replacement of KF and 18-crown-6 with TBAF (1.0 M in THF) generated a compound that was observed at 64.7 ppm by 19F NMR spectroscopy, which may have been the desired product (5.56, 5%, entry 5); the compound detected at 100.1 ppm by the previous method (vide supra) was never successfully confirmed to be the product. Similarly, attempts to further identify this compound through NMR spectroscopy or mass spectrometry failed. Performing the reaction in THF and using KF and 18-crown-6 yielded a similar result, with a signal noted at 67.8 ppm (5%, entry 6). In a final attempt to generate and identify the compound in greater yield, the reaction was performed in THF with KF and 18-crown-6, and DIPEA was added to reduce the acidity of the system (entry 7). This had no effect on the outcome, with the same signal observed at 67.8 ppm (5%). 211 5.2.3 The attempted synthesis of sulfonimidoyl fluorides via an iminosulfur oxydifluoride intermediate It was hypothesized that SOF2—as another sulfur(IV) compound—could perhaps directly undergo oxidative addition by chloramine T (5.47) to yield a sulfur(VI) iminosulfur oxydifluoride (5.40a, Figure 5.2), similar in principle to the SOF4-mediated approach by Sharpless et al. in 2018.242 This intermediate could be isolated and then carried forward in a second step with an appropriate carbon nucleophile (5.62) to yield the sulfonimidoyl fluoride (5.57). Since SOF2 can be easily removed from solution by sparging with an inert gas, it was hypothesized that an overall one-pot protocol could be developed as well. Figure 5.2. Envisioned approach for the rapid synthesis of sulfonimidoyl fluorides directly from SOF2, by way of a sulfur(VI) iminosulfur oxydifluoride intermediate.242 The synthesis of tosylsulfurimidoyl difluoride (5.40a) with SOF4 was reported by Sharpless et al., with a characteristic 19F NMR spectroscopic chemical shift of 49.0 ppm in CDCl3.242 In treating chloramine T with 1.0 equivalent of SOF2, a compound formed which was instead detected at 99.8 ppm by 19F NMR spectroscopy (Table 5.3, entry 1, 36%). This compound was clearly not the desired oxydifluoride species, yet it was hypothesized that it could perhaps be the same compound (5.56) as had been detected previously with the reaction between MISF (5.55) and chloramine T (5.47, Table 5.3). As the 19F NMR spectroscopic yield of this species was significantly greater than what had been observed before, optimization was attempted to improve the yield further. The addition of 2.0 equivalents of SOF2 to 5.47 resulted in a slightly improved 212 yield of 44% (entry 2), whereas a third equivalent of SOF2 unexpectedly depressed the yield (23%, entry 3). Further increasing the loading of SOF2 to 4.0 (entry 4), 5.0 (entry 5), or 6.0 equivalents (entry 6) failed to increase the yield of the fluorinated species beyond 31%. It appeared that 2.0 equivalents of SOF2 yielded the greatest amount of fluorinated product; however, attempts to isolate and/or identify this species through NMR spectroscopy or mass spectrometry failed. Upon extractive workup, the only compound recovered was 4-methylbenzenesulfonamide. Table 5.3. Initial attempts to synthesize iminosulfur oxydifluorides from SOF2 and chloramine T.a entry equivalents SOF2 19F NMR δ (ppm) 19F NMR yield of 5.56 (%)b 1 1.0 99.8 36 2 2.0 99.9 44 3 3.0 99.8 23 4 4.0 99.9 23 5 5.0 99.9 25 6 6.0 99.8 31 aReactions conditions: SOF2 (X equiv.) in MeCN, chloramine T (5.47, 1.0 mmol, 1 equiv.). 19F NMR spectroscopic yields determined with PhCF3 (20 μL) utilized as an internal standard. bThe 19F NMR spectroscopic yield was calculated assuming the species was monofluorinated. 5.2.4 The attempted synthesis of sulfonimidoyl fluoride precursors via ((arylsulfonyl)oxy)carbamates As a final attempt to synthesize a sulfonimidoyl fluoride precursor with MISF, ((arylsulfonyl)oxy)carbamates (5.63) were briefly examined (Scheme 5.16). It was hypothesized 213 that a sufficiently electron-deficient aryl moiety could be eliminated and favour the formation of a nitrene intermediate (5.64),266 which could then undergo the desired oxidative addition to MISF in lieu of chloramine T. Benzyl (((4-(trifluoromethyl)phenyl)sulfonyl)oxy)carbamate (5.63a) was treated with nBuLi—to generate 5.64a—and MISF (5.55) in THF, and an aliquot of the reaction mixture was then sampled for quantitative 19F NMR spectroscopic analyses. Unfortunately, no product (5.52a) was detected, and it appeared that the MISF had failed to react. Due to limited advancements, these approaches to sulfonimidoyl fluoride synthesis were abandoned in favour of more promising avenues (vide infra). Reaction conditions: 5.63a (0.25 mmol, 1.0 equiv.), nBuLi (1.0 equiv), THF (2 mL), 5.55 (1.1 equiv.), KF (2.0 equiv.). PhCF3 (25 μL) added as an internal standard. 5.63a was synthesized according to a literature procedure.266 Scheme 5.16. Attempted synthesis of a sulfonimidoyl fluoride precursor from MISF and an N-tosyloxy carbamate analogue. 5.2.5 A new approach: the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides from sulfinic acids With the previous attempts to synthesize sulfonimidoyl fluorides from MISF and SOF2-chloramine T adducts showing little promise, a new approach was necessary. The synthesis of SulfoxFluor (5.1d) by Hu et al. proceeded via a sulfinyl chloride intermediate through the use of SOCl2 (vide supra).254,255 This was interesting to the Sammis group as we had recently been exploring the synthetic applications of the analogous SOF2 with carboxylic acid substrates,34,45 and were beginning to expand the scope of the reagent to other substrates. Specifically, Brodie 214 Thomson—a PhD student in the Sammis group—was concurrently exploring the efficacy of a SOF2-mediated conversion of sulfinic acids (5.65) to the corresponding sulfinyl fluoride (5.54, Scheme 5.17). After extensive optimization, Thomson found that sulfinyl fluorides could be effectively synthesized in up to 97% yield by quantitative 19F NMR spectroscopy versus PhCF3 as an internal standard; however, the sulfinyl fluorides were not bench-stable and readily decomposed to the sulfinic acid or sulfonyl fluoride in the presence of water or oxygen, respectively. Scheme 5.17. Thomson’s SOF2-mediated conversion of sulfinic acids to the corresponding sulfinyl fluoride. It was hypothesized that the synthesis of sulfonimidoyl fluorides (5.1) could be enabled and drastically expedited through the use of SOF2, proceeding by way of a non-isolated sulfinyl fluoride intermediate (5.54, Scheme 5.18). At worst, using SOF2 in lieu of SOCl2 would immediately reduce the step-count of the overall protocol, obviating the need for a dedicated halogen exchange protocol. At best, since residual SOF2 can be removed from solution simply by sparging the reaction mixture with inert gas, the conversion of the sodium sulfinate or sulfinic acid (5.65) to the sulfonimidoyl fluoride (5.1) could potentially be simplified and completed in a single reaction pot. Briefly, sulfinyl fluorides have not been explored in great detail and there are few examples of their syntheses.267,268 In some cases, sulfinyl fluorides have been used as synthetic intermediates to access other sulfur-fluoride derivatives,269 although they have predominantly been reported as reaction by-products.270,271 215 Scheme 5.18. (a) A newly envisioned approach to the rapid synthesis of sulfonimidoyl fluorides, by way of a sulfinyl fluoride intermediate, and (b) the proposed mechanism of oxidative addition by chloramine T (5.47). Reaction development and optimization for the synthesis of sulfinyl fluorides was conducted independently by Thomson. His work will be detailed in his thesis and will not be reproduced here. This chapter will focus on my work in exploiting the sulfinyl fluoride intermediates towards the application of one-pot sulfonimidoyl fluoride syntheses. 5.2.6 Attempted one-pot synthesis of 4-methyl-N-tosylbenzenesulfonimidoyl fluoride from 4-methylbenzenesulfinic acid The initial reaction was attempted in a one-pot, stepwise manner. First, the sulfinic acid would be treated with SOF2 under the conditions developed separately by Thomson, and a nitrene source would then be added to the reaction mixture after the sulfinyl fluoride intermediate had formed in sufficient yield. For the reaction development and optimization, 4-methylbenzenesulfinic acid (5.65e) was selected as a representative sulfinic acid substrate; sulfinic 216 acids are of varying stability, and 5.65e was found to be bench-stable for several days when stored under inert gas. The sulfinic acid substrates studied in this project were synthesized from the corresponding commercially available sulfonyl chlorides (5.6) using a known protocol.256 Chloramine T (5.47) was selected as an initial representative nitrene source on account of its commercial availability, ease of handling, and successful use in the protocol described by Hu et al.254,255 The Hu protocol and reaction conditions also served as an initial model for the development of the SOF2-mediated reaction. While the sulfinyl fluoride-generation protocol developed by Thomson was already optimized as a standalone process, the reaction conditions were briefly revised in the context of the one-pot synthesis of sulfonimidoyl fluoride. Factors requiring study and optimization included: (1) the identity of and equivalency of the base, (2) the equivalency of anhydrous chloramine T, (3) the volume of toluene, (4) the reaction temperature in the second step, and (5) the tolerance of the reaction towards moisture (i.e. dried/non-dried solvent and glassware). Reaction development and optimization began with a base screen and optimization of the first step (Table 5.4). The reaction was performed using an excess of anhydrous chloramine T at 80 °C in the second step, in line with Hu’s protocol.256 Two equivalents of pyridine, Et3N, DIPEA, and DBU were all tested under the reaction conditions. In using two equivalents of pyridine and stirring overnight with 5.65e and anhydrous chloramine T (entry 1), two fluorinated species were detected by quantitative 19F NMR spectroscopy at 72.85 ppm and 65.08 ppm in 28% and 39% yields, respectively. The signal at 72.85 ppm was presumed to be the desired sulfonimidoyl fluoride (5.1e), per data published by Bolm et al. (73.77 ppm).248 The second signal at 65.08 ppm was attributed to the corresponding sulfonyl fluoride (5.5e),272 and was believed to have potentially formed as a result of a competing disproportionation of sulfinyl fluorides (5.54) to 5.5 and 5.66 217 (Scheme 5.19).273 To unequivocally confirm the identity of the presumed sulfonimidoyl fluoride, the candidate product was isolated through extractive workup and purified via flash column chromatography; the white powder was subsequently analyzed by each of 1H, 19F, and 13C{1H} NMR spectroscopy, with all data supporting the compound identity being 4-methyl-N-tosylbenzenesulfonimidoyl fluoride (5.1e). Table 5.4. Base optimization of the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides.a entry base equivalents 19F NMR yield of 5.1e (%) 19F NMR yield of 5.5e (%) 1 pyridine 2.0 28 39 2 Et3N 2.0 25 43 3 DIPEA 2.0 43 7 4 DBU 2.0 14 41 5 pyridine 0.90 85 10 6 pyridine 1.0 88 9 7 pyridine 1.1 51 22 aReactions conditions: 5.65 (0.25 mmol), base (X equiv.), SOF2 in MeCN (2 equiv.), chloramine T (5.47, 2 equiv.), toluene (2 mL). 19F NMR spectroscopic yields determined with PhCF3 (25 μL) utilized as an internal standard. Scheme 5.19. Potential disproportionation of sulfur(IV) sulfinyl fluorides into sulfur(VI) sulfonyl fluorides and sulfur(II) sulfenyl halides.273 The fact that 5.1e had been successfully generated through the SOF2-mediated protocol immediately confirmed the hypothesis that the overall route to access sulfonimidoyl fluorides could be conducted in two synthetic steps from the corresponding sulfonyl chloride (5.6). Using Et3N in place of pyridine, a similar ratio of 5.1e versus 5.5e was obtained (25% to 43%, respectively; entry 2), whereas a significantly greater proportion of 5.1e versus 5.5e was obtained 218 (43% to 7%, respectively) when DIPEA was used (entry 3). The reason for this difference was not determined, as the overall yield was low. Using DBU (entry 4) dramatically favoured the formation of the sulfonyl fluoride, with 19F NMR spectroscopy yields of 14% and 41% for 5.1e and 5.5e, respectively. Sulfinyl fluorides are known to racemize and even decompose over time in the presence of DBU,241,252 perhaps indicating that this base favoured an undesired reaction pathway. The initial base optimization results suggested that DIPEA was potentially best-suited to the reaction. However, Thomson’s initial optimization for the synthesis of sulfinyl fluorides had indicated that pyridine was the most suitable base. Therefore, pyridine was investigated further in the context of one-pot sulfonimidoyl fluoride synthesis. In an effort to both minimize the quantity of required base and reduce the potential for unexpected side processes, the reaction was repeated with reduced equivalents of pyridine; this change was highly effective. In using a slight deficit of pyridine (0.90 equivalents, entry 5), a significant increase in the yield of and selectivity for 5.1e (85%) over 5.5e (10%) was observed. Summed together, these yields further indicated near-quantitative conversion of the sulfinyl fluoride intermediate to the sulfonimidoyl fluoride. Utilizing 1.0 equivalent of pyridine (entry 6) led to a similar—if slightly improved—yield of 5.1e (88%) versus 5.5e (9%). It was noted that even a slight excess of pyridine (1.1 equivalents, entry 7) disrupted the reaction, with 5.1e produced in only 51% yield and the quantity of 5.5e increasing to 22%. It appeared that the strength of base had no effect on the degree of disproportionation to form sulfonyl fluoride by-product 5.5e. Pyridine was the weakest amine base tested, yielding 5.5e in similar quantities (39%, Table 5.4, entry 1) as both Et3N (43%, entry 2) and DBU (41%, entry 4). DIPEA is significantly more basic than pyridine, but less basic than DBU, yet the use of this base yielded 5.5e in only 7% yield by 19F NMR spectroscopy (entry 3). DIPEA is the most 219 sterically encumbered of the four bases, and it is this steric bulk which has been attributed to the notably lower formation of 5.5e compared to the reactions utilizing pyridine, Et3N, and DBU. The drastic decrease in spectroscopic yield of 5.1e with even a slight excess of basic pyridine suggested that pyridine was likely interfering in the formation of the sulfinyl fluoride intermediate in some way. It was hypothesized that any excess pyridine may have been nucleophilically out-competing fluoride during the final step of the formation of the sulfinyl fluoride (5.54), instead forming a sulfinyl pyridinium-type species (Scheme 5.20). The subsequent formation of 5.54 from this species may have been somewhat disfavoured, thereby reducing the yield of this crucial intermediate, and in turn, the yield of the sulfonimidoyl fluoride (5.1). This hypothesis may be supported by the fact that even 2.0 equivalents of DIPEA failed to favour the sulfonyl fluoride byproduct (5.5e) over the targeted sulfonimidoyl fluoride (5.1e); in comparison to the other bases, DIPEA may have been too sterically encumbered to nucleophilically out-compete fluoride. Scheme 5.20. Proposed mechanistic rationale for the negative impact of excess pyridine on the formation of sulfinyl fluorides (5.54) and sulfonimidoyl fluorides (5.1). The final results of the base optimization indicated that pyridine was the most suitable base for the one-pot reaction, and that no more than 1.0 equivalent of the base should be utilized. The amount of intermediate sulfinyl fluoride (5.54e) was not quantified by 19F NMR spectroscopy during these initial analyses, as it was found that the amount detected before and after sparging 220 with inert gas decreased significantly (i.e. often to the point where none was detected). The reason for this may be attributed to the inherent instability of sulfinyl fluorides, specifically their propensity to oxidation or hydrolysis in the presence of oxygen or water, respectively (vide supra). Next, the quantity of chloramine T required was investigated (Table 5.5). Utilizing a single equivalent of anhydrous chloramine T produced sulfonimidoyl fluoride 5.1e in 38% yield and sulfonyl fluoride 5.5e in 7% yield (entry 1). Increasing the quantity of chloramine T to 2.0 equivalents increased the generation of both 5.1e (67%) and 5.5e (19%, entry 2). The reason for the unexpected increase in yield of 5.5e is not known, but was not considered worth examining further as it was known that better product yields and ratios could be obtained with 3.0 equivalents of chloramine T (entry 3). Further increasing to 4.0 equivalents of 5.47 resulted in a significant reduction in yield of 5.1e (36%, entry 4). This data indicated that the original 3.0 equivalents of chloramine T were optimal for the reaction. Table 5.5. Optimization of chloramine T for the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides.a entry equiv. chloramine T (anh.) 19F NMR yield of 5.1e (%) 19F NMR yield of 5.5e (%) 1 1.0 38 7 2 2.0 67 19 3b 3.0 88 9 4 4.0 36 6 aReactions conditions: 5.65e (0.25 mmol), pyridine (1 equiv.), SOF2 in MeCN (2 equiv.), chloramine T (5.47, X equiv.), toluene (2 mL). 19F NMR spectroscopic yields determined with PhCF3 (25 μL) utilized as an internal standard. bEntry 3 is a duplicate of Table 5.4, entry 6, and is included here for comparison. The volume of toluene in the second step of the reaction was assessed next (Table 5.6). Solvents such as MeCN are not as effective as toluene in solubilizing chloramine T (5.47) at 221 elevated temperatures, and this was evident in the low yield of 5.1e (27%) when no toluene was used (entry 1). Increasing the volume of toluene to 1 mL led to an improvement in the yield of 5.1e (entry 2, 51%), although the use of 2 mL (entry 3, 88%) was still superior. It was observed that using more than 2 mL of toluene led to reduced yields of 5.1e, with 3 mL affording the product in only 67% yield (entry 4) and 5 mL depressing the yield even further to 55% (entry 5). This data indicated that too dilute solutions of chloramine T could disfavour the oxidative addition between 5.54e and 5.47. Table 5.6. Optimization of volume of toluene for the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides.a entry volume toluene (mL) 19F NMR yield of 5.1e (%) 19F NMR yield of 5.5e (%) 1 0 27 22 2 1 51 15 3b 2 88 9 4 3 67 15 5 4 55 18 aReactions conditions: 5.65e (0.25 mmol), pyridine (1 equiv.), SOF2 in MeCN (2 equiv.), chloramine T (5.47, 3 equiv.), toluene (X mL). 19F NMR spectroscopic yields determined with PhCF3 (25 μL) utilized as an internal standard. bEntry 3 is a duplicate of Table 5.4, entry 6, and is included here for comparison. The temperature of the second step of the reaction was examined next (Table 5.7). Since chloramine T is reported to react vigorously and even explode under reduced pressure at temperatures exceeding 80 °C, no reactions were performed above this temperature. The likelihood of a runaway reaction was negligible under the present reaction conditions as they were performed at standard atmospheric pressure on a small-scale, yet precautions (such as a blast shield) were taken nonetheless. Conducting the second step of the reaction at room temperature resulted in a 222 low 19F NMR spectroscopic yield of 5.1e (43%, entry 1). Increasing the temperature to 40 °C (entry 2) and 60 °C (entry 3) led to steady increases in the yield of 5.1e (66% and 69%), with the original conditions of 80 °C (entry 4) proving most effective. This result was not surprising, given that the analogous conversion of sulfinyl chlorides to sulfonimidoyl chlorides is performed at 80 °C as well.256 Table 5.7. Reaction temperature optimization for the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides.a entry temperature (°C) 19F NMR yield of 5.1e (%) 19F NMR yield of 5.5e (%) 1 rt 43 8 2 40 66 8 3 60 69 7 4b 80 88 9 aReactions conditions: 5.65e (0.25 mmol), pyridine (1 equiv.), SOF2 in MeCN (2 equiv.), chloramine T (5.47, 3 equiv.), toluene (2 mL). 19F NMR spectroscopic yields determined with PhCF3 (25 μL) utilized as an internal standard. bEntry 4 is a duplicate of Table 5.4, entry 6, and is included here for comparison. Lastly, the effects of moisture on the second step of the reaction were studied (Table 5.8). A handful of previous experiments had failed when either chloramine T trihydrate or improperly dried chloramine T were used in the reaction. Furthermore, sulfinyl fluorides will be hydrolyzed to the sulfinic acid in the presence of adventitious water (vide supra). Therefore, it was expected that the use of non-dried glassware and solvents may have a negative impact on the efficacy of both steps of the reaction. The goal of these experiments was to briefly assess the degree to which water introduced from these sources would affect the reaction. In using non-dried toluene and glassware, the product distribution of 5.1e (41%) versus 5.5e (25%) deteriorated significantly, confirming that anhydrous conditions were ideal (entry 1). Utilizing anhydrous toluene stored over 223 4 Å molecular sieves with non-dried glassware led to a slight improvement in yield and product distribution of 5.1e (63%) versus 5.5e (12%, entry 2), although the use of strictly anhydrous conditions and flame- or oven-dried glassware (entry 3) proved most effective (5.1e, 88%). The reduced yields were attributed to the sulfinyl fluoride intermediate (5.54e) likely being hydrolyzed to the corresponding sulfinic acid in the presence of any water. Table 5.8. Examination of the effects of moisture on the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides.a entry toluene glassware 19F NMR yield of 5.1e (%) 19F NMR yield of 5.5e (%) 1 non-dried non-dried 41 25 2 anhydrous non-dried 63 12 3 anhydrous flame-dried 88 9 aReactions conditions: 5.65e (0.25 mmol), pyridine (1 equiv.), SOF2 in MeCN (2 equiv.), chloramine T (5.47, 3 equiv.), toluene (2 mL). 19F NMR spectroscopic yields determined with PhCF3 (25 μL) utilized as an internal standard. bEntry 3 is a duplicate of Table 5.4, entry 6, and is included here for comparison. With these optimized conditions in hand, the reaction was then replicated on a 1.0 mmol scale to prepare for substrate scope development. The reaction was conducted according to the optimized protocol, with 5.1e observed in a 71% 19F NMR spectroscopic yield. Following isolation and purification, 5.1e was obtained in 64% yield, indicating that the isolation protocol was applied efficiently to this compound. 224 5.2.7 Substrate scope of sulfinic acids for the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides The initial substrate scope focused on sulfinic acid substrates. I was joined at this time by Carlota Bahri (Sorbonne Université, Paris, France) and William Yang (UBC), two undergraduate students in the Sammis group who assisted me in exploring the reaction scope. The following compounds were synthesized by Bahri under my direct supervision: 5.1e (as a replicate of my own work), 5.1g, 5.1i, 5.1o, and 5.1s. The following compounds were synthesized by Yang under my direct supervision: 5.1h, 5.1j–l, 5.1n, and 5.1p. Following the successful synthesis and isolation of 5.1e in 64% yield, this sulfonimidoyl fluoride was synthesized a second time by Bahri under my supervision in an effort to improve the product yield. During this attempt, the sulfinic acid substrate was synthesized with only one equivalent of hydrochloric acid instead of an excess. The rationale for this was that Thomson had noted that the sulfinic acids appeared to undergo deoxyfluorination more efficiently thereafter if an excess of acid was not used in their original synthesis. The subsequent deoxyfluorination-oxidative addition with SOF2 and anhydrous chloramine T proceeded effectively, generating the sulfonimidoyl fluoride in increased 19F NMR spectroscopic (99%) and isolated (86%) yields. This experiment confirmed that when greater than one equivalent of 6 M HCl was used to acidify the sodium sulfinate salt, the subsequent deoxyfluorination proceeded to form 5.54e—and by extension, the sulfonimidoyl fluoride product (5.1e)—in reduced 19F NMR spectroscopic yields. Conversely, when approximately 0.95–1.0 equivalents of acid were used, the resulting sulfinic acid yield suffered slightly, yet the subsequent deoxyfluorination process was far more effective. It was presumed that the addition of excess HCl may have resulted in residual acid persisting in the crude sulfinic acid sample utilized in the title reaction, consuming a portion of the pyridine base. As the detrimental effect of HCl was 225 determined part of the way through the development of this substrate scope, some of the early sulfinic acids trials are reported with an excess of HCl. Next, the synthesis of the ortho-substituted methyl isomer was attempted to assess the effects of steric bulk on different aryl positions in the sulfinic acid substrate. 2-Methylbenzenesulfinic acid (5.65f) reacted efficiently under the reaction conditions to afford 5.1f in 84% isolated yield. Next, 4-(tert-butyl)benzenesulfinic acid (5.65g) was examined to further investigate the effects of sterically bulky aliphatic substituents on the reaction. The corresponding sulfonimidoyl fluoride (5.1g) was isolated in 85% yield, indicating that the reaction could be effectively applied to aryl sulfinic acids with large, sterically bulky aliphatic groups. Propyl analogues 5.65h and 5.65i were tested next, generating the corresponding sulfonimidoyl fluorides—5.1h and 5.1i, respectively—in 71% and 56% isolated yields, each. These propyl analogues further supported the finding that sulfinic acids bearing aliphatic substituents are tolerated under the reaction conditions. Biphenyl derivative 5.65j was similarly efficiently applied to the one-pot reaction, with 5.1j isolated in 72% yield. Fluorinated sulfinic acids 5.65k, 5.65l, and 5.65m were tested next to investigate the electronic effects of substituents in different arene positions on the reaction. The deoxyfluorination-oxidative addition of 5.65k proceeded smoothly to afford 5.1k in 80% isolated yield. Treatment of the meta-fluorinated analogue (5.65l) with SOF2 and anhydrous chloramine T was similarly effective, generating 5.1l in 57% isolated yield, and the conversion of 5.65m to 5.1m produced the latter in 78% isolated yield. It appeared that the site of fluorination had little effect on the overall reaction outcome, with all three of 5.65k, 5.65l, and 5.65m synthesized in good yields. The meta-substituted product (5.1l) was arguably isolated in lower yield than the ortho- or 226 para-substituted isomers; however, a comparison of the corresponding quantitative 19F NMR spectroscopic yields of 5.1l (73%) and 5.1m (90%) suggest that this lower isolated yield may be a result of the isolation and purification process, rather than the reaction efficacy itself. aReaction conditions: 5.65 (1.0 mmol), SOF2 in MeCN (2.0 equiv.), pyridine (1.0 equiv.), 5.47 (3.0 equiv.). Isolated yields are reported. bAn excess (4.0 equiv.) of 6 M HCl was utilized to synthesize the sulfinic acid starting material, leading to a reduced yield of both the sulfinyl fluoride intermediate and sulfonimidoyl fluoride product. cData obtained by Bahri. dData obtained by Yang. Scheme 5.21. Sulfinic acid substrate scope for the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides from sulfinic acids. 227 The synthesis of 4-chloro-N-tosylbenzenesulfonimidoyl fluoride (5.1d, SulfoxFluor) was attempted next for two purposes: (1) to further evaluate the reaction’s effectiveness towards halogenated sulfinic acids, and (2) to draw comparisons between this, and the protocol reported by Hu et al.254,255 Hu’s original approach to SulfoxFluor proceeded by way of four distinct synthetic steps with an overall yield of 50%, and the improved protocol increased this to approximately 67%. One advantage of Hu’s method was that it is suitable for the synthesis of SulfoxFluor on scales of greater than 150 g. However, Hu’s approach is at a disadvantage in scenarios where ready access to smaller lab-scale quantities of a diverse library of sulfonimidoyl fluorides is advantageous (i.e. medicinal chemistry). The present SOF2-mediated approach cannot compete with Hu’s protocol on an industrial scale; however, the successful isolation of SulfoxFluor (5.1d, 80%) indicates this new method is superior for small-scale applications. The present approach benefits from a superior yield and a significantly more rapid synthetic route. In the future, it would be worth investigating if this SOF2-mediated reaction could be applied to the synthesis of 5.1d on a multi-gram scale. Treatment of iodinated sulfinic acid 5.65n with SOF2 and anhydrous chloramine T furnished the corresponding sulfonimidoyl fluoride (5.1n) in 79% isolated yield. In comparison of 5.1n to the para-substituted chloro- (5.1d) and fluoro- (5.1k) analogues (80% isolated, each), it appeared that the SOF2-mediated protocol was well-suited to halide-substituted aryl sulfinic acids, and that the reaction was equally tolerant of each halide. Additionally, no nucleophilic aromatic substitution by-products were observed with any of the aryl halide-containing substrates. The efficacy of the reaction towards electron-rich aryl sulfinic acids was studied next using 5.65o. Conversion of 5.65o to 5.1o proceeded efficiently and afforded the latter in 92% isolated yield, indicating that the SOF2-mediated protocol could be effectively applied to the synthesis of 228 sulfonimidoyl fluorides from electron-rich aryl sulfinic acids. Next, the suitability of the protocol to electron-poor sulfinic acids was studied using 5.65p, 5.65q, and 5.65r. The para-substituted –CF3 group of 5.65p was tolerated under the reaction conditions, affording 5.1p in 65% isolated yield. Similarly, para-nitro-substituted 5.65q was converted to 5.1q and isolated in 63% yield. The reaction with the ortho-nitro analogue (5.65r) was slightly more effective, affording 5.1r in 82% isolated yield. The successful syntheses of these three electron-deficient sulfonimidoyl fluorides indicates that the reaction can be effectively applied to electron-poor aryl sulfinic acid substrates. The synthesis of N-tosylnaphthalene-2-sulfonimidoyl fluoride (5.1s) was performed next, affording the target product in 92% isolated yield. This suggested that the SOF2-mediated protocol may be effectively applied to polycyclic aryl sulfinic acid substrates, enabling rapid access to polycyclic aryl sulfonimidoyl fluorides. Currently, the reaction scope is being investigated using 3-methylbenzenesulfinic acid (5.65t), 4-acetamidobenzenesulfinic acid (5.65u), and octane-1-sulfinic acid (5.65v, Figure 5.3). The addition of the meta-substituted methylbenzenesulfinic acid isomer would be a suitable addition to the substrate scope, as it would complete the scope of methylbenzenesulfinic acid derivatives and initial analysis of the effects of arene site-substitution on the reaction. The conversion of 5.1t to 5.65t has been successfully performed, with an isolated yield of less than 45%; at this time, the product has not been isolated in pure form. Efforts to isolate 5.1t in greater yield and purity are currently underway. Neither 5.65u nor 5.65v have yet successfully undergone conversion to the corresponding sulfonimidoyl fluorides (5.1u and 5.1v, respectively). In the reaction with 5.65u, none of the corresponding sulfinyl fluoride was detected by quantitative 19F NMR spectroscopy after the first stage of the reaction; consequently, no sulfonimidoyl fluoride (5.1u) formed during the reaction 229 either. It is presumed that the presence of the polar N-acetamido group may be interfering in the reaction between the sulfinic acid and SOF2. Efforts to apply the reaction to this substrate are ongoing, as it would further support the findings that the reaction can be efficiently applied to electron-rich aryl sulfinic acids. The reduction of octane-1-sulfonyl chloride (5.6v) to 5.65v has proven challenging, particularly the isolation of the sulfinic acid product. This is presumably due to the surfactant-like character of the highly lipophilic n-octyl backbone coupled with the polar sulfinic acid moiety complicating the aqueous workup. Once isolation of this sulfinic acid is optimized, the corresponding reaction to form 5.1v is expected to work well, ideally indicating applicability of the reaction to aliphatic sulfinic acid substrates. Figure 5.3. Sulfonimidoyl fluoride substrates under development in the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides from sulfinic acids. 5.3 Conclusions This project represents the first in-depth exploration of the synthetic applications of SOF2 outside of carboxylic acid activation. Through the use of SOF2-mediated activation of sulfinic acids, the rapid, one-pot synthesis of sulfonimidoyl fluorides has been achieved and can afford the target products in good-to-excellent yields. The protocol benefits from a significantly reduced step-count compared to several standard literature procedures and can generate sulfonimidoyl fluorides in significantly less time and greater overall yields as a result. Furthermore, the key deoxyfluorination-oxidative addition processes can be conducted in a single reaction pot, on account of the ease through which residual SOF2 can be removed from solution. This protocol has 230 been effectively applied to a wide array of electron-rich and -poor aryl sulfinic acids to equal effect, and sterically encumbered sulfinic acids have also been utilized successfully. It is anticipated that this protocol may find use for the rapid, small-scale syntheses of libraries of sulfonimidoyl fluorides, enabling more facile access to other pharmaceutically relevant sulfur(VI) derivatives. The future directions of this project are described in Chapter 6. 5.4 Experimental information 5.4.1 General methods All chemicals were sourced from the same commercial suppliers as described previously in Section 4.6.1. All reactions used the same equipment as described previously in Section 4.6.1. TLC, IR spectroscopy, melting point, mass spectrometry, and NMR spectroscopy analyses were conducted as described previously in Section 4.6.1. Anhydrous chloramine T (5.47) was prepared by heating the desired quantity of chloramine T trihydrate in a dry Schlenk tube at 80 °C overnight in vacuo. Anhydrous 5.47 was stored at room temperature under inert gas. 5.4.2 Procedure for the generation of thionyl fluoride (SOF2) Thionyl fluoride was generated as previously described in Section 4.6.2. 231 5.4.3 Procedure for the reduction of sulfonyl chlorides to sulfinic acids The reduction of sulfonyl chlorides to sulfinic acids was performed using a modified version of a reported procedure.256 To a 50 mL round-bottom flask equipped with a magnetic stir bar were added Na2SO3 (10 mmol, 1.0 equiv.), NaHCO3 (20 mmol, 2.0 equiv.), and deionized H2O (10.5 mL). A reflux condenser was attached to the flask, and the suspension was stirred at 80 °C until all solids were dissolved. To this solution was slowly added a solution of 5.6 (10 mmol, 1.0 equiv.) in THF (2.5 mL) over the course of 15 minutes, via syringe pump. A small aliquot of THF (~0.3 mL) was used to transfer the residual contents of the syringe to the refluxing solution. The solution was stirred at 80 °C for 45 minutes before being cooled to room temperature. Et2O (10 mL) was added to the solution, causing the sodium salt of the sulfinic acid to precipitate for some substrates. Deionized H2O (10 mL) was added to re-solubilize any precipitate and partition the solution. The organic phase was removed, and the aqueous phase was acidified with aq. HCl (1.6 mL, 1.0 equiv., 6 M). The aqueous phase was extracted with Et2O (3 x 20 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford the crude sulfinic acid (5.65). The product was analyzed by 1H NMR spectroscopy and carried forward without further purification. Note that the addition of an excess of aq. HCl (i.e. 4 equiv.) during isolation of 5.65 can inhibit the subsequent deoxyfluorination-oxidative addition reaction with SOF2 and chloramine T. 232 5.4.4 General procedure for the SOF2-mediated conversion of S(IV)-sulfinic acids to S(VI)-sulfonimidoyl fluorides 5.1d–t To a 20 mL vial equipped with a stir bar were added a solution of SOF2 in MeCN (11 mL, 0.18 M, 2.0 mmoles, 2.0 equiv.) and pyridine (81 µL, 1.0 mmol, 1.0 equiv.). The solution was stirred at room temperature for 10 minutes. To a 50 mL RBF equipped with a stir bar and septum was added sulfinic acid 5.65 (1.0 mmol, 1.0 equiv.). The RBF was purged with argon. To the 50 mL RBF was then added the SOF2/pyridine solution, and the reaction was stirred for 45 minutes at room temperature. To the 50 mL RBF was then added PhF as an internal standard (100 µL, 1.0 mmol, 1.0 equiv), and an aliquot was sampled for quantitative 19F NMR spectroscopic analyses. The reaction was then degassed with argon to remove all residual SOF2. To the 50 mL RBF were then added dry toluene (8 mL) and anhydrous chloramine T (5.47, 686 mg, 3.0 mmoles, 3.0 equiv.). The 50 mL RBF was equipped with a reflux condenser and placed under an argon atmosphere. The reaction was stirred at 80 °C overnight, after which the reaction mixture was cooled to room temperature, PhCF3 (100 µL, 0.8 mmol, 0.8 equiv.) was added as an internal standard, and an aliquot was sampled for quantitative 19F NMR spectroscopic analysis. The reaction mixture was filtered through a fine-porosity glass frit to remove suspended NaCl. MeCN (8 mL) was added to form an azeotrope with toluene and the reaction mixture was concentrated under reduced pressure. The crude reaction mixture was purified by silica gel flash chromatography using DCM and hexanes to yield the desired sulfonimidoyl fluoride. 233 5.4.5 Characterization data of compounds 5.1d–5.1t Compound 5.1d Compound spectral data is in agreement with previoufsly reported data.254 Following the general procedure using 4-chlorobenzenesulfinic acid, (5.1d) was obtained as a white powder (281 mg, 80% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.98 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.59 (dd, J = 7.9, 1.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 144.6, 143.5, 138.8, 131.6 (d, J = 21.8 Hz), 130.3, 129.9, 129.6, 127.3, 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 74.2. IR (cm-1): 3099, 3089, 2924, 1595, 1574, 1477, 1397, 1335, 1287, 1183, 1163, 1126, 1082, 1011, 814, 783, 704. HRMS (FD) m/z: [M]+ Calcd for C13H11Cl1F1N1O3S2 [M]+ 346.9853 found 346.9847. 234 Compound 5.1e Compound spectral data is in agreement with previously reported data.248 Following the general procedure using 4-methylbenzenesulfinic acid, (5.1e) was obtained as a white powder (282 mg, 86% yield). When the sulfinic acid was synthesized using 4.0 equivalents of aq. HCl (6 M), 5.1e was obtained as a white powder (212 mg, 64%). 1H NMR: (300 MHz, Chloroform-d) δ 7.92 (dd, J = 8.5, 7.1 Hz, 4H), 7.44 – 7.37 (m, 2H), 7.37 – 7.30 (m, 2H), 2.48 (d, J = 1.1 Hz, 3H), 2.43 (s, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 148.1, 144.4, 139.0, 130.5, 130.0 (d, J = 20.2 Hz), 129.8, 128.2, 127.2, 22.0, 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 73.8. IR (cm-1): 3363, 3264, 3086, 2923, 1592, 1335, 1279, 1184, 1162, 1119, 1083, 1069, 1012, 816, 776, 714. HRMS (FD) m/z: [M]+ Calcd for C14H14F1N1O3S2 [M]+ 327.0399 found 327.0408. Compound 5.1f Compound spectral data is in agreement with previously reported data.263 Following the general procedure using 2-methylbenzenesulfinic acid, (5.1f) was obtained as a white powder (275 mg, 84% yield). 235 1H NMR: (300 MHz, Chloroform-d) δ 8.06 – 7.98 (m, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.62 (td, J = 7.6, 1.4 Hz, 1H), 7.44 – 7.36 (m, 2H), 7.32 (dt, J = 7.9, 0.7 Hz, 2H), 2.62 (s, 3H), 2.43 (s, 3zH). 19F NMR: (282 MHz, Chloroform-d) δ 65.8. IR (cm-1): 3096, 2927, 2856, 1597, 1470, 1336, 1322, 1287, 1149, 1108, 1085, 760, 722, 662. HRMS (FD) m/z: [M]+ Calcd for C14H14F1N1O3S2 [M]+ 327.0399 found 327.0407. Compound 5.1g Compound spectral data is in agreement with previously reported data.248 Following the general procedure using 4-tert-butylbenzenesulfinic acid, (5.1g) was obtained as a white solid (169 mg, 85% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.95 (dd, J = 8.5, 4.8 Hz, 4H), 7.61 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 2.43 (s, 3H), 1.34 (s, 9H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 160.9, 144.3, 139.1, 130.0 (d, J = 20.4 Hz), 129.7, 128.2, 127.2, 126.9, 35.8, 31.0, 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 73.9. IR (cm-1): 2960, 2925, 2872, 1590, 1340, 1326, 1297, 1166, 1137, 1105, 1083, 1009, 840, 779, 703. HRMS (FD) m/z: [M]+ Calcd for C17H20F1N1O3S2 [M]+ 369.0869 found 369.0851. 236 Compound 5.1h Following the general procedure using 4-iso-propylbenzenesulfinic acid, (5.1h) was obtained as a yellow oil (258 mg, 71% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.94 (dd, J = 8.4, 3.3 Hz, 4H), 7.45 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 3.02 (hept, J = 6.9 Hz, 1H), 2.43 (3, 1H), 1.27 (d, J = 6.9 Hz, 6H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 158.6, 144.3, 139.1, 130.3 (d, J = 20.1 Hz), 129.8, 128.5, 128.0, 127z.2, 34.6, 23.6, 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 74.0. IR (cm-1): 2965, 2929, 2874, 1594, 1490, 1463, 1415, 1339, 1322, 1164, 1132, 1087, 1054, 1014, 838, 814, 783, 771, 706, 654. HRMS (FD) m/z: [M]+ Calcd for C16H18F1N1O3S2 [M]+ 355.0712 found 355.0719. Compound 5.1i Following the general procedure using 4-n-propylbenzenesulfinic acid, (5.1i) was obtained as a pale yellow oil (199 mg, 56% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.95 (dd, J = 8.4, 5.6 Hz, 4H), 7.39 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 2.69 (dd, J = 8.5, 6.7 Hz, 2H), 2.43 (s, 3H), 1.66 (h, J = 7.4 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). 237 13C{1H} NMR: (75 MHz, Chloroform-d) δ 152.1, 144.5, 140.0, 138.6, 129.8 (d, J = 9.6 Hz), 129.7, 127.7 (d, J = 77.5 Hz), 127.3 (d, J = 39.9 Hz), 38.1, 24.1, 21.8, 13.7. 19F NMR: (282 MHz, Chloroform-d) δ 74.1. IR (cm-1): 2962, 2931, 2872, 1590, 1410, 1340, 1285, 1163, 1109, 1086, 1012, 910, 729. HRMS (FD) m/z: [M]+ Calcd for C16H18F1N1O3S2 [M]+ 355.0712 found 355.0712. Compound 5.1j Following the general procedure using [1,1'-biphenyl]-4-sulfinic acid, (5.1j) was obtained as a white powder (282 mg, 72% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.09 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.63 – 7.56 (m, 2H), 7.55 – 7.42 (m, 3H), 7.34 (d, J = 8.2 Hz, 2H), 2.44 (s, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 149.4, 144.4, 139.0, 138.3, 131.4 (d, J = 20.7 Hz), 129.8, 129.5, 129.4, 128.8, 128.3, 127.6, 127.3, 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 74.4. IR (cm-1): 3064, 2924, 2854, 1589, 1478, 1449, 1402, 1338, 1315, 1164, 1157, 1129, 1084, 1006, 846, 815, 785, 763, 712, 676. HRMS (FD) m/z: [M]+ Calcd for C19H16F1N1O3S2[M]+ 389.0556 found 389.0537. 238 Compound 5.1k Following the general procedure using 4-fluorobenzenesulfinic acid, (5.1k) was obtained as a white powder (275 mg, 80% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.14 – 8.03 (m, 1H), 7.98 – 7.89 (m, 1H), 7.39 – 7.24 (m, 2H), 2.44 (s, 1H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 167.3 (d, J = 261.5 Hz), 144.6, 138.8, 131.4 (d, J = 10.3 Hz), 129.8, 129.0 (dd, J = 21.7, 3.3 Hz), 127.2, 117.5 (d, J = 23.4 Hz), 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 75.0, -97.6 (ddt, J = 7.9, 5.1, 2.6 Hz). IR (cm-1): 3106, 3064, 2930, 1927, 1590, 1491, 1410, 1334, 1241, 1166, 1124, 1082, 1012, 814, 780, 715, 677. HRMS (FD) m/z: [M]+ Calcd for C13H11F2N1O3S2 [M]+ 331.0148 found 331.0159. Compound 5.1l Following the general procedure using 3-fluorobenzenesulfinic acid, (5.1l) was obtained as an off-white powder (194 mg, 57% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.93 (d, J = 8.3 Hz, 2H), 7.86 (dt, J = 8.0, 1.4 Hz, 1H), 7.74 (dt, J = 7.6, 2.2 Hz, 1H), 7.70 – 7.57 (m, 1H), 7.49 (td, J = 8.1, 2.5 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 2.44 (s, 3H). 239 13C{1H} NMR: (75 MHz, Chloroform-d) δ 162.4 (d, J = 254.7 Hz), 144.7, 138.7, 134.9 (dd, J = 21.9, 7.8 Hz), 131.9 (d, J = 7.9 Hz), 129.9, 127.3, 124.1 (d, J = 3.6 Hz), 123.8 (d, J = 21.0 Hz), 115.7 (d, J = 26.2 Hz), 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 74.2, -106.9 (dd, J = 7.8, 5.1 Hz). IR (cm-1): 3085, 2923, 2852, 1593, 1480, 1344, 1306, 1231, 1164, 1131, 1084, 999, 896, 770, 678. HRMS (FD) m/z: [M]+ Calcd for C13H11F2N1O3S2 [M]+ 331.0148 found 331.0155. Compound 5.1m Following the general procedure using 2-fluorobenzenesulfinic acid, (5.1m) was obtained as a white powder (258 mg, 78% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.00 (ddd, J = 8.3, 6.7, 1.8 Hz, 1H), 7.97 – 7.87 (m, 2H), 7.86 – 7.72 (m, 1H), 7.44 – 7.25 (m, 4H), 2.44 (s, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 159.5 (dd, J = 264.0, 1.3 Hz), 144.6, 138.8 (d, J = 8.8 Hz), 130.8, 129.8, 127.2, 125.1 (d, J = 4.1 Hz), 122.2 (dd, J = 23.0, 12.8 Hz), 118.3, 118.1, 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 70.7, –105.1 (dddd, J = 15.3, 9.8, 6.8, 4.8 Hz). IR (cm-1): 3110, 2935, 1595, 1590, 1474, 1451, 1346, 1319, 1268, 1161, 1141, 1084, 1074, 762. HRMS (FD) m/z: [M]+ Calcd for C13H11F2N1O3S2 [M]+ 331.0148 found 331.0163. 240 Compound 5.1n Following the general procedure using 4-iodobenzenesulfinic acid, (5.1n) was obtained as a white solid (351 mg, 79% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.98 (d, J = 8.6 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 2.44 (s, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 144.6, 139.2, 138.7, 132.8 (d, J = 21.7 Hz), 129.8, 129.1, 127.2, 105.1, 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 74.2. IR (cm-1): 3357, 3261, 3094, 2922, 2853, 1595, 1564, 1389, 1335, 1320, 1191, 1136, 1090, 1053, 1004, 818, 804, 780, 693. HRMS (FD) m/z: [M]+ Calcd for C13H11F1I1N1O3S2 [M]+ 438.9209 found 438.9190. Compound 5.1o Following the general procedure using 4-methoxybenzenesulfinic acid, (5.1o) was obtained as a white solid (158 mg, 92% yield). 1H NMR: (300 MHz, Chloroform-d) δ 7.94 (t, J = 8.7 Hz, 4H), 7.32 (d, J = 8.0 Hz, 2H), 7.08 – 6.99 (m, 2H), 3.90 (s, 3H), 2.43 (s, 3H). 241 13C{1H} NMR: (75 MHz, Chloroform-d) δ 165.9, 144.3, 139.1, 130.8, 129.7, 127.2, 123.7 (d, J = 20.6 Hz), 115.1, 56.2, 21.7. 19F NMR: (282 MHz, Chloroform-d) δ 75.2. IR (cm-1): 2924, 2852, 1592, 1576, 1496, 1332, 1302, 1270, 1131, 1119, 1087, 1025, 805, 780, 716, 670. HRMS (FD) m/z: [M]+ Calcd for C14H14F1N1O4S2 [M]+ 343.0348 found 343.0332. Compound 5.1p Following the general procedure using 4-trifluoromethylbenzenesulfinic acid, (5.1p) was obtained as a pale yellow oil (249 mg, 65% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.19 (d, J = 8.4 Hz, 2H), 7.98 – 7.85 (m, 4H), 7.35 (d, J = 8.1 Hz, 2H), 2.44 (s, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 144.9, 138.6, 138.5 – 137.0 (m), 136.9 (d, J = 22.2 Hz), 129.9, 128.9, 127.3, 127.1 (q, J = 3.7 Hz), 122.7 (q, J = 273.6 Hz), 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 74.1, -63.5. IR (cm-1): 3106, 3060, 1600, 1407, 1319, 1134, 1111, 1062, 1015, 800, 776, 683. HRMS (FD) m/z: [M]+ Calcd for C14H11F4N1O3S2 [M]+ 381.0116 found 381.0133. 242 Compound 5.1q Compound spectral data is in agreement with previously reported data.254 Following the general procedure using 4-nitrobenzenesulfinic acid, (5.1q) was obtained as an off-white powder (227 mg, 63% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.49 – 8.42 (m, 2H), 8.26 (d, J = 9.0 Hz, 2H), 7.97 – 7.90 (m, 2H), 7.36 (dt, J = 7.9, 0.7 Hz, 2H), 2.46 (s, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 152.1, 145.1, 138.8 (d, J = 23.3 Hz), 138.4, 130.0, 129.8, 127.3, 125.0, 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 74.1. IR (cm-1): 3115, 2924, 2857, 1600, 1527, 1356, 1303, 1140, 1086, 1010, 854, 785, 686. HRMS (FD) m/z: [M]+ Calcd for C1H11F1N2O5S2 [M]+ 358.0093 found 358.0083. Compound 5.1r Following the general procedure using 2-nitrobenzenesulfinic acid, (5.1r) was obtained as a clear yellow oil (292 mg, 82% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.29 (dd, J = 7.9, 1.5 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.96 (td, J = 7.7, 1.5 Hz, 1H), 7.94 – 7.82 (m, 3H), 7.39 – 7.29 (m, 2H), 2.45 (s, 3H). 243 13C{1H} NMR: (75 MHz, Chloroform-d) δ 144.9, 138.0, 137.1, 133.5, 131.4 (d, J = 2.5 Hz), 129.8, 127.7 (d, J = 25.0 Hz), 127.3, 126.4, 126.4, 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 71.7. IR (cm-1): 3079, 3032, 1543, 1335, 1326, 1146, 1115, 1085, 774, 733, 690. HRMS (FD) m/z: [M]+ Calcd for C13H11F1N2O5S2 [M]+ 358.0093 found 358.0093. Compound 5.1s Following the general procedure using 2-naphthalenesulfinic acid, (5.1s) was obtained as an off-white powder (177 mg, 92% yield). 1H NMR: (300 MHz, Chloroform-d) δ 8.64 (d, J = 2.0 Hz, 1H), 8.09 – 7.88 (m, 6H), 7.73 (dddd, J = 20.5, 8.1, 6.9, 1.3 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 2.44 (s, 3H). 13C{1H} NMR: (75 MHz, Chloroform-d) δ 144.4, 139.1, 136.3, 131.7, 131.0, 131.0, 130.4, 129.9, 129.8, 128.7, 128.3, 127.3, 121.6, 21.8. 19F NMR: (282 MHz, Chloroform-d) δ 74.4. IR (cm-1): 3057, 2924, 1596, 1317, 1164, 1143, 1130, 1087, 814, 775, 761, 750, 705, 680. HRMS (FD) m/z: [M]+ Calcd for C17H14F1N1O3S2 [M]+ 363.0399 found 363.0406. 244 Compound 5.1t Following the general procedure using 3-methylbenzenesulfinic acid, (5.1t) was obtained as a pale yellow oil (147 mg, <45% yield). This product is not pure at this time, and the following data is provided as an initial confirmation that the product was generated successfully. 1H NMR: (300 MHz, Chloroform-d) δ 7.95 (dd, J = 8.7, 7.3 Hz, 2H), 7.88 – 7.78 (m, 2H), 7.51 (dddd, J = 16.2, 10.5, 8.2, 4.9 Hz, 2H), 7.38 – 7.28 (m, 2H), 2.48 – 2.39 (m, 6H). The multiplet between 2.48–2.39 ppm is attributed to the two methyl group protons in 5.1t, as well as an unknown impurity. 13C{1H} NMR: (75 MHz, Chloroform-d) δ 144.6, 144.4, 142.6, 140.7, 140.6, 139.0, 138.5, 137.1, 136.6, 132.9 (d, J = 19.6 Hz), 129.8, 129.8, 129.7, 129.7, 128.3, 127.6, 127.2, 127.0, 125.3, 124.1, 21.8, 21.8, 21.5, 21.4. This compound is predicted to possess 12 chemically inequivalent carbon centres, leading to 12 signals in the 13C{1H} spectrum. Practically, there are 24 signals present—including the ipso carbon (132.9 ppm, d, J = 19.6 Hz) of the sulfonimidoyl fluoride motif in 5.1t—indicating the presence of one of more impurities. 19F NMR: (282 MHz, Chloroform-d) δ 73.7. IR (cm-1): 2953, 2924, 2860, 1596, 1479, 1336, 1285, 1161, 1136, 1103, 1075, 994, 814, 771, 722, 675. HRMS (FD) m/z: [M]+ Calcd for C14H14F1N1O3S2 [M]+ 327.0399 found 327.0412. 245 Chapter 6: Conclusion This thesis describes four distinct research projects exploring novel synthetic applications of sulfuryl fluoride (SO2F2) and thionyl fluoride (SOF2, Scheme 6.1). Broadly, the first two investigate processes mediated by sulfuryl fluoride, a gaseous sulfur(VI) reagent; the second two focus on a number of new synthetic applications of thionyl fluoride, a sparsely studied sulfur(IV) reagent. Scheme 6.1. Summary of the one-pot sulfuryl fluoride (SO2F2)- and thionyl fluoride (SOF2)-mediated reactions developed and investigated in this thesis. 6.1 Chapter 2: conclusions and future work The synthesis of a series of 1,1-dihydrofluoroalkyl sulfides (6.1) from thiol nucleophiles (6.2), 1,1-dihydrofluoroalcohols (6.3), and sulfuryl fluoride was described in Chapter 2 (Scheme 6.2). The 1,1-dihydrofluoroalkylation reaction was chemoselective for thiols over other potentially nucleophilic sites, including free amines and alcohols. These findings were primarily based upon the competition reaction performed between benzyl mercaptan and pyrrolidine, the latter of which underwent only trace alkylation under the reaction conditions. In a complementary experiment with piperidine, aminoalkylation was disfavoured under the reaction conditions, even in the absence of any thiol nucleophile. The SO2F2-mediated reaction was more effective and more chemoselective for the 2,2,2-trifluoroethylation of the thiol moiety in glutathione than 2,2,2-246 trifluoroethyl triflate, a commercially available reagent commonly used for similar applications. The source of the observed chemoselectivity was the formation of a bis(1,1-dihydrofluoroalkyl)sulfate intermediate (6.4). Scheme 6.2. Summary of the contributions made to the SO2F2-mediated 1,1-dihydrofluoroalkylation of thiols described in Chapter 2. A representative thiol substrate scope was investigated, further exploring the chemoselectivity of the reaction and investigating the applications of the protocol to the 2,2,3,3,3-pentafluoropropylation of thiols. This SO2F2-mediated reaction may find future applications in the 1,1-dihydrofluoroalkylation of thiol motifs in pharmaceutically relevant compounds, such as polythiazide or a derivative of Cefazaflur (Chapter 2, Figure 2.2). 6.2 Chapter 3: conclusions and future work A series of experiments were conducted to study the rate of formation and consumption of acyl fluoride intermediates (6.5) in a one-pot SO2F2-mediated nucleophilic acyl substitution reaction of carboxylic acids (6.6, Scheme 6.3). Through the use of quantitative 19F NMR spectroscopy, it was found that the addition of tetrabutylammonium halides (TBAX) salts—most notably tetrabutylammonium bromide (TBAB) and chloride (TBAC)—significantly improved the rate of the overall reaction. The rate acceleration was attributed to more rapid formation of the acyl fluoride intermediate, on account of the halide salt enabling access to more reactive acyl halide 247 intermediates in situ. The investigations found that the rate of consumption of the acyl fluoride intermediate by a variety of nucleophiles was independent of the TBAX additive. Scheme 6.3. Summary of the contributions made to the SO2F2-mediated carboxylic acid activations and nucleophilic acyl substitutions described in Chapter 3. As a result of the NMR spectroscopic kinetic studies performed by myself in tandem with the IR kinetic analyses by Dr. Thomas C. Malig—a collaborator from the Hein group at the University of British Columbia—it was found that the rate of reaction could be as much as doubled with the addition of TBAC. The synthetic significance of this finding was demonstrated with the successful deoxyfluorination of 4-methoxybenzoic acid, which was converted to the corresponding acyl fluoride in quantitative yield after only six hours with TBAC, versus twelve hours without. The addition of TBAX salt additives can therefore accelerate the overall reaction to more synthetically applicable timescales. A short scope of activated esters (6.7), amides (6.8), and a thioester (6.9) were synthesized through the SO2F2-mediated protocol. These valuable synthetic intermediates can in turn be utilized in a variety of nucleophilic acyl substitution and/or addition processes, indicating that the reaction protocol can be applied effectively to general organic synthesis. The findings from this work were carried forward into the SOF2-mediated nucleophilic acyl substitutions and reductions described in Chapter 4. 248 6.3 Chapter 4: conclusions and future work The one-pot thionyl fluoride-mediated syntheses of activated esters (6.10 or 6.11), amides (6.12 or 6.13), and alcohols (6.14) was described in Chapter 4 (Scheme 6.4). The SOF2-mediated activation of carboxylic acid substrates (6.6) generated acyl fluoride intermediates (6.5) in situ, which were subsequently treated with an alcohol, an amine, or a reducing agent. Scheme 6.4. Summary of the contributions made to the SOF2-mediated carboxylic acid activations and nucleophilic acyl substitutions/reductions described in Chapter 4. A wide range of aliphatic and aromatic carboxylic acid substrates were investigated for the formation of N-hydroxyphthalimidyl (6.10) and N-hydroxysuccinimidyl esters (6.11). Both strongly electron-donating and -withdrawing motifs were tolerated under the reaction conditions. It was noted that some sterically encumbered acyl fluorides failed to react with the comparatively bulky N-hydroxysuccinimide and N-hydroxyphthalimide nucleophiles, presumably due to disfavourable steric interactions. The one-pot protocol generated the corresponding activated esters in up to quantitative isolated yields. Column chromatography was not required as any excess gaseous SOF2 can be removed from solution by sparging with an inert gas, and any fluorosulfite (FSO2–) salt by-product can also be removed with ease during the extractive workup. The synthesis of non-activated esters (6.15) was facilitated using pre-formed mixtures of the corresponding alkoxide. Both aliphatic and aromatic Weinreb (6.12) and morpholine amides (6.13) were 249 synthesized successfully under the reaction conditions, further underscoring the potential applications of this esterification/amidation protocol in mainstream synthetic organic chemistry. The SOF2-mediated one-pot reduction of carboxylic acids using NaBH4 also proceeded via the corresponding acyl fluoride intermediate. The reaction was successfully applied to a scope of substituted aliphatic and aromatic carboxylic acids, suggesting tolerance for both electron-rich and -poor substrates. The main limitation to the reduction protocol was the arduous column chromatography required. These reactions represent some of the first major investigations of the chemical utility of SOF2 as a reagent in synthetic organic chemistry, focusing exclusively on carboxylic acid activation and one-pot processes. The SOF2-mediated nucleophilic acyl substitution reactions serve as a synthetic advancement over those explored using SO2F2 (Chapter 3) as no additive or chromatographic purification were required. The SOF2-mediated reduction serves as the first published example of a one-pot reduction via an acyl fluoride intermediate. Future advancements of the SOF2-mediated esterification include a greater analysis into the synthesis of non-activated esters, as well as non-activated primary and secondary amides. The synthetic applicability of the SOF2-mediated reduction may be improved in the future through a re-optimization of the purification process. The reduction is effective in generating the alcohol products in high yields, yet the protocol is limited by the arduous column chromatography required to remove reaction by-products. 6.4 Chapter 5: conclusions and future work Finally, Chapter 5 details the experimental design, optimization, and syntheses of sulfonimidoyl fluorides (6.16) from the corresponding sulfinic acids (6.17, Scheme 6.5). The 250 reaction exploits a sulfinyl fluoride intermediate (6.18), accessed by the deoxyfluorination of 6.17 with SOF2. This stage of the reaction was originally developed independently by Brodie J. Thomson, a Ph.D. student in the Sammis group, before being repurposed and reoptimized in the context of one-pot sulfonimidoyl fluoride syntheses. The use of gaseous SOF2 in this application is believed to enable the overall one-pot nature of the reaction, as any residual SOF2 can easily be removed from solution by sparging with an inert gas prior to addition of the nitrene source. The oxidative addition step is analogous to a literature procedure utilizing sulfonimidoyl chloride substrates.254 This work represents the first widely investigated application of SOF2 as a synthetic reagent outside of the sphere of carboxylic acid activation. Scheme 6.5. Summary of the contributions made to the SOF2-mediated one-pot synthesis of sulfonimidoyl fluorides described in Chapter 5. The SOF2-mediated reaction avoids the discreet isolation of any oxidatively or hydrolytically unstable intermediates, a notable advancement over similar protocols that require the isolation of sulfonimidoyl chlorides. This new approach to the synthesis of sulfonimidoyl fluorides is greatly expedited over similar reports,254 with a single one-pot reaction effectively replacing a discreet three-step deoxychlorination, oxidative addition, and halogen exchange sequence, each requiring their own isolation protocols. This advancement is significant towards accessing these synthetically valuable sulfur(VI) motifs. It is expected that this one-pot SOF2-251 mediated reaction may be utilized in small-scale laboratory applications to enable rapid access to small libraries of other sulfur(VI) derivatives of pharmaceutical relevance, including sulfoximines, sulfonimidamides, and sulfonimidate esters. This project is currently ongoing, and there are a number of investigations worth pursuing that I unfortunately did not have the time to explore. Firstly, the scope of sulfinic acid substrates effectively surveys the breadth of suitable aryl sulfinic acids, yet the inclusion of a short list of additional substrates would be ideal in completing the investigation. In addition to the ongoing investigations described previously (Chapter 5), 4-bromobenzenesulfinic acid (6.17a) would be an excellent addition to the scope (Scheme 6.6). The synthesis of the corresponding sulfonimidoyl fluoride (6.16a) would complete the scope of para-substituted halogenated sulfinic acid substrates, providing the final piece of evidence that the SOF2-mediated protocol can be applied to halogenated aryl sulfinic acids. Additionally, the synthesis of (+)-camphor-derivative 6.16b would provide evidence that the protocol can potentially be applied to the functionalization of natural products. Given that (+)-camphorsulfinic acid (6.17b) is enantiopure, it’s functionalization with SOF2 and chloramine T under the reaction conditions should lead to the formation of two diastereomers. This reaction may provide insight into the diastereoselectivity of the one-pot reaction, as all substrates studied thus far have been racemates. 252 Scheme 6.6. Proposed additional sulfonimidoyl fluorides to be synthesized using the SOF2-mediated protocol. The scope of nitrene sources has yet to be developed; it is hypothesized that azides (6.19) may serve effectively as nitrene precursors in the reaction, and that their use could dramatically expand the scope of potential sulfonimidoyl fluorides accessible through this protocol (Scheme 6.7). Given that azides are readily accessible from the corresponding alkyl halide or alcohol via substitution processes257,274–277 and that some are commercially available as well, it is anticipated that they may serve as an effective representative nitrene precursor. Scheme 6.7. Proposed representative scope of alkyl azides as nitrene sources in the SOF2-mediated synthesis of sulfonimidoyl fluorides. It would be advantageous if the one-pot SOF2-mediated synthesis of sulfonimidoyl fluorides could be advanced further, enabling direct access to other sulfur(VI) motifs from sulfinic 253 acids (6.17) in an overall one-pot deoxyfluorination-oxidative addition-nucleophilic substitution sequence (Scheme 6.8). Redesigning the reaction to accommodate the directed syntheses of sulfoximines (6.20), sulfonimidamides (6.21), and/or sulfonimidate esters (6.22) would facilitate a unified strategy to access these valuable motifs, without the need for multiple isolation and purification processes. Scheme 6.8. (a) The proposed telescopic approach to the synthesis of other sulfur(VI) motifs directly from the sulfinic acid, utilizing the sulfonimidoyl fluoride as a reactive intermediate, and (b) the proposed direct-displacement mechanism. 6.5 Potential future directions of thionyl fluoride as a synthetic reagent This thesis has investigated some of the many synthetic applications of sulfuryl and thionyl fluoride in organic chemistry. The chemistry of thionyl fluoride is particularly interesting as SOF2-mediadted processes are still limited in number, and the field is in its infancy. There are undoubtably many more potential synthetic applications of SOF2, some of which are currently under investigation by the Sammis group. 254 One possible new application of SOF2 is to the Pummerer-type rearrangement of sulfoxides (6.23) to the corresponding α-fluorinated sulfide (6.24, Scheme 6.9a). As a possible extension to this methodology, the addition of a competitive nucleophile (NuH) and a fluoride trapping agent (i.e. trimethylsilyl chloride) could enable the one-pot synthesis of more complex α-substituted sulfide derivatives (6.25).Thionyl chloride (SOCl2) has been utilized in a similar application with 6.26 for the synthesis of the corresponding α-chlorinated sulfides (6.27, Scheme 6.9b),278 suggesting a potential extension of this chemistry to SOF2. The synthesis of α-fluorinated sulfides has also been accomplished utilizing SelectfluorTM.279 Scheme 6.9. (a) The proposed SOF2-mediated Pummerer-type rearrangement of sulfoxides, and (b) the SOCl2-mediadted approach by Hisashi et al.278 The use of SOCl2 and triphenylphosphine (PPh3) has been described for the reduction of sulfoxides (6.28) to the corresponding sulfide (6.29) as well (Scheme 6.10);280 it is possible that SOF2 could be applied to a similar effect. 255 Scheme 6.10. Thionyl chloride-mediated reduction of sulfoxides to sulfides280 and the proposed corresponding process with thionyl fluoride. 6.6 Summary of Conclusions Five novel synthetic applications of sulfuryl fluoride and thionyl fluoride have been investigated throughout the course of this work. These include: (1) a sulfuryl fluoride-mediated 1,1-dihydrofluoroalkylation of thiols; (2) a sulfuryl fluoride-mediated activation and nucleophilic acyl substitution of carboxylic acids; (3) a thionyl fluoride-mediated esterification and amidation of carboxylic acids; (4) a mild thionyl fluoride-mediated reduction of carboxylic acids to alcohols; and (5) a one-pot thionyl-fluoride mediated synthesis of sulfonimidoyl fluorides from sulfinic acids. The initial work performed using sulfuryl fluoride provided the foundation and experience necessary to develop these three new thionyl-fluoride mediated processes. The synthesis of sulfonimidoyl fluorides serves as the culmination of the work described in this dissertation, providing an expedited route to a synthetically and pharmaceutically relevant chemical motif. Our understanding of the synthetic utility of sulfuryl fluoride and thionyl fluoride has grown as a result of the work described herein. 256 References 1. Bolduc, T. 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Sci. 2022, 2, 6–7. 276 Appendices Appendix A Selected Spectra for Chapter 2 1H NMR (300 MHz, Chloroform-d) of 2.10d 19F NMR (282 MHz, Chloroform-d) of 2.10d 277 1H NMR (300 MHz, Chloroform-d) of 2.10e 13C{1H} NMR (75 MHz, Chloroform-d) of 2.10e 278 19F NMR (282 MHz, Chloroform-d) of 2.10e 1H NMR (300 MHz, Chloroform-d) of 2.10g 279 13C{1H} NMR (75 MHz, Chloroform-d) of 2.10g 19F NMR (282 MHz, Chloroform-d) of 2.10g 280 1H NMR (300 MHz, Chloroform-d) of 2.10h 13C{1H} NMR (75 MHz, Chloroform-d) of 2.10h 281 19F NMR (282 MHz, Chloroform-d) of 2.10h 1H NMR (300 MHz, Chloroform-d) of 2.10k 282 13C{1H} NMR (75 MHz, Chloroform-d) of 2.10k 19F NMR (282 MHz, Chloroform-d) of 2.10k 283 1H NMR (300 MHz, Chloroform-d) of 2.10l 13C{1H} NMR (75 MHz, Chloroform-d) of 2.10l 284 19F NMR (282 MHz, Chloroform-d) of 2.10l 1H NMR (300 MHz, Chloroform-d) of 2.11d 285 19F NMR (282 MHz, Chloroform-d) of 2.11d 1H NMR (300 MHz, Chloroform-d) of 2.11e 286 19F NMR (282 MHz, Chloroform-d) of 2.11e 1H NMR (300 MHz, Chloroform-d) of 2.11i 287 19F NMR (282 MHz, Chloroform-d) of 2.11i 1H NMR (300 MHz, Chloroform-d) of 2.11j 288 13C{1H} NMR (75 MHz, Chloroform-d) of 2.11j 19F NMR (282 MHz, Chloroform-d) of 2.11j 289 19F NMR (282 MHz, Chloroform-d) of 2.29a 19F NMR (282 MHz, Chloroform-d) of 2.29b 290 Appendix B Selected Spectra for Chapter 3 1H NMR (300 MHz, Chloroform-d) of 3.1g 19F NMR (282 MHz, Chloroform-d) of 3.1g 291 1H NMR (300 MHz, Chloroform-d) of 3.1h 19F NMR (282 MHz, Chloroform-d) of 3.1h 292 1H NMR (300 MHz, Chloroform-d) of 3.48f 1H NMR (300 MHz, Chloroform-d) of 3.48g This spectrum contains residual solvent signals from ethyl acetate and hexanes. The isolated yield has been corrected to reflect this. 293 19F NMR (282 MHz, Chloroform-d) of 3.48g 1H NMR (300 MHz, Chloroform-d) of 3.48h 294 1H NMR (300 MHz, Chloroform-d) of 3.48i 13C{1H} NMR (75 MHz, Chloroform-d) of 3.48i 295 1H NMR (300 MHz, Chloroform-d) of 3.48j This spectrum contains residual solvent signals from ethyl acetate and hexanes. The isolated yield has been corrected to reflect this. 1H NMR (300 MHz, Chloroform-d) of 3.58 296 1H NMR (300 MHz, Chloroform-d) of 3.59 13C {1H} NMR (75 MHz, Chloroform-d) of 3.59 297 1H NMR (300 MHz, Chloroform-d) of 3.60 13C{1H} NMR (75 MHz, Chloroform-d) of 3.60 298 Appendix C Selected Spectra for Chapter 4 19F NMR (282 MHz, Chloroform-d) of 4.3p 19F NMR (282 MHz, Chloroform-d) of 4.3q 299 1H NMR (300 MHz, Chloroform-d) of 4.5c 13C{1H} NMR (75 MHz, Chloroform-d) of 4.5c 300 1H NMR (300 MHz, Chloroform-d) of 4.5d 13C{1H} NMR (75 MHz, Chloroform-d) of 4.5d 301 1H NMR (300 MHz, Chloroform-d) of 4.6c 1H NMR (300 MHz, Chloroform-d) of 4.6f 302 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6f 19F NMR (282 MHz, Chloroform-d) of 4.6f 303 1H NMR (300 MHz, Chloroform-d) of 4.6h 1H NMR (300 MHz, Chloroform-d) of 4.6i 304 1H NMR (300 MHz, Chloroform-d) of 4.6j 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6j 305 1H NMR (300 MHz, Chloroform-d) of 4.6k 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6k 306 1H NMR (300 MHz, Chloroform-d) of 4.6l 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6l 307 1H NMR (300 MHz, Chloroform-d) of 4.6m 1H NMR (300 MHz, Chloroform-d) of 4.6n 308 1H NMR (300 MHz, Chloroform-d) of 4.6o 1H NMR (300 MHz, Chloroform-d) of 4.6p 309 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6p 1H NMR (300 MHz, Chloroform-d) of 4.6q 310 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6q 1H NMR (300 MHz, Chloroform-d) of 4.6r 311 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6r 1H NMR (300 MHz, Chloroform-d) of 4.6s 312 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6s 1H NMR (300 MHz, Chloroform-d) of 4.6t 313 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6t 1H NMR (300 MHz, Chloroform-d) of 4.6u 314 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6u 1H NMR (300 MHz, Chloroform-d) of 4.6v 315 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6v 1H NMR (300 MHz, Chloroform-d) of 4.6w 316 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6w 1H NMR (300 MHz, Chloroform-d) of 4.6x 317 13C{1H} NMR (75 MHz, Chloroform-d) of 4.6x 1H NMR (300 MHz, Chloroform-d) of 4.6y 318 1H NMR (300 MHz, Chloroform-d) of 4.6z 1H NMR (300 MHz, Chloroform-d) of 4.6aa 319 1H NMR (300 MHz, Chloroform-d) of 4.6ab 1H NMR (300 MHz, Chloroform-d) of 4.7e 320 13C{1H} NMR (75 MHz, Chloroform-d) of 4.7e 19F NMR (282 MHz, Chloroform-d) of 4.7e 321 1H NMR (300 MHz, Chloroform-d) of 4.7f 13C{1H} NMR (75 MHz, Chloroform-d) of 4.7f 322 19F NMR (282 MHz, Chloroform-d) of 4.7f 1H NMR (300 MHz, Chloroform-d) of 4.7g 323 13C{1H} NMR (75 MHz, Chloroform-d) of 4.7g 19F NMR (282 MHz, Chloroform-d) of 4.7g 324 1H NMR (300 MHz, Chloroform-d) of 4.7h 13C{1H} NMR (75 MHz, Chloroform-d) of 4.7h 325 1H NMR (300 MHz, Chloroform-d) of 4.7i 13C{1H} NMR (75 MHz, Chloroform-d) of 4.7i 326 1H NMR (300 MHz, Chloroform-d) of 4.7j 13C{1H} NMR (75 MHz, Chloroform-d) of 4.7j 327 1H NMR (300 MHz, Chloroform-d) of 4.7k 13C{1H} NMR (75 MHz, Chloroform-d) of 4.7k 328 1H NMR (300 MHz, Chloroform-d) of 4.7l 13C{1H} NMR (75 MHz, Chloroform-d) of 4.7l 329 1H NMR (300 MHz, Chloroform-d) of 4.7m 13C{1H} NMR (75 MHz, Chloroform-d) of 4.7m 330 1H NMR (300 MHz, Chloroform-d) of 4.7n 13C{1H} NMR (75 MHz, Chloroform-d) of 4.7n 331 1H NMR (300 MHz, Chloroform-d) of 4.7o 13C{1H} NMR (75 MHz, Chloroform-d) of 4.7o 332 1H NMR (300 MHz, Chloroform-d) of 4.8e 13C{1H} NMR (75 MHz, Chloroform-d) of 4.8e 333 19F NMR (282 MHz, Chloroform-d) of 4.8e 1H NMR (300 MHz, Chloroform-d) of 4.8f 334 13C{1H} NMR (75 MHz, Chloroform-d) of 4.8f 19F NMR (282 MHz, Chloroform-d) of 4.8f 335 1H NMR (300 MHz, Chloroform-d) of 4.8g 13C{1H} NMR (75 MHz, Chloroform-d) of 4.8g 336 19F NMR (282 MHz, Chloroform-d) of 4.8g 1H NMR (300 MHz, Chloroform-d) of 4.8h 337 13C{1H} NMR (75 MHz, Chloroform-d) of 4.8h 1H NMR (300 MHz, Chloroform-d) of 4.8i 338 13C{1H} NMR (75 MHz, Chloroform-d) of 4.8i 1H NMR (300 MHz, Chloroform-d) of 4.8j 339 13C{1H} NMR (75 MHz, Chloroform-d) of 4.8j 1H NMR (300 MHz, Chloroform-d) of 4.8k 340 13C{1H} NMR (75 MHz, Chloroform-d) of 4.8k 1H NMR (300 MHz, Chloroform-d) of 4.8l 341 13C{1H} NMR (75 MHz, Chloroform-d) of 4.8l 1H NMR (300 MHz, Chloroform-d) of 4.8m 342 13C{1H} NMR (75 MHz, Chloroform-d) of 4.8m 1H NMR (300 MHz, Chloroform-d) of 4.8n 343 13C{1H} NMR (75 MHz, Chloroform-d) of 4.8n 1H NMR (300 MHz, Chloroform-d) of 4.8o 344 13C{1H} NMR (75 MHz, Chloroform-d) of 4.8o 1H NMR (300 MHz, Chloroform-d) of 4.15a 345 13C{1H} NMR (75 MHz, Chloroform-d) of 4.15a 1H NMR (300 MHz, Chloroform-d) of 4.15b 346 13C{1H} NMR (75 MHz, Chloroform-d) of 4.15b 19F NMR (282 MHz, Chloroform-d) of 4.15b 347 1H NMR (300 MHz, Chloroform-d) of 4.16a 13C{1H} NMR (75 MHz, Chloroform-d) of 4.16a 348 1H NMR (300 MHz, Chloroform-d) of 4.16b 13C{1H} NMR (75 MHz, Chloroform-d) of 4.16b 349 19F NMR (282 MHz, Chloroform-d) of 4.16b 350 Appendix D Selected Spectra for Chapter 5 1H NMR (300 MHz, Chloroform-d) of 5.1d 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1d 351 19F NMR (282 MHz, Chloroform-d) of 5.1d 1H NMR (300 MHz, Chloroform-d) of 5.1e 352 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1e 19F NMR (282 MHz, Chloroform-d) of 5.1e 353 1H NMR (300 MHz, Chloroform-d) of 5.1f 19F NMR (282 MHz, Chloroform-d) of 5.1f 354 1H NMR (300 MHz, Chloroform-d) of 5.1g 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1g 355 19F NMR (282 MHz, Chloroform-d) of 5.1g 1H NMR (300 MHz, Chloroform-d) of 5.1h 356 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1h 19F NMR (282 MHz, Chloroform-d) of 5.1h 357 1H NMR (300 MHz, Chloroform-d) of 5.1i 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1i 358 19F NMR (282 MHz, Chloroform-d) of 5.1i 1H NMR (300 MHz, Chloroform-d) of 5.1j 359 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1j A minor quantity of grease was detected at 29.82 ppm in this spectrum. 19F NMR (282 MHz, Chloroform-d) of 5.1j 360 1H NMR (300 MHz, Chloroform-d) of 5.1k 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1k 361 19F NMR (282 MHz, Chloroform-d) of 5.1k 1H NMR (300 MHz, Chloroform-d) of 5.1l 362 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1l 19F NMR (282 MHz, Chloroform-d) of 5.1l 363 1H NMR (300 MHz, Chloroform-d) of 5.1m 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1m 364 19F NMR (282 MHz, Chloroform-d) of 5.1m 1H NMR (300 MHz, Chloroform-d) of 5.1n 365 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1n A minor quantity of grease was detected at 29.80 ppm in this spectrum. 19F NMR (282 MHz, Chloroform-d) of 5.1n 366 1H NMR (300 MHz, Chloroform-d) of 5.1o 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1o A minor quantity of grease was detected at 29.81 ppm in this spectrum. 367 19F NMR (282 MHz, Chloroform-d) of 5.1o 1H NMR (300 MHz, Chloroform-d) of 5.1p 368 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1p 19F NMR (282 MHz, Chloroform-d) of 5.1p 369 1H NMR (300 MHz, Chloroform-d) of 5.1q 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1q 370 19F NMR (282 MHz, Chloroform-d) of 5.1q 1H NMR (300 MHz, Chloroform-d) of 5.1r 371 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1r 19F NMR (282 MHz, Chloroform-d) of 5.1r 372 1H NMR (300 MHz, Chloroform-d) of 5.1s 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1s 373 19F NMR (282 MHz, Chloroform-d) of 5.1s 1H NMR (300 MHz, Chloroform-d) of 5.1t Compound 5.1t is not pure, as evidenced by the multiplet at 2.44 ppm. 374 13C{1H} NMR (75 MHz, Chloroform-d) of 5.1t Compound 5.1t is not pure, as evidenced by the extra 12 signals present in this spectrum. A minor quantity of grease was detected at 29.80 ppm in this spectrum. 19F NMR (282 MHz, Chloroform-d) of 5.1t281
Thesis/Dissertation
eng
Chemistry
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Sammis, Glenn
Investigations of one-pot synthetic transformations mediated by sulfuryl fluoride and thionyl fluoride
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