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Isomerization reactions of enesulfonamides and enecarbamates using platinum(II) and silver(I) catalysts Dodd, Jennifer Megan 2010

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ISOMERIZATION REACTIONS OF ENESULFONAMIDES AND ENECARBAMATES USING PLATINUM(II) AND SILVER(I) CATALYSTS  by  Jennifer Megan Dodd B. Sc., Simon Fraser University, 2005  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENCE in The Faculty of Graduate Studies (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  March 2010  ©Jennifer Megan Dodd, 2010  Abstract The scope of a platinum(II) chloride catalyzed isomerization of enesulfonamides and enecarbamates that proceeds by alkyne activation followed by Friedel-Crafts reaction was investigated. Seven enesulfonamide and enecarbamate derivatives with a variety of aromatics and heteroaromatics were synthesized.  Exposure to catalytic platinum chloride generated  tetracyclic products in 17 to 78% yield. The regioselectivity of the attack on the alkyne in this reaction varied from 8:1 to 1:0 mixtures of products. Additionally, a silver-catalyzed ring expansion reaction of enesulfonamides containing 2-alkynyl indoles to generate eight-membered rings was investigated.  A series of control reactions were performed to determine the  mechanism, which was found to proceed by interaction of the catalyst with the indole ring. Thirteen enesulfonamide derivatives containing aromatic, heteroaromatic and carbonyl substituents were submitted to silver and acid catalysis, yielding azocine derivatives in 0 to 97% yield.  ii  Table of Contents Abstract........................................................................................................................................... ii Table of Contents........................................................................................................................... iii List of Tables ...................................................................................................................................v List of Figures.................................................................................................................................vi List of Schemes............................................................................................................................ viii List of Abbreviations and Symbols .................................................................................................x Acknowledgements...................................................................................................................... xiii 1. Introduction..................................................................................................................................1 2. Platinum-Catalyzed Reactions...................................................................................................11 2.1. Synthesis of Substrates ...............................................................................................11 2.2. Platinum(II)-Catalyzed Reactions of Enecarbamate 2.7 ............................................17 2.3. Platinum(II)-Catalyzed Reactions of Enesulfonamides..............................................20 3. Rearrangement Reactions of Enesulfonamides .........................................................................26 3.1. Observation of New Product ......................................................................................26 3.2. Nitrogen-Containing Eight-Membered Rings ............................................................27 3.3. Possible Mechanism ...................................................................................................29 3.4. Synthesis of Substrates ...............................................................................................32 3.5. Scope of Rearrangement Reactions ............................................................................35 3.6. Discussion of Results..................................................................................................38 3.7. Reactions of Carbonyl Compounds ............................................................................40 4. Conclusion and Future Direction...............................................................................................44 5. Experimental Details .................................................................................................................46 5.1. General Experimental .................................................................................................46 5.2. Synthesis of Starting Materials ...................................................................................47 5.2.1. Synthesis of Enecarbamate 2.7 ....................................................................47 5.2.2. Synthesis of Terminal Alkyne 2.13 .............................................................50 5.2.3. Synthesis of Aryl Halides ............................................................................53 5.2.4. Sonogashira Cross-Coupling Reactions ......................................................58 5.3. Synthesis of Tetracyclic Products...............................................................................66 5.4. Synthesis of Ring-Expansion Products.......................................................................73 iii  References......................................................................................................................................85 Appendix A: Imidazole Chemistry................................................................................................89 A.1. Research.....................................................................................................................89 A.2. Selected Characterization Data..................................................................................95 A.3. References..................................................................................................................98 Appendix B: Selected Spectra .......................................................................................................99  iv  List of Tables Table 2.1: Synthesis of Aryl Halides for Sonogashira Coupling Reaction ...................................15 Table 2.2: Sonogashira Cross-Coupling Reaction Results ............................................................16 Table 2.3: Platinum(II)-Catalyzed Cyclization Conditions with Enecarbamate 2.7 .....................19 Table 2.4: Cyclization Reactions of Dimethoxybenzene Derivatives ...........................................21 Table 2.5: Cyclization Reactions of 2-Substituted Indole Derivatives..........................................24 Table 3.1: Ring Expansion Control Reactions on Substrate 2.22..................................................31 Table 3.2: Synthesis of Aryl Halides for use in Sonogashira Coupling Reaction .........................33 Table 3.3: Sonogashira Coupling Reaction Results ......................................................................34 Table 3.4: Synthesis of α,β-Alkynyl Carbonyl Substrates.............................................................35 Table 3.5: Rearrangement Reactions Attempted with Silver Hexafluoroantimonate ...................37 Table 3.6: Brønsted and Lewis Acid-Catalyzed Rearrangement Reaction Results.......................38 Table 3.7: Silver-Catalyzed Reactions with α,β-Alkynyl Carbonyl Substrates ............................41 Table 3.8: Cyclization Reactions of tert-Butyl Alkynyl Carbonyl 3.36........................................43 Table 5.1: COSY Data for 2.25 .....................................................................................................71 Table 5.2: NMR Data for 2.25.......................................................................................................72 Table 5.3: COSY Data for 3.1 .......................................................................................................75 Table 5.4: NMR Data for 3.1.........................................................................................................76 Table 5.5: X-Ray Crystallographic Data for 3.1............................................................................77 Table 5.6: COSY Data for 3.50 .....................................................................................................79 Table 5.7: 1H Selective NOE Data for 3.50...................................................................................79 Table 5.8: NMR Data for 3.50.......................................................................................................80 Table 5.9: COSY Data for 3.58 .....................................................................................................83 Table 5.10: NMR Data for 3.58.....................................................................................................84 Table B.1: X-Ray Crystallographic Data for A.19 ......................................................................129  v  List of Figures Figure 1.1: A General Description of Enesulfonamides and Enecarbamates..................................7 Figure 1.2: Rationale for Isomer Ratio of Product Observed ..........................................................9 Figure 2.1: Key COSY and HMBC Correlations for Cyclization Product 2.25............................18 Figure 3.1: Structure of Product 3.1 by X-Ray Crystallography and NMR Correlations .............27 Figure 3.2: The Parent Ring, Azocine ...........................................................................................27 Figure A.1: Target Imidazole and Fragmentation Pathway...........................................................89 Figure A.2: Preferred Sites of Electrophilic Aromatic Substitution..............................................90 Figure A.3: Installation of Nitro Group by Diazotization .............................................................90 Figure A.4: Solid State Molecular Structure of Compound A.19 .................................................92 Figure B.1: 3-(5-(4-Methoxyphenyl)pent-4-ynyl)piperidin-2-one 2.5 ..........................................99 Figure B.2: tert-Butyl 3-(5-(4-methoxyphenyl)pent-4-ynyl)-2-oxopiperidine1-carboxylate 2.6 ............................................................................................................. 100 Figure B.3: tert-Butyl 5-(5-(4-methoxyphenyl)pent-4-ynyl)-3,4-dihydropyridine-1(2H)carboxylate 2.7.................................................................................................................101 Figure B.4: 1-Methyl-2-(5-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)1H-indole 2.22 .................................................................................................................102 Figure B.5: 5-(5-(3,4-Dimethoxyphenyl)pent-4-ynyl)-1-tosyl-1,2,3,4tetrahydropyridine 2.19....................................................................................................103 Figure B.6: 5-(5-(Furan-2-yl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine 2.18...................104 Figure B.7: 2-(5-(1-Tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)-1H-indole 2.21 ............105 Figure B.8: 1-Methyl-3-(5-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)1H-indole 2.23 .................................................................................................................106 Figure B.9: 5-(5-(3,5-Dimethoxyphenyl)pent-4-ynyl)-1-tosyl-1,2,3,4tetrahydropyridine 2.20....................................................................................................107 Figure B.10: 1-Benzyl-2-(5-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)1H-indole 3.29 .................................................................................................................108 Figure B.11: 1-Phenyl-2-(5-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)1H-indole 3.30 .................................................................................................................109 Figure B.12: 5-(5-(1-Methyl-1H-pyrrol-2-yl)pent-4-ynyl)-1-tosyl-1,2,3,4tetrahydropyridine 3.33....................................................................................................110 vi  Figure B.13: 5-(5-(Benzofuran-2-yl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine 3.31 ......111 Figure B.14: Methyl 6-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)hex-2-ynoate 3.34 ....................112 Figure B.15: 7-(1-Tosyl-1,4,5,6-tetrahydropyridin-3-yl)hept-3-yn-2-one 3.35 ..........................113 Figure B.16: 2,2-Dimethyl-8-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)oct-4-yn-3-one 3.36.......114 Figure B.17: Tetracycle 2.25 .......................................................................................................115 Figure B.18: Tetracycle 2.29a .....................................................................................................116 Figure B.19: Tetracycle 2.26a and 2.26b....................................................................................117 Figure B.20: Tetracycle 2.30a .....................................................................................................118 Figure B.21: Tetracycle 2.31a .....................................................................................................119 Figure B.22: Tetracycle 2.33a .....................................................................................................120 Figure B.23: Tetracycle 2.27a and 2.27b....................................................................................121 Figure B.24 (E)-1-(1-Benzyl-1H-indol-2-yl)-3-tosyl-4,5,6,7,8,9-hexahydro-3Hcyclopenta[d]azocine 3.37 ...............................................................................................122 Figure B.25: (E)-1-(1-Methyl-1H-indol-2-yl)-3-tosyl-4,5,6,7,8,9-hexahydro-3Hcyclopenta[d]azocine 3.1 .................................................................................................123 Figure B.26: (E)-1-(1-Phenyl-1H-indol-2-yl)-3-tosyl-4,5,6,7,8,9-hexahydro-3Hcyclopenta[d]azocine 3.38 ...............................................................................................124 Figure B.27: (E)-5-(1-Methyl-1H-indol-2-yl)-3-tosyl-1,2,3,6,7,8hexahydrocyclopenta[d]azepine 3.44 ..............................................................................125 Figure B.28: Tricycle 3.50...........................................................................................................126 Figure B.29: 1-Tosyl-3,4,6,7,10,10a-hexahydrocyclopenta[e]quinolin-9(1H,2H,5H)-one 3.51 ..................................................................................................................................127 Figure B.30: (E)-2,2-Dimethyl-1-(3-tosyl-4,5,6,7,8,9-hexahydro-3Hcyclopenta[d]azocin-1-yl)propan-1-one 3.58 ..................................................................128  vii  List of Schemes Scheme 1.1: Generalized Mechanism of Platinum(II) Activation of an Alkyne.............................2 Scheme 1.2: Pal’s Benzothiazine Synthesis using Silver Catalysis ................................................3 Scheme 1.3: Fürstner’s Synthesis of Benzofurans by a Cyclization-Migration Process.................3 Scheme 1.4: Sames’ Metal-Catalyzed Friedel-Crafts Reaction ......................................................4 Scheme 1.5: Fürstner’s Platinum-Catalyzed Synthesis of Phenanthrenes.......................................4 Scheme 1.6: Nakamura’s Platinum-Catalyzed Cyclization Reaction of Alkoxyamides .................5 Scheme 1.7: Barluenga’s Platinum-Catalyzed Cyclization/Prins Reaction Sequence ....................5 Scheme 1.8: Murai’s Platinum-Catalyzed Reaction of an Alkene with an Alkyne.........................6 Scheme 1.9: Fürstner’s Platinum(II) Chloride Isomerization..........................................................6 Scheme 1.10: Bicyclic Products Generated from Reaction of Enesulfonamides............................7 Scheme 1.11: Dake’s Spirocyclization Reaction Using Enamine Derivatives................................8 Scheme 1.12: Platinum(II)-Catalyzed Cyclization to form Tetracyclic Products ...........................8 Scheme 1.13: Proposed Mechanism for the Formation of Tetracyclic Products ............................9 Scheme 1.14: Zhai’s Platinum Catalyzed Cyclization Towards Nakadomarin A .........................10 Scheme 2.1: Synthesis of 1-(5-Iodopent-1-ynyl)-4-methoxybenzene 2.3.....................................12 Scheme 2.2: Synthesis of Enecarbamate Derivative 2.7 ...............................................................13 Scheme 2.3: Synthesis of (5-Bromopent-1-ynyl)trimethylsilane 2.9 ............................................13 Scheme 2.4: Synthesis of Enesulfonamide Derivatives with Varied Aromatic Substituents........14 Scheme 2.5: Regioisomeric Cyclization Products not Observed ..................................................22 Scheme 2.6: Cyclization of Furan Derivative 2.18........................................................................23 Scheme 2.7: Attempted Cyclization of Indole 2.24.......................................................................24 Scheme 2.8: Cyclization of 3-Substituted Indole Derivative ........................................................25 Scheme 3.1: Reaction Forming New Product ...............................................................................26 Scheme 3.2: Voskressensky’s Benzazocine Synthesis..................................................................28 Scheme 3.3: Gil’s Formation of Azocine Derivatives by Cycloaddition/Ring-Opening ..............28 Scheme 3.4: Kozmin’s Silver-Catalyzed Cyclobutene Synthesis .................................................29 Scheme 3.5: Krische’s Alkyne-Carbonyl Cyclization with Silver Hexafluoroantimonate ...........29 Scheme 3.6: Possible Mechanisms from Initial Silver-Catalyzed Activation of Alkyne..............30  viii  Scheme 3.7: Proposed Mechanism of Silver-Catalyzed Rearrangement Reaction .......................32 Scheme 3.8: Proposed Mechanism for Formation of Tetracyclic Product 2.33a..........................39 Scheme 3.9: Proposed Mechanism for Formation of Lactone 3.50 ..............................................41 Scheme 3.10: Wenkert’s Synthesis of the Core of Deethylvincadifformine.................................42 Scheme 4.1: Proposed Cyclization of Methyl Enecarbamate Derivative......................................44 Scheme 4.2: Proposed Iminium Catalysis .....................................................................................45 Scheme 4.3: Proposed Future Tetrafluoroboric Acid Rearrangement Reactions..........................45 Scheme A.1: Reported Synthesis of Target A.1 ............................................................................91 Scheme A.2: Proposed Synthesis of Compound A.1 ....................................................................91 Scheme A.3: Synthesis of Imidazole Dimer..................................................................................92 Scheme A.4: Attempted Reactions with N-Butyl Imidazole A.20 ................................................93 Scheme A.5: General Description of Reactions Attempted with TFAA/Metal Nitrates...............93 Scheme A.6: Attempted Ipso-Substitution Reaction .....................................................................94 Scheme A.7: Attempted Reaction with Isoamyl Nitrite ................................................................94 Scheme A.8: Attempted Nucleophilic Substitution.......................................................................95 Scheme A.9: Buchwald’s Palladium-Catalyzed Nitration.............................................................95  ix  List of Abbreviations and Symbols δ  chemical shift  δ  delta  Å  angstrom  Ac  acetyl  Anal.  analysis  APCI  atmospheric pressure chemical ionization  Ar  aryl  B  base  Bn  benzyl  Boc  tert-butyloxycarbonyl  br  broad  Bu  butyl  °C  degrees Celcius  calcd  calculated  cm-1  reciprocal centimeters  cod  1,5-cyclooctadiene  COSY  correlational spectroscopy  d  doublet  dd  doublet of doublets  DCE  1,2-dichloroethane  dec  decomposed  DIBAL-H  diisobutylaluminum hydride  DMAP  N,N-(dimethylamino)pyridine  DMF  N,N-dimethylformamide  DMSO  dimethylsulfoxide  dt  doublet of triplets  equiv  equivalent  ESI  electrospray ionization  Et  ethyl  g  gram(s) x  h  hour(s)  HMBC  heteronuclear multiple bond correlation  HRMS  high resolution mass spectrum  IR  infrared  J  coupling constant  JohnPhos  (2-biphenylyl)di-tert-butylphosphine  L  ligand  μL  microliter  M  metal, molarity  m  multiplet  MHz  megahertz  min  minute(s)  mmHg  millimetres of mercury  mmol  millimole(s)  MS  molecular sieves, mass spectrum  Me  methyl  mg  milligram(s)  mL  millilitre(s)  m.p.  melting point  Ms  methanesulfonyl  n  normal  NMR  nuclear magnetic resonance  NOE  nuclear Overhauser effect  Nuc  nucleophile  Ph  phenyl  ppm  parts per million  R  undefined portion of a molecule  rsm  recovered starting material  rt  room temperature  s  singlet  t  triplet  TBS  tert-butyldimethyl silyl xi  TDA  tris[2-(2-methoxyethoxy)ethyl]amine  TFAA  trifluoroacetic anhydride  THF  tetrahydrofuran  TIPS  triisopropyl silyl  TLC  thin layer chromatography  TMEDA  N,N,N’,N’-tetramethylethylenediamine  TMS  trimethyl silyl  Ts  p-toluenesulfonyl  UV  ultraviolet  wt %  weight percent  X  halide  xii  Acknowledgements Firstly, I would like to thank my supervisor, Gregory Dake, for his guidance throughout my studies and for his patience in teaching me many aspects of chemistry. I would particularly like to acknowledge his support during the imidazole project.  I would also like to thank the members of the Dake group, past and present. I am grateful to Leah Easton and Tyler Harrison for sharing their wisdom with me in the beginning. I am also grateful to Jennifer Kozak, Krystle Guieb, Emmanuel Castillo and Julien Dugal-Tessier for interesting discussions and for sharing the ups and downs of grad school with me.  In particular, I would like to thank Julien Dugal-Tessier for his endless support, encouragement and belief in me. I would also like to thank my family for their support and understanding during my studies.  Finally, I would like to acknowledge the staff from the University of British Columbia NMR, mass spectroscopy and crystallography facilities for assistance with analysis, and Julie Daoust for advice on NMR experiments.  xiii  1. Introduction Although the synthesis of a large number of complex organic molecules has been achieved, many of these syntheses are lengthy and generate unwanted products. As a result, these types of syntheses are impractical and inefficient, especially on an industrial scale. Complex organic molecules produced on large scale are important for industries such as the pharmaceutical industry, which relies on efficient synthetic methods for production.  New  methods to make complex molecules continue to be developed to address the challenges of length and efficiency. Recently, the transition-metal activation of alkynes has been an area of intense investigation. As a result of their ability to bond through d-orbitals, transition metals have unique electronic properties compared to other elements, which translates to unique interactions with organic molecules. In particular, late transition metals have a special affinity to alkenes and alkynes. Alkynes and transition metals can undergo reactions that are not otherwise possible or would require many operations to accomplish the same goal.  Classically, alkynes are electron-rich unsaturated molecules and undergo reactions with electrophilic reagents such as bromine and Brønsted acids, in a similar fashion as alkenes. Electrophilic transition metal catalysts such as Pd(II), Ru(II), Rh(I), Ir(I), Ag(I), Au(I), Au(III), and Pt(II) will also react with alkynes.1-4 In contrast to other electrophilic reagents, once an alkyne has reacted with an electrophilic metal catalyst, it itself becomes electrophilic and is then activated to react further with a nucleophilic species. The metal catalysts most commonly used to activate alkynes are Pt(II), Au(I) and Ag(I). Many aspects of this area of research have been investigated and therefore, it has been thoroughly reviewed.5-13 Consequently, a detailed review will not be undertaken.  A representation of the activation of an alkyne by platinum(II) is shown in Scheme 1.1. Electrophilic platinum(II), gold(I) and silver(I) catalysts react with electrons in the π-system of an alkyne. For this reason they are sometimes referred to as π-acids.14 As previously noted, the complexed alkene or alkyne is made sufficiently electron-poor to be attacked by a nucleophile. The platinum or gold species have been depicted both in terms a non-classical cationic mechanism and a metal-stabilized carbene mechanism, and may be a continuum between the 1  two.5,6 The cationic mechanism is generally used to depict reactions where the alkyne only acts as a nucleophile. The vinyl platinum species then reacts with a proton (structure 1.3) to release the catalyst. The metal carbene mechanism is generally used to depict a mechanism where the alkyne reacts first as an electrophile and then as a nucleophile.  This area of chemistry represents a mechanistic strategy rather than a concrete functional group transformation. The examples presented have been chosen to convey the variety of nucleophiles that have been reacted with activated alkynes and the subsequent sequences of reactions that can be carried out after nucleophilic attack on an activated alkyne.  Scheme 1.1. Generalized Mechanism of Platinum(II) Activation of an Alkyne PtLn Nuc Pt   PtLn   H  H B Nuc  1.3  1.4  Nuc  Nuc: 1.1  1.2  PtLn  E+  PtLn E  Nuc 1.5  Nuc 1.6  The choice of nucleophile has varied from heteroatoms and aromatic rings to alkenes. Heteroatoms are an obvious choice as nucleophiles. A common use of silver catalysts is to activate alkynes for attack from heteroatom nucleophiles.  A synthesis of benzothiazine  derivatives from a sulfonamide and an alkyne-substituted benzene ring was reported in 2007 which demonstrates the use of silver catalysis (Scheme 1.2).15 Although triethylamine is used in these reaction conditions, the authors claim that the base is not necessary for reaction, but accelerates it. This is likely due to an increase in the concentration of deprotonated sulfonamide in solution, making it a better nucleophile. Electrophilic metal catalysts are useful for simple transformations, but more complex nucleophiles leading to more complex products can also be used.  2  Scheme 1.2. Pal’s Benzothiazine Synthesis using Silver Catalysis15 Cl AgSbF6 (15 mol %) NEt3 (3 equiv) S O  H N  Me  O  EtOH 80 °C 90%  Cl O  1.7  S  NMe O  1.8  The use of ethers as nucleophiles represents such a complex heteroatom nucleophile and has been reported by Fürstner (Scheme 1.3). This benzofuran synthesis uses ethers containing an allyl or a benzyl substituent, since this group must undergo cationic migration during the reaction.16 Additionally, the use of carbon monoxide as an additive is an interesting variation on platinum catalysis. It is believed that carbon monoxide is able to coordinate reversibly to the metal. Due to its electron-withdrawing nature, it makes the metal centre more electrophilic and, presumably, a more active catalyst.17 However heteroatoms are not the only nucleophiles that have been used to react with metal-activated alkynes. Scheme 1.3. Fürstner’s Synthesis of Benzofurans by a Cyclization-Migration Process16  O  PtCl2 (5 mol %) CO (1 atm) toluene 80 °C 88%  1.9  O  O  PtLn  1.10  1.11  Aromatic rings have also been used in these reactions. Aromatic rings undergo FriedelCrafts-type reactions with alkynes to yield products containing new carbon bonds to aromatic rings. The following two examples are typical of this reactivity. Platinum(II) chloride has been used by Sames to promote a cyclization towards chromene derivatives (Scheme 1.4).18 Electrondonating substituents on the aromatic ring were necessary, however, for a good yield using platinum(II). Platinum(IV) chloride, a more electrophilic metal catalyst, was found to be more reactive and was able to promote Friedel-Crafts reactions with aromatic rings that did not contain electron-donating substituents.  3  Scheme 1.4. Sames’ Metal-Catalyzed Friedel-Crafts Reaction18 Me  Me  Me  Me Me H  PtCl2 (5 mol %) toluene O  80 °C 87%  Me  1.12  Me  Me  PtLn Me  O 1.13  O 1.14  A similar result was observed by Fürstner during the development of a synthesis of phenanthrene derivatives (Scheme 1.5).19 Electrophilic aromatic substitution of the biphenyl derivative with a pendant alkyne was catalyzed by platinum(II) chloride. The yields of the electron-rich aromatics were high, but lower yields resulted from aromatics without electrondonating substituents. These two examples indicate that electrophilic aromatic substitution with alkynes requires activated substrates or a very electrophilic metal catalyst, but nevertheless, activated alkynes are electrophilic enough to undergo this reaction. Scheme 1.5. Fürstner’s Platinum-Catalyzed Synthesis of Phenanthrenes19 Me  Me  Me Me  Me H Me  PtCl2 (5 mol %) toluene 80 °C 89%  1.15  Me  Me Me  PtLn  1.16  1.17  Nakamura has extended the range of possible reactions to include bifunctional nucleophiles by using alkoxyamides in a cyclization reaction (Scheme 1.6).20 The incorporation of an N-alkoxy bond creates a leaving group (structure 1.19). This produces a mechanism for the formation of a stabilized metal carbene and an imine. The electrophilic carbene can then undergo Friedel-Crafts reaction with the aromatic ring. This strategy allows both sides of the alkyne to be involved in the reaction, which is generally not the case.  4  Scheme 1.6. Nakamura’s Platinum-Catalyzed Cyclization Reaction of Alkoxyamides20 Ph Ph  PtI4 (10 mol %) 1,4-dioxane  O N Me  N  100 °C 92%  N OMe  N Me  O  1.23  1.18  OMe LnPt  Ph N N Me  LnPt  N  OMe O  N Me  1.19  Ph LnPt  Ph H LnPt  Ph  N  N O  N Me  1.20  N Me  O  1.21  O  1.22  Sequences of reactions can also be created after the initial activation of the alkyne. An example has been published by Barluenga in which a platinum-catalyzed activation of an alkyne is coupled with a Prins reaction (Scheme 1.7).21 Attack of the hydroxyl group on the activated alkyne yields a pyran ring containing an exocyclic alkene. Further activation of this exocyclic alkene leads to attack from an allyl group in a Prins reaction, and the remaining carbocation reacts with methanol to yield the product. Scheme 1.7. Barluenga’s Platinum-Catalyzed Cyclization/Prins Reaction Sequence21 OH  [PtCl2(cod)] (2 mol %) MeOH  OMe O O  65 °C 95% 1.24  1.25  1.26  It has further been observed that some substrates undergo rearrangement using Pt(II) and Au(I) catalysis, particularly if an alkene is used as a nucleophile. Murai has reported an example where a terminal alkyne reacts intramolecularly with an alkene and a five-membered ring and a diene result through a series of alkyl shifts (Scheme 1.8).  5  Scheme 1.8. Murai’s Platinum-Catalyzed Reaction of an Alkene with an Alkyne22 TBSO PtCl2  TBSO  Pt  TBSO  TBSO  Pt  toluene 80 °C 93% 1.27  1.28  1.29  1.30  Another rearrangement reaction using platinum(II) was investigated by Fürstner during a synthesis of the antibiotic (±)-streptorubin (Scheme 1.9).23 An alkene in an eight-membered ring was reacted with an alkynyl ketone, leading to the formation of a five-membered ring and a tenmembered ring due to ring expansion.  A similar terminal alkyne had previously been  demonstrated by Murai22, although it lacked nitrogen functionality. The isomerization of this particular substrate was catalyzed by acids including BF3•OEt2, SnCl2, ZnCl2 and HBF4, as well as PtCl2. Scheme 1.9. Fürstner’s Platinum(II) Chloride Isomerization23 Ts N  Ts N  PtCl2 (5 mol %) toluene 50 °C 79%  Ts N  LnPt  LnPt O  O  1.31  Ts  N  O  O  1.32  1.33  1.34  The Dake group has investigated the use of enesulfonamides and enecarbamates as another possible nucleophile in metal-catalyzed alkyne activation reactions. These enamine derivatives  contain  an  electron-withdrawing  group  at  nitrogen,  commonly  a  p˗toluenesulfonamide or a tert-butyl carbamate (Figure 1.1). While this electron-withdrawing group diminishes the nucleophilicity of this functional group relative to classical enamines, it also provides stability to hydrolysis. These enamine derivatives react as nucleophiles in a number of reactions.24 A useful feature of this functional group is that nitrogen is incorporated into the products of a reaction. Enesulfonamides and enecarbamates had not previously been examined as nucleophiles in the metal-catalyzed activation of alkynes.  6  Figure 1.1. A General Description of Enesulfonamides and Enecarbamates N O S O R enesulfonamide  N O  OR  enecarbamate  Enesulfonamides and enecarbamates were shown to act as nucleophiles in electrophilic metal-catalyzed reactions with alkynes in 2004.25 These examples formed bicyclic products from reaction between the enesulfonamide and an alkynyl side chain attached to the 4position of the six-membered ring (Scheme 1.10). In addition, this cyclization could be brought about using both platinum and silver catalysts. Scheme 1.10. Bicyclic Products Generated from Reactions of Enesulfonamides25,26 CO2Me  CO2Me PtCl2 (10 mol %) N Ts 1.35  toluene 80 °C 69%  O  N Ts 1.36  O  CO2Me  CO2Me AgOTf (2 mol %) N Ts 1.37  THF/CH2Cl2 80 °C 73%  N Ts 1.38  Reactions of enesulfonamide and enecarbamate derivatives with alkyl chains at the 3˗position of the ring was then investigated using catalytic platinum(II) chloride (scheme 1.11).27 In this case, the rearrangement resulted in spirocyclic products. The reactions were run in the presence of methanol for two reasons: first, this provided a nucleophile to react with the iminium ion formed in the reaction and second, it provided a proton, which was necessary for catalyst turnover.  7  Scheme 1.11. Dake’s Spirocyclization Reaction Using Enamine Derivatives27 BF3•OEt2 Et3SiH  PtCl2 (10 mol %) toluene N R  N R  80 °C MeOH (2 equiv.) 1.39  OMe  R  toluene rt  Ts Boc CO2Me  N R  1.40  Yield (%) 80 69 73  1.41  This spirocyclization reaction was also carried out using aromatic-substituted alkynes. This used a sequence of reactions beginning with the activation of the alkyne. Tetracyclic products were isolated as mixtures of isomers rather than simple spirocyclic products (Scheme 1.12). The proposed mechanism begins with coordination of platinum to the alkyne followed by nucleophilic attack of the enesulfonamide on the alkyne, producing an iminium-type ion (Scheme 1.13). This carbocation then undergoes a Friedel-Crafts reaction with the aromatic. Subsequent rearomatization and protodemetallation of the platinum catalyst with the proton lost in the rearomatization yields the tetracyclic products observed.28 This proposed mechanism can also be used to explain the formation of two isomers. Scheme 1.12. Platinum(II)-Catalyzed Cyclization to form Tetracyclic Products27 PtCl2 (10 mol %) toluene N Ts  OMe  110 °C 65% 19:1 1.43a:1.43b  1.42  + N H Ts  N H Ts OMe  OMe 1.43a  1.43b  PtCl2 (10 mol %) toluene N Ts  CF3  1.44  110 °C 67% 1:1 1.45a:1.45b  + N H Ts  N H Ts CF3 1.45a  CF3 1.45b  8  Scheme 1.13. Proposed Mechanism for the Formation of Tetracyclic Products28 PtLn  PtLn N Ts  5-exo PtLn  N Ts  N H Ts OMe  MeO    N Ts  1.46  OMe  1.47  1.43b  OMe 1.42 6-endo  PtLn  PtLn N Ts  N Ts  N Ts H  OMe  OMe  OMe 1.48  1.49  1.43a  The isomeric mixture of tetracyclic products derives from the initial attack on the alkyne by the enesulfonamide. This attack can be in either 5-exo or 6-endo fashion, leading to the isomeric products observed. Isomer 1.43a, derived from an initial 6-endo attack on the alkyne, is sometimes referred to as the 6-endo isomer. Similarly, isomer 1.43b from initial 5-exo attack is referred to as the 5-exo isomer. The reported examples display a trend favouring the isomer from 6-endo attack when electron-rich aromatics are used. The observed selectivity is proposed to be due to electronic polarization of the alkyne. Although coordination of platinum activates both sides of the alkyne, the aromatic group also influences the polarization of this bond. An electron-donating group pushes electrons towards one side of the alkyne, making an electronrich site that is more nucleophilic towards the electrophilic metal. It also makes the other side of the alkyne more electrophilic for attack from the enesulfonamide (Figure 1.2). This hypothesis agrees with the observed results for the reported enamide derivatives.  Figure 1.2. Rationale for Isomer Ratio of Product Observed Pt2+ PtLn • N Ts  OMe  N Ts  OMe  N Ts OMe  1.42  1.50  1.48  9  The only other example of a platinum-catalyzed isomerization of enecarbamates to tetracyclic products has been reported in a synthesis by Zhai.29 This synthesis takes advantage of Dake’s research to catalyze the isomerization of a 3-furanyl alkyne with an enecarbamate. The tetracyclic product was used as an intermediate towards a core synthesis of the natural product nakadomarin A (1.53). Although this substrate is more functionalized than those previously reported, a large catalyst loading was required for a moderate yield of this compound, which indicated that some work exploring the scope and reaction conditions of this procedure was needed. Scheme 1.14. Zhai’s Platinum Catalyzed Cyclization Towards Nakadomarin A29 N Ts MeO2C  O  PtCl2 (18 mol%) toluene 110 °C slow addition  N Boc  1.51  Ts  N  N H  MeO2C  N H Boc  1.52  O  N  H  O  1.53  These few examples of this interesting synthesis of tetracyclic products are the only examples have been reported and so this procedure was further studied. The research undertaken had two goals: to investigate the scope of this platinum-catalyzed synthesis of tetracyclic products and to examine a different isomerization reaction of enesulfonamides observed during the course of these studies.  10  2. Platinum-Catalyzed Reactions 2.1. Synthesis of Substrates Substrates were synthesized based on literature precedent,27 beginning with the alkylation of δ-valerolactam with an alkyl halide containing an alkyne. In the synthesis of enecarbamate derivative 2.7, a methoxybenzene alkyne was used, as this resulted in the shortest synthesis for one single enecarbamate analogue.  In the synthesis of enesulfonamide derivatives, a  trimethylsilyl-protected alkynyl side-chain was used. This was later deprotected for coupling to the aromatic portion of the substrates. This strategy lengthened the overall sequence by two steps, but allowed the different enesulfonamides to be synthesized from a common intermediate. Otherwise, the syntheses are similar and involve the synthesis of an alkyl halide, alkylation of δ˗valerolactam and functional group manipulation to yield enecarbamates and enesulfonamides.  Synthesis of enecarbamate derivative 2.7 began with the synthesis of alkyl halide 1-(5iodopent-1-ynyl)-4-methoxy benzene 2.3 (Scheme 2.1). In the first step, methoxyphenyl alkyne 2.2 was synthesized by reacting 4-pentynol 2.1 under Sonogashira cross-coupling conditions. Product formation was indicated by two doublets with a coupling constant of 8.7 Hz in the 1H NMR spectrum at 7.33 and 6.82 ppm.  The hydroxyl group was displaced using  triphenylphosphine and iodine to generate iodide 2.3.  This product was identified by the  presence of a triplet at 3.37 ppm in the 1H NMR spectrum, as well as the disappearance of the O˗H stretch in the IR spectrum.  With this alkyl iodide in hand, the alkylation step was  undertaken.    Some parts of this section and corresponding experimental details have been previously published. Reproduced in part with permission from: Kozak, J. A.; Dodd, J. M; Harrison, T. J.; Jardine, K. J.; Patrick, B. O.; Dake, G. R.; J. Org. Chem. 2009, 74, 6929 – 6935. Copyright 2009, American Chemical Society  11  Scheme 2.1. Synthesis of 1-(5-Iodopent-1-ynyl)-4-methoxybenzene 2.3 (PPh3)2PdCl2 CuI NEt3/CH2Cl2 rt  HO  I  I2 PPh3  HO  OMe OMe 94%  2.1  2.2  I  imidazole CH2Cl2 rt 98%  OMe 2.3  The synthesis of enecarbamate 2.7 was continued by analogy to literature precedent (Scheme 2.2). Alkylation of δ-valerolactam 2.4 was carried out by deprotonation using two equivalents of butyllithium to generate the dianion of lactam 2.4, followed by substitution with iodide 2.3. The resulting lactam 2.5 shows an N-H stretch at 3286 cm-1 and a C=O stretch at 1661 cm-1 in the IR spectrum and doublets at 7.31 and 6.79 ppm with coupling constants of 8.7 Hz in the 1H NMR spectrum. This data, as well as a mass of 294 corresponding to a mass of (M + Na)+, confirm that the desired product was formed. Deprotonation of this substituted lactam with butyllithium followed by reaction of the resulting anion with di-tert-butyl dicarbonate resulted in protected lactam 2.6. The identity of this compound is established by a singlet of nine protons at 1.52 ppm in the 1H NMR spectrum and a mass of 394, corresponding to mass of (M + Na)+ for the desired product. Lactam 2.6 was reduced using diisobutylaluminum hydride. The resulting hydroxyl group was converted to the mesylate using triethylamine and methanesulfonyl chloride and subsequently eliminated to give enecarbamate 2.7.  The  appearance of singlets at 6.72 and 6.57 ppm in the 1H NMR spectrum, as well as the disappearance of the signal at 174.0 ppm in the 13C NMR spectrum supports the formation of an enecarbamate. A signal at 6.48-6.64 ppm in the 1H NMR spectrum has been observed for an analogous compound by our group, which is consistent with the observed shift for enecarbamate 2.7.30 After completing the synthesis of enecarbamate 2.7, enesulfonamide derivatives were synthesized.  12  Scheme 2.2. Synthesis of Enecarbamate Derivative 2.7 a) BuLi THF –78 °C N H  O  N H  b) I  O OMe  2.3 2.4  62%  2.5  OMe  1) DIBAL-H –78 °C CH2Cl2  a) BuLi THF –78 °C b) Boc2O 91%  N O  O OMe  O 2.6  2) MsCl NEt3 DMAP CH2Cl2 0 °C-rt 71%  N O  OMe  O 2.7  Enesulfonamide derivatives were synthesized in similar fashion to enecarbamate 2.7. The synthesis of bromide 2.9 also began with 4-pentynol (Scheme 2.7). 4-Pentynol 2.1 was reacted with two equivalents of butyllithium and the dianion generated was quenched with an excess of chlorotrimethylsilane. After treatment with 1M hydrochloric acid, pentynol 2.8 was isolated.  This is demonstrated by the singlet at 0.16 ppm in the 1H NMR spectrum that  integrates to nine protons. Conversion of the hydroxyl group in 2.8 to its tosylate was carried out with p-toluenesulfonyl chloride and pyridine. The crude product of this reaction was stirred with sodium bromide in dimethylformamide to obtain bromide 2.9 which was identified by a triplet at 3.52 ppm in the 1H NMR spectrum as well as a singlet at 0.16 ppm. This alkyl bromide was then used in the alkylation of δ-valerolactam.  Scheme 2.3. Synthesis of (5-Bromopent-1-ynyl)trimethylsilane 2.9 a) BuLi (2 equiv) THF –78 °C  HO  2.1  b) Me3SiCl c) 1M HCl 76%  1) TsCl pyridine CH2Cl2 0 °C-rt  HO SiMe3 2.8  2) NaBr DMF 60 °C 80%  Br SiMe3 2.9  At this point, the synthesis of enesulfonamide 2.13 was performed in a similar manner to the synthesis of enecarbamate derivative 2.7 (Scheme 2.4). δ-Valerolactam was again treated with two equivalents of butyllithium and the dianion was reacted with bromide 2.9 to yield 13  lactam 2.10. The product of this reaction had a broad singlet at 5.64 ppm in the 1H NMR spectrum, corresponding to the N-H proton and a singlet at 0.15 ppm corresponding to the trimethylsilyl group. Compound 2.10 was protected as its N-sulfonamide using butyllithium and p-toluenesulfonyl chloride to yield substituted lactam 2.11, demonstrated by the singlet at 2.44 ppm in the  1  H NMR spectrum.  The protected lactam 2.11 was next reduced with  diisobutylaluminum hydride. The resulting hydroxyl group was again immediately converted to the mesylate using methanesulfonyl chloride and triethylamine and eliminated in one pot to generate enamine 2.12. This compound shows a singlet at 6.49 ppm in the 1H NMR spectrum. The trimethylsilyl group was removed from the alkyne of enesulfonamide derivative 2.12 using potassium carbonate in methanol to give terminal alkyne 2.13. In addition to the disappearance of the singlet at 0.16 ppm, the 1H NMR spectrum of compound 2.13 also shows a triplet at 1.97 ppm that integrates for one proton corresponding to the proton of a terminal alkyne and a singlet at 6.48 ppm corresponding to an enesulfonamide proton. All of the steps to reach this terminal alkyne proceeded in good yield, allowing access to terminal alkyne 2.13 to be used in coupling reactions.  Scheme 2.4. Synthesis of Enesulfonamide Derivatives with Varied Aromatic Substituents a) BuLi (2 equiv) THF –78 °C N H  O b) Br  2.9 74%  a) BuLi THF –78 °C  SiMe3  N H  SiMe3  O  2.4  b) TsCl 92%  2.10  1) DIBAL-H –78 °C CH2Cl2 2) MsCl NEt3 DMAP CH2Cl2 0 °C-rt 79%  SiMe3  2.12  MeOH rt 97%  SiMe3  O  2.11  (PPh3)2PdCl2 CuI  K2CO3 N Ts  N Ts  Ar-X NEt3/CH2Cl2 rt  N Ts  N Ts  Ar  2.13  Enesulfonamide derivatives that differed by their aromatic side-chains were then synthesized through Sonogashira cross-coupling reactions with terminal alkyne 2.13 and a variety of aryl halides. Some of the aryl halides to be used in this reaction were first synthesized from their parent aromatics. The results for the synthesis of these halides are summarized in Table 2.1.  2-Bromofuran 2.14 was synthesized by electrophilic aromatic substitution with 14  bromine. The product shows three aromatic signals in the 1H NMR spectrum at 7.43, 6.37-6.40 and 6.31 ppm, indicating the desired product. 2-Iodoindole 2.15 was synthesized by protection of the nitrogen as the lithium carboxylate, followed by deprotonation at the 2-position with tertbutyllithium and final quenching of the anion with diiodoethane. The characteristic signals for this compound are a singlet at 6.74 ppm in the 1H NMR spectrum, as well as a signal at 3379 cm˗1 in the IR spectrum.  2-Iodoindoles 2.16 and 2.17 with substitution at nitrogen were  synthesized by deprotonation of iodide 2.15 followed by quenching of the anion with methyl iodide and acetic anhydride respectively. Iodoindole 2.16 was identified by the appearance of a signal at 3.79 ppm and iodoindole 2.17 was identified by a signal at 2.88 ppm in the 1H NMR spectrum.  All of the alkyl halides were synthesized in good yield with the exception of  2˗bromofuran. However the synthesis of this halide still yielded enough material for subsequent reactions.  Table 2.1. Synthesis of Aryl Halides for Sonogashira Coupling Reaction entry  starting aromatic O  1 H N  4  I  H N  I  H N  product  NaH, THF, rt; MeI  O  Br  Br2, DMF, −20-rt nBuLi, THF, −78°C; CO2; tBuLi; 1,2-diiodoethane  2  3  conditions  I  H N  I  Me N  yield (%) 2.14  20  2.15  83  2.16  93  2.17  55  O  NaH, THF, 0 °C; Ac2O  I  N  The results of the Sonogashira cross-coupling reactions between terminal alkyne 2.13 and aromatic halides are summarized in Table 2.2. The cross-couplings were run using 5 mol % bis(triphenylphosphino)palladium dichloride and 10 mol % copper iodide in a triethylaminedichloromethane solvent system. All of the examples proceeded in moderate to good yield. Product formation was identified by the disappearance of the triplet at 1.97 ppm and the continued presence of the singlet for an enesulfonamide proton between 6.45 and 6.65 ppm in the 1H NMR spectrum. The mass of the product was also confirmed by mass spectrometry. The 15  successful installation of the aromatic portion of the molecule completes the synthesis of enesulfonamide substrates to subject to the isomerization by platinum chloride. Table 2.2. Sonogashira Cross-Coupling Reaction Results (PPh3)2PdCl2 CuI N Ts  Ar-X NEt3/CH2Cl2 rt  Ar  N Ts  2.13  entry  Ar-X O  Br  1  time (h) 20  product  yield (%) O  N Ts  2.18  78  2.19  89  2.20  58  1.42  88  2.21  85  2.22  80  2.23  50  2.24  76  I a  2  OMe  2  N Ts  OMe  I  OMe OMe  OMe  OMe  b  3  22  N Ts OMe  OMe  I b  4  4 OMe  5  6  N Ts  OMe  H N  I  2.5 Me N  I  2.5  H N N Ts  Me N N Ts  I a  7  20 N Me  N Ts O  O  8 a  I  N Me  N  4  N N Ts  Aromatic halide synthesized by Jennifer Kozak. bCommercially-available aromatic halide  16  2.2. Platinum(II)-Catalyzed Reactions of Enecarbamate 2.7 Platinum chloride-catalyzed isomerization reactions were carried out on the enecarbamate and enesulfonamide derivatives synthesized. Enecarbamate 2.7 was investigated first.  Table 2.3 shows a summary of the different reaction conditions examined for this  substrate. The reactions were all run in sealed vessels under an atmosphere of nitrogen, in keeping with precedent. Not all the reactions went to completion with this substrate and the product was inseparable from the starting material on silica gel in conventional ethyl acetate or ether-based systems.  A mixture of petroleum ether and dichloromethane was found to be  effective for purification of this derivative by column chromatography. Once the product was separated, it was characterized by standard methods including two-dimensional NMR.  The identity of the product was confirmed by signals corresponding to the vinyl proton at 5.68-5.74 ppm in the 1H NMR spectrum and signals at 5.66 and 5.29 ppm corresponding to the benzylic proton as two conformational isomers. The shift for the vinyl proton is slightly upfield, but consistent with a shift of 5.83 ppm for the vinyl proton reported for enesulfonamide cyclization product 1.43.27  Formation of the expected product is also supported by two  dimensional NMR data. The important correlations observed are illustrated in Figure 2.1. The HMBC data shows a correlation between benzylic proton H-11b and quaternary carbon C-3a and a correlation between benzylic proton H-11b and tetrasubstituted alkene carbon C-7a. It also shows a correlation between the methylene proton H-1 with benzylic carbon C-11b. The product can be assigned as the 6-endo isomer based on a chemical shift of 5.87 ppm in deuterochloroform in the 1H NMR spectrum for proton H-7, compared with a reported shift of 5.83 ppm for the analogous sulfonamide.27 The expected product was formed based on this evidence. The crude 1H NMR spectrum was used to determine the ratio of isomers formed. No isomeric product of initial 5-exo attack of the alkyne was observed for this analogue. However, small amounts of 5-exo isomer may not have been detected because the signals of the vinylic and benzylic protons were broadened and doubled. The 6-endo isomer still remains the major isomer, confirming qualitatively that electron-rich aromatics react primarily in 6-endo fashion in enecarbamates as well as enesulfonamides. Moreover, the 6-endo isomer was formed in all of the different reaction conditions attempted (Table 2.3).  17  Figure 2.1. Key COSY and HMBC Correlations for Cyclization Product 2.25 H H 6 3a  H H  7  H  7a  COSY correlation HMBC correlation  1  N BocH  11b  OMe  Although the reaction proceeded with good regioselectivity, the conditions were optimized to improve the yield of the reaction. The cyclization reaction did not proceed under thermal conditions, as seen in entry 1 of Table 2.3, although a small amount of decomposition was seen by 1H NMR. At catalyst loadings of 20 mol % (entry 2) the starting material was consumed when the reaction mixture was heated at 110 °C for fourteen hours, yielding 30% product. In fact, all of the starting material was consumed when the reaction mixture was heated at 110 °C for only two hours (entry 3), although the yield of product remained low (23%). This indicated that the starting material was consumed very quickly at 110 °C, to either form product or decomposition materials. The decomposition products could originate from either the product or the starting material. To avoid decomposition, lower temperatures were attempted. At 60 °C however, the reaction did not go to completion even after five days with 10 mol % catalyst loading, yielding 45% recovered starting material (entry 5). On the other hand, at higher catalyst loading (20 mol %), a yield of 48% 2.25 was observed after forty hours (entry 6). The reaction was also attempted under an atmosphere of carbon monoxide (entry 7). A more electrophilic platinum species should be able to more strongly activate alkynes but this system also resulted in a low yield (entry 7), and recovered starting material was still observed after forty hours. From these results, entry 6 has the highest-yielding reaction conditions using 20 mol % platinum chloride at 60 °C for 48 hours.  18  Table 2.3. Platinum(II)-Catalyzed Cyclization Conditions with Enecarbamate 2.7 PtCl2 N Boc  toluene OMe  N H Boc OMe  2.7  entry  2.25 a  loading  temperature  time  product  (mol %)  (°C)  (h)  (%)  (%)  1  none  110  13  0  93  2  20  110  14  30  0  3  20  110  2  23  0  4  20  130  2  30  0  5  10  60  5d  17  45  6  20  60  40  48  8  10  80  40  8  34  c  7  8 50 80 7 Only 6-endo cyclization product was observed by 1H NMR. c Reaction was run under an atmosphere of CO. a  b  recovered s.m. b  58 0 Some decomposition was observed by 1H NMR.  The results of these experiments give some indication of why the product is formed in low yield. Since the yield of the reaction is similar between two hours and fourteen hours at 20 mol % catalyst (entries 2 and 3), it does not appear that the product is being formed and then subsequently decomposed under the reaction conditions. There is not a large amount of decomposition of the starting material, however, at high temperatures in the absence of catalyst (entry 1). From these results, it would appear that the starting material decomposes under the reaction conditions.  The presence of the platinum catalyst may be causing decomposition in some way. Previous spirocyclization reactions with enecarbamates have been observed to proceed with similar reaction times and yields as enesulfonamides.25,27 Reactions of enecarbamates with silver and cationic gold catalysts, on the other hand, have been observed to be acidic enough to remove the tert-butyl carbamate group.31 It was noted during the experiments on tetracycle 2.25 that it decomposed after exposure to deuterated chloroform, which can be slightly acidic. The starting enecarbamate 2.7 also decomposed over time at 4 °C. For these reasons, it is possible that although other enecarbamates are stable under platinum(II) chloride conditions, substrate 2.7 is prone to decomposition. To account for entries 3 and 4 where the yield is similar between 19  reactions that were run for 14 and 2 hours, either the starting material is unstable but the product is stable, or the decomposition products formed from product decomposition deactivate the catalyst. Since the more electrophilic platinum chloride and carbon monoxide catalyst system gives a lower yield and large amount of remaining starting material, it appears that the catalyst is deactivated in some way during the reaction. This could be examined by spiking the reaction with catalyst at intervals, although this would require opening the sealed reaction tube. This derivative was not studied further because the yield of the reaction was only moderate with a high catalyst loading. Instead the scope of the aromatic portion of the molecule was studied.  2.3. Platinum(II)-Catalyzed Reactions of Enesulfonamides The cyclization reactions of enesulfonamides using platinum(II) were next examined. The same standard conditions were used as for the enecarbamate derivative: 10 mol % platinum chloride in toluene at 110 °C. As well, since the reactions could not be monitored by thin layer chromatography, reactions were run initially for a standard time of 16 hours based on previously-reported reaction times.  Once synthesized, the products were characterized primarily using NMR spectroscopy. Mass spectrometry was used to confirm that the products observed were an isomerization of the starting material, but it did not indicate the structure of the product. The distinctive features in the 1H NMR spectrum of these products are the signals for the vinyl proton and the benzyl proton. The reported values for the vinylic proton of the 6-endo isomer are 5.83 to 6.00 ppm in the 1H NMR spectrum and 6.11 to 6.24 ppm for the 5-exo isomer.27 The observed signals for the vinylic proton were a triplet in the range of 5.60 to 5.95 ppm, which correlates well with the reported values. The observed chemical shift was also used as an indication of the isomer formed. It was previously observed that the signal for the 5-exo isomer was found downfield of the signal for the 6-endo isomer, but the value of the chemical shift was also used to identify the isomer when a single isomer was formed. In all cases, the major isomer observed was the 6endo isomer. The other characteristic signal, the benzylic proton, was observed between 4.76 and 5.29 ppm in the 1H NMR spectrum, which compared with the reported values of 4.89 to 4.91 ppm.27  20  Aromatic rings with methoxy substituents were first examined (Table 2.4). An example with a single methoxy substituent had previously been reported27 and so enesulfonamide derivatives with two methoxy substituents were considered: 3,4-methoxy-substituted enesulfonamide 2.19 and 3,5-methoxy substituted enesulfonamide 2.20. Enesulfonamide 2.19 reacted under standard conditions to yield 42% with the 6-endo isomer 2.26a as the major isomer (entry 1). The observed isomer ratio of 20:1 for tetracycles 2.26a:2.26b is comparable to the reported ratio of 19:1 for tetracycles 1.43a:1.43b derived from substrate 1.42 with a single methoxy-substituted aromatic ring. However, the yield of 42% is lower than the yields that have been previously observed but significant side-products were not seen in the crude 1H NMR spectrum to account for the lost material.  Side-reactions involving oligomerization or  polymerization were possibly occurring due to the electron-rich nature of the alkyne. The reaction was run at 80 °C, but the reaction did not go to completion at this temperature resulting in fifty percent recovered starting material. Dilution of the reaction at 110 °C however, (entry 3) increased the yield to 61%. In this way, a moderate yield of this compound was achieved with a good selectivity for one isomer.  Table 2.4. Cyclization Reactions of Dimethoxybenzene Derivatives PtCl2 OMe (10 mol %) N Ts  R2 R1  toluene 16 h  + N H Ts  OMe R1  R2  R1  R2  OMe R2  a  entry  N H Ts R1  temperature yield (°C) (%) 1 H OMe 110 42 2 H OMe 80 28 b 3 H OMe 110 61 4 OMe H 110 69 5 OMe H 130 51 a 1 b Determined by crude H NMR. Reaction run at 0.03 M (compared with ~0.1 M).  b  product 2.26 2.26 2.26 2.27 2.27  a  ratio a:b 20:1 95:5 15:1 8:1 5:1  This particular enesulfonamide derivative also has the possibilty of regioisomeric products 2.28a and 2.28b (Scheme 2.6) derived from the Friedel-Crafts portion of the sequence. The possible sites of electrophilic aromatic substitution are the 2- and 5-positions of the aromatic 21  ring, which are electronically similar because both positions are ortho- or para- to one methoxy group and meta- to the other. These regioisomeric products were not observed by crude 1H NMR of the reaction mixture, likely due to steric hindrance in theoretical products 2.28a and 2.28b. Despite having four possible products, very good selectivity was observed with this substrate.  Scheme 2.6. Regioisomeric Cyclization Products not Observed  PtCl2 N Ts  OMe OMe 2.19  110 °C toluene  + N H Ts MeO  OMe  N H Ts MeO OMe  2.28a  2.28b  The symmetrically-substituted enesulfonamide 2.20 behaved very differently from the unsymmetrical enesulfonamide 2.19. When reacted under standard conditions, this derivative gave a reasonable yield of 69%, but was less selective for the 6-endo isomer with a 6-endo:5-exo ratio of 8:1 (Table 2.4, entry 4). This greater proportion of tetracycle 2.27b from 5-exo attack is probably because the methoxy substituents are not in a position on the aromatic ring to donate electron density to the alkyne, making it less electron-rich than analogues with methoxy substitution at the 4-position. The reaction was also attempted at 130 °C (entry 5), which resulted in a slight decrease in yield and was no advantage over the standard conditions. This dimethoxy analog reacted in good yield, but with less isomeric selectivity, in contrast to the previous dimethoxy derivative 2.19, demonstrating the importance of the aromatic group on the reaction.  The next aromatic substituents to be studied were heteroaromatics.  When the first  derivative, a 2-alkynyl furan analogue 2.18 was submitted to standard cyclization conditions, a yield of just 32% was isolated (Scheme 2.7). Only the isomer of 6-endo attack was seen by 1H NMR spectroscopy, indicating that the reaction was very selective, although it is possible that decomposition products from the 5-exo isomer account for some of the unrecovered material. An attempt to reduce the temperature to 70 °C gave mostly starting material by 1H NMR spectroscopy, although the ratio of endo:exo isomers remained 95:5. Although this cyclization 22  proceeded in low yield, no further optimization was carried and attention was turned to nitrogencontaining heteroaromatics.  Scheme 2.7. Cyclization of Furan Derivative 2.18  O N Ts  PtCl2 toluene  2.18  O N H Ts  2.29a  + N H Ts  O  2.29b  Indole derivatives were investigated beginning with 2-alkynyl indole derivatives (Table 2.5). Using standard conditions, the parent indole derivative 2.21 produced only the 6-endo tetracyclic product 2.30a, although in low yield (entry 2). Control reactions show that heating the starting enesulfonamide 2.21 without catalyst does not result in either product or decomposition products, indicating that the starting material, at least, is thermally stable. It is possible that the unsubstituted nitrogen is able to coordinate to the platinum catalyst and reduce its efficiency or even deactivate it. N-methyl indole derivative 2.22 was reacted under standard conditions (entry 6), producing a yield of 35% of tetracycle 2.31, similar to indole 2.30 with an unsubstituted nitrogen atom. This initially seemed to disprove the theory that an unsubstituted nitrogen atom was affecting the course of the reaction. However increasing the temperature to 130 °C (entry 7) gave tetracycle 2.31 in good yield (78%), with only the 6-endo isomer visible by 1H NMR spectroscopy. On the other hand, increasing the temperature to 130 °C did not improve the yield of the unsubstituted indole 2.30 (entry 3). Indoles substituted at the 2-position were very successful in this reaction, at least when the indole nitrogen was substituted with an alkyl group.  23  Table 2.5. Cyclization Reactions of 2-Substituted Indole Derivatives R N N Ts  PtCl2 toluene 16 h  N  R  +  a  entry  b  loading  temperature  yield  (mole %)  (°C)  (%)  product  ratio  a  a:b  b,c  1  H  0  110  0  2.30  -  2  H  10  110  38  2.30  95:5  3  H  10  130  25  4  a  R  N R  N H Ts  N H Ts  Me  0  110  2.30  95:5  b,c  2.31  -  d  0  5  Me  10  80  27  2.31  95:5  6  Me  10  110  35  2.31  95:5  7  Me  10  130  78  2.31  1  b  95:5  c  1  Determined by crude H NMR. Starting material was recovered. No decomposition observed by H NMR. Calculated based on 73 % recovery of a 1.75:1 mixture of starting material:product.  d  An N-acetyl indole derivative, substrate 2.24, was briefly examined to determine the effect of an electron-withdrawing group on the indole ring (Scheme 2.8).  Reaction with  platinum chloride under the standard conditions did not lead to product, rather 15% starting material was recovered. Platinum may coordinate to the oxygen atom of the carbonyl since it is near the alkyne, even though platinum is not known to coordinate to oxygen.  Scheme 2.8. Attempted Cyclization of Indole 2.24 O  O  PtCl2 (10 mol %) N toluene 110 °C  N Ts  2.24  N N H Ts  2.32a  O  + N H Ts  N  2.32b  To contrast the effectiveness of heteroaromatics with different substitution patterns, the platinum(II) cyclization reaction was attempted with 3-alkynyl indole 2.23 (Scheme 2.9). Although a control reaction had showed that the starting material was thermally stable, reaction 24  with platinum(II) chloride yielded only 17% of tetracycle 2.33a. Again, none of the 5-exo isomer 2.33b was visible by 1H NMR spectroscopy. This is a challenging substrate. The Friedel-Crafts reaction must occur at the 2-position of the indole, which is less-favoured than the 3-position. The alkene found in the product is also in direct conjugation with the indole nitrogen lone pairs and would be expected to be acid sensitive. It was noted that this product was isolated as a clear, colourless film which initially created a clear, colourless solution in deuterated chloroform but became an orange solution over two hours.  This may be a sign of acid  decomposition and could be a contributing factor in the low yield of this product. While the 2˗substituted indole was successful in this cyclization reaction, the 3-substituted indole was much more difficult and was synthesized in lower yield.  Scheme 2.9. Cyclization of 3-Substituted Indole Derivative  +  PtCl2 N Ts  N Me 2.23  toluene  N H Ts  N Me  2.33a  N H N Ts Me 2.33b  Almost all of the substrates attempted resulted in the formation of at least some tetracyclic product. This shows that the reaction is reasonably general. Some limitations were observed with potentially acid-sensitive substrates, however and the reaction conditions were optimized in some cases to increase the yield of the reaction. The only other generalized observation to note is that reaction conditions which should accelerate the reaction, such as higher catalyst loading, generally resulted in a reaction that was less selective for the 6-endo isomer.  25  3. Rearrangement Reactions of Enesulfonamides 3.1. Observation of New Product A second isomerization reaction of enesulfonamides was observed and further investigated.  While optimizing the platinum-catalyzed reaction with N-methyl indole  enesulfonamide 2.22, a cationic gold catalyst consisting of 10 mol % PPh3AuCl and 10 mol % AgSbF6 was attempted as an alternative to platinum chloride.  When reacted with  enesulfonamide 2.22 at room temperature this catalyst system gave cyclization product 2.31 as well as 37% of an unknown compound. It was found that 10 mol % AgSbF6 alone as a catalyst at 80 °C yielded this new product in 83% yield (Scheme 3.1).  Scheme 3.1. Reaction Forming New Product 3 1  4  6  N Ts  Me N  AgSbF6 (10 mol%) toluene unknown product 80 °C 83%  2.22  NMR studies of this product were undertaken to determine the structure. This new compound had a signal in the mass spectrum of 455, which corresponded to a mass of (M + Na)+ of the starting material, indicating an isomerization reaction. The 1H NMR spectrum also showed singlets at 6.91 and 6.26 ppm. These shifts are similar to those of the enesulfonamide proton (6.45 ppm) and the C-3 indole proton (6.60 ppm) in the starting material. These two signals disappear when tetracyclic products are formed and their presence in the unknown product suggested that a Friedel-Crafts reaction had not taken place. Two-dimensional NMR spectroscopy gave some indication of the structure of this product (Figure 3.1).  COSY  correlations confirmed that the three-carbon alkyl units C-1 to C-3 and C-4 to C-6 were unchanged. The protons H-1 should be the most downfield of the alkyl protons and can be identified by the chemical shift. These protons correlate to the C-8 carbon in the HMBC spectrum, which indicates that this carbon must be found adjacent to the nitrogen atom. Unfortunately, the structure could not be conclusively determined by standard NMR spectroscopy because the signals for two of the quaternary carbons were coincident in the  13  C  26  NMR spectrum. X-ray crystallography was finally used to determine the unknown product (Figure 3.1). Unexpectedly, the product was a fused eight-five ring system.  Figure 3.1. Structure of Product 3.1 by X-Ray Crystallography and NMR Correlations 4 3  H O  1  N 8 S H O  6  Me N 9  COSY correlation HMBC correlation  3.2. Nitrogen-Containing Eight-Membered Rings Eight-membered rings containing nitrogen are derivatives of azocine (Figure 3.2). Although this heterocycle is an unstable 8π-electron system, derivatives of this ring have been observed as part of some natural products and have been used as synthetic intermediates.32  Figure 3.2. The Parent Ring, Azocine  N 3.2  Nitrogen-containing eight membered rings have been synthesized in a number of ways, but most methods have not been applied generally. Traditionally, the strategy has either been to form ring systems that can be fragmented or to join the two ends of an eight-membered tether. The methods used have included ring-closing metathesis33-35, Heck-type reaction36-39 and intramolecular cycloaddition reactions.40,41,42  Echavarren demonstrated that indole-fused  azocine derivatives can be made by reactions of alkynes with gold(III) chloride.43 Although this often gave seven-membered rings as by-products, Van der Eyken used mercury catalysts for this reaction, to give only eight-membered rings.43,44  27  Alkynes have been used as a two-carbon unit in ring-expansion reactions in two cases: in a reaction with tetrahydroisoquinolines and in a reaction with enamine derivatives. Benzenefused azocines have been made from a tetrahydroisoquinoline with an electron deficient alkyne (Scheme 3.2).45-48 The nitrogen portion of the tetrahydroisoquinoline attacks methyl propiolate in a Michael fashion. The zwitterion formed in this way then collapses to generate an eightmembered ring. This carbocation can be made because it is stabilized by two electron-rich aromatic rings. This is a potential limitation to the products that can be generated in this way. Scheme 3.2. Voskressensky’s Benzazocine Synthesis48 MeO N  MeO  +  MeO  CO2Me CH3CN  Et  MeO N  MeO  rt  N  Et MeO  CO2Me  CO2Me  OMe  MeO  OMe  3.3  Et  3.4  3.5  The second ring-expansion method is between an enamine and an electron-deficient alkyne.  This was originally demonstrated with dihydropyridine derivatives49,50 but it has  recently been observed with enamine derivatives as well.51-53 These reactions are thought to occur by [2+2] cycloaddition between the enamine and alkyne, followed by electrocyclic ring opening to generate the ring-expanded azocine derivatives (Scheme 3.3). However, very few examples of these cycloaddition reactions have been reported and the product yields decrease substantially when R is not a methyl group.  This reaction shows some similarity to the  enesulfonamide isomerization that was observed using a silver catalyst, although and electrondeficient alkyne was used in this case, rather than an electron-rich alkyne. Scheme 3.3. Gil’s Formation of Azocine Derivatives by Cycloaddition/Ring-Opening51 MeO  OMe R N Bn 3.6 R=Me 3.7 R=Et  MeO  R  R  CO2Et CH3CN reflux  N Bn 3.8  CO2Et  N Bn  CO2Et  3.9 R=Me 94% 3.10 R=Et 57%  28  3.3. Possible Mechanism The eight-membered ring product 3.1 observed from the reaction of enesulfonamide 2.22 with silver hexafluoroantimonate must also arise from a ring-expansion reaction, which is equivalent to the product of a [2+2] cycloaddition between the enesulfonamide and the alkyne, followed by ring-opening. There are two important instances where silver has been used to promote a [2+2]-type reaction in the literature.  Kozmin has reported the formation of  cyclobutene products from α,β-unsaturated ketones and siloxy alkynes (Scheme 3.4).54 Krische has reported a related reaction to form α,β-unsaturated carbonyl compounds from alkynes and carbonyl compounds (Scheme 3.5).55 Since then, other reactions between carbonyls or epoxides and alkynes or allenes have been reported using silver catalysts.56-58 In both Kozmin and Krische’s reactions, it is unclear if the mechanism proceeds through Lewis-acid activation of the carbonyl or transition-metal activation of the alkyne. It has been shown by others that silver coordinates to alkynes, similarly to other late-transition metals such as platinum(II) and gold(I).25,26  13  C NMR experiments conducted on both Kozmin and Krische’s systems show  shifts of the alkyne carbon signals in the presence of silver catalysts. It is also known in the literature that silver can act as a Lewis acid in some situations.59 In both of these systems, product can be isolated using more traditional Lewis and Brønsted acids.60-62  These two  examples demonstrate that there is no clear literature precedent to suggest a mechanism for this ring expansion. Scheme 3.4. Kozmin’s Silver-Catalyzed Cyclobutene Synthesis54 O  AgNTf2 (10 mol %) CH 2Cl2  OTIPS +  Me  H  O  Me  rt 73% 3.11  TIPSO  H  3.12  3.13  Scheme 3.5. Krische’s Alkyne-Carbonyl Cyclization with Silver Hexafluoroantimonate55 Ph  O  AgSbF6 (10 mol %) 80 °C  O  Ph  O O  Cl  Cl 81%  3.14  3.15  29  Since enesulfonamide 2.22 does not contain any carbonyl functionality and silver catalysts have been known to activate alkynes, it could be hypothesized that silver initially coordinates to the alkyne.  After electrophilic activation of the alkyne by silver, either a  concerted [2+2] cycloaddition of the enesulfonamide with the activated alkyne followed by ring opening (Scheme 3.6, path A), or a stepwise cationic rearrangement would lead to product (path B). These two pathways represent the extremes of a common mechanism. It is interesting to note that a stepwise reaction would involve an initial 5-exo attack on the alkyne, while only 6˗endo attack was observed with platinum chloride.  This proposal was then tested  experimentally.  Scheme 3.6. Possible Mechanisms from Initial Silver-Catalyzed Activation of Alkyne  A N Ts  N Ts  Ar  3.16  Ar  N Ts  Ar  3.1  3.17  Ag B Ar  N Ts 3.16  Ar N Ts  Ag  3.18  N Ts  Ar Ag 3.19  Ar  N Ts 3.1  Some control reactions were carried out to investigate the mechanism of rearrangement (Table 3.1). Heating enesulfonamide 2.22 to 110 °C gave entirely recovered starting material. This indicates that the starting material is not undergoing a thermally-induced [2+2] cycloaddition reaction. A reaction under a 300 W light without catalyst also resulted in only recovered starting material while the corresponding reaction carried out in the dark with silver hexafluoroantimonate gave a good yield of ring-expanded product 3.1 (entry 3), ruling out the possibility that the reaction was being promoted by ambient light. The experiments with a Lewis acid and a Brønsted acid (entries 5 and 6) are more informative. Both acids can catalyze the reaction and give a good yield of product, consistent with Kozmin54 and Krische’s55 observations. Additionally, if 2,6-lutidine is added to the reaction, only starting material is recovered using silver hexafluoroantimonate as a catalyst (entry 7).  A reaction using a 30  phosphine ligand (JohnPhos) for silver was also attempted (entry 8), based on a silver-ligand catalyst system for alkyne isomerization by Echavarren.63  This reaction also led to only  recovered starting material, possibly because the phosphine ligand is also acting as a base. These results clearly demonstrate that the rearrangement is acid-catalyzed as well as silvercatalyzed.  Table 3.1. Ring Expansion Control Reactions on Substrate 2.22 Me N  Me N  N Ts  N Ts 2.22  entry  catalyst  loading  3.1  additive  solvent  (mol %) 1  temperature  time  yield  (°C)  (h)  (%) f  none  0  -  toluene  110  18  0  a  none  0  -  toluene  80  2  0  3  b  AgSbF6  10  -  toluene  80  2  81  4  AgNTf2  10  -  DCE  rt  4  80  5  BF3•OEt2  10  -  DCE  rt  0.5  81  6  HBF4  10  -  2  f  DCE  rt  18  92  c  DCE  80  20  0  d,e  DCE  80  20  0  7  AgSbF6  10  2,6-lutidine  8  AgSbF6  10  JohnPhos  f f  a  Reaction run under a 300 W incandescent light. bReaction run in the dark. c1 equivalent 2,6-lutidine used. JohnPhos refers to (2-biphenylyl)di-tert-butylphosphine. e20 mol % phosphine used. fStarting material was recovered. d  If silver is acting in a manner similar to HBF4 and BF3•OEt2, the reaction likely proceeds by another mechanism than electrophilic activation of the alkyne (Scheme 3.7). In this second proposed mechanism, it is the indole ring that reacts with silver at the C-3 position. This generates a carbocation next to the alkyne. This alkyne is then activated for a Michael-type attack from the enesulfonamide. After rearrangement of this species to structure 3.22 containing an indole and an exocyclic alkene, the alkene reacts with the iminium ion. Fragmentation of the strained four-membered ring generates an eight-membered ring and another iminium ion. Elimination of silver regenerates the catalyst and the product is obtained. Coordination of silver to the π-system of an indole or a pyrrole has been previously proposed.64,65 An investigation of different substrates can suggest if AgSbF6 and HBF4 are acting by a common mechanism. 31  Scheme 3.7. Proposed Mechanism of Silver-Catalyzed Rearrangement Reaction Me N N Ts  Me N N Ts  Ag 2.22  • N Ts  Ag 3.20  Ag N Ts  N Me  3.22  N Me  3.23  Ag 3.21  Me N  Ag  Ag  N Ts  Me N  N Ts  N  Me  3.24  N Ts  3.1  3.4. Synthesis of Substrates The observed product was interesting because two different isomerization products could be obtained selectively from the same enesulfonamide depending on the reaction conditions but also because eight-membered rings have traditionally been difficult to synthesize.32  To  determine if this reaction was generally applicable to enesulfonamide derivatives, other enesulfonamides were tested under these conditions.  Specifically, substrates with different  aromatic groups were examined to see how electronics affected the alkyne.  Substrates were synthesized in a similar fashion to the enesulfonamide substrates for platinum(II) catalysis. A Sonogashira cross-coupling reaction of the terminal alkyne 2.13 with aryl halides was used as the key step. The synthesis of aromatic halides to use in these coupling reactions is summarized in Table 3.2. Benzyl-protected 2-iodoindole 3.25 was synthesized by deprotonation of 2-iodoindole with potassium hydroxide in dimethylformamide followed by reaction with benzyl bromide. N-Phenyl-2-iodoindole 3.26 was synthesized in two steps by Ullman-type C-N coupling between indole and iodobenzene followed by deprotonation with butyllithium in ether at reflux and reaction with iodine. The desired 2-iodoindole was generated, although still mixed with starting material. It has been reported that heating N-methyl indole with butyllithium in refluxing ether for three hours and quenching with iodine gives 2-iodoindole in good yield,66 but only about 50% product was observed even after eight hours of reflux for 32  N˗phenylindole. Both the product and starting material are very non-polar and eluted together by column chromatography even in a solvent system of hexanes and therefore the crude mixture was used in the next reaction.  Table 3.2. Synthesis of Aryl Halides for use in Sonogashira Coupling Reaction entry  starting  conditions  product  yield  aromatic  1  I  H N  a  2  (%)  KOH, DMF, rt; BnBr  nBuLi, Et2O, reflux; I2  N  O a  a  N  3.25  35  I  N  3.26  ~50  I  O  3.27  ~90  3.28  68  tBuLi, Et2O, −78 °C; I2  3  4  I  Me N  nBuLi, TMEDA, 50 °C; I2, THF  I  Me N  Used without purification.  2-Iodobenzofuran 3.27 was synthesized by deprotonation of benzofuran with tertbutyllithium, followed by trapping of the anion generated with iodine according to literature procedure.67 This reaction yielded approximately 90% yield of the desired product, with a small amount of starting material. This mixture was also used without purification. Not only were the two products co-polar by thin layer chromatography, it has also been previously demonstrated that the non-halogenated impurity is not detrimental in a Sonogashira cross-coupling reaction.67 N-Methyl-2-iodopyrrole 3.28 was synthesized by deprotonation of N-methyl pyrrole with butyllithium in the presence of N,N,Nʹ,Nʹ-tetramethylethylene diamine and again, the anion generated was trapped with iodine.68 The 2-substituted heterocyclic halides were identified by mass spectrometry and by the disappearance of a signal in the 1H NMR spectrum relative to the starting material. 33  Enesulfonamide 2.13 was then coupled to the aromatic halides using Sonogashira crosscouplings (Table 3.3). All of the reactions were run under the same conditions as those used in the platinum(II)-catalyzed reactions of enesulfonamides. With the exception of N-phenyl indole 3.30 which only gave 59% yield, all of the reactions proceeded in yields from 73-96%. The products were identified as before by the disappearance of the triplet at 1.97 ppm in the 1H NMR spectrum.  Table 3.3. Sonogashira Coupling Reaction Results (PPh3)2PdCl2 CuI N Ts  Ar-X NEt3/CH2Cl2 rt  Ar  N Ts  2.13  entry  Ar-X  time  product  yield  (h)  1  2  I  N  3  I  N  5  I  O  (%)  N  3.29  92  3.30  59  3.31  86  3.32  96  1.44  96  3.33  73  N Ts  N N Ts  3  2  O N Ts  I  a  4  22  N Ts  I a  5  22 CF3  6 a  I  Me N  1  N Ts  CF3  Me N N Ts  Commercially-available starting material.  34  A series of α,β-alkynyl carbonyl enesulfonamides were also synthesized for use in this reaction (Table 3.4). Deprotonation of terminal alkyne 2.13 with butyllithium, followed by quenching with an acid chloride or an anhydride gave the propiolate derivatives.  The  characteristic NMR signals include a singlet at 2.39 ppm in the 1H NMR spectrum which integrates to three protons and a signal at 153.9 ppm in the  13  C NMR spectrum for ester 3.34.  The formation of methyl ketone 3.35 was indicated by a singlet at 2.34 ppm in the 1H NMR spectrum that integrates to three protons and a signal at 184.7 ppm in the  13  C NMR spectrum.  tert-Butyl ketone 3.36 was characterized by the signal at 1.19 ppm in the 1H NMR spectrum and a signal at 194.2 ppm in the  13  C NMR spectrum. All three of these compounds also showed  alkyne C-C stretches between 2205 and 2235 cm-1 in the IR spectrum.  Table 3.4. Synthesis of α,β-Alkynyl Carbonyl Substrates entry  conditions  product  yield (%)  1  nBuLi, THF, −78 °C; ClCOOMe  2  nBuLi, THF, −78 °C; Ac2O, 0 °C  3  nBuLi, THF, −78 °C; ClCOC(Me)3  O N Ts  3.33  81  3.35  55  3.36  73  OMe  O N Ts O N Ts  3.5. Scope of Rearrangement Reactions The ring-expansion reaction scope was first investigated by exposing the enesulfonamide substrates to silver hexafluoroantimonate (Table 3.5). The reaction solvent was changed to 1,2dichloroethane from toluene to improve the solubility of the silver catalyst. The products were confirmed by comparison of the 1H NMR spectra with the spectrum of the known indolesubstituted azocine derivative 3.1. The key features of these NMR spectra are the downfield shift of the enesulfonamide proton from the range of 6.39-6.60 ppm to 6.85-7.05 ppm and the downfield shift of the methylene protons near the enesulfonamide from between 3.22-3.39 ppm  35  to 3.63-3.74 ppm. The relative number of aromatic and aliphatic carbons relative to the starting material also indicated that the product contained two rings.  Generally, the indole analogues underwent rearrangement to yield the product.  An  excellent yield of 92% was obtained for N-methyl indole 2.22 in 1,2-dichloroethane, which is slightly higher than the yield obtained in toluene (entry 1). Benzyl-substituted indole 3.29, a closely-related indole, produced the product in 97% yield (entry 2). When the substitution of the indole nitrogen was changed to an electron-rich phenyl ring, the product was also obtained, however in a much lower yield (40%) than the other indoles (entry 3). On the other hand, when the 3-substituted N-methylindole 2.23 was submitted to the reaction conditions (entry 4), no eight-membered ring product was observed. In fact, the 6-endo isomer of the same tetracyclic product 2.33a formed in the platinum-catalyzed reaction was observed. Although the other indoles gave eight-membered rings in this reaction, based on this example, the position of the alkyne on the indole ring affects product formation.  Other aromatics, including heteroaromatics containing oxygen, were less successful. Furan derivative 2.18 did not give the expected product, either at 80 °C or 60 °C (entries 5 and 6).  Many decomposition products were observed by thin layer chromatography with this  substrate. This may imply some instability of this furan-containing enesulfonamide. The more stable benzofuran 3.31 (entry 7) generated some unidentified decomposition products, but unreacted starting material also remained. Similarly, enesulfonamides with a phenyl aromatic substituent 3.32 and trifluoromethyl aromatic substituent 1.44 also gave recovered starting material with some decomposition (entries 9-11). The aromatic substituent obviously has a large impact on this rearrangement reaction.  The rearrangement of different substrates was performed using acid-catalyzed reaction conditions as well (Table 3.6).  Tetrafluoroboric acid was generally used to promote the  rearrangement, although BF3•OEt2 was also used and gave similar results for the most part. All of the indole substrates gave rearrangement products when they were treated with acid (entries 1˗3), including a five-membered enesulfonamide to generate a seven-membered ring (entries 5 and 6). 3-Substituted indole 2.23 gave tetracyclic product 2.33a once more when exposed to tetrafluoroboric acid, which demonstrates that this product can be accessed by acid catalysis. 36  Pyrrole 3.33, although also a nitrogen heteroaromatic, did not generate the desired product unlike the indoles. Only recovered starting material and unidentified decomposition products were observed.  Finally, benzofuran 3.31 did not give a ring-expanded product under acidic  conditions. All of these results are consistent with the results obtained using a silver catalyst.  Table 3.5. Rearrangement Reactions Attempted with Silver Hexafluoroantimonate AgSbF6 R  N Ts  entry  1  2  3  R  Me N  Bn N  Ph N  4  Cl  Cl  N Ts  R  loading  temp.  time  yield  product  (mol %)  (°C)  (h)  (%)  10  80  2  92  3.1  10  80  4  97  3.37  10  80  6.5  40  3.38  10  80  1.5  29  b  3.39  10  80  16  0  c  3.40  c  3.40  c  3.41  c  N Me  5  O  6  10  60  6  0 (10 % rsm)  7  10  80  20  0 (30 % rsm)  8  10  80  24  0 (54 % rsm)  3.42  9  10  80  18  0 (rsm)  3.43  20  80  18  0 (rsm)  O  10 a  Unknown compound. observed.  CF3 b  Tetracyclic compound 2.34a was formed.  c  c  3.43  Decomposition of starting material was  37  Table 3.6. Brønsted and Lewis Acid-Catalyzed Rearrangement Reaction Results catalyst rt n  entry  n=  1  1  2  1  3  4  1  1  N Ts  R  Me N  Bn N  Ph N  R  Cl  Cl  n  N Ts  R  catalyst  time  yield  product  (10 mol %)  (h)  (%)  HBF4  18  92  3.1  BF3•OEt2  0.5  81  3.1  HBF4  2  80  3.37  HBF4  20  53  3.38  HBF4  7  54  3.44 3.44  a  0  6  a  0  BF3•OEt2  20  69  7  1  HBF4  18  58  3.39  BF3•OEt2  5  0  c  3.41  HBF4  3  0 (25% rsm)  c  3.45  BF3•OEt2  20  0 (33% rsm)  c  3.45  5  Me N  N Me  b  O  8  1  9  1  10  1  Me N  a  Substrate synthesized by Hyukin Kwon. bTetracyclic compound 2.34a was formed. cDecomposition and recovered starting material observed.  3.6. Discussion of Results The rearrangement reactions attempted give an interesting perspective on the generality and mechanism of the reaction. The ring-expansion reaction yields an eight-membered ring in a number of examples, but these examples are limited to 2˗substituted indoles. It is somewhat surprising that benzofuran 3.31 does not react under these conditions. This heteroaromatic 38  should be very similar to indole 2.22, particularly if the reaction proceeds by activation of the alkyne. Nonetheless, even if the substrate is activated by reaction of the catalyst with the πsystem of the indole, a similar π-system exists in benzofuran. The difference may be that benzofuran has a second lone pair which is not involved with the π-system. This lone pair may coordinate to the silver or acid catalyst and deactivate it in the same way that the presence of base inhibited the control reactions.  It is also interesting that 3-substituted indole 2.23 generates tetracyclic products, unlike the other indole substrates. In particular, it is interesting that no rearranged product is observed with this indole and no trace of tetracyclic product is observed for the 2-substituted indole substrates. This can be accounted for however, if the silver or acid catalyst interacts with the π˗system of the indole. The cation formed is no longer in a position to activate the alkyne to Michael attack and the activation is effectively the same as platinum(II) activation of the alkyne (Scheme 3.8).  Scheme 3.8. Proposed Mechanism for Formation of Tetracyclic Product 2.33a Ag N Ts  Ag  Ag N Me  2.23  N Ts  •  N Ts  N Me  N Me 3.47  3.46  Ag Ag N Ts  N Me  2.33a  N H N Ts Me 3.49  N Ts  N Me 3.48  The mechanism in which the catalyst interacts with the π-system of the indole also accounts for some of the other observations. Firstly, the reason that the yield of N-phenyl indole 3.38 is lower than that of the other indoles can be explained. The lone pair on the nitrogen of 39  this indole is involved in a second π-system and is less nucleophilic and less reactive. This allows time for side-reactions to occur. In addition, this mechanism accounts for the lack of reactivity of some other substrates. The phenyl and trifluoromethyl benzene derivatives do not have a nucleophilic site for the electrophilic catalyst to react with, such as a lone pair or a nucleophilic π-system. Without a productive interaction, the silver catalyst interacts weakly with unsaturation such as the enesulfonamide and alkyne functionalities and causes generalized decomposition. Both the control reactions and the observations made while examining the reaction scope indicate that a different enesulfonamide rearrangement is observed with silver than with platinum because silver is interacting with the indole ring, rather than the alkyne. This opens the possibility of other substrates to use in this reaction.  3.7. Reactions of Carbonyl Compounds The reactions with aromatics showed that the alkyne in this reaction is acting as a Michael acceptor and so more traditional α,β-unsaturated carbonyl compounds were examined (Table 3.7). First, a methyl ester and a methyl ketone were first reacted with 10 mol % silver hexafluoroantimonate. Although these are both good Michael acceptors, the eight-membered ring was not observed for either of these substrates. Instead, tricyclic structures 3.50 and 3.51 were observed in which the initial Michael reaction occurred followed by reaction of the iminium ion with either lone pairs from the ester oxygen or the enol form of the ketone (Scheme 3.8). As silver is somewhat oxophilic, the carbonyl is activated in the proposed mechanism.14 The methyl group from the ester is also lost in the final product either by reaction with trace water contamination or by deprotonation, which leads to a formal loss of carbene.  The  mechanism is unknown, but a proton from the methyl group becomes the vinyl proton, and carbene is formally lost. The loss of this methyl group may be the reason much longer reaction times are needed than for methyl ketone 3.35. These examples show that, not surprisingly, forming of a six-membered ring when a suitable nucleophile is available is faster than forming the strained four-membered ring necessary for eight-membered rings.  40  Table 3.7. Silver-Catalyzed Reactions with α,β-Alkynyl Carbonyl Substrates AgSbF6 (10 mol %) R  N Ts  entry  R  X  1  80 °C  solvent  N Ts  X  O  temperature  time  yield  (°C)  (h)  (%)  product  O  DCE  80  48  32  3.50  O  toluene  80  48  48  3.50  CH2  DCE  80  1.5  52  3.51  O OMe  2 O  3  Scheme 3.8. Proposed Mechanism for Formation of Lactone 3.50 Ag  Ag O N Ts   N Ts H3CO  OCH3 3.34  OAg  N Ts  3.52  O  O  O  3.50  CH3  3.53  Ag  demethylation N Ts  O  N Ts  O  H C H O H  3.54  The identification of these products was straightforward. Lactone 3.50 was characterized by a singlet at 5.76 ppm in the 1H NMR spectrum corresponding to an alkene proton and a singlet at 5.78 ppm corresponding to the hemiaminal proton. The product is from 5-exo attack on the alkyne, which was determined from the  13  C NMR shifts of the enone. The substituted  carbon is found at 164.2 ppm while the unsubstituted carbon is at 111.6 ppm. The 4-position of the enone is expected to have the most downfield shift and indicates that this isomer is formed. The signals were also assigned by two-dimensional NMR spectroscopy. Tricyclic product 3.51 contained a singlet at 5.86 ppm in the 1H NMR spectrum for the alkene as well as a doublet at 4.19 ppm corresponding to the bridgehead proton. This strategy of using an enamide-type group 41  as a nucleophile in a Michael reaction followed by reaction of the Michael acceptor with the iminium ion has also been used by Wenkert (Scheme 3.10) and was not pursued for this reason.69 Scheme 3.10. Wenkert’s Synthesis of the Core of Deethylvincadifformine69 O  O N  O N  N H  BF3 1:1 3.56:3.57  N  H +  H N H H  O  H  H N H H  O  O 3.55  3.56  3.57  To see if the eight-membered ring would be observed if there was no possible nucleophile next to the carbonyl, tert-butyl ketone 3.36 was examined (Table 3.8). When this substrate was submitted to silver-catalysis, azocine derivative 3.58 resulted in moderate yield (entry 1). If the reaction is catalyzed by HBF4 or BF3•OEt2, azocine derivative 3.58 is obtained, as well as a product resulting from trapping the iminium ion with water, 3.59 (entries 2 and 3). This product also appears when the reaction is run in the presence of anhydrous magnesium sulfate and 5 Å molecular sieves. The source of the water is unknown, particularly when drying agents are used in the reaction. Overall, AgSbF6 appears to be better for this transformation than HBF4 or BF3•OEt2 for this particular substrate but eight-membered rings are in fact synthesized using this substrate.  42  Table 3.8. Cyclization Reactions of tert-Butyl Alkynyl Carbonyl 3.36 O catalyst (10 mol %)  O N Ts  Cl  Cl  O  3.36  entry  3.58  additive  OH 3.59  temperature  time  yield (%)  (°C)  (h)  3.58  3.59  1  AgSbF6  -  80  0.75  57  0  2  HBF4  -  rt  20  27  32  3  BF3•OEt2  -  rt  0.5  8  45  rt  4  8  51  rt  0.75  17  48  4 5 a  catalyst  + N Ts  N Ts  HBF4 HBF4  MgSO4  a  5 Å M.S.  b b  1.5 equivalents anhydrous MgSO4 were used. 2 mg/mg substrate of powdered 5 Å molecular sieves were used.  43  4. Conclusion and Future Direction These studies extended the scope of the platinum-catalyzed isomerization of enamide derivatives. Seven new examples were synthesized, which extended this method to heterocyclic aromatic derivatives as well as enecarbamate derivatives. All of the substrates examined were very selective for the isomer from 6-endo attack, ranging from 8:1 for dimethoxy benzene 2.21 to one observed isomer for heteroaromatic substrates.  Although many of the examples  proceeded in good yield, some of the heteroaromatic substrates, for example, methyl indole 2.24 did not.  Further optimization of these reaction conditions, possibly including other metal  catalysts may be needed in this case.  Reaction of the tert-butyl enecarbamate also proceeded in lower yield than hoped, perhaps because it was somewhat unstable to the reaction conditions. For this reason, a methyl enecarbamate may be an alternative that would be worth investigating (Scheme 4.1).  Scheme 4.1. Proposed Cyclization of Methyl Enecarbamate Derivative PtCl2 (10 mol %) + N  N MeO  OMe  O  MeO  H O  N OMe  MeO  H O OMe  4.1  4.2a  4.2b  Additionally, a new isomerization of enesulfonamides to make eight-membered rings was investigated. Five examples of this new product were synthesized. This product was synthesized in moderate to excellent yield using enesulfonamide derivatives with non-enolizable ketone and indole-substituted alkynes. A derivative with an enolizable ketone and an ester were found to give tricyclic structures instead of the expected eight-membered ring. A solution to this problem for carbonyl substrates may be the use of iminium catalysis (Scheme 4.2).  44  Scheme 4.2. Proposed Iminium Catalysis  O N Ts  N H  (30 mol %) O  HBF4 (30 mol %) toluene  N Ts  4.3  4.4  It would also be interesting to explore the scope of this reaction. A methyl carbamate, which is expected to be stable under acid conditions, would be an alternative to an enesulfonamide. Vinyl ether-based substrates, rather than enamide derivatives would also be interesting to test.  Scheme 4.3. Proposed Future Tetrafluoroboric Acid Rearrangement Reactions Me N  Me N  HBF4  N O  N O  OMe  OMe 4.5  4.6  Me N  Me N  HBF4  O  O  4.7  4.8  In summary, two different aspects of enamide isomerizations were explored, which resulted in the synthesis of 32 previously unknown compounds.  45  5. Experimental Details 5.1. General Experimental All reactions were run under nitrogen in flame-dried glassware unless otherwise noted. Dichloromethane, 1,2-dichloroethane and triethylamine, were distilled from calcium hydride. Tetrahydrofuran was distilled from sodium benzophenone ketyl. Toluene was distilled from sodium and degassed by sparging with argon. Dimethylformamide was distilled from anhydrous magnesium sulfate. Dry diethyl ether was obtained by purification through a column of alumina. Acid chlorides were redistilled before use.  The reagents TMEDA, chlorotrimethylsilane,  pyridine and methanesulfonyl chloride were also distilled from calcium hydride.  Acetic  anhydride was purified by sequential stirring over phosphorous pentoxide and distillation from anhydrous potassium carbonate. Butyllithium was titrated against N-benzyl benzamide before use.  Thin layer chromatography was carried out on DC-Fertigplatten SIL G-25 UV254 precoated TLC plates. All purifications by column chromatography were carried out on Silicycle  SiliaFlash® F60 (40-63 μm, 230-400 mesh) silica gel. All silica was triethylamine-washed prior to use, obtained by sequentially flushing a packed column with triethylamine, ethyl acetate or diethyl ether and hexanes or petroleum ether.  Melting points were measured on a Mel-Temp II apparatus and are uncorrected. Infrared spectra were recorded on a Nicolet 4700 FT-IR. Mass spectra were recorded on a Walters LC-MS (low resolution) or a Waters/Micromass LCT (high resolution).  X-ray crystallographic  measurements were taken on a Bruker X8 APEX II diffractometer. Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectra were recorded in deuterochloroform or deuterobenzene on a Bruker AV-300, Bruker WH-400 or Bruker AV-400 spectrometer. Chemical shifts are recorded in parts per million (ppm) and are referenced to the centerline of deuterochloroform (δ 7.27 ppm 1H NMR; δ 77.0 ppm 13C NMR) or deuterobenzene (δ 7.15 ppm 1H NMR; δ 128.06 ppm 13C NMR). Coupling constants are given in Hertz (Hz). Not all peaks of the isomeric mixtures formed could be unequivocally assigned. Peaks attributable to the minor isomer are not listed for mixtures less than 8:1.  46  5.2. Synthesis of Starting Materials 5.2.1. Synthesis of Enecarbamate 2.7 5-(4-Methoxyphenyl)pent-4-yn-1-ol (2.2)70 (PPh3)2PdCl2 CuI NEt3/CH2Cl2  HO  HO  I OMe OMe  Triethylamine (25 mL) was added to flask charged with copper iodide (0.20 g, 1.1 mmol) and bis(triphenylphosphine)palladium dichloride (0.42 g, 0.59 mmol). To this yellow slurry was added a solution of 4-pentyn-1-ol (1.5 mL, 16 mmol) and 4-iodoanisole (2.5 g, 11 mmol) in triethylamine (8 mL) and dichloromethane (8 mL) and the mixture was stirred at room temperature protected from the light for 4.5 h. The black solution was filtered through silica, using ether as the eluant. After purification of the crude material by column chromatography on silica gel (3:2 → 1:1 hexanes: ethyl acetate), 1.9 g (94%) of the title compound was isolated as an orange solid, m.p. 35-38 °C. IR (thin film, CDCl3): 3353, 1607, 1509, 1247 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.33 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 3.76-3.88 (m, 5H), 2.54 (t, J = 6.9 Hz, 2H), 1.87 (quintet, J = 6.9 Hz, 2H), 1.45-1.54 (m, 1H). 1-(5-Iodopent-1-ynyl)-4-methoxybenzene (2.3)70 PPh3 imidazole  HO  OMe  NEt3 CH2Cl2  I  OMe  Triphenylphosphine (2.9 g, 11 mmol), imidazole (0.76 g, 11 mmol) and iodine (2.8, 11 mmol) were added to a flask charged with dichloromethane (30 mL). A solution of pentynol 2.2 (1.7 g, 9.1 mmol) dissolved in dichloromethane (10 mL) was added to this cloudy orange solution, the flask was washed with dichloromethane (6 mL), and the mixture was stirred at room temperature for 1.5 h. The solution was then filtered through silica gel, using ether as the eluant. After the dark brown oil was purified by column chromatography on silica gel (hexanes → 85:15 hexanes: ethyl acetate), 2.7 g (98%) of the title compound was isolated as a yellow oil. IR (thin film, CDCl3): 2930, 1606, 1246 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.34 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H), 3.37 (t, J = 6.9 Hz, 2H), 2.55 (t, J = 6.9 Hz, 2H), 2.09 (quintet, J = 6.9 Hz, 2H).  47  3-(5-(4-Methoxyphenyl)pent-4-ynyl)piperidin-2-one (2.5) n-BuLi THF 78 ºC N H  O  N H  I  O OMe  OMe  A solution of n-butyllithium (30.0 mL, 1.60 M in hexanes, 48.0 mmol) was added dropwise to a solution of δ-valerolactam (2.11 g, 21.3 mmol) in tetrahydrofuran (100 mL) at −78 ºC. The yellow solution was stirred for 0.5 h at −78 ºC and then 0.5 h at 0 ºC. A solution of 1-(5iodopent-1-ynyl)-4-methoxybenzene 2.3 (7.16 g, 23.8 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture at −78 ºC, which was stirred for 0.5 h then warmed to 0 ºC and stirred for a further 0.5 h. The bright yellow reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and the aqueous phase was extracted three times with ether. The combined organic fractions were washed with brine, dried over magnesium sulfate and concentrated by rotary evaporation. Purification of the crude material by column chromatography on silica gel (hexanes → 5:3 hexanes: ethyl acetate → 1:1 hexanes:acetone) gave 3.3 g (57%) of the title compound as a white solid that was recrystallized from dichloromethane/hexanes. m.p. 100-101 ºC. IR (thin film, CDCl3): 3286, 3299, 1661, 1508 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.31 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 6.43 (s, 1H), 3.78 (s, 3H), 3.23-3.32 (m, 2H), 2.36-2.47 (m, 2H), 2.28-2.36 (m, 1H), 1.94-2.09 (m, 2H), 1.82-1.92 (m, 1H), 1.50-1.77 (m, 5H). 13C NMR (75 MHz, CDCl3): δ 174.9, 158.9, 132.8, 116.1, 113.7, 88.3, 80.4, 55.1, 42.3, 40.6, 31.0, 26.4, 26.1, 21.3, 19.5. MS (ESI): 294 (M + Na)+. Anal Calcd for C17H21NO2: C, 75.25; H, 7.80; N, 5.16; Found: C, 75.21; H, 7.81; N, 5.14. tert-Butyl 3-(5-(4-methoxyphenyl)pent-4-ynyl)-2-oxopiperidine-1-carboxylate (2.6) n-BuLi Boc2O N H  O OMe  THF 78 ºC  N O Boc  OMe  A solution of n-butyllithium (2.2 mL, 1.43 M in hexanes, 3.2 mmol) was added dropwise to a stirred solution of piperidinone 2.5 (0.80 g, 2.9 mmol) in tetrahydrofuran (30 mL) at −78 ºC and the reaction mixture was warmed to −15 ºC over 0.5 h. During this time the colourless solution became yellow. A solution of di-tert-butyl dicarbonate (1.63 g, 7.5 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture at −78 ºC over 10 min. Stirring was continued for 0.5 h at −78 ºC before the reaction mixture was quenched with a solution of saturated ammonium chloride (20 mL) and water (20 mL). The aqueous layer was extracted three times with ether and the combined organic fractions were washed with brine, dried over magnesium sulfate and concentrated by rotary evaporation. Purification of the crude yellow oil by column chromatography on silica gel (3:1 hexanes: ethyl acetate) gave 0.99 g (91%) of the title compound as a slightly yellow oil. 48  IR (thin film, CDCl3): 1767, 1714, 1510, 1200, 1247, 1148 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.31 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H), 3.73-3.78 (m, 1H), 3.54-3.61 (m, 1H), 2.37-2.48 (m, 3H), 1.99-2.09 (m, 2H), 1.76-1.93 (m, 2H), 1.56-1.73 (m, 3H), 1.52 (s, 9H). 13 C NMR (100 MHz, CDCl3): δ 174.0, 159.0, 152.9, 132.8, 116.1, 113.7, 88.1, 82.6, 80.5, 55.2, 45.5, 43.3, 30.4, 28.0, 26.4, 26.1, 21.6, 19.5. HRMS (ESI): Calcd for C22H29NO4Na: 394.1994. Found: 394.1997. tert-Butyl 5-(5-(4-methoxyphenyl)pent-4-ynyl)-3,4-dihydropyridine-1(2H)-carboxylate (2.7) 1. DIBAL-H CH 2Cl2 78 ºC N O Boc  OMe  2. MsCl NEt3 DMAP CH 2Cl2 rt  N Boc  OMe  A solution of diisobutylaluminum hydride (25.0 mL, 1 M in hexanes, 25.0 mmol) was added slowly to a solution of carboxylate 2.6 (4.55 g, 12.3 mmol) in dichloromethane (100 mL) at −78 ºC. The reaction mixture was stirred at −78 ºC for 2 h buffered ammonium chloride solution (6.0 mL pH 8) was added and allowed to warm slowly to room temperature. Magnesium sulfate (18 g) was then added to the reaction mixture and stirring was continued at room temperature for 1 h. The resulting white suspension was filtered through Celite and concentrated by rotary evaporation. The crude material was taken up in dichloromethane (100 mL) and triethylamine (6.8 mL, 48.8 mmol) and 4-(dimethylamino)pyridine (81 mg, 0.66 mmol) were added. After cooling to 0 ºC, methanesulfonyl chloride (1.9 mL, 24.6 mmol) was added and the reaction mixture was allowed to warm to room temperature over 16 h. The resulting mixture was washed with water and brine. The combined aqueous layers were extracted with dichloromethane. The combined organic layers were then dried over magnesium sulfate and concentrated by rotary evaporation. Purification by column chromatography on silica gel (8:1 → 5:1 hexanes:ethyl acetate) gave 2.30 g (53%) of the title compound as a clear, colourless oil. IR (thin film, CDCl3): 1697, 1509, 1395, 1248, 1162 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.31 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 6.72 (s, 0.5H), 6.57 (s, 0.5H), 3.76 (s, 3H), 3.383.56 (m, 2H), 2.30-2.40 (m, 2H), 2.08-2.17 (m, 2H), 1.90-2.01 (m, 2H), 1.63-1.86 (m, 4H), 1.47 (s, 9H). 13C NMR (75 MHz, CDCl3): including resolved rotational isomer signals δ 158.9, 152.6, 152.2, 132.7, 120.9, 120.5, 117.1, 116.5, 116.0, 113.6, 88.2, 88.1, 80.5, 80.1, 80.0, 55.0, 42.0, 41.0, 34.4, 28.2, 26.9, 24.8, 21.6, 18.7. HRMS (ESI): Calcd for C22H29NO3Na: 378.2045. Found: 378.2054.  49  5.2.2. Synthesis of Terminal Alkyne 2.13 5-(Trimethylsilyl)pent-4-yn-1-ol (2.8)71 a) n-BuLi THF 78 °C  HO  HO  b) TMSCl c) 1M HCl  SiMe3  A solution of n-butyllithium was added dropwise over 2.5 h to a solution of pent-4-yn-1-ol (18 mL, 190 mmol) in tetrahydrofuran (600 mL) at −78 °C and stirred for a further 45 min. Chlorotrimethylsilane (90 mL, 630 mmol) was added over 45 min to the yellow solution and the reaction mixture was stirred at −78 °C for 0.5 h before warming to room temperature. An aqueous solution of 1 M hydrochloric acid (300 mL) was added and the mixture was stirred 3 h. After this time, the layers were separated, the aqueous layer was extracted three times with ether, and the organic layer were washed once with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. After purification by distillation (93-95 °C, 1 mmHg), 28 g (76%) of a clear, colourless oil was isolated as the title compound. IR (neat): 3334, 2176, 1250 cm-1. 1H NMR (300 MHz, CDCl3): δ 3.78 (quartet, J = 5.9 Hz, 2H), 2.62 (s, 1H), 2.37 (t, J = 6.9 Hz, 2H), 1.79 (quintet, J = 6.7 Hz, 2H), 0.16 (s, 9H). (5-Bromopent-1-ynyl)trimethylsilane (2.9)71 1.TsCl NEt3 CH2Cl2 0°C - rt  HO SiMe3  2. NaBr DMF 60°C  Br SiMe3  Pyridine (34 mL, 420 mmol) was added over 10 min to a solution of 5-(trimethylsilyl)pent-4-yn1-ol 2.8 (28 g, 180 mmol) and p-toluenesulfonyl chloride (38 g, 200 mmol) in dichloromethane (250 mL) at 0 °C. The reaction mixture was stirred for 16 h, warming gradually to room temperature. The colourless solution with white precipitate was washed three times with 1M hydrochloric acid (100 mL). The aqueous layer was extracted twice with dichloromethane and the combined organics were dried over sodium sulfate and concentrated by rotary evaporation. The waxy white solid obtained was dissolved in dimethylformamide (250 mL). Sodium bromide (22 g, 220 mmol) was added and the mixture was heated to 60 °C for 4 h. Water and ether were added and the layers were separated. The aqueous layer was extracted three times with ether and the combined organics were washed with five portions of brine, dried over sodium sulfate and concentrated by rotary evaporation. Distillation of the crude yellow oil (67-70 °C, 1 mmHg) gave 31 g (80%) of the title compound as a clear, colourless oil. IR (neat): 2960, 2177, 1249 cm-1. 1H NMR (400 MHz, CDCl3): δ 3.52 (t, J = 6.5 Hz, 2H), 2.42 (t, J = 6.8 Hz, 2H), 2.05 (quintet, J = 6.6 Hz, 2H), 0.16 (s, 9H).  50  3-(5-(Trimethylsilyl)pent-4-ynyl)piperidin-2-one (2.10)27 a) n-BuLi THF 78 °C N H  O  N H  b) Br 78 °C - rt  O  SiMe3  SiMe3  A solution of n-butyllithium (65 mL, 1.60 M in hexanes, 100 mmol) was added over 15 min to a solution of δ-valerolactam (4.8 g, 49 mmol) in tetrahydrofuran (250 mL) at −78 °C. The yellow solution formed was stirred for 45 min at −78 °C before warming to 0 °C. After a further 45 min, (5-bromopent-1-ynyl)trimethylsilane 2.9 (15 g, 69 mmol) was added and the mixture was stirred at 0 °C for 4 h. An aqueous solution of ammonium chloride (25 mL) and water (10 mL) were added, the layers were separated and the aqueous layer was extracted three times with dichloromethane. The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. After purification of the crude yellow oil by column chromatography on silica gel (hexanes → 1:1 → 3:1 hexanes:ethyl acetate), 8.6 g (74%) of the title compound was isolated as an off-white solid, m.p. 61-63 °C. IR (thin film, CDCl3): 3211, 2173, 1666 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.64 (br s, 1H), 3.25-3.35 (m, 2H), 2.19-2.35 (m, 3H), 1.84-2.07 (m, 3H), 1.49-1.80 (m, 5H), 0.15 (s, 9H). 1-Tosyl-3-(5-(trimethylsilyl)pent-4-ynyl)piperidin-2-one (2.11)27 a) n-BuLi THF 78 °C N H  O  SiMe3  TsCl 78 °C - rt  N Ts  O  SiMe3  A solution of n-butyllithium (25 mL, 1.55 M in hexanes, 39 mmol) was added over 5 min to a solution of piperidone 2.10 (8.4 g, 35 mmol) in tetrahydrofuran (125 mL). The reaction mixture was stirred 0.5 h at −78 °C before a solution of p-toluenesulfonyl chloride (14 g, 71 mmol) in tetrahydrofuran (50 mL) was added. After warming to room temperature over 2 h, water was added, the layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. After purification by column chromatography on silica gel (10:1 → 8:1 → 5:1 hexanes:ethyl acetate), 11 g (77%) of the title compound was isolated as a colourless oil. IR (thin film): 2957, 2173, 1694, 1352, 1169 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.90 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 3.85-4.02 (m, 2H), 2.44 (s, 3H), 2.27-2.40 (m, 1H), 2.142.21 (m, 2H), 1.93-2.04 (m, 2H), 1.78-1.93 (m, 2H), 1.42-1.55 (m, 4H).  51  1-Tosyl-5-(5-(trimethylsilyl)pent-4-ynyl)-1,2,3,4-tetrahydropyridine (2.12)27 1. DIBAL-H CH2Cl2 78 °C N Ts  O  SiMe3  N Ts  2. MsCl NEt3 DMAP  SiMe3  A solution of diisobutylaluminum hydride (35 mL, 1.0 M in hexanes, 35 mmol) was added over 15 min to a solution of toluenesulfonamide 2.11 (6.4 g, 16 mmol) in dichloromethane (20 mL) at −78 °C and the reaction mixture was stirred at that temperature for 1 h. Buffered ammonium chloride solution (9 mL, pH 8) was added and the mixture was warmed gradually to room temperature. Magnesium sulfate (25 g) was added and stirring was continued at room temperature for 1 h, after which the solution was filtered through Celite and concentrated by rotary evaporation. The slightly yellow oil was re-dissolved in dichloromethane (220 mL), 4(dimethylamino)pyridine (0.11 g, 0.87 mmol), triethylamine (8.4 mL, 65 mmol) were added and the mixture was cooled to 0 °C. Methanesulfonyl chloride (2.6 mL, 33 mmol) was added and the mixture was stirred 20 h, warming gradually to room temperature. The light yellow solution was washed with water and brine. The aqueous layer was extracted three times with dichloromethane and the combined organics were dried over sodium sulfate and concentrated by rotary evaporation. After purification by column chromatography on silica gel (15:1 →10:1 hexanes:ethyl acetate), 4.9 g (79%) of the title compound was isolated as a colourless oil. IR (thin film, CDCl3): 2956, 2173, 1164 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.68 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 6.49 (s, 1H), 3.27-3.34 (m, 2H), 2.43 (s, 3H), 2.03-2.18 (m, 4H), 1.78-1.86 (m, 2H), 1.53-1.68 (m, 4H), 0.18 (s, 9H). 5-(Pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine (2.13)27 K 2CO3 N Ts  SiMe3  MeOH rt  N Ts  A mixture of enesulfonamide 2.12 (4.9 g, 13 mmol) and potassium carbonate (3.6 g, 26 mmol) in methanol (80 mL) was stirred open to the atmosphere for 15 h. The mixture was then concentrated by rotary evaporation and the residue was dissolved with water and ether. The layers were separated, the aqueous layer was extracted three times with ether and the combined organics were dried over sodium sulfate and concentrated by rotary evaporation. After purification of the orange oil by column chromatography on silica gel (15:1 → 14:1 → 10:1 hexanes:ethyl acetate), 3.6 g (91%) of the title compound was isolated as an off-white solid, m.p. 52-54 °C. IR (thin film, CDCl3): 3288, 2933, 1164 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 6.48 (s, 1H), 3.29-3.39 (m, 2H), 2.42 (s, 3H), 2.03-2.14 (m, 4H), 1.97 (t, J = 2.6 Hz, 1H), 1.77-1.85 (m, 2H), 1.53-1.65 (m, 4H). 52  5.2.3. Synthesis of Aryl Halides 2-Iodo-1H-indole (2.15)72 a) n-BuLi THF 78 °C b) CO2  H N  I  H N  c) t-BuLi THF 78 °C I  I  A solution of n-butyllithium (18 mL, 1.53 M in hexanes, 28 mmol) was added slowly to a solution of indole (3.1 g, 26 mmol) in tetrahydrofuran (80 mL) at −78 °C and the mixture was stirred at −78 °C for 1 h. Carbon dioxide was bubbled through the white slurry formed for 10 min to give a clear, colourless solution, which was concentrated in vacuo without exposure to the atmosphere. The white solid formed was redissolved in tetrahydrofuran (80 mL), cooled to −78 °C and a solution of tert-butyllithium (19 mL, 1.41 M in pentane, 27 mmol) was added dropwise. The bright yellow reaction mixture was stirred at −78 °C for 1 h, after which diiodoethane (7.5 g, 27 mmol) was added as a solution of tetrahydrofuran (20 mL). The resulting cloudy white solution was stirred at −78 °C for 20 min, water was added (3 mL) and the mixture was warmed to room temperature and poured into a saturated aqueous solution of ammonium chloride (200 mL). The aqueous layer was extracted three times with ether, washed once with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. After purification by column chromatography on silica gel (8:1 → 5:1 hexanes: diethyl ether), 6.0 g (83%) of the title compound was isolated as a brown solid, m.p. 76 °C (dec). IR (thin film, CDCl3): 3379, 1453, 785, 749 cm-1. 1H NMR (400 MHz, CDCl3): δ 8.21 (br s, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.04 - 7.16 (m, 2H), 6.74 (s, 1H). 2-Iodo-1-methyl-1H-indole (2.16)72 I  H N  a) NaH THF rt  I  Me N  b) MeI  A solution of 2-iodo-1H-indole 2.15 (0.49 g, 2.0 mmol) in tetrahydrofuran (5 mL) was added to a slurry of sodium hydride (0.057 g, 2.4 mmol) in tetrahydrofuran (10 mL) at room temperature. The mixture was stirred at room temperature for 0.5 h. Methyl iodide (0.16 mL, 2.6 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. Water (20 mL) was added and the aqueous layer was extracted three times with ether, the combined organic fractions were washed once with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. After purification of the crude brown solid by column chromatography on silica gel, 0.49 g (93%) of the title compound was isolated as an off-white solid. IR (thin film, CDCl3): 1456, 1322, 745 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.2 Hz, 1H), 7.34-7.40 (m, 1H), 7.24-7.33 (m, 1H), 7.17-7.24 (m, 1H), 6.92 (s, 1H), 3.79 (s, 3H). 53  1-Benzyl-2-iodo-1H-indole (3.25)73  I  H N  KOH DMF  I  N  BnBr  Dimethylformamide (1 mL) was added to a flask charged with 2-iodo-1H-indole 2.15 (0.28 g, 1.1 mmol) and powdered potassium hydroxide (0.19 g, 3.4 mmol) and the mixture was stirred at room temperature for 1 h. After cooling to 0 °C, benzyl bromide (0.20 mL, 1.2 mmol) was added to the green-brown solution, which was then stirred at 0 °C for 15 min. Water and ether were added, the aqueous layer was extracted three times with ether and the combined organic layers were washed three times with water, once with brine and dried over sodium sulfate. The crude brown oil was purified by column chromatography on silica gel to give 0.14 g (35%) of the title compound as a white solid, m.p. 108-110 °C. IR (thin film, CDCl3): 1453, 1249, 746 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.53-7.59 (m, 1H), 7.20-7.35 (m, 4H), 7.01-7.14 (m, 4H), 6.88 (s, 1H), 5.42 (s, 2H). 1-(2-Iodo-1H-indol-1-yl)ethanone (2.17) I  H N  a) NaH THF 0 °C  O I  N  b) Ac2O rt  A solution of 2-iodo-1-methyl-1H-indole 2.15 (1.2 g, 5.0 mmol) in tetrahydrofuran (5 mL) was added to a slurry of sodium hydride (0.13 g, 5.4 mmol) in tetrahydrofuran (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 45 min before acetic anhydride (1.5 mL, 15.9 mmol) was added to the yellow solution. The mixture was then warmed to room temperature and stirred for a further 1.5 h. Water (15 mL) was added and the aqueous layer was extracted three times with ether, dried over sodium sulfate and concentrated by rotary evaporation. After purification by column chromatography on silica gel, 0.79 g (55%) of the title compound was isolated as a beige solid. IR (thin film, CDCl3): 3066, 1709, 1468, 1289 cm-1. 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 8.2 Hz, 1H), 7.44-7.50 (m, 1H), 7.20-7.30 (m, 2H), 7.03 (s, 1H), 2.88 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 137.8, 131.1, 124.7, 123.6, 123.3, 119.4, 115.1, 73.5, 28.4. MS (APCI): 286 (M + H)+.  54  2-Bromofuran (2.14)74 O  Br2 DMF  Br  O  20-rt  Bromine (12 mL, 230 mmol) was added dropwise to dimethylformamide (50 mL) at −20 °C and the red-brown solution was warmed to room temperature. The bromine solution was added dropwise to a solution of furan (25 mL, 340 mmol) in dimethylformamide (50 mL) at room temperature, keeping the internal temperature less than 35 °C. The dark green solution was stirred at room temperature 1 h and then poured on to ice. The purple solution was extracted three times with 1-isopropyl-4-methylbenzene and the combined organics were washed twice with brine and dried over magnesium sulfate to give a brown solution. N,Ndiisopropylethylamine (1 mL) was added and the product was isolated by distillation (28-32 °C, 1 mm Hg) to give 7.8 g of a clear, colourless oil of the title compound as a 7:1 mixture with 1isopropyl-4-methylbenzene (89 wt%, ~20% yield). IR (neat): 2960, 1475, 1161 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.43 (dd, J = 2.2 and 0.9 Hz, 1H), 6.37-6.40 (m, 1H), 6.31 (dd, J = 3.5 and 0.9 Hz, 1H). 1-Phenyl-1H-indole67,75 CuI proline K2CO3  H N  N  I DMSO 90 °C  A 100 mL sealable tube was charged with copper iodide that had been purified by washing with tetrahydrofuran (0.26 g, 1.4 mmol), indole (1.5 g, 13 mmol), iodobenzene (1.7 mL, 15 mmol), Lproline (0.25 g, 2.2 mmol) and anhydrous potassium carbonate (3.5 g, 25 mmol). After evacuating the tube and backfilling with nitrogen twice, dimethylsulfoxide (18 mL) was added, the tube was sealed and the mixture was heated to 90 °C for 48 h. The dark green solution and precipitate were then poured into water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate, the combined organics were washed once with brine, dried over sodium sulfate and evaporated by rotary evaporation. After purification of the resulting crude brown oil by column chromatography on silica gel, 1.9 g (79%) of the title compound was isolated as a colourless oil. IR (thin film, CDCl3): 3052, 1596, 1455 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.71 (d, J = 7.3 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.49-7.56 (m, 4H), 7.31-7.42 (m, 2H), 7.09-7.26 (m, 2H), 6.70 (d, J = 2.7 Hz, 1H).  55  2-Iodo-1-phenyl-1H-indole (3.26) a) n-BuLi Et2O reflux N  b) I2 Et2O rt  I  N  A solution of n-butyllithium (2.3 mL, 1.40 M in hexanes, 3.2 mmol) was added to a solution of 1-phenyl-1H-indole (0.51 g, 2.6 mmol) in ether (8 mL) at room temperature. The slightly yellow solution was then heated to moderate reflux for 8 h. The yellow solution formed was cooled to room temperature and a solution of iodine (0.83 g, 3.3 mmol) in ether (10 mL) was added slowly to give a brown solution. A solution of sodium thiosulfate was added and the aqueous layer was extracted three times with ether. The combined organics were washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The crude brown oil was passed through a plug of silica gel (hexanes) to remove colour and the 3:2 mixture of the title compound and 1-phenyl-1H-indole was used without further purification. IR (thin film, CDCl3): 1476, 1435, 1296, 743 cm-1. 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 6.8 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.267.33 (m, 1H), 7.11-7.26 (m, 3H), 7.02 (s, 1H), 6.89 (d, J = 7.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 139.9, 131.2, 130.8, 129.3, 122.5, 120.5, 119.4, 113.4, 110.9. Benzofuran76 O HO  O HO  Cl  +  NaOH  O  HO H  H 2O 100 °C O  KOAc Ac2O  O  AcOH reflux  H O  An aqueous solution of sodium hydroxide (18 mL, 0.8 g/mL, 360 mmol) was added to a solution of salicylaldehyde (19 mL, 170 mmol) and chloroacetic acid (16 g, 170 mmol) in water (75 mL), forming a yellow solution with a white precipitate that was heated to reflux for 3 h. The mixture was then subjected to a steam-distillation until the distillate contained only water and then cooled to room temperature, forming a light brown precipitate. The mixture was then filtered, washing with water and the precipitate was dried under vacuum for 16 h to give 9.6 g light brown solid. To this solid was added acetic anhydride (50 mL, 530 mmol), acetic acid (50 mL, 870 mmol) and potassium acetate (23 g, 240 mmol) and the mixture was heated to reflux for 8 h. The brown solution was poured into ice water (250 mL) and the aqueous layer was extracted twice with ether. The organic layer was washed with once with water, 5 % aqueous sodium hydroxide until basic (~250 mL), once with water, once with brine and dried over sodium sulfate. After purification by distillation (760 mmHg, 30 °C-121 °C), 2.6 g (13%) benzofuran was isolated as a clear, colourless oil. IR (neat): 1452, 1249, 1030, 746 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.61-7.67 (m, 2H), 7.517.57 (m, 1H), 7.23-7.36 (m, 2H), 6.81 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 154.9, 144.9, 127.4, 124.2, 122.7, 121.2, 111.4, 106.5. 56  2-Iodobenzofuran (3.27)77 O  a) t-BuLi Et2O 78 °C  I  O  b) I2  A solution of tert-butyllithium (1.5 mL, 1.55 M in pentane, 2.3 mmol) was added dropwise to a solution of benzofuran (0.25 g, 2.1 mmol) in diethyl ether (5 mL) at −78 °C and the reaction mixture was stirred for 0.5 h. A solution of iodine (0.59 g, 2.3 mmol) in diethyl ether (10 mL) was added to the slightly yellow solution. After stirring the resulting red coloured solution for 0.5 h at −78 °C, a saturated solution of ammonium chloride was added. The layers were separated and the aqueous layer was extracted with three portions of diethyl ether, washed once with a saturated solution of sodium thiosulfate, once with water, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The resulting pink oil (0.49 g, 95% yield, ~90% pure) was used in the next reaction without further purification. 1 H NMR (400 MHz, CDCl3): δ 7.45-7.55 (m, 2H), 7.18-7.26 (m, 2H), 6.97 (s, 1H). 2-Iodo-1-methyl-1H-pyrrole (3.28)68 Me N  a) n-BuLi TMEDA 50 °C  I  Me N  b) I2 THF 78 °C  A solution of n-butyllithium (7.2 mL, 1.56 M in hexanes, 11 mmol) was added quickly to a stirred mixture of N-methyl pyrrole (1.0 mL, 11 mmol) and N,N,Nʹ,Nʹtetramethylethylenediamine (1.7 mL, 11 mmol) at room temperature. The cloudy yellow solution was immersed in a room temperature oil bath, which was heated to 50 °C once the mixture started to cool. After 0.5 h the thick cloudy orange solution was cooled to 0 °C and dissolved in tetrahydrofuran (6 mL). The mixture was then cooled to −78 °C and a solution of iodine (2.60 g, 10 mmol) in tetrahydrofuran (10 mL) was added over 15 min. The brown solution was warmed to room temperature and a saturated solution of sodium thiosulfate was added. The aqueous layer was extracted four times with ether, the organic layers were washed twice with a saturated solution of ammonium chloride, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. After purification of the dark brown oil by column chromatography on silica gel (hexanes → 20:1 hexanes: ethyl acetate), 1.4 g (68%) of the title compound was isolated as a clear, colourless oil. 1 H NMR (300 MHz, CDCl3): δ 6.84 (d, J = 2.0 Hz, 1H), 6.36 (dd, J = 3.7 Hz and 1.8 Hz, 1H), 6.16 (t, J = 3.7 Hz, 1H), 3.62 (s, 3H).  57  5.2.4. Sonogashira Cross-Coupling Reactions General Experimental for Sonogashira Coupling Reactions: 1-Methyl-2-(5-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)-1H-indole (2.22) Me N N Ts  Argon-degassed triethylamine (2 mL) was added to a flask charged with bis(triphenylphosphine)palladium(II) chloride (0.022 g, 0.031 mmol) and copper iodide (0.022 g, 0.11 mmol). To this yellow slurry was added 2-iodo-1-methyl-1H-indole 2.16 (0.22 g, 0.84 mmol) and enesulfonamide 2.13 (0.20 g, 0.66 mmol) dissolved in triethylamine (2 mL) and argon-degassed dichloromethane (1 mL), washing with dichloromethane (1 mL). The resulting black solution was covered with foil and stirred at room temperature for 2.5 h. The brown solution and precipitate were filtered through a pipette of silica gel using ethyl acetate as the eluant, and concentrated by rotary evaporation to give a brown solid and oil. After purification by column chromatography on triethylamine-washed silica gel (10:1 → 8:1 → 6:1 → 4:1 hexanes:ethyl acetate), 0.23 g (80%) of the title compound was isolated as a brown solid that could be recrystallized from chloroform/methanol m.p. 108-111 ºC. IR (thin film, CH2Cl2): 2931, 1342, 1163 cm-1. 1H NMR (CDCl3, 400 MHz): δ 7.69 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 7.3 Hz, 1H), 7.25-7.33 (m, 4H), 7.15 (dt, J = 8.1 and J = 1.5 Hz, 1H), 6.60 (s, 1H), 6.45 (s, 1H), 3.83 (s, 3H), 3.31-3.39 (m, 2H), 2.45 (t, J = 7.3, 2H), 2.43 (s, 3H), 2.18 (t, J = 7.3 Hz, 2H), 1.84-1.90 (m, 2H), 1.75 (quintet, J = 7.3 Hz, 2H), 1.60-1.70 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 143.5, 136.9, 134.9, 129.7, 127.2, 127.0, 122.6, 122.5, 120.6, 120.5, 119.9, 119.8, 109.3, 106.2, 95.9, 72.8, 43.6, 34.2, 30.5, 26.5, 24.3, 21.5, 20.8, 18.8. MS (APCI): 433 (M + H)+. Anal. Calcd for C26H28N2O2S: C, 72.19; H, 6.52; N, 6.48. Found: C, 71.86; H, 6.54; N, 6.43. 5-(5-(3,4-Dimethoxyphenyl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine (2.19) N Ts  OMe OMe  Enesulfonamide 2.13 (0.18 g, 0.61 mmol), bis(triphenylphosphine)palladium(II) chloride (0.022 g, 0.031 mmol), copper iodide (0.011 g, 0.058 mmol), and 4-iodo-1,2-dimethoxybenzene (0.135 g, 0.76 mmol) were combined according to the general procedure above, except that the reaction mixture was stirred for 2 h. Silica gel was added to the reaction mixture, which was then evaporated to dryness and purified directly by column chromatography on triethylamine-washed silica gel (gradient 10:1 to 1:1 hexanes:ethyl acetate) to yield 0.24 g (89%) of the title compound as an orange oil. IR (thin film, CDCl3): 1514, 1350, 1093, 1027 cm -1. 1H (CDCl3, 400 MHz): δ 7.67 (d, 2H, J = 8.3 Hz), 7.29 (d, 2H, J = 7.8 Hz), 7.01 (dd, 1H, J = 8.3 and 1.7 Hz), 6.95 (d, 1H, J = 1.7 Hz), 58  6.78 (d, 1H, J = 8.3 Hz), 6.54 (s, 1H), 3.87 (s, 3H), 3.28-3.31 (m, 2H), 2.41 (s, 1H), 2.31 (t, 2H, J = 7.0 Hz), 2.13 (t, 2H, J = 7.2 Hz), 1.84 (t, 2H, J = 6.1 Hz), 2.58-1.69 (m, 4H). 13C (CDCl3, 100 MHz): δ 150.1, 149.6, 144.4, 135.9, 130.6, 128.1, 125.6, 121.5, 121.0, 117.1, 115.4, 112.0, 88.9, 56.9, 44.6, 35.1, 27.5, 25.3, 22.5, 21.8, 19.4. HRMS (ESI): calcd for C25H29NO4Na32S: 462.1715. Found: 462.1718. 5-(5-(Furan-2-yl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine (2.18) O N Ts  Enesulfonamide 2.13 (0.20 g, 0.66 mmol), bis(triphenylphosphine)palladium(II) chloride (0.021 g, 0.030 mmol), copper iodide (0.007 g, 0.04 mmol), and 2-bromofuran 2.14 (0.19 g, 89 wt %, 1.2 mmol) were combined according to the general procedure above, except that the reaction mixture was stirred for 20 h. After purification by column chromatography on silica gel (8:1 → 5:1 hexanes:ethyl acetate), 0.19 g (78%) of the title compound was isolated as a brown oil. IR (thin film, CDCl3): 1350, 1165, 1093 cm-1. 1H NMR (CDCl3, 400 MHz): δ 7.66 (d, 2H, J = 8.3 Hz), 7.31-7.32 (m, 1H), 7.29 (d, 2H, J = 8.3 Hz), 6.48-6.50 (m, 2H), 6.35 (dd, 1H, J = 3.3 Hz and J = 1.3 Hz, 1H), 3.28-3.31 (m, 2H), 2.41 (s, 3H), 2.33 (t, 2H, J = 7.2 Hz), 2.08-2.12 (m, 2H), 1.81-1.84 (m, 2H), 1.59-1.69 (m, 4H). 13C NMR (CDCl3, 100 MHz): δ 143.6, 142.9, 137.9, 135.0, 129.8, 127.2, 120.6, 120.0, 113.9, 110.8, 94.2, 71.6, 43.7, 34.3, 26.2, 24.5, 21.6, 20.9, 18.7. MS (APCI): 370 (M + H)+. Anal. Calcd for C21H23NO3S: C, 68.27; H, 6.27; N, 3.79. Found: C, 68.40; H, 6.48; N, 3.92.  2-(5-(1-Tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)-1H-indole (2.21) H N N Ts  Enesulfonamide 2.13 (0.20 g, 0.67 mmol), bis(triphenylphosphine)palladium(II) chloride (0.021 g, 0.030 mmol), copper iodide (0.012 g, 0.063 mmol) and 2-iodoindole 2.14 (0.20 g, 0.80 mmol) were combined according to the general procedure above and stirred for 2.5 h. After purification by column chromatography on silica gel (4:1 → 2:1 hexanes:ethyl acetate), 0.24 g (85%) of the title compound was isolated as a brown solid m.p. 125-126 ºC. IR (thin film, CH2Cl2): 3385, 1452, 1349, 1163 cm-1. 1H NMR (CDCl3, 400 MHz): δ 8.75 (s, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.31, (d, J = 8.3 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.72 (s, 1H), 6.65 (s, 1H), 3.31-3.37 (m, 2H), 2.42 (s, 3H), 2.37-2.44 (m, 3H), 2.18 (t, J = 7.0, 2H), 1.81-1.87 (m, 2H), 1.70 (quintet, J = 7.0 Hz, 2H), 1.59-1.63 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 143.7, 136.0, 134.8, 129.8, 127.7, 127.1, 122.9, 120.7, 120.4, 120.1, 119.8, 119.4, 110.9, 107.2, 92.9, 74.1, 43.6, 33.7, 25.6,  59  24.0, 21.5, 20.7, 18.4. M.S. (APCI): 419 (M + H)+. Anal. Calcd for C25H26N2O2S: C, 71.71; H, 6.26; N, 6.69. Found: C, 71.34; H, 6.60; N, 6.41. 1-Methyl-3-(5-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)-1H-indole (2.23) N Ts  N Me  Enesulfonamide 2.13 (0.20 g, 0.67 mmol), bis(triphenylphosphine)palladium(II) chloride (0.022 g, 0.031 mmol), copper iodide (0.009 g, 0.048 mmol) and 3-iodo-1-methyl-1H-indole (0.21 g, 0.83 mmol) were combined according to the general procedure above except that the reaction mixture was stirred for 20 h. After purification by column chromatography on silica gel (10:1 → 7:1 → 5:1 hexanes:ethyl acetate), 0.13 g (50%) of the title compound was isolated as a brown oil that was recrystallized from chloroform/methanol to give a brown crystalline solid m.p. 126-127 ºC. IR (thin film, CH2Cl2): 1348, 1163, 1092, 963 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.77 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.15-7.37 (m, 6H), 6.57 (s, 1H), 3.78 (s, 3H), 3.26-3.37 (m, 2H), 2.37-2.48 (m, 5H), 2.19 (t, J = 7.4 Hz, 2H), 1.84-1.93 (m, 2H), 1.72 (quintet, J = 7.7 Hz, 2H), 1.57-1.68 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 143.6, 136.3, 135.1, 131.8, 129.8, 129.5, 127.3, 122.3, 120.6, 120.2, 109.6, 97.6, 90.7, 74.2, 43.8, 34.3, 33.1, 27.1, 24.6, 21.7, 21.0, 19.1. MS (APCI): 433 (M + H)+. Anal. Calcd for C26H28N2O2S: C, 72.19; H, 6.52; N, 6.47; Found: C, 72.01; H, 6.58; N, 6.38.  5-(5-(3,5-Dimethoxyphenyl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine (2.20) OMe N Ts OMe  Enesulfonamide 2.13 (0.18 g, 0.61 mmol), bis(triphenylphosphine)palladium(II) chloride (0.043 g, 0.061 mmol), copper iodide (0.012 g, 0.065 mmol), and 1-bromo-3,5-dimethoxybenzene (0.16 g, 0.74 mmol) were combined according to the general procedure above, except that the reaction mixture was stirred for 22 h. After purification by column chromatography on silica gel (10:1 → 8:1 → 6:1 → 4:1 hexanes: ethyl acetate), 0.15 g (58%) of the title compound was isolated as a yellow oil. IR (thin film, CDCl3): 1596, 1349, 1156 cm-1. 1H NMR (CDCl3, 400 MHz): δ 7.68 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 6.59 (d, J = 2.3 Hz, 2H), 6.54 (s, 1H), 6.42 (t, J = 2.3 Hz, 1H), 3.79 (s, 6H), 3.30-3.33 (m, 2H), 2.42 (s, 3H), 2.32 (t, J = 7.0 Hz, 2H), 2.13 (t, J = 7.2 Hz, 2H), 1.82-1.88 (m, 2H), 1.67 (quintet, J = 7.1 Hz, 2H), 1.59-1.65 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 161.5, 144.4, 136.0, 130.7, 128.1, 126.2, 121.5, 121.0, 110.4, 102.2, 90.3, 82.2, 56.4,  60  44.6, 35.1, 27.4, 25.4, 22.5, 21.8, 19.5. MS (ESI): 440 (M + H)+, 462 (M + Na)+. Anal. Calcd for C25H29NO4S: C, 68.31; H, 6.65; N, 3.19. Found: C, 68.11; H, 6.65; N, 3.17. 1-(2-(5-(1-Tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)-1H-indol-1-yl)ethanone (2.24) O N N Ts  Enesulfonamide 2.13 (0.22 g, 0.71 mmol), bis(triphenylphosphine)palladium(II) chloride (0.025 g, 0.035 mmol), copper iodide (0.021 g, 0.11 mmol), and 1-(2-iodo-1H-indol-1-yl)ethanone 2.17 (0.26 g, 0.92 mmol) were combined according to the general procedure above, except that the reaction mixture was stirred for 4 h. After purification by column chromatography on silica gel (8:1 → 6:1 hexanes: ethyl acetate), 0.25 g (76%) of the title compound was isolated as a brown solid, which could be recrystallized from chloroform/methanol to yield a brown crystalline solid, m.p. 82-83 °C. IR (thin film, CDCl3): 1704, 1447, 1304, 1164 cm-1. 1H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.30 (d, J = 7.8 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 6.91 (s, 1H), 6.54 (s, 1H), 3.31-3.36 (m, 2H), 2.88 (s, 3H), 2.38-2.48 (m, 4H), 2.14 (t, J = 7.2 Hz, 2H), 1.82-1.90 (m, 2H), 1.72 (quintet, J = 7.2 Hz, 2H), 1.59-1.68 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 170.2, 143.3., 136.2, 134.7, 129.4, 128.5, 126.8, 125.7, 123.7, 120.3, 120.0, 119.5, 117.1, 116.8, 98.5, 73.9, 43.3, 34.1, 26.5, 26.0, 24.2, 21.3, 20.6, 18.8. MS (APCI): 461 (M + H)+. Anal. Calcd for C27H28N2O3S: C, 70.41; H, 6.13; N, 6.08. Found: C, 70.23; H, 6.11; N, 6.04. 5-(5-(4-Methoxyphenyl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine (1.42)27 N Ts  OMe  Enesulfonamide 2.13 (0.84 g, 2.8 mmol), bis(triphenylphosphine)palladium(II) chloride (0.097 g, 0.14 mmol), copper iodide (0.052 g, 0.27 mmol), and 4-iodoanisole (0.79 g, 0.74 mmol) were combined according to the general procedure above, except that the reaction mixture was stirred for 4 h. After purification by column chromatography on silica gel (8:1 → 6:1 → 4:1 hexanes: ethyl acetate), 1.0 g (88%) of the title compound was isolated as an orange oil that solidified to an orange solid, m.p. 84-87 °C. IR (thin film, CDCl3): 2933, 1606, 1509, 1164 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.68 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 9.0 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 6.53 (s, 1H), 3.80 (s, 3H), 3.29-3.33 (m, 2H), 2.42 (s, 3H), 2.31 (t, J = 7.0 Hz, 2H), 2.13 (t, J = 7.2 Hz, 2H), 1.82-1.88 (m, 2H), 1.59-1.71 (m, 4H).  61  1-Benzyl-2-(5-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)-1H-indole (3.29)  N N Ts  Enesulfonamide 2.13 (0.18 g, 0.60 mmol), bis(triphenylphosphine)palladium(II) chloride (0.025 g, 0.036 mmol), copper iodide (0.014 g, 0.074 mmol), and 1-benzyl-2-iodo-1H-indole 3.25 (0.24 g, 0.72 mmol) were combined according to the general procedure above, except that the reaction mixture was stirred for 3 h. After purification by column chromatography silica gel (10:1 → 8:1 → 6:1 → 4:1 hexanes: ethyl acetate), 0.28 g (92%) of the title compound was isolated as a brown oil that could be recrystallized from hexanes/ethyl acetate to give a brown crystalline solid, m.p. 82-85 °C. IR (thin film, CDCl3): 3061, 1454, 1347, 1163 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 7.5, 1H), 7.25-7.32 (m, 5H), 7.20-7.24 (m, 1H), 7.12-7.20 (m, 3H), 7.07-7.12 (m, 1H), 6.77 (s, 1H), 6.48 (s, 1H), 5.46 (s, 2H), 3.27-3.33 (m, 2H), 2.35-2.45 (m, 4H), 2.05 (t, J = 7.05, 2H), 1.76-1.82 (m, 2H), 1.58-1.70 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 143.4, 137.7, 136.3, 134.8, 129.5, 128.5, 127.4, 127.2, 126.9, 126.5, 122.7, 122.5, 120.7, 120.3, 120.0, 119.8, 109.8, 106.8, 96.1, 72.8, 47.7, 43.5, 34.0, 26.3, 24.2, 21.4, 20.7, 18.7. MS (APCI): 509 (M + H)+. Anal. Calcd for C32H32N2O2S: C, 75.56; H, 6.34; N, 5.51. Found: C, 75.51; H, 6.34; N, 5.72. 1-Phenyl-2-(5-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)-1H-indole (3.30)  N N Ts  Enesulfonamide 2.13 (0.20 g, 0.64 mmol), bis(triphenylphosphine)palladium(II) chloride (0.023 g, 0.033 mmol), copper iodide (0.016 g, 0.084 mmol), and 2-iodo-1-phenyl-1H-indole 3.26 (0.54 g, ~50 % purity, ~0.67 mmol) were combined according to the general procedure above, except that the reaction mixture was stirred for 5 h. After purification by column chromatography on silica gel (10:1 → 8:1 → 5:1 hexanes: ethyl acetate), 0.19 g (59%) of the title compound was isolated as a brown oil that could be recrystallized from hexanes/ethyl acetate to give a brown crystalline solid, m.p. 118-119 °C. IR (thin film, CH2Cl2): 1596, 1500, 1350, 1163 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.60-7.69 (m, 3H), 7.48-7.57 (m, 4H), 7.40-7.46 (m, 1H), 7.23-7.31 (m, 3H), 7.11-7.23 (m, 2H), 6.86 (s, 1H), 6.39 (s, 1H), 3.27-3.33 (m, 2H), 2.42 (s, 3H), 2.25 (t, J = 6.8 Hz, 2H), 1.91 (t, J = 7.3 Hz, 2H), 1.72-1.79 (m, 2H), 1.58-1.66 (m, 2H), 1.47-1.57 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 143.4, 137.7, 137.2, 134.9, 129.6, 129.0, 127.5, 127.4, 127.0, 123.1, 122.5, 120.64, 120.60, 120.3, 119.8, 73.1, 43.5, 33.8, 26.0, 24.3, 21.5, 20.7, 18.6. MS (APCI): 495 (M + H)+. Anal. Calcd for C31H30N2O2S: C, 75.27; H, 6.11; N, 5.66. Found: C, 74.94; H, 6.05; N, 5.80. 62  5-(5-(1-Methyl-1H-pyrrol-2-yl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine (3.33) Me N N Ts  Enesulfonamide 2.13 (0.20 g, 0.67 mmol), bis(triphenylphosphine)palladium(II) chloride (0.027 g, 0.039 mmol), copper iodide (0.015 g, 0.078 mmol), and 2-iodo-1-methyl-1H-pyrrole 3.28 (0.19 g, 0.93 mmol) were combined according to the general procedure above, except that the reaction mixture was stirred for 1 h. After purification by column chromatography on silica gel (10:1 → 8:1 → 5:1 hexanes: ethyl acetate), 0.19 g (73%) of the title compound was isolated as a brown oil that could be recrystallized from hexanes/ethyl acetate to give a brown crystalline solid, m.p. 117-119 °C. IR (thin film, CDCl3): 1349, 1163, 1092, 962 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 6.60 (s, 1H), 6.52 (s, 1H), 6.30-6.35 (m, 1H), 6.02-6.08 (m, 1H), 3.67 (s, 3H), 3.29-3.34 (m, 2H), 2.43 (s, 3H), 2.37 (t, J = 7.2 Hz, 2H), 2.13 (t, J = 7.2 Hz, 2H), 1.82-1.87 (m, 2H), 1.58-1.72 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 143.4, 134.8, 129.6, 127.0, 122.6, 120.3, 120.0, 116.1, 113.4, 107.5, 92.8, 72.7, 43.5, 34.4, 34.0, 26.6, 24.3, 21.4, 20.7, 18.6. MS (ESI): 405 (M + Na)+. Anal. Calcd for C22H26N2O2S: C, 69.08; H, 6.85; N, 7.32. Found: C, 69.23; H, 6.81; N, 7.54. 5-(5-(Benzofuran-2-yl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine (3.31) O N Ts  Enesulfonamide 2.13 (0.26 g, 0.84 mmol), bis(triphenylphosphine)palladium(II) chloride (0.032 g, 0.046 mmol), copper iodide (0.020 g, 0.10 mmol), and 2-iodobenzofuran 3.27 (0.41 g, ~1.7 mmol) were combined according to the general procedure above, except that the reaction mixture was stirred at rt for 2 h. After purification by column chromatography on silica gel (10:1 → 8:1 → 6:1 → 4:1 hexanes: ethyl acetate), 0.30 g (86%) of the title compound was isolated as a brown oil that solidified in the freezer to become a brown solid, m.p. 59-62 °C. IR (thin film, CH2Cl2): 1567, 1350, 1164, 1092 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.25-7.33 (m, 3H), 7.21 (t, J = 7.5 Hz, 1H), 6.85 (s, 1H), 6.53 (s, 1H), 3.29-3.34 (m, 2H), 2.34-2.43 (m, 4H), 2.12 (t, J = 7.2 Hz, 2H), 1.79-1.84 (m, 2H), 1.69 (quintet, J = 7.2 Hz, 2H), 1.55-1.65 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 154.3, 143.4, 138.9, 134.7, 129.5, 127.6, 126.9, 125.0, 123.0, 120.9, 120.4, 119.6, 110.9, 110.2, 96.2, 71.6, 43.4, 34.0, 25.9, 24.2, 21.4, 20.7, 18.6. HRMS (ESI) calcd for C25H25NO3Na32S (M + Na)+: 442.1453. Found: 442.1459.  63  5-(5-Phenylpent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine (3.32)27 N Ts  Enesulfonamide 2.13 (0.31 g, 1.0 mmol), bis(triphenylphosphine)palladium(II) chloride (0.038 g, 0.055 mmol), copper iodide (0.027 g, 0.14 mmol), and iodobenzene (0.15 mL, 1.3 mmol) were combined according to the general procedure above, except that the reaction mixture was stirred for 22 h. After purification by column chromatography on silica gel (10:1 → 8:1 → 5:1 hexanes: ethyl acetate), 0.37 g (96%) of the title compound was isolated as an orange solid, m.p. 84-86 °C. IR (thin film, CDCl3): 2932, 1350, 1164 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.68 (d, J = 8.2 Hz, 2H), 7.36-7.45 (m, 2H), 7.27-7.34 (m, 5H), 6.54 (s, 1H), 3.27-3.35 (m, 2H), 2.43 (s, 3H), 2.33 (t, J = 7.1 Hz, 2H), 2.14 (t, J = 7.3 Hz, 2H), 1.81-1.89 (m, 2H), 1.58-1.75 (m, 4H). 1-Tosyl-5-(5-(4-(trifluoromethyl)phenyl)pent-4-ynyl)-1,2,3,4-tetrahydropyridine (1.44)27 N Ts  CF3  Enesulfonamide 2.13 (0.38 g, 1.3 mmol), bis(triphenylphosphine)palladium(II) chloride (0.045 g, 0.064 mmol), copper iodide (0.026 g, 0.14 mmol), and 1-iodo-4-(trifluoromethyl)benzene (0.23 g, 1.6 mmol) were combined according to the general procedure above, except that the reaction mixture was stirred for 22 h. After purification by column chromatography on silica gel (10:1 → 8:1 hexanes: ethyl acetate), 0.54 g (96%) of the title compound was isolated as a brown solid, m.p. 70-73 °C. IR (thin film, CDCl3): 2934, 1615, 1165, 1125 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.68 (d, J = 8.2 Hz, 2H), 7.48-7.59 (m, 4H), 7.22-7.35 (m, 2H), 6.54 (s, 1H), 3.28-3.36 (m, 2H), 2.43 (s, 3H), 2.36 (t, J = 7.1 Hz, 2H), 2.14 (t, J = 7.5 Hz, 2H), 1.81-1.91 (m, 2H), 1.58-1.77 (m, 4H). Methyl 6-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)hex-2-ynoate (3.34) a) n-BuLi THF 78 °C N Ts  b) Cl  O  OMe THF 78 °C-rt  O N Ts  OMe  A solution of n-butyllithium (0.67 mL, 1.48 M in hexanes, 1.0 mmol) was added to a solution of 5-(pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine 2.13 in tetrahydrofuran (10 mL) at −78 °C and stirred at for 45 min. Methyl chloroformate (0.10 mL, 1.3 mmol) was added to the resulting slightly yellow solution at −78 °C and the mixture was stirred a further 0.5 h before warming to room temperature and stirring for 2 h. A saturated solution of sodium bicarbonate (5 mL) was 64  added to the reaction mixture, which was then extracted three times with ether, washed with brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. After purification of the resulting clear, colourless oil by column chromatography (10:1 → 8:1 → 6:1 hexanes:ethyl acetate), 0.26 g (81%) of the title compound as isolated as a white solid, which could be recrystallized from dichloromethane/hexanes to yield a white crystalline solid, m.p. 8486 °C. IR (thin film, CDCl3): 2234, 1713, 1257, 1164 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.61 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 6.43 (s, 1H), 3.73 (s, 3H), 3.22-3.31 (m, 2H), 2.39 (s, 3H), 2.21 (t, J = 7.3 Hz, 2H), 2.04 (t, J = 7.3 Hz, 2H), 1.75-1.83 (m, 2H), 1.54-1.69 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 153.9, 143.4, 134.6, 129.5, 126.8, 120.4, 119.2, 88.9, 73.1, 52.4, 43.3, 33.9, 25.1, 24.1, 21.3, 20.5, 17.5. MS (ESI): 384 (M + Na)+. Anal Calcd for C19H23NO4S: C, 63.13; H, 6.41; N, 3.88. Found: C, 63.21; H, 6.53; N, 4.09. 7-(1-Tosyl-1,4,5,6-tetrahydropyridin-3-yl)hept-3-yn-2-one (3.35) a) n-BuLi THF 78 °C N Ts  b)Ac2O THF 78 °C-rt  O N Ts  A solution of n-butyllithium (0.54 mL, 1.42 M in hexanes, 0.77 mmol) was added to a solution of 5-(pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine 2.13 (0.21 g, 0.70 mmol) in tetrahydrofuran (8 mL) at −78 °C and the resulting mixture was stirred at −78 °C for 1 h. The resulting yellow solution was added by cannula to a solution of acetic anhydride (0.09 mL, 0.95 mmol) in tetrahydrofuran (5 mL) at 0 °C, becoming a clear, colourless solution, which was stirred at 0 °C for 1 h. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted three times with ether. The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. After purification by column chromatography (10:1 → 8:1 → 6:1 → 4:1 hexanes:ethyl acetate), 0.13 g (55%) of the title compound as isolated was a clear, colourless oil. IR (thin film, CH2Cl2): 2210, 1674, 1350, 1163 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 6.49 (s, 1H), 3.29-3.34 (m, 2H), 2.43 (s, 3H), 2.34 (s, 3H), 2.29 (t, J = 7.5 Hz, 2H), 2.07 (t, J = 7.5 Hz, 2H), 1.78-1.87 (m, 2H), 1.58-1.71 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 184.7, 143.5, 134.9, 129.6, 126.9, 120.6, 119.3, 93.1, 81.7, 43.4, 34.1, 32.7, 25.5, 24.2, 21.4, 20.7, 18.0. HRMS (ESI) calcd for C19H23NO3Na32S (M + Na)+: 368.1296. Found: 368.1290.  65  2,2-Dimethyl-8-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)oct-4-yn-3-one (3.36) a) n-BuLi THF 78 °C b) N Ts  O  O  Cl THF 78 °C-rt  N Ts  A solution of n-butyllithium (0.44 mL, 1.44 M in hexanes, 0.63 mmol) was added to a solution of 5-(pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine 2.13 (0.17 g, 0.57 mmol) in tetrahydrofuran (7 mL) at −78 °C and stirred at for 0.5 h. Pivaloyl chloride (0.10 mL, 0.81 mmol) was added to the resulting solution at -78 °C and the mixture was stirred a further 0.5 h. A saturated solution of sodium bicarbonate (5 mL) was added to the reaction mixture, which was then extracted three times with ether, washed with brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. After purification by column chromatography (8:1 → 6:1 → 4:1 hexanes:ethyl acetate), 0.16 g (73%) of the title compound as isolated as a clear, colourless oil. IR (thin film, CDCl3): 2209, 1667, 1351, 1164, 1093 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.62 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 6.45 (s, 1H), 3.26-3.31 (m, 2H), 2.40 (s, 3H), 2.89 (t, J = 6.8 Hz, 2H), 2.06 (t, J = 7.2 Hz, 2H), 1.76-1.83 (m, 2H), 1.57-1.69 (m, 4H), 1.19 (s, 9H). 13 C NMR (100 MHz, CDCl3): δ 194.2, 143.5, 134.8, 129.6, 126.9, 120.5, 119.4, 94.8, 79.1, 44.5, 43.4, 34.1, 26.0, 25.8, 24.3, 21.4, 20.7, 18.1. HRMS (ESI) calcd for C22H29NO3Na32S (M + Na)+: 410.1766. Found: 410.1767.  5.3. Synthesis of Tetracyclic Products General Procedure for PtCl2 Cyclization Reactions Tetracycle (2.29a)  O N H Ts  Toluene (1.0 mL) was added to enesulfonamide 2.18 (35 mg, 0.096 mmol) and platinum(II) chloride (2.7 mg, 0.010 mmol) in a 15 mL sealed tube. The brown solution was heated to 110 °C for 16 h. The resulting dark brown solution was filtered through a pipette of silica gel using ethyl acetate as an eluant to give a dark brown film. After purification by column chromatography on silica gel (10:1 → 6:1 hexanes: ethyl acetate), 11 mg (32%) of the title compound was isolated as a colourless film. IR (thin film, CDCl3): 2932, 1336, 1155, 1096, 663 cm-1. 1H NMR (100 MHz, CDCl3): δ 7.77 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 7.8, 2H), 7.17 (d, J = 1.7, 1H), 5.60 (t, J = 3.7 Hz, 1H), 5.38 (d, J = 2.2, 1H), 4.76 (s, 1H), 3.88-3.95 (m, 1H), 2.85-2.93 (m, 1H), 2.47 (s, 3H), 2.06-2.62 (m, 2H), 66  2.00 (dt, J = 12.6 and 3.3 Hz, 1H), 1.82-1.91 (m, 1H), 1.51-1.77 (m, 5H), 1.41-1.50 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 159.1, 145.8, 143.3, 138.1, 135.2, 129.9, 127.4, 126.2, 114.0, 108.8, 60.8, 49.7, 42.0, 31.1, 29.8, 23.9, 21.7, 21.5, 17.9. HRMS (ESI) calcd for C21H24NO332S: 370.1477. Found: 370.1474. Tetracycle (2.26a and 2.26b)  + N H Ts  OMe OMe  N H Ts  OMe OMe  Enesulfonamide 2.19 (25 mg, 0.058 mmol), platinum(II) chloride (1.6 mg, 0.006 mmol) and toluene (2.0 mL) were combined according to the general procedure above. After purification by column chromatography on silica gel (1:1 hexanes:dichloromethane → dichloromethane → 99:1 dichloromethane:ethyl ether), 15 mg (61%) of the title compound was isolated of a 20:1 mixture of 2.26a and 2.26b as a colourless film. IR (thin film, CH2Cl2): 2934, 1495, 1300, 1164, 1151 cm-1. 1H NMR (400 MHz, CDCl3): for the major isomer 2.26a δ 7.81 (d, J = 8.3, 2H), 7.32 (d, J = 8.3, 2H), 6.86 (s, 1H), 6.56 (s, 1H), 5.81 (t, J = 3.7, 1H), 4.86 (s, 1H), 3.90-3.98 (m, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 2.91 (td, J = 12.9, 2.4 Hz, 1H), 2.44 (s, 3H), 2.10-2.20 (m, 2H), 1.52-1.78 (m, 4H), 1.18-1.50 (m, 4H). 13C NMR (100 MHz, CDCl3): for the major isomer 2.26a δ 149.7, 149.5, 144.0, 143.1, 139.2, 132.8, 132.5, 129.79, 127.2, 116.7, 106.8, 103.8, 75.2, 56.2, 56.1, 44.6, 41.9, 29.4, 29.3, 24.6, 21.6, 21.1, 18.3. HRMS (ESI) calcd for C25H29NO4Na32S: 462.1715. Found: 462.1710. Tetracycle (2.30a)  NH N H Ts  Enesulfonamide 2.21 (20 mg, 0.048 mmol), platinum(II) chloride (2.0 mg, 0.008 mmol) and toluene (1.0 mL) were combined according to the general procedure above. After purification by column chromatography on silica gel (6:1 → 5:1 hexanes:ethyl acetate), 7 mg (36%) of the title compound was isolated a colourless film. IR (thin film, CDCl3): 3384, 2935, 1447, 1326, 1151, 735 cm -1. 1H NMR (400 MHz, CDCl3): δ 7.98 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.13 (dt, J = 8.2 and 1.2 Hz, 1H), 6.99 (t, J = 8.2 Hz, 1H), 5.63 (t, J = 3.7 Hz, 1H), 5.13 (s, 1H), 3.90-3.96 (m, 1H), 3.06 (dd, J = 10.4 and 3.2 Hz, 1H), 2.47 (s, 3H), 2.02-2.31 (m, 2H), 1.79-1.86 (m, 2H), 1.44-1.74 (m, 3H), 1.31-1.37 (m, 2H), 1.07-1.15 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 143.1, 142.7, 140.7, 139.3, 137.8, 129.8, 127.2, 124.7, 122.4, 120.5, 67  119.54, 119.49, 115.7, 111.6, 62.2, 49.1, 42.1, 31.4, 29.9, 24.3, 21.7, 21.2, 18.1. HRMS (ESI) calcd for C25H27N2O232S: 419.1793. Found: 419.1788. Tetracycle (2.31a)  N  Me  N H Ts  Enesulfonamide 2.22 (25 mg, 0.058 mmol), platinum(II) chloride (1.5 mg, 0.007 mmol) and toluene (1.0 mL) were combined according to the general procedure above, except that the reaction mixture was stirred at 130 ºC for 16 h. After purification by column chromatography on silica gel (1:1 → 1:2 hexanes:dichloromethane → dichloromethane → 98:2 dichloromethane:diethyl ether), 17 mg (78%) of the title compound was isolated a colourless film. IR (thin film, CDCl3): 2934, 1458, 1331, 1166, 1150, 735 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 7.5 Hz, 2H), 7.24 (d, J = 8.2 Hz, 1H), 7.13-7.18 (m, 2H), 6.98 (t, J = 7.2 Hz, 1H), 5.80 (t, J = 3.8 Hz, 1H), 5.14 (s, 1H), 3.88-3.96 (m, 1H), 3.78 (s, 3H), 3.04 (dd, J = 10.9 and 2.7 Hz, 1H), 2.47 (s, 3H), 2.12-2.33 (m, 2H), 1.80-1.89 (m, 2H), 1.66-1.74 (m, 2H), 1.45-1.66 (m, 3H), 1.29-1.38 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 143.8, 143.0, 142.1, 139.3, 138.2, 129.8, 127.2, 124.1, 121.8, 119.9, 119.5, 117.8, 116.4, 109.4, 62.2, 49.3, 42.0, 31.3, 31.0, 29.8, 24.6, 21.7, 21.3, 18.0. HRMS (ESI) calcd for C26H29N2O232S: 433.1950 Found: 433.1960. Tetracycle (2.33a)  N H Ts  N Me  Enesulfonamide 2.23 (47 mg, 0.11 mmol), platinum(II) chloride (2.8 mg, 0.011 mmol) and toluene (1.0 mL) were combined according to the general procedure above. After purification by column chromatography on silica gel (10:1 → 8:1 hexanes:ethyl acetate), 8 mg (17%) of the title compound was isolated a colourless film. IR (thin film, CDCl3): 2931, 1337, 1163, 739 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 7.8, 1H), 7.35 (d, J = 7.8 Hz, 2H), 7.33 (d, J = 8.2, 1H), 7.23 (dt, J = 8.2 and 1.2 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 5.64 (t, J = 3.5 Hz, 1H), 5.29 (s, 1H), 4.02-4.08 (m, 1H), 3.83 (s, 3H), 3.05-3.15 (m, 1H), 2.88-2.95 (m, 1H), 2.48 (s, 3H), 2.04-2.28 (m, 2H), 1.781.86 (m, 1H), 1.55-1.70 (m, 2H), 1.25-1.47 (m, 3H), 1.22 (t, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 143.5, 142.4, 142.3, 139.5, 138.9, 129.9, 127.3, 121.87, 120.4, 120.1, 119.9, 68  112.0, 110.0, 62.5, 48.8, 43.3, 31.1, 30.1, 30.0, 24.0, 21.7, 20.2, 18.2. HRMS (ESI) calcd for C26H29N2O232S: 433.1950. Found: 433.1946. Tetracycle (2.27a and 2.27b)  + N H Ts MeO  OMe  N H Ts MeO  OMe  Enesulfonamide 2.20 (33 mg, 0.074 mmol), platinum(II) chloride (2.0 mg, 0.008 mmol) and toluene (1.0 mL) were combined according to the general procedure above. After purification by column chromatography on silica gel (1:1 hexanes:dichloromethane → dichloromethane → 99:1 dichloromethane:ethyl ether → 98:2), 23 mg (69%) of an 8:1 mixture of 2.27a and 2.27b was isolated a colourless film. IR (thin film, CDCl3): 2936, 1591, 1330, 1152 cm-1. 1H (400 MHz, CDCl3): δ 7.81 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 6.50 (d, J = 2.0 Hz, 1H), 6.27 (d, J = 2.0 Hz, 1H), 5.95 (t, J = 4.1 Hz, 1H), 5.15 (s, 1H), 3.81 (s, 3H), 3.63-3.71 (m, 1H), 3.56 (s, 3H), 2.84 (dd, J = 11.6 and 2.7 Hz, 1H), 2.44 (s, 3H), 2.13-2.22 (m, 2H), 1.97 (dt, J = 12.3 and 3.4 Hz, 1H), 1.56-1.80 (m, 3H), 1.43 (m, 2H), 1.30-1.40 (m, 1H), 1.19-1.29 (m, 1H). Peaks associated with minor isomer: 7.44 (d, J = 8.2 Hz, 2H), 7.26 (m, 2H), 6.25 (d, J = 2.7 Hz, 1H), 6.18 (d, J = 2.0 Hz, 1H), 6.05 (br s, 1H), 5.22 (s, 1H), 3.78 (s, 3H), 3.42 (s, 3H), 2.94-3.03 (m, 1H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.6, 159.9, 159.1, 158.3, 153.2, 144.3, 143.4, 142.4, 142.0, 141.0, 139.6, 138.9, 129.3, 127.5, 127.0, 119.0, 118.7, 111.1, 104.1, 98.3, 97.3, 96.8, 65.0, 62.6, 55.6, 55.3, 55.04, 54.97, 46.8, 44.7, 42.3, 41.8, 35.6, 29.9, 29.7, 29.4, 26.3, 24.8, 22.2, 21.7, 21.0, 20.8, 18.4. HRMS (ESI) calcd for C25H29NO4Na32S: 462.1715. Found: 462.1711. Tetracycle (2.25)  N H Boc OMe  Enecarbamate 2.7 (66 mg, 0.19 mmol), platinum(II) chloride (0.010 mg, 0.037 mmol) and toluene (1.5 mL) were combined according to the general procedure above, except that the reaction mixture was stirred at 60 ºC for 48 h. After purification by column chromatography on silica gel (4:1 dichloromethane: petroleum ether → dichloromethane), 31 mg (48%) of the title compound was isolated as a slightly yellow film. IR (thin film, C6D6): 1692, 1482, 1463, 1283, 1149 cm-1. 1H NMR (400 MHz, C6D6): observed as a 3:2 mixture of rotational isomers δ 7.20-7.26 (m, 1H), 6.87-6.92 (m, 1H), 6.77 (dd, J = 8.2 and 2.2 Hz, 1H), 5.68-5.74 (m, 1H), 5.66 (s, 0.4H), 5.29 (s, 0.6H), 4.40-4.48 (m, 0.6H), 3.984.06 (m, 0.4H), 3.32 (s, 3H), 2.71 (td, J = 12.6 and 2.4 Hz, 0.4H) and 2.61 (td, J = 12.6 and 2.4 69  Hz, 0.6H), 1.88-2.11 (m, 3H), 1.18-1.64 (m, 14H), 0.83-1.05 (m, 2H). 13C NMR (100 MHz, C6D6): including resolved rotational isomer signals δ 160.7, 160.5, 155.9, 155.8, 144.4, 144.0, 133.4, 133.1, 122.2, 122.1, 116.5, 114.3, 114.1, 108.8, 108.5, 79.3, 79.2, 66.2, 65.0, 54.9, 45.3, 45.0, 41.1, 40.0, 30.2, 30.1, 29.9, 29.8, 28.3, 24.9, 21.7, 21.2, 18.4. HRMS (ESI) calcd for C22H29NO3Na: 378.2045. Found: 378.2037.  70  Table 5.1: COSY Data for 2.25  6  5  2 1  O  7  4  3  7a 7b  3a  N 12  8 9  11a  O  11  10  O  13  15  14  Proton No.  1  H a,b,c δ (ppm)(mult. J(Hz))  COSY Correlation  H-1  4.40-4.48 (m)/3.98-4.06 (m)  H-1a, H-11b, H-2  H-1’  2.71 (td, 12.6, 2.4)/2.61 (td, 12.6, 2.4)  H-1, H-2  H-2  0.83-1.05 (m)  H-1, H-1’  H-3  1.18-1.64 (m)  H-4  1.18-1.64 (m)  H-5  1.18-1.64 (m)  H-6  1.88-2.11 (m)  H-7  H-7  5.68-5.74 (m)  H-6  H-8  7.20-7.26 (m)  H-9  H-9  6.77 (dd, 8.2, 2.2)  H-8  H-11  6.87-6.92 (m)  H-1, H-11b  H-11b  5.66 (s)/5.29 (s)  H-11  H-14  1.18-1.64 (m)  d  H-15 3.32 (s) Recorded at 400 MHz. bAssignments made based on HMQC, HMBC and COSY data. cSignal pairs due to slow conformational change are listed together. dOnly correlations which could be unambiguously assigned are recorded. a  71  Table 5.2: NMR Data for 2.25  6  5  N  7a 7b 8 11a 11b 9  12  O  2 1  O  7  4  3  3a  13  11  10  O  15  14  Carbon  a  13  C  1  Mult. a,c  H  HMBC b,c,d,e  No. 1  (ppm) 41.1/40.0  Correlations H-11b  CH2  (ppm)(mult. J (Hz)) H-1 (4.40-4.48, m/3.98-4.06, m) H-1’ (2.71, td, 12.6, 2.4/2.61, td, 12.6, 2.4) H-2 (0.83-1.05, m)  CH2  2  21.2/21.7  3  29.8/29.9 or 30.1/30.2  CH2  H-3 (1.18-1.64, m)  H-11b  3a  45.3/45.0  Q  4  29.8/29.9 or 30.1/30.2  CH2  H-4 (1.18-1.64, m)  H-6, H-11b H-11b  5  18.4  CH2  H-5 (1.18-1.64, m)  H-6, H-7  6  24.9  CH2  H-6 (1.88-2.11, m)  H-7  H-7 (5.68-5.74, m)  H-6  7  116.5  CH  7a  144.4  Q  H-7,H-11b  7b  133.1/133.4  Q  H-9, H-11  8  122.1/122.2  CH  H-8 (7.20-7.26, m)  9  114.1/114.3  CH  H-9 (6.77,dd, 8.2, 2.2)  10  160.5/160.7  Q  11  108.5/108.8  CH  11a  144.0  Q  11b  65.0/66.2  CH  12  155.9/155.8  Q  H-1’, H-11b  13  79.2/79.3  Q  H-14  14  28.3  CH3  15  54.9  CH3  b  H-11 H-8, H-9, H-11, H-15  H-11 (6.87-6.92, m)  H-9 H-8  H-11b (5.66, s/5.29, s)  H-14 (1.18-1.64, m)  H-9  H-14  H-15 (3.32, s) c  Recorded at 100 MHz. Recorded at 400 MHz. Signal pairs due to slow conformational change are listed together. dAssignments are based on HMQC data. eOnly correlations which could be unambiguously assigned were recorded.  72  5.4. Synthesis of Ring-Expansion Products (E)-1-(1-Benzyl-1H-indol-2-yl)-3-tosyl-4,5,6,7,8,9-hexahydro-3H-cyclopenta[d]azocine (3.37)  N N Ts  HBF4 (10 mol %) DCE N rt  N Ts  General Procedure for Acid-promoted Isomerization Reactions: A solution of tetrafluoroboric acid (0.04 mL, 54 wt% in ether diluted 50.0 μL in 2.0 mL dichloroethane, 0.0061 mmol) was added to a solution of enesulfonamide 3.29 (0.032 g, 0.063 mmol) in dichloroethane (0.5 mL) at room temperature. The dark brown solution was stirred at room temperature for 2 h, after which triethylamine (4 drops) was added and the light brown solution was concentrated by rotary evaporation. After purification of the brown film by column chromatography on silica gel (10:1 → 8:1 → 6:1 hexanes:ethyl acetate), 0.026 g (80%) of the title compound was isolated as a brown oil. General Procedure for Silver-Catalyzed Isomerization Reactions A solution of silver hexafluoroantimonate (0.06 mL, 23 mg/mL, 0.0041 mmol) was added to a solution of enesulfonamide 3.29 (0.018 g, 0.034 mmol) in dichloroethane (0.5 mL) at room temperature. The dark brown solution was stirred at 80 °C for 5 h. After cooling to room temperature, the reaction mixture was filtered through a pipette of silica, using EtOAc as an eluant and the brown solution was concentrated by rotary evaporation. After purification of the brown film by column chromatography on silica gel (10:1 → 8:1 → 6:1 hexanes:ethyl acetate), 0.017 g (97%) of the title compound was isolated as a brown oil. IR (thin film, CDCl3): 3061, 1604, 1460, 1351, 1163, 940, 911 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.57-7.65 (m, 3H), 7.22-7.31 (m, 5H), 7.07-7.22 (m, 3H), 6.89-6.99 (m, 3H), 6.39 (s, 1H), 5.17 (s, 2H), 3.71 (t, J = 5.3 Hz, 2H), 2.44 (s, 3H), 2.19-2.27 (m, 2H), 2.13-2.28 (m, 2H), 2.04-2.13 (m, 2H), 1.50-1.61 (m, 2H), 1.38-1.49 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 143.7, 141.6, 138.3, 138.2, 137.7, 136.2, 133.5, 129.8, 128.4, 128.1, 128.0, 126.93, 126.86, 126.1, 121.5, 120.2, 119.7, 109.9, 102.8, 46.9, 44.3, 36.8, 36.1, 24.9, 22.3, 21.5, 19.2. HRMS (ESI) calcd for C32H33N2O232S (M + H)+: 509.2263. Found: 509.2252.  73  (E)-1-(1-Phenyl-1H-indol-2-yl)-3-tosyl-4,5,6,7,8,9-hexahydro-3H-cyclopenta[d]azocine (3.38)  N N Ts  A solution of tetrafluoroboric acid (0.03 mL, 54 wt % in ether diluted 50.0 μL in 2.0 mL dichloroethane, 0.0046 mmol) and enesulfonamide 3.30 were combined according to the general procedure except that the red-brown mixture was stirred for 20 h. After purification by column chromatography on silica gel (10:1 → 8:1 → 6:1 hexanes: ethyl acetate), 0.0098 g (53%) of the title compound was isolated as a light brown oil. IR (thin film, CDCl3): 3057, 1596, 1498, 1452, 1352, 1163, 1026 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.2 Hz, 2H), 7.61-7.64 (m, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.21-7.35 (m, 6H), 7.11-7.17 (m, 2H), 7.05 (s, 1H), 6.46 (s, 1H), 3.60-3.66 (m, 2H), 2.49 (s, 3H), 2.01 (t, J = 7.2 Hz, 2H), 1.83-1.95 (m, 4H), 1.35-1.52 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 143.8, 141.7, 138.6, 138.0, 136.3, 132.1, 129.8, 128.5, 127.8, 127.2, 127.0, 126.8, 121.9, 120.3, 120.2, 110.0, 103.3, 44.3, 36.4, 35.9, 24.7, 22.3, 21.6, 19.4. HRMS (ESI) calcd for C31H31N2O232S (M + H)+: 495.2106. Found: 495.2102. (E)-1-(1-Methyl-1H-indol-2-yl)-3-tosyl-4,5,6,7,8,9-hexahydro-3H-cyclopenta[d]azocine (3.1) Me N N Ts  A solution of tetrafluoroboric acid (1.0 μL, 8.0 M in water, 0.0080 mmol) and enesulfonamide 2.22 (0.021 g, 0.049 mmol) were combined according to the general procedure except that the reaction was stirred 18 h. After purification of the light brown solid by column chromatography on silica gel (1:1 → 1:4 hexanes:dichloromethane → dichloromethane), 0.20 g (92%) of the title compound was isolated as a light brown solid, which was recrystallized from ethanol to yield Xray quality crystals, m.p. 140-143 °C. IR (thin film, CDCl3): 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.25-7.29 (m, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H), 6.91 (s, 1H), 6.26 (s, 1H), 3.74 (t, J = 5.5 Hz, 2H), 3.51 (s, 3H), 2.47 (s, 3H), 2.35-2.47 (m, 4H), 2.09-2.15 (m, 2H), 1.78 (quintet, J = 7.4 Hz, 2H), 1.54-1.64 (m, 2H). 13C NMR (150 MHz, CDCl3): δ 144.0, 141.8, 137.9, 137.7, 136.1, 133.8, 129.9, 127.7, 127.6, 126.2, 121.2, 120.1, 119.4, 109.0, 101.6, 44.6, 36.9, 36.1, 29.8, 25.1, 22.8, 21.6, 19.7. HRMS (ESI) calcd for C26H28N2O2Na32S: 455.1769. Found: 455.1775. 74  Table 5.3: COSY Data for 3.1  4  5  3 3a  2 1  N 8 O S O 21  6a  6 9  7  15  Me N 14a  13  10 10a  16  14  11  12  17  20 19  18  22  Proton No.  1  H a,b δ (ppm)(mult. J(Hz))  COSY Correlation  H-1  3.74 (t, 5.5)  H-2  H-2  1.54-1.64 (m)  H-1, H-3  H-3  2.35-2.47 (m)  H-2,  H-4  2.35-2.47 (m)  H-6  H-5  1.78 (quintet, 7.4)  H-4, H-6  H-6  2.09-2.15 (m)  H-4  H-8  6.91 (s)  H-10  6.26 (s)  H-11  7.25-7.29 (m)  H-12  H-12  7.20 (t, 7.8)  H-11, H-13  H-13  7.10 (t, 7.3)  H-14, H-12  H-14  7.57 (d, 7.8)  H-13  H-15  3.51 (s)  H-17  7.75 (d, 8.2)  H-18  H-18  7.34 (d, 8.2)  H-17, H-22  c  H-22 2.47 (s) H-18 Recorded at 400 MHz. bAssignments made based on HMQC, HMBC and COSY data. cOnly correlations which could be unambiguously assigned are recorded. a  75  Table 5.4: NMR Data for 3.1  4  5  3 3a  2 1  N 8 O S O 21  16  6a  7  6 9  15  Me N 14a  14 13  10 10a 11  12  17  20  18  19 22  Carbon  13  No.  (ppm)  1  44.6  CH2  H-1: 3.74 (t, 5.5)  H-8  2  19.7  CH2  H-2: 1.54-1.64 (m)  H-1  3  25.1  CH2  H-3: 2.35-2.47 (m)  H-1  3a  137.9/137.7/133.8  Q  4  36.9  CH2  H-4: 2.35-2.47 (m)  5  22.8  CH2  H-5: 1.78 (quintet, 7.4)  H-4, H-6  6  36.1  CH2  H-6: 2.09-2.15 (m)  H-5  6a  137.9/137.7/133.8  Q  7  137.9/137.7/133.8  Q  8  127.7  CH  9  141.8  Q  10  101.6  CH  10a  127.6  Q  11  109.0  12  C  1  Mult. a  H  (ppm)(mult. J (Hz))  HMBC b,c,d  Correlations  H-8: 6.91 (s) H-8, H-15 H-10: 6.26 (s)  H-14  CH  H-11: 7.25-7.29 (m)  H-13  121.2  CH  H-12: 7.20 (t, 7.8)  H-14  13  119.4  CH  H-13: 7.10 (t, 7.3)  H-11  14  120.1  CH  H-14: 7.57 (d, 7.8)  H-12  14a  137.9  Q  15  29.8  CH3  16  136.1  Q  17  126.9  CH  H-17: 7.75 (d, 8.2)  H-17, H-18  18  129.9  CH  H-18: 7.34 (d, 8.2)  H-18, H-22  19  144.0  Q  H-15: 3.51 (s) H-18  H-17, H-22  22 21.6 CH3 H22: 2.47 (s) H-18 Recorded at 150 MHz. bRecorded at 400 MHz. cAssignments are based on HMQC data. dOnly correlations which could be unambiguously assigned were recorded. a  76  Table 5.5: X-Ray Crystallographic Data for 3.1 Empirical Formula  C26H28N2O2S  Formula Weight  432.56  Crystal Color, Habit  colourless, plate  Crystal Dimensions  0.10 X 0.35 X 0.52 mm  Crystal System  monoclinic  Lattice Type  primitive  Lattice Parameters  a = 18.584(3) Å b = 8.1860(8) Å c = 15.069(2) Å a = 90.0  o  b = 101.358(5) g = 90.0  o  o  V = 2247.6(5) Å3 Space Group  P 21/c (#14)  Z value  4  Dcalc  1.278 g/cm3  F000  920  m(MoKa)  1.70 cm-1  77  (E)-5-(1-Methyl-1H-indol-2-yl)-3-tosyl-1,2,3,6,7,8-hexahydrocyclopenta[d]azepine (3.44) Me N N Ts  A solution of tetrafluoroboric acid (0.04 mL, 54 wt % in diethyl ether, diluted 20 μL in 2.0 mL dichloroethane, 0.0049 mmol) and 1-methyl-2-(5-(1-tosyl-4,5-dihydro-1H-pyrrol-3-yl)pent-1ynyl)-1H-indole (0.020 g, 0.047 mmol) were combined according to the general procedure except that the mixture was stirred for 7 h. After purification by column chromatography on silica gel (10:1 → 8:1 → 6:1 hexanes: ethyl acetate), 0.011 g (54%) of the title compound was isolated as a brown oil. IR (thin film, CDCl3): 1597, 1463, 1348, 1320, 1163 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 7.9 Hz, 1H), 7.25-7.37 (m, 3H), 7.22 (t, J = 7.2 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 6.85 (s, 1H), 6.34 (s, 1H), 3.68 (t, J = 4.8 Hz, 2H), 3.57 (s, 3H), 2.40-2.58 (m, 4H), 2.06-2.18 (m, 2H), 1.70 (quintet, J = 7.5 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 144.0, 141.1, 137.0, 136.0, 131.6, 129.9, 129.5, 127.7, 127.0, 121.2, 120.3, 119.5, 113.7, 109.2, 101.1, 46.3, 39.9, 37.0, 32.8, 30.0, 22.2, 21.5. HRMS (ESI) calcd for C25H27N2O232S (M + H)+: 419.1793. Found: 419.1800. Tricycle (3.50)  N Ts  O  O  A solution of silver hexafluoroantimonate (0.36 mL, 0.013 g/mL of dichloromethane, 0.014 mmol) was added to the reaction vessel and evaporated to dryness. Enesulfonamide 3.34 (0.032 g, 0.089 mmol) and toluene (0.5 mL) were added and the mixture was heated to 80 °C for 48 h protected from the light. After cooling to room temperature, the dark brown solution was filtered through a pipette of silica gel, using ethyl acetate as the eluant. Purification of column chromatography on silica gel (5:1 → 3:1 →1:1 hexanes: ethyl acetate) gave 0.016 g (48%) of the title compound as an off-white solid, which could be recrystallized from dichloromethane/hexanes, m.p. 150-153 °C. IR (thin film, CDCl3): 1726, 1340, 1224, 1162, 942 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 5.79 (s, 1H), 5.77 (s, 1H), 3.61-3.68 (m, 1H), 2.86 (td, J = 12.3 Hz and 2.9 Hz, 1H), 2.52-2.74 (m, 2H), 2.43 (s, 3H), 2.00-2.08 (m, 1H), 1.76-1.98 (m, 3H), 1.61-1.74 (m, 3H), 1.41-1.53 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 172.9, 164.2, 144.1, 135.1, 129.6, 128.2, 111.6, 88.2, 45.5, 40.3, 32.1, 30.2, 27.0, 22.0, 21.5, 20.4. HRMS (ESI) calcd for C18H21NO4Na32S (M + Na)+: 370.1089. Found: 370.1081.  78  Table 5.6: COSY Data for 3.50  5  6  4 2  3  6a 7  3a  1  N 8a O O S O  8  O  9 10  14 13  11 12 16  Proton No.  1  H a,b,c δ (ppm)(mult. J(Hz))  COSY Correlation  H-1  3.61-3.68(m)  H-1’  H-1’  2.86 (td, 12.3, 2.9)  H-1, H-2  H-2  1.74-1.86 (m)  H-1, H-3  H-2’  1.61-1.74 (m)  H-3  1.41-1.53 (m)  H-3’  1.61-1.74 (m)  H-4  2.00-2.08 (m)  H-4’  1.61-1.74 (m)  H-5  1.86-1.97 (m)  H-6, H-4 H-5  d  H-2 H-5  H-6  2.52-2.74 (m)  H-8a  5.76 (s)  H-9  5.78 (s)  H-11  7.78 (d, 8.2)  H-12  H-12  7.33 (d, 7.9)  H-11  H-16 2.43 (s) a Recorded at 400 MHz. bAssignments made based on HMQC, HMBC and COSY data. cH-X and H-Xʹ are assigned arbitrarily. dOnly correlations which could be unambiguously assigned are recorded.  Table 5.7: 1H Selective NOE Data for 3.50 Proton Irradiated  1  1  H H Selective NOE Correlation a δ (ppm)(mult., J (Hz)) H-8a 5.76 (s) H-11 H-2’/H-3’/H-4’ 1.61-1.74 (m) H-4, H-3, H-8a a Recorded at 400 MHz. bOnly those correlations that could be unambiguously assigned are recorded.  b  79  Table 5.8: NMR Data for 3.50  5  6  4 2  3  6a 7  3a  1  N 8a O O S O  8  O  9 10  14 13  11 12 16  Carbon  13  No.  (ppm)  1  40.3  CH2  2  20.4  CH2  3  27.0  CH2  3a  45.5  Q  C  1  Mult. a  H  (ppm)(mult. J (Hz)) H-1: 3.61-3.68 (m) H-1’: 2.86 (td, 12.3, 2.9) H-2: 1.74-1.86 (m) H-2’: 1.61-1.74 (m) H-3: 1.41-1.53 (m) H-3’: 1.61-1.74 (m)  HMBC b,c,d  Correlations H-8a, H-2, H-3 H-1, H-1’, H-3 H-1, H-1’, H-2, H-4, H-8a H-3, H-4, H-5, H-6, H-7  4  32.1  CH2  H-4: 2.00-2.08 (m) H-4’: 1.61-1.74 (m)  5  22.0  CH2  H-5: 1.86-1.97 (m)  H-4, H-6  6  30.2  CH2  H-6: 2.52-2.74 (m)  H-4, H-5, H-7  6a  164.2  Q  7  111.6  CH  H-5, H-3, H-8a  H-7 H-7: 5.76 (s)  H-6  8  172.9  Q  8a  88.2  CH  H-4, H-6, H-8a  9  135.1  Q  10  128.2  CH  H-11: 7.78 (d, 8.2)  H-11, H-12  11  129.6  CH  H-12: 7.33 (d, 7.9)  H-12, H-16  12  144.1  Q  H-8a: 5.78 (s)  H-1, H-1’, H-4 H-11, H-12  H-11, H-16  16 21.5 CH3 H-12 H-13: 2.43 (s) a b c Recorded at 100 MHz. Recorded at 400 MHz. Assignments are based on HMQC data. dOnly correlations which could be unambiguously assigned were recorded.  80  1-Tosyl-3,4,6,7,10,10a-hexahydrocyclopenta[e]quinolin-9(1H,2H,5H)-one (3.51)  N Ts  O  A solution of enesulfonamide 3.35 (0.033 g, 0.092 mmol) and silver hexafluoroantimonate (0.17 mL, 0.019 g/mL in dichloroethane, 0.0093 mmol) in dichloroethane was heated to 80 °C for 1.5 h protected from the light. After cooling to room temperature, the dark brown mixture was filtered through a pipette of silica gel, using ethyl acetate as the eluant. Purification by column chromatography on silica gel (6:1 → 2:1 → 1:1) hexanes:ethyl acetate, gave 0.017 g (52%) of the title compound as a brown film. IR (thin film, CDCl3): 1660, 1334, 1159, 1092 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 5.86 (s, 1H), 4.19 (dd, J = 13.0 and 5.5 Hz, 1H), 3.87 (dd, J = 13.3 Hz and 4.4 Hz, 1H), 2.91 (td, J = 13.0 and 2.7 Hz, 1H), 2.50-2.76 (m, 2H), 2.43 (s, 3H), 2.13-2.22 (m, 1H), 2.00-2.08 (m, 1H), 1.73-1.91 (m, 3H), 1.53-1.72 (m, 3H), 1.42-1.53 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 197.5, 177.1, 143.4, 137.8, 129.9, 126.8, 122.1, 57.2, 46.1, 39.5, 34.8, 34.6, 31.3, 27.1, 21.5, 20.8, 20.7. HRMS calcd for C19H23NO3Na32S: 368.1296. Found: 368.1304. (E)-2,2-Dimethyl-1-(3-tosyl-4,5,6,7,8,9-hexahydro-3H-cyclopenta[d]azocin-1-yl)propan-1one (3.58) O N Ts  A solution of tetrafluoroboric acid (0.06 mL, 54 wt % in diethyl ether diluted 20.0 μL in 2.0 mL dichloroethane, 0.0037 mmol) and enesulfonamide 3.36 (0.014 g, 0.035 mmol) were combined according to the general procedure except that the yellow mixture was stirred for 20 h. After purification by column chromatography on silica gel (8:1 → 6:1 → 4:1 hexanes: ethyl acetate), 0.0039 g (27%) of the title compound was isolated as a clear, colourless film. IR (thin film, CDCl3): 1684, 1608, 1354, 1163, 930 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.69 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.88 (s, 1H), 3.54 (t, J = 5.5 Hz, 2H), 2.44 (s, 3H), 2.24-2.33 (m, 6H), 1.82 (quintet, J = 7.3 Hz, 2H), 1.44-1.56 (m, 2H), 1.21 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 211.5, 144.3, 139.1, 135.9, 131.8, 129.9, 128.0, 127.0, 118.0, 45.1, 44.0, 36.4, 27.9, 24.9, 22.9, 21.5, 20.0. HRMS (ESI) calcd for C22H29NO3Na32S: 410.1766. Found: 410.1771.  81  Using this method, hemiaminal 3.59 was also isolated (0.0045 g, 32%) as a clear, colourless film. O  N Ts  OH  IR (thin film, CDCl3): 3493, 1678, 1610, 1335, 1163 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 6.48 (s, 1H), 5.09 (s, 1H), 3.58-3.65 (m, 1H), 2.783.07 (m, 3H), 2.43 (s, 3H), 2.09-2.21 (m, 2H), 2.04 (td, J = 13.1 and 4.4 Hz, 1H), 1.53-1.86 (m, 4H), 1.38-1.49 (m, 1H), 1.12 (s, 9H). Peaks associated with minor isomer: 7.78 (d, J = 8.2 Hz, 2H), 5.36 (br s, 1H), 3.65-3.72 (m, 1H), 1.21 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 206.4, 205.6, 168.1, 165.5, 143.6, 136.7, 136.5, 130.0, 129.7, 127.4, 127.3, 118.3, 81.5, 78.4, 53.1, 43.7, 40.0, 39.1, 38.6, 35.0, 33.4, 30.0, 28.5, 26.7, 26.4, 22.0, 21.5, 20.8, 20.1. MS (ESI): 428 (M + Na)+, 388 (M − OH)+. Isomerization using Silver Hexafluoroantimonate: Enesulfonamide 3.36 (0.042 g, 0.11 mmol) was combined with a solution of silver hexafluoroantimonate (0.27 mL, 0.014 g/mL in dichloroethane, 0.011 mmol) in dichloroethane (0.5 mL) and stirred at 80 °C for 0.5 h. The dark blue solution was filtered through a pipette of silica gel, using ethyl acetate as the eluant. Purification of the crude brown oil by column chromatography on silica gel (10:1 → 8:1 → 5:1 hexanes:ethyl acetate) gave 0.024 g (57%) of the title compound 3.58 as a clear, colourless film.  82  Table 5.9: COSY Data for 3.58  4  5  3 6  3a  2  6a  1  N 8 O S O 17 12  7  O 9 10 11  13  16  15 14 18  Proton No.  1  H a,b δ (ppm)(mult. J(Hz))  COSY Correlation  H-1  3.54 (t, 5.5)  H-2  H-2  1.44-1.56 (m)  H-1  H-3  2.24-2.33 (m)  H-4/6  2.24-2.33 (m)  H-5 H-4/6  c  1.82 (quintet, 7.3) 2.24-2.33 (m)  H-8  6.88 (s)  H-11  1.21 (s)  H-13  7.69 (d, 8.2)  H-14  H-14  7.33 (d, 8.2)  H-13, H-18  H-18 2.44 (s) H-18 Recorded at 400 MHz. bAssignments made based on HMQC, HMBC and COSY data. cOnly correlations which could be unambiguously assigned are recorded. a  83  Table 5.10: NMR Data for 3.58  4  5  3  1  O 17  6  3a  2  6a  N 8 S O 12  7  O 9 10 11  13  16  15 14 18  Carbon  13  No.  (ppm)  1  44.0  CH2  H-1: 3.54 (t, 5.5)  H-8  2  20.0  CH2  H-2: 1.44-1.56 (m)  H-1  3  24.9  CH2  H-3: 2.24-2.33 (m)  H-1  C  1  Mult. a  H  (ppm)(mult. J (Hz))  HMBC b,c,d  Correlations  3a  139.1  Q  4/6  24.9/36.4  CH2  H-4/H-6: 2.24-2.33 (m)  H-4/6, H-5  5  22.9  CH2  H-5: 1.82 (quintet, 7.3)  4/6  24.9/36.4  CH2  H-4/H-6: 2.24-2.33 (m)  6a  131.8  Q  H-4/6, H-5  7  118.0  Q  H-8  8  128.0  CH  9  211.5  Q  H-8, H-11  10  45.1  Q  H-11  11  27.9  CH3  12  135.9  Q  13  127.0  CH  H-13: 7.69 (d, 8.2)  H-13  14  129.9  CH  H-14: 7.33 (d, 8.2)  H-14, H-18  15  144.3  Q  H-8: 6.88 (s)  H-11: 1.21 (s)  H-1  H-11 H-14  H-13, H-18  18 21.5 CH3 H-18: 2.44 (s) H-14 Recorded at 150 MHz. bRecorded at 400 MHz. cAssignments are based on HMQC data. dOnly correlations which could be unambiguously assigned were recorded. a  84  References (1) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317-1382. (2) Michelet, V.; Toullec, P. Y.; Genêt, J.-P. Angew. Chem. Int. Ed. 2008, 47, 4268-4315. (3) Chianese, A. R.; Lee, S. J.; Gagné, M. R. Angew. Chem. Int. Ed. 2007, 46, 4042-4059. (4) Sohel, S. M. A.; Lin, R.-S. Chem. Soc. 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A. Tetrahedron 2006, 62, 11371-11380. (62) González-Rodríguez, C.; Escalante, L.; Varela, J. A.; Castedo, L.; Saá, C. Org. Lett. 2009, 11, 1531-1533. (63) Porcel, S.; Echavarren, A. M. Angew. Chem. Int. Ed. 2007, 63, 2672-2676. 87  (64) Roy, S.; Gribble, G. W. Tetrahedron Lett. 2005, 46, 1325-1328. (65) Agarwal, S.; Knölker, H.-J. Org. Biomol. Chem. 2004, 2, 3060-3062. (66) Bergman, J.; Eklund, N. Tetrahedron 1980, 36, 1439-1443. (67) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164-5173. (68) Mal’kina, A. G.; Brandsma, L.; Vasilevsky, S. F.; Trofimov, B. A. Synthesis 1996, 589-590. (69) Wenkert, E. Pure & Appl. Chem. 1981, 53, 1271-1276. (70) Campi, E. M.; Chong, J. M.; Jackson, W. R.; Van Der Schoot, M. Tetrahedron 1994, 50, 2533-2542. (71) Davison, E. C.; Forbes, I. T.; Holmes, A. B.; Warner, J. A. Tetrahedron 1996, 52, 1160111624. (72) Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57, 2495-2502. (73) Merlic, C. A.; You, Y.; McInnes, D. M.; Zechman, A. L.; Miller, M. M.; Deng, Q. Tetrahedron 2001, 57, 5199-5212. (74) Keegstra, M. A.; Klomp, A. J. A.; Brandsma, L. Synth. Comm 1990, 20, 3371-3374. (75) Nishio, T. J. Org. Chem. 1988, 53, 1323-1326. (76) Burgstahler, A. W.; Worden, L. R. Org. Synth. Coll. Vol. 5 1973, 251-254. (77) Zhang, H. M.; Larock, R. C. J. Org. Chem. 2002, 67, 7048-7056.  88  Appendix A: Imidazole Chemistry A.1. Research A significant amount of time during my studies (~6 months) was spent working on a different project in collaboration other researchers. The goal of this project was to examine the impact of having a drug for use in cancer therapy linked to a “trigger” or prodrug that would allow the drug to be delivered to a tumour in a specific manner. Under reducing (low-oxygen) conditions, which includes radiation therapy, the nitro group of the prodrug (Figure A.1) would be reduced, causing a fragmentation of the imidazole ring and release of the linked drug.1 The goal of my portion of the project was to synthesize the trigger, (1-methyl-2-nitro-1H-imidazol-5yl)methanol A.1 (Figure A.1). Figure A.1. Target Imidazole and Fragmentation Pathway1 4  HO  5  N N 2 NO2 Me A.1  N X  O  N Me A.2  N  reduction NO2  X  O  N Me  N NH2  A.3  N Me A.4  NH  +  X  OH  A.5  This seemingly simple molecule presented several challenges. The most challenging aspect of this molecule is the installation of the nitro group at the 2-position of the imidazole ring. Many conditions have been developed for the nitration of aromatic rings. In large part, however, these conditions have been developed for electrophilic aromatic substitution reactions. The favoured positions of an imidazole ring for electrophilic aromatic substitution are the 4- and 5- positions and not the 2-position (Figure A.2). The result is that most of these methods are not applicable in an approach to this molecule. The standard method for installation of a nitro group at the 2-position of an imidazole is by the diazotization of an amine (Figure A.3). The imidazole core is generally synthesized by condensation of acyclic staring material to have an amine in this position. One consideration of using an amine to install the nitro group is that the fragmentation of the ether linkage will occur when there is an amine at the 2-position. The group replacing the alcohol must be converted to an alcohol in the presence of the nitro group. 89  Figure A.2. Preferred Sites of Electrophilic Aromatic Substitution 4 5  N H  E  4  N  N  N  5  2  E+  N H  N H  5  4  4  N  N H  2  +  E  N  5  N H  2  Figure A.3. Installation of Nitro Group by Diazotization N RO O  N R1  N NH2  RO O  N R1  N N N NO2 M  RO O  N R1  NO2  A second challenge is the characterization of the products from a reaction.  The  imidazole ring in question contains only a methyl proton, a proton at the 2-position, a proton at the 5-position and methylene protons belonging to the side-chain, all four of which are singlets in a 1H NMR spectrum. The disappearance of a signal does not indicate the nature of the substitution. Infrared spectroscopy was somewhat helpful, but was complicated by the tendency for the strong signals arising from the imidazole ring to overshadow the usually strong nitro signals.  The reported synthesis of this compound relies on a diazotization reaction of a 2˗imidazolyl amine (Scheme A.1).2,3 The synthesis was carried out (jointly with Emmanuel Castillo) to obtain the target compound. Approximately 100 mg of the target imidazole was synthesized in total. The conditions used in this route suffered from low yields at a number of stages however, particularly the condensation reaction to form imidazole A.11 and the coppermediated diazotization to obtain nitroimidazole A.12.  Consequently, a different route was  proposed for the purpose of scaling up the synthesis.  90  Scheme A.1. Reported Synthesis of Target A.12,3 O O  H N  HO  EtOH/HCl  O  Me  a) H  H HCl N Me  EtO  O OH , H  ONa  b) Ac2O  O  O N  EtO  H  1. NaOEt,  Me  O H  A.6  A.7  O HCl  H N  EtO  EtOH  EtO  Me  N C NH2 HCl  OEt  O  EtO O  A.10  HCl  N Me  NH2  Cu HBF4 NaNO2  O  A.11  N Me  Me  OH  OEt A.9  N EtO  H N  EtO  A.8  N  O  N  NaBH4 HO  NO2  A.12  N Me  NO2  A.1  Since the diazotization was one of the poor-yielding steps of the previous synthesis, an alternative method was planned to install the nitro group at the 2-position (Scheme A.2). The proton at the 2-position of an imidazole can be deprotonated with a strong base.4 Theoretically, the nitro group could be installed by deprotonation and reaction with a suitable electrophile. In the route proposed, the synthesis and protection of the imidazole core would be accomplished in three steps using known procedures4-6 followed by deprotonation and quenching with isopropyl nitrate. Isopropyl nitrate has been used as an electrophile to nitrate a 2-lithio-1-trityl imidazole.7 Final deprotection of the TBS group would yield the target compound in five steps.  Scheme A.2. Proposed Synthesis of Compound A.1 KSCN (1.5 equiv) MeNH2•HCl (1.25 equiv)  O HO  OH  N HO  N Me  AcOH n-butanol rt A.13  SH  HO HNO3 (2.4 M) rt  A.14  TBSCl (1.1 equiv) imidazole (3 equiv)  N TBSO  DMF rt  N  NaNO2 (4 mol %)  N Me A.16  A.15  nBuLi –78 °C THF  N TBSO  O  NO2  N Me  N Me A.17  N  HCl NO2  HO MeOH  N Me  NO2  A.1  This route was then used towards the synthesis of nitroimidazole A.1. The synthesis of protected imidazole A.16 (with Emmanuel Castillo) was very successful and was carried out on 20 gram scale. At this time, the nitration reaction was attempted which yielded 38% product. 91  The 1H NMR spectrum of this compound was identical to a sample of the TBS-protected target imidazole A.17 from the first synthesis in deuterated chloroform. Once deprotected though, this compound did not match analytical and physical characteristics of nitroimidazole A.1. A small shift in the signal for the methyl group in the 1H NMR spectrum was observed as well as a melting point of 199-200 °C compared with the literature melting point of 140 °C.8 The melting point data, in particular indicated that another product had been formed. A solid state molecular structure was obtained by X-ray crystallography, which confirmed that the compound obtained was a dimer of imidazole rings (Figure A.3).  This dimerization is also mentioned in the  literature.7 Although unwanted oxygen in the system could theoretically be responsible for the oxidation, deprotonation of the imidazole followed by stirring at room temperature only led to recovered starting material. This indicates that isopropyl nitrate is acting as an oxidant in this reaction, rather than an electrophile, at least with this N-methyl imidazole.  Scheme A.3. Synthesis of Imidazole Dimer N TBSO  N Me A.16  a)nBuLi (1.1 equiv) –78 °C THF  N TBSO  b) NO2 O (1.5 equiv) 39%  N  N N Me Me  N  HCl (conc) OTBS  HO  MeOH  N  N N Me Me  A.18  OH  A.19  Figure A.4. Solid State Molecular Structure of Compound A.19 OH  CH3 N N N  N H3C HO A.19  Considering that the 2-nitro product was formed with a trityl imidazole, but was unsuccessful with an N-methyl imidazole, the synthesis of the imidazole ring was repeated to make an N-butyl imidazole to test the reaction. However, a dimeric product was also observed when this derivative was deprotonated and reacted with isopropyl nitrate. The 2-nitro product may be observed with an N-trityl derivative because the trityl group is so big that dimer formation may be disfavoured. Although the structure of the imidazole affects the substitution reaction somewhat, the nature of the electrophile seems to be more important. 92  Scheme A.4. Attempted Reaction with N-Butyl Imidazole A.20 N TBSO  N  a)nBuLi (1.1 equiv) –78 °C THF TBSO  b) O  N  N  N  N  OTBS  NO2  (1.5 equiv) A.20  A.21  The next electrophile examined in this reaction was a mixed anhydride.  A patent  procedure9 outlining the nitration of imidazoles at the 2-position with trifluoroacetic anhydride and an inorganic nitrate10 was attempted. These reagents generate a mixed anhydride in-situ to act as an electrophile (Scheme A.5). Reactions with this electrophile were also unsuccessful. The most commonly isolated product was trifluoromethyl imidazole, either from unreacted trifluoroacetic anhydride or from reaction of the imidazole with the trifluoroacetate portion of the mixed anhydride. Many variation of these conditions were attempted including the use of AgNO3, KNO3, (NH4)NO3, LiNO3, reactions run neat or in THF, additions of the electrophile to the nucleophile and the reverse and varying the temperature, all without success.  Scheme A.5. General Description of Reactions Attempted with TFAA/Metal Nitrates O F3 C  O O  A.22  CF3  + MNO3  O  O N  O O  N CF3  + TBSO  A.23  N Me A.24  N Li  X  TBSO  N Me  NO2  A.17  The next strategy involved the use of ipso-substitution to achieve the desired nitration. Trimethylsilyl chloride was added after deprotonation of the imidazole to presumably form a silyl-imidazole in situ, although it is expected to be unstable to hydrolysis and could not be observed by thin-layer chromatography. It has been demonstrated that acylation of imidazoles at the 2-position can be carried out using this method.11,12 Neither the anhydride of TFAA/KNO3 or isopropyl nitrate gave any of the desired product when used as electrophiles in the reaction (Scheme A.6). In all cases the starting material was recovered or a trifluoroacetate-substituted imidazole and minor unknown impurities were recovered. Since these two electrophiles had not been successful, attention was turned to other electrophiles.  93  Scheme A.6. Attempted Ipso-Substitution Reaction N TBSO  N Me  N  TMSCl TBSO  Li  A.24  N Me  Si(CH3)3  NO2 O or X TFAA KNO3  N TBSO  A.25  N Me  NO2  A.17  The oxidation state of the electrophile was then changed and the reaction was attempted using isoamyl nitrite. Once substitution occurred the resulting nitroso group would be oxidized to the nitro oxidation state. Oxidation of aryl nitroso groups to aryl nitro groups is known in the literature.13,14 Deprotonation of imidazole A.16 to yield 2-lithioimidazole A.24 and reaction with isoamyl nitrite was duly carried out, but resulted in decomposition of the starting material. Using nitrite compounds as electrophiles ended the attempts at nucleophilic substitution from a lithiated imidazole.  Scheme A.7. Attempted Reaction with Isoamyl Nitrite N TBSO  N Me A.24  Li  +  O N  O  decomposition  A.26  Nucleophilic substitution on a halogenated imidazole was then attempted. 2-Chloro and 2-bromo imidazoles were synthesized by deprotonation of the imidazole ring and reaction with carbon tetrachloride or bromine. The 2-haloimidazoles were heated with NaNO2 in a number of solvents without result. The halogenated starting materials were also heated with hydroxylamine in the presence of a base to attempt substitution of a nitrogen atom at this position. In almost every case, only starting material was recovered. The exception was when imidazole A.27 was heated with hydroxylamine NaOEt/EtOH, which merely deprotected the TBS group.  94  Scheme A.8. Attempted Nucleophilic Substitution N TBSO  N Me  X  NaNO2 or H2N-OH•HCl X DMF, DMSO, DCE or EtOH  N TBSO  A.27a X=Cl A.27b X=Br  N Me  NO2  A.17  An improved synthesis for this compound has not been found to date. A small number of examples of nitration under anionic conditions have been reported with nitrogen dioxide.15 This toxic gas is commercially-available and could be a potentially be a solution to this problem. Another potential solution is the palladium-catalyzed nitration of aromatic halides that has been recently published by Buchwald (Scheme A.9).16  Scheme A.9. Buchwald’s Palladium-Catalyzed Nitration Pd2(dba)3 (0.5 mol %) L (1.2 mol %)  Cl +  NaNO2 TDA tBuOH 130 °C  nBu  NO2 nBu  A.28  OMe iPr L= iPr  A.29  OMe P(tBu)2 iPr A.30  A.2. Selected Characterization Data 5-((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-imidazole (A.16) N  Si O  N Me  1  H NMR (300 MHz, CDCl3): δ 7.41 (s, 1H), 6.91 (s, 1H), 4.66 (s, 2H), 3.68 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 138.8, 130.8, 128.0, 55.1, 31.5, 25.7, 18.1, -5.4. (1-methyl-2-nitro-1H-imidazol-5-yl)methanol (A.1) HO  N N Me  NO 2  95  IR (neat): 1488, 1347, 1329, 1187, 1036 cm-1. 4.66 (s, 2H), 4.04 (s, 3H). MS (EI): 157 (M)+.  1  H NMR (400 MHz, CD3OD): δ 7.10 (s, 1H),  5-((tert-butyldimethylsilyloxy)methyl)-1-methyl-2-nitro-1H-imidazole (A.17) N  Si O  NO2  N Me  IR (thin film, CH2Cl2): 1539, 1494, 1064, 840 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.04 (s, 1H), 4.70 (s, 2H), 4.05, (s, 3H), 0.90 (s, 9H), 0.10 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 136.6, 127.0, 55.3, 34.3, 25.6, 18.1, -5.4. MS (APCI): 272 (M + H)+. 4',5-bis((tert-butyldimethylsilyloxy)methyl)-1,3'-dimethyl-2,2'-bi(1H-imidazole) (A.18) N  Si O  N Me  N  O Si N Me  IR (thin film, CH2Cl2): 2924, 1360, 1252, 832 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.02 (s, 1H), 4.71 (s, 2H), 4.00 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 139.5, 132.4, 127.0, 55.4, 32.4, 25.7, 18.2, -5.4. MS (ESI): 451 (M + H)+. (3,3'-dimethyl-2,2'-bi(3H-imidazole)-4,4'-diyl)dimethanol (A.19) N  HO  N  N Me  OH N Me  1  H NMR (400 MHz, CD3OD): δ 7.10 (s, 2H), 4.66 (s, 4H), 3.79 (s, 6H). CD3OD): δ 139.9, 135.3, 128.1, 54.4, 32.2. MS (EI): 222 (M)+.  13  C NMR (100 MHz,  1-butyl-5-((tert-butyldimethylsilyloxy)methyl)-1H-imidazole (A.20) N  Si O N  IR (thin film, CH2Cl2): 1497, 1471, 1257, 1060, 838 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.43 (s, 1H), 6.89 (s, 1H), 4.64 (s, 2H), 3.96 (t, J = 7.5 Hz, 2H), 1.78 (quartet, J = 7.5 Hz, 2H), 1.36 (sextet, J = 7.5 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 138.1, 130.4, 128.1, 55.1, 44.9, 32.9, 25.7, 19.9, 18.1, 13.6, -5.4. MS (APCI): 269 (M + H)+.  96  4',5-bis((tert-butyldimethylsilyloxy)methyl)-1,3'-dimethyl-2,2'-bi(1H-imidazole) (A.21) N  Si O  N  N  O Si N  1  H NMR (400 MHz, CDCl3): δ 6.99 (s, 1H), 4.70 (s, 2H), 4.40 - 4.49 (m, 2H), 1.57 - 1.70 (m, 2H), 1.26 (sextet, J = 7.5 Hz, 2H), 0.80 - 0.98 (m, 12H), 0.08 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 139.2, 131.9, 127.4, 55.5, 44.6, 33.0, 25.8, 19.9, 18.2, 13.6, -5.3. MS (APCI): 535 (M + H)+. 5-((tert-butyldimethylsilyloxy)methyl)-2-chloro-1-methyl-1H-imidazole (A.27a) Si O  N N Me  Cl  IR (thin film, CH2Cl2): 2928, 1471, 1257, 1043, 842 cm-1. 1H NMR (300 MHz, CDCl3): δ 6.67 (s, 1H), 4.48 (s, 2H), 3.48 (s, 3H), 0.77 (s, 9H), -0.05 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 132.7, 132.2, 55.2, 30.7, 25.4, 17.8, -5.7. MS (APCI): 261, 263 (M + H)+. 2-bromo-5-((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-imidazole (A.27b) Si O  N N Me  Br  IR (thin film, CH2Cl2): 1470, 1258, 1037, 841 cm-1. 1H NMR (300 MHz, CDCl3): δ 6.87 (s, 1H), 4.62 (s, 2H), 3.61 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 133.7, 128.0, 121.6, 55.6, 32.3, 25.7, 18.1, -5.4. MS (ESI): 305, 307 (M + H)+.  97  A.3 References (1) Naylor, M. A.; Thomson, P. Mini-Rev. Med. Chem. 2001, 1, 17-29. (2) Sartori, G.; Lancini, G. C.; Cavalleri, B. J. Labelled Compd. Rad. 1978, 15, 673-680. (3) Gbadamassi, M.; Barascut, J.-L.; Imbach, J.-L.; Gayral, P. Eur. J. Med. Chem. 1988, 23, 225232. (4) de Figueiredo, R. M.; Coudray, L.; Dubois, J. Org. Biomol. Chem. 2007, 5, 3299-3309. (5) Dener, J. M.; Zhang, L.-H.; Rapoport, H. J. Org. Chem. 1993, 58, 1159-1166. (6) Collman, J. P.; Zhong, M.; Costanzo, S.; Zhang, C. J. Org. Chem. 2001, 66, 8252-8256. (7) Davis, D. P.; Kirk, K. L.; Cohen, L. A. J. Heterocyclic Chem. 1982, 19, 253. (8) Cavalleri, B.; Ballotta, R.; Lancini, G. C. J. Heterocyclic Chem. 1972, 9, 979-984. (9) Rajaraman, S.; Yaqub, U. United States Patent US 2008/0045722 A1, 2008. (10) Crivello, J. V. J. Org. Chem. 1981, 46, 3056-3060. (11) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. J. Org. Chem. 1989, 54, 693-702. (12) Bakhtiar, C.; Smith, E. H. J. Chem. Soc. Perkin Trans. 1 1994, 239-243. (13) Havlik, A. J. United States Patent 3,267,158, 1966. (14) Taylor, E. C.; Tseng, C.-P.; Rampal, J. B. J. Org. Chem. 1982, 47, 552-555. (15) Martin, J.; Johnson, F. United States Patent 3,828,064, 1974. (16) Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 12898-12899.  98  Appendix B: Selected Spectra Figure B.1: 3-(5-(4-Methoxyphenyl)pent-4-ynyl)piperidin-2-one 2.5 N H  O OMe  9.5  9.0  8.5  8.0  7.5  190  180  170  160  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  99  Figure B.2: tert-Butyl 3-(5-(4-methoxyphenyl)pent-4-ynyl)-2-oxopiperidine-1-carboxylate 2.6  N O  O OMe  O  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  100  Figure B.3: tert-Butyl 5-(5-(4-methoxyphenyl)pent-4-ynyl)-3,4-dihydropyridine-1(2H)carboxylate 2.7 N O  OMe  O  9.5  220  9.0  200  8.5  8.0  180  7.5  160  7.0  6.5  140  6.0  5.5  120  5.0  100  4.5  4.0  80  3.5  3.0  60  2.5  40  2.0  1.5  20  1.0  0.5ppm  0  ppm  101  Figure B.4: 1-Methyl-2-(5-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)-1H-indole 2.22 Me N N Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  102  Figure B.5: 5-(5-(3,4-Dimethoxyphenyl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine 2.19 N Ts  OMe OMe  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  103  Figure B.6: 5-(5-(Furan-2-yl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine 2.18 O N Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  104  Figure B.7: 2-(5-(1-Tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)-1H-indole 2.21 H N N Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  105  Figure B.8: 1-Methyl-3-(5-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)-1H-indole 2.23 N Ts  N Me  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  106  Figure B.9: 5-(5-(3,5-Dimethoxyphenyl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine 2.20 OMe N Ts OMe  9.5  9.0  8.5  8.0  7.5  190  180  170  160  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  107  Figure B.10: 1-Benzyl-2-(5-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)-1H-indole 3.29 N N Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  108  Figure B.11: 1-Phenyl-2-(5-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)-1H-indole 3.30 N N Ts  9.5  9.0  8.5  8.0  7.5  190  180  170  160  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  109  Figure B.12: 5-(5-(1-Methyl-1H-pyrrol-2-yl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine 3.33 Me N N Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  110  Figure B.13: 5-(5-(Benzofuran-2-yl)pent-4-ynyl)-1-tosyl-1,2,3,4-tetrahydropyridine 3.31 O N Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  1.5  1.0  0.5ppm  30  20  10  0 ppm  111  Figure B.14: Methyl 6-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)hex-2-ynoate 3.34 O N Ts  OMe  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  112  Figure B.15: 7-(1-Tosyl-1,4,5,6-tetrahydropyridin-3-yl)hept-3-yn-2-one 3.35 O N Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  113  Figure B.16: 2,2-Dimethyl-8-(1-tosyl-1,4,5,6-tetrahydropyridin-3-yl)oct-4-yn-3-one 3.36 O N Ts  9.5  9.0  8.5  8.0  7.5  190  180  170  160  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  114  Figure B.17: Tetracycle 2.25  N H Boc OMe  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  115  Figure B.18: Tetracycle 2.29a  O N H Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  1.5  1.0  0.5ppm  30  20  10  0 ppm  116  Figure B.19: Tetracycle 2.26a and 2.26b  + N H Ts  N H Ts  OMe OMe  OMe OMe  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  117  Figure B.20: Tetracycle 2.30a  NH N H Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  118  Figure B.21: Tetracycle 2.31a  N  Me  N H Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  1.5  1.0  0.5ppm  30  20  10  0 ppm  119  Figure B.22: Tetracycle 2.33a  N H Ts  N Me  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  120  Figure B.23: Tetracycle 2.27a and 2.27b  + N H Ts MeO  N H Ts MeO  OMe  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  OMe  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  121  Figure B.24: (E)-1-(1-Benzyl-1H-indol-2-yl)-3-tosyl-4,5,6,7,8,9-hexahydro-3Hcyclopenta[d]azocine 3.37  N N Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  1.5  1.0  0.5ppm  30  20  10  0 ppm  122  Figure B.25: (E)-1-(1-Methyl-1H-indol-2-yl)-3-tosyl-4,5,6,7,8,9-hexahydro-3Hcyclopenta[d]azocine 3.1 Me N N Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  123  Figure B.26: (E)-1-(1-Phenyl-1H-indol-2-yl)-3-tosyl-4,5,6,7,8,9-hexahydro-3Hcyclopenta[d]azocine 3.38  N N Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  124  Figure B.27: (E)-5-(1-Methyl-1H-indol-2-yl)-3-tosyl-1,2,3,6,7,8hexahydrocyclopenta[d]azepine 3.44 Me N N Ts  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  1.5  1.0  0.5ppm  30  20  10  0 ppm  125  Figure B.28: Tricycle 3.50  N Ts  O  O  9.5  9.0  8.5  8.0  190  180  170  160  7.5  150  7.0  140  6.5  130  6.0  120  5.5  110  5.0  100  4.5  90  4.0  80  70  3.5  60  3.0  50  2.5  40  2.0  30  1.5  1.0  0.5ppm  20  10  0 ppm  126  Figure B.29: 1-Tosyl-3,4,6,7,10,10a-hexahydrocyclopenta[e]quinolin-9(1H,2H,5H)-one 3.51  N Ts  O  9.5  220  210  9.0  200  8.5  190  8.0  180  7.5  170  7.0  160  150  6.5  140  6.0  5.5  130  120  5.0  110  4.5  100  4.0  90  80  3.5  3.0  70  60  2.5  50  2.0  40  1.5  30  1.0  20  10  0.5ppm  ppm  127  Figure B.30: (E)-2,2-Dimethyl-1-(3-tosyl-4,5,6,7,8,9-hexahydro-3H-cyclopenta[d]azocin-1yl)propan-1-one 3.58  O N Ts  9.5  220  210  9.0  200  8.5  190  8.0  180  7.5  170  7.0  160  150  6.5  140  6.0  5.5  130  120  5.0  110  4.5  100  4.0  90  80  3.5  3.0  70  60  2.5  50  2.0  40  1.5  30  1.0  20  10  0.5ppm  ppm  128  Table B.1: X-Ray Crystallographic Data for A.19 Empirical Formula  C10H14N4O2  Formula Weight  222.25  Crystal Color, Habit  colourless, prism  Crystal Dimensions  0.12 X 0.22 X 0.34 mm  Crystal System  monoclinic  Lattice Type  C-centered  Lattice Parameters  a = 18.8276(6) Å b = 6.7027(2) Å c = 18.5008(5) Å a = 90  o  b = 116.063(1) g = 90  o  o  V = 2097.3(1) Å3 Space Group  C 2/c (#15)  Z value  8  Dcalc  1.408 g/cm3  F000  944  m(MoKa)  1.02 cm-1  129  

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