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Synthetic strategies for self-assembled schiff-base macrocycles Provençal, Alexandre 2009

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SYNTHETIC STRATEGIES FOR SELF-ASSEMBLED SCHIFF-BASE MACROCYCLES  by  Alexandre Provençal B.Sc., Université du Québec à Montréal, 2006  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 2009  © Alexandre Provençal, 2009  Abstract  Schiff-base macrocycles have interesting properties that could be used in new materials such as chemical sensors, catalysts and discotic liquid crystals. Triangular [3+3] Schiff-base macrocycles, for example, have been extensively studied in the MacLachlan group. However, few examples of [4+4] Schiff-base macrocycles have been reported. A square [4+4] Schiff-base macrocycle requires a precursor with the appropriate geometry such as compound 18. Synthesis of compound 18, however, proved to be problematic because of the formation of isomers, poor solubility and low yields. To avoid these issues, compound 36 was synthesized by Sonogashira coupling and was characterized by 1H NMR spectroscopy, IR spectroscopy and HR-EI-MS. Reaction between compounds 36 and 37 led to the formation of an insoluble red solid. Although the characterization of this solid by NMR spectroscopy was not possible, MALDI-TOF data suggested that this solid contained the [4+4] Schiff-base macrocycle as the major product. A new synthetic approach to compound 11, widely used for the formation of [3+3] Schiff-base macrocycles, was devised. The overall yield is about 10% higher than the original synthesis of compound 11. Aside from the higher yield, this synthetic approach has other advantages over the previous one such as it does not require a large excess of reagents or expensive chemicals, all steps can be achieved on large scales and little purification between each step is required. All new intermediates were characterized by 1H NMR spectroscopy,  13  C  NMR spectroscopy, IR spectroscopy and HR-EI-MS.  ii  Tables of Contents  Abstract........................................................................................................................................... ii Tables of Contents ......................................................................................................................... iii List of Figures................................................................................................................................. v List of Schemes............................................................................................................................. vii List of Symbols and Abbreviations ............................................................................................... ix Acknowledgements........................................................................................................................ xi  Chapter 1: Introduction................................................................................................................... 1 1.1 - Macrocycles ....................................................................................................................... 1 1.2 - Schiff-Base Macrocycles.................................................................................................... 4 1.3 - Thesis Objectives ............................................................................................................... 9  Chapter 2: [4+4] Schiff-Base Macrocycle.................................................................................... 11 2.1 - Background and Objectives.............................................................................................. 11 2.2 - Attempts to Synthesize 3,7-Diformyl-2,8-dihydroxydibenzofuran (18).......................... 15 2.3 - Synthesis of a [4+4] Schiff-base Macrocycle .................................................................. 33 2.4 - Experimental .................................................................................................................... 39  Chapter 3: A New Route to 3,6-Diformylcatechol (11) ............................................................... 50 3.1 - Background and Objectives.............................................................................................. 50 3.2 - New Synthetic Approach to 3,6-Diformylcatechol (11) .................................................. 52 3.3 - Attempted Syntheses of 4,5-dialkoxy-3,6-Diformylcatechol Derivatives ....................... 65 iii  3.4 - Experimental .................................................................................................................... 69  Chapter 4: Conclusions and Future Work .................................................................................... 78 4.1 - Conclusions ...................................................................................................................... 78 4.2 - Future Work ..................................................................................................................... 79  Bibliography ................................................................................................................................. 80  iv  List of Figures  Figure 1.1: Examples of crown ethers ............................................................................................ 1 Figure 1.2: Phenyleneethynylene macrocycle ................................................................................ 2 Figure 1.3: Example of a cyclodextrin ........................................................................................... 3 Figure 1.4: Porphine (5) and heme b (6)......................................................................................... 3 Figure 1.5: Robson-type macrocycle (9) and McKee-type macrocycle (10) ................................. 6 Figure 1.6: Example of [3+3] Schiff-base macrocycles using phenanthrene-based salicylate and acetylene linker............................................................................................................................... 8 Figure 1.7: Target [4+4] Schiff-base Macrocycle 15 ..................................................................... 9 Figure 2.1: Example of a triangular [3+3] Schiff-base macrocycle ............................................. 11 Figure 2.2: [6+6] Schiff-base macrocycle .................................................................................... 12 Figure 2.3: 1H NMR spectrum (300 MHz, CDCl3) of compound 21 after column chromatography ........................................................................................................................... 16 Figure 2.4: 1H NMR spectrum (300 MHz, CDCl3) of the crude products upon bromination of 21 ...................................................................................................................................................... 17 Figure 2.5: 1H NMR spectrum (300 MHz, CDCl3) of the aromatic region upon bromination of 21 ...................................................................................................................................................... 17 Figure 2.6: 1H NMR spectrum (300 MHz CDCl3) of compound 22 ............................................ 19 Figure 2.7: 1H NMR spectrum (300 MHz, C6D6) of compound 24 ............................................. 19 Figure 2.8: 1H NMR spectrum (300 MHz, CDCl3) of crude product upon lithiation and formylation of 22 .......................................................................................................................... 22 Figure 2.9: 1H NMR spectrum (300 MHz, acetone-d6) of compound 26..................................... 23 Figure 2.10: 1H NMR spectrum (300 MHz, CDCl3) of compound 27 ......................................... 24 v  Figure 2.11: 1H NMR spectrum (300 MHz, CDCl3) of crude product obtained upon bromination of compound 27 ............................................................................................................................ 25 Figure 2.12: 1H NMR spectrum (400 MHz, CDCl3) of compound 28 ......................................... 26 Figure 2.13: 1H NMR spectrum (400 MHz, CDCl3) of compound 29 ......................................... 27 Figure 2.14: 1H NMR spectrum (300 MHz, CDCl3) of compound 30 ......................................... 28 Figure 2.15: 1H NMR spectrum (300 MHz, CDCl3) of compound 31 ......................................... 29 Figure 2.16: 1H NMR spectrum (300 MHz, acetone-d6) of compound 32................................... 31 Figure 2.17: 1H NMR spectrum (300 MHz, DMSO-d6) of compound 36 ................................... 35 Figure 2.18: MALDI-TOF spectrum of [4+4] macrocycle 38 ..................................................... 37 Figure 3.1: 1H NMR spectrum (300 MHz, CDCl3) of compound 45 ........................................... 53 Figure 3.2: 1H NMR spectrum (300 MHz, CDCl3) of the product obtained upon cyclization of 45 with A15 ....................................................................................................................................... 55 Figure 3.3: 1H NMR spectrum (300 MHz, CDCl3) of compound 49 ........................................... 58 Figure 3.4: 1H NMR spectrum (400 MHz, CDCl3) of compound 50 ........................................... 59 Figure 3.5: 13C NMR spectrum (100 MHz, CDCl3) of compound 50.......................................... 59 Figure 3.6: 1H NMR spectrum (300 MHz, CDCl3) of the crude after ozonolysis of compound 49 using dimethyl sulfide for the reductive work-up......................................................................... 60 Figure 3.7: 1H NMR spectrum (300 MHz, CDCl3) of compound 52 (inset alkene region) ......... 63 Figure 3.8: 13C NMR spectrum (75 MHz, CDCl3) of compound 52............................................ 63  vi  List of Schemes  Scheme 1.1: Synthesis of expanded porphyrins using Schiff-base condensation .......................... 4 Scheme 1.2: Synthesis of [3+3] Schiff-base Macrocycles ............................................................. 7 Scheme 2.1: Synthesis of the target [4+4] Schiff-base macrocycle 15 ........................................ 13 Scheme 2.2: Original route to 3,7-diformyl-2,8-dihydroxydibenzofuran (18)............................. 14 Scheme 2.3: Bromination of dibenzofuran (19) ........................................................................... 15 Scheme 2.4: Methoxylation of 2,8-dibromodibenzofuran (21) .................................................... 15 Scheme 2.5: Bromination of 2,8-dimethoxydibenzofuran (21).................................................... 18 Scheme 2.6: Attempt lithiation and formylation of compound 22 ............................................... 20 Scheme 2.7: Synthesis of 2,8-dihydroxydibenzofuran (26) ......................................................... 23 Scheme 2.8: Synthesis of 2,8-dihexyloxydibenzofuran (27)........................................................ 24 Scheme 2.9: Synthesis of 2,8-diethoxydibenzofuran (28)............................................................ 26 Scheme 2.10: Bromination of 2,8-diethoxydibenzofuran (28)..................................................... 27 Scheme 2.11 : Iodination of compound 28................................................................................... 28 Scheme 2.12: Lithiation and formylation of 3,7-dibromo-2,8-dimethoxydibenzofuran (29) ...... 30 Scheme 2.13: Synthesis of compound 36 by Sonogashira coupling ............................................ 34 Scheme 2.14: [4+4] Schiff-Base Macrocycle 38.......................................................................... 36 Scheme 3.1: Synthesis of 3,6-diformylcatechol (11) ................................................................... 50 Scheme 3.2: Synthesis of naphthodifuran (43)............................................................................. 52 Scheme 3.3: Synthesis of 3,6-diformylcatechol (11) through oxidation of benzodifuran (46).... 53 Scheme 3.4: Cyclization of compound 47 using A15 .................................................................. 56 Scheme 3.5: Suggested alternative synthetic route to compound 11............................................ 57 Scheme 3.6: Alternative synthetic route to compound 11............................................................ 62 vii  Scheme 3.7: Synthesis of compound 55 ....................................................................................... 65 Scheme 3.8: Synthesis of compound 59 ....................................................................................... 67  viii  List of Symbols and Abbreviations  n-BuLi  butyllithium  ca.  circa (about)  13  carbon-13 nuclear magnetic resonance  C NMR  d  deuterium (NMR)  d  doublet (NMR)  dd  doublet of doublets (NMR)  δ  chemical shift  DCM  dichloromethane  DMF  N,N-dimethylformamide  DMSO  dimethylsulfoxide  EI-MS  electron impact mass spectrometry  equiv.  equivalent  EtO  ethoxy group  EtOAc  ethyl acetate  FTIR  Fourier transform infrared spectroscopy  g  grams  h  hours  1  proton nuclear magnetic resonance  H NMR  HMTA  hexamethylenetetramine  HR-EI-MS  high resolution electron impact mass spectrometry  Hz  hertz  IR  infrared  J  coupling constant  LR-EI-MS  low resolution electron impact mass spectrometry  m  multiplet (NMR)  M  moles/L  ix  MALDI-TOF-MS  matrix-assisted laser desorption/ionization time-of-flight mass spectrometry  MeCN  acetonitrile  MeO  methoxy group  MeOH  methanol  μmol  micromoles  mg  milligrams  min  minutes  mL  millilitres  mmol  millimoles  m/z  mass to charge ratio  NaOMe  sodium methoxide  NBS  N-bromosuccinimide  NMR  nuclear magnetic resonance  ppm  parts per million  q  quartet (NMR)  s  singlet (NMR)  TMEDA  N-N-N’-N’-tetramethyleneethylenediamine  t  triplet (NMR)  THF  tetrahydrofuran  TLC  thin layer chromatography  x  Acknowledgements  I would like to thank the people who helped me during my graduate studies at UBC. First, I would like to thank my supervisor, Dr. Mark J. MacLachlan, for his support, enthusiasm and contagious laugh. To all the MacLachlan members, both past and present, that I had the chance to meet, thank you for your help and serious and not so serious discussions. You are all amazing people and I wish that you may all get the beast! Thank you to the staff of the NMR facilities and the UBC Microanalytical Services Laboratory. Thank you to the Ciufolini group for the use of the ozonator. Thanks to Maria Zlotorzynska from the Sammis group for sharing some of that osmium tetroxide solution. I’d like to thank all my amazing friends (you know who you are) from the Chemistry department. Thanks for all the laughs and good times, I will miss you all! Finalement, un merci tout spécial à ma famille et mes amis du Québec. Merci pour votre amour sincère et votre support inconditionnel. Je vous aime tous.  xi  Chapter 1: Introduction 1.1 - Macrocycles  Macrocyclic compounds have been extensively studied over the years because of their interesting properties in many different fields of research. For example, in the field of material chemistry, some macrocycles exhibit columnar liquid crystallinity1,2 while others aggregate to form nanotubes. Perhaps one of the best known types of macrocycle is crown ethers discovered by Charles Pedersen (Figure 1.1).3 These flexible polycyclic ethers can selectively bind or trap metal ions in their cavity depending on their size. The smaller crown ether 15-crown-5 (1) has a high affinity for sodium ions while the bigger 18-crown-6 (2) will interact preferentially with potassium ions. Crown ethers have been utilized as phase transfer catalysts.4  O  O O  O O  O 1  O  O  O  O O 2  Figure 1.1: Examples of crown ethers  Shape-persistent, rigid macrocycles such as phenyleneethynylene macrocycle (3) (Figure 1.2) have also been synthesized.5,6 Using a step-wise approach, this conjugated macrocycle was built with benzene rings and alkyne spacers. Analogous macrocycles have since been synthesized and their abilities to aggregate through π-π interactions and in polar solvents have been widely studied.7,8 1  R  R  R  R  R  R 3  Figure 1.2: Phenyleneethynylene macrocycle  Macrocycles can also be synthesized by self-assembly9 or by using a templating methodology.10,11 The first method relies on the judicious choice of components that must have some type of directing ability that favours addition of the next component in the correct orientation combined with reversibility to self-correct any incorrect additions to form the desired macrocycle. The latter method requires the presence of a templating agent, like a transition metal, to bring all the components of the macrocycle together in orientations that favour formation of the desired product. Macrocycles are also found in nature. Starch, for example, can be transformed into a rigid macrocycle known as cyclodextrin (Figure 1.3) by enzymatic activity. This macrocycle, composed of glucopyranose units, has a hydrophilic periphery while the cavity is hydrophobic. This structure allows cyclodextrin to be soluble in water while their cavity can host non-polar guests such as cholesterol.12  2  OH HO  O  O  OH O HO O OH  O  OH O  OH  OH  HO O  HO  HO OH O  OH O HO  OH HO O  O  OH  O  HO 4  Figure 1.3: Example of a cyclodextrin  Macrocyclic compounds known as porphyrins (Figure 1.4) play important roles in biological processes. In hemoglobin, the porphyrin unit coordinates iron and this complex is responsible for oxygen transport. Similar to hemes, porphyrins also coordinate magnesium as in chlorophyll, which is involved in photosynthesis.  NH  N  N  N  Fe  HN  N  N  N COOH  HOOC 5  6  Figure 1.4: Porphine (5) and heme b (6)  3  1.2 - Schiff-Base Macrocycles  Porphyrins are appealing compounds due to their ability to bind metals. A lot of effort has been devoted toward the synthesis of expanded porphyrins with larger pore sizes. One methodology employed in the synthesis of these highly conjugated macrocycles is the Schiffbase condensation discovered by Hugo Schiff.13 A Schiff-base, also known as an imine, is obtained when a primary amine is reacted with a ketone or an aldehyde. One example of these expanded porphyrins synthesized by Schiff-base condensation is the [2+2]a macrocycle made by Sessler and coworkers.14,15 This expanded porphyrin was prepared by reacting two carbonyl moieties with two amine moieties (Scheme 1.1). Analogous expanded porphyrins with different cavity sizes have been reported. It was found that these expanded porphyrins are capable of binding rare-earth metals15,16 and both inorganic and organic anions.15,17  O  H N  O  2  6  + MeO  NH2  MeO  NH2  2 7  MeO  N  MeO  N  N H H N  N  OMe  N  OMe  8  Scheme 1.1: Synthesis of expanded porphyrins using Schiff-base condensation  a  The use of this notation, in the present work, is not in any way related to pericyclic reactions, such as the Diels-  Alder reaction. This notation, accepted in the field of macrocycle chemistry, is to illustrate the number of each component present in the macrocycle.  4  Over the last few decades, a vast collection of Schiff-base macrocycles of different sizes and shapes has been made. Robson-type macrocycles (9) are among the smallest Schiff-base macrocycles, being the [2+2] variety (Figure 1.5). These can be obtained by reacting two dialdehyde components with two diamine components in a similar manner to the expanded porphyrins made by Sessler. The first versions of Robson-type macrocycles were synthesized using metal-templating methodologies10,18-20 before metal-free syntheses11 were developed. Robson-type macrocycles have two N2O2 pockets capable of coordinating transition metals. Many binuclear metallic complexes (homo and heteronuclear) have been made using these [2+2] Schiff-base macrocycles and different transition metals such as copper, nickel and cobalt.10 Due to the proximity of the two metals in the N2O2 cavity, these metallated Robsontype macrocycles were investigated for metal-metal interactions and magnetic exchange,21 and binuclear metal reactivity.22 Expanded versions of the Robson-type macrocycles were later synthesized by McKee and co-workers (Figure 1.5). Unlike the early Robson-type macrocycles, the McKee-type Schiff-base macrocycle (10) can coordinate up to four metals atoms in its four binding sites. Using the McKee-type macrocycles, a series of homotetranuclear23 and heterotetranuclear24 metal complexes have been synthesized and studied.  5  R''  R'  R  N  OH N  R  R  N  OH N  R  N  OH N  OH  HO  N  OH N  R' 9  R'' 10  Figure 1.5: Robson-type macrocycle (9) and McKee-type macrocycle (10)  [3+3] Schiff-base macrocycles were also synthesized. One of the first examples of this type of macrocycle was reported by Nabeshima and co-workers25 by reacting 3,6diformylcatechol (11) with 1,2-phenylenediamine using the self-assembly approach. The resulting [3+3] macrocycle, however, was highly insoluble in most solvents and the reaction took two weeks to reach completion. Major improvements on the synthesis of [3+3] Schiff-base macrocycles were done in the MacLachlan group. The introduction of alkoxy chains on the diamine (12) component greatly improved the solubility of the macrocycle (Scheme 1.2) and made the diamine more reactive toward the Schiff-base condensation, reducing the reaction time to minutes at reflux.26  6  RO 3  O  HO  OH  O  N  N  OH HO  11 +  N  RO  NH2  RO  NH2  3  OR  RO  OH N  HO  HO  OH  N  RO  12  N OR OR  R = alkyl chains 13  Scheme 1.2: Synthesis of [3+3] Schiff-base macrocycles  Since then, a variety of [3+3] Schiff-base macrocycles has been made in the MacLachlan group, mostly by changing the dialdehyde moiety and the alkoxy chains27 on the diamine component. For example, phenanthrene28 and triphenylene-based salicylates were used instead of 3,6-diformylcatechol (11) in the synthesis of the macrocycle. Larger versions of these macrocycles were also synthesized using an acetylene spacer (linker) (Figure 1.6). More recently, highly soluble [3+3] Schiff-base macrocycles were made by the introduction of alkyl chains on the 3,6-diformylcatechol component.29  7  RO  OR  N  N  OH HO R'O R'O  RO  OR' MeO  OMe  N  OR'  MeO  OMe  HO  OH HO N  MeO  OMe  RO  OH N  N OR OR  R'O  OR'  R, R' = alkyl chains 14  Figure 1.6: Example of [3+3] Schiff-base macrocycles using phenanthrene-based salicylate and acetylene linker [3+3] Schiff-base macrocycles have three N2O2 pockets that can coordinate transition metals in a similar matter to the Robson-type macrocycles. Furthermore, a heptanuclear complex was formed when [3+3] Schiff-base macrocycles were treated with seven equivalents of zinc(II) acetate.30 [3+3] Macrocycles also showed high affinites for alkali metal cations as they aggregate into dimeric and trimeric species.26  8  1.3 - Thesis Objectives  A large array of [2+2] and [3+3] Schiff-base macrocycles have been synthesized and studied over the years. There are, however, few examples of larger Schiff-base macrocycles in the literature, aside from a hexagonal [6+6] macrocycle.9 Our first goal was to develop new [4+4] Schiff-base macrocycles (Figure 1.7) by designing a dialdehyde moiety that, upon reacting with a 1,2-phenylenediamine component, would lead to the formation of the desired macrocycle.  RO  OR  O  RO N  OR  N  N HO  OH  N HO  OH  O  O HO  OH N RO RO  HO N  N  OH N O  OR OR  R = alkyl chains 15  Figure 1.7: Target [4+4] Schiff-base macrocycle 15  [3+3] Schiff-base macrocycles are extensively synthesized and studied in the MacLachlan group. These experiments require significant amount of 3,6-diformylcatechol (11). The current synthesis of compound 11 requires substantial amounts of n-BuLi and gives low 9  yields. The second goal of this work was to design a new synthetic route to compound 11 that would be more cost and yield efficient.  10  Chapter 2: [4+4] Schiff-Base Macrocycle 2.1 - Background and Objectives  Schiff-base macrocycles come in different shapes and sizes depending on the components used for their synthesis. Reacting 3,6-diformylcatechol (11) and a 4,5-dialkoxy-1,2phenylenediamine ring, for example, will lead to the formation of a triangular [3+3] Schiff-base macrocycle 16 (Figure 2.1).  OC2H5  H5C2O  N  N  OH  HO  OH  HO  N  N HO  H5C2O  OH  N  N  H5C2O  OC2H5 OC2H5  16  Figure 2.1: Example of a triangular [3+3] Schiff-base macrocycle  The condensation of compound 11 with a 1,2-phenylenediamine ring forms a triangular [3+3] macrocycle because of the geometry of compound 11. The angle between the two hydroxyl groups of compound 11 is 60°, predisposing the resulting macrocycle to have a triangular geometry. By varying the angle between the two hydroxyl groups different macrocycle geometries can be obtained. Another example was the synthesis of a hexagonal 11  [6+6]9 Schiff-base macrocycle 17 (Figure 2.2) by using 4,6-diformyl-1,3-dihydroxybenzene that has its two hydroxyl groups separated by 120°.  R  R  R  R N N  N  HO  N  OH  OH  HO  R  N  OH  OH  N  R  R  N  OH  OH  N  R  OH N  HO HO  OH  N  N  N  R  R R  R = OC6H13  R  17  Figure 2.2: [6+6] Schiff-base macrocycle  Therefore, our goal was to design and synthesize new square-shaped macrocycles. To do so, we require a precursor with hydroxyl groups orientated near 90°. Such a precursor could be obtained by using dibenzofuran as the starting material. Spartan calculations have shown that the angle between the hydroxyl groups in 3,7-diformyl-2,8-dihydroxydibenzofuran (18) would be around 90°. By reacting this dibenzofuran derivative with a 4,5-dialkoxy-1,2-phenylenediamine derivative, we expect to obtain the square [4+4] macrocycle 15 with 4 N2O2 pockets (Scheme 2.1). 12  RO RO  O 4  O  O HO  OR  O  N  OH  OR  N  N HO  OH  N HO  OH  18 O  O + RO  NH2  RO  NH2  HO  OH N  4 RO  12  RO  HO N  N  OH N O 15  OR OR  R = alkyl chains  Scheme 2.1: Synthesis of the target [4+4] Schiff-base macrocycle 15  In order to obtain the target [4+4] macrocycle 15, it is necessary to first synthesize 3,7diformyl-2,8-dihydroxydibenzofuran (18) from dibenzofuran. Scheme 2.2 shows the planned route to the desired compound.  13  O  O  a Br  19  20  O  b MeO  Br  OMe 21 c  O O  O HO  OH 18  O  e O MeO  d O OMe  23  O Br  Br  MeO  OMe 22  Scheme 2.2: Original route to 3,7-diformyl-2,8-dihydroxydibenzofuran (18) a) NBS, MeCN; b) NaOMe/MeOH, CuBr, EtOAc; c) NBS, MeCN; d) n-BuLi, DMF e) BBr3 This chapter will describe the attempts to synthesize compound 18 and other dibenzofuran derivatives needed to yield the target macrocycle.  14  2.2 - Attempts to Synthesize 3,7-Diformyl-2,8-dihydroxydibenzofuran (18)  The first step in the synthesis of compound 18 was straightforward. Dibenzofuran was brominated selectively at the 2 and 8 positions using NBS in acetonitrile in good yield (85%) (Scheme 2.3).31 As NMR spectroscopy indicated that the compound was pure, compound 20 was used for the next step without further purification.  5 4  6  O  3  7 2  9  1  NBS, 2.1 equiv CH3CN, 70 oC  8  O  Br  Br  19  20  Scheme 2.3: Bromination of dibenzofuran (19) and numbering system  The bromides were then substituted by methoxy groups using sodium methoxide in methanol in presence of catalytic amounts of copper(I) bromide and ethyl acetate (Scheme 2.4).32,33 This reaction afforded 2,8-dimethoxydibenzofuran (21) in high yield (90%) as a white solid (Figure 2.3). It was, however, necessary to purify the compound by column chromatography to remove small amounts of monosubstitued product (2-bromo-8methoxydibenzofuran).  25 wt. % NaOMe in MeOH EtOAc, Toluene, CuBr  O  Br  20  Br  N2, 80 oC  O  MeO  21  OMe  Scheme 2.4: Methoxylation of 2,8-dibromodibenzofuran (21) 15  Figure 2.3: 1H NMR spectrum (300 MHz, CDCl3) of compound 21 after column chromatography (* = CHCl3) Following the methoxylation, another bromination was needed, this time at positions 3 and 7 of compound 21 (Scheme 2.6). The bromination of compound 21, reported in 1944,34 led to the formation of two isomers: 3,7-dibromo-2,8-dimethoxydibenzofuran and 1,9-dibromo-3,8dimethoxy-dibenzofuran. If this was the case, the 1H NMR spectrum of the crude mixture should show two singlets (for 3,7-dibromo-2,8-dimethoxydibenzofuran) and two doublets (for 1,9dibromo-2,8-dimethoxydibenzofuran from ortho coupling) in the aromatic region and two methoxy signals (one signal for each isomer). Upon reacting NBS with compound 21, however, the 1H NMR spectrum revealed a different pattern than the expected one (Figures 2.4 and 2.5). The 1H NMR spectrum showed three distinct methoxy signals and three singlets and two doublets in the aromatic region.  16  Figure 2.4: 1H NMR spectrum (300 MHz, CDCl3) of the crude products upon bromination of 21 (* = CHCl3)  Figure 2.5: 1H NMR spectrum (300 MHz, CDCl3) of the aromatic region upon bromination of 21 (* = CHCl3) 17  In 1944, the two isomers synthesized by bromination of compound 21 were separated by adding boiling acetone to the mixture dissolving only one of the two isomers.34 Upon trying this procedure, however, both isomers were dissolved in the boiling acetone. The two isomers could not be separated in this way. It is worth mentioning that in 194434 when these two isomers were synthesized, they were only characterized using melting points and elemental analyses. Each isomer had a distinct melting point and elemental analysis of both isomers corresponded to the calculated one. Although elemental analysis is a valuable technique to investigate the composition of compounds, it cannot distinguish between isomers. It is possible that the two solids obtained in 1944 were, in fact, two different mixtures of the two isomers which could explain the different melting points. I found that the isomers could be separated on silica using 10% THF in hexanes. In order to do the column chromatography, however, I had to use dry loading since the two isomers were not soluble in the eluant. 1H NMR analysis revealed that the two isomers are in fact 3,7-dibromo2,8-dimethoxydibenzofuran (22) and 1,7-dibromo-2,8-dimethoxydibenzofuran (24) (Figures 2.6 and 2.7). The 1H NMR spectrum of compound 22 showed two singlets in the aromatic region and one singlet for the methoxy signal as expected. Compound 22 was obtained in 16% yield. The low yield of this reaction can be explained by taking into account that compound 24 is the statistically favored isomer (66% of the crude mixture, by integration of the methoxy signal from the 1H NMR spectrum) and that chromatography was needed to separate these two isomers.  O  NBS, 2.1 equiv. o OMe CH3CN, 70 C  MeO 21  O  O Br  Br  MeO  OMe 22  Br  + MeO  Br 24  OMe  Scheme 2.5: Bromination of 2,8-dimethoxydibenzofuran (21) 18  Figure 2.6: 1H NMR spectrum (300 MHz CDCl3) of compound 22 (* = CHCl3)  Figure 2.7: 1H NMR spectrum (300 MHz, C6D6) of compound 24 (* = C6H6) 19  The 1H NMR spectrum (Figure 2.8) of the second isomer clearly showed that this compound is 1,7-dibromo-2,8-dimethoxydibenzofuran (24) since two methoxy signals and two aromatic environments (two singlets and two doublets) are observed. The next step needed was the introduction of aldehyde groups on the dibenzofuran ring. It is known that brominated compounds can be formylated by bromine-lithium exchange34,35 at low temperature36 followed by quenching with anhydrous DMF and acid hydrolysis.37 Therefore, this methodology was applied to compound 22 in an attempt to synthesize the formylated compound. The major problem I encountered during this reaction was the low solubility of compound 22 in the solvent (THF or diethyl ether) at -78 °C. I tried the same experiment at higher temperatures (0 °C and room temperature) but this did not sufficiently increase the solubility of compound 22. The reaction was still carried out, despite the solubility issue, to formylate compound 22. Typically, the mixture was cooled to -78 °C for 15 min before 2.5 equiv. of n-BuLi were added. The mixture was stirred for 10 min at -78 °C and then 3 equiv. of anhydrous DMF were added. After workup, a bright yellow solid was formed.  O Br  Br  MeO  OMe  1) n-BuLi, THF, -78 oC, N2 2) anhydrous DMF  O Br  O MeO  22  OMe 25  Scheme 2.6: Attempted lithiation and formylation of compound 22  20  The 1H NMR spectrum (Figure 2.8) and LR-EI-MS suggested that the yellow solid was the  mono-formylated  compound  7-bromo-3-formyl-2,8-dimethoxydibenzofuran  (25)  (Scheme2.6). First of all, a signal at 10.59 ppm for the aldehyde proton was observed. Second, four singlets in the aromatic region can be seen which should be expected as the protons in positions 1, 4, 6 and 9 are in different environments. Also, two of these aromatic signals (7.76 and 7.37 ppm) have very similar chemical shifts to the chemical shifts of the starting material (22). The 1H NMR analysis also suggests that the bromine was not replaced by hydrogen since all the aromatic signals are singlets. If the bromine had been replaced by a hydrogen, ortho or meta coupling would have been observed and, as a result, the pattern of the aromatic signals would have been more complex. Finally, the 1H NMR spectrum showed two methoxy environments (4.08 and 4.02 ppm). Only traces of other, unidentified products were observed in the 1H NMR spectrum.  21  Figure 2.8: 1H NMR spectrum (300 MHz, CDCl3) of crude product upon lithiation and formylation of 22 (* = CHCl3) In another attempt to synthesize the desired compound, the lithiation was performed for a longer period of time, up to 1 h, before adding anhydrous DMF. 1H NMR analysis showed a mixture of species such as monoformylated and diformylated compounds and 21. The poor solubility of compound 22 in THF or diethyl ether hindered the lithiation and formylation. In order to increase the solubility of compound 22, modifications on the dibenzofuran ring had to be made. Longer alkoxy substituents generally improve solubility in organic solvents.26 Since the solubility of compound 22 at room temperature in most solvents was limited, we decided to incorporate longer alkoxy chains before performing the bromination on position 3 and 7 of the dibenzofuran ring. To remove the methoxy groups, compound 21 was treated with boron tribromide in DCM (Scheme 2.7). The reaction gave the desired product, 2,8dihydroxydibenzofuran (26), in high yield (above 90%) and no further purification was needed,  22  as shown by 1H NMR spectrum of the crude product, to carry out the next step. All the starting material had been consumed as no methoxy signals were observed around 4 ppm (Figure 2.9).  O  O  BBr3, 5 equiv. o OMe DCM, N2, 0 C  MeO  HO  21  OH 26  Scheme 2.7: Synthesis of 2,8-dihydroxydibenzofuran (26)  Figure 2.9: 1H NMR spectrum (300 MHz, acetone-d6) of compound 26 (* = acetone)  A Williamson ether synthesis was then performed by treating compound 26 with sodium hydride  followed  by  1-bromohexane  (Scheme  2.8).  The  desired  compound,  2,8-  dihexyloxydibenzofuran (27), was obtained in moderate yield (63%) (see 1H NMR spectrum, Figure 2.10). 23  NaH, 3 equiv 1-bromohexane, 2.4 equiv  O  O  DMF, 70 oC, N2 HO  OH 26  H13C6O  OC6H13 27  Scheme 2.8: Synthesis of 2,8-dihexyloxydibenzofuran (27)  Figure 2.10: 1H NMR spectrum (300 MHz, CDCl3) of compound 27 (* = CHCl3)  Compound 27 was then brominated using similar conditions as described before. Just like the bromination of compound 21, this reaction gave a light yellow oil containing two isomers as seen in the 1H NMR spectrum (Figure 2.11).  24  Figure 2.11: 1H NMR spectrum (300 MHz, CDCl3) of crude product obtained upon bromination of compound 27 (* = CHCl3) Unlike the two dibromo-2,8-dimethoxydibenzofuran isomers, the two dibromo-2,8dihexyloxydibenzofuran isomers are quite soluble in most solvents. Although the longer alkoxy chains increased the solubility of those isomers, it did, however, make their polarity so similar that they could not be separated by chromatography using a variety of conditions. We decided then to add a shorter alkoxy chain to dibenzofuran, hoping to increase its solubility while still permitting separation of the two isomers. I reacted compound 26 under typical Williamson ether synthesis with 1-bromoethane to give 2,8-diethoxydibenzofuran (28) (Scheme 2.9) in good yield (83%) (see 1H NMR spectrum, Figure 2.12).  25  NaH, 3 equiv. bromoethane, 2,4 equiv.  O  DMF, 70 oC, N2 HO  26  OH  O  EtO  28  OEt  Scheme 2.9: Synthesis of 2,8-diethoxydibenzofuran (28)  Figure 2.12: 1H NMR spectrum (400 MHz, CDCl3) of compound 28 (* = CHCl3)  Compound 28 was then brominated with NBS to give the two expected isomers (Scheme 2.10). The solubility of the two isomers had increased sufficiently with the introduction of ethoxy groups that the column chromatography did not require dry loading. Furthermore, unlike the dibromo-2,8-dihexyloxydibenzofuran isomers, the introduction of ethoxy groups did not significantly affect their polarity and the two isomers could be resolved by TLC on silica gel using 10% THF in hexanes. Column chromatography was performed and the two isomers were separated (Figures 2.13 and 2.14). 3,7-Dibromo-2,8-diethoxydibenzofuran (29) was obtained in 26  low yield (12%). This yield can be explained by the same reasons for the poor yield of the synthesis of compound 22. O  NBS, 2.1 equiv. o OEt CH3CN, 70 C  EtO 28  O  O Br  Br  EtO  OEt  Br  + EtO  29  OEt  Br 30  Scheme 2.10: Bromination of 2,8-diethoxydibenzofuran (28)  Figure 2.13: 1H NMR spectrum (400 MHz, CDCl3) of compound 29 (* = CHCl3)  27  Figure 2.14: 1H NMR spectrum (300 MHz, CDCl3) of compound 30 (* = CHCl3)  Bromination of compound 28 was problematic since it favored the formation of the unwanted isomer. In an effort to synthesize the desired isomer in higher yield, we thought an iodination may be more selective than bromination. Since iodide is slightly bigger than bromide, it might favor the position 3 instead of 1 in order to avoid any interaction with the proton on position 9. The iodination of compound 28 (Scheme 2.11), however, led to the formation of a single isomer, 3,8-diethoxy-1,7-diiododibenzofuran (31) (see 1H NMR, Figure 2.15).  O  EtO  O  I2, KIO3 OEt  CH3COOH, 80 oC  28  I EtO  OEt  I 31  Scheme 2.11 : Iodination of compound 28  28  Figure 2.15: 1H NMR spectrum (300 MHz, CDCl3) of compound 31 (* = CHCl3)  Reverting back to the brominated compound, 29 was dissolved in THF or diethyl ether to attempt a lithium-bromine exchange followed by a formylation. Even with the improved solubility, formylation on positions 3 and 7 was problematic. Most attempts led to the formation of mixture of compounds such as 28, mono and diformylated species and chromatography could not separate them. One attempt, however, seemed to have yielded the desired compound as the major product of the reaction (Scheme 2.12). The crude yellow solid that was obtained in a 29% yield was recrystallized multiple times in a mixture of 1:1 DCM:hexanes. The 1H NMR spectrum (Figure 2.16) and LR-EI-MS suggested that this yellow compound is in fact 2,8-diethoxy-3,7diformyldibenzofuran (32). The 1H NMR spectrum showed one aldehyde signal, two singlets in the aromatic region and the appropriate pattern for the alkoxy chains.  Also, the proton  integration was as expected. Unfortunately, further attempts to synthesize more of compound 32 29  in order to fully characterize it and continue the synthesis toward the [4+4] macrocycle were unsuccessful.  O Br  Br  EtO  OEt 29  1) n-BuLi, THF, -78 oC, N2 2) anhydrous DMF  O O  O EtO  OEt 32  Scheme 2.12: Lithiation and formylation of 3,7-dibromo-2,8-dimethoxydibenzofuran (29)  The synthesis of compound 32 proved to be somewhat difficult. Also, it was important to keep in mind the goal of the project which was to synthesize a [4+4] macrocycle. Even if synthesizing compound 32 was not as difficult, two steps remained in order to synthesize the [4+4] macrocycle 15: removal of the alkoxy chain and Schiff-base condensation between compound 18 and compound 12. The removal of alkoxy chains with boron tribromide usually gives moderate to high yields (70 to 90%),38 but the formation of the macrocycle by Schiff-base condensation can be problematic as the yield can range from low39 to high (20 to 90%).26-28 It is easy to see that the overall yield starting from the bromination of dibenzofuran to the desired macrocycle, if it does form the [4+4] macrocycle, would be extremely low. Also, future studies of the [4+4] macrocycle such as its behavior in solution, its ability to bind different metals or to form any types of aggregates or capsules will require a significant amount of the macrocycle. Therefore, this synthetic approach to the [4+4] macrocycle did not seem to be viable.  30  Figure 2.16: 1H NMR spectrum (300 MHz, acetone-d6) of compound 32 (* = acetone)  Other synthetic approaches toward compound 18 that were attempted will be described. First, I tried the Reimer-Tiemann40 reaction which is known to ortho-formylate phenols by treating the substrate using a strong base (sodium hydroxide) and chloroform. One drawback of this reaction is the low yields40 usually obtained. Compound 26 was treated using the typical conditions of the Reimer-Tiemann reaction and the 1H NMR spectrum of the crude product was complicated showing multiple aldehyde and aromatic signals. One explanation for this is the possible formation of different isomers as ortho-formylation can occur at positions 1, 3, 7 and 9. Therefore, three different diformylated isomers (if each phenyl ring is formylated once) can be synthesized and will show multiple aldehyde and aromatic signals. Besides these diformylated isomers, it is also possible that compound 26 was only formylated once in any of those four positions adding more complexity to the 1H NMR spectrum. Attempts to purify the mixture by column chromatography on silica gel were not successful. 31  I also tried to put aldehyde groups on compounds 21 and 26 using Vilsmeier-Haack41,42 conditions. This reaction is done by the formation of a chloroiminium ion from phosphorus oxychloride (POCl3) and a substituted amide such as DMF that then reacts with an activated arene. Using these conditions with our substrate, however, did not yield any formylated compounds and 1H NMR spectroscopy showed only starting material. Numerous attempts under different temperatures and lengths of the reaction were unsuccessful. One possible explanation is that the substrate is not activated enough to undergo the formylation. Similar difficulties using the Vilsmeier-Haack reaction were reported previously in the MacLachlan group in attempt to formylate 4,5-dialkyl-1,2-dimethoxybenzene derivatives.29  32  2.3 - Synthesis of a [4+4] Schiff-base Macrocycle  The synthesis of the original precursor of the [4+4] macrocycle 15, compound 18, proved to be more challenging than expected as shown in section 2.2. In order to achieve our goal to synthesize a [4+4] Schiff-base macrocycle, we had to design another molecule that still had hydroxyl groups orientated near 90° but could be synthesized more easily. We came up with compound 36, 2,8-bis(5-ethynylsalicylaldehyde)dibenzofuran, that could be synthesized by Sonogashira coupling43 between 5-ethynylsalicylaldehyde (34) and 2,8diiododibenzofuran (35). This approach to the [4+4] macrocycle precursor has an advantage over the original precursor as it avoids the formation of isomers. It is important to mention that even though the hydroxyl and formyl groups will not be attached directly to the dibenzofuran ring, the angle between the two hydroxyls groups should still be around 90°. The resulting larger [4+4] Schiff-base macrocycle would still have four N2O2 pockets that could coordinate transition metals. The two starting materials needed had been reported in the literature and were easily synthesized. 5-Ethynylsalicylaldehyde (34)44 was synthesized in two steps: first a Sonogashira coupling  between  5-bromosalicylaldehyde  with  trimethylsilylacetylene  to  give  5-  trimethylsilylethynylsalicylaldehyde (33), then the trimethysilyl protecting groups were removed with potassium hydroxide (overall yield 64%). Dibenzofuran was treated with iodine in presence of glacial acetic acid and potassium iodate to give 2,8-diiododibenzofuran (35)45 in moderate yield (68%).  33  O  I  2  35 +  HO O  O I  (PPh3)2PdCl2, 0.04 equiv. PPh3, 0.06 equiv. CuI, 0.1 equiv. THF Et3N  O  O HO  OH 36  34  Scheme 2.13: Synthesis of compound 36 by Sonogashira coupling  Compounds 34 and 35 were reacted together under Sonogashira coupling conditions (Scheme 2.13) to give the desired compound 36 in 38% yield. The yield might seem low at first, but considering that two couplings were performed, that yield was acceptable. The 1H NMR spectrum of the crude product revealed that no purification was required as all signals observed were accounted for by proton integration. It is important to mention that the solubility of compound 36 in most solvents was limited, so its 1H NMR spectrum (Figure 2.17) was obtained by dissolving compound 36 in hot DMSO-d6.  34  Figure 2.17: 1H NMR spectrum (300 MHz, DMSO-d6) of compound 36 (* = DMSO)  With compound 36 in hand, I attempted to synthesize the target [4+4] macrocycle. I first reacted compound 36 with 4,5-bis(hexyloxy)benzene-1,2-diamine (37) in a 1:1 mixture of chloroform and acetonitrile. The mixture was heated to reflux for 24 h to give a bright red precipitate that proved to be insoluble in most solvents. Attempts to dissolve it in warm DMSO were not successful to elucidate its structure as the 1H NMR spectrum showed broad signals that had chemical shifts close to those of the starting materials. No imine signals were observed, instead aldehyde signals appeared in the spectrum. This may be due to hydrolysis of the Schiffbase macrocycle during attempts to dissolve it.  35  O OC6H13  H13C6O +  4 O HO  4 H2 N  O  NH2  OH  36  37 CHCl3 : CH3CN 1 :1  C6H13O  OC6H13  N O  N  OH HO  O  C6H13O  N  OH  OH N  OC6H13  C6H13O  N  OH  OH N  OC6H13  O  OH HO N  O  N  C6H13O  OC6H13  38  Scheme 2.14: [4+4] Schiff-Base Macrocycle 38  The red solid was, however, characterized by solvent-free MALDI-TOF-MS. The MALDI-TOF spectrum showed strong evidence that the [4+4] macrocycle was the main product 36  obtained (Figure 2.18). The most intense signal on the MALDI-TOF spectrum (m/z = 2915.4) corresponds to molecular weight of the [4+4] Schiff-base macrocycle [M+H]+.  Figure 2.18: MALDI-TOF spectrum of [4+4] macrocycle 38  The signal at 2977.3 in the spectrum can be attributed to the [4+4] macrocycle with two sodium atoms and a molecule of water. The signal at 2305.0 could not be identified as it doesn’t correspond to the mass of any expected fragments or components of the macrocycle. The MALDI-TOF spectrum also suggested that [3+3] or [5+5] macrocycles or polymers were not  37  formed during the reaction. This result obtained by MALDI-TOF-MS supports our choice of a dibenzofuran derivative as a [4+4] Schiff-base macrocycle precursor. One way to purify macrocycles from a mixture of oligomers is to wash macrocycles with hot dichloromethane.1 This is done in order to dissolve any oligomers that typically have a higher solubility than the macrocycle. This technique, however, did not work for our mixture of compounds. It should not be surprising since compound 36 has a limited solubility in most solvents. Although the MALDI-TOF spectrum showed strong evidence of a [4+4] macrocycle, we wanted to synthesize a more soluble macrocycle so that it could be further characterized. One way to increase its solubility would be to use a 4,5-dialkoxy-1,2-phenylenediamine with longer alkoxy chains. I reacted compound 36 with 4,5-bis(2-ethylhexyloxy)benzene-1,2-diamine (39) under the same conditions as before. Once again, a bright red solid precipitated during the reaction. The use of compound 39 did not increase the solubility as this solid was also insoluble in most solvents. Also, MALDI-TOF-MS revealed that this reaction also led to the formation of the desired [4+4] macrocycle but also to a larger number of byproducts. Unlike our first attempt, the target [4+4] macrocycle was not the main product formed in the reaction. Attempts to purify this macrocycle by trituration with hot dichloromethane proved to be unsuccessful. In summary, the original precursor of the [4+4] Schiff-base macrocycle, compound 18, could not be synthesized due to the formation of isomers, poor solubility and low yields. I was, however, able to synthesize, using an acetylene linker, compound 36 that had the right geometry to make a square [4+4] Schiff-base macrocycle. The reaction between compound 36 and compound 37 led to the formation of an insoluble red solid. Although NMR data could not be obtained, MALDI-TOF data suggested strong evidence that this solid contained the [4+4] macrocycle, compound 38, as the main product. 38  2.4 - Experimental  Materials. Dibenzofuran, N-bromosuccinimide, glacial acetic acid, copper(I) bromide, 25 wt.% NaOMe in MeOH, boron tribromide, anhydrous N,N-dimethylformamide, sodium hydride, 1bromohexane, bromoethane, potassium iodate, n-BuLi (1.6 M in hexanes), sulfuric acid, 5bromosalicylaldehyde,  triphenylphosphine,  copper(I)  iodide,  trimethylsilyacetylene,  triethylamine, potassium hydroxide, bis(triphenylphoshine)palladium(II) chloride were obtained from Aldrich, Fisher Scientific or TCI America. Diethyl ether and THF were distilled from sodium and benzophenone ketyl under nitrogen. Triethylamine was dried over sodium hydroxide and stored in a Schlenk bomb. Chloroform and acetonitrile used for the syntheses of macrocycles were degassed by sparging with nitrogen. Deuterated solvents were purchased from Cambridge Isotope  Laboratories,  Inc.  4,5-bis(hexyloxy)benzene-1,2-diamine  (37)  and  4,5-bis(2-  ethylhexyloxy)-benzene-1,2-diamine (39) were synthesized by fellow group members according to the literature procedures.46,47  Equipment: All reactions were carried out under a nitrogen atmosphere unless stated otherwise. 300 MHz 1H NMR and 75.5 MHz 13C NMR spectra and 400 MHz 1H NMR and 100 MHz 13C NMR spectra were recorded on Bruker AV-300 and AV-400 spectrometers, respectively.  13  C  NMR spectra were calibrated to deuterated solvent and 1H spectra were calibrated to residual protonated solvent. IR spectra were obtained neat on a Thermo Fisher Nicolet 6700 FTIR spectrophotometer. Low and high resolution electron impact mass spectra, and matrix-assisted laser desorption/ionization time-of-flight mass spectra were obtained by the UBC Microanalytical Services Laboratory.  39  Synthesis of 2,8-dibromodibenzofuran (20):31 Dibenzofuran (19) (4g, 23.8 mmol) dissolved in MeCN (120 mL) in a 250 mL round bottom flask was stirred for 10 min at room temperature and then NBS (8.9g, 49.9 mmol) and glacial acetic acid (40 mL) were added. The mixture was heated at 70 °C. After 8 h, a white solid had precipitated, the round bottom flask was then cooled to room temperature and placed in the freezer. The next morning, the white solid was filtered and washed with a small amount of cold MeCN yielding 6.55 g of compound 20 (73 mmol, 85% yield from 19). The characterization of this compound conformed to that reported in reference 31. 1  H NMR (300 MHz, CDCl3): δ (ppm) 8.04 (d, J = 1.5 Hz, 2H, aromatic CH), 7.59 (dd, J = 8.7  Hz, J = 1.5 Hz, 2H, aromatic CH), 7.46 (d, J = 8.7 Hz, 2H, aromatic CH).  Synthesis of 2,8-dimethoxydibenzofuran (21): To a 100 mL round bottom flask containing compound 20 (1.16 g, 3.56 mmol), copper (I) bromide (51 mg, 0.36 mmol), toluene (3 mL) and ethyl acetate (1 mL) was added 25 wt. % NaOMe in MeOH (20 mL). The blue mixture was stirred at 80 °C under nitrogen for 24 h. The reaction was then cooled to room temperature and poured into cold water (100 mL). The aqueous mixture was then extracted with DCM (3x50 mL). The organic layer was dried over anhydrous MgSO4 and filtered, and the solvent was removed in vacuo affording a white solid. Column chromatography on silica gel using 4:6 DCM:hexanes as eluant yielded 731 mg (3.20 mmol, 90%) compound 21 as a white solid. 1  H NMR (300 MHz, CDCl3): δ (ppm) 7.46 (d, J = 9 Hz, 2H, aromatic CH), 7.39 (d, J = 2.7 Hz,  aromatic CH), 7.06 (dd, J = 8.7 Hz, J = 2.7 Hz, aromatic CH), 3.93 (s, 6H, OCH3);  13  C NMR  (75.5 MHz, CDCl3): δ (ppm) 155.6, 151.6, 124.8, 115.2, 112.1, 103.3, 55.9; IR (neat): υ = 3002, 40  2958, 2830, 1847, 1596, 1463, 1145, 1022, 837, 779 cm-1; HR-EI-MS: m/z = 288.07864 (calculated), 228.07810 (found).  Synthesis of 3,7-dibromo-2,8-dimethoxydibenzofuran (22): Compound 21 (690 mg, 3.03 mmol) was dissolved in MeCN (50 mL) and then NBS (1.13 g, 6.36 mmol) and glacial acetic acid (15 mL) were added. The mixture was heated at 70 °C and, after 45 min, the solution had turned yellow and a white precipitate was formed. The mixture was stirred for an additional 2 h, then cooled to room temperature and placed in the freezer overnight. The precipitate was filtered and washed with cold MeCN yielding 1.01 g of a white solid containing two isomers : 3,7-dibromo-2,8-dimethoxydibenzofuran (22) and 1,7-dibromo2,8-dimethoxydibenzofuran (24). The two isomers were separated by column chromatography on silica gel using 1:9 THF: hexanes as the eluant affording 185 mg of compound 22 (0.479 mmol, 16%) and 612 mg of compound 24 (1.58 mmol, 52%).  3,7-dibromo-2,8-dimethoxydibenzofuran (22) 1  H NMR (300 MHz, CDCl3): δ (ppm) 7.77 (s, 2H, aromatic CH), 7.37 (s, 2H, aromatic CH),  4.02 (s, 6H, OCH3);  13  C NMR (75.5 MHz, CDCl3): δ (ppm) 156.2, 155.0, 126.0, 123.8, 116.7,  102.5, 57.01; IR (neat): υ = 3079, 2844, 1460, 1431, 1191, 1042, 854, 783 cm-1; HR-EI-MS: m/z = 383.89967 (calculated), 383.90078 (found)  1,7-dibromo-2,8-dimethoxydibenzofuran (24) 1  H NMR (300 MHz, C6D6): δ (ppm) 7.93 (s, 1H, aromatic CH), 7.62 (s, 1H, aromatic CH), 7.04  (d, J = 9.3 Hz, 1H, aromatic CH), 6.38 (d, J = 9 Hz, 1H, aromatic CH), 3.42 (s, 3H, OCH3), 3.31 (s, 3H, OCH3); 13C NMR (75.5 MHz, C6D6): δ (ppm) 152.5, 152.3, 151.9, 151.7, 116.4, 112.8, 41  111.7, 110.6, 107.2, 107.0, 105.0, 104.9, 56.7, 56.2; IR (neat): υ = 3096, 2994, 2942, 1480, 1450, 1264, 1085, 1028, 789, 782 cm-1; HR-EI-MS: m/z = 383.89967 (calculated), 383.00076 (found)  Synthesis of 7-bromo-3-formyl-2,8-dimethoxydibenzofuran (25): Compound 22 (155 mg, 0.402 mmol) was dissolved in dry THF. The colourless solution was stirred at -78 °C before n-BuLi (0.63 mL, 1.00 mmol) was added dropwise. After 30 min, anhydrous DMF (0.09 mL, 1.21 mmol) was added to the solution and the dry ice/acetone bath was removed. The solution was stirred for 30 min at room temperature. A yellow solid precipitated as the solution was poured into a diluted aqueous HCl solution. The yellow solid was filtered and washed with water and then dried. Yield (59%). 1  H NMR (300 MHz, CDCl3): δ (ppm ) 10.58 (s, 1H, CH=O), 8.03 (s, 1H, aromatic CH), 7.64 (s,  1H, aromatic CH), 7.49 (s, 1H, aromatic CH), 7.37 (s, 1H, aromatic CH), 4.07 (s, 3H, OCH3), 4.01 (s, 3H, OCH3); LR-EI-MS : m/z = 333.9 (calculated), 334.0 (found).  Synthesis of 2,8-dihydroxydibenzofuran (26): Compound 21 (1.00 g, 4.39 mmol) was dissolved in DCM (50 mL). The solution was then cooled to 0 °C in an ice bath and stirred for an additional 10 min under nitrogen before boron tribromide (2.1 mL, 21.9 mmol) was added dropwise. The yellow solution was stirred under nitrogen overnight, warming slowly to room temperature. The next morning, the yellow solution was poured into cold water (100 mL). The aqueous layer was then extracted with DCM (3x50 mL) and the combined organic layers were dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo affording 858 mg (4.29 mmol, 97%) of compound 26 as a gray solid. 42  The characterization of this compound conformed to that reported in reference 48. 1  H NMR (300 MHz, acetone-d6): δ (ppm) 8.28 (s, 2H, OH), 7.38 (m, 4H, aromatic CH), 6.98  (dd, J = 8.7 Hz, J = 2.1 Hz, 2H, aromatic CH).  Synthesis of 2,8-dihexyloxydibenzofuran (27): To compound 26 (175 mg, 0.875 mmol) was added DMF (2 mL) and the resulting mixture was stirred for 10 min under nitrogen before sodium hydride (63 mg, 2.63 mmol) was added. The mixture was stirred for 15 min at 70 °C and then 1-bromohexane (0.295 mL, 2.1 mmol) was added dropwise. After the mixture was stirred overnight at 70 °C, it was poured into a beaker containing water (50 mL). The aqueous layer was extracted with hexanes (3x50 mL). The combined organic layers were washed with water (5x50 mL), dried over anhydrous MgSO4 and filtered. The solvent was removed in vacuo affording 203 mg (0.551 mmol, 63%) of compound 27 as a yellow solid. 1  H NMR (300 MHz, CDCl3): δ (ppm) 7.43 (d, J = 8.7 Hz, 2H, aromatic CH), 7.38 (d, J = 2.7 Hz,  2H, aromatic CH), 7.04 (dd, J = 8.7 Hz, J = 2.1 Hz, 2H, aromatic CH), 4.07-4.03 (m, 4H, OCH2), 1.90-1.81 (m, 4H, CH2), 1.55-1.50 (m, 4H, CH2), 1.42-1.38, (m, 8H, CH2), 0.98-0.93 (m, 6H, CH3); 13C NMR (75.5 MHz, CDCl3): δ (ppm) 155.1, 151.6, 124.9, 115.7, 112.0, 104.4, 68.9, 31.6, 29.4, 25.8, 22.6, 14.0; IR (neat): υ = 2952, 2937, 2856, 1600, 1455, 1167, 809. 729 cm-1; HR-EI-MS: m/z = 368.23515 (calculated), 368.23497 (found).  Synthesis of 2,8-diethoxydibenzofuran (28): To compound 26 (11.8 g, 5.4 mmol) was added DMF (25 mL) and the resulting mixture was stirred for 10 min before sodium hydride (389 mg, 16.2 mmol) was added. The mixture was stirred for 15 min at 70 °C and then bromoethane (1.33 mL, 13.5 mmol) was added dropwise. 43  The mixture was stirred overnight at 70 °C, and then was poured into a beaker containing water (150 mL). The aqueous layer was extracted with hexanes (3x100 mL). The combined organic layers are washed with water (5x50 mL), dried over anhydrous MgSO4 and filtered. The solvent was removed in vacuo affording 1.15 g (4.47 mmol, 83%) of compound 28 as a slightly yellow solid. 1  H NMR (400 MHz, CDCl3): δ (ppm) 7.43 (d, J = 8.4 Hz , 2H, aromatic CH), 7.37 (d, J = 2.8  Hz, 2H, aromatic CH), 7.03 (dd, J = 9.2 Hz, J = 2.4 Hz, 2H, aromatic CH), 4.14 (q, J = 7.1 Hz, 4H, OCH2CH3), 1.48 (t, J = 7.1 Hz, 6H, OCH2CH3);  13  C NMR (75.5 MHz, CDCl3): δ (ppm)  154.9, 151.6, 124.9, 115.8, 112.1, 104.5, 64.4, 15.0; IR (neat): υ = 2974, 2932, 1598, 1450, 1390, 1156, 1040, 820, 794 cm-1; HR-EI-MS: m/z = 256.10994 (calculated), 256.11032 (found).  Synthesis of 3,7-dibromo-2,8-diethoxydibenzofuran (29): Compound 28 (1.04g, 4.06 mmol) was dissolved in MeCN (70 mL) and then NBS (1.152 g, 8.52 mmol) was added. The mixture was heated at 70 °C. After 2 h, the solution had turned yellow and thin layer chromatography (1:9 THF:hexanes) showed that the starting material had all been consumed. The mixture was stirred for an additional 2 h, and thin layer chromatography did not show any changes. The mixture was cooled to room temperature and poured into a beaker containing an aqueous solution of sodium hydroxide (200 mL, 0.5 M). The aqueous layer was extracted with hexanes (5x50 mL), the combined organic layers were washed with water, dried over MgSO4 and the solvent was removed in vacuo to give 1.2 g of a crude white solid containing two isomers : 3,7-dibromo-2,8-diethoxydibenzofuran (29) and 1,7-dibromo-2,8diethoxydibenzofuran (30). The two isomers were separated by column chromatography on silica gel using 1:9 THF: hexanes as the eluant affording 200 mg of compound 29 (0.483 mmol, 12%) and 627 mg of compound 30 (1.51 mmol, 37%). 44  3,7-dibromo-2,8-diethoxydibenzofuran (29) 1  H NMR (400 MHz, CDCl3): δ (ppm) 7.75 (s, 2H, aromatic CH), 7.35 (s, 2H, aromatic CH),  4.20 (q, J = 7.2 Hz, 4H, OCH2CH3), 1.55 (t, J = 7.1 Hz, 6H, OCH2CH3); 13C NMR (300 MHz, CDCl3): δ (ppm) 156.8, 154.8, 125.6, 123.7, 116.4, 102.6, 66.2, 15.4; IR (neat): υ = 2976, 2930, 1437, 1391, 1157, 1043, 897, 786 cm-1; HR-EI-MS: m/z = 411.93097 (calculated), 411.93097 (found). 1,7-dibromo-2,8-diethoxydibenzofuran (30) 1  H NMR (300 MHz, CDCl3): δ (ppm) 8.08 (s, 1H, aromatic CH), 7.76 (s, 1H, aromatic CH),  7.43 (d, J = 9 Hz, 1H, aromatic CH), 7.08 (d, J = 8.7 Hz, 1H, aromatic CH), 4.28-4.15 (m, 4H, OCH2CH3), 1.58-1.50 (m, 6H, OCH2CH3);  13  C NMR (75 MHz, CDCl3): δ (ppm) 152.7, 152.1,  151.9, 151.6, 127.8, 126.1, 121.4, 113, 111.8, 104.1, 86.2, 79.4, 66.2, 65.4, 15.2, 14.6; IR (neat): υ = 2982, 2937, 2881, 1446, 1264, 1251, 1043, 852, 786 cm-1; HR-EI-MS: m/z = 411.93097 (calculated), 411.93086 (found).  Synthesis of 3,8-diethoxy-1,7-diiododibenzofuran (31): Compound 28 (102 mg, 0.398 mmol) was placed in a 50 mL round bottom flask containing glacial acetic acid (10 mL). To this mixture was added iodine (121 mg, 0.478 mmol) and potassium iodate (34 mg, 0.159 mmol) and the resulting purple solution was stirred under nitrogen at 80 °C for 16 h. The solution was cooled to room temperature and upon cooling a white solid appeared. The round bottom flask was then stored in the freezer overnight. The next day, the white solid was filtered, washed with water and dried under vacuum to give compound 31 (185 mg, 0.364 mmol, 91%). 1  H NMR (300 MHz, CDCl3): δ (ppm) 8.27 (s, 1H, aromatic CH), 7.98 (s, 1H, aromatic CH),  7.44 (d, J = 8.7 Hz, 1H, aromatic CH), 7.01 (d, J = 8.4 Hz, 1H, aromatic CH), 4.29-4.14 (m, 4H, 45  OCH2CH3), 1.59, (m, 6H, OCH2CH3);  13  C NMR (75.5 MHz, CDCl3): δ (ppm) 152.5, 152.2,  152.0, 151.7, 127.4, 126.0, 121.7, 112.6, 111.5, 103.9, 86.5, 79.2, 66.6. 65.9, 15.0, 14.8; IR (neat): υ = 2978, 2912, 2877, 1437, 1388, 1175, 1038, 892, 786; HR-EI-MS: m/z = 507.90325 (calculated), 507.90304 (found).  Synthesis of 2,8-diethoxy-3,7-diformyldibenzofuran (32): Compound 29 (185 mg, 0.447 mmol) was dissolved in dry THF (10 mL). The colourless solution was cooled to -78 °C. The solution was stirred under nitrogen at -78 °C before n-butyllithium (0.70 mL, 1.12 mmol) was added dropwise. After 30 min, anhydrous DMF (0.10 mL, 1.34 mmol) was added to the solution and the dry ice/acetone bath was removed. The solution was stirred for 30 min at room temperature. A yellow solid precipitated as the solution was poured into a dilute aqueous HCl solution. The yellow solid was filtered and washed with water and then dried. The yellow solid, obtained in a 29% yield, was recrystallized multiple times from a mixture of DCM and hexanes to give the desired product 32. 1  H NMR (300 MHz, CDCl3): δ (ppm ) 10.58 (s, 2H, CH=O), 7.98 (s, 2H, aromatic CH), 7.90 (s,  2H, aromatic CH), 4.34 (q, 4H, J = 7.0 Hz, OCH2CH3), 1.53 (t, 6H, J = 7.0 Hz, OCH2CH3); LREI-MS : m/z = 312.1 (calculated), 312.0 (found).  Synthesis of 5-trimethylsilylethynylsalicylaldehyde (33):44 To a 100 mL Schlenk flask, 5-bromosalicylaldehyde (3.00 g, 14.9 mmol), triphenylphosphine (117 mg, 44.3 mmol), copper(I) iodide (117 mg, 0.443 mmol) and (Ph3P)2PdCl2 (209.5 mg, 0.299 mmol) were added. The flask was then placed under vacuum for 5 min and then backfilled with nitrogen. This process was repeated 2 times. Trimethylsilylacetylene (5.2 mL, 36.8 mmol) was then added, followed by dry triethylamine (15 mL) and dry THF (15 mL). The reaction was 46  stirred overnight at 85 °C. The reaction was then cooled to room temperature and the salts were filtered off on celite. The celite was washed with THF until filtrate was colourless. The solvent was removed in vacuo to give a dark brown solid that was dissolved in DCM and washed with an aqueous solution of ammonium chloride. DCM was removed in vacuo to give a brown solid that was purified by column chromatography on silica gel using DCM:hexane 1:1 as eluant. The desired compound 33 was isolated as a yellow solid (2 g, 9.95 mmol, 67%). The characterization of this compound conformed to that reported in reference 44. 1  H NMR (400 MHz, CDCl3): δ (ppm) 11.1 (s, 1H, OH), 9.86 (s, 1H, CH=O), 7.71 (d, J = 2.4 Hz,  1H, aromatic CH), 7.61 (dd, J = 8.6 Hz, J = 2.4 Hz, 1H, aromatic CH), 6.94 (d, J = 9.2 Hz, 1H, aromatic CH), 0.259, (s, 9H, CH3).  Synthesis of 5-ethynylsalicylaldehyde (34): 44 5-Trimethylsilylethynylsalicylaldehyde (1.23 g, 4.78 mmol) was dissolved in THF (20 mL), then a solution of potassium hydroxide (402 mg, 7.17 mmol) in methanol (20 mL) was added. The resulting orange solution was stirred overnight at room temperature. The solvent was then removed in vacuo to give a brown solid to which ethyl acetate (50 mL) and water (50 mL) were added. The aqueous layer was extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with dilute acetic acid and with water before being dried over MgSO4. The solvent was then removed in vacuo to give compound 34 (671 mg, 4.59 mmol, 96%) as a yellow solid. The characterization of this compound conformed to that reported in reference 44. 1  H NMR (400 MHz, CDCl3): δ (ppm) 11.1 (s, 1H, OH), 9.88 (s, 1H, CH=O), 7.73 (d, J = 2.0 Hz,  1H, aromatic CH), 7.63 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H, aromatic CH), 6.97 (d, J = 8.8 Hz, 1H, aromatic CH), 3.05 (s, 1H, C≡CH). 47  Synthesis of 2,8-diiododibenzofuran (35): 45 Water (3.1 mL) and glacial acetic acid (31 mL) were combined in a 100 mL round bottom flask. Dibenzofuran (19) (500 mg, 2.79 mmol) was then added followed by iodine (830 mg, 3.27 mmol) and potassium iodate (255 mg, 1.19 mmol). To the dark red solution, concentrated sulfuric acid (0.3 mL) was added dropwise and the reaction was stirred at reflux. After 24 h, the white precipitate was filtered, washed with water and dried to give the desired compound 35 (830 mg, 1.98 mmol, 67%). The characterization of this compound conformed to that reported in reference 45. 1  H NMR 300 MHz, CDCl3): δ (ppm) 8.23 (s, 2H, aromatic CH), 7.76 (dd, J = 8.7 Hz, 2.1 Hz,  2H, aromatic CH), 7.35 (d, J = 8.7 Hz, 2H, aromatic CH).  Synthesis of 2,8-bis(5-ethynylsalicylaldehyde)dibenzofuran (36): To a 100 mL Schlenk flask were added compound 35 (250 mg, 0.595 mmol), compound 34 (261 mg, 1.79 mmol), triphenylphosphine (9.4 mg, 0.036 mmol), copper(I) iodide (11 mg, 0.060 mmol) and (Ph3P)2PdCl2 (16.7 mg, 0.024 mmol). The flask was put under vacuum for 5 min and then purged with nitrogen. This process was repeated 2 times. Dry triethylamine (5 mL) and dry THF (10 mL) were added and the resulting yellow mixture was stirred at 85 °C overnight. The reaction was then brought to room temperature and the salts were filtered through Celite. The celite was washed with THF until the filtrate was colourless. The solvent was removed in vacuo and upon adding DCM, a light brown solid precipitated. The solid was filtered to give the desired compound 36 (102 mg, 0.224 mmol, 38%). 1  H NMR (400 MHz, DMSO-d6): δ (ppm) 11.2 (s, 2H, OH), 10.3 (s, 2H, CH=O), 8.44 (s, 2H,  aromatic CH), 7.84-7.73 (m, 8H, aromatic CH), 7.08 (d, J = 8.4 Hz, 2H, aromatic CH); IR  48  (neat): υ = 2860, 2112, 1659, 1487, 1277, 1195, 819, 743 cm-1; HR-EI-MS: m/z = 456.09977 (calculated), 456.10059 (found).  Attempted synthesis of [4+4] Schiff-base Macrocycle (38): To a 100 mL Schlenk flask containing compound 37 (27 mg, 87.6 μmol) was added deoxygenated MeCN (5 mL) and CHCl3 (5 mL). The solution was stirred for 5 min under nitrogen before adding compound 36 (40 mg, 87.6 μmol). The resulting red solution was stirred at reflux overnight. The next day, the bright red solid was filtered and MALDI-TOF-MS revealed the presence of a mixture of species including the desired compound as the main product. MALDI-TOF-MS: m/z = 2915.4 (M+H)+. No NMR data was obtained as the solid was not soluble in most solvents.  Attempted synthesis of [4+4] Schiff base Macrocycle: To a 100 mL Schlenk flask containing compound 39 (36 mg, 98.8 μmol) was added degassed MeCN (5 mL) and CHCl3 (5 mL). The solution was stirred for 5 min under nitrogen before adding compound 36 (45 mg, 98.8 μmol). The resulting red solution was stirred at reflux overnight. The next day, the bright red solid was filtered off and MALDI-TOF-MS revealed the presence of a mixture of species including the desired compound. MALDI-TOF-MS: m/z = 3143.5 (M+H)+. No NMR data was obtained as the solid was not soluble in most solvents.  49  Chapter 3: A New Route to 3,6-Diformylcatechol (11) 3.1 - Background and Objectives  One of the most studied macrocycles in the MacLachlan group is the [3+3] Schiff-base macrocycle. This type of macrocycle is obtained by the condensation of 3,6-diformylcatechol (11) with a 4,5-dialkoxy-1,2-phenylenediamine derivative. Various [3+3] macrocycles have been made by varying the alkoxy group on the phenylenediamine ring.27 Numerous NMR studies have been done on the [3+3] to elucidate its behavior in solution and its capacity to aggregate.26 Different metals such as zinc30 and cadmium49 have been incorporated in the macrocycles through the N2O2 binding sites. The metallation of these macrocycles led to the formation of interesting metal clusters (metallocavitands). These macrocycles, and their metal-containing versions, have been investigated for their potential to exhibit discotic liquid crystallinity.50 All of these experiments require substantial amounts of 3,6-diformylcatechol (11) and 4,5-dialkoxy-1,2-phenylenediamine derivatives. The 4,5-dialkoxy-1,2-phenylenediamine moiety can be prepared on a large scale (>100 g) with high yields and is inexpensive. On the other hand, the synthesis of 11 could be improved. O OMe  1) n-BuLi, TMEDA Et2O  OH  OMe  2) DMF then H2O 3) BBr3  OH  40  O 11  Scheme 3.1: Synthesis of 3,6-diformylcatechol (11)  50  Compound 11 is synthesized in two steps from 1,2-dimethoxybenzene (Scheme 3.1).25 First, formylation of 1,2-dimethoxybenzene (40) is done by ortho-lithiation using n-butyllithium and TMEDA followed by quenching with DMF. 3,6-Diformyl-1,2-dimethoxybenzene is then recrystallized multiple times to obtain a pure enough sample suitable for the next step. Second, the methoxy groups are removed using boron tribromide. Although compound 11 can be synthesized on large scales, it is done in low to moderate yields (20 to 30%)6 and with a large excess of n-BuLi to get dilithiation. Our goal was to find a new synthetic route to compound 11 that could be achieved in high yields and on large scales while using inexpensive chemicals even if additional steps were required. This chapter will mainly focus on the different synthetic routes to compound 11. Also, attempts to synthesize 4,5-dialkoxy-3,6-diformylcatechol derivatives will be briefly discussed.  51  3.2 - New Synthetic Approach to 3,6-Diformylcatechol (11)  The first synthetic route I tried toward compound 11 came from an article about the synthesis of naphthodifurans.51 The authors reacted 2,3-dihydroxynaphthalene (41) with bromoacetaldehyde dimethylacetal to give 2,3-bis(2,2-dimethoxyethoxy)naphthalene (42). Cyclization of compound 42 under anhydrous acidic conditions (phosphorus pentoxide and phosphoric acid) gave naphtho[2,1-b : 3,4-b’]difuran (43) (Scheme 3.2).  OH  Base BrCH2CH(OMe)2  OH  OMe O O  OMe OMe  O  P2O5, H3PO4  O  OMe 41  42  43  Scheme 3.2: Synthesis of naphthodifuran (43)  We believed that by applying this methodology to catechol (44) we would be able to synthesize benzo[2,1-b : 3,4-b']difuran (46). Compound 46 could be oxidized to compound 11 using oxidative methods such as ozonolysis or osmium tetroxide with sodium periodate. It is known that ozonolysis (with reductive work-up)52 or osmium tetroxide53,54 can oxidize alkenes to aldehydes or ketones. This synthetic approach was interesting as it would only require three steps to compound 11 (Scheme 3.3).  52  O  OEt  K2CO3 OH BrCH2CH(OEt)2  O  OH  O  OEt OEt  O O3, PPh3 or OsO4, NaIO4 O  P2O5, H3PO4  OEt 44  45  46  OH OH O 11  Scheme 3.3: Proposed synthetic route of 3,6-diformylcatechol (11) through oxidation of benzodifuran (46) Compound 44 was reacted with bromoacetaldehyde diethylacetal under standard conditions for Williamson ether synthesis to give the desired product 45 in good yield (72%). Besides the removal of bromoacetaldehyde diethylacetal by distillation, the compound did not require any further purification as seen by the 1H NMR spectrum (Figure 3.1) of the crude product.  Figure 3.1: 1H NMR spectrum (300 MHz, CDCl3) of compound 45 (* = CHCl3)  53  Our first attempts to perform the cyclization of compound 45 were done under the same conditions as reported for the cyclization of compound 42. Polyphosphoric acid was first made by mixing phosphorus oxide with phosphoric acid in toluene. Compound 45 was then added to the polyphosphoric acid and toluene mixture and the new mixture was heated to reflux for several hours. TLC on silica gel revealed the presence of several compounds in the mixture. After quenching the reaction, the crude product was analyzed by 1H NMR spectroscopy and LREI-MS. Both of these techniques did not show any evidence of the desired product, benzodifuran. The 1H NMR spectrum was extremely complicated, while LR-EI-MS results showed that the mixture contained compounds with high molecular mass, probably polymerized material. Attempts were made by varying the experimental conditions such as the temperature and the duration of the experiments, but similar results were obtained. Attempts to purify the mixture by column chromatography on silica gel were futile. It has been reported that cyclization of functionalized phenoxyacetals using organic acids such as polyphosphoric acid is done in poor yield as a polymerized mixture is usually obtained.55 It came to our attention that the cyclization of phenoxyacetals can be done by using a catalytic amount of a sulfonic acid cation exchange resign (Amberlyst A15)55 in refluxing toluene. It was also mentioned that the ring-closure step must be done with a Dean-Stark apparatus to avoid polymerization. Armed with this knowledge, I tried the cyclization of compound 45 using the reported procedure. The first thing I noticed was that the reaction led to fewer products compared to the one using polyphosphoric acid. Only one major product was revealed by TLC on silica gel along with fewer minor by-products. 1H NMR spectroscopy and LR-EI-MS of the purified product, however, indicated that this product was not the target compound. Unexpected signals around 9.3 ppm and 4.8 ppm were attributed to aldehyde and methylene groups, respectively (Figure 3.2). Based on the NMR and LR-EI-MS data, this 54  product is in fact 2-(benzofuran-7-yloxy)acetaldehyde. It is worth mentioning that the use of a Dean-Stark apparatus was not necessary for our experiments as we obtained similar results with or without it.  Figure 3.2: 1H NMR spectrum (300 MHz, CDCl3) of the product obtained upon cyclization of 45 with A15 (* = CHCl3) To complete the cyclization of compound 45, I tried to do the reaction for a longer period of time (up to 24 h). Unfortunately, this was not sufficient and the ring-closing step could not be completed. To make sure that the conditions used (refluxing toluene with A15 as catalyst) were adequate to perform a double ring-closure, I synthesized 2,3-bis(2,2-diethoxyethoxy)naphthalene (47) from 2,3-dihydroxynaphthalene using analogous conditions as the synthesis of compound 45. We found that the cyclization conditions discussed above were, in fact, sufficient to transform compound 47 into naphthodifuran (43) (Scheme 3.4). It was somewhat surprising that, while the cyclization of compound 47 would work, it could not be done with compound 45. One possible explanation is the different electronic environment of both compounds. 55  OEt O O  OEt OEt  toluene, A15  O  reflux  O  OEt 47  43  Scheme 3.4: Cyclization of compound 47 using A15  While we did not investigate the reasons why the ring-closure of compound 45 would not work under those conditions, we decided to come up with another synthetic route to compound 11 (Scheme 3.5). We were hopeful that each of these reactions, based on the literature,52-57 could be done in good yields thereby offsetting the large number of steps required. Compound 48 was synthesized from compound 44 using allyl bromide with potassium carbonate in acetone. This was done in high yield (ca. 90%) and no purification was required before the next step. After this Williamson ether synthesis, I performed a Claisen rearrangement simply by heating compound 48 neat for a few hours. It has been reported57 that the Claisen rearrangement of compound 48 leads to the formation of two isomers: 3,6-diallylcatechol and 3,4-diallylcatechol. To separate these two isomers, I first had to convert the hydroxyl groups to methoxy groups. Catechol derivatives, such as those two isomers, are known to be air sensitive, especially when adsorbed on silica gel.57 At first, I did attempt to purify the two isomers with the hydroxyl groups, but, just as expected, it did not work.  56  OH OH 44  a  O  OMe  b, c  O  O OMe  d  OMe  OMe O  48 49  50  e  O OH  O  g  OH O 11  O OH  f  OH O  O 46  51  Scheme 3.5: Suggested alternative synthetic route to compound 11 a) Allyl bromide, K2CO3, Acetone; b) Heat; c) (CH3)2SO4, K2CO3, Acetone; d) O3, PPh3 or OsO4, NaIO4; e) BBr3, DCM; f) H3PO4, heat; g) O3, PPh3 or OsO4, NaIO4 After protecting the hydroxyl groups as methyl ethers by a Williamson ether synthesis, I was able to separate the two isomers by column chromatography on silica gel and obtained compound 49 in moderate yield (50%). The 1H NMR spectrum (Figure 3.3) confirmed that the right isomer was obtained as there is only one aromatic and one methoxy signal.  57  Figure 3.3: 1H NMR spectrum (300 MHz, CDCl3) of compound 49 (* = CHCl3)  Ozonolysis of compound 49 was performed in order to cleave the alkene to yield the desired aldehyde. Compound 49 was reacted at -78 °C with ozone to give the appropriate ozonide that was then reduced to the aldehyde using triphenylphosphine. Compound 50 was purified using column chromatography on silica gel in order to remove the excess triphenylphosphine and the triphenylphosphine oxide formed during the reaction. 1H and  13  C  NMR analyses (Figures 3.4 and 3.5) suggest that compound 49 was successfully oxidized to compound 50. Signals around 5.1 and 6.0 ppm in the 1H NMR spectrum due to the alkene protons have been replaced by a signal at 9.7 ppm for the aldehyde. The 13C NMR spectrum of compound 50 showed the expected six signals including the characteristic carbonyl signal around 200 ppm.  58  Figure 3.4: 1H NMR spectrum (400 MHz, CDCl3) of compound 50 (* = CHCl3)  Figure 3.5: 13C NMR spectrum (100 MHz, CDCl3) of compound 50 (* = CHCl3) 59  To circumvent the purification of compound 50 using column chromatography, I also tried the ozonolysis of compound 49 using another common ozonide reducing agent, dimethylsulfide. Dimethylsulfide is oxidized to dimethylsulfoxide upon reducing the ozonide. Therefore, the organic layer could be washed with water to remove dimethylsulfoxide. The excess dimethylsulfide can easily be removed under reduced pressure. The 1H NMR spectrum of the crude product (Figure 3.6) revealed, however, that the reaction did not yield compound 50 upon using dimethylsulfide as the reducing agent. Although an aldehyde signal is seen in the spectrum, the presence of a multiplet in the aromatic region and in the methoxy region strongly suggest that this crude product was not compound 50. Dimethylsulfide was oxidized to dimethylsulfoxide (signal at 2.63 ppm) meaning that a reductive reaction took place. Several attempts were done and all of them gave similar results.  Figure 3.6: 1H NMR spectrum (300 MHz, CDCl3) of the crude after ozonolysis of compound 49 using dimethylsulfide for the reductive work-up (* = CHCl3) 60  These results were unexpected as the use of dimethylsulfide as a reducing agent is well known.9 1H NMR analyses of compound 49, dimethylsulfide and DCM did not show any abnormalities that could explain these results. The next step of the synthesis toward compound 11 was the removal of the methoxy groups. My first attempt was done by treating compound 50 in presence of boron tribromide. This type of reaction has been used often in the MacLachlan group to transform veratrole derivatives to the catechol derivatives and the yields obtained are usually satisfactory (60-90%). The reaction with compound 50 proved, however, to be unsuccessful. Upon quenching the reaction, a brown crude solid was obtained that was poorly soluble in most solvents. 1H NMR analysis suggested that this crude product was not the desired compound. Alternative methods to remove the methoxy groups were not investigated as another synthetic route was elaborated. This new synthetic route (Scheme 3.6) had two advantages over the previous attempted one (Scheme 3.5). First, the synthesis of compound 11 would be carried out with one fewer step. Second, only one ozonolysis or osmium oxidation would be required.  61  OH  O  a  OH  OMe  b, c  O 48  44  OMe  d  OMe  OMe  49 52 e O  O OH OH  O 11  f  OMe OMe O 53  Scheme 3.6: Alternative synthetic route to compound 11 a) Allyl bromide, K2CO3, Acetone; b) Heat; c) (CH3)2SO4, K2CO3, Acetone; d) t-BuOK, THF e) O3, PPh3 or OsO4, NaIO4; f) BBr3, DCM Terminal alkenes can be isomerized to the more stable trans alkene in presence of strong base.58 Therefore, compound 49 was treated with potassium tert-butoxide to do a double bond migration. The isomerization of compound 49 was done in quantitative yield to give compound 52 in high purity. 1H and  13  C NMR spectra (Figures 3.7 and 3.8) of the crude product showed  that compound did not require any purification.  62  Figure 3.7: 1H NMR spectrum (300 MHz, CDCl3) of compound 52 (inset alkene region) (* = CHCl3)  Figure 3.8: 13C NMR spectrum (75 MHz, CDCl3) of compound 52 (* = CDCl3) 63  Another method to cleave alkenes to aldehydes or ketones is to use osmium tetroxide with a strong oxidizing agent. Osmium(VIII) tetroxide reacts with alkenes to form a vicinal diol and, in the process, is reduced to osmium(VI). A strong oxidizing agent, such as sodium periodate, will oxidize the vicinal diol to the aldehyde and will also regenerate the catalyst by oxidizing osmium(VI) to osmium(VIII). Using this methodology, compound 52 was oxidized to compound 53 using a catalytic amount of osmium tetroxide and sodium periodate. 1H and  13  C  NMR analyses confirmed that compound 53 was synthesized. Oxidation of compound 52 to compound 53 could also be done using ozonolysis just like the synthesis of compound 50. Compound 53 was treated with boron tribromide and compound 11 was finally obtained in 40% overall yield. Although this new synthetic route is three steps longer than the original one, the overall yield is about 10% higher. Also, all of the reactions leading to compound 11 can easily be done on big scales and, unlike the original synthetic approach, do not require a large excess of reagents. Finally, assuming that oxidation of compound 52 is done by ozonolysis, most reagents used are fairly cheap. The only major drawback of this synthetic approach is that it takes slightly more time than the original one.  64  3.3 - Attempted Syntheses of 4,5-dialkoxy-3,6-Diformylcatechol Derivatives  Compound 11 is the most frequently used catechol derivative in the synthesis of triangular [3+3] Schiff-base macrocycles in the MacLachlan group. Aside from 4,5-dialkyl-3,6diformylcatechol derivatives, few catechol derivatives have been synthesized or used within the MacLachlan group. We were interested in synthesizing 4,5-dialkoxy-3,6-diformylcatechol derivatives in order to expand the variety of components available for the synthesis of [3+3] Schiff-base macrocycles. Our initial approach to these compounds was similar to the synthetic route employed to 4,5-dialkyl-3,6-diformylcatechol derivatives.29 In that synthetic approach, 4,5dialkylcatechols were first synthesized before the introduction of aldehyde groups by a Duff reaction.59,60 First, 4,5-dimethoxy-1,2-benzoquinone (54) was prepared from compound 40 and sodium iodate in methanol according to the literature (Scheme 3.7).61 This reaction was interesting as the alkoxy group introduced on the ring depends on the solvent used. For example, by doing this reaction in ethanol, using catalytic amounts of 18-crown-6, 4,5-diethoxy-1,2benzoquinone would be obtained.62  OMe  a  OMe 40  MeO  O b  MeO  OH  MeO  O  MeO  OH  54  55  Scheme 3.7: Synthesis of compound 55 a) NaIO3, MeOH, b) Na2S2O4, DCM  65  The orange compound 54 was reduced using sodium hydrosulfite to the white solid, 4,5dimethoxycatechol (55). Although a solid sample of compound 55 is relatively stable under air, a solution of this compound will slowly (few hours) be oxidized back to compound 54. This can be easily observed as the clear colourless solution will turn bright orange. Dihydroxybenzene derivatives, such as 1,4-hydroquinone and catechol,57 are known to be sensitive to oxidation and easily form benzoquinone derivatives.62 The presence of methoxy groups on compound 55 makes the ring more electron rich and probably more prone to oxidation. Performing reactions on compound 55 proved to be problematic even if all necessary precautions such as using inert atmosphere and degassing all solvents with nitrogen were taken. Attempts to formylate compound 55 using the Duff reaction failed as these conditions were probably too harsh for compound 55. 1H NMR analysis showed that the crude product extracted after the Duff reaction was in fact the oxidized starting material, compound 54. This was expected as the solution rapidly turned orange when all the reagents were added. I also tried to protect the vicinal hydroxyl groups with an acetal using typical literature procedures such as dry acetone (or 2,2-dimethoxypropane) with catalytic amounts of paratoluenesulfonic acid.63 These conditions led to the formation of a viscous dark solid. Attempts to purify the compound by column chromatography were not successful and 1H NMR analysis of the crude product did not suggest the presence of the desired compound. This protection was needed in order to prevent oxidation as I tried to brominate positions 3 and 6 before attempting a bromine-lithium exchange35 and eventually a formylation.37 Direct bromination of compound 55 with NBS did oxidize it to compound 54. I also tried both Reimer-Tiemann40 and Vilsmeier-Haack41 reactions on compound 55 in attempt to formylate it. Both conditions, however, oxidized compound 55 back to compound 54. Another synthetic approach to introduce aldehydes on a phenyl ring is done by treating the 66  starting material in the presence of magnesium chloride, triethylamine and paraformaldehyde.64 This method, however, did not seem to work with compound 55. 1H NMR analysis of the crude product did not show any aldehyde signal. The crude product obtained was mostly starting material compound 55 and the oxidized compound 54. One possible explanation for the lack of reactivity is that the magnesium might be chelating with both hydroxyl groups, rendering it inactive for the reaction. While we were working on the cyclization of compound 45 using acidic conditions, we thought this methodology could be applied to the synthesis of 4,5-dialkoxy-3,6diformylcatechol.  Starting  with  compound  40,  1,2-bis(2,2-diethoxyethoxy)-4,5-  dimethoxybenzene (59) was obtained in four steps (Scheme 3.8).  OMe  a  OMe  Br  OMe  Br  OMe  40  b  56  Br  OH  Br  OH 57  c  OEt MeO  O  MeO  O  OEt OEt  OEt d  Br  O  Br  O  OEt 59  OEt OEt OEt  58  Scheme 3.8: Synthesis of compound 59 a) NBS, CH3CN; b) BBr3, DCM; c) K2CO3, BrCH2CH(OEt)2, Acetone; d) NaOMe in MeOH, CuBr, EtOAc  67  We were hopeful that the cyclization might work as the methoxy substituents make the ring more electron rich. Attempted cyclizations of compound 59 gave similar results to those of compound 45. LR-EI-MS and 1H NMR analyses of the crude product suggested that the compound obtained from the attempted cyclization of compound 59 was actually 2-(4,5dimethoxybenzofuran-7-yloxy)acetaldehyde. Overall, a new synthetic approach to compound 11 was devised. Starting from catechol, compound 11 was obtained in five steps using fairly cheap chemicals with a 10% higher overall yield than the original synthetic approach. All of the steps could be easily performed on a large scale. Attempts to synthesize 4,5-dialkoxy-3,6-diformyl catechol derivatives were not successful, however, as compound 55 was easily oxidized back to compound 54 under different formylation conditions (Duff, Reimer-Tiemann and Vilsmeier-Haack conditions).  68  3.4 - Experimental  Materials. Catechol, sodium iodate, sodium hydrosulfite, bromoacetaldehyde diethylacetal, 2,3dihydoxynaphthalene, amberlyst A15, N-bromosuccinimide, 1,2-dimethoxybenzene, copper (I) bromide, 25 wt.% NaOMe in MeOH, boron tribromide, triphenylphosphine, sodium iodide, allyl bromide, dimethyl sulfate, potassium tert-butoxide in THF and sodium periodate were obtained from Aldrich, Fisher Scientific or TCI America. Diethyl ether and THF were distilled from sodium and benzophenone ketyl under nitrogen. Ozonolysis was performed using the ozonator in the Ciufolini group at UBC. Osmium tetroxide solution was obtained from the Sammis Group at UBC. Deuterated solvents were purchased from Cambridge Isotope Laboratories, Inc.  Equipment: All reactions were carried out under a nitrogen atmosphere unless stated otherwise. 300 MHz 1H NMR and 75.5 MHz 13C NMR spectra and 400 MHz 1H and 100 MHz 13C NMR spectra were recorded on Bruker AV-300 and AV-400 spectrometers respectively.  13  C NMR  spectra were calibrated to deuterated solvent and 1H spectra were calibrated to residual protonated solvent. IR spectra were obtained neat on a Thermo Fisher Nicolet 6700 FTIR spectrophotometer. Low and high resolution electron impact mass spectra were obtained from the UBC Microanalytical Services Laboratory.  Synthesis of 1,2-bis(2,2-diethoxyethoxy)benzene (45): Catechol (44) (0.5 g, 4.54 mmol) was dissolved in DMF (10 mL) before anhydrous potassium carbonate (1.88 g, 13.6 mmol) and bromoacetaldehyde diethylacetal (1.5 mL, 9.99 mmol) were added. The mixture was heated at 80 °C under for 72 h. The brown solution was then poured into 69  water (100 mL) and the aqueous layer was extracted with diethyl ether (3x50 mL). The combined organic layers were washed with a 0.1 M NaOH solution (50 mL) and then water. The organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed in vacuo. The excess bromoacetaldehyde diethylacetal was removed by vacuum distillation to leave the desired product as brown oil (1.12 g, 3.27 mmol, 72%). Compound 45 was used without further purification. 1  H NMR (300 MHz, CDCl3): δ (ppm) 6.92 (s, 4H, aromatic CH), 4.86 (t, 2H, J = 5.2 Hz, CH),  4.05 (d, 4H, J = 5.3 Hz, OCH2), 3.72 (m, 8H, OCH2CH3), 1.25 (t, 12H, J = 7.1 Hz, OCH2CH3); 13  C NMR (100 MHz, CDCl3): δ (ppm) 148.8, 121.2, 115.0, 100.7, 70.0, 62.6, 15.2; IR (neat) : υ  = 2975, 2931, 2878, 1594, 1501, 1256, 1126, 1066, 933, 740 cm-1; HR-EI-MS: m/z = 342.20423 (calculated), 342.20478 (found).  Synthesis of 2,3-bis(2,2-diethoxyethoxy)naphthalene (47): Compound 47 was synthesized using 2,3-dihydroxynaphthalene as starting material and analogous conditions to those for the preparation of compound 45. Compound 47 was obtained as a brown oil (54%). The compound was used without further purification. 1  H NMR (400 MHz, CDCl3): δ (ppm) 7.65 (dd, 2H, J = 3.3 Hz, J = 6.1 Hz, aromatic CH), 7.32  (dd, 2H, J = 3.2 Hz, J = 6.2 Hz, aromatic CH), 7.16 (s, 2H, aromatic CH), 4.93 (t, 2H, J = 5.2 Hz, CH), 4.15 (d, 4H, J = 5.2 Hz, OCH2), 3.75 (m, 8H, OCH2CH3), 1.27 (t, 12H, J = 7.1 Hz, OCH2CH3);  13  C NMR (100 MHz, CDCl3): δ (ppm) 149.0, 129.6, 126.5, 124.4 108.9, 101.6,  69.9, 62.6, 15.3; IR (neat) : υ = 2975, 2880, 1580, 1495, 1261, 1116 1054, 745 cm-1; LR-EI-MS : m/z = 392.4 (calculated), 392 (found).  70  Synthesis of naphtho[2,1-b: 3,4-b’]difuran (43): Compound 47 (530 mg, 1.35 mmol) was dissolved in toluene (15 mL) and molecular sieves A15 (55 mg) were added. The mixture was heated to reflux for 7 h. While the mixture was still hot, the molecular sieves were removed by vacuum filtration and the solvent was removed in vacuo. The brown oil was purified by column chromatography on silica gel using diethyl ether:hexanes 1:9 to give the desired compound 43 as a slighty yellow solid (75 mg, 0.36 mmol, 27%). The 1H NMR and EI-MS data of this compound conformed to the compound reported in reference 51. 1  H NMR (400 MHz, CDCl3): δ (ppm) 8.21 (dd, 2H, J = 6.2 Hz, J = 3.2 Hz, aromatic CH), 7.81  (d, 2H, J = 2.8 Hz, OCH=CH), 7.60 (dd, 2H, J = 6.2 Hz, J = 3.2 Hz, aromatic CH), 7.36 (d, 2H, J = 2.8 Hz, OCH=CH); LR-EI-MS : m/z = 208 (calculated), 208 (found).  Synthesis of 1,2-bis(allyloxy)benzene (48):56 A 500 mL round bottom flask was charged with catechol (15 g, 136 mmol), anhydrous potassium carbonate (56.5 g, 409 mmol) and sodium iodide (2.04 g, 13.6 mmol) , and acetone (250 mL). The mixture was stirred at room temperature for 15 min before allyl bromide (29 mL, 341 mmol) was added. The reaction was stirred for 24 h, the salts were removed by filtration, and the solvent was removed in vacuo to give the desired product (23 g, 121 mmol, 89%). Compound 48 was used without further purification. The characterization of this compound conformed to that reported in reference 56. 1  H NMR (300 MHz, CDCl3): δ (ppm) 6.90 (s, 4H, aromatic CH), 5.98 (m, 2H, CH=CH2), 5.31  (dd, 2H, J = 1.5 Hz, J = 17.3 Hz, CH=CHH), 5.17 (dd, 2H, J = 1.4 Hz, J = 10.4 Hz, CH=CHH), 4.50 (dd, 4H, J = 1.4 Hz, J = 3.8 Hz, OCH2).  71  Synthesis of 1,4-diallyl-2,3-dimethoxybenzene (49): 57 Compound 48 (5 g, 26.3 mmol) was deoxygenated for 15 min and then was heated to 175 °C for 4 h. The dark mixture was then cooled to room temperature. Deoxygenated acetone (50 mL), anhydrous potassium carbonate (21.8 g, 158 mmol) and dimethyl sulfate (11.3 mL, 118 mmol) were added and the mixture was heated to reflux for 24 h. The next day, the salts were removed by filtration and washed with acetone. The solvent was removed in vacuo, giving a crude brown oil that was purified by column chromatography using 1:9 diethyl ether:hexanes. Compound 49 was obtained as a clear and colourless oil (3.1 g, 14.2 mmol, 54%) The characterization of this compound conformed to that reported in reference 57. 1  H NMR (300 MHz, CDCl3): δ (ppm) 6.86 (s, 2H, aromatic CH), 5.98 (tdd, 2H, J = 6.5 Hz, J =  9.5 Hz, J = 16.1 Hz, CH=CH2), 5.08 (dd, 2H, J = 1.5 Hz, J = 3.4 Hz, CH=CHH), 5.03 (s, 2H, CH=CHH) 3.84 (s, 6H, OCH3) 3.38 (d, 4H, J = 6.5 Hz, CH2).  Synthesis of 2,2'-(2,3-dimethoxy-1,4-phenylene)diacetaldehyde (50): Compound 49 (400 mg, 1.83 mmol) was dissolved in DCM (40 mL) and the colourless solution was cooled to -78 °C. Ozone was then bubbled through the solution until it turned blue. While the solution was still at -78 °C, nitrogen was bubbled through the solution until the blue colour disappeared and, then triphenylphosphine (3.84 g, 14.7 mmol) was added. The mixture was stirred overnight letting it warm to room temperature. The next day, the solvent was removed in vacuo and the crude mixture was purified by column chromatography using ethyl acetate:hexanes 1:9 to give the desired product 50 as a colourless oil (150 mg, 0.675 mmol, 37%). 1  H NMR (400 MHz, CDCl3): δ (ppm) 9.74 (t, 2H, J = 1.9 Hz, CH=O), 6.90 (s, 2H, aromatic  CH), 3.82 (s, 6H, OCH3), 3.69 (d, 4H, J = 1.9 Hz, CH2); 13C NMR (100 MHz, CDCl3) : δ (ppm) 72  199.3, 151.6, 141.5, 126.7, 60.1, 45.2; IR (neat): υ = 2939, 2830, 2728, 1719, 1460, 1415, 1270, 1073, 1009. 815; HR-EI-MS: m/z = 222.08921 (calculated), 222.08934 (found).  Synthesis of 2,3-dimethoxy-1,4-di((E)-prop-1-enyl)benzene (52): Compound 49 (300 mg, 1.74 mmol) was dissolved in dry THF (15 mL) and the mixture was cooled to 0 °C. Potassium tert-butoxide in THF (1 M, 5.5 mL, 5.50 mmol) was added dropwise while maintaining the solution at 0 °C. The mixture was stirred under nitrogen at 0 °C for 3 h. The mixture was then poured into a beaker containing water (100 mL), the aqueous layer was extracted with diethyl ether (3x25 mL) and the combined organic layers were dried over anhydrous MgSO4 and filtered. The solvent was removed in vacuo to give a yellow oil that solidified upon standing. The desired product 52 was obtained in quantitative yield (300 mg, 1.73 mmol) as a yellow solid. 1  H NMR (300 MHz, CDCl3): δ (ppm) 7.14 (s, 2H, aromatic CH), 6.67 (dd, 2H, J = 1.6 Hz, J =  15.9Hz, CH=CH), 6.25 (qd, 2H, J = 6.6 Hz, J = 15.8 Hz, CH=CH), 3.85 (s, 6H, OCH3), 1.92 (dd, 6H, J = 1.6 Hz, J = 6.6 Hz, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 150.2, 130.7, 126.5, 125.0, 120.9, 60.7, 18.8; IR (neat): υ = 2991, 2932, 2856, 1650, 1592, 1443, 1403, 1274, 1053, 1024, 961, 914 cm-1; HR-EI-MS: m/z = 218.130681 (calculated), 218.13078 (found).  Synthesis of 2,3-Dimethoxy-1,4-benzenedicarboxaldehyde (53): Compound 52 (100 mg, 0.458 mmol) was dissolved in acetone:water 6:1 mixture then 4% wt. OsO4 aqueous solution (56 μL, 9.16 μmol) was added turning the solution brown. The mixture was stirred for 5 min before sodium periodate (390 mg, 1.83 mmol) was added. The reaction was stirred in the dark for 24 h at room temperature. The yellow solution was poured into a beaker containing water (50 mL). The aqueous layer was extracted with diethyl ether (3x20 mL), dried 73  with MgSO4 and filtered. The solvent was removed in vacuo to give the desired product as a dark green solid, pure by 1H NMR (74 mg, 0.380 mmol, 83%). Recrystallization using DCM and hexanes to remove the colored impurities yielded a yellow solid. The characterization of this compound conformed to that reported in reference 53. 1  H NMR (300 MHz, CDCl3): δ (ppm) 10.4 (s, 2H, CH=O), 7.63 (s, 2H, aromatic CH), 4.05 (s,  6H, OCH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 109.2, 156.6, 134.2, 122.8, 62.4.  Synthesis of 3,6-diformylcatechol (11):68 Compound 53 (7.28 g, 37.5 mmol) was dissolved in DCM (200 mL). The solution was then cooled to 0 °C in an ice bath and stirred for an additional 10 min before boron tribromide (15.9 mL, 168 mmol) was added dropwise. The yellow solution was stirred overnight warming up slowly to room temperature. The next morning, the yellow solution was slowly poured into cold water (500 mL). The aqueous layer was extracted with DCM (3x150 mL), and the combined organic layers were dried over anhydrous Na2SO4 and filtered. After the solvent was removed in vacuo, the crude product was recrystallized from dichloromethane to give the desired product (5.86 g, 35.25 mmol, 94%) as green solid. The characterization of this compound conformed to that reported in reference 68. 1  H NMR (300 MHz, CDCl3): δ (ppm) 10.93, (s, 2H, OH), 10.06 (s, 2H, CH=O), 7.26 (s, 2H,  aromatic CH).  Synthesis of 4,5-Dimethoxy-1,2-benzoquinone (54):61 Methanol (100 mL) was added to a 250 mL round bottom flask containing catechol (1.1 g, 10 mmol) and the reaction was stirred for 5 min under nitrogen before sodium iodate (4 g, 20 mmol) was added. The yellow solution was stirred at 60 °C for about 20 h. The resulting black solution 74  was then filtered to remove the salts and the dark solution was concentrated to 30 mL and then put in the freezer overnight. The black precipitate was filtered and washed with diethyl ether. Flash chromatography on silica gel using chloroform as eluant followed by a recrystallization from methanol gave compound 54 as a bright orange solid (520 mg, 3.09 mmol, 31%). The characterization of this compound conformed to that reported in reference 61. 1  H NMR (300 MHz, CDCl3): δ (pm) 5.77 (s, 2H, C=CH), 3.91 (s, 6H, OCH3).  Synthesis of 4,5-dimethoxycatechol (55): Compound 54 (500 mg, 2.97 mmol) was dissolved in DCM (20 mL) and put in a separatory funnel with an aqueous solution of Na2S2O4 (5 g, 29.7 mmol in 100 mL of water). The funnel was vigorously shaken turning the orange organic solution colourless. The aqueous layer was extracted with DCM (5x20 mL) and the combined organic layers were dried with anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give compound 55 (430 mg, 2.53 mmol, 85%) as a white solid. The characterization of this compound conformed to that reported in reference 65. 1  H NMR (300 MHz, CDCl3): δ (ppm) 6.55 (s, 2H, aromatic CH), 3.81 (s, 6H, OCH3).  Synthesis of 1,2-dibromo-4,5-dimethoxybenzene (56): 1,2-dimethoxybenzene (5 mL, 39.3 mmol) was dissolved in MeCN (150 mL) and NBS (15.4 g, 86.4 mmol) was added. The mixture was stirred for 24 h at room temperature before 1 M NaOH solution (100 mL) and water (200 mL) were added. The aqueous layer was extracted with DCM (3x150 mL) and the combined organic layers were dried over MgSO4 and filtered. The solvent was removed in vacuo to give the desired product 56 as a white solid (10.6 g, 35.8 mmol, 91%). The characterization of this compound conformed to that reported in reference 66. 75  1  H NMR (300 MHz, CDCl3): δ (ppm) 7.06 (s, 2H, aromatic CH), 3.85 (s, 6H, OCH3).  Synthesis of 4,5-dibromocatechol (57):67 Compound 56 (4.00 g, 13.5 mmol) was dissolved in DCM (25 mL). The solution was then cooled to 0 °C in an ice bath and stirred for an additional 10 min before boron tribromide (6.5 mL, 68.8 mmol) was added dropwise. The yellow solution was stirred under nitrogen overnight warming up slowly to room temperature. The next morning, the yellow solution was slowly poured into cold water (150 mL). The aqueous layer was extracted with DCM (3x50 mL), and the combined organic layers were dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give the desired product 57 (3.5 g, 13.1 mmol, 97%) as a slightly gray solid. The characterization of this compound conformed to that reported in reference 67. 1  H NMR (300 MHz, CDCl3): δ (ppm) 7.15 (s, 2H aromatic CH), 5.21 (s, 2H, OH).  Synthesis of 1,2-dibromo-4,5-bis(2,2-diethoxyethoxy)benzene (58): Compound 58 was synthesized from compound 56 using analogous conditions to those for the preparation of compound 45. Compound 58 was obtained as a slightly brown solid (56% yield). 1  H NMR (400 MHz, CDCl3): δ (ppm) 7.13 (s, 2H, aromatic CH), 4.81 (t, 2H, J = 5.2 Hz, CH),  3.99 (d, 4H, J = 5.2 Hz, OCH2), 3.68 (m, 8H, OCH2CH3), 1.23 (t, 12H, J = 7.0 Hz, OCH2CH3); 13  C NMR (100 MHz, CDCl3): δ (ppm) 148.6, 119.2, 115.4, 100.4, 70.3, 62.8, 15.3; IR (neat): υ =  2975, 2930, 2877, 1580, 1495, 1355, 1250, 1207, 1052, 825 cm-1 ; HR-EI-MS: m/z = 498.02526 (calculated), 498.02596 (found).  76  Synthesis of 1,2-bis(2,2-diethoxyethoxy)-4,5-dimethoxybenzene (59): To a 50 mL round bottom flask containing compound 58 (700 mg, 1.40 mmol), copper (I) bromide (20 mg, 0.14 mmol), toluene (0.5 mL) and ethyl acetate (1 mL) was added 15 mL of 25 wt. % NaOMe in MeOH. The blue mixture was stirred 80°C under nitrogen for 24 h. The reaction was then cooled to room temperature and poured into cold water (100 mL). The aqueous mixture was then extracted with DCM (3x50 mL). The organic layer was dried over anhydrous MgSO4 and filtered, and the solvent was removed in vacuo affording compound 59 as yellow oil (250 mg, 0.62 mmol, 45%, ca 85% pure by NMR integration). 1  H NMR (300 MHz, CDCl3): δ (ppm) 7.63 (s, 2H, aromatic CH), 4.81 (t, 2H, J = 5.2 Hz, CH),  4.02 (d, 4H, J = 5.2 Hz, OCH2), 3.81 (s, 6H, OCH3), 3.69 (m, 8H, OCH2CH3), 1.24 (t, 12H, J = 7.0 Hz, OCH2CH3); IR (neat) υ = 2977, 2928, 2882, 1593, 1497, 1058 cm-1; LR-EI-MS : m/z = 402.2 (calculated), 402.0 (found).  77  Chapter 4: Conclusions and Future Work 4.1 - Conclusions  The original synthetic approach to compound 18 proved to be difficult due to the formation of poorly soluble isomers upon bromination of compound 21. Lithiation and formylation of compound 22 could not be done successfully. The more soluble brominated compound 29 was synthesized, but lithiation and formylation still proved to be problematic. To achieve the formation of a [4+4] Schiff-base macrocycle, I synthesized compound 36. Compound 36 was characterized by 1H NMR, IR, and HR-EI-MS. Reaction of compound 36 with compound 37 led to the formation of a bright red insoluble solid. Although, the red solid could not be characterized by NMR spectroscopy, MALDI-TOF mass spectrometry revealed strong evidence that this red solid contained the [4+4] Schiff-base macrocycle 38 as the main product. This supports our hypothesis that a dibenzofuran derivative could lead to the formation of a [4+4] Schiff-base macrocycle. An alternative synthetic approach to compound 11 was elaborated. While this new synthetic approach requires three more steps than the original, the overall yield is about 10% higher (unoptimized) and most steps, besides the Claisen-rearrangement, don’t require purification. Furthermore, all the steps could be easily done on large scales and don’t require excess reagents or expensive chemicals. Intermediate compounds 50 and 52 were characterized by 1H and 13C NMR spectroscopy, IR spectroscopy and HR-EI-MS.  78  4.2 - Future Work  The synthesis of a more soluble [4+4] Schiff-base macrocycle that could be fully characterized is an interesting avenue. To do so, one could use a similar synthetic approach to compound 36 but using carbazole instead of dibenzofuran. This would allow the introduction of an alkyl chain on the nitrogen of the ring that would possibly improve the solubility of the precursor and eventually of the [4+4] macrocycle. Another possible way to improve the solubility of the macrocycle would be to use diamines that have long alkoxy chains. The next step would be to metallate the [4+4] macrocycle in a similar manner to the [3+3] Schiff-base macrocycles. 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