ABSTRACT
Synthesis of New Chiral Pyrylium Salts, the Corresponding Phosphinine and Pyridine Derivatives and the Kinetic Studies of the Epimerization of Pyrylium Salts
Nelson A. van der Velde, Ph.D.
Mentor: Charles M. Garner, Ph.D.
Despite the versatility of pyrylium salts as precursors to many heteroaromatic
systems, chiral pyrylium salts are almost unknown in the literature. One reason for this
scarcity is that pyrylium salts are often involved as intermediates rather than as isolated
and characterized materials. Another is that many pyrylium salts preparations tend to
result in non-characterizable black solid due to polymerization reactions. We have
developed the synthesis of several new chiral pyrylium salts and their conversion to the
corresponding pyridines and phosphinines. This work almost triples the number of
reported chiral pyrylium salts, and also represents the first racemizable/epimerizable
pyrylium salts. The derived phosphinines and pyridines represent rare alpha-chiral ligands for transition metals. Interestingly, only a few examples of chiral phosphinines have been reported in the literature. Incorporation of chirality directly (i.e., alpha to aromatic ring) onto these planar ring systems has proven to be difficult. From our pyrylium salts we have synthesized new phosphinines with the chirality as close as possible to the phosphorus center. Two known pyridinium salts were also prepared with the thiosemicarbazone moiety. The cytotoxicity and inhibition of cruzain were evaluated and found to be non-actives.
Our interest in chiral pyrylium salts led us to investigate the configurational stability of chiral centers alpha to the pyrylium ring. Although no epimerizable (or even racemizable) pyrylium salts have been reported, deuterium exchange at ortho and especially para benzylic positions is well-known, suggesting that epimerization is possible. Described here is the first study of the base-catalyzed epimerization of chiral pyrylium salts. In one case, this required identifying all components of a complex mixture of diastereomers. It was found that the base-catalyzed epimerization mechanism of the pyrylium salts studied is first order on the pyrylium and first order on the pseudobase formed.
Copyright © 2013 by Nelson A. van der Velde
All rights reserved
TABLE OF CONTENTS
LIST OF FIGURES ...... vii
LIST OF TABLES ...... ix
LIST OF SCHEMES...... x
LIST OF ABBREVIATIONS ...... xiii
ACKNOWLEDGMENTS ...... xvi
DEDICATION ...... xx
CHAPTER ONE ...... 1 Introduction ...... 1 Background ...... 1 Synthesis ...... 6 Two Synthons ...... 7 Three Synthons ...... 8 Chiral Pyrylium Salts ...... 10 Metal Catalyzed Asymmetric Synthesis ...... 11 Phosphinines ...... 12 Background ...... 12 Synthesis ...... 13 Pyrylium method ...... 13 Dibutyl-dihydrostannine method ...... 14 Phosphaalkyne method ...... 14 Chiral Phosphinines...... 15 Pyrydines...... 16 Background ...... 16 Synthesis ...... 16 The [5+1] condensation route ...... 17 The Hantzsch reaction ...... 17 The [3+3] condensation route ...... 17 The [4+2] inverse electron demand aza-Diels-Alder reaction...... 18 Chiral Pyridines ...... 18 Novel Pyrylium Salts and Their Corresponding Phosphinine and Pyridine Derivatives ...... 19
CHAPTER TWO ...... 21 Early Attempts to Synthesize Unsymmetrical and Symmetrical Chiral Pyrylium Salts ...... 21
iv
Menthone/pulegone Route ...... 21 Pinene Route ...... 25 Chalcone Route ...... 28 [C1 + C3 + C1] Synthons Route ...... 32
CHAPTER THREE ...... 33 Synthesis of New Chiral Pyrylium Salts and Their Phosphinine and Pyridine Derivatives...... 33 Asymmetric Compounds...... 33 Asymmetric Pyrylium Salts ...... 33 Asymmetric Phosphinines ...... 35 Asymmetric Pyridines ...... 38 Symmetric Compounds...... 41 Symmetric Pyrylium Salts ...... 41 Symmetric Pyridines ...... 44 Symmetric Phosphinines ...... 45
CHAPTER FOUR ...... 47 First Kinetic Studies of the Epimerization/equilibration of Asymmetric and Symmetric Pyrylium Salts ...... 47 Introduction...... 47 Epimerization/equilibration Studies ...... 48 Experimental Optimization ...... 48 Epimerization/equilibration Experiments ...... 50 Kinetic Analysis ...... 52 Assumption of the Model ...... 54 Application of the Model to the Pyrylium Systems ...... 57 2-(2-methyl-cyclohexyl)-4,6-diphenylpyrylium tetrafluoroborate (45d) (System 1) ...... 57 2,6-bis(2-methyl-cyclohexyl)-4-methyl-pyrylium tetrafluoroborate (49a) (System 2) ...... 58 2,6-bis(4-t-butyl-cyclohexyl)-4-methyl-pyrylium tetrafluoroborate (49b) (System 3) ...... 60
CHAPTER FIVE ...... 63 Possible Pharmaceutical Applications of Pyryliums and Derivatives ...... 63 Combretastatin Derivative ...... 63 Thiosemicarbazone Derivative ...... 67 Biological Activity Evaluation ...... 68 Cytotoxic Results ...... 68 Inhibition of Cruzain ...... 69
CHAPTER SIX ...... 70 Materials and Methods ...... 70 General Section ...... 70 Partial resolution of cis-2-methylcyclohexanecarboxylic acid ...... 71
v
General Procedure for the Preparation of the Acyl Chlorides ...... 72 Asymmetric Compounds...... 72 General Procedure for the Preparation of the Pyrylium Salts (45a-f) ...... 72 General Procedure for the Preparation of the Phosphinines (46a-f) ...... 76 General Procedure for the Preparation of the Pyridines (47a-f) ...... 80 Symmetric Compounds...... 84 General Procedure for the Preparation of the Pyrylium Salts (49a-b) ...... 84 General Procedure for the Preparation of the Pyridines (50a-b) ...... 86 Pyridinium Compounds ...... 87 General Procedure for the Preparation of the Pyridiniums 64 and 65 ...... 87 Epimerization Experiments ...... 89 Base Solution Preparation ...... 89 Base-catalyzed Epimerization Experiments ...... 89 Epimerization of 49a with different bases ...... 89 Epimerization of 49b with different concentration of N-methylmorpholine ...... 89 Epimerization of pyryliums 45d, 49a, and 49b with 5 mol% solution of N-methylmorpholine ...... 89 Reversibility of pseudobase formation for pyrylium 45d with TEA...... 90 Pseudobase formation study for pyrylium 45e with N-methylmorpholine...... 90
APPENDIX ...... 91 Appendix A ...... 92 Selected NMR spectra...... 92
BIBLIOGRAPHY ...... 151
vi
LIST OF FIGURES
Figure 1.1. Pyrylium salt ...... 1
Figure 1.2. 1H and 13C chem. shifts of an unsubstitued pyrylium salt ...... 3
Figure 1.3. 2,4,6-triphenylpyrylium ...... 4
Figure 1.4. Heteroaromatic compounds obtained from pyryliums ...... 5
Figure 1.5. Number of publications of pyrylium over the past century ...... 5
Figure 1.6. Existing chiral pyryliums ...... 10
Figure 1.7. 2,4,6-triphenylphosphinine and phosphinine ...... 12
Figure 1.8. Existing chiral phosphinines ...... 16
Figure 1.9. First chiral pyridines reported ...... 18
Figure 1.10. Chiral bipyridines and terpyridines reported ...... 19
Figure 1.11. Proposed chiral pyrylium salts that are the focus of this work ...... 20
Figure 2.1. (s)-BINOL-PCl (40) ...... 31
Figure 3.1. Methyl region 1H NMR of methylcyclohexanoic a. and pyrylium (45d) ..... 37
Figure 3.2. Acyl chlorides that do not yield the desired pyryliums ...... 40
Figure 3.3. 1H NMR of 49a ...... 43
Figure 3.4. 1H NMR of 49b ...... 44
Figure 4.1. Pyryliums 49a and 49b ...... 48
Figure 4.2. Equilibration rate of 49a with different bases ...... 49
Figure 4.3. 1H NMR of 45d at different time after addition of methylmorpholine ...... 51
Figure 4.4. Acid/base study for pyrylium 45d ...... 52
Figure 4.5. 1H NMR of 49a ...... 53
vii
Figure 4.6. 1H NMR of 49b ...... 53
Figure 4.7. Comparison of the experimental rate of pyrylium 45d ...... 57
Figure 4.8. Comparison of the experimental rate of pyrylium 49a ...... 59
Figure 4.9. Comparison of the experimental rate of pyrylium 49b ...... 61
Figure 4.10. Energy potential diagram for the epimerization of pyryliums ...... 62
Figure 5.1. Combretastatin A-4 ...... 63
Figure 5.2. Pyrylium 54 used in the photochemical cancer treatment ...... 64
viii
LIST OF TABLES
Table 2.1. Reagents used for the attempted conversion of 31 ...... 27
Table 3.1. Yields of compounds 45 (a-f), 46 (a-f) and 47 (a-f) ...... 36
Table 3.2. Yields of symmetric pyryliums 49 (a-b) ...... 42
Table 3.3. Yields of symmetric pyridines 50 (a-b) ...... 45
Table 4.1. Optimized values of the pseudo first order rate constants k’ and k” ...... 56
Table 5.1. Yields of pyridiniums 65 and 66 ...... 68
Table 5.2. Cytotoxicity results for compounds 65 and 66 ...... 69
Table 5.3. Inhibition of cruzain results for compounds 65 and 66 ...... 69
ix
LIST OF SCHEMES
Scheme 1.1. Example of a nucleophilic substitution to a pyrylium ring ...... 2
Scheme 1.2. Example of an electrophilic substitution on a pyrylium ring ...... 2
Scheme 1.3. Resonance structures of the pyrylium cation ...... 2
Scheme 1.4. Retrosynthetic analysis for pyrylium salts ...... 6
Scheme 1.5. Example of synthesis of pyryliums employing a [C1 + C4] route ...... 7
Scheme 1.6. Example of synthesis of pyryliums employing [C2 + C3] route ...... 8
Scheme 1.7. [C1 + C3 + C1] and [C2 + C2 + C1] synthons approach ...... 8
Scheme 1.8. [C2 + C1 + C2] synthons approach ...... 9
Scheme 1.9. Example of synthesis of pyryliums employing [C1 + C3 + C1] route ...... 9
Scheme 1.10. Example of synthesis of pyryliums employing [C2 + C2 + C1] route ...... 9
Scheme 1.11. Example of synthesis of pyryliums employing [C2 + C1 + C2] route ...... 10
Scheme 1.12. Copper catalyzed cyclopropanation of styrene ...... 12
Scheme 1.13. Synthesis of 2,4,6-phosphinine ...... 14
Scheme 1.14. Synthesis of phosphinine ...... 14
Scheme 1.15. Synthesis of phosphinine from phosphaalkynes ...... 15
Scheme 1.16. The [5+1] condensation route to substituted pyridines ...... 17
Scheme 1.17. The Hantzsch reaction ...... 17
Scheme 1.18. The [3+3] condensation route to substituted pyridines ...... 17
Scheme 1.19. The [4 + 2] inverse electron demand aza-Diels-Alder reaction ...... 18
Scheme 2.1. Synthesis of biscamphorpyrylium salt ...... 21
Scheme 2.2. Pulegone alkylation ...... 22
x
Scheme 2.3. Halogenation attempt of 24 ...... 22
Scheme 2.4. Mechanism for nucleophilic substitution at a vinylic carbon ...... 23
Scheme 2.5. Vinyl halide route attempted by Bell in the synthesis of pyrylium 27 ...... 24
Scheme 2.6. Enolate trapping attempt ...... 24
Scheme 2.7. Synthesis of 29 from menthone ...... 24
Scheme 2.8. Proposed synthetic route for bis-pinenepyrylium salt ...... 26
Scheme 2.9. Mechanism for the formation of bis-allylic alcohol 30 ...... 27
Scheme 2.10. Retroaldol mechanism to produce nopinone ...... 27
Scheme 2.11. Alcohol protection attempts for 31 ...... 28
Scheme 2.12. Olefin metathesis/oxidation-ring opening attempt ...... 28
Scheme 2.13. Synthesis of 2,3,4,6-tetraphenylpyrylium tetrafluoroborate (36) ...... 28
Scheme 2.14. Chalcone attempts ...... 29
Scheme 2.15. Self-condensation mechanism of chalcone ...... 30
Scheme 2.16. Synthesis of pyrylium 38...... 30
Scheme 2.17. Synthesis of symmetric pyrylium 39 ...... 30
Scheme 2.18. Functionalizable pyrylium salts derived from -tetralone ...... 31
Scheme 2.19. Synthesis of 2-tert-butyl-4,6-diphenyl-pyrylium tetrafluoroborate (42) .....31
Scheme 2.20. Synthesis of 2,6-di-tert-butyl-4-methyl-pyrylium (43 and 44) ...... 32
Scheme 3.1. Preparation of asymmetric pyryliums from dypnone ...... 34
Scheme 3.2. Amine-catalyzed epimerization mechanism ...... 37
Scheme 3.3. Synthesis of substituted asymmetric phosphinines (46a-f) ...... 38
Scheme 3.4. Synthesis of substituted asymmetric pyridines (47a-f) ...... 40
Scheme 3.5. Formation of triphenyl pyrylium salt from dypnone ...... 40
xi
Scheme 3.6. Synthesis of symmetric pyryliums from tert-butanol ...... 41
Scheme 3.7. Synthesis of symmetric pyridines ...... 45
Scheme 4.1. Mechanism of methyl deuteration by isotopic exchange with D2O ...... 47
Scheme 4.2. Proposed mechanism of equilibration of pyryliums with base ...... 49
Scheme 4.3. Amine-catalyzed epimerization mechanism for pyrylium 45d ...... 57
Scheme 4.4. Amine-catalyzed epimerization mechanism for pyrylium 49a ...... 59
Scheme 4.5. Amine-catalyzed epimerization mechanism for pyrylium 49b ...... 61
Scheme 5.1. Proposed synthesis for pyryliums derived from Combretastatin A-4 ...... 65
Scheme 5.2. Synthesis of deoxybenzoin analogues 59 and 60 ...... 66
Scheme 5.3. Synthesis of pyrylium 61...... 66
Scheme 5.4. Synthesis of pyrylium 62...... 66
Scheme 5.5. Synthesis of pyridiniums 65 and 66 ...... 67
xii
LIST OF ABBREVIATIONS