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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.

iv

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

v

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

vi

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

vii

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

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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

ix

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

x

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

xi

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

xii

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

xiii

LIST OF ABBREVIATIONS average

Ac acetyl Ac2O acetic anhydride BINOL-PCl 2,2_-Binaphthylene phosphorochloridite n-Bu normal butyl t-Bu tertiary butyl oC Celsius cat. catalytic d. density DMAP dimethylamine pyridine DME dimethoxyethane DMF dimethylformamide ee enantiomeric excess equiv equivalents EI electronic ionization ESI electrospray ionization Et ethyl EtOAc ethyl acetate EtOH ethanol g grams GC gas chromatography

xiv

GC-MS gas chromatography-mass spectrometry h hours HPLC high performance liquid chromatography HRMS high resolution mass scpectrometry Hz hertz IC50 half maximal inhibitory concentration J coupling constant L liters LDA lithium diisopropyl amide M molarity min minute mg miligram mL milliliter mmol milimole L microliter Me methyl m.p. melting point MS mass spectrometry NMR nuclear magnetic resonance ppm parts per million Ph phenyl PCC pyridinium chlorochromate St. d. standard deviation

xv

TEA triethylamine TBS tert-butyldimethylsilyl THF tetrahydrofuran TLC thin layer chromatography TMEDA tetramethylethylenediamine TMS trimethylsilyl Tf2O trifluoroacetic anhydride

xvi

ACKNOWLEDGMENTS

I would like to acknowledge and thank my advisor Dr. Charles Garner for his

support, his enthusiasm, his patience and, more importantly, for letting me satisfy my

intellectual curiosity by allowing me to experiment with my own ideas in the lab. Your

guidance has helped make me a more analytical and critical-thinking scientist and person.

Thank you for believing in me and for giving me the opportunity to become part of your

group. I really enjoyed working with you.

I am also thankful to the members of my committee Drs. Darrin Bellert, Kevin

Pinney, Bob Kane, and Bessie Kebaara. Thank you for your time and ideas during this

project and for helping me complete the last requirement of my Ph.D. by serving as my

dissertation committee members. In particular, I would like to thank Dr. Darrin Bellert

for his time and dedication to help me solve the complex kinetic problem that was

presented in this dissertation; I certainly could not have done it without your help.

I would like to thank the Donors of the American Chemical Society Petroleum

Research Fund (grant #47942-AC1) and the Robert A. Welch Foundation (grant #AA-

1395) for supporting this research.

I would like to thank Dr. Carlos Manzanares for giving me the opportunity to

become part of this institution, for his support and also for his kinetic class; I hope that

the kinetic portion of my dissertation proves that I really learned the material from his

class. I hope that I did not disappoint you.

xvii

The faculty, in particular, I would like to thank Dr. Chambliss, Dr. Riz

Klausmeyer, Dr. Shaw, Dr. Primrose, and Dr. Jones. Thank you for your guidance,

support and friendship.

Special thanks to the past and present members of the Garner group. Thank you

for providing support, motivation, friendship and hours of laughter throughout this

process. Jason Bell and his family, for your friendship, all your help and being there

when I needed. Dana Horgen, for your friendship, motivation, being there when I needed,

for your help editing my English and any idea that came out of my head. Sheree Allen,

for supporting me, and for your friendship. Tiffany Hayden (Turner), thanks for inspiring

me and motivating me. Nathan Duncan, thanks for your help and guidance. Eric Bauch,

for your friendship. Matthew Jackson and Molly Hutcherson, welcome to the group! I

wish you the best in this long and exciting journey. Please do not hesitate to ask for help

as I will always be available for you. I would like to give special thanks to Holland

Korbitz, it was a real pleasure to work with you. I have no doubt that you will be

successful in any project or goal that you embark on. I learned a lot from you and I hope

that you had a great time working with me in the lab. The lab would be empty if we did

not have the great undergrads that work or worked here; thanks to Adam Gann, Jason

Schaffer (Ginger), Harry Shen, Priscila Delgado, Alice Crain, Mariel Valdez, Clara

Dutton, Eric Wallace, Jason Stanton, Julia Vickery and Jessica Almond.

I would also like to thank the staff, without them we would be lost in space,

Nancy Kallus, Adonna Cook, Barbara Rauls, Virginia Haynek, Craig Moehnke, Jim

Karban, Cody Rogers, Andrea Johnson and Natalia Anderson.

xviii

I am deeply thankful to my family for their constant support and encouragement

throughout my life and especially while I pursued this degree. Mom and Dad, I cannot

thank you enough for the support and the love you have given me. Thank you both for the

way that you raised me, for motivating me to improve myself every day and for

cultivating my curiosity for learning about different subjects and cultures. Someday, I

hope I can raise my children the way that you have raised me. Thank you Sister for

always being there, for supporting me and motivating me when I needed, but especially

thank you for bringing Christian into this world. I love him deeply and my life certainly

changed the day he was born. Thanks to my brother-in-law Christian, also for motivating

me.

My life time friends, which are my second family. I would have not been able to

get here without your constant support, motivation, brotherly love and great times. I hope

one day we can all live in the same place again. Special thanks to Jean Phillip (Pipo), for

inspiring me and motivating me to get my Ph.D. and for the long discussions of

chemistry; Carlos (Carlitos) and Bethzabé, Alberto (chiquito), José (Gordito), Adriana

(Bombón) and Camille, Daniel, Paola and Samuel, Satur and Angela, Javier and Laura,

Jair, Petey, Oswaldo and Lizmara, Jorge, Juan Carlos (Huerta), Miguel Angel (Cecoto),

Jesús, Carlos (Patata), Amilcar, Alejandro, Alfonso, Ivanny, Iván and Katherine, Manuel,

Tato, Marcela, Mary Joelle, Nenela, Nando and Ivonne. I would also like to thank their

families.

To my friends here at Baylor, I owe you special thanks for being there and

supporting me every day during these past five years. Katie Benjamin, for supporting and

motivating me these past months when I really needed it. Thank you for all of your help

xix

correcting and editing my English. To Ots, Austin, Ivanna, David, Alfredo (Light bulb),

Denka, Mieke, Alejandro, Gustavo, Franklin, Pilar, Roberto (Bobby), Gennie, Alexandra,

Lindsay, Sara, Tara, Alonso, Francisco, Daniel, Gabriela, Jenny, Sergio (Inca), Gerda,

Carrie, Christine, Lauren, Jele, Querube, Csilla, Diana, Taylor (TO), Karo, Sarah Bliss,

Gilda and María.

Thanks to my extended family, my uncles and aunts, Hector, Charo, Luis,

Manuel, Conchita, Alicia, Gloria, Yolanda and Jesús. Thanks to my cousins, Hector and

Gilder, Patricia, Jesús and Michelle, Juan, Mireya, and Mercedes.

Thanks to my friends from college and back home. Eugenio, Sorena, Natalia,

Tito, Isabella, Nutabi, Jhom, Rauseo, Enif, Gaby, Chuo, Jimmy, Desirée, Miloa, Gabriel,

Israel, Rafael, Oscar, José Antonio, Orlando and Leonardo.

Special thanks to my professors from college for inspiring me and creating a

curiosity for chemistry within me. Drs. María Rodriguez, Masahisa Hasegawa, María

Ranaudo, Gastón Escobar, Julio Osuna, Reinaldo Compagnone, Bernardo Mendez and

Luis Cortés and Valentina de Sola.

My High School Colegio San Agustin del Paraiso, for providing me my first

contact to science and to inspiring me to study chemistry. Special thanks to Abel

Valdivieso, Jose Gonzalez, Marina Fuentes, and Jose Silva.

Thanks to my Waco friends for making me feel at home. Ed, Brett, Kenny, Tom,

Kim, Robert, Troy, Mark, Charles, James, Bobby, Bill, Tim, Mark and Gary.

I know that I might be forgetting people, but I want to thank all of you for your

support and encouragement.

xx

DEDICATION

To

My grandparents

Esperanza, Perina and Hector

Thank you for all the time that we spent together, and thank you for teaching me the meaning of love, family values, compassion, dedication and hard work

1

CHAPTER ONE

Introduction

Background

Pyrylium salts are six-membered hetereoaromatic compounds with a positive

charge located on the oxygen (Figure 1.1).1 The counteranions must be non-nucleophilic,

with the most common being the halides, tetrafluoroborate, perchlorate,

hexafluorophosphate, bisulfate, and triflate.1 The oxygen atom in the pyryliums

represents the most electronegative heteroatom found in an aromatic ring. Although

fluorine is the most electronegative element found in the periodic table, it cannot become

sp2-hybridized.1

Figure 1.1. Pyrylium salt. Due to this remarkable electronic perturbation, pyryliums react quite differently

than analogous benzene or pyridine compounds. This reactivity results from both the

polarization and the limited aromaticity of the pyrylium ring; the latter has been

estimated to be as low as 56% of that of benzene.2 Pyryliums are susceptible to

nucleophilic attack at the positions 2, 4 and 6 of the ring. Due to the low aromaticity of

the pyrylium, the ring is easily opened upon nucleophilic attack at the alpha-position

(unlike analogous compounds, benzene or pyridine), yielding a 1,5-diketone. Depending

2

on the stability of the 1,5-diketone three possibilities can occur; it can remain as the

diketone, recyclize by dehydration to reform the pyrylium ring, or form a non-

heteroaromatic compound (Scheme 1.1).

Scheme 1.1. Example of a nucleophilic substitution to a pyrylium ring.3

In contrast, due to the electronic deficiency of the pyrylium ring, electrophilic

aromatic substitutions occur only when several electron-donating substituents, such as

dialkylamino groups, are present in the 2, 4, or 6 positions of the ring (Scheme 1.2).4

Scheme 1.2. Example of an electrophilic substitution on a pyrylium ring.4

Although the positive charge of the pyrylium ring is located on the oxygen, this

charge is delocalized over positions 2, 4 and 6 (Figure Scheme 1.3). This provides an

explanation for the susceptibility of these positions for nucleophilic attack.

Scheme 1.3. Resonance structures of the pyrylium cation.

3

Predominantly, the -positions (2 and 6) are more reactive towards nucleophiles

than the -position (4). The electron deficiency located at the -positions is caused by the

vicinal oxygen atom and by resonance, and is more pronounced than in the -position;

this was confirmed by NMR spectroscopy and theoretical calculations.1 The positive

charge on the pyrylium ring causes a strong electron withdrawing effect on the system

that is clearly observed by NMR (1H and 13C) (Figure 1.2). These data agree with the

electrophilicity of the -positions.

Figure 1.2. 1H and 13C chemical shifts of an unsubstitued pyrylium salt.1

An interesting feature of the chemistry of the pyryliums is that because of their

salt character they are insoluble in non-polar organic solvents, such as diethyl ether. This

represents a tremendous advantage because both starting materials and byproducts can be

easily removed from crude reaction mixtures, providing high purity products without the

need of expensive or tedious purification techniques. However, polymerization can

compete with cyclization and is a major complication in some pyrylium synthesis, as it

results in tar formation.

Although it was not identified at the time, the first pyrylium was observed by von

Kostanecki and Rossbach in 18965 as a strong green fluorescent material formed when

treating acetophenone with sulfuric acid. It was not until 1916 that Dilthey6 recognized

that the fluorescence was caused by compound 1 (Figure 1.3). Sulfuric acid acted as a

4

condensing agent by both dehydrogenating and dehydrating the intermediates, yielding

the pyrylium salts.

Figure 1.3. 2,4,6-triphenylpyrylium.6

In addition to pyrylium salts’ fluorescent character, which is utilized in

photosensitizers in electrophotography, fluorescent dyes, and laser dyes, pyryliums have

also been used as anticorrosives, photoinduced electron-transfer agents for initiating

polymerizations and photo-cross-linking agents.7

Pyrylium salts are mainly of value because of the ease of replacement of the

oxygen with nucleophilic atoms. This feature allows pyryliums to be precursors to a wide

variety of heterocyclic systems, including pyridines, pyridiniums, thiopyryliums, and the

relatively unknown phosphinines (phosphabenzenes).1, 7 In addition, carbon nucleophiles

can convert pyryliums into benzene derivatives3 and in some cases allow production of

azulenes (Figure 1.4).8

It is not unexpected that the number of publications on properties and reactions of

pyrylium salts have increased rapidly during the last 100 years (Figure 1.5). The upward

trend began in the fifties spurred by work of Balaban, Prail, Nenitzescu, and Dimroth.

The peak, found in the seventies, was due to Katrikzky’s and Balaban’s contributions.9

Because of the difficulties in synthesizing these compounds, the amount of research in

1

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Synthesis

Some pyryliums (especially 2,4,6-triaryl ones) are easily prepared, for example,

by the acid promoted condensation of acetophenone. But other pyryliums require more

careful synthetic approaches.

Retrosynthetic analysis of the pyrylium salt suggests a C5 synthon (Scheme 1.4),

an unsaturated 1,5-diketone. To make this precursor, two possible approaches can be

envisioned: two synthons [C1 + C4] or [C2 + C3] and three synthons [C1 + C3 + C1], [C2 +

C2 + C1] or [C2 + C1 + C2].1

Scheme 1.4. Retrosynthetic analysis for pyrylium salts.

Pyrylium formation is catalyzed by Lewis or Brønsted acids. The most common

Lewis acids employed include boron trifluoride-diethyl ether complex (BF3•OEt2),

antimony (V) chloride (SbCl5), iron (III) chloride (FeCl3), aluminum trichloride (AlCl3),

[C1 + C4] [C2 + C3]

7

tin (IV) chloride (SnCl4) and zinc (II) chloride (ZnCl2). The most common Brønsted acids

include 70% aqueous perchloric acid (HClO4), 96% sulfuric acid (H2SO4),

tetrafluoroboric acid (HBF4) (48 % aqueous solution or 40% solution in anhydrous

diethyl ether), 60% aqueous hexafluorophosphoric acid (HPF6) and

trifluoromethanesulfonic acid (CF3SO3H).

Two Synthons

The [C1 + C4] route involves the acylation of an ,-unsaturated ketone (in

equilibrium with the ,-unsaturated ketone isomer) (Scheme 1.5). The acylating agents

are carboxylic acid derivatives such as acyl chloride and anhydrides. When using an

anhydride, either Lewis or Brønsted acids can be employed as catalysts, whereas the acyl

chloride only works when a Lewis acid is used.

Scheme 1.5. Example of synthesis of pyryliums employing a [C1 + C4] route.10

For the [C2 + C3] route, two different approaches can be utilized. The Michael

addition of a methyl(ene) ketone to an ,-unsaturated ketone (or a synthetic equivalent)

with subsequent dehydrocyclization, or the condensation between a 1,3-diketone (or a

synthetic equivalent) and a methyl(ene) ketone (Scheme 1.6).

8

Scheme 1.6. Example of synthesis of pyryliums employing [C2 + C3] route.11

Three Synthons

The one-pot reaction with three synthons occurs in two steps. First, formation of

the ,-unsaturated ketone intermediate from two synthons followed by subsequent

Michael addition of the remaining component. The three synthons route possibilities are:

[C1 + C3 + C1], [C2 + C2 + C1] (Scheme 1.7) or [C2 + C1 + C2] (Scheme 1.8).

Scheme 1.7. [C1 + C3 + C1] and [C2 + C2 + C1] synthons approach.

The [C1 + C3 + C1] route begins with the acylation of an alkene (Scheme 1.9).

This method is preferred when symmetrical alkyl substituents compounds are desired

(same substituents in positions 2 and 6).

[C1 + C3 + C1]

[C2 + C2 + C1]

9

Scheme 1.8. [C2 + C1 + C2] synthons approach.

Scheme 1.9. Example of synthesis of pyryliums employing [C1 + C3 + C1] route.

The [C2 + C2 + C1] method begins with the condensation of two molecules of a

methyl(ene) ketone. This method is preferred when asymmetric compounds are desired

(Scheme 1.10).


The [C2 + C1 + C2] method involves aryl methyl(ene) ketones and aromatic

aldehydes or trialkylorthoformates. The mechanism is similar to the [C2 + C2 + C1]

Cl

O+2

O

Ph

Ph

FeCl3

FeCl4

Ph

O

10

method. This route is preferred when symmetrical aryl substituents compounds are

desired (same substituents located in positions 2 and 6) (Scheme 1.11).


Chiral Pyrylium Salts

Considering the importance of pyryliums as precursors to other heteroaromatic

compounds, it is surprising that chiral pyrylium salts are almost unknown in the

literature. Perhaps the lack of progress in this field is due to difficulties often encountered

in the synthesis of non-aryl-substituted pyryliums, resulting in tars due to polymerization.

To date only three examples have been reported (Figure 1.6): a C2-chiral pyrylium

recently synthesized in our group (2),12 a racemic atropisomeric example (3)13 and an

unsymmetrical chiral camphor derivative (4).14

Figure 1.6. Existing chiral pyryliums.12-14

2 3 4

11

Metal-catalyzed Asymmetric Synthesis

Asymmetric catalysis is one of the most powerful methods used for synthesizing

enantiomerically pure compounds. It consists of the addition of small amounts of a chiral

promoter to produce chiral compounds in relatively large quantities. This chiral promoter

is generally a metal complex. The catalytic activity is generally determined by the

metallic center, while the enantioselectivity is controlled by chiral organic ligands that

are coordinated to the metallic center. The last four decades has seen intensive

development of new catalysts to obtain highly enantiomerically pure compounds. In fact,

the importance of asymmetric catalysis was highlighted with the Nobel Prize for

Chemistry in 2001 to Noyori, Knowles, and Sharpless for their work in the area.

The first report of a metal-mediated asymmetric catalysis was by Noyori in 1966

(Scheme 1.12).15 A modest enantiomeric excess of 6% was obtained by a chiral copper

complex in the cyclopropanation of styrene with ethyl diazoacetate. The ligand was a

chiral imine made from salicylaldehyde and -methylbenzylamine. Many advances have

been made since, and now several types of reactions have reliable asymmetric variants

available.

Although natural product derivatives were widely employed as ligands in

asymmetric synthesis at the early stages, researchers soon realized the limitations of the

structural diversity of the “chiral pool”. New and creative ligand designs have

incorporated atoms such as P, N and S, and this has increased the variety of ligands

exponentially, therefore widening the scope of asymmetric catalysis.16

When designing ligands an important feature to consider is the symmetry. C2-

symmetric complexes have been shown to have better performance than non-symmetric

12

types. C2-symmetric complexes have less substrate-metal interactions, thus decreasing

the number of ways an undesirable enantiomer might be formed.

Scheme 1.12. Copper catalyzed cyclopropanation of styrene.15

Phosphinines

Background

Phosphinines are the phosphorus analog of pyrydines. The aromaticity calculated

is 97% of that of benzene. In 1966 Märkl17 synthesized the first substituted phosphinine

(5), and later (1971) Ashe18 reported the unsubstituted parent 6 (Figure 1.7).

Figure 1.7. 2,4,6-triphenylphosphinine (5) and phosphinine (6).17-18

5 6

13

Phosphinines show interesting electronic properties that differ markedly from the

pyridines. Interestingly, the phosphorus lone-pair occupies the HOMO-2 orbital, which is

more diffuse and less directional than that of its nitrogen counterpart. This translates into

phosphinines having poor -donating ability. On the other hand, the LUMO orbital of

phosphinine is located in a lower energy level compared to the LUMO of pyridine,

making phosphinines comparatively strong -acceptors.19

The phosphinines’ combination of poor -donating ability with strong -

accepting capacity makes them attractive ligands for electron-rich metal centers, creating

strong back donation interactions. It has been observed that phosphinines coordinate

more readily with the electron rich late transition metals such as nickel, palladium,

platinum, and rhodium. Phosphinines are non-basic (pKa of C5H6P+ = -16.1) and non-

nucleophilic due to their poor -donating ability, unlike the pyridines and phosphines.19-

20

Synthesis

Pyrylium method. The first reported phosphinine (5) was synthesized by Märkel

from 2,4,6-triphenyl pyrylium (1) and tris(hydroxymethylene)phosphine (P(CH2OH)3) in

refluxing pyridine (Scheme 1.13). Loss of the formaldehyde leaving group regenerates

the nucleophilic lone pair for subsequent attacks.17

Other reagents used to form phosphinines are phosphine (PH3),21 phosphonium

iodide (PH4I),21 and tris(trimethylsilyl)phosphine (P(TMS)3).

22 Phosphine gives the

highest yields but its use is avoided because its toxicity and pyrophoricity, and the

difficulty in handling gases. The most commonly employed reagent despite its pyrophoric

14

property is P(TMS)3. Typical yields are low to moderate (10-50%) but the non-polar

phosphinines can be obtained in high purity by column chromatography.

Scheme 1.13. Synthesis of 2,4,6-phosphinine.17

Dibutyl-dihydrostannine method. This method was employed by Ashe to obtain

the unsubstituted phosphinine. A dialkyne was reacted with dibutylstannane to form a

stannacyclohexadiene intermediate.18 Subsequent Sn/P exchange and treatment with base

furnished phosphinine (Scheme 1.14).18 It is important to note that the pyrylium method

could not have been used due to the instability of the unsubstituted pyrylium.

Scheme 1.14. Synthesis of phosphinine.18

Phosphaalkyne method. Phosphaalkynes can be combined with various 1,3-dienes

to obtain phosphinines (Scheme 1.15). Examples of the dienes employed are: pyrones,

1,3-cyclohexadienes, and activated cyclopentadienes.19

Different substituents on the phosphinines can be obtained by this method;

however, the limitation of this route is that a t-butyl group is always present ortho to the

phosphorous.

1

15

Scheme 1.15. Synthesis of phosphinine from phosphaalkynes.19

Chiral Phosphinines

Only a few examples of chiral phosphinines have been reported in the literature.

The phosphorus is relatively far from the chiral centers in the majority of these ligands

(Figure 1.8).22b, 23 Incorporation of chirality directly (i.e., alpha to aromatic ring) onto

these planar ring systems has proven to be difficult.

Muller and Vogt13 developed an atropisomeric example (11); this was the first

phosphinine made that had the chiral information in close proximity to the phosphorus.

They introduced substituents in specific positions in both the alpha aryl substituent and

the heterocycle to generate axial chirality. The first C2-symmetrical phosphinine (12) was

recently made in our group by Bell12 from the corresponding pyrylium salt.

16

Figure 1.8. Existing chiral phosphinines.

Pyridines

Background

Pyridine is a six-member heteroaromatic ring with a lone pair of electrons

localized on the nitrogen atom. Pyridine is considered a weak base with a pKa = 5.1, and

a good ligand which forms complexes with various metals.

The first pyridine isolated was picoline in 1846 by Anderson. The elucidation of

the structure by Körner and Dewar in 1869 and 1871, respectively, marked the

inauguration of pyridine chemistry.24 Pyridines are an important class of heteroaromatic

compounds found in natural products, pharmaceuticals, and catalysts.25

Synthesis

Classical synthetic methods to obtain pyridines are based on condensations of

amine and carbonyl compounds. Typically ammonia is most frequently used as the

nitrogen source, but other alternatives like alkyl or vinyl amines are employed as well.24

7 8

9

10 11 12

17

The [5+1] condensation route.24 A 1,5-diketone refluxed with ammonium acetate

and acetic acid furnishes a tetrahydroquinoline, as shown in Scheme 1.16.

Scheme 1.16. The [5+1] condensation route to substituted pyridines.24

The Hantzsch reaction.24 This reaction allows the preparation of pyridine

derivatives through the condensation of an aldehyde with two equivalents of a β-ketoester

in the presence of ammonia. Subsequent dehydrogenation/aromatization gives pyridine-

3,5-dicarboxylates, which may be further decarboxylated (Scheme 1.17).

Scheme 1.17. The Hantzsch reaction.24

The [3+3] condensation route.24 This method consists of a 1,3-dicarbonyl

derivative condensation with a vinylogous amide, as displayed in Scheme 1.18.

Scheme 1.18. The [3+3] condensation route to substituted pyridines.24

O H

OR

H

EtO2C

O R

CO2Et

NH

EtO2C CO2Et

RR

NH3

N

EtO2C CO2Et

RR

HNO3

18

The [4+2] inverse electron demand aza-Diels-Alder reaction.24 Developed by

Boger26 in 1982, this reaction consists of an inverse electron demand aza-Diels-Alder

reaction between enamines and 1,2,4-triazine (Scheme 1.19).

Scheme 1.19. The [4 + 2] inverse electron demand aza-Diels-Alder reaction.24

Chiral Pyridines

Their high stability against moisture and oxygen, and their extensive coordination

chemistry make pyridines attractive ligands for metal-catalyzed asymmetric catalysis.27

The first report of the use of a chiral pyridine (13) for catalysis was in 1981 (Figure

1.9);28 however, the first chiral pyridines (14, 15) were reported in 1974.29

Figure 1.9. First chiral pyridines reported.28-29

Pyridine rings can be incorporated into a large variety of polydentate ligands such

as bipyridines (bipy) (16)30 and terpyridine (terpy) (17) (Figure 1.20).31

13 14 15

19

Figure 1.10. Chiral bipyridines and terpyridines reported.

Chiral pyridines have been studied much more than their phosphorus analogues,

the phosphinines. Interestingly, no examples can be found in the literature that involves

the conversion of chiral pyrylium salts to the corresponding chiral pyridines.

Novel Pyrylium Salts and Their Corresponding Phosphinine and Pyridine

Derivatives

Despite the fact that pyrylium salts are precursors of phosphinines and pyridines,

which are of interest for metal-catalyzed asymmetric reactions, it is surprising that to date

only three chiral pyrylium salts have been reported.

One of the goals of this project is to synthesize new pyrylium salts with chirality

located as close as possible to the oxygen (18, 19). The production of such pyrylium salts

would subsequently allow us to obtain the corresponding chiral phosphinines and

pyridines. It is surprising that there are very few examples of chiral phosphinines

reported. The phosphorus is relatively far from the chiral centers in the majority of these

ligands. Furthermore, this will be the first time that chiral pyridines are obtained from

pyryliums.

In addition, we are interested in study the configurational stability of chiral

centers alpha to the pyrylium ring, including those with hydrogens present that could

undergo epimerization. Epimerization of pyrylium has not been studied (because so few

16 17

20

chiral examples), though deuterium incorporation experiments suggests that

epimerization should be possible, even rapid.

Figure 1.11. Proposed chiral pyrylium salts that are the focus of this work.

18 19

21

CHAPTER TWO

Early Attempts to Synthesize Unsymmetrical and Symmetrical Chiral Pyrylium Salts

Menthone/pulegone Route

The first attempt to synthesize a chiral pyrylium salt was inspired by a method

developed in our group by Bell et al.12 to synthesize (+)-biscamphorpyrylium salt

(Scheme 2.1). In this method, the natural product (+)-camphor is used as the starting

material due to its availability in enantiomerically pure form and low cost. Our early

attempts to obtain symmetrical chiral pyrylium salts focused on (+)-pulegone, which is

commonly found in nature, and (-)-menthone (100% ee) which is obtained from the

oxidation of (-)-menthol.

Scheme 2.1. Synthesis of biscamphorpyrylium salt.12

It was first attempted the alkylation of (+)-pulegone via a 1,4-addition employing

Grignard reagents with the aid of copper (I)32 to obtain 22 in 82% yield and 23 in 75%

yield (Scheme 2.2). These two compounds, along with menthone, were utilized as the

starting materials in the attempt to synthesize symmetric pyryliums.

21

2

20

22

Scheme 2.2. Pulegone alkylation.

The first step in the synthesis was the formation of 2-benzoylmenthone (24)

(Scheme 2.3).33 The enolate was generated under kinetic control by slowly adding

menthone to 1.1 equiv. solution of LDA prepared in situ at -78oC.34 These conditions

were used in order to avoid as much epimerization of the alpha-chiral center as possible.

Benzoyl chloride was then added to trap the enolate. The 1,3 diketone 24 was obtained in

30% yield, and no O-acylation product was observed by GC-MS and NMR. This O-

acylation product would have shown one olefinic proton in the 1H NMR. Unfortunately,

when the diketone 24 was refluxed with PCl3 in excess, none of the desired vinyl chloride

25 product was observed by GC-MS. Attempts utilizing PBr3 were unsuccessful as well.

Scheme 2.3. Halogenation attempt of 24.

One of the requirements for the formation of vinyl chloride 25 is that the diketone

24 has to be in the enol form as shown in Scheme 2.4. The hydroxyl group undergoes

nucleophilic substitution at the vinylic carbon by chlorine. This reaction occurs under an

addition-elimination mechanism. When analyzing diketone 24 by NMR a doublet at 4.03

ppm was observed, corresponding to the methine group alpha to both ketones coupled to

24 25

23

the vicinal methine (position 3 of the ring). The same spectral information for diketone

24 was reported by Hosomi.33a This provides clear evidence of the presence of the 1,3-

diketone, rather than the expected enol. The enol would not have shown any protons

between 4-7 ppm (corresponding to the olefinic region).

Scheme 2.4. Mechanism for nucleophilic substitution at a vinylic carbon.

Similar problems were experienced by Bell when attempting to synthesize

pyrylium 27 (Scheme 2.5).35 The benzoylcyclohexanone 26 also appears to exist

exclusively as the diketone, which fails to form the desired product, instead of the enol

form. In contrast, benzoylcamphor 20 was successfully transformed into the desired vinyl

chloride 21 and by 1H NMR is seen to exist exclusively as the enol form instead of the

diketone tautomer.36 This provides an explanation regarding the lack of reactivity of

diketone 24 towards halogenating agents.

We tried to form the enolate of the diketone 24 followed by the trapping with

triflic anhydride in order to obtain the vinyl triflate 28 as shown in Scheme 2.6 (O-

alkylation of enolates is well-known under these conditions).37 This triflate could act as a

leaving group in the next step of the synthesis much as chlorine would. However, several

24

attempts with different bases (TEA, NaH and Na2CO3) failed to produce the desired vinyl

triflate 28 (checked by GC-MS), and only starting material was recovered.

Scheme 2.5. Vinyl halide route attempted by Bell in the synthesis of pyrylium 27.35

Scheme 2.6. Enolate trapping attempt.

The next approach attempted was to form the 1,5-diketone, 29, by using two

equivalents of menthone and one equivalent of benzaldehyde (Scheme 2.7). This route

was inspired by the synthesis of pyrylium 27 by Bell (Scheme 2.5), obtained in 27%

yield.35 The benzoylmenthone reaction was monitored by GC-MS and the product was

observed in a 15% yield. The product yield was unable to be improved by changing

reaction conditions.

Scheme 2.7. Synthesis of 29 from menthone.

27

28

29

26

25

Pinene Route

The next attempt was to prepare 1,5-diketone, 30, from a bis-allylic alcohol (31)

obtained from (-)--pinene (Scheme 2.8).38 This method was designed to obtain the

diketone in a two-step procedure, hopefully allowing formation of the pyrylium salt

conveniently by using HBF4 or HClO4. The bis-allylic alcohol 31 was prepared by first

reacting (-)--pinene with n-butyllithium in the presence of TMEDA (allylic metalation)

to obtain the intermediate pinenyllithium•TMEDA complex 32.38 Allylic lithium

compounds have been studied extensively, and they are regarded as -anions, existing as

3-complexes.39 This delocalization would potentially produce a mixture of isomers when

complex 32 is treated with an electrophile. To control the regiochemistry, the complex 32

was treated with MgBr2 to obtain the corresponding allylic Grignard 33, which is

believed to be a -bonded species.40 The reaction of these allylic Grignards to carbonyls

typically proceeds by allylic rearrangement to give substitution at the most substituted

allylic carbon, due to magnesium’s preference to bond to the terminal and least

substituted allylic carbon.38, 40 Allylic Grignard 33 reacts twice with esters as expected,

forming a connecting bridge between two individual pinene rings (Scheme 2.9).38

The next step of the synthesis was the oxidation of the terminal olefins of bis-

allylic alcohol 31 to produce the diketone 30. Although we tried several oxidative

methods41 that are known to perform the oxidation of olefins to ketones, all failed to give

the desired product, or showed no reactivity. These results are summarized in Table 2.1

below. The reactions were monitored by GC-MS and TLC, and in some cases we saw

mixtures of nopinone and unreacted starting material. We believe that the product, when

26

formed, undergoes a retro-aldol type reaction, producing nopinone rather than the desired

product (Scheme 2.10).

Scheme 2.8. Proposed synthetic route for bis-pinenepyrylium salt.

To avoid the retro-aldol reaction, we studied protecting the hydroxyl group of 31

by methylation or acetylation (Scheme 2.11). Unfortunately, neither of these methods

worked; only starting material was recovered. This is possibly due to the steric hindrance

around the hydroxyl group.

Another approach was to first attempt a ring-closing metathesis employing second

generation Grubbs catalyst and then perform oxidative ring opening with ozonolysis

(Scheme 2.12). It was decided to use second generation Grubbs catalysts because it has

known high reactivity when performing ring closing reactions.42 Several ring closing

metathesis attempts were made, yet only the starting material was recovered from this

reaction. We believe that the bis-allylic alcohol 31 is too sterically hindered to perform a

ring closing to obtain a five membered ring.

31 30

27

Scheme 2.9. Mechanism for the formation of bis-allylic alcohol 30.38

Table 2.1 Reagents used for the attempted conversion of 31.

Reagent Result

O341a GC-MS 50% nopinone, 27% starting material

KMnO4/Al2O3(H+)41b No reaction

NaIO4/RuCl3·H2O41c GC-MS 30% nopinone, 13% starting material

OsO4/NaIO4/pyridine41d No reaction

OsO4/NaIO4/2,6-lutidine41d GC-MS 30% nopinone, 13% starting material

Scheme 2.10. Retroaldol mechanism to produce nopinone.

32 33

31

28

Scheme 2.11. Alcohol protection attempts for 31.

Scheme 2.12. Olefin metathesis/oxidation-ring opening attempt.

Chalcone Route

Chalcone (34) reacts with ketones in the presence of Lewis acids to produce

pyrylium salts.11 This method was explored in order to obtain symmetrical and

unsymmetrical chiral pyrylium salts. The first attempt was a model reaction between the

enone 34 and deoxybenzoin (35), producing pyrylium 36 in 43% yield (Scheme 2.13).11

Scheme 2.13. Synthesis of 2,3,4,6-tetraphenylpyrylium tetrafluoroborate (36).11

Due to the success of the model reaction, we decided to use some of the chiral

ketones described above. Enone 34 was treated with (-)-menthone, methylated 22 and

OH

GrubbsX

OH[O]

O

OOH

34 35 36

29

phenylated 23 derivatives in the presence of BF3•Et2O as shown in Scheme 2.14. All of

the attempts failed to produce a desired product. Rather, the reaction produced pyryliums

1 and 37.

Scheme 2.14. Chalcone attempts.

Enone 34 was also reacted with BF3•Et2O without a ketone, obtaining pyryliums 1

and 37 as well. From these attempts, we concluded that the ketones were not reactive

enough to perform a Michael addition to the -unsaturated enone 34, a necessary step

for the formation of the desired pyrylium. Enone 34 undergoes a BF3-catalyzed retroaldol

to produce acetophenone and benzaldehyde, which both react again with remaining enone

34 to furnish pyrylium 1.11 Also, enone 34 undergoes self-condensation catalyzed by BF3

to produce pyrylium 37 (Scheme 2.15).43

The next attempt was to use -tetralone as the building block for the pyrylium

salt. The known44 pyrylium 38 was prepared from enone 34, -tetralone and BF3•Et2O in

26% yield (Scheme 2.16).

The symmetrical pyrylium 39 was produced in 14% yield; this product was

similarly prepared from -tetralone and 2-benzyldine--tetralone (Scheme 2.17).44

Ph Ph

O

+

O

Ph

Ph Ph

BF3.OEt2

BF4

reflux

O

Ph

Ph Ph

BF4

PhO

R

R = -CH3 (22)-Ph (23)-H

+

1 37

30

Scheme 2.15. Self-condensation mechanism of chalcone.43

Scheme 2.16. Synthesis of pyrylium 38.44

Scheme 2.17. Synthesis of symmetric pyrylium 39.44

We envisioned that this route could be a convenient way to obtain pyrylium salts

that, when converted to the phosphinine derivative, can be easily functionalized by use of

a chiral auxiliary such as (s)-BINOL-PCl (40) to obtain chiral symmetric and asymmetric

ligands.45 A similar approach has been used by Müller and coworkers to obtain

phosphinine 10.22b

37

38

39

34

31

Scheme 2.18. Functionalizable pyrylium salts derived from -tetralone.

Figure 2.1. (s)-BINOL-PCl (40).

Furthermore, the reaction that was first developed by LeFevre46 and modified by

Katritkzky and co-workers10 that employs dypnone (41) and an acyl chloride in the

presence of the condensing agent BF3•Et2O to obtain asymmetric pyrylium salts was

explored (Scheme 2.19). The known pyrylium 42 was synthesized from pivaloyl chloride

and dypnone in a 30% yield.

Scheme 2.19. Synthesis of 2-tert-butyl-4,6-diphenyl-pyrylium tetrafluoroborate (42).

41 42

dypnone

32

This reaction would enable us to obtain chiral pyrylium salts in a one-pot reaction

starting from a chiral carboxylic acid and dypnone in moderate yields. More importantly,

this reaction could be performed without the use of a chiral auxiliary. This method was

pursued further with success and the discussion of the results will be presented (Chapter

Three).

[C1 + C3 + C1] Synthons Route

The three-synthon approach to obtain symmetric pyryliums was attempted. The

known symmetric pyrylium triflate 43 was obtained in 41% yield from a one-pot reaction

of tert-butanol and pivaloyl chloride, with triflic acid as the condensing agent.47 The

condensing agent was changed to tetrafluoroboric acid (ethereal solution) and the known

pyrylium tetrafluoroborate 44 was obtained in 56% yield (Scheme 2.20).

Scheme 2.20. Synthesis of 2,6-di-tert-butyl-4-methyl-pyrylium (43 and 44).47

This reaction would enable us to obtain symmetrical chiral pyrylium salts in a

one-pot reaction starting from a chiral carboxylic acid and tert-butanol in moderate yields

and with no need of chiral auxiliaries. This method was explored further with success and

the discussion of the results will be presented (Chapter Three).

33

CHAPTER THREE

Synthesis of New Chiral Pyrylium Salts and Their Phosphinine and Pyridine Derivatives

This chapter published as: van der Velde, Nelson A., Korbitz, Holland T., Garner,

Charles M. Tet. Lett. 2012, 53 (43), 5742-5743.

Asymmetric Compounds

Asymmetric Pyrylium Salts

The reaction of acyl chlorides with dypnone (41), first developed by LeFevre46

and modified by Katritkzky and co-workers,10 was found to be widely applicable to the

preparation of simple chiral pyryliums (Scheme 3.1). Four chiral pyryliums (45 a-d) and

two non-chiral examples (45 e,f) were made and characterized (Table 3.1).48 The yields

were modest (23-70%), as is typical for many pyrylium syntheses. The pyrylium

products were isolated by simple dilution with ether, taking advantage of their near-

universal insolubility in that solvent.1 The 13C NMR spectrum exhibited the characteristic

pyrylium peaks (165-185 ppm), further downfield than the typical aromatic region.

Pyryliums 45a and 45b were prepared from campholic and fenchoilic acids,

respectively, and derived from (+)-camphor and (-)-fenchone, respectively, by the

method of Whitesides.49 (+)-Camphor50 is regarded as enantiomerically pure material

while (-)-fenchone51 is commercially available as 96% ee. Pyrylium 45c was prepared

from ibuprofen. Pyrylium 45d was prepared from the commercially available 86:14

mixture of cis:trans 2-methylcyclohexanecarboxylic acid.52 We found that the cis isomer

had a larger coupling (7.1 Hz) for the methyl doublet than did the trans isomer (6.5 Hz),

and this was consistent (6.3-6.5 Hz) in all of the derivatives 45d, 46d and 47d, allowing

assignment of the stereochemistry. Also consistent was that the methyl doublet for the

34

cis isomer was always downfield of that for the trans. Finally, the benzylic tertiary

hydrogen in every case exhibited two large axial-axial couplings (11-15.6 Hz) consistent

with the trans isomer. Pyrylium 45e was isolated as a single diastereomer, even though it

was made from 4-tert-buytlcyclohexane carboxylic acid which was a 95:5 mixture of

trans:cis isomers.

Scheme 3.1. Preparation of asymmetric pyryliums from dypnone.48

It is evident from this work that pyryliums with alphachiral centers bearing a

hydrogen are relatively easily racemized or epimerized. To our knowledge, no

epimerizable pyryliums have been reported previously in the literature. The only

indication that epimerization would be possible has been inferred from deuterium

exchange experiments.53 The diastereomer ratios (39:61cis:trans) for pyrylium 45d

(determined by 1H NMR) deviate measurably from the cis:trans ratio (89:11) of the

carboxylic acid starting material (Figure 3.1).54 This could, of course, be attributed to

several factors: equilibration during acid chloride formation, differential reactivity in

dypnone

41 45a-f

a b c

d e f

35

pyrylium formation, or isolation efficiency, especially given the low yields. All of these

are probably occurring to some extent.

Indeed, when (S)-ibuprofen was used to prepare 45c, racemic pyrylium (having

no optical rotation) was obtained. More significantly, however, we have observed that

pyrylium 45d is readily epimerized by catalytic amounts of N-methylmorpholine,

yielding a 9:91 ratio of cis:trans isomers (Scheme 3.2). This clearly proceeds through the

well-known10 “pseudobase” intermediates (48), which can be observed or even isolated

when any of the pyryliums 45c, 45d, 45e or 45f are treated with stoichiometric

triethylamine. A detailed study of the epimerization of these and other pyryliums is

discussed in Chapter Four.

Pyrylium salts are also of interest because of the potential to convert them to the

corresponding phosphinines and pyridines, which are often good ligands for transition

metals.

Asymmetric Phosphinines

Phosphinines have a combination of poor -donating ability with strong -

accepting capacity that makes them attractive ligands for the stabilization of highly

electron-rich metal centers.19

Interestingly, only a few examples of chiral phosphinines have been reported in

the literature. The phosphorus is relatively far from the chiral centers in the majority of

these ligands. Incorporation of chirality directly (i.e., alpha to aromatic ring) onto these

planar ring systems has proven to be difficult. From pyrylium salts (45a-f) we have

synthesized new phosphinines with the chirality as close as possible to the phosphorus

center.48

36

Table 3.1. Yields of pyryliums 45 (a-f), phosphinines 46 (a-f) and pyridines 47 (a-f).48

R =

45a (23%) 46a (46%) 47a (90%)

45b (25%) 46b (57%) 47b (98%)

45c (23%) 46c (31%) 47c (79%)

45d (25%; 39:61 cis:trans)

46d (38%; 10:90 cis:trans)

47d (77%; 22:78 cis:trans)

45e (70%, trans) 46e (70%, trans) 47e (85%, trans)

45f (49%) 46f (49%) 46f (80%)

The pyrylium salts were converted to the corresponding phosphinines by

treatment with excess of tris-(trimethylsilyl)phosphine (P(TMS)3) in refluxing anhydrous

acetonitrile for 24 h (Scheme 3.3).22a After column chromatography, the phosphinines

were obtained as brown oils. The phosphinines showed the typical downfield resonance

at 180 ppm in the 31P NMR spectrum. The 13C NMR of these compounds show carbon-

phosphorus coupling as far as four bonds. Also, ortho carbons of the phosphinines

showed (around 180 ppm) C-P coupling constant around 51-59 Hz.48

37

Scheme 3.2. Amine-catalyzed epimerization mechanism.48

Figure 3.1. Methyl region 1H NMR of (a) methylcyclohexanoic acid and (b) methylcyclohexyl pyrylium derivative (45d).

When synthesizing phosphinine 46c, and after running column chromatography

two compounds were observed by GC-MS and NMR. These two compounds correspond

to the desired product and the pseudobase of the pyrylium starting material in a 73:23

ratio respectively. The mixture was treated with 1M HCl to regenerate the pyrylium from

the pseudobase, which upon treatment with diethyl ether precipitated allowing for the

extraction of the desired phosphinine.

O

Ph

Ph O

Ph

Ph

O

Ph

Ph

R3N

R3NH

R3NH

R3N

0.36

3.00

0.93

0.94

0.96

0.97

10.0

0

6.29

0.91

0.93

0.94

0.95

cis 45d

trans 45d

48

J (7.15)

J (6.51)

cis

trans

cis

trans

38

Scheme 3.3. Synthesis of substituted asymmetric phosphinines (46a-f).48

Pyrylium 45b failed to form the corresponding phosphinine (46b) on several

attempts. We were able to find success when we distilled out the hexane from the

commercially available P(TMS)3 solution (10% solution in hexane) before adding the

pyrylium. After column chromatography, the desired phosphinine 46b was obtained. We

believe that distilling out the hexane could have increased the polarity of the reaction

mixture or have allowed the temperature of the reaction mixture to increase.

Asymmetric Pyridines

Chiral pyridine ligands have been known for some time but the development of

their applications in asymmetric catalysis had been lacking until 1981, when the first

report of chiral pyridine ligands and their application in asymmetric catalysis appeared.27

Chiral pyridines have been studied more than the phosphorus analogous phosphinines,

because of their ability to coordinate transition metals, high stability against moisture and

oxygen and the diversity of their structures.49 Interestingly, no examples can be found in

45a-f 46a-f

a b c

d e f

39

the literature that uses the conversion of chiral pyrylium salts to the corresponding chiral

pyridines.

The pyridine derivatives were obtained in high yields by simply stirring the

pyrylium salts with ammonium hydroxide and diethyl ether for 30 minutes (Scheme 3.4).

In the case of the most hindered pyrylium salt (47b), the reaction required reflux with

ammonium hydroxide for 6h. After acid/base workup and without further purification the

compounds were obtained as brown oils (Scheme 3.4).55 The 13C NMR spectrum

displayed downfield aromatic peaks indicative of the trisubstituted pyridine (five peaks

between 140-167 ppm).

In the course of our investigation, we found that certain acyl chlorides did not

form the desired pyrylium salt, the reaction instead produced triphenyl pyrylium

tetrafluoroborate (1). We believe that when the acyl chloride is not reactive enough, the

dypnone undergoes a retroaldol to produce acetophenone. Excess acetophenone in the

presence of boron trifluoride is known to yield triphenyl pyrilium salt. The formation of

triphenyl pyrylium salt from dypnone was also reported by Balaban (Scheme 3.5).56 We

notice that acyl chlorides that bear ether or ester functionalities (Figure 3.2) inevitably

fail to produce the desired pyrylium, perhaps because these functionalities are reacting

with the excess boron trifluoride.

40

Scheme 3.4. Synthesis of substituted asymmetric pyridines (47a-f).48

Figure 3.2. Acyl chlorides that do not yield the desired pyryliums.48

Scheme 3.5. Formation of triphenyl pyrylium salt from dypnone.56

47a-f 45a-f

1 dypnone

41

a b c

d e f

41

Symmetric Compounds

Symmetric Pyrylium Salts

Symmetric pyrylium salts were obtained in moderate yields from a one-pot

reaction of tert-butanol and an acyl chloride, with etherate tetrafluoroboric acid as a

condensing agent (Scheme 3.6).47 Addition of ether precipitated the compounds as white

powders and, after recrystallization from methanol, white needles were obtained. The 13C

NMR spectrum of the symmetric pyryliums displayed peaks further downfield than the

typical aromatic region (three sets of peaks between 183, 175 and 123 ppm), which are

indicative of the deshielded carbons in the aromatic pyrylium ring.

Scheme 3.6. Synthesis of symmetric pyryliums from tert-butanol.

Pyrylium 49a was prepared from the commercially available 86:14 mixture of

cis:trans 2-methylcyclohexanecarboxylic acid, resulting in a complex mixture of

diastereomers. To characterize the mixture, the starting carboxylic acid was partially

resolved by repeated crystalization with (S)-(-)--methylbenzylamine. After extraction,

from acid a 5.2:1 ratio (68% ee) of (+):(-) diastereomer of 2-methylcyclohexane

carboxylic acid was obtained. Any pyrylium made from this would be expected to be

depleted in the diastereomer derived from the (-)-acid. The pyrylium with the resolved

49a-b

a b

42

carboxylic acid was prepared and, as expected, observed variations in the 1H NMR peak

intensities which aided greatly in the analysis (Figure 3.3). This led us to conclude that

the mixture is composed of six diastereomers but two of all which exhibited separate

aromatic signals.

Table 3.2. Yields of symmetric pyryliums 49 (a-b).

Isomer

Racemic starting material

(37% yield)

68% ee (+) starting material

(33% yield)

Isomer (43% yield)

(+)-cis/(-)-cis (+)-cis/(+)-trans (+)-cis/(-)-trans (+)-cis/(+)-cis

(+)-trans/(+)-trans and (+)-trans/(-)-trans

24 24 24 22 6

15.5 30 14 36

4.5

trans/trans cis/trans cis/cis

28 57 15

In the 1H NMR for 49a we clearly observed the presence of three symmetrical

isomers (single peak for both protons meta to oxygen) and two non-symmetrical isomers

(two peaks for each proton meta to oxygen) (Figure 3.3). This information, combined

with the results obtained from base-catalyzed epimerization of pyrylium 49a presented

later in Chapter Four, provided us sufficient evidence to determine the approximate

identity of each stereoisomer. As depicted in Fig. 3.3, the peak at = 7.81 ppm ((+)t/(+)t)

corresponds to the thermodynamically more stable stereoisomer, the substituents in both

rings are trans; the (+)-trans/(+)-trans and (+)-trans/(-)-trans diastereomer give a single

signal in this region. The unsymmetrical isomer at = 7.79 and 7.73 ppm ((+)c/(-)t)

43

corresponds to the configuration (+)-cis/(-)-trans or (+)-cis/(+)-trans diastereomers. The

unsymmetrical isomer at = 7.77 and 7.74 ppm ((+)c/(+)t) corresponds to the

configuration (+)-cis/(+)-trans. The symmetrical isomer at = 7.70 ppm ((+)c/(+)c)

corresponds to the less thermodynamically favored stereoisomer, where the substituents

in both rings are (+)-cis/(+)-cis. Finally, the symmetrical isomer at =7.68 ppm ((+)c/(-

)c) corresponds to the configuration (+)-cis/(-)-cis.

Figure 3.3. 1H NMR of 49a (a) pyrylium obtained from 86:14 mixture of cis:trans starting material, (b) pyrylium obtained from 5.2:1 mixture of (+):(-) starting material, (c) pyrylium at equilibrium.

Pyrylium 49b was made from a 95:5 mixture of trans:cis isomers of 4-tert-

buytlcyclohexane carboxylic acid resulting in a mixture of three isomers. From the meta

protons in the aromatic region of the 1H NMR for 49b, we observed the presence of two

symmetrical isomers (single peak for both protons meta to oxygen) and one non-

7.68

7.71

7.73

7.78

7.74

7.79

7.82

7.70

7.68

7.74

7.77

7.73

7.79

7.81

7.81

7.74

7.73

7.79

7.78

(+)t/(+)t and (+)t/(-)t

(+)c/(-)t (+)c/(-)t(+)c/(+)t (+)c/(+)t (+)c/(+)c (+)c/(-)c

49a

44

symmetrical isomer (two broader singlets for each proton meta to oxygen). With the

results shown in Chapter Four obtained from base-catalyzed epimerization of pyrylium

49b, we were able to identify each stereoisomer. The most downfield peak = 7.86 ppm

corresponds to the thermodynamically less stable stereoisomer (substituents in both rings

are cis to each other). The unsymmetrical isomer at = 7.82 and 7.71 ppm has one cis

ring and one trans. The non-equivalent meta protons apparently contribute to unresolved

coupling, resulting in broader peaks. Finally, the symmetrical isomer at =7.69 ppm

corresponds to the thermodynamically more stable isomer (substituents in both rings are

trans to each other).

Figure 3.4. 1H NMR of 49b. (a) 49b, (b) pyrylium at equilibrium.

Symmetric Pyridines

The symmetric pyridine derivatives were obtained in high yields by stirring the

pyrylium salts 50a and 50b with ammonium hydroxide and diethyl ether for 30 minutes.

7.697.727.757.787.817.847.87f1 (ppm)

a

b

cis/cis cis/trans cis/trans trans/trans49b

45

After acid/base workup and without further purification the compounds were obtained as

brown oils (Scheme 3.7).14 The 13C NMR spectrum displayed downfield aromatic peaks

indicative of the trisubstituted pyridine (three sets of peaks at 165, 146 and 120 ppm).

Scheme 3.7. Synthesis of symmetric pyridines.

Table 3.3. Yields of symmetric pyridines 50 (a-b).

R =

50a (77%; 47:32:16:5)

50b (78%; 60:35:5)

Symmetric Phosphinines

We failed to obtain the phosphinine derivatives on several attempts, perhaps

because of steric hindrance surrounding the alpha-carbons to the pyrylium. We attempted

the procedure employed to make phosphinine 46b, distilling out the hexane before the

addition of the pyrylium, but this was unsuccessful.

OR R

BF4

NH4OH

78% y~

R =

NR R

49a-b 50a-b

a b

46

In summary, we have synthesized six new unsymmetrical pyrylium salts, four of

them chiral, and the corresponding phosphinine and pyridine derivatives. Also, two new

symmetric pyrylium salts, one of them chiral, and the corresponding pyridine derivative.

This provides the first racemizable/epimerizable chiral pyryliums, and kinetic studies of

the equilibration of these are discussed in Chapter Four.

47

CHAPTER FOUR

First Kinetic Studies of the Epimerization/equilibration of Asymmetric and Symmetric Pyrylium Salts

Introduction

Our interest in chiral pyryliums led us to investigate the configurational stability

of chiral centers alpha to the pyrylium ring. Although no epimerizable (or even

racemizable) pyryliums have been reported, deuterium exchange at ortho and especially

para benzylic positions is well-known (Scheme 4.1).53b, 57 For example, in 2,4,6-

trimethylpyrylium it was observed that 4-methyl () hydrogens exchange faster than the

2/6-methyl () hydrogens by one order of magnitude.57b These proceed via the

‘pseudobase’ intermediates (e.g. 51, 52) which can sometimes be isolated.1, 10 Detailed

studies carried out by Williams58 on the hydrolysis of pyryliums found that the pKa of

2,4,6-trimethylpyrylium in water was 6.7.

Scheme 4.1. Mechanism of methyl deuteration by isotopic exchange with D2O.

For ease of equilibration studies, we sought to prepare pyryliums that would form

diastereomers upon inversion at a benzylic center. The synthesis of asymmetric48 and

symmetric pyrylium salts were previously described in Chapter Three. Here we report the

first study of the base-catalyzed epimerization of chiral pyrylium salts.

51 52

48

Epimerization/equilibration Studies We were interested in studying the equilibrium between the diastereomers of the

pyryliums. Although we had observed base-catalyzed pyrylium epimerization,48 the

thermal stability of diastereomers had not been established. We heated non-equilibrium

diastereomeric mixtures pyryliums 49a and 49b (Figure 4.1) in CD3CN at 40 oC for a

week without any detectable changes in the 1H NMR. Therefore, the pyryliums are

configuration stable in the absence of base. All the remaining experiments discussed in

this chapter were performed at room temperature (25 oC).

Figure 4.1. Pyryliums 49a and 49b.

Experimental Optimization

In order to find appropriate base catalysts we treated pyrylium 49a with 5 mol%

of various amine bases covering a range of pKa values such as triethylamine (pKa =

10.8), N-methyl morpholine (pKa = 7.4), and pyridine (pKa = 5.1). We decided to use

small concentrations of base to slow the equilibration to a rate convenient for NMR

studies and avoid the extensive formation of the pseudobase. The concentration of each

diastereomer over time in the presence of different bases was plotted for comparison

(Figure 4.2). Interestingly, while the weakly basic pyridine gave slower reaction,

triethylamine caused the molecule to reach equilibrium at the same rate as N-methyl

morpholine. Thus, the conversion rate is independent of the pKa of the base, when the

49a 49b

pKa o

2,4,6

once

Schem

of the amine

-trimethylpy

it begins, t

me 4.2.

Scheme 4

O

**

Mixture ofpredominan

e ≥ 7.4. This

yrylium salt

the pseudoba

Figure 4.

4.2. Proposed

O

H

**

f stereoisomerstly the less stable

s is consisten

in water. Th

ase formed

.2. Equilibra

d mechanism

base

5 mol%

49

nt with the p

he reactions

drives the r

ation rate of 4

m of equilibr

O

O

**

Mixture of sterpredominantly the

pKa of 6.7 re

s are initiate

reaction to

49a with dif

ration of pyry

H

**

reoisomerse more stable

equilibration/epim

eported by W

ed by the ba

equilibrium

fferent bases

ylium salt w

O

merization

Williams58 fo

se added, bu

as shown i

s.

with base.

O

OH

or

ut

in

50

To further optimize the equilibration conditions, pyrylium 49b was treated with

different concentrations (1.25-5 mol%) of N-methyl morpholine. We found that when we

decreased the concentration of base, the system took inconveniently long to reach

equilibrium (more than 130 mins). We decided that 5 mol% would provide the desired

equilibration in reasonable time.

Epimerization/equilibration Experiments

Unsymmetrical pyrylium 45d in CD3CN at 25 oC was treated with a catalytic

amount (5 mol%) of N-methyl morpholine and 1H NMR was taken at different time

intervals (Figure 4.3). At the beginning, before the addition of base, two diastereomers

were present in a 39:61 cis:trans ratio. These stereosimers were identified by two set of

doublets corresponding to the methyl group, the cis ( = 0.94 ppm, J = 7.2 Hz) and the

trans ( = 0.92 ppm, J = 6.5 Hz). We then monitored the changes on these peaks caused

by the addition of base. We noticed the gradual disappearance of the more downfield

doublet whereas the integral of the more upfield doublet increased. At equilibrium, the

ratio for cis:trans isomers was 9:91. The equilibrium ratio was consistent with

predominance of the thermodynamically more stable trans stereoisomer. The steric effect

of axial methyl on cis 45d (cis:trans 9:91) is similar to known equatorial preference of

the methyl group in methylcyclohexane (cis:trans 5:95).59

We briefly studied a scheme to modify pyrylium cis/trans ratios by conversion to

the pseudobase followed by treatment with acid to regenerate the pyrylium. We treated

pyrylium 45d (mixture of 39:61 cis:trans ratio) with 1 equiv. of TEA to form the

corresponding pseudobase (Figure 4.4). The pseudobase was confirmed by 1H NMR with

the presence of two major isomers on the methyl region (E and Z stereoisomers), and also

51

by two new peaks that appeared on the olefinic region. When treated the pseudobase with

excess of etherate HBF4 to regenerate the pyrylium 45d, the 1H NMR showed evidence

of pyrylium formation and, more importantly, a change in the cis:trans ratio to 62:38. We

did not study synthetic applications of this diastereomer conversion.

Figure 4.3. 1H NMR of 45d at different times after addition of N-methyl morpholine (5 mol%). (a) t = 0 min, (b) t = 6 min, (c) t = 119 min (equilibrium).

We then studied the first of our symmetrical pyryliums. Pyrylium 49a was treated

with a catalytic amount (5 mol%) of N-methyl morpholine and 1H NMR was taken at

progressive time intervals (Figure 4.5). Before addition of the base, six stereoisomers

were present; however, at equilibrium only one major peak labeled ((+)t/(+)t) was present

in the 1H NMR. We attributed this peak to the most thermodynamically stable

stereoisomer, as the other isomers had converted almost completely to this. This helped

us assign the identities of various diastereomers, but the use of mostly (+)-acid in the

preparation was also critical (Chapter Three).

0.9160.9320.948f1 (ppm)

a

b

c45d

cis trans

52

Figure 4.4. Acid/base study for pyrylium 45d. (a) pyrylium 45d, (b) pyrylium 45d regenerated with HBF4 solution after treatment with TEA.

For the analysis of the epimerization data the (+)/(+) and (+)/(-) of any given

cis/trans diastereomers were integrated together. We observed (Figure 4.8) that while the

cis/cis isomers were decreasing, the cis/trans isomers increased until they reached a

maximum level and then started to decline. This is consistent with the cis/cis isomers

converting to cis/trans isomers as an intermediate step before converting all the way to

the trans/trans isomer.

We then studied the rate of equilibration for the second symmetrical pyrylium

49b. We treated 49b with catalytic amount (5 mol%) of N-methyl morpholine and 1H

NMR was taken at different time intervals (Figure 4.6). Just as with 49a, we saw

equilibration of the compound to one major stereoisomer, presumably trans/trans.

Kinetic Analysis

This analysis was done by Dr. Darrin Bellert of Baylor University. Equation 1

represent forms of the equilibration mechanism for the pyrylium salts studied. The

53

cis/trans terminology refers to the geometric isomers of pyrylium present in

epimerization studies (Figures 4.3, 4.4, 4.5 and 4.6). The term PB stands for pseudo-base.

Figure 4.5. 1H NMR of 49a. (a) pyrylium obtained from racemic 86:14 mixture of cis:trans starting material, (b) pyrylium obtained from 5.2:1 mixture of (+):(-) starting material, (c) pyrylium at equilibrium.

Figure 4.6. 1H NMR of 49b. (a) 49b, (b) pyrylium at equilibrium

7.68

7.71

7.73

7.78

7.74

7.79

7.82

7.70

7.68

7.74

7.77

7.73

7.79

7.81

7.81

7.74

7.73

7.79

7.78

(+)t/(+)t and (+)t/(-)t

(+)c/(-)t (+)c/(-)t (+)c/(+)t (+)c/(+)t (+)c/(+)c (+)c/(-)c

49a

49b

54

Equations 2-4 are analytic expressions that determine the time dependent

concentrations of the reactant, intermediate, and product indicated in equation 1. These

expressions were derived from a series of differential equations extracted from the

mechanism given in equation 1. Equations 2-4 are used to model the time-varying

concentrations as determined from NMR measurements. Various assumptions are

required to both integrate these differential expressions, as well as to apply the resulting

model. These are discussed here.

2) ⁄ ⁄ ⁄

3) ⁄ "

⁄ " ⁄

4) ⁄ ⁄ ⁄ ⁄ ⁄⁄

Assumptions of the Model

a) It is assumed that k4 >> k-4 and that the reverse reaction in step 4 (eq.1) can be

ignored. The trans form of the isomer has the greatest concentration at equilibrium.

Thus, it is likely that the rate of the forward reaction in step 4 is greater than the reverse.

Without this assumption, the derivation of equation 3 is not possible.

55

b) For those systems that show the build-up of the cis/trans intermediate, it is

assumed that k2 >> k-1 and that the reverse reaction in step 1 (eq. 1) can be ignored. That

k2 >> k-1 must be true since a time-varying signal for the [cis/trans] concentration is

measured. The assumption that the reverse reaction of step 1 (eq.1) can be ignored

allows for the derivation of equation 2.

c) It is assumed that the [cis PB] and [trans PB] concentrations are in steady state.

Signals for these intermediates are not observed in the NMR; as such, these intermediates

must remain in low concentrations. This suggests that the concentrations of these

intermediates remain constant relative to the [cic/cis], [cis/trans], or [trans/trans]

concentrations.

d) The k’ and k” in equations 2 and 3 are pseudo first order rate constants

containing the unchanging pseudo-base concentration.

e) In systems where stereoisomers exist, it is assumed that only the geometric

(cis/trans) isomerization is kinetically important, and that (+) or (-) stereochemistries do

not affect rates.

f) The precise starting time of the reaction is not known experimentally and is a

variable parameter in the model. This subsequently means that the initial concentrations

of the pyrylium isomers must also be variable parameters in the model. The synthesis of

the pyrylium salts resulted in a measureable concentration of the least kinetically stable

cis-form of the isomer, making equilibration studies possible. The concentrations of the

isomers varied somewhat from batch to batch. It is presumed that precipitation quenched

any isomerization reactions until the salts were dissolved in the NMR solvent with N-

methylmorpholine base added.

56

Application of these assumptions essentially reduce the four step mechanism of

equation 1 into a two-step mechanism, with the rate constants k’ and k” of equations 2

and 3. The initiating reaction to form pseudo-base may be associated with k’, while k”

may be considered to be the effective rate constant governing the remaining subsequent

reactions to produce the trans-form of the isomer. This simplification allows the direct

comparison between the k’ and k” values acquired between the kinetic studies of the

various pyrylium salts. This also permits the attribution of such differences to the

structural characteristics unique to each system.

The values of the rate constants, k’ and k”, as well as the reaction start time and

the initial concentration of the cis-form of the isomer, [cis/cis]o; are determined by a

squared residual minimization procedure. The relative time-varying concentrations of the

reactant, intermediate, and product are calculated from equations 2-4 using logical initial

values for these parameters. The parameter values are simultaneously, programmatically

varied while minimizing the sum of the squared residuals to the fit. Parameter

optimizations are re-run while varying the input decks to verify that the optimization

procedure consistently yielded the same output values.

Table 4.1. Optimized values of the pseudo first order rate constants k’ and k” (min-1) and

relative equilibrium concentrations of the pyrylium systems.

System k’ k” [cis/cis]eq [cis/trans]eq [trans/trans]eq 1 (pyrylium 45d) 0.32 0.026 0.09 - 0.91 2 (pyrylium 49a) 0.011 0.0082 0.022 0.21 0.77 3 (pyrylium 49b) 0.30 0.077 0.024 0.14 0.84

Appli

The

pyryl

symm

equat

form

(cons

with

Figurtheor

ication of the

2-(2-meth

isomerizatio

lium studied

metry and c

tion 1. Thus

the trans-i

sistent with

step 4).

Scheme 4

re 4.7. Compretical model

cis 45d

e Model to th

hyl-cyclohexy

on reaction

d and is labe

annot have

s, the cis-py

isomer. The

step 1) foll

4.3. Amine-c

parison of tl after additi

he Pyrylium

yl)-4,6-diphe

of the cis t

eled system

a cis/trans

rylium react

e isomerizat

owed by th

catalyzed epi

he experimeon of N-met

48

57

Systems

enylpyrylium

to trans for

1 (Scheme

intermediat

ts to form it

ion reaction

e rate-limiti

imerization m

ental equilibthyl morphol

m tetrafluoro

rm of pyryli

4.3). This p

te. This elim

ts pseudo-ba

n is modele

ing formatio

mechanism

bration rate line (5mol%

tran

oborate (45d

ium 45d is

pyrylium lac

minates step

ase, which t

ed as a fast

on of produc

for pyrylium

of pyrylium%)

ns 45d

d) (System 1

the simple

cks a plane o

s 2 and 3 i

then reacts t

t equilibrium

ct (consisten

m 45d.

m 45d and th

).

st

of

in

to

m

nt

he

58

Application of the model to this system yields a single rate constant, k” = 0.026

min-1, which corresponds to the rate-limiting conversion to the trans-isomer product

(Figure 4.7). The model results in a single exponential that fits the data well at large time

values, however systematically underestimates the [cis]t concentration at time values less

than 15 minutes. This is likely due to the assumption that the fast equilibrium to form

pseudo-base is kinetically unimportant. Fitting the [cis]t relative concentration

measurements as a bi-exponential decay significantly improves the fit at early times

(solid line of Figure 4.7) and suggests a value for the rate constant associated with the

production of pseudo-base, k’ = 0.32 min-1. The rate constants as well as the relative

equilibrium concentration values are provided in table 4.1.

2,6-bis(2-methyl-cyclohexyl)-4-methyl-pyrylium tetrafluoroborate (49a) (System

2). The catalyzed conversion of the cis/cis to trans/trans form of pyrylium 49a is slow

relative to systems 1 and 3. Pyrylium 49a also contains a possible plane of symmetry and

the NMR signals from the cis/trans intermediate were identified both by symmetry and

by response to base-catalyzed epimerization. The temporal response of each of the three

geometric isomers was monitored. Again, equations 2-4 were used to model this time

dependence.

The calculated time-varying concentration of each of the isomers is represented as

solid curves in Figure 4.8. The agreement between the model and observation (symbols)

is obvious. Again, the reaction initiation time was varied to fit the observations. The

cis/cis form of the isomer decays to form the cis/trans intermediate. The conversion of

this intermediate to product is slow enough such that the cis/trans isomer concentration is

obser

rate c

Figurtheordiaste

rved to grow

constants ext

Schem

re 4.8. Compretical modeereomers we

w, reach a ma

tracted from

me 4.4. Amin

parison of tel after addiere integrated

cis/cis

trans/tra

aximum valu

equations 2

ne-catalyzed

the experimeition of N-md together.

ans

59

ue, and then

2-4 are presen

d epimerizati

ental equilibmethyl morp

cis P

t

decay into t

nted in table

ion mechani

bration rate pholine (5mo

PB

trans PB

trans/trans p

e 4.1.

ism for pyry

of pyryliumol%). (+)/(+

cis/tr

products. Th

ylium 49a.

m 49a and th+) and (+)/(

rans

he

he -)

60

2,6-bis(4-t-butyl-cyclohexyl)-4-methyl-pyrylium tetrafluoroborate (49b) (System

3). Pyrylium 49b contains a plane of symmetry and signals from all three geometric

isomers, cis/cis, cis/trans, and trans/trans were identified in NMR spectra. Consistent

with system 2, the cis/cis form of the isomer is least stable and undergoes base-catalyzed

epimerization to form first the cis/trans isomer then the trans/trans isomer. The

integrated signals from each of these isomers were measured and equations 2-4 used to

model the time dependent relative concentrations.

Values for the initial [cis/cis]o concentration, the reaction start time, and each rate

constant were optimized to minimize the residuals to the fit. The cis/cis form of the

isomer is rapidly converted to the cis/trans intermediate, which then decays more slowly

to the trans/trans product. The solid curves of Figure 4.9 are the calculated time

dependent concentrations of the isomers while the symbols show the relative NMR

concentration measurements. The rate constants are provided in Table 4.1. It is

noteworthy that the k’ values are similar for systems 1 and 3.

In summary, we observed that all the systems discussed showed k’ >> k” (Figure

4.10). This indicates that for system 1 the rate limiting step is the conversion of the

pseudobase to the trans isomer and for systems 2 and 3, the rate limiting step is the

conversion of the cis/trans isomer to the trans/trans isomer. Systems 1 and 3 (pyryliums

45d and 49b) showed similar k’ values, which are larger than the k’ value for system 2

(pyrylium 49a). We believe that the steric hindrance of the proton alpha to the pyrylium

in 49a played an important role in the first step, the base-catalyzed pseudobase formation.

In addition, we believe pyrylium 45d formed pseudobase at a rate comparative to 49b,

because the pseudobase formed is highly conjugated.

Figurtheor

Schem

re 4.9. Compretical model

cis

tran

me 4.5. Amin

parison of tl after additi

s/cis

ns/trans

ne-catalyzed

he experimeon of N-met

61

d epimerizati

ental equilibthyl morphol

cis P

trans PB

ion mechani

bration rate line (5mol%

PB

B

ism for pyry

of pyrylium%).

cis/trans

lium 49b.

m 49b and th

s

he

62

Figure 4.10. Energy potential diagram for the epimerization of pyryliums.

63

CHAPTER FIVE

Possible Pharmaceutical Applications of Pyryliums and Derivatives

Combretastatin Derivative

Combretastatin A-4 (53) is a known vascular disruptive agent for cancer cells. It

was first isolated from the bark of the African bush willow tree, Combretum caffrum, in

1982 by Pettit et al.60 This compound is currently under investigation in human clinical

trials as an anticancer drug.61

Figure 5.1. Combretastatin A-4.

A common way to increase the water solubility of the molecule is by substituting

the phenolic H with phosphate groups.62 Based upon our experience in the preparation of

pyrylium salts, we have designed a synthetic route, starting from Combretastatin A-4, to

obtain a new pyrylium that would contain the general features of this interesting

molecule. Due to the ionic nature of pyrylium salts, the solubility of these compounds in

water and polar organic solvents could be of great advantage for possible bioavailability.

An example of the use of pyryliums as pharmaceutical agents is pyrylium 54.63 This

compound is used in the photochemical treatment of cancer. The mechanism of action of

the drug towards cancer cells when irradiated with light is not completely understood.

However, the inventors found that the pyrylium attacks double stranded nucleic acid.

H3CO OCH3

H3CO

OCH3

OH

53

64

Moreover, it is believed that pyrylium 54 works by a different mechanism from that of

the known porphyrin compounds used for photochemical cancer treatment.

Figure 5.2. Pyrylium 54 patented used in the photochemical cancer treatment.63

The synthetic route that we designed was inspired by a method previously

discussed in chapter two (Scheme 2.13), where chalcone (34) reacts with deoxybenzoin

(35) in the presence of BF3•Et2O to obtain pyrylium 36 in 47% yield. We envisioned the

preparation of a deoxybenzoin analogue by a series of synthetic modifications of

Combretastatin A-4. This deoxybenzoin analogue would, subsequently when treated with

chalcone, allow us to obtain the desired pyryliums 61 and 62 (Scheme 5.1).

We first performed hydroboration oxidation on Combretastatin A-4 to obtain an

inseparable mixture of alcohols 55 and 56 in a 67:33 ratio. We continued the synthesis

hoping to separate the mixtures in subsequent steps. The next step was the oxidation of

the hydroxyls using PCC to obtain the ketones (deoxybenzoin analogues). However, no

product formation was seen by GC-MS. We believe that the phenolic group oxidizes; as

such, this can interfere with the reaction by possibly forming quinones.

We then decided to protect the phenolic group with TBSCl before starting the

synthesis (Scheme 5.2). Combretastatin A-4 was treated with imidazole and then TBSCl,

O

I

N

N

65

and the protected alcohol 57 was obtained as an oil in 88% yield; the product was

confirmed by 1H NMR. We then performed the hydroboration oxidation of the protected

Combretastatin, and obtained a mixture of alcohols (58) in an overall yield of 92%. The

products were confirmed by GC-MS.

Scheme 5.1. Proposed synthesis for pyryliums derived from Combretastatin A-4.

The alcohol mixture was then treated with PCC. As expected, a mixture of

ketones was obtained. The mixture was then separated using a Chromatotron, and ketones

5964 and 6065 were obtained in a 32% and 15% yield, respectively (by GC-MS). The

compounds were identified by MS.

The next step in the synthesis was to treat each ketone, 59 and 60, with chalcone

in BF3•Et2O to obtain the pyryliums (Schemes 5.3 and 5.4). Each reaction produced the

desired pyrylium 61 or 62 respectively mixed with the byproducts 1 and 37, obtained

from the self-condensation of chalcone that was discussed in chapter two. We were able

to identify the products by HRMS using ESI technique and by 1H and 13C NMR.

55 56

66

Although, we tried to separate the mixture chromatographically even with HPLC, we

were unsuccessful in our attempts.

Scheme 5.2. Synthesis of deoxybenzoin analogues 5964 and 60.65

Scheme 5.3. Synthesis of pyrylium 61.

Scheme 5.4. Synthesis of pyrylium 62.

Ar Ar'

O

O

Ph

Ph

BF3.OEt2

BF4OCH3

OCH3

OCH3

OH

OCH3

O

Ph

Ph Ph

BF4

O

Ph

Ph Ph

BF4

Ph++

Ph Ph

O+

58 57

59 60

61

62

1 37

1 37

59

60

67

Thiosemicarbazone Derivative

Cathepsin L is one of the eleven members of the human protease family.66

Numerous studies have suggested that they are involved in tumor progression,

hyperproliferation, apoptosis, angiogenesis and metastasis by malignant cells.67 Recent

studies have demonstrated the effectiveness of the thiosemicarbazone moiety for

inhibition of cruzain (cathepsin L-like, cysteine protease)66, 68 directly involved with

Chagas disease.

The known pyryliums 63 and 64 were prepared previously in our lab. Pyrylium 63

was made following the procedure developed by Balaban, from tert-butanol, acetic

anhydride, and tetrafluoroboric acid.69 Pyrylium 64 was prepared from acetophenone,

para-methylbenzaldehyde and tetrafluoroboric acid.70

From pyryliums 63 and 64, we prepared two known pyridinium salts with the

thiosemicarbazone moiety 65 and 66.71 These pyridiniums have never been tested as

possible cruzain inhibitors. We were interested to study the effects of the positive charge

delocalized in the ring in conjunction with the thiosemicarbazone moiety, toward the

inhibition of cruzain.

Scheme 5.5. Synthesis of pyridiniums 65 and 66.

68

Table 5.1. Yields of pyridiniums 65 and 66.

R, R’ =

65 (R, R’ = CH3) 77% 66 ( R = Ph, R’ = p-toluoyl) 37%

Pyridiniums 65 and 66 were obtained as white powder in 77% and 37% yield

respectively by refluxing pyryliums 63 and 64 with thiosemicarbazide in ethanol. The

products were identified by HRMS, 1H and 13C NMR. (Scheme 5.5).71

Biological Activity Evaluation Cytotoxicity studies for human prostate cancer cells (DU-145) and inhibition of

cruzain (cathepsin L-like, cysteine protease) were performed for compounds 65 and 66

by the Trawick group from the department of Chemistry and Biochemistry at Baylor

University.

Cytotoxic results. Doxorubicin was used as a positive control for these

experiments. The IC50 value for compound 65 was calculated to be ˃ 177 μM for DU-145

cells indicating that it was not cytotoxic for this cell line. The IC50 value for compound

66 was calculated to be 24.4 ± 4.00 μM for DU-145 cells indicating that it was not very

cytotoxic for this cell line (Table 5.1).

69

Table 5.2. Cytotoxicity results for human prostate cancer cells (DU-145) for compounds 65 and 66.

Doxorubicin 65 66

g/mL M g/mL M g/mL M 0.0295 0.0544 ˃ 50 ˃ 177 11.1 23.0 0.0276 0.0508 ˃ 50 ˃ 177 14.4 29.8 0.0289 0.0531 ˃ 50 ˃ 177 9.80 20.3 = 0.0287 = 0.0528 ˃ 50 ˃ 177 = 11.77 = 24.4

st. d. = 0.00089 st. d. = 0.0015 - - st. d. = 1.94 st. d. = 4

Inhibition of cruzain. Compound 65 inhibited the activity of cruzain by 15.6% at a

concentration of 10 μM. Inhibition of > 50% at this concentration is required in order to

determine an IC50 value. Compound 66 inhibited the activity of cruzain by 5.2% at a

concentration of 10 μM.

Table 5.3. Inhibition of cruzain results for compounds 65 and 66.

value 65 66

15.58 % 5.18 % st. d. 3.91 % 2.06 %

In summary, compound 65 was not cytotoxic toward human prostate cancer cells

and it did not show inhibitory activity toward cruzain. Compound 66 exhibited an

average IC50 of 24.4 M, which is considered not very cytotoxic, and also, it was inactive

in the inhibition of cruzain. Functionalizing compound 66 could open a new window for

more cytotoxic studies.

70

CHAPTER SIX

Materials and Methods

General Section Reagents and solvents were generally purchased from the Aldrich Chemical

Company or from Alfa Aesar, and were used as received unless otherwise noted.

Dypnone was purchased from Frinton Laboratories. Tris-(trimethylsilyl)phosphine was

obtained from Strem Chemical as a 10 wt% solution in hexanes (d = 0.68 g/mL, 0.27 M).

Fenchoic and campholic acid were previously synthesized following Whiteside’s

procedure (see ref. 49 McCreary, M., Lewis, D., Wernick, D., Whitesides, G. J. Am.

Chem. Soc. 1974, 96,1038). 2,4,6-trimethyl-pyrylium tetrafluoroborate (62) was

previously synthesized following Ballaban’s procedure (see ref. 67 Balaban, A. T.,

Boulton, A. J., Org. Synth., Coll. Vol. V 1973, 1112) and 2,6-diphenyl-4-tolouyl-pyrylium

tetrafluoroborate (63) was previously synthesized following Lombard’s procedure (see

ref. 68 Lombard, R.; Stephan, J. P., Bull. Soc. Chim. Fr. 1958, 1458–1462). 2-

methylcyclohexane carboxylic acid (Aldrich) was an 86:14 mixture of cis and trans

isomers, resp., based on NMR analysis and literature precedent (see ref. 54 in: Besson,

M.; Delbecq, F.; Gallezot, P.; Neto, S.; Pinel, C. Chem. Eur. J. 2000, 6, 949-958.).

Hexanes, ethyl acetate, and methylene chloride were distilled prior to use. NMR spectra

were obtained using a Varian 500 MHz NMR operating at 500 MHz for 1H, 126 MHz for

13C, and 202 MHz for 31P. Spectra obtained in CDCl3 were referenced to TMS (0 ppm)

for 1H and to CDCl3 (77.16 ppm) for 13C. Spectra in acetone-d6 were referenced to 2.05

ppm for 1H and to 206.26 ppm for 13C, and CD3CN solutions were referenced to 1.94

71

ppm for 1H and to 118.26 ppm for 13C. 31P spectra were referenced to an external

standard of 85% H3PO4 (0 ppm).

Partial Resolution of cis-2-methylcyclohexanecarboxylic acid

To 5.520 g (38.8 mmol) of commercial carboxylic acid that was an 86:14 mixture

of cis:trans isomers54 by 1H NMR [cis = 0.97 ppm (d, J = 8.2 Hz), trans = 0.94 ppm (d, J

= 6.5 Hz)] dissolved in 50 mL of hexanes was cautiously added 5.00 mL (38.8 mmol) of

(S)-(-)--methylbenzylamine (Aldrich). The resulting precipitate was heated to 60-65° C

and isopropanol was slowly added with swirling until the solid was just dissolved. Upon

slow cooling, fine needles formed that trapped the free solvent; however, vigorous

shaking broke up the solid and allowed for filtration on a coarse frit. After washing with

hexanes and drying under vacuum, the recrystallization procedure was repeated twice

more by suspending the solid in hexanes (8 mL per gram) and isopropanol added until

just dissolved. The enantiomer ratio was monitored by 1H NMR of the salt (~ 10 mg in

0.7 mL of CDCl3); chemical shifts were somewhat concentration dependent, but the less-

soluble of the cis diasteromers was consistently downfield by about 0.015 ppm (0.877 vs

0.863 ppm) from the more soluble cis diastereomer. Because the center peaks of the cis

diastereomers overlapped, integration of the outer peak of each doublet was used for

quantitation. There were small amounts of the trans isomer also evident upfield (0.837

ppm), the diastereomers of which were apparently unresolved. In this way was obtained

2.250 g of a 5.2:1 ratio (68% ee) of the cis diastereomer containing 2-3% of the trans

diastereomer. This was portioned between 10 mL of 2 M HCl and dichloromethane, the

organic phase dried with MgSO4 and concentrated to give 1.140 g (8.03 mmol) of cis-2-

methylcyclohexanecarboxylic acid; []D20 = +3.2 (c = 0.7, EtOAc).

72

General Procedure for the Preparation of the Acyl Chlorides

1 equiv. of the carboxylic acid and 1.5 equiv. of oxalyl chloride were treated with

a catalytic amount (3 μL) of DMF and stirred for 1h under nitrogen. Excess oxalyl

chloride was then removed by rotary evaporation and the product formation was

confirmed by GC-MS. The compound was used without further purification.

Asymmetric Compounds

General Procedure for the Preparation of the Pyrylium Salts 45a-f

1 equiv. of dypnone, 2 equiv. of acyl chloride and 2.1 equiv. of boron trifluoride

diethyl etherate (47% BF3, 8.0 M) were heated at 100 oC for 2 h. The solution turned

deep green. After cooling to room temperature the reaction mixture was poured into

diethyl ether and the pyrylium salt precipitated from the reaction mixture.

Recrystallization from methanol gave yellow needles.

2-(1R,3R-1-methyl-3-isopropyl-cyclopentyl)-4,6-diphenylpyrylium tetrafluoroborate (45a)

From 0.35 mL (1.6 mmol) of dypnone, 0.600 g (3.2 mmol) of (1R,3R)-1-methyl-

3-isopropylcyclopentanoyl chloride and 0.46 mL (3.7 mmol) of boron trifluoride diethyl

etherate, compound 45a obtained as yellow needles (0.163 g, 0.37 mmol, 23% yield). Mp

145-147 oC; [α]D20 -20.9 (c = 1, CH3CN); 1H NMR (500 MHz, acetone-d6): δ 9.05 (s, 1H,

ArH), 8.57 (s, 1H, ArH), 8.52 (d, J = 7.7 Hz, 2H, ArH), 8.46 (d, J = 7.7 Hz, 2H, ArH),

7.90-7.83 (m, 2H, ArH), 7.78 (t, J = 7.7 Hz, 2H, ArH), 7.76 (t, J = 7.7 Hz, 2H, ArH),

2.67-2.56 (m, 1H), 2.35 (dd, J = 10.8, 5.2 Hz, 1H), 2.21-2.08 (m, 4H), 1.75 (s, 3H), 1.73-

1.66 (m, 1H), 1.56 (dd, J = 13.7, 6.8 Hz, 1H), 0.98 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 6.4

73

Hz, 3H). 13C NMR (126 MHz, acetone-d6): δ 187.2 (C), 172.8 (C), 167.8 (C), 136.1

(CH), 135.9 (C), 134.0 (C), 130.9 (CH), 130.8 (two coincident CH), 130.3(CH), 129.5

(CH), 116.8 (CH), 116.2 (CH), 50.7 (C), 47.1 (CH), 45.0 (CH), 38.8 (CH2), 34.4 (CH2),

30.4 (CH2), 26.9 (CH3), 21.8 (CH3), 21.7 (CH3). HRMS (ESI): calculated for C26H29O

[M+] 357.2213, found 357.2214.

2-(1R,3R-1,2,2,3-tetramethyl-cyclopentyl)-4,6-diphenylpyrylium tetrafluoroborate (45b)

From 0.35 mL (1.6 mmol) of dypnone, 0.602 g (3.2 mmol) of (1R,3R)-1,2,2,3-

tetramethylcyclopentanoyl chloride and 0.46 mL (3.7 mmol) of boron trifluoride diethyl

etherate, compound 45b obtained as yellow needles (0.77 g, 1.73 mmol, 25% yield). Mp

187-189 oC; [α]D20 +80 (c = 1, CH3CN); 1H NMR (500 MHz, acetone-d6): δ 9.17 (s, 1H,

ArH), 8.59 (s, 1H, ArH), 8.56-8.52 (m, 2H, ArH), 8.49-8.46 (m, 2H, ArH), 7.92-7.83 (m,

2H, ArH), 7.81 (t, J = 7.8 Hz, 2H, ArH), 7.76 (t, J = 7.9 Hz, 2H, ArH), 3.08 (td, J = 12.5,

6.3 Hz, 1H), 2.37-2.26 (m, 1H), 2.25-2.14 (m, 1H), 1.98 (ddd, J = 9.6, 7.8, 4.2 Hz, 1H),

1.74 (s, 3H), 1.63 (dddd, J = 13.4, 11.8, 9.5, 4.2 Hz, 1H), 1.25 (s, 3H), 0.98 (d, J = 6.8

Hz, 3H), 0.75 (s, 3H). 13C NMR (126 MHz, acetone-d6): δ 185.0 (C), 173.1 (C), 167.4

(C), 136.2 (CH), 136.0 (C), 133.9 (C), 131.0 (CH), 130.9 (two coincident CH), 130.3

(CH), 129.6 (CH), 118.3 (CH), 116.6 (CH), 57.0 (C), 49.8 (C), 42.8(CH), 33.9 (CH2),

29.5 (CH2), 22.9 (CH3), 22.1 (CH3), 19.8 (CH3), 14.9 (CH3). HRMS (ESI): calculated for

C26H29O [M+] 357.2213, found 357.2215.

2-(1-(4-isobutylphenyl)-ethyl)-4,6-diphenylpyrylium tetrafluoroborate (45c)

From 0.28 mL (1.3 mmol) of dypnone, 0.580 g (2.6mmol) of ibuprofen acid

chloride and 0.35 mL (2.8 mmol) of boron trifluoride diethyl etherate, compound 45c

74

obtained as yellow needles (0.144 g, 0.30 mmol, 23% yield). Mp 174-176 oC; 1H NMR

(500 MHz, acetone-d6): δ 9.11 (s, 1H, ArH), 8.67 (s, 1H, ArH), 8.43 (d, J = 8.1 Hz, 4H,

ArH), 7.85 (t, J = 7.4 Hz, 2H, ArH), 7.74 (t, J = 7.6 Hz, 4H, ArH), 7.58 (d, J = 8.1 Hz,

2H, ArH), 7.26 (d, J = 8.0 Hz, 2H, ArH), 5.03 (q, J = 7.2 Hz, 1H), 2.5 (d, 2H), 2.07-2.03

(m, 3H), 1.87 (tt, J = 13.5, 6.8 Hz, 1H), 0.88 (d, J = 6.6 Hz, 6H). 13C NMR (126 MHz,

acetone-d6): δ 182.3 (C), 173.2 (C), 168.1 (C), 142.5 (C), 138.2 (C), 136.3 (C), 136.3

(CH), 133.8 (CH), 131.1 (CH), 131.0 (CH), 130.9 (CH), 130.9 (CH), 130.16 (C), 129.7

(CH), 129.0 (CH), 118.3 (CH), 116.5 (CH), 45.8 (CH), 45.6 (CH2), 31.0 (CH), 22.7

(CH3), 19.1 (CH3). HRMS (ESI): calculated for C27H29O [M+] 393.2213, found

393.2213.

2-(2-methyl-cyclohexyl)-4,6-diphenylpyrylium tetrafluoroborate (45d)

From 0.35 mL (1.6 mmol) of dypnone, 0.512 g (3.2 mmol) of 2-methyl-

cyclohexanoyl chloride and 0.46 mL (3.7 mmol) of boron trifluoride diethyl etherate,

compound 45d obtained as yellow needles (0.166 g, 0.50 mmol, 25% yield). Mp 155-156

oC; 1H NMR (500 MHz, CD3CN) δ 8.69 – 8.68 (m), 8.35 – 8.30 (m), 8.23 – 8.19 (m),

8.18 (d, J = 1.8 Hz), 8.10 (d, J = 1.7 Hz), 3.56 – 3.51 (m), 2.93 (ddd, J = 12.0, 11.0, 3.4

Hz), 2.61 (dt, J = 10.8, 3.7 Hz), 1.89 – 1.73 (m), 1.70 – 1.58 (m), 1.58 – 1.38 (m), 1.30 –

1.18 (m), 0.94 (d, J = 7.2 Hz), 0.92 (d, J = 6.5 Hz). 13C NMR (126 MHz, CD3CN) δ

183.69 (C), 183.66 (C), 173.13 (C), 172.91 (C), 171.60 (C), 171.54 (C), 167.47 (C),

167.27, 136.34, 136.30, 136.29, 136.21, 133.62, 133.57, 131.04, 131.02, 130.97, 130.94,

130.58, 130.57, 129.98, 129.45, 129.44, 119.02, 118.66, 116.67, 116.55, 60.92, 52.48,

47.65, 36.96, 35.50, 34.24, 33.19, 32.86, 26.32, 25.90, 23.30, 21.11, 20.80, 20.65, 14.48,

13.92. HRMS (ESI): calculated for C24H25O [M+] 329.1900, found 329.1907.

75

2-(4-t-butyl-cyclohexyl)-4,6-diphenylpyrylium tetrafluoroborate (45e)

From 0.35 mL (1.6 mmol) of dypnone, 0.651 g (3.2 mmol) of 4-t-butyl-

cyclohexanoyl chloride and 0.46 mL (3.7 mmol) of boron trifluoride diethyl etherate,

compound 45e obtained as yellow needles (0.511 g, 1.38 mmol, 70% yield). Mp 180-182

oC; 1H NMR (500 MHz, acetone-d6): δ 9.10 (d, J = 1.5 Hz, 1H, ArH), 8.58 (d, J = 1.5 Hz,

1H, ArH), 8.57-8.53 (m, 2H, ArH), 8.45 (dd, J = 8.4, 1.0 Hz, 2H, ArH), 7.86 (q, J = 7.7

Hz, 2H, ArH), 7.79 (t, J = 7.9 Hz, 2H, ArH), 7.73 (t, J = 7.9 Hz, 2H, ArH), 3.45 (tt, J =

12.2, 3.4 Hz, 1H), 2.46 (dd, J = 14.5, 2.0 Hz, 2H), 2.08 (d, J = 2.6 Hz, 1H), 2.01-1.89 (m,

2H), 1.44-1.21 (m, 4H), 0.93 (s, 9H). 13C NMR (126 MHz, acetone-d6) δ 184.4 (C), 173.0

(1), 167.7 (C), 136.1 (CH), 133.8 (C), 131.0 (CH), 130.9 (CH), 130.8 (CH), 130.3 (C),

129.6 (CH), 118.0 (CH), 116.3 (CH), 48.0 (CH), 45.0 (CH), 33.1 (C), 32.0 (CH2), 27.9

(CH3), 27.6 (CH2). HRMS (ESI): calculated for C27H31O [M+] 371.2369, found

371.2370.

2-(cyclohexyl)-4,6-diphenylpyrylium tetrafluoroborate (45f)

From 0.35 mL (1.6 mmol) of dypnone, 0.472 g (3.2 mmol) of cyclohexanoyl

chloride and 0.46 mL (3.7 mmol) of boron trifluoride diethyl etherate, compound 45f

obtained as yellow needles (0.309 g, 0.98 mmol, 48% yield). Mp 145-146 oC; 1H NMR

(500 MHz, acetone-d6): δ 9.10 (d, J = 1.4 Hz, 1H, ArH), 8.58 (d, J = 1.5 Hz, 1H, ArH),

8.54 (d, J = 7.6 Hz, 2H, ArH), 8.45 (d, J = 7.5 Hz, 2H, ArH), 7.88 (d, J = 7.6 Hz, 1H,

ArH), 7.84 (d, J = 7.6 Hz, 1H, ArH), 7.82-7.71 (m, 4H, ArH), 3.51 (td, J = 11.8, 3.2 Hz,

1H), 2.37 (d, J = 11.9 Hz, 2H), 2.02-1.87 (m, 4H), 1.82 (d, J = 13.0 Hz, 1H), 1.65-1.50

(m, 2H), 1.50-1.36 (m, 1H). 13C NMR (126 MHz, acetone-d6): δ 184.2 (C), 173.0 (C),

167.7 (C), 136.1 (two coincident CH), 133.8 (C), 131.0 (CH), 130.9 (CH), 130.8 (CH),

76

130.3 (C), 129.6 (CH), 118.0 (CH), 116.3 (CH), 44.9 (CH), 31.5 (CH2), 26.5 (CH2), 26.2

(CH2). HRMS (ESI): calculated for C23H23O [M+] 315.1743, found 315.1744.

General Procedure for the Preparation of the Phosphinines (46a-f)

1 equiv. of the pyrylium tetrafluoroborate salt was dissolved in anhydrous

acetonitrile and was placed carefully under nitrogen. Then was added 2 equiv. of

P(TMS)3 (10 wt% solution in hexanes, d = 0.68 g/mL, 0.27 M) and the solution was

refluxed for 24 h, turning dark red in the process. After cooling to room temperature, the

solvent was removed by rotary evaporation and the phosphinine was purified by silica gel

column chromatography (5% ethyl acetate in hexanes).

2-(1R,3R-1-methyl-3-isopropyl-cyclopentyl)-4,6-diphenylphosphinine (46a)

From 0.141 g (0.32 mmol) of pyrylium 45a, and 3 mL (0.8 mmol) of P(TMS)3

solution dissolved in 3 mL of acetonitrile, compound 46a obtained as a brown oil (0.055

g, 0.15 mmol, 46% yield). [α]D20 -15 (c = 1.1, EtOAc) 1H NMR (500 MHz, CDCl3): δ

8.04 (dd, J = 5.7, 0.9 Hz, 1H, ArH), 8.01-7.98 (m, 1H, ArH), 7.69 (d, J = 8.1 Hz, 2H,

ArH), 7.65-7.62 (m, 2H, ArH), 7.51-7.42 (m, 4H, ArH), 7.42-7.36 (m, 2H, ArH), 2.26

(dd, J = 12.1, 6.3 Hz, 1H), 2.23-2.16 (m, 1H), 2.13-2.05 (m, 1H), 2.05-2.00 (m, 1H),

2.00-1.90 (m, 2H), 1.82-1.75 (m, 2H), 1.44 (s, 3H), 0.94 (d, J = 6.6, Hz, 3H), 0.93 (d, J =

6.6, Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 186.5 (C, d, J = 57.3 Hz), 170.5 (C, d, J =

51.6 Hz), 144.1 (C, d, J = 24.6 Hz), 143.4 (C, d, J = 14.3 Hz), 142.9 (C, d, J = 3.0 Hz),

130.9 (CH, d, J = 12.0 Hz), 130.6 (CH, d, J = 12.2 Hz), 129.1 (CH, s), 128.9 (CH,s),

128.0 (CH, s), 127.9 (CH, s), 127.8 (CH, s), 127.8 (CH, d, J = 1.6 Hz), 51.4 (C, d, J =

19.7 Hz), 46.4 (CH2, d, J = 13.4 Hz), 45.6 (CH), 40.3 (CH2, d, J = 13.1 Hz), 34.3 (CH),

77

32.3 (CH3, d, J = 6.9 Hz), 29.0 (CH2), 21.6 (CH3), 21.5 (CH3). 31P NMR (202 MHz,

CDCl3): δ 184.67 (s). HRMS (EI): calculated for C26H29P [M+] 372.2007, found

372.2006.

2-(1,2,2,3-tetramethyl-cyclopentyl)-4,6-diphenylphosphinine (46b)

From 0.090 g (0.2 mmol) of pyrylium 45b, and 1.5 mL (0.4 mmol) of P(TMS)3

solution dissolved in 3 mL of acetonitrile, compound 46b obtained as brown oil (0.042 g,

0.11 mmol, 57% yield). [α]D20 +42 (c = 0.9, EtOAc). 1H NMR (500 MHz, CDCl3): δ 8.14

(dd, J = 6.6, 0.8 Hz, 1H, ArH), 8.08 (dd, J = 5.6, 0.8 Hz, 1H, ArH), 7.73 (d, J = 8.1 Hz,

2H, ArH), 7.69- 7.65 (m, 2H, ArH), 7.53-7.45 (m, 4H, ArH), 7.45-7.38 (m, 2H, ArH),

3.18-3.08 (m, 1H), 2.21 (tt, J = 15.4, 6.8 Hz, 1H), 2.15-2.06 (m, 1H), 1.73 (ddd, J = 12.7,

9.4, 3.1 Hz, 1H), 1.51 (s, 3H), 1.50-1.42 (m, 1H), 1.17 (s, 3H), 0.97 (d, J = 6.8 Hz, 3H),

0.53 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 181.4 (C, d, J = 59.4 Hz), 169.6 (C, d, J =

6.8 Hz), 144.0 (C, d, J = 24.9 Hz), 143.1 (C, d, J = 3.1 Hz), 143.0 (C, d, J = 14.1 Hz),

131.2 (CH, d, J = 12.2 Hz), 130.7 (CH, d, J = 11.7 Hz), 129.1 (CH, s), 128.9 (2CH, s),

127.9 (CH, s), 127.8 (CH s), 127.8 (CH, s), 127.7 (CH, d, J = 1.6 Hz), 55.9 (C, d, J =

16.7 Hz), 46.3 (C, d, J = 2.2 Hz), 41.9 (CH, d, J = 1.4 Hz), 36.1 (CH2, d, J = 26.0 Hz),

29.1 (CH2, d, J = 2.3 Hz), 26.7 (CH3, d, J = 8.8 Hz), 22.1 (CH3, d, J = 3.1 Hz), 20.1 (CH3,

s), 15.6 (CH3, s). 31P NMR (202 MHz, CDCl3): δ 192.04. HRMS (EI): calculated for

C26H29P [M+] 372.2007, found 372.2013.

2-(1-(4-isobutylphenyl)-ethyl)-4,6-diphenylphosphinine (46c)

From 0.155 g (0.3 mmol) of pyrylium 45c, and 3 mL (0.8 mmol) of P(TMS)3

solution dissolved in 3 mL of acetonitrile, compound 46c obtained as a brown oil (0.038

78

g, 0.09 mmol, 31% yield). 1H NMR (500 MHz, CDCl3): δ 8.03 (d, J = 5.5 Hz, 1H, ArH),

7.84 (d, J = 6.6 Hz, 1H, ArH), 7.67 (d, J = 7.9 Hz, 2H, ArH), 7.55 (d, J = 7.5 Hz, 2H,

ArH), 7.46-7.41 (m, 4H, ArH), 7.37 (ddd, J = 7.3, 2.8, 1.3 Hz, 2H, ArH), 7.28 (d, J = 8.0

Hz, 2H, ArH), 7.08 (d, J = 8.0 Hz, 2H, ArH), 4.59 (dq, J = 14.2, 7.1 Hz, 1H), 2.43 (d, J =

7.2 Hz, 2H), 1.83 (sept, J = 6.8 Hz, 1H), 1.85 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.6 Hz,

6H). 13C NMR (126 MHz, CDCl3): δ 179.8 (C, d, J = 53.7 Hz), 171.2 (C, d, J = 51.3 Hz),

143.8 (C, d, J = 3.6 Hz), 143.7 (C, d, J = 5.9 Hz), 143.4 (C, d, J = 5.4 Hz), 142.5 (C, d, J

= 3.1 Hz), 139.8 (C, s), 131.9 (CH, d, J = 12.4 Hz), 131.5 (CH, d, J = 12.2 Hz), 129.4

(CH, s), 129.01 (CH, s), 128.9 (CH, s), 127.9 (CH, s), 127.8 (CH, s), 127.7 (CH, s), 127.5

(CH, s), 127.5 (CH, s), 48.0 (CH, d, J = 29.6 Hz), 45.2 (CH2, s), 30.3 (CH, s), 23.8 (CH3,

d, J = 12.4 Hz), 22.6 (CH3, s). 31P NMR (202 MHz, CDCl3): δ 187.81. HRMS (EI):

calculated for C29H29P [M+] 408.2007, found 408.1996.

2-(2-methyl-cyclohexyl)-4,6-diphenylphosphinine (46d)

From 0.122 g (0.3 mmol) of pyrylium 45d, and 3 mL (0.8 mmol) of P(TMS)3

solution dissolved in 3 mL of acetonitrile, compound 46d obtained as a brown oil (0.046

g, 0.13 mmol, 38% yield). 1H NMR (500 MHz, CDCl3): δ 8.06 (dd, J = 5.6, 1.1 Hz, 1H,

ArH), 7.81 (d, J = 7.4 Hz, 1H, ArH), 7.72-7.68 (m, 2H, ArH), 7.66-7.62 (m, 2H, ArH),

7.50-7.42 (m, 4H, ArH), 7.41-737 (m, 2H, ArH), 2.58 (ddd, J = 15.6, 12.8, 3.4 Hz, 1H),

1.99-1.92 (m, 1H), 1.92-1.77 (m, 2H), 1.74-1.65 (m, 2H), 1.49-1.38 (m, 2H), 1.22-1.12

(m, 2H), 0.79 (d, J = 6.3 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 179.6 (C, d, J = 53.3

Hz), 171.6 (C, d, J = 51.3 Hz), 143.9 (C, d, J = 23.5 Hz), 143.6 (C, d, J = 14.9 Hz), 142.7

(C, d, J = 3.1 Hz), 131.6 (CH, d, J = 12.3 Hz), 129.0 (CH, s), 128.9 (CH, s), 127.9 (CH,

s), 127.8 (CH, s), 127.8 (CH, s), 127.8 (CH, s), 127.7 (CH, s), 56.1 (CH, d, J = 26.6 Hz),

79

39.1 (CH, d, J = 8.3 Hz), 38.5 (CH2, d, J = 8.9 Hz), 36.1 (CH2, s), 27.4 (CH2 , s), 26.8

(CH2, s), 21.1 (CH3, s). 31P NMR (202 MHz, CDCl3): δ 190.05 HRMS (EI): calculated

for C24H25P [M+] 344.1694, found 344.1693.

2-(4-t-butyl-cyclohexyl)-4,6-diphenylphosphinine (46e)

From 0.191 g (0.4 mmol) of pyrylium 4e, and 3.5 mL (0.95 mmol) of P(TMS)3

solution dissolved in 3 mL of acetonitrile, compound 46e obtained as a brown oil (0.108

g, 0.28 mmol, 70% yield). 1H NMR (500 MHz, CDCl3): δ 8.06 (dd, J = 5.6, 1.1 Hz, 1H,


7.48-7.41 (m, 4H, ArH), 7.39-7.35 (m, 2H, ArH), 2.91 (qt, J = 12, 3.4 Hz, 1H), 2.11 (dd,

J = 13.6, 3.1 Hz, 2H), 1.98-1.91 (m, 2H), 1.72 (qd, J = 12.6, 2.6 Hz, 2H), 1.27-1.12 (m,

3H), 0.90 (s, 9H). 13C NMR (126 MHz, CDCl3): δ 181.0 (C, d, J = 54.0 Hz), 171.4 (C, d,

J = 51.3 Hz), 144.0 (C, d, J = 23.9 Hz), 143.6 (C, d, J = 14.7 Hz), 142.7 (C, d, J = 3.1

Hz), 131.6 (CH, d, J = 12.3 Hz), 131.1 (CH, d, J = 12.4 Hz), 129.0 (CH, s), 128.9 (CH,

s), 127.9 (CH, d, J = 1.2 Hz), 127.8 (CH, d, J = 2.2 Hz), 127.8 (CH, d, J = 1.3 Hz), 127.7

(CH, s), 48.7 (CH, d, J = 27.2 Hz), 47.7 (CH, s), 37.2 (CH2, d, J = 10.3 Hz), 32.6 (C, s),

28.0 (CH2, s), 27.8 (CH3, s). 31P NMR (202 MHz, CDCl3): δ 187.29. HRMS (EI):

calculated for C26H29P [M+] 386.2163, found 386.2161.

2-(cyclohexyl)-4,6-diphenylphosphinine (46f)

From 0.250 g (0.62 mmol) of pyrylium 45f, and 3.5 mL (1.24 mmol) of P(TMS)3

solution dissolved in 3 mL of acetonitrile, compound 46f obtained as a brown oil (0.082

g, 0.25 mmol, 49% yield). 1H NMR (500 MHz, CDCl3) δ 8.06 (dd, J = 5.7, 1.0 Hz, 1H,

ArH), 7.87 (d, J = 7.0 Hz, 1H, ArH), 7.69 (d, J = 8.1 Hz, 2H, ArH), 7.66-7.62 (m, 2H,

80

ArH), 7.52-7.42 (m, 4H, ArH), 7.42-7.36 (m, 2H, ArH), 2.97 (qt, J = 12.0, 3.4 Hz, 1H),

2.07-2.01 (m, 2H), 1.95-1.87 (m, 2H), 1.83-1.76 (m, 1H), 1.70 (qd, J = 12.4, 3.5 Hz, 2H),

1.52-1.42 (m, 2H), 1.37-1.28 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 181.3 (C, d, J =

54.1 Hz), 171.4 (C, d, J = 51.1 Hz), 144.0 (C, d, J = 24 Hz), 143.6 (C, d, J = 14.8 Hz),

142.7 (C, d, J = 3.2 Hz), 131.6 (CH, d, J = 12.3 Hz), 131.1 (CH, d, J = 12.4 Hz), 129.0

(CH, s), 129.0 (CH, s), 127.9 (CH, d, J = 1.6 Hz), 127.9 (CH, d, J = 2.7 Hz), 127.8 (CH,

d, J = 1.8 Hz), 127.7 (CH, s), 48.8 (CH, d, J = 27.3 Hz), 36.8 (CH2, d, J = 10.2 Hz), 27.2

(CH2, s), 26.1 (CH2, s). 31P NMR (202 MHz, CDCl3) δ 177.39. HRMS (EI) calculated for

C23H23P [M+] 330.1537, found 330.1541.

General Procedure for the Preparation of the Pyridines (47a-f)

1 equiv. of pyrylium tetrafluoroborate salt was added to a mixture of 14 equiv. of

ammonium hydroxide (25 M) and 1 mL of diethyl ether, and stirred at room temperature

for 30 minutes until the solid disappeared completely. The ether layer was separated, the

aqueous layer extracted with diethyl ether, and the combine ethereal extracts were treated

with an excess of 1 M hydrochloric acid. The aqueous solution was separated, extracted

once with diethyl ether, and then made alkaline with aqueous sodium hydroxide. The

separated oil was extracted with diethyl ether, dried over magnesium sulfate, filtered and

concentrated under vacuum. For the synthesis of pyridine 47b the reaction required reflux

with ammonium hydroxide for 6h.

2-(1R,3R-1-methyl-3-isopropyl-cyclopentyl)-4,6-diphenylpyridine (47a)

From 0.050 g (0.1 mmol) of pyrylium 45a, and 60 μL (1.4 mmol) of NH4OH and

1 mL of diethyl ether, compound 47a obtained as a brown oil (0.035 g, 0.10 mmol, 90%

81

yield). [α]D20 -13 (c = 0.7, EtOAc). 1H NMR (500 MHz, CDCl3): δ 8.19-8.15 (m, 2H,


7.48-7.40 (m, 3H, ArH), 2.39 (ddd, J = 12.8, 9.9, 5.8 Hz, 1H), 2.07 (d, J = 5.2 Hz, 1H),

2.05-1.98 (m, 1H), 1.95 (ddd, J = 8.7, 7.7, 3.4 Hz, 2H), 1.88 (tdd, J = 12.8, 6.6, 2.7 Hz,

1H), 1.58-1.50 (m, 2H), 1.48 (s, 3H), 0.98 (d, J = 3.4 Hz, 3H), 0.96 (d, J = 3.4 Hz, 3H).

13C NMR (126 MHz, CDCl3): δ 170.4 (C), 156.2 (C), 149.5 (C), 140.2 (C), 139.8 (C),

129.1 (CH), 128.8 (CH), 128.8 (CH), 128.8 CH), 127.4 (CH), 127.1 (CH), 116.8 (CH),

115.6 (CH), 49.9 (C), 46.6 (CH), 45.1 (CH2), 39.1 (CH2), 34.1 (CH), 30.0 (CH2), 28.9

(CH3), 21.8 (CH3), 21.8 (CH3). HRMS (ESI): calculated for C26H29N [M+] 356.2373,

found 356.2372.

2-(1R,3R-1,2,2,3-tetramethyl-cyclopentyl)-4,6-diphenylpyridine (47b)

From 0.050 mg (0.1 mmol) of pyrylium 45b, 60 μL (1.4 mmol) of NH4OH and 1

mL of diethyl ether, compound 47b obtained as a brown oil (0.035 g, 0.10 mmol, 98%

yield). [α]D20 +82 (c = 0.7, EtOAc). 1H NMR (500 MHz, CDCl3): δ 8.15 (m, 2H, ArH),

7.76 (d, J = 1.4 Hz, 1H, ArH), 7.70-7.66 (m, 2H, ArH), 7.52-7.45 (m, 4H, ArH), 7.45-

7.37 (m, 3H, ArH), 2.98 (td, J = 12.4, 6.8 Hz, 1H), 2.22-2.10 (m, 1H), 2.10-1.96 (m, 1H),

1.73-1.62 (m, 1H), 1.46-1.37 (m, 1H), 1.41 (s, 3H), 1.22 (s, 3H), 0.92 (d, J = 6.9 Hz, 3H),

0.46 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 167.6 (C), 155.7 (C), 149.0 (1C), 140.2

(C), 139.9 (C), 129.1 (CH), 128.8 (CH), 128.7 (CH), 128.7 (CH), 127.4 (CH), 127.1

(CH), 118.0 (CH), 115.4 (CH), 54.7 (C), 46.5 (C), 42.2 (CH), 35.0 (CH2), 29.2 (CH2),

25.2 (CH3), 22.5 (CH3), 19.5 (CH3), 15.2 (CH3). HRMS (ESI): calculated for C26H29N

[M+] 356.2373, found 356.2372.

82

2-(1-(4-isobutylphenyl)-ethyl)-4,6-diphenylpyridine (47c)

From 0.050 g (0.1 mmol) of pyrylium 45c, 60 μL (1.4 mmol) of NH4OH and 1

mL of diethyl ether, compound 47c obtained as a brown oil (0.052 g, 0.13 mmol, 79%

yield). 1H NMR (500 MHz, CDCl3): δ 8.12 (m, 2H, ArH), 7.74 (d, J = 1.4 Hz, 1H, ArH),

7.62-7.58 (m, 2H, ArH), 7.51-7.39 (m, 6H, ArH), 7.32 (d, J = 8.0 Hz, 2H, ArH), 7.25-

7.21 (m, 1H, ArH), 7.08 (d, J = 8.1 Hz, 2H, ArH), 4.39 (q, J = 7.2 Hz, 1H), 2.43 (d, J =

7.2 Hz, 2H), 1.84 (sept., J = 7.8 Hz, 1H), 1.80 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.6 Hz,

6H). 13C NMR (126 MHz, CDCl3): δ 165.7 (C), 157.0 (C), 149.7 (C), 142.7 (C), 140.0

(C), 139.7 (C), 139.3 (C), 129.3 (CH), 129.1 (CH), 128.9 (CH), 128.9 (CH), 128.8 (CH),

127.7 (CH), 127.3 (CH), 127.2 (CH), 119.0 (CH), 116.3 (CH), 47.5 (CH), 45.2 (CH2),

30.4 (CH), 22.6 (CH3), 21.3 (CH3). HRMS (ESI): calculated for C29H29N [M+] 392.2373,

found 392.2376.

2-(2-methyl-cyclohexyl)-4,6-diphenylpyridine (47d)

From 0.043 g (0.1 mmol) of pyrylium 45d, and 60 μL (1.4 mmol) of NH4OH and

1 mL of diethyl ether, compound 47d obtained as a brown oil (0.025 g, 0.08 mmol, 77%

yield). 1H NMR (500 MHz, CDCl3): δ 8.10-8.06 (m, 2H, ArH), 7.73 (t, J = 2.1 Hz, 1H,

ArH), 7.71-7.67 (m, 2H, ArH), 7.51-7.45 (m, 4H, ArH), 7.45-7.38 (m, 2H, ArH), 7.25 (d,

J = 1.5 Hz, 1H, ArH), 2.51-2.41 (m, 1H), 2.00-1.89 (m, 2H), 1.89-1.78 (m, 3H), 1.78-

1.65 (m, 1H), 1.50-1.36 (m, 2H), 1.21-1.12 (m, 1H), 0.77 (d, J = 6.5 Hz, 3H). 13C NMR

(126 MHz, CDCl3): δ 166.4 (C), 157.3 (C), 149.3 (C), 140.3 (C), 139.4 (C), 129.1 (CH),

128.8 (CH), 128.8 (CH), 128.8 (CH), 127.3 (CH), 127.3 (CH), 118.9 (CH), 116.3 (CH),

54.6 (CH), 36.8 (CH), 35.7 (CH2), 34.4 (CH2), 26.8 (CH2), 26.7 (CH2), 21.0 (CH3).

HRMS (ESI): calculated for C24H25N [M+] 328.2059, found 328.2060.

83

2-(4-t-butyl-cyclohexyl)-4,6-diphenylpyridine (47e)

From 0.140 g (0.3 mmol) of pyrylium 45e, and 170 μL (4.2 mmol) of NH4OH and

1 mL of diethyl ether, compound 47e obtained as a brown oil (0.109 g, 0.3 mmol, 85%

yield). 1H NMR (500 MHz, CDCl3): δ 8.11-8.06 (m, 2H, ArH), 7.74 (d, J = 1.5 Hz, 1H,

ArH), 7.68 (dt, J = 8.3, 1.8 Hz, 2H, ArH), 7.53-7.37 (m, 6H, ArH), 7.30 (d, J = 1.5 Hz,

1H, ArH), 2.79 (tt, J = 12.2, 3.6 Hz, 1H), 2.18-2.12 (m, 2H), 1.99-1.91 (m, 2H), 1.68 (qd,

J = 12.6, 2.5 Hz, 2H), 1.27-1.12 (m, 3H), 0.91 (s, 9H). 13C NMR (126 MHz, CDCl3): δ

167.0 (C), 157.2 (C), 149.6 (C), 140.2 (C), 139.5 (C), 129.1 (CH), 128.9 (CH), 128.8

(CH), 128.8 (CH), 127.3 (CH), 127.3 (CH), 117.7 (CH), 116.3 (CH), 47.9 (CH), 47.0

(CH), 33.6 (CH2), 32.7 (C), 27.8 (CH3), 27.6 (CH2). HRMS (ESI): calculated for C29H31N

[M+] 370.2529, found 370.2535.

2-(cyclohexyl)-4,6-diphenylpyridine (47f)

From 0.080 g (0.2 mmol) of pyrylium 45f, and 110 μL (2.8 mmol) of NH4OH and

1 mL of diethyl ether, compound 47f obtained as a brown oil (0.055 g, 0.18 mmol, 80%

yield). 1H NMR (500 MHz, CDCl3): δ 8.10-8.06 (m, 2H, ArH), 7.73 (s, 1H, ArH), 7.67

(d, J = 7.2 Hz, 2H), 7.51-7.45 (m, 4H, ArH), 7.45-7.37 (m, 2H, ArH), 7.30 (s, 1H, ArH),

2.85 (tt, J = 12.0, 3.2 Hz, 1H), 2.12-2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.78 (d, J = 12.9

Hz, 1H), 1.67 (qd, J = 12.5, 3.1 Hz, 2H), 1.54-1.40 (m, 2H), 1.40-1.25 (m, 1H). 13C NMR

(126 MHz, CDCl3): δ 167.1 (C), 157.2 (C), 149.6 (C), 140.2 (C), 139.5 (C), 129.1 (CH),

128.8 (CH), 128.8 (CH), 128.8 (CH), 127.3 (CH), 127.2 (CH), 117.7 (CH), 116.3 (CH),

46.9 (CH), 33.2 (CH2), 26.8 (CH2), 26.4 (CH2). HRMS (ESI): calculated for C23H23N

[M+] 314.1903, found 314.1912.

84

Symmetric Compounds

General Procedure for the Preparation of the Pyrylium Salts 49a-b

1 equiv. of tert-butanol, 4 equiv. of acyl chloride and 3 equiv. of tetrafluoroboric

acid diethyl etherate (51-57% HBF4 in diethyl ether, 7.3 M) were heated at 85 oC for 2 h.

The solution turned deep red. After cooling to room temperature the reaction mixture was

poured into diethyl ether and the pyrylium salt precipitated from the reaction mixture.

Recrystallization from methanol gave white needles.

2,6-bis(2-methyl-cyclohexyl)-4-methyl-pyrylium tetrafluoroborate (49a)

From 0.17 mL (1.9 mmol) of tert-butanol, 1.270 g (8 mmol) of 2-methyl-

cyclohexanoyl chloride and 0.8 mL (5.8 mmol) of tetrafluoroboric acid diethyl etherate

(51-57% HBF4 in diethyl ether, 7.3 M) pyrylium 49a was obtained as white needles.

Unresolved starting material. Compound obtained as white needles (0.272 g, 0.73

mmol, 37% yield). Mp 127-129 oC. 1H NMR (500 MHz, CDCl3) δ 7.81 (s, minor

stereoisomer 7% of total), 7.79 (s, second stereoisomer 24% of total), 7.77 (s, major

stereoisomer 26% of total), 7.74 (s, major stereoisomer), 7.73 (s, second stereoisomer),

7.70 (s, fifth stereoisomer 21% of total), 7.68 (s, fourth stereoisomer 22% of total). 13C

NMR (126 MHz, CDCl3) δ 183.5 (ortho-pyrylium), 183.3 (ortho-pyrylium), 183.3

(ortho-pyrylium), 183.2 (ortho-pyrylium), 175.3 (para-pyrylium), 174.7 (para-

pyrylium), 123.0 (meta-pyrylium), 122.9 (meta-pyrylium), 122.7 (meta-pyrylium), 122.4

(meta-pyrylium), 51.6, 46.5, 46.4, 46.3, 36.6, 36.2, 34.7, 34.6, 33.5, 33.5, 33.3, 32.6,

32.5, 32.5, 32.2, 31.7, 25.7, 25.5, 25.5, 25.1, 25.1, 25.0, 25.0, 24.2, 24.1, 22.5, 22.3, 22.2,

85

20.6, 20.1, 19.9, 19.9, 14.0 (CH3), 13.8 (CH3), 13.7 (CH3). HRMS (ESI): calculated for

C20H31O [M+] 287.2369, found 287.2371.

Partially resolved starting material. Compound obtained as white needles (0.250

g, 0.67 mmol, 33% yield). 1H NMR (500 MHz, CDCl3) δ 7.81 (s, minor stereoisomer

4.5% of total), 7.79 (s, fourth stereoisomer 14% of total), 7.77 (s, second stereoisomer

30% of total), 7.74 (s, second stereoisomer), 7.73 (s, fourth stereoisomer), 7.70 (s, minor

stereoisomer 36% of total), 7.68 (s, third stereoisomer 15.5% of total), 0.79 (d, J = 7.0

Hz, minor stereoisomer 19.5% of total), 0.78 (d, J = 7.1 Hz, major stereoisomer 49.8% of

total), 0.78 (d, J = 7.4 Hz, second stereoisomer 30.7% of total). 13C NMR (126 MHz,

CDCl3) δ 183.4 (ortho-pyrylium), 183.4 (ortho-pyrylium), 183.3 (ortho-pyrylium), 175.2

(para-pyrylium), 174.6 (para-pyrylium), 123.0 (meta-pyrylium), 123.0 (meta-pyrylium),

122.6 (meta-pyrylium), 122.4 (meta-pyrylium), 51. 8, 51.7, 46.6, 46.5, 46.4, 36.7, 36.3,

34.8, 33.5, 33.3, 32.6, 32.6, 32.5, 31.8, 25.7, 25.5, 25.2, 25.1, 25.0, 24.3, 24.3, 24.2, 22.5,

22.3, 22.2, 20.7, 20.1, 19.9, 19.7, 14.0, 13.9 (CH3), 13.8 (CH3), 13.8 (CH3).

2,6-bis(4-t-butyl-cyclohexyl)-4-methyl-pyrylium tetrafluoroborate (49b)

From 0.11 mL (1.25 mmol) of tert-butanol, 1.002 g (4.9 mmol) of 4-t-butyl-

cyclohexanoyl chloride and 0.5 mL (3.65 mmol) of tetrafluoroboric acid diethyl etherate

(51-57% HBF4 in diethyl ether, 7.3 M), compound 49b obtained as white needles (0.241

g, 0.53 mmol, 43% yield). Mp 212-214 oC. 1H NMR (500 MHz, CDCl3) δ 7.84 (s, minor

stereoisomer 15% of total), 7.80 (s, major stereoisomer 57% of total), 7.77 (s, major

stereoisomer), 7.73 (s, third stereoisomer 28% of total), 2.82 (s, CH3-Ar minor

stereoisomer), 2.79 (s, major stereoisomer), 2.77 (s, third stereoisomer), 0.87 (s, t-butyl

86

major stereoisomer), 0.82 (s, third stereoisomer), 0.79 (s, minor stereoisomer). 13C NMR

(126 MHz, CDCl3) δ 183.7 (ortho-pyrylium), 183.6 (ortho-pyrylium), 183.5 (ortho-

pyrylium), 183.2 (ortho-pyrylium), 175.7 (para-pyrylium), 175.1 (para-pyrylium), 174.2

(para-pyrylium), 123.1 (meta-pyrylium), 122.8 (meta-pyrylium), 121.9 (meta-pyrylium),

121.7 (meta-pyrylium), 47.8, 47.8, 47.1, 47.1, 43.8, 43.7, 39.1, 39.0, 32.7, 32.6, 32.6,

31.1, 31.0, 28.5, 28.3, 27.5 (t-butyl), 27.5 (t-butyl), 27.4 (t-butyl), 26.6, 26.6, 24.2, 24.1,

24.1, 23.7, 23.7. HRMS (ESI): calculated for C26H43O [M+] 371.3308, found 371.3310.

General Procedure for the Preparation of the Pyridines 50a-b

Same procedure used for the synthesis of the unsymmetrical pyridines (47 a-f).

2,6-bis(2-methyl-cyclohexyl)-4-methyl-pyridine (50a)

From 0.050 g (0.13 mmol) of 49a, 60 μL (1.5 mmol) of NH4OH and 1 mL of

diethyl ether, compound 50a obtained as a brown oil (0.028 g, 0.10 mmol, 77% yield). 1H

NMR (500 MHz, CDCl3) δ 6.71 (s, third stereoisomer 13.6% of total), 6.70 (s, minor

stereoisomer 4% of total), 6.69 (s, second stereoisomer 23.6% of total), 6.68 (s, major

stereoisomer 58.8% of total ), 2.29 (s, CH3-Ar), 2.28 (s, CH3-Ar), 0.65 (d, J = 6.2 Hz,

minor stereoisomer 5% of total), 0.64 (d, J = 7.2 Hz, major stereoisomer 47% of total),

0.63 (d, J = 6.4 Hz, third stereoisomer 16% of total), 0.61 (d, J = 7.2 Hz, second

stereoisomer 32% of total), 0.61 (d, J = 7.2 Hz, second stereoisomer). 13C NMR (126

MHz, CDCl3) δ 164.8 (ortho-pyridine), 164.1 (ortho-pyridine), 164.0 (ortho-pyridine),

146.5 (para-pyridine), 146.4 (para-pyridine), 146.3 (para-pyridine), 146.0 (para-

pyridine), 119.8 (meta-pyridine), 119.7 (meta-pyridine), 119.7 (meta-pyridine), 119.4

(meta-pyridine), 119.3 (meta-pyridine), 54.3, 54.2, 54.2, 50.2, 50.2, 48.4, 48.2, 48.1,

87

48.1, 37.3, 37.1, 36.9, 36.6, 35.8, 35.7, 35.7, 35.7, 35.3, 35.3, 35.3, 35.3, 34.7, 34.7, 34.7,

34.4, 34.31, 34.29, 34.1, 33.5, 33.5, 33.4, 33.3, 33.3, 32.6, 31.4, 31.4, 31.3, 30.9, 26.9,

26.8, 26.8, 26.8, 26.7, 26.6, 26.5, 26.6, 26.4, 26.4, 24.9, 24.9, 24.8, 24.7, 21.5, 21.4, 21.4,

21.4, 22.0, 21.0, 20.9, 20.75, 20.70, 20.7 (Ar-CH3), 20.7, 20.6 (Ar-CH3), 13.2 (CH3), 13.2

(CH3), 13.1 (CH3). HRMS (ESI): calculated for C20H32N [M+] 286.2529, found 286.2536.

2,6-bis(4-t-butyl-cyclohexyl)-4-methyl-pyridine (50b)

From 0.050 g (0.11 mmol) of 49b, 60 μL (1.5 mmol) of NH4OH and 1 mL of

diethyl ether, compound 50b obtained as a brown oil (0.032 g, 0.09 mmol, 78% yield).

1H NMR (500 MHz, CDCl3) δ 6.88 (s, major stereoisomer 60% of total), 6.87 (s, minor

stereoisomer 5% of total), 6.77 (s, third stereoisomer 35% of total), 6.73 (s, major

stereoisomer), 2.29 (s, CH3-Ar), 2.28 (s, CH3-Ar), 0.88 (s, major stereoisomer 60% of

total), 0.88 (s, third stereoisomer 35% of total), 0.81 (s, major stereoisomer), 0.79 (s,

minor stereoisomer 5% of total). 13C NMR (126 MHz, CDCl3) δ 165.9 (ortho-pyridine),

165.5 (ortho-pyridine), 165.1 (ortho-pyridine), 164.1 (ortho-pyridine), 147.3 (para-

pyridine), 146.7 (para-pyridine), 146.6 (para-pyridine), 120.1 (meta-pyridine), 119.5

(meta-pyridine), 118.8 (meta-pyridine), 118.4 (meta-pyridine), 48.7, 48.5, 47.9, 46.6,

46.6, 39.2, 33.7, 33.5, 32.8, 32.6, 30.5, 30.3, 27.8, 27.8, 27.7, 27.7, 27.6, 27.6, 23.2, 23.1,

21.4, 21.4. HRMS (ESI): calculated for C26H44N [M+] 370.3468, found 371.3478.

Pyridinium Compounds

General Procedure for the Preparation of the Pyridiniums 64 and 6571

1 equiv. of pyrylium tetrafluoroborate and 1.5 equiv. of semithiocarbazide were

refluxed in ethanol for 1 h. After cooling to room temperature the reaction mixture was

88

left in the freezer overnight. Compound 64 precipitated as a white powder, and was

removed by filtration. Compound 65 formed a brown paste that was filtered. Sonication

of the paste with diethyl ether allowed us to obtain the pyridinium as a white solid.

Pyridinium 64

From 0.682 g (7.5 mmol) of thiosemicarbazide, 1.005 g of (5.0 mmol) 2,4,6-

trimethylpyrylium tetrafluoroborate and 5 mL ethanol, compound 64 obtained as a white

powder (1.094 g, 3.86 mmol, 77% yield). 1H NMR (500 MHz, acetone-d6) δ 8.98 (s, 1H,

NH), 8.10 (s, 2H, NH2), 7.89 (s, 2H), 2.77 (s, 6H), 2.67 (s, 3H). 13C NMR (126 MHz,

acetone-d6) δ 183.6 (C), 162.0 (C), 159.2 (CH), 128.7 (C), 22.0 (CH3), 19.4 (CH3).

HRMS (ESI): calculated for C9H14N3S [M+] 196.0903, found 196.0903.

Pyridinium 65

From 0.170 g (1.8 mmol) of thiosemicarbazide, 0.503 g (1.2 mmol) of 2,6-

diphenyl-4-(p-toluoyl)pyrylium tetrafluoroborate and 5 mL ethanol, compound 65

obtained as a white powder (0.179 g, 0.37 mmol, 30% yield). 1H NMR (500 MHz,

acetone-d6) δ 11.06 (s, 1H, NH), 8.56 (s, 2H), 8.24 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 7.3

Hz, 4H), 7.63 (dt, J = 24.6, 7.2 Hz, 8H), 7.51 (d, J = 8.0 Hz, 2H), 2.47 (s, 3H). 13C NMR

(126 MHz, acetone-d6) δ 160.4 (C), 158.6 (C), 145.0 (C), 132.2 (C), 131.9 (CH), 131.7

(C), 131.4 (CH), 130.9 (CH), 129.8 (CH), 129.4 (CH), 126.1 (CH), 21.5 (CH3). HRMS

(ESI): calculated for C25H22N3S [M+] 396.1529, found 396.1509.

89

Epimerization Experiments

Base Solution Preparation

Stock solutions of TEA, N-methylmorpholine and pyridine were prepared by

dissolving 10 L of the amine in 990 L of the deuterated solvent, which was chosen

according to the NMR resolution. The concentration of the solutions were [TEA] = 0.072

M, [N-methylmorpholine] = 0.091 M and [pyridine] = 0.124 M.

Base-catalyzed Epimerization Experiments

Epimerization of 49a with different bases. A solution of 0.022 M of pyrylium 49a

in CDCl3 was prepared by dissolving 8 mg (0.022 mmoles) in 990 L of the solvent in a

NMR tube. Base (5 mol%, 0.0011 M) was added, either 16 L of the TEA stock solution,

12 L of the N-methylmorpholine stock solution, or 9 L of the pyridine stock solution,

to the solution and 1H NMR was taken at different time intervals.

Epimerization of 49b with different concentration of N-methylmorpholine. A

solution of 0.022 M of pyrylium 49b in CD3CN was prepared by dissolving 10 mg (0.022

mmoles) in 990 L of the solvent in a NMR tube. N-methylmorpholine stock solution

was added, either 12 L (5 mol% of base, 0.0011 M), 9.8 L (4 mol% of base, 0.0008

M), 6.5 L (2.7 mol% of base, 0.0006 M) or 3.25 L (1.4 mol% of base, 0.0003 M) to

the solution and 1H NMR was taken at different time intervals.

Epimerization of pyryliums 45d, 49a, and 49b with 5 mol% solution of N-

methylmorpholine. A solution of 0.022 M of pyrylium in deuterated solvent (CD3CN or

90

CDCl3) was prepared by dissolving 8-10 mg (0.022 mmoles) in 990 L of the solvent in a

NMR tube. 5 mol% of base (0.0011 M) was added to the solution and 1H NMR was taken

at different time intervals. For pyrylium 45d, 9 mg (0.022 mmoles) of pyrylium were

dissolved in CD3CN and 13 L of the stock solution were added. For pyrylium 49a, 8 mg

(0.022 mmoles) of pyrylium were dissolved in CDCl3 and 12 L of the stock solution

were added. For pyrylium 49b, 10 mg (0.022 mmoles) of pyrylium were dissolved in

CD3CN and 12 L of the stock solution were added.

Reversibility of pseudobase formation for pyrylium 45d with TEA. A solution of

10 mg (0.022 mmoles) of pyrylium 45d in 990 L of CD3CN was prepared. The

pseudobase was formed by adding 3.3 L (1 equiv.) of TEA and the 1H NMR was taken.

The solution was neutralized with 3.6 L (1.2 equiv.) of tetrafluoroboric acid (51-57%

HBF4 in diethyl ether, 7.3 M) and the 1H NMR was taken.

Pseudobase formation study for pyrylium 45e with N-methylmorpholine. A

solution of 10 mg (0.022 mmoles) of pyrylium 45e in 990 L of CD3CN was prepared.

Subsequent additions of 0.1 equiv. (24 L) of the stock solution of N-methylmorpholine

were added until addition of 1 equiv., and 1H NMR was taken at each addition.

91

APPENDIX

92

APPENDIX A

Selected NMR Spectra

Spectra page A.1 1H NMR (acetone-d6, 500 MHz) of Compound 45a ..................................................95 A.2 13C NMR (acetone-d6, 125 MHz) of Compound 45a .................................................96 A.3 1H NMR (acetone-d6, 500 MHz) of Compound 45b ..................................................97 A.4 13C NMR (acetone-d6, 125 MHz) of Compound 45b .................................................98 A.5 1H NMR (acetone-d6, 500 MHz) of Compound 45c ...................................................99 A.6 13C NMR (acetone-d6, 125 MHz) of Compound 45c ................................................100 A.7 1H NMR (CD3CN, 500 MHz) of Compound 45d .....................................................101 A.8 13C NMR (CD3CN, 125 MHz) of Compound 45d....................................................102 A.9 1H NMR (acetone-d6, 500 MHz) of Compound 45e .................................................103 A.10 13C NMR (acetone-d6, 125 MHz) of Compound 45e..............................................104 A.11 1H NMR (acetone-d6, 500 MHz) of Compound 45f ...............................................105 A.12 13C NMR (acetone-d6, 125 MHz) of Compound 45f ..............................................106 A.13 1H NMR (CD3Cl, 500 MHz) of Compound 46a .....................................................107 A.14 13C NMR (CD3Cl, 125 MHz) of Compound 46a ...................................................108 A.15 31P NMR (CDCl3, 202 MHz) of Compound 46a ....................................................109 A.16 1H NMR (CD3Cl, 500 MHz) of Compound 46b ....................................................110 A.17 13C NMR (CD3Cl, 125 MHz) of Compound 46b ...................................................111 A.18 31P NMR (CDCl3, 202 MHz) of Compound 46b ....................................................112 A.19 1H NMR (CD3Cl, 500 MHz) of Compound 46c .....................................................113

93

A.20 13C NMR (CD3Cl, 125 MHz) of Compound 46c ....................................................114 A.21 31P NMR (CDCl3, 202 MHz) of Compound 46c ....................................................115 A.22 1H NMR (CD3Cl, 500 MHz) of Compound 46d ....................................................116 A.23 13C NMR (CD3Cl, 125 MHz) of Compound 46d ...................................................117 A.24 31P NMR (CDCl3, 202 MHz) of Compound 46d ....................................................118 A.25 1H NMR (CD3Cl, 500 MHz) of Compound 46e .....................................................119 A.26 13C NMR (CD3Cl, 125 MHz) of Compound 46e ....................................................120 A.27 31P NMR (CDCl3, 202 MHz) of Compound 46e ....................................................121 A.28 1H NMR (CD3Cl, 500 MHz) of Compound 46f .....................................................122 A.29 13C NMR (CD3Cl, 125 MHz) of Compound 46f ....................................................123 A.30 31P NMR (CDCl3, 202 MHz) of Compound 46f .....................................................124 A.31 1H NMR (CD3Cl, 500 MHz) of Compound 47a .....................................................125 A.32 13C NMR (CD3Cl, 125 MHz) of Compound 47a ...................................................126 A.33 1H NMR (CD3Cl, 500 MHz) of Compound 47b ....................................................127 A.34 13C NMR (CD3Cl, 125 MHz) of Compound 47b ...................................................128 A.35 1H NMR (CD3Cl, 500 MHz) of Compound 47c .....................................................129 A.36 13C NMR (CD3Cl, 125 MHz) of Compound 47c ....................................................130 A.37 1H NMR (CD3Cl, 500 MHz) of Compound 47d ....................................................131 A.38 13C NMR (CD3Cl, 125 MHz) of Compound 47d ...................................................132 A.39 1H NMR (CD3Cl, 500 MHz) of Compound 47e .....................................................133 A.40 13C NMR (CD3Cl, 125 MHz) of Compound 47e ....................................................134 A.41 1H NMR (CD3Cl, 500 MHz) of Compound 47f .....................................................135 A.42 13C NMR (CD3Cl, 125 MHz) of Compound 47f ....................................................136

94

A.43 1H NMR (CD3Cl, 500 MHz) of Compound 49a (unresolved starting material) ..........................................................................................137 A.44 13C NMR (CD3Cl, 125 MHz) of Compound 49a (unresolved starting material) ..........................................................................................138 A.45 1H NMR (CD3Cl, 500 MHz) of Compound 49a (resolved starting material) ..............................................................................................139 A.46 13C NMR (CD3Cl, 125 MHz) of Compound 49a (resolved starting material) ..............................................................................................140 A.47 1H NMR (CD3Cl, 500 MHz) of Compound 49b ....................................................141 A.48 13C NMR (CD3Cl, 125 MHz) of Compound 49b ...................................................142 A.49 1H NMR (CD3Cl, 500 MHz) of Compound 50a .....................................................143 A.50 13C NMR (CD3Cl, 125 MHz) of Compound 50a ...................................................144 A.511H NMR (CD3Cl, 500 MHz) of Compound 50b .....................................................145 A.52 13C NMR (CD3Cl, 125 MHz) of Compound 50b ...................................................146 A.53 1H NMR (acetone-d6, 500 MHz) of Compound 65 ................................................147 A.54 13C NMR (acetone-d6, 125 MHz) of Compound 65 ...............................................148 A.55 1H NMR (acetone-d6, 500 MHz) of Compound 66 ................................................149 A.56 13C NMR (acetone-d6, 125 MHz) of Compound 66 ...............................................150

95

Spe

ctra

A.1

1 H N

MR

(ac

eton

e-d 6

, 500

MH

z) o

f C

ompo

und

45a

96

Spe

ctra

A.2

13C

NM

R (

acet

one-

d 6, 1

25 M

Hz)

of

Com

poun

d 45

a

97

Spe

ctra

A.3

1 H N

MR

(ac

eton

e-d 6

, 500

MH

z) o

f C

ompo

und

45b

98

Spe

ctra

A.4

13C

NM

R (

acet

one-

d 6, 1

25 M

Hz)

of

Com

poun

d 45

b

Ph

OP

h

BF

4

99

Spe

ctra

A.5

1 H N

MR

(ac

eton

e-d 6

, 500

MH

z) o

f C

ompo

und

45c

Ph

OP

h

BF

4

100

Spe

ctra

A.6

13C

NM

R (

acet

one-

d 6, 1

25 M

Hz)

of

Com

poun

d 45

c

101

Spe

ctra

A.7

1 H N

MR

(C

D3C

N, 5

00 M

Hz)

of

Com

poun

d 45

d

00.

51.

01.

52.

02.

53.

03.

54.

04.

55.

05.

56.

06.

57.

07.

58.

08.

59.

0f1

(pp

m)

0.91

0.92

0.93

0.94

0.95

0.96

f1 (

ppm

)

(d)

0.94

J(7.

15)

(d)

0.92

J(6.

51)

OPh

Ph

BF

4

102

Spe

ctra

A.8

13C

NM

R (

CD

3CN

, 125

MH

z) o

f C

ompo

und

45d

010

2030

4050

6070

8090

100

110

120

130

140

150

160

170

180

190

f1 (

ppm

)

OPh

Ph

BF

4

Ph

OP

h

BF

4

103

Spe

ctra

A.9

1 H N

MR

(ac

eton

e-d 6

, 500

MH

z) o

f C

ompo

und

45e

Ph

OP

h

BF

4

104

Spe

ctra

A.1

0 13

C N

MR

(ac

eton

e-d 6

, 125

MH

z) o

f C

ompo

und

45e

Ph

OP

h

BF

4

105

Spe

ctra

A.1

1 1 H

NM

R (

acet

one-

d 6, 5

00 M

Hz)

of

Com

poun

d 45

f

Ph

OP

h

106

BF

4

Spe

ctra

A.1

2 13

C N

MR

(ac

eton

e-d 6

, 125

MH

z) o

f C

ompo

und

45f

107

Spe

ctra

A.1

3 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

46a

108

Spe

ctra

A.1

4 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 46

a

109

Spe

ctra

A.1

5 31

P N

MR

(20

2 M

Hz,

CD

Cl 3

) of

Com

poun

d 46

a

110

Spe

ctra

A.1

6 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

46b

111

Spe

ctra

A.1

7 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 46

b

112

Spe

ctra

A.1

8 31

P N

MR

(20

2 M

Hz,

CD

Cl 3

) of

Com

poun

d 46

b

113

Spe

ctra

A.1

9 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

46c

114

Spe

ctra

A.2

0 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 46

c

115

Spe

ctra

A.2

1 31

P N

MR

(20

2 M

Hz,

CD

Cl 3

) of

Com

poun

d 46

c

116

Spe

ctra

A.2

2 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

46d

117

Spe

ctra

A.2

3 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 46

d

118

Spe

ctra

A.2

4 31

P N

MR

(20

2 M

Hz,

CD

Cl 3

) of

Com

poun

d 46

d

119

Spe

ctra

A.2

5 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

46e

120

Spe

ctra

A.2

6 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 46

e

121

Spe

ctra

A.2

7 31

P N

MR

(20

2 M

Hz,

CD

Cl 3

) of

Com

poun

d 46

e

122

Spe

ctra

A.2

8 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

46f

+ =

Met

hyl

cycl

open

tane

123

Spe

ctra

A.2

9 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 46

f

124

Spe

ctra

A.3

0 31

P N

MR

(20

2 M

Hz,

CD

Cl 3

) of

Com

poun

d 46

f

125

Spe

ctra

A.3

1 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

47a

126

Spe

ctra

A.3

2 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 47

a

Ph

NP

h

127

Spe

ctra

A.3

3 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

47b

Ph

NP

h

128

Spe

ctra

A.3

4 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 47

b

Ph

129

NP

h

Spe

ctra

A.3

5 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

47c

130

Spe

ctra

A.3

6 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 47

c

Ph

NP

h

131

Spe

ctra

A.3

7 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

47d

Ph

NP

h

132

Spe

ctra

A.3

8 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 47

d

133

Spe

ctra

A.3

9 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

47e

134

Spe

ctra

A.4

0 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 47

e

135

Spe

ctra

A.4

1 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

47f

136

Spe

ctra

A.4

2 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 47

f

137

Spe

ctra

A.4

3 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

49a

(unr

esol

ved

star

ting

mat

eria

l)

138

Spe

ctra

A.4

4 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 49

a (u

nres

olve

d st

arti

ng m

ater

ial)

139

Spe

ctra

A.4

5 1 H

NM

R (

CD

3Cl,

500

MH

z) o

f C

ompo

und

49a

(res

olve

d st

arti

ng m

ater

ial)

140

Spe

ctra

A.4

6 13

C N

MR

(C

D3C

l, 12

5 M

Hz)

of

Com

poun

d 49

a (r

esol

ved

star

ting

mat

eria

l)

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