Preparation of Heteroatom-Substituted 1,3-Thiazoles As Building Blocks for Liquid Crystal Synthesis

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PREPARATION OF HETEROATOM-SUBSTITUTED 1,3-THIAZOLES AS BUILDING BLOCKS FOR LIQUID CRYSTAL SYNTHESIS

A dissertation submitted

to Kent State University in partial

fulfillment of the requirements for the

degree of Doctor of Philosophy

Alan M. Grubb

December, 2011

Dissertation written by Alan M. Grubb B.S., Marietta College, USA, 2005 Ph.D., Kent State University, USA, 2011

Approved by

, Chair, Doctoral Dissertation Committee Dr. Paul Sampson

, Chair, Doctoral Dissertation Committee Dr. Alexander Seed

, Members, Doctoral Dissertation Committee Dr. Robert Twieg

Dr. Soumitra Basu

Dr. Brett Ellman

Dr. Philip Bos

Accepted by

, Chair, Department of Chemistry Dr. Michael Tubergen

, Dean, College of Arts and Sciences Dr. John R. D. Stalvey ii

TABLE OF CONTENTS

LIST OF FIGURES ...... vi

LIST OF SCHEMES ...... ix

LIST OF TABLES ...... xvii

LIST OF ABBREVIATIONS ...... xix

ACKNOWLEDGMENTS ...... xxiv

CHAPTER 1. INTRODUCTION ...... 1

1.1. Introduction to smectic C* liquid crystal phases ...... 1

1.2. General structure of ferroelectric liquid crystals ...... 9

1.3. Use of sulfur-based heterocycles in liquid crystals...... 11

1.4. Rationale for targeting alkoxy-1,3-thiazole-based liquid crystals ...... 14

1.5. Reactivity of 1,3-thiazole rings ...... 20

1.6. Overview of dissertation goals...... 22

CHAPTER 2. SYNTHESIS OF 5-ALKOXY-1,3-THIAZOLE LIQUID CRYSTAL TARGETS ...... 23

2.1. Literature approaches to 5-alkoxy-1,3-thiazoles...... 23

2.2. Synthesis of 5-alkoxy-1,3-thiazole-containing liquid crystals via a Lawesson’s reagent-mediated ring closing strategy ...... 25

CHAPTER 3. DIHALO-1,3-THIAZOLES AS BUILDING BLOCKS FOR ORGANIC SYNTHESIS ...... 31

3.1. Introduction to dihalo-1,3-thiazoles as building blocks for organic synthesis ...... 31

3.2.1. Literature approaches to 2,5-dibromo-1,3-thiazole (3.3) ...... 31

3.2.2. A new approach for the preparation of 2,5-dibromo-1,3-thiazole (3.3) ...... 33

iii

3.3.1. Literature approaches to 2,5-dichloro-1,3-thiazole (3.8) ...... 36

3.3.2. A new approach for the preparation of 2,5-dichloro-1,3-thiazole (3.8) ...... 36

3.4.1. Literature approaches to 2,4-dibromo-1,3-thiazole (3.11) ...... 37

3.4.2. A new approach for the preparation of 2,4-dibromo-1,3-thiazole (3.11) ...... 38

3.5.1. Introduction to mixed dihalo-1,3-thiazole building blocks ...... 39

3.5.2. Literature approaches to mixed 2,5-dihalo-1,3-thiazoles ...... 40

3.5.3. New approaches for the preparation of mixed 2,5-dihalo-1,3-thiazoles ...... 42

3.5.4. Alternative approach to the preparation 5-bromo-2-iodo-1,3-thiazole (3.18) ...... 49

CHAPTER 4. SYNTHESIS OF 2-ALKOXY-1,3-THIAZOLE LIQUID CRYSTAL TARGETS ...... 51

4.1. Literature approaches to 2-alkoxy-1,3-thiazoles...... 51

4.2. Preparation of 2-alkoxy-1,3-thiazole-containing liquid crystal targets via selective SNAr chemistry of 2,5-dibromo-1,3-thiazole (3.3) ...... 53

CHAPTER 5. 4-FLUORO-1,3-THIAZOLE LIQUID CRYSTALS ...... 73

5.1. Rationale for targeting 4-fluoro-1,3-thiazole-based liquid crystals ...... 73

5.2. Literature approaches to 4-fluoro-1,3-thiazoles ...... 75

5.3. De novo approaches to 4-fluoro-1,3-thiazoles ...... 78

5.4. Halogen-metal exchange approaches leading to 4-fluoro-1,3-thiazoles ...... 84

5.5. Fluorination via nucleophilic sources of fluorine ...... 95

5.6. Preparation of 4-fluoro-1,3-thiazole-containing liquid crystal targets via fluorination using electrophilic aromatic substitution ...... 100

CHAPTER 6. 2- AND 5-CARBOXY-1,3-THIAZOLE LIQUID CRYSTALS ...... 115

6.1. Rationale for targeting 2- and 5-carboxy-1,3-thiazole-based liquid crystals ...... 115

6.2. Synthesis of 5-carboxy-1,3-thiazole-based liquid crystals via selective Suzuki coupling of 2,5-dibromo-1,3-thiazole (3.3) ...... 115 iv

6.3. Attempted synthesis of 2-carboxy-1,3-thiazole-based liquid crystals ...... 119

CHAPTER 7. TRANSITION TEMPERATURES AND COMPARISON OF LIQUID CRYSTALLINE TARGETS ...... 129

7.1.1. Liquid crystalline properties of synthesized alkoxy-4-cyanophenyl-1,3-thiazole- based liquid crystals ...... 129

7.1.2. Comparison of alkoxy-4-cyanophenyl-1,3-thiazole-based liquid crystals ...... 133

7.2.1. Liquid crystalline properties of synthesized 1,3-thiazole containing (S)-4-(1- methylheptyloxy)phenyl-based liquid crystals ...... 136

7.2.2. Comparison of (S)-4-(1-methylheptyloxy)phenyl-based liquid crystals ...... 141

CHAPTER 8. ELECTRO-OPTICAL STUDIES ...... 150

8.1. Determination of pitch in relation to temperature ...... 150

8.2. Determination of polarization current ...... 151

8.3. Determination of tilt angle ...... 153

8.4. Determination of switching time ...... 155

CHAPTER 9. CONCLUSIONS ...... 158

CHAPTER 10. EXPERIMENTAL ...... 163

10.1. Experimental for Chapter 2 ...... 164

10.2. Experimental for Chapter 3 ...... 191

10.3. Experimental for Chapter 4 ...... 197

10.4. Experimental for Chapter 5 ...... 220

10.5. Experimental for Chapter 6 ...... 265

CHAPTER 11. REFERENCES ...... 273

LIST OF FIGURES

Figure 1.1: Typical ordering of common mesophases...... 1

Figure 1.2: McMillan’s model for the origin of tilted smectic phases...... 2

Figure 1.3: Wulf’s model for the origin of tilted smectic phases...... 3

Figure 1.4: Schematic arrangement of molecules for the achiral smectic C phase (top) and the chiral smectic C* phase (bottom)...... 4

Figure 1.5: Helical structure of the smectic C* phase...... 6

Figure 1.6: General structure of ferroelectric liquid crystals...... 9

Figure 1.7: Central linkages which promote formation of the smectic C phase...... 10

Figure 1.8: Terminal groups which promote formation of the smectic C phase...... 10

Figure 1.9: Previously synthesized liquid crystalline targets containing sulfur-based heterocycles...... 11

Figure 1.10: Strength and orientation of the dipole moments for thiophene, fluorothiophene, 1,3-thiazole, and 1,3,4-thiadiazole rings...... 12

Figure 1.11: Angle formed between the substituents of 2,5- and 2,4-substituents in sulfur- based heterocycles...... 12

Figure 1.12: Numbering system for the 1,3-thiazole ring...... 16

Figure 1.13: A representative selection of known 1,3-thiazole-containing mesogens. .... 17

Figure 1.14: General structure of the targeted 1,3-thiazole-based liquid crystals...... 17

Figure 1.15: Four variations of the targeted liquid crystals with the 1,3-thiazole ring occupying “Ring 1” or “Ring 2.” ...... 18

Figure 1.16: Illustration of the steric crowding experienced by Structure II which leads to a larger interannular torsion angle...... 19

Figure 1.17: General reactivity for each of the three carbons of 1,3-thiazole...... 21

Figure 5.1: Strength and orientation of the dipole moment for 1,3-thiazole and 4-fluoro-

1,3-thiazole...... 74

Figure 7.1: Plot of transition temperatures (°C) of compounds 2.8a-2.8e...... 130

Figure 7.2: Plot of transition temperatures (°C) of compounds 5.48a-5.48e...... 131

Figure 7.3: Plot of transition temperatures (°C) of compounds 4.5a-4.5e...... 133

Figure 7.4: Plot of transition temperatures (°C) of compounds 2.12a-2.12e...... 137

Figure 7.5: Plot of transition temperatures (°C) of compounds 5.76a-5.76e...... 139

Figure 7.6: Plot of transition temperatures (°C) of compounds 4.12a-4.12e...... 140

Figure 7.7: Plot of transition temperatures (°C) of compounds 7.3a-7.3e...... 142

Figure 8.1: Representative polarizing optical microscope textures of 25 μm thick films

(scale bars represent 200 μm). Left: compound 4.12e at 98.4 °C; Middle: compound

2.12e at 87.5 °C; Right: compound 5.76e at 64.3 °C...... 151

Figure 8.2: Typical time dependence of the electric current for compounds 4.12e, 2.12e, and 5.76e flowing through 5 μm thick films with triangular shaped voltages applied on the sandwich cells between the ITO electrodes...... 152

Figure 8.3: Integration of the electric current curves from Figure 8.2 as a function of the applied voltages...... 152

Figure 8.4: Plot of temperature versus spontaneous polarization for compounds 4.12e,

2.12e, and 5.76e...... 153

vii

Figure 8.5: Plot of voltage versus the tilt angle measured in 25 μm thick films of compounds 4.12e, 2.12e, and 5.76e...... 154

Figure 8.6: Plot of temperature versus the tilt angle for compounds 4.12e, 2.12e, and

5.76e...... 155

Figure 8.7: Plot of voltage versus the switching times at 80 °C for compounds 4.12e and

2.12e and 54 °C for compound 5.76e measured in 5 μm thick films...... 156

Figure 8.8: Plot of temperature versus the switching times for compounds 4.12e, 2.12e, and 5.76e measured at 10 V in 5 μm thick films...... 157

viii

LIST OF SCHEMES

Scheme 2.1: Synthesis of 5-alkoxy-1,3-thiazoles using P2S5 or Lawesson’s reagent...... 23

Scheme 2.2: Synthesis of 5-alkoxy-1,3-thiazoles using SNAr chemistry...... 24

Scheme 2.3: Qiao’s synthesis of 5-methoxy-2,4-diphenyl-1,3-thiazole...... 25

Scheme 2.4: Retrosynthetic analysis of the target compounds 2.12a-2.12e...... 26

Scheme 2.5: Synthesis of -acylamino esters 2.5a-2.5e...... 27

Scheme 2.6: Synthesis of 5-alkoxy-1,3-thiazoles 2.7a-2.7e via Lawesson’s reagent- mediated ring closure...... 28

Scheme 2.7: Synthesis of carboxylic acids 2.9a-2.9e...... 29

Scheme 2.8: Attempted synthesis of compound 2.9e from compound 2.7e...... 29

Scheme 2.9: Synthesis of (S)-4-(1-methylheptyloxy)phenyl 4-(5-alkoxy-1,3-thiazol-2- yl)benzoates 2.12a-2.12e...... 30

Scheme 3.1: Synthesis of 2,5-dibromo-1,3-thiazole (3.3) from 1,3-thiazole (3.1)...... 32

Scheme 3.2: Synthesis of 2,5-dibromo-1,3-thiazole (3.3) from 2-bromo-1,3-thiazole (3.2).

...... 32

Scheme 3.3: Synthesis of 2,5-dibromo-1,3-thiazole (3.3) from 2-amino-5-bromo-1,3- thiazole (3.4)...... 33

Scheme 3.4: Synthesis of 2-halo-1,3-thiazoles 3.2 and 3.6 from 2-amino-1,3-thiazole

(3.5)...... 34

Scheme 3.5: Synthesis of 2,5-dibromo-1,3-thiazole (3.3) from 2-bromo-1,3-thiazole (3.2).

...... 35

Scheme 3.6: Synthesis of 2,5-dichloro-1,3-thiazole (3.8) from 2-amino-5-chloro-1,3- thiazole (3.7)...... 36

Scheme 3.7: Synthesis of 2-chloro-1,3-thiazole (3.9) from 2-amino-1,3-thiazole (3.5). . 36

Scheme 3.8: Attempted synthesis of 2,5-dichloro-1,3-thiazole (3.8) from 2-chloro-1,3- thiazole (3.9)...... 37

Scheme 3.9: Synthesis of 2,4-dibromo-1,3-thiazole (3.11)...... 37

Scheme 3.10: Literature synthesis of 2-bromobenzo[d]thiazole (3.13)...... 38

Scheme 3.11: Synthesis of 2,4-dibromo-1,3-thiazole (3.11) from 1,3-thiazolidine-2,4- dione (3.10)...... 39

Scheme 3.12: Literature methods for synthesizing 2-bromo-5-iodo-1,3-thiazole (3.14). 41

Scheme 3.13: Literature methods for synthesizing 5-bromo-2-chloro-1,3-thiazole (3.16).

...... 41

Scheme 3.14: Literature method for synthesizing 2-bromo-5-chloro-1,3-thiazole (3.17) from 2-amino-5-chloro-1,3-thiazole (3.7)...... 42

Scheme 3.15: Literature method for synthesizing 5-bromo-2-iodo-1,3-thiazole (3.18) from compound 3.15...... 42

Scheme 3.16: Attempted synthesis of 2-bromo-5-chloro-1,3-thiazole (3.17) from 2- bromo-1,3-thiazole (3.2)...... 43

Scheme 3.17: Reaction of 2,5-dibromo-1,3-thiazole (3.3) with NCS and 2-chloro-1,3- thiazole (3.9)...... 45

Scheme 3.18: Reaction of 2,5-dibromo-1,3-thiazole (3.3) with NCS, BHT, and 10 mol%

2-chloro-1,3-thiazole (3.9)...... 47

Scheme 3.19: Reaction of 2-bromo-1,3-thiazole (3.2) with NCS and BHT...... 48

Scheme 3.20: Attempted synthesis of 5-bromo-2-iodo-1,3-thiazole (3.18) from 2,5- dibromo-1,3-thiazole (3.3)...... 50

Scheme 4.1: Klein’s synthesis of 2-methoxy-1,3-thiazole 4.2...... 51

Scheme 4.2: Use of SNAr chemistry for the synthesis of 2-heteroatom-substituted 1,3- thiazoles...... 52

Scheme 4.3: Synthesis of 2-alkoxy-5-halo-1,3-thiazoles using SNAr chemistry...... 52

Scheme 4.4: Retrosynthetic analysis of the target compounds 4.12a-4.12e...... 54

Scheme 4.5: Synthesis of 2-alkoxy-5-bromo-1,3-thiazoles 4.3a-4.3e...... 54

Scheme 4.6: Mechanism for formation of 2-alkoxy-5-bromo-1,3-thiazoles 4.3a-4.3e. ... 55

Scheme 4.7: Mechanism for formation of dialkyl carbonates...... 57

Scheme 4.8: Synthesis of 2-alkoxy-5-(4-cyanophenyl)-1,3-thiazoles 4.5a-4.5e...... 59

Scheme 4.9: Synthesis of 4-(2-alkoxy-1,3-thiazol-5-yl)benzoic acids 4.11a-4.11c and attempted synthesis of 4.11e...... 60

Scheme 4.10: Attempted Negishi coupling of 2-dodecyloxy-1,3-thiazol-5-yl zinc chloride and methyl 4-bromobenzoate...... 61

Scheme 4.11: Attempted Suzuki coupling of 2-dodecyloxy-1,3-thiazol-5-ylboronic acid

(4.7) with methyl 4-bromobenzoate...... 62

Scheme 4.12: Mechanisms for homocoupling of an aryl halide and protodeboronation of the boronic acids during Suzuki coupling...... 62

Scheme 4.13: Attempted Suzuki coupling of 4-carboxyphenylboronic acid (4.8) with compound 4.3e...... 63

Scheme 4.14: Synthesis of 4-(2-alkoxy-1,3-thiazol-5-yl)benzaldehydes 4.9c-4.9e...... 64

Scheme 4.15: Mechanism for the formation of 4-(1,3-thiazol-5-yl)benzaldehyde (4.10). 67

Scheme 4.16: Synthesis of 4-(2-alkoxy-1,3-thiazol-5-yl)benzoic acids 4.11c-4.11e...... 68

Scheme 4.17: Synthesis of (S)-4-(1-methylheptyloxy)phenyl 4-(2-(alkoxy)-1,3-thiazol-5- yl)benzoates 4.12a-4.12e...... 69

Scheme 4.18: Alternate synthesis of (S)-4-(1-methylheptyloxy)phenyl 4-(2-(octyloxy)-

1,3-thiazol-5-yl)benzoate (4.12a)...... 70

Scheme 5.1: Synthesis of 4-fluoro-1,3-thiazole 5.2 via lithiation...... 75

Scheme 5.2: Synthesis of 4-fluoro-1,3-thiazoles 5.4, 5.6, and 5.9 via electrophilic aromatic substitution...... 76

Scheme 5.3: Synthesis of 4-fluoro-1,3-thiazole 5.11 via SNAr chemistry...... 77

Scheme 5.4: Synthesis of 2-bromo-4-fluoro-1,3-thiazole (5.13) via a Balz-Schiemann reaction...... 77

Scheme 5.5: Synthesis of 4-fluoro-1,3-thiazole 5.16 from a side-reaction of SF4...... 78

Scheme 5.6: Required substrate for synthesis of a 4-fluoro-1,3-thiazole via ring closing.

...... 79

Scheme 5.7: Sheldrake’s synthesis of 5-aryl-1,3-thiazole 5.18...... 79

Scheme 5.8: Targeted precursor for the synthesis of 5-ethoxy-4-fluoro-1,3-thiazole

(5.21)...... 80

Scheme 5.9: Synthesis of trisubstituted-1,3-oxazole 5.24 from diazo compound 5.23. ... 81

Scheme 5.10: Synthesis of 4-bromo-1,3-oxazole 5.28 from ethyl diazobromoacetate

(5.26)...... 81

xii

Scheme 5.11: Synthesis of 5-fluoro-1,3-thiazol-4-one 5.30...... 82

Scheme 5.12: Synthesis of 2-(4-methoxyphenylthioamido)acetic acid (5.33)...... 83

Scheme 5.13: Synthesis of 4-fluoro-1,3-thiazol-4-one 5.35...... 83

Scheme 5.14: Synthesis of 4-fluoro-2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.44)...... 86

Scheme 5.15: Attempted synthesis of 4-fluoro-2-octyloxy-1,3-thiazole (5.46)...... 87

Scheme 5.16: Attempted synthesis of 2-(4-cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole

(5.48a)...... 89

Scheme 5.17: Proposed mechanism for silver-catalyzed fluorination...... 90

Scheme 5.18: Attempted synthesis of 1,3-thiazole-based boronate ester 5.49...... 91

Scheme 5.19: Attempted synthesis of 2-(4-cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole

(5.48a) via silver-catalyzed fluorination...... 92

Scheme 5.20: Attempted synthesis of 2-octyloxy-4-fluoro-1,3-thiazole (5.52) via silver- catalyzed fluorination...... 93

Scheme 5.21: Mechanism for the formation of 5-fluoro-2-(octyloxy)-1,3-thiazol-4(5H)- one (5.54)...... 94

Scheme 5.22: Proposed pathway for formation of 4-fluoro-2-(octyloxy)-1,3-thiazol-

5(4H)-one (5.59)...... 94

Scheme 5.23: Synthesis of 2,4-diamino-1,3-thiazole hydrochloride (5.62)...... 96

Scheme 5.24: Attempted synthesis of 2,4-difluoro-1,3-thiazole (5.63) via the Balz-

Schiemann reaction...... 97

Scheme 5.25: Attempted synthesis of 2,4-difluoro-1,3-thiazole (5.63) via fluorodeoxygenation using DAST or DeoxoFluor®...... 98

xiii

Scheme 5.26: Synthesis of 2,5-bis(4-methoxyphenyl)-1,3-thiazol-4-ol (5.68)...... 99

Scheme 5.27: Attempted synthesis of 4-fluoro-2,5-bis(4-methoxyphenyl)-1,3-thiazole

(5.44) via fluorodeoxygenation...... 99

Scheme 5.28: Attempted synthesis of 2,4-difluoro-1,3-thiazole (5.63) from P2O5 and

Bu4NF...... 100

Scheme 5.29: Synthesis of 4-fluoro-2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.44) through electrophilic aromatic substitution...... 101

Scheme 5.30: Attempted synthesis of 2,5-dibromo-4-fluoro-1,3-thiazole (5.69) through electrophilic aromatic substitution...... 102

Scheme 5.31: Attempted synthesis of 5-bromo-2-dodecyloxy-4-fluoro-1,3-thiazole (5.70) through electrophilic aromatic substitution...... 102

Scheme 5.32: Synthesis of 4-fluoro-5-octyloxy-1,3-thiazoles 5.48a, 5.72, and 5.73 via electrophilic aromatic substitution...... 103

Scheme 5.33: Synthesis of 5-alkoxy-2-(4-cyanophenyl)-4-fluoro-1,3-thiazoles 5.48a-

5.48e via electrophilic aromatic substitution...... 111

Scheme 5.34: Synthesis of 4-(5-alkoxy-4-fluoro-1,3-thiazol-2-yl)benzaldehydes 5.74a-

5.74e via DIBAl-H reduction...... 113

Scheme 5.35: Synthesis of 4-(5-alkoxy-4-fluoro-1,3-thiazol-2-yl)benzoic acids 5.75a-

5.75e via the Pinnick oxidation...... 113

Scheme 5.36: Synthesis of (S)-4-(1-methylheptyloxy)phenyl 4-(5-alkoxy-4-fluoro-1,3- thiazol-2-yl)benzoates 5.76a-5.76e...... 114

xiv

Scheme 6.1: Synthesis of 2-(4-(dodecyloxy)phenyl)-1,3-thiazole-5-carboxylic acid (6.3) via a lithiation-based approach...... 116

Scheme 6.2: Synthesis of 5-bromo-2-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.5) via selective Suzuki coupling of 2,5-dibromo-1,3-thiazole (3.3)...... 117

Scheme 6.3: Synthesis of 2-(4-(dodecyloxy)phenyl)-5-formyl-1,3-thiazole (6.7)...... 118

Scheme 6.4: Synthesis of (S)-4-(1-methylheptyloxy)phenyl 2-(4-(dodecyloxy)phenyl)-

1,3-thiazole-5-carboxylate (6.8)...... 119

Scheme 6.5: Previously proposed synthesis of 5-(4-(dodecyloxy)phenyl)-1,3-thiazole-2- carboxylic acid (6.13) via a lithiation-based approach...... 120

Scheme 6.6: Synthesis of 5-(4-(dodecyloxy)phenyl)-2-octyloxy-1,3-thiazole (6.15) via

Suzuki coupling...... 121

Scheme 6.7: Attempted synthesis of 5-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.12). .... 121

Scheme 6.8: Resonance structures of compounds 4.5c-4.5e and 6.15...... 122

Scheme 6.9: Attempted synthesis of 5-bromo-2-cyano-1,3-thiazole (6.17)...... 122

Scheme 6.10: Proposed synthesis of 2-cyano-5-(4-(dodecyloxy)phenyl)-1,3-thiazole

(6.18)...... 123

Scheme 6.11: Attempted synthesis of methyl 5-bromo-1,3-thiazole-2-carboxylate using carbonylative coupling (6.19)...... 124

Scheme 6.12: Reaction of 2,5-dibromo-1,3-thiazole (3.3) with n-BuLi followed by quenching with H2O...... 124

Scheme 6.13: Attempted synthesis of 1,3-thiazole-2-carboxylic acid (6.20)...... 125

Scheme 6.14: Synthesis of 2-formyl-1,3-thiazole (6.21)...... 125

Scheme 6.15: Attempted synthesis of 5-(4-(dodecyloxy)phenyl)-1,3-thiazole-2- carbaldehyde (6.22)...... 126

Scheme 6.16: Attempted synthesis of ethyl 1,3-thiazole-2-carboxylate (6.23)...... 126

Scheme 6.17: Attempted synthesis of 2-(trimethylsilyl)-1,3-thiazole (6.9)...... 127

Scheme 6.18: Proposed synthesis of (S)-4-(1-methylheptyloxy)phenyl 5-(4-

(dodecyloxy)phenyl)-1,3-thiazole-2-carboxylate (6.14)...... 128

Scheme 7.1: Resonance structures for Structures II and III...... 149

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LIST OF TABLES

Table 3.1: Synthesis of 2,5-dibromo-1,3-thiazole (3.3) with varying amounts of NaHCO3 and isolation techniques...... 35

Table 3.2: Product distribution for the reaction of 2-bromo-1,3-thiazole (3.2) with the new supply of NCS at 60 °C...... 44

Table 3.3: Reaction of 2,5-dibromo-1,3-thiazole (3.3) with NCS and 2-chloro-1,3- thiazole (3.9)...... 46

Table 3.4: Reaction of 2,5-dibromo-1,3-thiazole (3.3) with NCS, BHT and 10 mol% 2- chloro-1,3-thiazole (3.9)...... 47

Table 3.5: Reaction of 2-bromo-1,3-thiazole (3.2) with NCS and BHT...... 48

Table 4.1: Synthesis of 2-alkoxy-5-bromo-1,3-thiazoles 4.3a-4.3e utilizing different solvents and additives...... 56

Table 4.2: Optimization for synthesis of 4-(2-alkoxy-1,3-thiazol-5-yl)benzaldehydes

4.9c-4.9e...... 66

Table 4.3: Optimization for conversions of 4.11a-4.11e to 4.12a-4.12e...... 71

Table 5.1: Optimization for the synthesis of 4-fluoro-5-octyloxy-1,3-thiazoles 5.48a,

5.72, and 5.73 (Scheme 5.32) via electrophilic aromatic substitution...... 107

Table 7.1: Transition temperatures (°C) of compounds 2.8a-2.8e with transition enthalpies (J/g) given as italicized numbers in parentheses...... 130

Table 7.2: Melting points (°C) of compounds 5.48a-5.48e...... 131

Table 7.3: Transition temperatures (°C) of compounds 4.5a-4.5e with transition enthalpies (J/g) given as italicized numbers in parentheses...... 132 xvii

Table 7.4: Transition temperatures (°C) of compounds 7.1a-7.1e...... 134

Table 7.5: Transition temperatures (°C) of compounds 7.2a-7.2e...... 135

Table 7.6: Transition temperatures (°C) of compounds 2.12a-2.12e with transition enthalpies (J/g) given as italicized numbers in parentheses...... 137

Table 7.7: Transition temperatures (°C) of compounds 5.76a-5.76e with transition enthalpies (J/g) given as italicized numbers in parentheses...... 138

Table 7.8: Transition temperatures (°C) of compounds 4.12a-4.12e with transition enthalpies (J/g) given as italicized numbers in parentheses...... 140

Table 7.9: Transition temperatures (°C) of compound 6.8 with transition enthalpies (J/g) given as italicized numbers in parentheses...... 141

Table 7.10: Transition temperatures (°C) of compounds 7.3a-7.3e...... 141

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LIST OF ABBREVIATIONS

Å angstrom(s)

AcOH acetic acid

AIBN 2,2’-azobisisobutyronitrile

Anal. Calcd elemental analysis calculated aq. aqueous app. apparent

BF3•Et2O boron trifluoride diethyl etherate

BHT 2,6-di-t-butyl-4-methylphenol

B2O3 boric anhydride

B(OMe)3 trimethyl borate br. broad

Bu butyl t-Bu tertiary butyl t-BuOH tert-butanol

Bu3SnCl tributyltin chloride

Bu4NX tetrabutylammonium halide (X = F, Br, or I)

°C degrees Celsius

CH2Cl2 dichloromethane

CHCl3 chloroform

CH2N2 diazomethane

Cryst crystal xix

δ chemical shift d density and doublet

D debye(s)

DABCO 1,4-diazabicyclo[2.2.2]octane

DAST diethylaminosulfur trifluoride

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCC N, N’-dicyclohexylcarbodiimide

Decomp. decomposition

DeoxoFluor® bis-(2-methoxyethyl)aminosulfur trifluoride

DIBAl-H diisobutylaluminium hydride

DMA N,N-dimethylacetamide

DMAP 4-(N,N-dimethylamino)pyridine

DME dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

EA elemental analysis

Et ethyl

Et3N triethylamine

Et2O diethyl ether

EtOAc ethyl acetate

EtOH ethanol g gram(s)

GC gas chromatography

Hz hertz

Hunig’s base N,N-diisopropylethylamine

IR infrared

Iso. Liq. isotropic liquid

J coupling constant

LC liquid crystal

LDA lithium diisopropylamide

M moles per liter m multiplet

Me methyl

MeCN acetonitrile

MeOH methanol

MHz megahertz mL milliliter(s) mmHg millimeter(s) of mercury mol mole(s) mmol millimole(s)

Mp melting point

MS mass spectrometry

N nematic liquid crystal phase

NaBHT sodium 2,6-tert-butyl-4-methylphenoxide

xxi

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NFSI N-fluorobenzenesulfonimide

NMR nuclear magnetic resonance

OTf trifluoromethanesulfonate or triflate p pitch

Pd(OAc)2 palladium(II) acetate

Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)

Ph phenyl iPr isopropyl proton sponge 1,8-bis(dimethylamino)naphthalene

Ps spontaneous polarization ppm parts per million q quartet quint. quintet

Rec. recrystallized

Rf retention factor

RT room temperature s singlet

SelectFluor™ 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane

bis(tetrafluoroborate) sext. sextet

xxii

SmA smectic A liquid crystal phase

SmB smectic B liquid crystal phase

SmC achiral smectic C liquid crystal phase

SmC* chiral smectic C liquid crystal phase

SmX unknown smectic liquid crystal phase

SOCl2 thionyl chloride

SSFLC surface stabilized ferroelectric liquid crystal t triplet tt triplet of triplets

THF tetrahydrofuran

TLC thin layer chromatography

TMS tetramethylsilane and trimethylsilyl

TMSCl trimethylsilyl chloride

μ micro

Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

xxiii

ACKNOWLEDGMENTS

I would like to thank my family and friends for all their support, encouragement, and understanding over the years, especially my mom, dad, sister, Lynn, and the entire

Book family. I would also like to give my sister, Beth, a special thank you for all her help with proofreading and for providing me with some photo shop work presented within this dissertation.

I would like to thank my research advisors, Drs. Paul Sampson and Alex Seed, for their patience, guidance, and all their efforts during my time here at Kent State

University. I would also like to thank both current and past members of our research group, especially Matthew Barchok and Pritha Subramanian, who have assisted me along the way with research, teaching, and course work.

I would like to thank Dr. Robert Twieg for his useful input from time to time as well as for the use of chemicals for several test reactions and for use of his instrumentation, especially his DSC. I would also like to thank the current and former members of his research group who have provided me with assistance.

I would like to thank Dr. Mahinda Gangoda for his assistance with instrumentation and in obtaining numerous types of spectra. I would also like to thank numerous members of the chemistry department support staff, especially Erin Michael,

Lisa Stamper, Arla Dee McPherson, Larry Maurer, Erica Lilly, and Rochelle Gray.

I would also like to thank Cuiyu Zhang and Dr. Antal Jákli for their work in analyzing several of the final targets, the results of which are discussed in Chapter 8.

xxiv

CHAPTER 1. INTRODUCTION

1.1. Introduction to smectic C* liquid crystal phases

In the field of liquid crystals, numerous mesophases have been characterized. Of these, the most commonly observed in mesogenic materials are the nematic (N), smectic

A (SmA), and smectic C (SmC) phases. These phases vary greatly in the degree of order observed within and between the “layers” of aligned molecules (see Figure 1.1).1

Although the term “layer” is often used when describing the order of smectic phases, it is not an accurate description. The order for smectic phases is with respect to the center of mass for each molecule which is aligned with other molecules to create what is referred to as the “layers.”

Figure 1.1: Typical ordering of common mesophases.

The smectic C phase possesses “layers” which are ordered with respect to one another and the constituent molecules are tilted with respect to the layer plane. The smectic C phase is frequently the first mesophase to be observed upon heating a crystalline material.

Upon further heating, the smectic A phase can often be observed, which is similar to the

smectic C phase, except that the molecules are orthogonal to the layer plane. If the material is heated further, the nematic phase may often be observed. The nematic phase is the least ordered of the commonly observed mesophases, as it possesses only orientational ordering of molecules with no layer ordering, as shown in Figure 1.1. If the material is heated further, the remaining degree of order from the nematic phase is lost and the material reaches the isotropic liquid and thus will no longer exhibit liquid crystalline properties, unless the material is cooled back to the temperature range of the nematic phase.

The observed tilt of the smectic C phase has previously been explained through models proposed by McMillan and Wulf. In McMillan’s model, dipoles of the liquid crystalline molecules in the smectic A phase are thought to become “frozen-in” as the temperature is lowered. Once at the smectic A – smectic C phase transition temperature, the dipoles become aligned, thus creating a torque which tilts the molecules (see Figure

1.2).2

Figure 1.2: McMillan’s model for the origin of tilted smectic phases.

However, McMillan’s model fails to explain the existence of the smectic C phase for compounds which lack a lateral dipole. According to the model proposed by Wulf, the overall zigzag shape of mesogenic molecules leads to the formation of the smectic C phase. As shown in Figure 1.3, at temperatures corresponding to the smectic A phase, the rigid cores align while the aliphatic chains are free to move about randomly. As the temperature is lowered, the motion of the aliphatic chains become more restricted and the chains begin to align with one another. Upon additional cooling, the cores also align but in a tilted orientation as a means of alleviating steric crowding, thus giving rise to the characteristic tilt of the smectic C phase.

Figure 1.3: Wulf’s model for the origin of tilted smectic phases.

While the two proposed models vary greatly in explaining the origins of the smectic C phase, neither model is thought to be entirely accurate and “the real situation is probably best described by a combination of these two theories.”2

For the achiral smectic C phase, the molecules arrange randomly in a head-to-tail fashion and the phase possesses several symmetry operations including: “a center of inversion, a mirror plane normal to the layers, and a C2 axis (two fold axis of rotation) parallel to the layers and normal to the tilt direction” (see top of Figure 1.4).3

Figure 1.4: Schematic arrangement of molecules for the achiral smectic C phase

(top) and the chiral smectic C* phase (bottom).

As a result of the highly symmetrical arrangement of the molecules in the achiral smectic

C phase, achiral liquid crystals do not exhibit spontaneous polarization, which as discussed later, makes them less useful for display purposes. Chiral racemic materials also fail to exhibit spontaneous polarization since they still possess a center of symmetry

and a mirror plane, which results in a net spontaneous polarization of zero. For the smectic C* phase, which is only exhibited by chiral non-racemic compounds, the molecules still arrange randomly in a head-to-tail fashion but the symmetry operations

3 are reduced to a single C2 axis normal to the tilt direction (see bottom of Figure 1.4).

Since the individual molecules are polar, “an inequivalence with respect to the dipoles

3 along the C2 axis” develops as a result of a slight resistance to rotation about the long axis caused by the molecules being chiral. This inequivalence allows for a spontaneous polarization to develop along the C2 axis, “parallel to the layer planes and perpendicular to the tilt direction of the molecular long axes,”3 as shown in the bottom portion of Figure

1.4. Thus, each layer contains its own spontaneous polarization, which for the bulk phase creates a problem. As a result of the required chirality of the smectic C* phase, the tilted layers arrange into a helix as shown in Figure 1.5 (figure taken from cited reference).4

Since each layer exhibits its own spontaneous polarization, the net overall spontaneous polarization is zero as the helix rotates over a 360° turn (pitch, p). Fortunately, several solutions have been developed which still allow for a net spontaneous polarization to exist. In the presence of an external electric field, the spontaneous polarization aligns with the electrical field which causes the helix to unwind.2 Mixing of the chiral liquid crystal with other achiral liquid crystals causes the pitch length to become infinitely long, which prevents the spontaneous polarization from averaging to zero.2 Finally, the development of surface-stabilized ferroelectric liquid crystal (SSFLC) displays has also been effective in allowing for spontaneous polarization. In SSFLC displays, the layer of liquid crystalline material is kept extremely thin, about 1 μm, which is usually smaller

than the pitch length and thus prevents the spontaneous polarization from averaging to zero.4

Figure 1.5: Helical structure of the smectic C* phase.

In recent years, liquid crystal display technology has shifted its focus more towards the development of devices which exploit the smectic phases, in particular the smectic C* phase. The use of the smectic C* phase for display purposes offers several

advantages compared to nematic phase-based displays. Displays which utilize the smectic C* phase tend to be of higher resolution and possess faster switching speeds when compared to displays utilizing the nematic phase.5 These improvements are a result of the smectic C* phase being ferroelectric, meaning the material exhibiting the smectic

C* phase possesses a spontaneous polarization whose orientation can be reversed by the application of an external electric field. For nematic phase-based displays, individual pixels of the display are turned off and on by applying an external electric field and then discontinuing the electric field, respectively. Once the electric field is discontinued, the molecules merely return to a more stable orientation which then allows for the pixel to be in the on-state. For smectic C* phase-based displays, since the phase is ferroelectric, individual pixels can be turned on and off by simply reversing the orientation of the applied electric field. Studies have shown that the “relaxation” process of the nematic phase-based displays is much slower when compared to the switching process of the smectic C* phase-based displays,5 thus allowing for faster switching speeds of the resulting smectic C* phase-based display. Another advantage of the faster switching speeds of the smectic C* phase-based displays, is that it allows for displays with higher resolution. As a result of the slower switching speeds of nematic phase-based displays, individual pixels are required for the colors red, green, and blue, thus giving the resulting image a more grainy appearance. On the other hand, smectic C* phase-based displays create color images through color sequential illumination, where the colors red, green, and blue are emitted from a single pixel for specific amounts of time to generate different colors and thus creates images with a higher resolution.6

While the use of smectic C* phases offers several advantages, there are other drawbacks which have hindered their development for display purposes. In order for the liquid crystal to exhibit ferroelectric properties, the molecule should be chiral non- racemic. Synthetically, creating chiral non-racemic liquid crystals is not difficult; however, incorporating chiral non-racemic moieties into the structure adds significant costs to its synthesis. In addition to cost, the primary drawback for use of smectic C* phases is the zigzag defect which is a result of the liquid crystal cooling from the smectic

A to the smectic C* phase. As shown in Figure 1.1, in the smectic A phase the molecules are orthogonal to the layer plane; however, in the smectic C* phase the molecules become tilted. Thus, when the liquid crystal cools from the smectic A phase to the smectic C* phase, it is believed to undergo layer shrinkage, creating areas in which the liquid crystalline material lacks order and, as a result, creates zigzag lines in the display which are known as chevron defects.6 Liquid crystalline materials which do not exhibit chevron defects and do not undergo layer shrinkage are known as de Vries materials and are quite rare. To date, only about twenty mesogens have previously been reported as being de Vries materials,1,7-18 nearly all of which contain an organosiloxane, semifluoroalkyl, or a perfluoroalkyl group. Of the reported de Vries materials, only a single mesogen contains a sulfur-based heterocycle which was previously synthesized within our own group (see Figure 1.9, structure IV).1 Unfortunately, there currently exists no model for predicting which mesogens will be de Vries materials, although we believe it to be a conformationally driven phenomenon.

1.2. General structure of ferroelectric liquid crystals

As previously discussed, the formation of the smectic C phase is dependent on the molecules possessing a zigzag shape as well as a dipole moment (see Chapter 1.1). With this in mind and from studies of chiral and achiral systems, general guidelines have been established which are useful for designing molecules which are likely to generate the smectic C phase.2

Figure 1.6: General structure of ferroelectric liquid crystals.

As shown in Figure 1.6, most ferroelectric liquid crystals possess a pair of rigid core units which can be either aromatic, heteroaromatic, or aliphatic, although the latter is usually avoided since they tend to suppress the formation of smectic phases.2 The rigid core may also contain lateral substituents (L) such as fluorine, chlorine, bromine, nitrile, trifluoromethyl or nitro groups.19 The addition of lateral substituents is often done to create a strong lateral dipole as well as to lower the melting point of the resulting liquid crystal by disrupting the packing efficiency of the liquid crystal molecules. This can be attractive for device applications, where having mesophases close to ambient temperature are desired. However, the size of the lateral substituent must remain small as larger substituents suppress the formation of smectic phases.2 Thus, fluorine is the most

commonly employed lateral substituent as a result of its small size and high electronegativity.19 Between the rigid cores is often a central linkage which increases the overall polarizability of the molecule and also imparts a small degree of flexibility.

Studies have shown Schiff’s bases to be the best central linking groups for promoting the formation of the smectic C phase (see Figure 1.7);2 however, because of their low chemical stability, they tend to be avoided.

Figure 1.7: Central linkages which promote formation of the smectic C phase.

For the terminal groups, McMillan’s model shows that polar groups help to promote the formation of the smectic C phase. Thus, ethers and esters tend to give rise to the smectic

C phase more than other terminal groups (see Figure 1.8).2

Figure 1.8: Terminal groups which promote formation of the smectic C phase.

For the encouragement of the smectic C phase, the length of the terminal aliphatic chains should ideally be between eight and fifteen carbons, depending upon the presence of certain terminal groups and central linkages.2 The terminal aliphatic chain is often the location of the stereogenic center (which is required for the formation of the smectic C* phase) due to its ease of chemical synthesis. For example, terminal chiral ethers and

esters can be easily introduced using a selected commercially available chiral non- racemic alcohol via the use of the Mitsunobu reaction.

1.3. Use of sulfur-based heterocycles in liquid crystals

As part of an ongoing study within our research group, the incorporation of various sulfur-based heterocycles into liquid crystalline targets has been explored (see

Figure 1.9). The explored sulfur-based heterocycles include: thiophene (structures I and

II), fluorothiophene (structures III and IV), 1,3-thiazole (structures V and VI), and 1,3,4- thiadiazole (structures VII and VIII) rings.1,20-22

Figure 1.9: Previously synthesized liquid crystalline targets containing sulfur-based

heterocycles.

As part of these studies, the sulfur-based heterocycle was changed to better understand its effect on the mesogenic properties of the resulting materials. In switching the sulfur- based heterocycle, three significant properties are altered. As shown in Figure 1.10, the

strength of the lateral dipole moment can be significantly altered by changing which sulfur-based heterocycle is placed into the liquid crystalline structure.1,23

Figure 1.10: Strength and orientation of the dipole moments for thiophene,

fluorothiophene, 1,3-thiazole, and 1,3,4-thiadiazole rings.

Since the sulfur-based heterocycle is always located within the liquid crystalline core, the ring is always disubstituted. The two substituents are not linear for sulfur-based heterocycles (see Figure 1.11)1,23 as would be observed for a para-disubstituted benzene ring. Therefore, incorporation of sulfur-based heterocycles creates a slight bend in the core of the resulting liquid crystal which can often lead to lower melting points.24 In switching between the sulfur-based heterocycles, the severity of the bend can be altered from 148° to 153° to 162° through the incorporation of either a thiophene, 1,3-thiazole, or a 1,3,4-thiadiazole ring, respectively. The 2,4-disubstitution pattern of thiophene and

1,3-thiazole are rarely used due to the bend being too great which often suppresses the formation of liquid crystal phases.25,26

Figure 1.11: Angle formed between the substituents of 2,5- and 2,4-substituents in

sulfur-based heterocycles.

The interannular torsion angle can be altered by changing sulfur-based heterocycles, which can also have an effect on the mesogenic properties. As a result of the varying interannular torsion angle, the amount of conjugation between the two halves of the biaryl core fluctuates. For biaryl cores with smaller interannular torsion angles, better partial charge separation is experienced which favors the formation of tilted smectic phases. For 2,5-disubstituted sulfur-based heterocycles such as 1,3-thiazole or

1,3,4-thiadiazole, which possess nitrogen as part of the ring, the interannular torsion angle of the biaryl core is smaller due to less steric repulsion experienced from the ortho- hydrogens of the adjacent phenyl ring. In the case of 1,3-thiazole-based biaryl cores, the position of the phenyl ring can greatly alter the interannular torsion angle of the biaryl core as shown in Figure 1.16. For 1,3-thiazole rings possessing a phenyl substituent at the 5-position, its interannular torsion angle will be larger and will more closely resemble that of thiophene. On the other hand, if the phenyl substituent is placed at the 2-position of 1,3-thiazole, its interannular torsion angle will be smaller and will more closely resemble that of a 1,3,4-thiadiazole ring.

Although the properties for each of the sulfur-based heterocycles shown in

Figures 1.10 and 1.11 differ greatly, some similarities exist which allows us to better understand the expected changes in mesogenic properties observed upon switching the sulfur-based heterocycle. For example, 2,5-disubstituted thiophenes and fluorothiophenes would have similar angles for their two substituents but the nature of their dipole moments is drastically different. The same would also be expected for a 2,5- disubstituted-1,3-thiazole ring and a similarly substituted 4-fluoro-1,3-thiazole ring. On

the other hand, a 2,5-disubstituted-fluorothiophene ring is similar to the 2,5-disubstituted-

1,3-thiazole ring in terms of its dipole moment, but varies with respect to the angles of their two substituents. The same would also be expected for a 4-fluoro-1,3-thiazole ring and the 1,3,4-thiadiazole ring. Through such a systematic study, our group seeks to develop a thorough understanding of the observed changes in mesogenic properties based on the presence of particular sulfur-based heterocycles. Ultimately, these studies could potentially lead to an explanation for why structure IV from Figure 1.9 is a deVries material (studies on its non-fluorinated analog, structure I from Figure 1.9, were not performed to determine if it was a de Vries material) yet its phenyl-based analog does not exhibit such properties.

1.4. Rationale for targeting alkoxy-1,3-thiazole-based liquid crystals

With respect to the biaryl core of the liquid crystalline targets shown in Figure

1.9, all the structural isomers of the 2,5-disubstituted thiophene-based liquid crystals have been synthesized by our group (structures I and II) and several of the structural isomers of the 1,3,4-thiadiazole-based liquid crystals have been synthesized (structures VII and

VIII). For fluorothiophenes, four different 2,5-disubstituted structural isomers are possible; two of these targets have been prepared by our group (Figure 1.9, structures III and IV) and studies are currently underway within our group to produce the remaining two fluoroalkoxythiophene-based mesogens. On the other hand, representative members from only two of the possible four structural isomers of the 1,3-thiazole-based liquid crystals have been prepared (Figure 1.9, structures V and VI) while no members from the remaining two families, the 2-alkoxy- and 2-carboxy-1,3-thiazole-based liquid crystals,

have been synthesized. Additionally, the synthesis of fluorothiophenes have been a significant portion of our study of sulfur-based heterocycles in liquid crystals;21,27 however, our work to this point has not included a study of the synthesis and physical properties of 4-fluoro-1,3-thiazole-based liquid crystals. To date, the synthesis of 4- fluoro-1,3-thiazole-based liquid crystals has not been investigated and the synthesis of such a ring system has not been reported outside the patent literature. Therefore, to help complete our study of sulfur-based heterocycles in liquid crystals, the synthesis of several

1,3-thiazole as well as 4-fluoro-1,3-thiazole-based liquid crystals is required.

The 1,3-thiazole ring has been incorporated into a variety of mesogenic structures and imparts a number of favorable physical properties, including low viscosity

(anticipated due to the more compact nature of the ring compared to a benzene ring), high birefringence,24 and a significant lateral dipole moment (1.6D) as shown in Figure

1.10.1,23 The more compact nature of the 1,3-thiazole ring compared to a phenyl ring also allows for the liquid crystal to occupy a smaller unit cell, which may lead to faster switching speeds. This is also dependent upon coupling of the ring dipole with the dipole of the stereocenter, the magnitude of which is difficult to predict prior to its synthesis. As previously mentioned, the 1,3-thiazole ring possesses a significant in-built, lateral dipole moment, which has advantages when compared to phenyl-based liquid crystals. Since the stability of smectic phases partly depends upon dipole-dipole interactions,28 the addition of a lateral dipole may lead to more stable smectic phases. However, phenyl rings lack such a lateral dipole and so a lateral substituent, such as a halogen or a nitrile, must be added to the phenyl ring in order to create a lateral dipole; however, the addition

of a lateral substituent to a phenyl ring often reduces the appearance of liquid crystal phases as a result of the additional molecular width created by such a substituent.2 The presence of a lateral dipole also leads to a larger spontaneous polarization, which can lead to faster switching speeds when used in electro-optical applications.2

As previously discussed, within the biaryl core the 1,3-thiazole ring can be either

2,5- or 2,4-disubstituted (see Figure 1.12 for the numbering system of the 1,3-thiazole ring); however, 2,5-disubstitution is the favored arrangement since it creates a more linear substitution pattern (see Figure 1.11)23 which leads to enhanced mesophase thermal stability.

Figure 1.12: Numbering system for the 1,3-thiazole ring.

The range of substituents that have been incorporated into mesogens containing a 2,5- disubstituted-1,3-thiazole ring includes 2,5-diphenyl,29,30 2-alkenyl-5-phenyl,29 5-alkyl-2- phenyl,29 2-alkyl-5-phenyl29, 2,5-bisalkynyl,31,32, 2-phenyl-5-thiazolo[5,4-d]-1,3- thiazole,33 and 5-alkyl-2-benzylideneamino34 moieties. For the 2,4-substitution pattern, substituents incorporated are limited to 4-phenyl-2-(1,3-thiazol-2-yl),29 4-(arylamino)-2- benzylideneamino-,35-40 and 2-benzylideneamino-4-(p-nitrophenoxy).39-41 Less than 100 mesogenic 1,3-thiazoles have been reported in the open literature (LiqCryst database, version 4.6) and a number of additional structures have also been reported in the patent literature.42-47 A selection of representative examples is given in Figure 1.13.

Figure 1.13: A representative selection of known 1,3-thiazole-containing mesogens.

Figure 1.14: General structure of the targeted 1,3-thiazole-based liquid crystals.

Shown in Figure 1.14 is a generalized structure of the 1,3-thiazole-based liquid crystals targeted in this dissertation, where a 1,3-thiazole ring represents “Ring 1” or

“Ring 2” (the other ring is a 1,4-disubstituted phenyl moiety). The remaining portions of the liquid crystal structure remain constant throughout our study and were chosen for specific reasons which are discussed below. Given the advantages of incorporating a 2,5- disubstituted 1,3-thiazole ring into liquid crystals, one could envision four different combinations in which a 1,3-thiazole is exchanged for “Ring 1” or “Ring 2” of Figure

1.14 (see Figure 1.15).

Figure 1.15: Four variations of the targeted liquid crystals with the 1,3-thiazole ring

occupying “Ring 1” or “Ring 2.”

According to McMillan’s model, liquid crystal phases are most stable when the structure allows for better partial charge separation as well as “conjugation of the delocalized π- electrons of the core.”2 In other words, when one end of the molecule possesses a strong electron-donating group and the other end possesses a strong electron-withdrawing group, liquid crystal phases tend to be much more stable. Although each structure in

Figure 1.15 contains the electron-donating alkoxy group and electron-withdrawing ester group, the stabilities of their liquid crystal phases are not predicted to be the same.

According to McMillan’s model, Structure I should exhibit the most stable liquid crystal phases while Structures III and IV would be expected to exhibit the least stable liquid crystal phases. Structure I is considered ideal because the nitrogen of the 1,3-thiazole ring is on the “internal side” of the structure and so there should be no steric crowding experienced between the ortho-hydrogens of the phenyl ring and the 4-position hydrogen of the 1,3-thiazole (see Figure 1.16). Thus, the interannular torsion angle between the two rings should be smaller. The interannular torsion angle seen for a similar structure

[2-(4-bromophenyl)-5-dodecyloxy-1,3-thiazole] was reported to be 4.5°.48 On the other hand, in Structures II and IV the 4-position hydrogen of 1,3-thiazole is on the “internal

side” of the core so it experiences more steric crowding from the ortho-hydrogens of the phenyl ring which causes the rings to rotate slightly to alleviate this steric crowding and thus results in a larger interannular torsion angle (see Figure 1.16; the interannular torsion angle for Structure II is estimated to be about 6° based on similar structures available in the open literature49,50). This smaller interannular torsion angle allows for better conjugation between the two rings which leads to better partial charge separation and potentially, more stable liquid crystal phases.

Figure 1.16: Illustration of the steric crowding experienced by Structure II which

leads to a larger interannular torsion angle.

Another factor which contributes to Structure I being the ideal arrangement relates to the angle of the lateral dipole which, for the 1,3-thiazole ring in Structure I and as illustrated in Figure 1.10, helps pull electron density away from the alkoxy chain and towards the ester functionality. Although the dipole of Structure IV is also oriented in a favorable direction, its liquid crystal phases are not expected to be as stable as for

Structure I due to its larger interannular torsion angle. As for Structures II and III, the dipole of their 1,3-thiazole ring is tilted in the opposite direction, thus it no longer helps pull electron density away from the alkoxy chain. Instead, the dipole of the 1,3-thiazole ring in these cases is opposing the push of electrons created by the alkoxy chain and ester

group which allows for less partial charge separation and thus would be expected to lead to less stable liquid crystal phases.

The use of alkoxy side chains in liquid crystalline materials leads to increased mesophase thermal stability, higher polarizability, higher birefringence, and higher dielectric anisotropy when compared to the analogous alkyl chain derivatives.51 Despite these favorable properties, the only prior report of mesogens containing an alkoxy- substituted 1,3-thiazole moiety came from a very limited earlier study in our group.52

Therefore, we embarked on a more extensive study of mesogens bearing an alkoxy-1,3- thiazole moiety. The range of lengths for the alkoxy side chain was chosen as octyloxy through dodecyloxy since studies have shown that, when a central ester linkage is present, as is the case for our targets, the “terminal chain lengths must approach, or be greater than, seven” carbons in order to observe the smectic C* mesophase.2

Placing the ester linkage between the two central cores and locating the terminal ether group directly on the core both enhance the probability of titled smectic phases.2

The chiral (S)-4-(1-methylheptyloxy)phenyl ester moiety was chosen as several groups have shown this moiety to favor the exhibition of smectic C* liquid crystal phases in other systems.53-56

1.5. Reactivity of 1,3-thiazole rings

For several reactions discussed later in this dissertation, their selectivity is a direct result of the varying electronic nature of the 1,3-thiazole ring, which is unique in that each of the three carbons of the 1,3-thiazole ring offers a different degree of reactivity for

0 several reactions, including SNAr reactions, Pd -catalyzed cross-coupling, electrophilic

aromatic substitution, and lithiation (see Figure 1.17).57-61 The carbon at the 5-position is the most electron-rich, and thus will undergo electrophilic aromatic substitution most readily.23 The 4-position is also moderately electron-rich, but not to the extent of the 5- position; thus, the 4-position will only undergo electrophilic aromatic substitution if the

5-position is already substituted.23 Due to the electron-rich nature of the 4- and 5- positions, these positions are less reactive towards nucleophile-based reactions (such as

SNAr chemistry) when compared to the 2-position. The 4-position will only undergo nucleophilic attack if there is a strong electron-withdrawing group at the 5-position.23

Figure 1.17: General reactivity for each of the three carbons of 1,3-thiazole.

On the other hand, the 2-position will not undergo electrophilic aromatic substitution23 since it is the most electron-poor carbon of the 1,3-thiazole ring. As a result of the 2-position being so electron-poor, its hydrogen is the most acidic (pKa

29.4)62 which allows for selective lithiation at the 2-position. The low electron density at the 2-position also facilitates nucleophile-based reactions such as SNAr chemistry. This electron-deficiency at the 2-position also allows for selective Pd0-catalyzed cross- coupling in dihalo-substituted 1,3-thiazoles, which is shown to occur first at the most electron-poor carbon.57,63

1.6. Overview of dissertation goals

Discussed within this dissertation are five 1,3-thiazole-based research projects. In

Chapter 2, the synthesis of a series of 5-alkoxy-1,3-thiazole-based liquid crystals

(Structure I from Figure 1.15) is presented. In Chapter 3, the synthesis of several dihalo-

1,3-thiazoles are discussed which serve as building blocks for numerous other 1,3- thiazole-based projects. Starting from 2,5-dibromo-1,3-thiazole, whose synthesis is presented in Chapter 3, the synthesis of a series of 2-alkoxy-1,3-thiazole-based liquid crystals (Structure II from Figure 1.15), which are analogous to the series from Chapter

2, is discussed within Chapter 4. In Chapter 5, a fluoro substituent is incorporated onto the 1,3-thiazole ring at the 4-position to generate a series of 5-alkoxy-4-fluoro-1,3- thiazole-based liquid crystals which are fluorinated analogs of those presented in Chapter

2. Finally, in Chapter 6 the synthesis of a 5-carboxy-1,3-thiazole-based liquid crystal

(Structure III from Figure 1.15) is presented along with attempted methods for preparing a 2-carboxy-1,3-thiazole-based liquid crystal (Structure IV from Figure 1.15). Chapter 7 provides a detailed, comparative discussion of the mesophase properties of the liquid crystalline targets prepared in each preceding chapter, each of which we hope to be de

Vries materials. In Chapter 8, the results of some electro-optical studies on three of the final targets, which were performed by Cuiyu Zhang and Dr. Antal Jákli, are presented.

Finally, Chapter 9 provides a discussion of the conclusions drawn from this work.

CHAPTER 2. SYNTHESIS OF 5-ALKOXY-1,3-THIAZOLE LIQUID CRYSTAL

TARGETS

The first series of 1,3-thiazole-based liquid crystals to be discussed are the 5- alkoxy-1,3-thiazole-based liquid crystals which correspond to Structure I from Figure

1.15.

Figure 1.15: Four variations of the targeted liquid crystals with the 1,3-thiazole ring

occupying “Ring 1” or “Ring 2.”

2.1. Literature approaches to 5-alkoxy-1,3-thiazoles

5-Alkoxy-1,3-thiazoles are most commonly synthesized through ring closure of an appropriately substituted -acylamino carbonyl compound with either P2S5 or

Lawesson’s reagent as shown in Scheme 2.1.64

Scheme 2.1: Synthesis of 5-alkoxy-1,3-thiazoles using P2S5 or Lawesson’s reagent.

The use of P2S5 for the synthesis of 5-alkoxy-1,3-thiazoles has been well documented in mainstream organic chemistry but the yields vary greatly (44-88%) and the longest alkoxy chain investigated was only a propyloxy unit.65-69 Additionally, reactions using

P2S5 for the synthesis of sulfur-based heterocycles have a tendency to be somewhat capricious.70 A search of the literature reveals that the use of Lawesson’s reagent for the synthesis of 5-alkoxy-1,3-thiazoles is less explored and only three groups have utilized this methodology. The seminal publication in this area, by Lawesson et al, involved the construction of 5-ethoxy-2-phenyl-1,3-thiazole from the appropriate -acylamino carbonyl precursor in 85% yield.71 5-Methoxy-2-pyridyl-1,3-thiazoles have also been prepared with yields ranging from 50-58% (2-, 3-, and 4-pyridyl units);72 these reports utilized Lawesson’s reagent in refluxing xylene and toluene, respectively. Subsequent to

Lawesson’s work we published the first solvent-free microwave approach to a 5- dodecyloxy-1,3-thiazole derivative in good yield (83%).52 This represents the only previous literature report for the synthesis of a long-chain 5-alkoxy-1,3-thiazole.

As shown in Scheme 2.2, 5-alkoxy-1,3-thiazoles have also been generated via

SNAr chemistry of 5-halo-1,3-thiazoles (Br, Cl, or F) with alkoxides; methoxy, ethoxy, benzyloxy, 2,4,6-trimethoxybenzyloxy, and 4-(2,2-dimethyldioxalanyl)methoxy moieties were investigated with yields ranging from 46-100%.73-84 The yields of 5-alkoxy-1,3- thiazoles generated through this method vary greatly, and again only short length alkoxy chains have been incorporated via this SNAr approach.

Scheme 2.2: Synthesis of 5-alkoxy-1,3-thiazoles using SNAr chemistry.

A third approach starts from ester 2.1 (see Scheme 2.3), which is hydrolyzed under basic conditions using K2CO3 and the resulting alkoxide is quenched in situ with dimethyl sulfate to give the desired 5-methoxy-2,4-diphenyl-1,3-thiazole (2.2).85

Although this method is high yielding, it has not been examined for the synthesis of a

1,3-thiazole ring which bears a hydrogen at the 4-position, nor has it been evaluated for generating longer-chain 5-alkoxy-1,3-thiazoles.

Scheme 2.3: Qiao’s synthesis of 5-methoxy-2,4-diphenyl-1,3-thiazole.

2.2. Synthesis of 5-alkoxy-1,3-thiazole-containing liquid crystals via a Lawesson’s reagent-mediated ring closing strategy

Retrosynthetically, the final targets of this study (compounds 2.12a-2.12e) could be obtained through a DCC/DMAP (N, N’-dicyclohexylcarbodiimide/4-(N,N- dimethylamino)pyridine) esterification and the key 5-alkoxy-1,3-thiazole moiety could be obtained via a Lawesson’s reagent-mediated ring closing of the corresponding - acylamino esters 2.5a-2.5e (see Scheme 2.4).

Scheme 2.4: Retrosynthetic analysis of the target compounds 2.12a-2.12e.

As outlined in Scheme 2.5, -acylamino esters 2.5a-2.5e were obtained by first esterifying glycine (2.3) with the corresponding alcohol86 followed by N-acylation with

4-bromobenzoyl chloride. The synthesis of compounds 2.4c-2.4e was accomplished utilizing the same procedure as described for 2.4a, except that the crude reaction solution was not cooled before filtering and instead it was stirred at room temperature. This change in procedure was made to prevent the starting alcohol from crystallizing along with the desired compounds 2.4c-2.4e. In cases where contamination from the starting alcohol occurred, it was easily removed through recrystallization.

Scheme 2.5: Synthesis of -acylamino esters 2.5a-2.5e.

Previously published work by our group has shown that 5-alkoxy-1,3-thiazoles can be generated in high yield via reaction of an -acylamino ester with Lawesson’s reagent using microwave irradiation.52 However, due to the scale at which our reactions would be performed (~10 g), we chose the more traditional solvent-based reaction to eliminate any potential scale-up issues. Our first attempt at this transformation was in

THF at room temperature since, in previously unpublished work, we have had good success in synthesizing 2,5-diaryl-1,3-thiazoles utilizing Lawesson’s reagent under such conditions. However, when compound 2.5e was reacted with Lawesson’s reagent in THF at room temperature, thioamide 2.6 was the sole product instead of the desired 1,3- thiazole 2.7e (see Scheme 2.6). Similar conditions have previously been employed for the formation of thioamides.87,88 Thioamide 2.6 was also heated under reflux in THF with Lawesson’s reagent, but only starting material was present by crude 1H NMR analysis after 18 hours. In contrast, in refluxing toluene, compounds 2.5e and 2.6 could be converted to the desired 1,3-thiazole 2.7e in good yield (92%, and 83% over 2 steps, respectively) using Lawesson’s reagent. Lawesson’s reagent was found to be necessary for the transformation of 2.6 to 2.7e as only starting thioamide was recovered after

heating 2.6 in either refluxing THF or refluxing toluene for 5 hours in the absence of

Lawesson’s reagent.

Scheme 2.6: Synthesis of 5-alkoxy-1,3-thiazoles 2.7a-2.7e via Lawesson’s reagent-

mediated ring closure.

While Lawesson’s reagent is invaluable for generating sulfur-based heterocycles, a common problem with its use is the removal of the Lawesson’s reagent-based byproducts. A recent publication reports that this problem may be alleviated through the use of a fluorous derivative of Lawesson’s reagent and subsequent fluorous solid-phase extraction.89,90 However, the high cost of the fluorous reagent makes this approach less attractive. We have found that simply washing the crude reaction mixture obtained from the Lawesson’s reagent-mediated reaction with aqueous KOH, followed by recrystallizing the residual product from EtOH, allows for the desired 5-alkoxy-1,3- thiazole products 2.7a-2.7e to be isolated in pure form with little or no loss of product or formation of side products. This protocol also eliminates the need for silica gel chromatography and thus allows for the 5-alkoxy-1,3-thiazoles 2.7a-2.7e to be generated and purified on large scales.

The aryl bromides 2.7a-2.7e so obtained were efficiently converted to the corresponding nitrile targets 2.8a-2.8e using a modification of a procedure developed by

Friedman, where compounds 2.7a-2.7e were allowed to react with copper cyanide in refluxing DMF.91 Carboxylic acids 2.9a-2.9e were prepared through basic hydrolysis

(sodium hydroxide in ethanol) of nitriles 2.8a-2.8e as shown in Scheme 2.7.

Scheme 2.7: Synthesis of carboxylic acids 2.9a-2.9e.

Previously, the synthesis of carboxylic acid 2.9e was attempted through lithiation of compound 2.7e using n-BuLi followed by quenching with excess CO2, but this was found to be an ineffective approach due to competing deprotonation of the 1,3-thiazole ring at the 4-position (see Scheme 2.8) leading to the formation of a mixture of compounds 2.9e and 2.10.52

Scheme 2.8: Attempted synthesis of compound 2.9e from compound 2.7e.

Esterification of carboxylic acids 2.9a-2.9e with phenol 2.11, whose synthesis has previously been reported,56 was accomplished using DCC/DMAP to give the final targets

2.12a-2.12e as shown in Scheme 2.9.

Scheme 2.9: Synthesis of (S)-4-(1-methylheptyloxy)phenyl 4-(5-alkoxy-1,3-thiazol-2-

yl)benzoates 2.12a-2.12e.

In summary, the desired 5-alkoxy-1,3-thiazoles 2.7 were successfully generated via a Lawesson’s reagent-mediated ring closing strategy. The resulting 5-alkoxy-1,3- thiazoles 2.7 were subsequently converted to the final target compounds 2.12. From this six step sequence, only the final reaction required the use of silica gel chromatography.

Products from the other steps were purified through recrystallization or an aqueous KOH extraction which was used to remove unreacted Lawesson’s reagent, thus allowing for the reactions to be easily performed on a 10 g scale. The mesophase properties of these 5- alkoxy-1,3-thiazole targets 2.12a-2.12e are discussed in Chapter 7.

CHAPTER 3. DIHALO-1,3-THIAZOLES AS BUILDING BLOCKS FOR

ORGANIC SYNTHESIS

3.1. Introduction to dihalo-1,3-thiazoles as building blocks for organic synthesis

Haloaromatic compounds are extremely versatile intermediates that can be used for a wide array of reactions. While numerous methods exist for the synthesis of halobenzenes and heteroaromatic compounds, significantly fewer methods are known for the synthesis of halo-1,3-thiazoles and only a handful of methods are known for synthesizing dihalo-1,3-thiazoles. This is surprising given their synthetic versatility;

92,93 dihalo-1,3-thiazoles can be selectively reacted at the 2-position for SNAr chemistry, halogen-metal exchange94 (halogen metal exchange of 2,5-dibromo-1,3-thiazole (3.3) leads to ring opening),95 and Pd0-catalyzed cross-coupling,61 thus leaving a residual halogen at the 4- or 5-position intact for further functionalization of the molecule without any additional steps. This selectivity is a result of the differences in electron density at each of 1,3-thiazole’s carbons (see Chapter 1.5). Thus, dihalo-1,3-thiazoles are considered to be powerful building blocks for the synthesis of 1,3-thiazole-containing structures such as the mesogens prepared in Chapters 4, 5 and 6.

3.2.1. Literature approaches to 2,5-dibromo-1,3-thiazole (3.3)

While 2,5-dibromo-1,3-thiazole (3.3) is commercially available ($24/g), its two halogens account for approximately two-thirds of its molecular mass, thus making it very expensive on a per mole basis ($5786/mol), especially when considering these halogens are lost when the 2- and 5-positions are functionalized through various reactions.

Methods for synthesizing 2,5-dibromo-1,3-thiazole (3.3) have previously been reported; however, all the reported methods are either low yielding, require air sensitive reagents, or proceed through synthetic intermediates that cannot be stored. One such method involves the reaction of relatively expensive 1,3-thiazole ($196/mol) with AlCl3 and Br2 at 100-150 °C to yield a mixture of 2-bromo-1,3-thiazole (3.2) (10%) and 2,5-dibromo-

1,3-thiazole (3.3) (5%) (see Scheme 3.1).96

Scheme 3.1: Synthesis of 2,5-dibromo-1,3-thiazole (3.3) from 1,3-thiazole (3.1).

A second reported method utilizes the reaction of 2-bromo-1,3-thiazole (3.2) with HBr in

57 H2O followed by heating under reflux with Br2 for three hours (see Scheme 3.2). While this method appears to work as well as reported, the material could not be purified by vacuum sublimation and required silica gel chromatography in order to be purified, thus making this approach expensive and inconvenient for the large scale preparation of 2,5- dibromo-1,3-thiazole (3.3).

Scheme 3.2: Synthesis of 2,5-dibromo-1,3-thiazole (3.3) from 2-bromo-1,3-thiazole

(3.2).

The most efficient literature method uses Sandmeyer chemistry on 2-amino-5-bromo-1,3- thiazole (3.4) to give 2,5-dibromo-1,3-thiazole (3.3) with reported yields ranging from

65-72% (see Scheme 3.3).97-99 While this method generated 2,5-dibromo-1,3-thiazole

(3.3) in good yield, the requisite precursor, 2-amino-5-bromo-1,3-thiazole (3.4), was reported to be “unstable in air and could not be stored.”98

Scheme 3.3: Synthesis of 2,5-dibromo-1,3-thiazole (3.3) from 2-amino-5-bromo-1,3-

thiazole (3.4).

3.2.2. A new approach for the preparation of 2,5-dibromo-1,3-thiazole (3.3)

Starting from commercially inexpensive 2-amino-1,3-thiazole (3.5; $0.17/g), 2- bromo-1,3-thiazole (3.2) was synthesized in 86% yield using a modification of a procedure originally developed by Ganapathi et al (see Scheme 3.4).100 Interestingly, use of 2-amino-1,3-thiazole (3.5) purchased from Alfa Aesar gave the reported yield on a consistent basis. In contrast, 2-amino-1,3-thiazole (3.5) purchased from Acros Organics resulted in an isolated yield of 2-bromo-1,3-thiazole (3.2) of only 40%, despite the starting 2-amino-1,3-thiazole (3.5) being purified through vacuum sublimation. We have no explanation for this variation in yield based on the source of the starting material 3.5.

Presumably, trace contaminants were interfering with the reaction, but we could find no evidence for the presence of such impurities in the material used. Although Ganapathi did not report the synthesis of 2-iodo-1,3-thiazole (3.6), we found that replacing NaBr in this modified procedure with NaI, yielded 2-iodo-1,3-thiazole (3.6) in 66% yield (see

Scheme 3.4). This is a significant improvement over the only literature method for

converting 2-amino-1,3-thiazole (3.5) to 2-iodo-1,3-thiazole (3.6), which proceeds in

101 40% yield using H2SO4, NaNO2, and KI.

Scheme 3.4: Synthesis of 2-halo-1,3-thiazoles 3.2 and 3.6 from 2-amino-1,3-thiazole

(3.5).

Our first attempt at synthesizing 2,5-dibromo-1,3-thiazole (3.3) was based on a procedure for brominating 2,2’-bithiazole.102 2-Bromo-1,3-thiazole (3.2) and N-bromosuccinimide

(NBS) were dissolved DMF and heated at 60 °C for 76 hours, which yielded 2,5- dibromo-1,3-thiazole (3.3) in 18% yield. The most efficient preparation of 2,5-dibromo-

1,3-thiazole (3.3) again stemmed from the modification of a procedure previously used for the bromination of 2,2’-bithiazole,58 which utilized an excess of elemental bromine in the presence of solid NaHCO3. Using this procedure, which involved the sequential addition of three aliquots of 0.5 equivalents of NaHCO3 over the course of the reaction,

2,5-dibromo-1,3-thiazole (3.3) was obtained in 62% yield (see Scheme 3.5; Table 3.1 entry 1). Given that NaHCO3 is not particularly soluble in the solvent (CHCl3), it seemed logical to use a larger excess of NaHCO3 and add the entire portion at the start of the reaction. By doing so, 2,5-dibromo-1,3-thiazole (3.3) was generated in 70% yield (Table

3.1, entry 2). The use of an even larger excess of NaHCO3 enhanced the yield to 79%

(Table 3.1, entry 3). Upon scaling up the procedure (8.65 g and 14.29 g), it was found that the crude product could be purified through vacuum sublimation with minimal loss

of product (see Table 3.1, entries 3 versus 4 and 6) which allowed for 2,5-dibromo-1,3- thiazole (3.3) to be synthesized and purified on larger scales while avoiding the need for silica gel chromatography. This procedure provides the first scalable, high yielding method for the preparation of 2,5-dibromo-1,3-thiazole (3.3). It proceeds from commercially inexpensive starting materials, does not require the preparation of unstable intermediates or the use of air-sensitive reagents and costs only $0.70/g to synthesize 2,5- dibromo-1,3-thiazole (3.3) starting from 2-amino-1,3-thiazole (3.5).

Scheme 3.5: Synthesis of 2,5-dibromo-1,3-thiazole (3.3) from 2-bromo-1,3-thiazole

(3.2).

Table 3.1: Synthesis of 2,5-dibromo-1,3-thiazole (3.3) with varying amounts of

NaHCO3 and isolation techniques.

a b Entry Quantity of 3.2 (g) Eq NaHCO3 Yield of 3.3 (%) 1 2.5 3 x 0.5c 62 2 2.5 2.01 70 3 2.5 3.06 79 4 8.7 3.10 79d 5 1.0 3.11 81d 6 14.3 3.55 75d

a Equivalents of NaHCO3 added to the reaction relative to 2- bromo-1,3-thiazole (3.2) b Isolated yield of purified product c Every 24 hours, half an equivalent of NaHCO3 was added d Product was isolated by vacuum sublimation

3.3.1. Literature approaches to 2,5-dichloro-1,3-thiazole (3.8)

The synthesis of 2,5-dichloro-1,3-thiazole (3.8) has only been reported by one group; it was synthesized from 2-amino-5-chloro-1,3-thiazole (3.7) in 48% yield using

Sandmeyer chemistry (see Scheme 3.6).103 However, considering that 2-amino-5-bromo-

1,3-thiazole (3.4) was reported to be unstable, 2-amino-5-chloro-1,3-thiazole (3.7) is likely to suffer the same downfall.

Scheme 3.6: Synthesis of 2,5-dichloro-1,3-thiazole (3.8) from 2-amino-5-chloro-1,3-

thiazole (3.7).

3.3.2. A new approach for the preparation of 2,5-dichloro-1,3-thiazole (3.8)

With the improved approach to 2,5-dibromo-1,3-thiazole (3.3) in hand, we next attempted to extended the chemistry to the synthesis of 2,5-dichloro-1,3-thiazole (3.8).

This required the initial preparation of 2-chloro-1,3-thiazole (3.9). The synthesis of 2- chloro-1,3-thiazole (3.9) was accomplished in 25% yield from 2-amino-1,3-thiazole (3.5) using the approach developed by Ganapathi et al (Scheme 3.7).100

Scheme 3.7: Synthesis of 2-chloro-1,3-thiazole (3.9) from 2-amino-1,3-thiazole (3.5).

Unfortunately, utilizing similar chemistry to that employed for the formation of 2,5- dibromo-1,3-thiazole (3.3) was not as successful when applied to the synthesis of 2,5-

dichloro-1,3-thiazole (3.8). Stirring 2-chloro-1,3-thiazole (3.9) in CHCl3 with solid

NaHCO3 and Cl2 gas at room temperature for 84 hours yielded very impure 2,5-dichloro-

1,3-thiazole (3.8) which was contaminated with starting 2-chloro-1,3-thiazole (3.9; about

27% starting material by crude 1H NMR analysis). Dissolving 2-chloro-1,3-thiazole (3.9) and 2.5 equivalents of N-chlorosuccinimide (NCS) in MeCN and heating at 60 °C for 116 hours gave a low yield (< 32%) of the desired 2,5-dichloro-1,3-thiazole (3.8) which proved difficult to purify (see Scheme 3.8). At this point, further developments along these lines were abandoned.

Scheme 3.8: Attempted synthesis of 2,5-dichloro-1,3-thiazole (3.8) from 2-chloro-1,3-

thiazole (3.9).

3.4.1. Literature approaches to 2,4-dibromo-1,3-thiazole (3.11)

A single approach for the synthesis of 2,4-dibromo-1,3-thiazole (3.11) has previously been reported, involving the reaction of POBr3 with 1,3-thiazolidine-2,4-dione

(3.10) to yield 2,4-dibromo-1,3-thiazole (3.11) as shown in Scheme 3.9.

Scheme 3.9: Synthesis of 2,4-dibromo-1,3-thiazole (3.11).

However, the yields seem to vary greatly from nearly quantitative to only about 50% depending upon how much POBr3 is used. When 7.6 equivalents of POBr3 was used, a

57 99% isolated yield was reported. In contrast, when only 3.0 equivalents of POBr3 were used, the isolated yield was reported as only 68%.104 In our hands, when 3.0 equivalents of POBr3 was used for this reaction, the isolated yield of 2,4-dibromo-1,3-thiazole (3.11) was only 59%. Using such a large excess of POBr3 makes this chemistry quite unattractive: POBr3 is somewhat expensive ($89/25g) and any excess POBr3 is destroyed at the end of reaction to generate toxic, gaseous HBr. As a result of the required large excess of POBr3 and its high cost, generating 2,4-dibromo-1,3-thiazole (3.11) through this approach is actually more expensive than purchasing it ($20/g). For example, performing the reaction on a scale of 1.25 g with 3.0 equivalents of POBr3 would require

9.2 g or $33 worth of POBr3. Assuming a yield of 60%, 1.56 g of 2,4-dibromo-1,3- thiazole (3.11) would be generated at cost of about $22/g.

3.4.2. A new approach for the preparation of 2,4-dibromo-1,3-thiazole (3.11)

Since the literature method for synthesizing 2,4-dibromo-1,3-thiazole (3.11) is expensive (requiring the use of a large excess of POBr3), does not give a satisfactory yield, and releases gaseous HBr, alternative approaches to 2,4-dibromo-1,3-thiazole

(3.11) were investigated. In the open literature, benzo[d]thiazol-2-ol (3.12) was converted to 2-bromobenzo[d]thiazole (3.13) in 95% yield using P2O5 and Bu4NBr

(Scheme 3.10).105

Scheme 3.10: Literature synthesis of 2-bromobenzo[d]thiazole (3.13).

This procedure was applied to the bromination of 1,3-thiazolidine-2,4-dione (3.10) as shown in Scheme 3.11, which gave 2,4-dibromo-1,3-thiazole (3.11) in excellent yield

(95%). This allows for 2,4-dibromo-1,3-thiazole (3.11) to be synthesized with a similar yield while using cheaper and safer chemicals at a cost of $1.48/g.

Scheme 3.11: Synthesis of 2,4-dibromo-1,3-thiazole (3.11) from 1,3-thiazolidine-2,4-

dione (3.10).

We had anticipated that we might be able to generate 2,4-diiodo-1,3-thiazole using a similar approach. However, when Bu4NI was used in place of Bu4NBr in this reaction, only unreacted starting material (3.10) resulted from the reaction.

3.5.1. Introduction to mixed dihalo-1,3-thiazole building blocks

As previously mentioned, 2,5-dihalo-1,3-thiazoles which possess the same halogen at the 2- and 5-positions react selectively at the 2-position for several different reactions. However, a study has never been performed in which this selectivity is reversed; in other words, where reactions are forced to occur at the 5-position while leaving the 2-position halogen intact. For Pd0-catalyzed cross-coupling, this might be accomplished by either placing iodine, a more reactive halogen, at the 5-position and / or by placing chlorine, a less reactive halogen, at the 2-position. For SNAr chemistry, reactions might be forced to occur first at the 5-position by placing smaller, more reactive

halogens such as fluorine or chlorine at the 5-position and / or by placing larger, less reactive halogens such as iodine at the 2-position.

3.5.2. Literature approaches to mixed 2,5-dihalo-1,3-thiazoles

In the open literature, only five mixed 2,5-dihalo-1,3-thiazoles have been reported. Many of the methods for their synthesis suffer from the same drawbacks as those associated with the synthesis of 2,5-dibromo-1,3-thiazole (3.3). 2-Bromo-5-iodo-

1,3-thiazole (3.14) has been produced through three different methods, as shown below in

Scheme 3.12. Although 2-bromo-5-iodo-1,3-thiazole (3.14) is obtained in high yield for the first two methods, they all require the use of air-sensitive reagents either during the halogenation step or during the preparation of the requisite starting materials.57,106,107

Unfortunately, in our hands, attempts at reproducing the preparation of 2-bromo-5-iodo-

1,3-thiazole (3.14) from 2-bromo-1,3-thiazole (3.2) via LDA-mediated lithiation / iodination failed and yielded only unreacted starting material. Similarly, attempts to apply this approach to the synthesis of 5-chloro-2-iodo-1,3-thiazole and 2,5-diiodo-1,3- thiazole were met with failure as none of the desired product was obtained and only unreacted starting material was recovered.

Scheme 3.12: Literature methods for synthesizing 2-bromo-5-iodo-1,3-thiazole

(3.14).

The synthesis of 5-bromo-2-chloro-1,3-thiazole (3.16) has been reported twice; both methods are shown below in Scheme 3.13. Again, the approaches employed are low yielding and / or require unstable starting materials as is the case for the second method.108,109

Scheme 3.13: Literature methods for synthesizing 5-bromo-2-chloro-1,3-thiazole

(3.16).

Only a single, low yielding method is described for the synthesis of 2-bromo-5-chloro-

1,3-thiazole (3.17, Scheme 3.14).110 Given that 2-amino-5-bromo-1,3-thiazole (3.4) was reported to be unstable, 2-amino-5-chloro-1,3-thiazole (3.7) would likely display similar properties. In addition, attempts to prepare compound 3.7 from 2-amino-1,3-thiazole

(3.5) and HCl, H2O and either chlorine gas or N-chlorosuccinimide (NCS) were unsuccessful as none of the desired product was obtained.

Scheme 3.14: Literature method for synthesizing 2-bromo-5-chloro-1,3-thiazole

(3.17) from 2-amino-5-chloro-1,3-thiazole (3.7).

Again, only a single low yielding method is available for the synthesis of 5-bromo-2- iodo-1,3-thiazole (3.18, Scheme 3.15). Furthermore, the preparation of 2-

(trimethylsilyl)-5-(trimethylstannyl)-1,3-thiazole (3.15) requires highly toxic and air- sensitive reagents.107

Scheme 3.15: Literature method for synthesizing 5-bromo-2-iodo-1,3-thiazole (3.18)

from compound 3.15.

3.5.3. New approaches for the preparation of mixed 2,5-dihalo-1,3-thiazoles

Given the success of forming 2,5-dibromo-1,3-thiazole (3.3) in excellent yield using electrophilic aromatic substitution, the synthesis of mixed 2,5-dihalo-1,3-thiazoles was attempted using similar methods; however, this approach was met with little success.

In preliminary studies, the synthesis of 2-bromo-5-chloro-1,3-thiazole (3.17) was attempted as shown in Scheme 3.16.

Scheme 3.16: Attempted synthesis of 2-bromo-5-chloro-1,3-thiazole (3.17) from 2-

bromo-1,3-thiazole (3.2).

By reacting 2-bromo-1,3-thiazole (3.2) with NCS in refluxing MeCN, a 49:51 mixture of

2-bromo-5-chloro-1,3-thiazole (3.17) and 2,5-dibromo-1,3-thiazole (3.3) was obtained.

Unfortunately, this method gave a low isolated yield of organic material (23% with respect to the mass of starting material) and the two resulting products could not be separated using silica gel chromatography. Using conditions more similar to those used for the synthesis of 2,5-dibromo-1,3-thiazole (Cl2 gas and solid NaHCO3 in CHCl3) gave only trace amounts of 2-bromo-5-chloro-1,3-thiazole (3.17) and mostly 2,5-dibromo-1,3- thiazole (3.3). Given that Cl2 gas gave such poor results, it was postulated that Cl2 gas, which was present in the NCS, as evidenced by the strong odor, may have been responsible for the low yield of 2-bromo-5-chloro-1,3-thiazole (3.17) obtained when using NCS as the chlorinating agent. Thus, a newly purchased source of NCS was employed. It was also decided to reduce the reaction temperature to 60 °C in an attempt to suppress any side reactions leading to the formation of 2,5-dibromo-1,3-thiazole (3.3).

The use of newly purchased NCS at lower temperatures gave poor, but slightly different results (see Table 3.2) when compared to the reaction performed at reflux with the older supply of NCS.

Table 3.2: Product distribution for the reaction of 2-bromo-1,3-thiazole (3.2) with

the new supply of NCS at 60 °C.

Reaction Ratio of 1,3-thiazole-based componentsa time (h) 3.2 3.9 3.3 3.8 3.17 0 100 0 0 0 0 20 26 38 20 4 12 44 48 19 5 8 20 68b 47 16 6 9 22 92 0 0 0 24 76 116 0 0 0 23 77

a Determined by crude 1H NMR analysis b Another 1.25 equivalents of NCS was added

During the initial stages of the reaction, crude 1H NMR analysis showed 2-bromo-1,3- thiazole (3.2) was consumed to form mostly 2-chloro-1,3-thiazole (3.9) and 2,5-dibromo-

1,3-thiazole (3.3) along with trace amounts of 2,5-dichloro-1,3-thiazole (3.8) and 2- bromo-5-chloro-1,3-thiazole (3.17). After 44 hours, the reaction had stopped, but 47% of the starting material still remained. Therefore, a second addition of NCS was made which completely consumed the 2-bromo-1,3-thiazole (3.2) as well as the previously formed 2-chloro-1,3-thiazole (3.9). At the conclusion of the reaction, the major product was the desired 2-bromo-5-chloro-1,3-thiazole (3.17) along with some 2,5-dichloro-1,3- thiazole (3.8). Both byproducts, 2,5-dibromo-1,3-thiazole (3.3) and 2-chloro-1,3-thiazole

(3.9), which were initially formed during the reaction, were completely consumed. These results are somewhat puzzling as the reaction appears to behave very differently after the second addition of NCS, i.e. it might be expected that more 2,5-dibromo-1,3-thiazole

(3.3) and 2-chloro-1,3-thiazole (3.9) would form when more NCS was added instead of these species being consumed.

From the above study, it appeared that a compound was being generated during the reaction which lead to the consumption of 2,5-dibromo-1,3-thiazole (3.3). To probe this hypothesis, 2,5-dibromo-1,3-thiazole (3.3) was stirred with NCS in MeCN and heated at 60 °C (Scheme 3.17).

Scheme 3.17: Reaction of 2,5-dibromo-1,3-thiazole (3.3) with NCS and 2-chloro-1,3-

thiazole (3.9).

After stirring for 68 hours, only unreacted starting material (3.3) was present. At this point, 10 mol% of 2-chloro-1,3-thiazole (3.9) was added to the reaction mixture. Within

24 hours, the 2-chloro-1,3-thiazole (3.9) was completely consumed and partial consumption of 2,5-dibromo-1,3-thiazole (3.3) was also observed, leading to the formation of 2-bromo-5-chloro-1,3-thiazole (3.17) and 2,5-dichloro-1,3-thiazole (3.8).

The reaction was allowed to proceed for almost 12 days (284 hours) before the reaction had finally stopped, at which point more NCS was added. After nearly 20 days (476 hours), only trace amounts of the starting 2,5-dibromo-1,3-thiazole (3.3) remained and about equal amounts of 2,5-dichloro-1,3-thiazole (3.8) and 2-bromo-5-chloro-1,3-thiazole

(3.17) were present (see Table 3.3). From this study it appears that 2-chloro-1,3-thiazole

(3.9) is somehow responsible for the consumption of 2,5-dibromo-1,3-thiazole (3.3).

Table 3.3: Reaction of 2,5-dibromo-1,3-thiazole (3.3) with NCS and 2-chloro-1,3-

thiazole (3.9).

Reaction Ratio of 1,3-thiazole-based componentsa time (h) 3.3 3.8 3.17 Unknown 0 100 0 0 0 20 100 0 0 0 44 100 0 0 0 68b 100 0 0 0 92c 79 5 13 4 116 67 4 26 4 140 50 9 35 6 164 40 12 43 6 212d 39 11 45 5 284e 38 11 46 5 308 35 14 45 6 332 31 16 45 8 356 25 24 43 8 380 20 38 33 10 428 4 53 41 3 476 9 44 34 12

a Determined by crude 1H NMR analysis b 10mol% of 2-chloro-1,3-thiazole (3.9) added c No NCS detected by 1H NMR d Reaction at room temperature for hours 164-260 e 1.15 equivalents of NCS added

In order to evaluate whether these reactions were proceeding via radical intermediates, the reaction from Scheme 3.17 was repeated in the presence of 10 mol% of the radical trap 2,6-di-t-butyl-4-methylphenol (BHT), with 10 mol% of 2-chloro-1,3- thiazole (3.9) added at the beginning of the experiment (see Scheme 3.18 and Table 3.4).

With BHT present, the desired reaction as well as the halogen scrambling still occurred but at a much slower rate. By comparing the first 24 hours after 2-chloro-1,3-thiazole

(3.9) was added (92 hours for Table 3.3 and 24 hours for Table 3.4), the consumption of

2,5-dibromo-1,3-thiazole (3.3) decreased by a factor of 2.6, the formation of 2-bromo-5- chloro-1,3-thiazole (3.17) decreased by a factor of 1.6, and 2,5-dichloro-1,3-thiazole (3.8) was not detected in the crude 1H NMR until after 72 hours.

Scheme 3.18: Reaction of 2,5-dibromo-1,3-thiazole (3.3) with NCS, BHT, and 10

mol% 2-chloro-1,3-thiazole (3.9).

Table 3.4: Reaction of 2,5-dibromo-1,3-thiazole (3.3) with NCS, BHT and 10 mol%

2-chloro-1,3-thiazole (3.9).

Reaction Ratio of 1,3-thiazole-based componentsa time (h) 3.3 3.8 3.17 Unknown 0 100 0 0 0 24 92 0 8 0 48 88 0 12 0 72 77 3 17 3 96 51 6 37 6 120 50 5 43 3 168 43 8 39 10 216 51 4 40 5

a 1 Determined by crude H NMR analysis

Since BHT was shown to at least slow the halogen scrambling, the reaction from Scheme

3.16 was repeated, but in the presence of BHT and at 60 °C (see Scheme 3.19).

Unfortunately, the halogen scrambling was not stopped but instead the major product appeared to be an N-chloro-2-bromo-1,3-thiazolium salt (3.19, Table 3.5). Since the various 2,5-dihalo-1,3-thiazole products formed could not be separated by silica gel chromatography and their boiling points were very close as suggested by close GC

retention times, separation was impossible and the synthesis of 2-bromo-5-chloro-1,3- thiazole (3.17) was abandoned.

Scheme 3.19: Reaction of 2-bromo-1,3-thiazole (3.2) with NCS and BHT.

Table 3.5: Reaction of 2-bromo-1,3-thiazole (3.2) with NCS and BHT.

Reaction Ratio of 1,3-thiazole-based componentsa time (h) 3.2 3.3 3.8 3.17 3.19 Unknown 0 100 0 0 0 0 0 24 61 3 6 6 22 3 48 59 3 6 6 24 3

a 1 Determined by crude H NMR analysis

Unfortunately, the mechanism for the observed halogen scrambling was not determined; however, the results of the reactions shown in Scheme 3.17 / Table 3.3 and

Scheme 3.18 / Table 3.4 suggest that ipso substitution and SNAr chemistry are not likely explanations. As shown by the reaction in Scheme 3.17 / Table 3.3, no reaction occurs, even in the presence of NCS, until a catalytic amount of 2-chloro-1,3-thiazole (3.9) is added at which point the halogen scrambling starts. Since the halogen scrambling does not start until 2-chloro-1,3-thiazole (3.9) is added, ipso substitution is not a likely explanation since it would lead to the formation of 2-bromo-5-chloro-1,3-thiazole (3.17) before the addition of 3.9. SNAr chemistry can be eliminated as a likely explanation for

two reasons. First, there are no obvious sources of nucleophilic halogens. Second, as discussed in Chapter 3.1, the 2-position of 2,5-dibromo-1,3-thiazole (3.3) is the more active position of 1,3-thiazole for SNAr chemistry. Therefore, the formation of 2,5- dichloro-1,3-thiazole (3.8) should be much faster than the formation of 2-bromo-5- chloro-1,3-thiazole (3.17). Additionally, SNAr chemistry should lead to the formation of

5-bromo-2-chloro-1,3-thiazole (3.16), yet according to the crude 1H NMR spectrum there were no signs for its formation. The most likely explanation for the observed halogen scrambling is a radical-based mechanism since with the addition of sub-stoichiometric amounts of the radical trap BHT, the rate at which the halogen scrambling occurred was at least decreased. Further studies would be needed to develop a deeper understanding of these results. However, we elected not to continue these studies at this time.

3.5.4. Alternative approach to the preparation 5-bromo-2-iodo-1,3-thiazole (3.18)

Since 2,5-dibromo-1,3-thiazole (3.3) will undergo selective SNAr chemistry at the

2-position, we envisioned that the 2-position bromine could be replaced by another halogen via SNAr chemistry through the use of a nucleophilic source of halogen, such as

NaI. Through the use of Finkelstein conditions, the NaI would have the best opportunity to displace the 2-position bromine of 2,5-dibromo-1,3-thiazole (3.3) since the resulting

NaBr is insoluble in anhydrous acetone and therefore unable to react to regenerate the starting material. However, attempts to prepare 5-bromo-2-iodo-1,3-thiazole (3.18) from

2,5-dibromo-1,3-thiazole (3.3) and NaI in anhydrous acetone were unsuccessful (Scheme

3.20); only unreacted 2,5-dibromo-1,3-thiazole (3.3) was recovered.

Scheme 3.20: Attempted synthesis of 5-bromo-2-iodo-1,3-thiazole (3.18) from 2,5-

dibromo-1,3-thiazole (3.3).

In conclusion, we were successful in finding alternative approaches to the synthesis of 2,5- and 2,4-dibromo-1,3-thiazoles (3.3 and 3.11) which offered several advantages to the previously reported methods for their synthesis. Unfortunately, we were unsuccessful in finding an efficient entry to mixed dihalo-1,3-thiazole building

0 blocks. Thus, our proposed study to reverse the selectivity of SNAr chemistry and Pd - catalyzed cross-coupling reactions on 2,5-dihalo-1,3-thiazoles was abandoned.

CHAPTER 4. SYNTHESIS OF 2-ALKOXY-1,3-THIAZOLE LIQUID CRYSTAL

TARGETS

The second series of 1,3-thiazole-based liquid crystals to be discussed are the 2- alkoxy-1,3-thiazole-based liquid crystals (Structure II from Figure 1.15) which are structural analogs of the 5-alkoxy-1,3-thiazole-based liquid crystals I described in

Chapter 2.

Figure 1.15: Four variations of the targeted liquid crystals with the 1,3-thiazole ring

occupying “Ring 1” or “Ring 2.”

4.1. Literature approaches to 2-alkoxy-1,3-thiazoles

One approach to 2-alkoxy-1,3-thiazoles involves the reaction of 2-thiazolone (4.1)

111 with diazomethane in Et2O to yield 2-methoxy-1,3-thiazole (4.2) in 35% yield. 2-

Methoxy-1,3-thiazole is the only 2-alkoxy-1,3-thiazole which has been made utilizing this methodology. In addition to the low yield, synthesis of 2-methoxy-1,3-thiazole through this approach requires the use of hazardous diazomethane. Thus, extension of this approach to longer chain diazoalkanes is not an attractive option.

Scheme 4.1: Klein’s synthesis of 2-methoxy-1,3-thiazole 4.2.

Another logical approach would involve the SNAr reaction of a 2-halo-1,3- thiazole with an alkoxide ion nucleophile. In general, the use of amines, phenols, and thiophenols as nucleophiles in SNAr chemistry of 2-nitro- and 2-halo-1,3-thiazoles is well-precedented (see Scheme 4.2).92,98,112-114

Scheme 4.2: Use of SNAr chemistry for the synthesis of 2-heteroatom-substituted

1,3-thiazoles.

However, introducing alkoxy chains onto the 2-position of the 1,3-thiazole ring via SNAr chemistry is considerably less well explored. SNAr chemistry has been performed at the

2-position of 2-bromo-, 2-chloro-, and 2-nitro-1,3-thiazoles with short chain alkoxides

(MeO-, EtO-, and tBuO-),82,111,115-117 but the use of long-chain alkoxides has not been investigated. The synthesis of 2-alkoxy-5-halo-1,3-thiazoles (Hal = Br or Cl) has been accomplished through a similar approach starting from 2,5-dihalo- or 5-halo-2-nitro-1,3- thiazoles,59,117,118 but only with a methoxide ion (see Scheme 4.3).

Scheme 4.3: Synthesis of 2-alkoxy-5-halo-1,3-thiazoles using SNAr chemistry.

In our study, we intended to explore the synthesis of long-chain 2-alkoxy-1,3- thiazoles in order to generate a series of liquid crystals analogous to the 5-alkoxy-1,3- thiazoles 2.12. Considering that we had previously developed an efficient entry to 2,5-

dibromo-1,3-thiazole (3.3; see Chapter 3.2.2), we considered the use of this building black as a viable starting material for the synthesis of a series of 2-alkoxy-1,3-thiazole- based liquid crystals.

4.2. Preparation of 2-alkoxy-1,3-thiazole-containing liquid crystal targets via selective SNAr chemistry of 2,5-dibromo-1,3-thiazole (3.3)

Retrosynthetically, the final targets of this study (compounds 4.12a-4.12e) could be obtained through a DCC/DMAP esterification. The biaryl bond of compounds 4.5a-

4.5e could be created via Suzuki coupling of synthetic intermediates 4.3a-4.3e and 4.4

(see Scheme 4.4). Synthetic intermediates 4.3a-4.3e could be accessed utilizing selective

SNAr chemistry on the easily accessible 2,5-dibromo-1,3-thiazole (3.3), whose synthesis was discussed in Chapter 3.2.2.

Scheme 4.4: Retrosynthetic analysis of the target compounds 4.12a-4.12e.

Starting from 2,5-dibromo-1,3-thiazole (3.3), the synthesis of 2-alkoxy-5-bromo-

1,3-thiazoles 4.3a-4.3e was accomplished using an excess of the appropriate sodium alkoxide in refluxing Et2O or refluxing THF in the presence of CuO and KI as shown in

Scheme 4.5. We were delighted to ascertain that this chemistry proceeded with exclusive regioselectivity at the 2-position.

Scheme 4.5: Synthesis of 2-alkoxy-5-bromo-1,3-thiazoles 4.3a-4.3e.

Using an approach based on the work of Barlow et al.,83 the addition of catalytic amounts of CuO and KI culminated in a slight increase in yield (see Table 4.1 entries 1 and 2) for

the formation of compound 4.3a. In the presence of CuO and KI, the reaction most likely no longer proceeds via SNAr chemistry. Based on proposed mechanisms from the literature,119,120 the reaction likely proceeds via oxidative addition of CuO at the weaker carbon-bromine bond of the 2-position of 2,5-dibromo-1,3-thiazole (3.3) to give intermediate I (see Scheme 4.6). Displacement of bromide by iodide results in intermediate II, which upon displacement of iodide by the sodium alkoxides, gives intermediate III. After reductive elimination, the catalyst, CuO, is regenerated along with the desired 2-alkoxy-5-bromo-1,3-thiazoles 4.3a-4.3e.

Scheme 4.6: Mechanism for formation of 2-alkoxy-5-bromo-1,3-thiazoles 4.3a-4.3e.

Given this result we decided to employ CuO and KI in all of the analogous nucleophilic substitution reactions. Presumably due to the low solubility of sodium dodecyloxide in

Et2O, the synthesis of compound 4.3e failed, but in refluxing THF compound 4.3e was obtained in 94% yield (see Table 4.1 entries 7 and 8).

Table 4.1: Synthesis of 2-alkoxy-5-bromo-1,3-thiazoles 4.3a-4.3e utilizing different

solvents and additives.

Entry RO Solvent Product Yield (%)a

1 C8H17O Et2O 4.3a 91% b 2 C8H17O Et2O 4.3a 86%

3 C9H19O Et2O 4.3b 86%

4 C10H21O Et2O 4.3c 82%

5 C10H21O THF 4.3c 78%

6 C11H23O THF 4.3d 88%

7 C12H25O Et2O 4.3e trace

8 C12H25O THF 4.3e 94%

a Isolated yield of pure product b No CuO or KI was added

Since the sodium decyloxide used in the formation of compound 4.3c was sparingly soluble in Et2O, and the formation of compound 4.3e failed in Et2O, it was assumed that the formation of compound 4.3d would also be prone to failure when using Et2O as the solvent. Synthesis of 4.3d was therefore carried out using THF as the solvent with an

88% yield being obtained (reaction with Et2O as solvent was not attempted).

As noted in the work of Bartoli, the reaction of 2,5-dichloro-1,3-thiazole

(compound 3.4) with excess sodium methoxide led to the formation of 2,5-dimethoxy-

1,3-thiazole.59 However, during our studies with 2,5-dibromo-1,3-thiazole (3.3), no 2,5- dialkoxy-1,3-thiazoles were observed, probably due to the higher resistance to SNAr chemistry experienced at the 5-position of the resulting 2-alkoxy-5-bromo-1,3-thiazole.

The observed resistance to SNAr chemistry of the 2-alkoxy-5-bromo-1,3-thiazoles 4.3a-

4.3e compared to 2-alkoxy-5-chloro-1,3-thiazoles is due to the size difference between bromine and chlorine as well as the more electronegative nature of the smaller halogen.121

The rate-determining addition of alkoxide to the 2-alkoxy-5-chloro-1,3-thiazole is accelerated by the higher electrophilicity and lower steric crowding at the 5-position carbon of the 2-alkoxy-5-chloro-1,3-thiazole. Although no aromatic side products were detected, small amounts of dialkyl carbonate (confirmed by comparison with literature 1H and 13C NMR data122) were formed during purification of each 2-alkoxy-5-bromo-1,3- thiazole. 1H NMR analysis of the crude reaction mixture did not show the presence of any dialkyl carbonate; however, following silica gel chromatographic purification, small amounts of the dialkyl carbonate had formed. Thus, it appears that adventitious water as well as acidic sites on the silica gel in the presence of excess alcohol led to the formation of the dialkyl carbonates. A reasonable mechanism for this chemistry is presented in

Scheme 4.7.

Scheme 4.7: Mechanism for formation of dialkyl carbonates.

No evidence of byproduct I was ever observed; however, this is to be expected since the dialkyl carbonates were formed during silica gel chromatography and byproduct I would be extremely polar, and thus would never be isolated from the silica gel column.

Since the dialkyl carbonate could not be removed via silica gel chromatography, chemical reactions were explored which could be used to destroy it in a way that would provide easy separation from the desired products. Several conditions were examined, but eventually it was found that vigorous stirring of the material overnight in dilute methanolic NaOH123 caused the dialkyl carbonate to be converted into the corresponding alcohol. The resulting alcohol could be removed via silica gel chromatography, although again trace amounts (determined through 1H NMR analysis) of the dialkyl carbonate formed during this process as well. In hindsight, formation of the dialkyl carbonates could have potentially been prevented through pre-treating the silica gel with triethylamine; however, this was never explored. Fortunately, the presence of dialkyl carbonate did not interfere with the next step of the synthesis and the slightly impure 2- alkoxy-5-bromo-1,3-thiazoles 4.3a-4.3e were subjected to Suzuki coupling124 with 4- cyanophenylboronic acid (4.4) to efficiently yield compounds 4.5a-4.5e.

Scheme 4.8: Synthesis of 2-alkoxy-5-(4-cyanophenyl)-1,3-thiazoles 4.5a-4.5e.

The synthesis of carboxylic acids 4.11a and 4.11b was straightforward and was accomplished efficiently using a refluxing mixture of EtOH, H2O, and NaOH to affect hydrolysis of the corresponding nitriles 4.5a and 4.5b. However, the hydrolysis of compound 4.5c was less efficient (62% isolated yield) as the reaction initially yielded a mixture of carboxylic acid 4.11c and the corresponding amide. After three sequential hydrolysis reactions under the same conditions, the mixture of the corresponding amide and carboxylic acid 4.11c was completely converted to the carboxylic acid 4.11c. When the hydrolysis of compound 4.5e was attempted under the aforementioned conditions, 1H

NMR analysis indicated that the hydrolysis appeared to stop at the corresponding amide and could not be further driven to the carboxylic acid through sequential rounds of hydrolysis as was observed with 4.11c (see Scheme 4.9).

Scheme 4.9: Synthesis of 4-(2-alkoxy-1,3-thiazol-5-yl)benzoic acids 4.11a-4.11c and

attempted synthesis of 4.11e.

Compound 4.5e was exposed to numerous hydrolysis conditions (see below) and, remarkably, all failed to afford compound 4.11e. We initially postulated that the key issue was the low solubility of compound 4.5e and therefore proceeded to attempt the reaction in a variety of aqueous solvent mixtures. The use of water / THF (1:1 ratio) and

NaOH yielded unreacted starting material 4.5e (verified by IR spectroscopy), while hydrolysis in 1,4-dioxane / THF / H2O (2:1:1 ratio) with NaOH afforded the corresponding amide. The use of a higher boiling solvent system of ethylene glycol and water (90:1 ratio)125 appeared to generate a mixture of products with a trace amount of the desired carboxylic acid. The use of hydrogen peroxide in 1,4-dioxane with KOH126 also failed to yield compound 4.11e as the amide was again produced in addition to another unidentified aromatic compound that was not the desired product. Highly acidic

127 conditions (a 10:1 mixture of AcOH and H2SO4 under reflux) were found to be much too harsh for the 2-alkoxy-1,3-thiazole moiety as an aromatic carboxylic acid was obtained but the alkoxy chain of the 1,3-thiazole ring had been cleaved in the process as confirmed by 1H NMR analysis.

The use of an alternate Pd0-catalyzed cross-coupling was also explored as a means of synthesizing compound 4.11e. Negishi coupling of 2-(dodecyloxy-1,3-thiazol-5-

yl)zinc chloride with methyl 4-bromobenzoate (see Scheme 4.10) was expected to lead to the methyl 4-(2-(dodecyloxy)-1,3-thiazol-5-yl)benzoate (4.6) from which saponification would give 4.11e.

Scheme 4.10: Attempted Negishi coupling of 2-dodecyloxy-1,3-thiazol-5-yl zinc

chloride and methyl 4-bromobenzoate.

However, the coupling reaction completely failed as the 2-dodecyloxy-1,3-thiazol-5-yl zinc chloride coupling partner was found to decompose upon warming to room

1 temperature. The crude H NMR spectrum lacked the diagnostic signal for the OCH2 group of the 2-alkoxy-1,3-thiazole. Performing the reaction at colder temperatures of -30

°C and -15 °C, prevented decomposition of the 1,3-thiazole-based zinc species but coupling was not observed at these lower temperatures. Lithiation at the 5-position of

4.3e was not an issue as we were able to generate 2-dodecyloxy-1,3-thiazol-5-ylboronic acid (4.7) in excellent yield (80%) via reaction of n-BuLi and 4.3e followed by quenching with trimethyl borate and subsequent hydrolysis. However, attempted Suzuki coupling of

2-dodecyloxy-1,3-thiazol-5-ylboronic acid (4.7) with methyl 4-bromobenzoate (see

Scheme 4.11) also met with failure, giving 2-dodecyloxy-1,3-thiazole and the homodimer

4,4’-dicarbomethoxybiphenyl (the 1H NMR spectrum was identical to that reported in the literature128).

Scheme 4.11: Attempted Suzuki coupling of 2-dodecyloxy-1,3-thiazol-5-ylboronic

acid (4.7) with methyl 4-bromobenzoate.

As reported in the literature, homocoupling of the aryl halide is a common side reaction of Suzuki coupling.129 Protodeboronation of the boronic acid, especially those on heterocycles, is also quite common130 and as a result, 1,3-thiazole-based boronic acids are rarely employed in synthesis.60 Mechanisms129,130 for both side reactions are shown in

Scheme 4.12.

Scheme 4.12: Mechanisms for homocoupling of an aryl halide and

protodeboronation of the boronic acids during Suzuki coupling.

A third Pd0-catalyzed cross-coupling was attempted with 4-carboxyphenylboronic acid

(4.8; prepared from 4-bromotoluene according to the literature131) and compound 4.3e being used as starting materials which would give direct access to 4.11e (see Scheme

4.13). However, once again the reaction met with failure as compound 4.3e and 2- dodecyloxy-1,3-thiazole were the only identifiable products.

Scheme 4.13: Attempted Suzuki coupling of 4-carboxyphenylboronic acid (4.8) with

compound 4.3e.

Since basic hydrolysis of compound 4.5e failed and the Pd0-catalyzed cross- coupling routes also failed to yield compound 4.11e, an alternative route was explored.

The literature clearly demonstrates that nitriles can be reduced to aldehydes through the use of DIBAl-H,132 and oxidation of aldehydes to carboxylic acids can be achieved through the use of the Pinnick oxidation.133 Therefore, we explored the application of this reduction-oxidation approach to the synthesis of carboxylic acids 4.11a-4.11e.

Reduction of nitriles 4.5c-4.5e using DIBAl-H was high yielding, but rather challenging given that the starting nitrile 4.5 could not be separated from the desired aldehyde 4.9 via silica gel chromatography (see Scheme 4.14). The use of excess DIBAl-H was found to be detrimental since the alkoxy chain was cleaved to yield 4-(1,3-thiazol-5- yl)benzaldehyde (4.10, the 1H NMR spectrum matched the literature data)134 and the corresponding alcohol. Normally, DIBAl-H reductions should require only one equivalent to work efficiently; however, with our substrate the reaction reached only 55% completion when 1.11 equivalents of DIBAl-H were used (see Table 4.2, entry 2). On the other hand, when a large excess (more than 2.10 equivalents) of DIBAl-H was used

(see Table 4.2, entries 1 and 8), a substantial amount of compound 4.10 was formed at the cost of the desired product. These results demonstrated that the reduction of the nitrile is selective, but that the 2-alkoxy-1,3-thiazole ring will also be reduced in the presence of

excess DIBAl-H. Thus, the best yields for desired aldehydes 4.9c-4.9e were obtained when an intermediate amount of DIBAl-H (about 1.6 equivalents) was added.

Scheme 4.14: Synthesis of 4-(2-alkoxy-1,3-thiazol-5-yl)benzaldehydes 4.9c-4.9e.

During the process of optimizing the DIBAl-H reduction, several reaction variables were deemed to be inconsequential or unfavorable. Since more than one equivalent of DIBAl-H was necessary for an efficient conversion, it was considered that perhaps there was an equilibrium occurring in which the DIBAl-H coordinated to the nitrogen of the 1,3-thiazole ring, which was then released on workup without reducing the 2-alkoxy-1,3-thiazole ring. If this were true, longer reaction times might lead to a higher yield of the desired product. However, this did not appear to be the case as more unreacted starting material was recovered with longer reaction times (see Table 4.2, entries 5-7). It was also considered that reduction of the 2-alkoxy-1,3-thiazole ring might have occurred as the reaction mixture was allowed to warm to room temperature; however, quenching the crude reaction mixture with ethanol at -78 °C did not prevent over- reduction of the substrate (see Table 4.2, entry 8). The temperature at which the reduction was performed also appeared to be non-critical, since nearly quantitative yields were obtained at temperatures of -78 °C and -40 °C (see Table 4.2, entries 3 and 9). The rate at which the DIBAl-H was added was also eliminated as a significant variable as the same volume of DIBAl-H was added over varying periods of time with no effect on the

isolated yield (see Table 4.2, entries 10 and 11). Interestingly, the scale at which the reaction was performed seemed to require varying conditions. When the reaction was performed on very small scales such (~0.13 mmol to 0.27 mmol), the use of about 2.0 equivalents of DIBAl-H gave nearly quantitative yields (see Table 4.2, entries 9 and 3).

However, when the same conditions were applied to a scaled up reaction of 0.54 mmol or

1.35 mmol of substrate, the isolated yield dropped dramatically (see Table 4.2, entries 10 and 4) to 66% and 56%, respectively. Thus it seemed that fewer equivalents of DIBAl-H were required for larger scale reactions (see Table 4.2, entry 12). This observation led us to the conditions that allowed for the most efficient synthesis of aldehydes 4.8c-4.8e on a reasonable scale. For substrates 4.5c-4.5e, the best yields were obtained when about 1.6 equivalents of DIBAl-H were added, which consumed all but a trace of starting material.

Using the relative integrations from the crude 1H NMR spectra, the exact amount of

DIBAl-H required to consume the remaining starting material was subsequently added.

In doing so, aldehydes 4.9c-4.9e were generated with isolated yields of 75-83% (see

Table 4.2, entries 13-16) with a minimal amount of 4-(1,3-thiazol-5-yl)benzaldehyde

(4.10) being formed. Since the formation of 4-(1,3-thiazol-5-yl)benzaldehyde (4.10) was not a desired target of the project, no attempts were made to optimize the conditions for its synthesis.

Table 4.2: Optimization for synthesis of 4-(2-alkoxy-1,3-thiazol-5-yl)benzaldehydes

4.9c-4.9e.

Eq. Rate Starting Compound mmol of Alkoxy Rxn Time c f Entry a b Product d e Isolated 4.5 Chain DIBAl (mL/min) (hrs) Material 4.10 g 1 0.54 C12H25 2.38 1.72 5 75% 0% 25% 47% g 2 0.54 C12H25 1.11 0.8 3 55% 42% 3% NA g 3 0.27 C12H25 1.96 0.018 1 94% 0% 6% 96%

4 1.35 C12H25 1.93 0.029 1 75% 0% 25% 56%

5 0.27 C12H25 1.96 0.016 1 92% 0% 8% 79% h 6 0.27 C12H25 1.96 0.016 8 78% 21% 1% NA h 7 0.13 C12H25 2.00 0.016 24 62% 36% 2% NA h 8 0.13 C12H25 4.44 0.016 24 21% 0% 79% 12% i 9 0.13 C12H25 2.00 0.016 1 ------99% i 10 0.54 C12H25 2.03 0.053 1 85% 0% 15% 66% i 11 0.54 C12H25 2.03 0.016 1 85% 0% 15% 67% i 12 0.54 C12H25 1.76 0.036 1 90% 0% 11% 80%

i 1.53 88% 7% 5% 13 0.54 C12H25 0.036 1 83% +0.11 93% 0% 7%

i 1.60 85% 6% 9% 14 1.92 C12H25 0.13 1 81% +0.10 85% 0% 15%

i 1.61 90% 4% 6% 15 2.41 C11H23 0.16 1 75% +0.06 90% 0% 10% 1.60 80% 14% 6% i 16 1.96 C10H21 +0.39 0.16 1 88% 3% 9% 76% +0.04 90% 0% 10%

All experiments performed at -78 °C unless otherwise noted a Equivalents of DIBAl added to the reaction in relation to nitrile 4.5c-4.5e. Numbers with + in front correspond to a second or third addition of DIBAl. b Rate at which DIBAl was added via syringe pump c Percentage of product as indicated by crude 1H NMR analysis d Percentage of nitrile 4.5c-4.5e as indicated by crude 1H NMR analysis e Percentage of yield compound 4.10 as indicated by crude 1H NMR analysis f Isolated yield of aldehyde 4.9c-4.9e after chromatographic separation g Approximate rate at which DIBAl was added manually via syringe h Reaction quenched with EtOH while at -78 °C i Reaction performed at -40 °C

The formation of 4-(1,3-thiazol-5-yl)benzaldehyde (4.10) is not surprising, considering that the nitrogen of an unsubstituted 1,3-thiazole is rather nucleophilic and has been shown to react with methyl iodide.135 With the addition of a strong electron- donor (such as the alkoxy chain in our system) in conjugation with the nitrogen, the nitrogen becomes even more nucleophilic, thus allowing for the nitrogen to coordinate to the Lewis acidic aluminum of DIBAl-H (see Scheme 4.15). As shown in the proposed mechanism, once the nitrogen has coordinated to the aluminum, the 2-position carbon of the 1,3-thiazole ring becomes extremely electrophilic which allows for the hydride to attack at this position. Upon acidic workup, the 1,3-thiazole ring re-aromatizes and the alkoxy chain is lost, thus producing 4-(1,3-thiazol-5-yl)benzaldehyde (4.10) and the corresponding alcohol.

Scheme 4.15: Mechanism for the formation of 4-(1,3-thiazol-5-yl)benzaldehyde

(4.10).

Using a modification of a procedure from the work of Nicolaou,136 the Pinnick oxidation was used to efficiently oxidize aldehydes 4.9c-4.9e to afford compounds 4.11c-

4.11e in excellent yield (93-95%; see Scheme 4.16). Due to solubility concerns, a three

component solvent system of t-BuOH, THF, and H2O (ratio of about 10:5:2.2) was used which completely dissolved the starting aldehyde (4.9c-4.9e) but allowed for carboxylic acids 4.11c-4.11e to precipitate out of solution as they formed.

Scheme 4.16: Synthesis of 4-(2-alkoxy-1,3-thiazol-5-yl)benzoic acids 4.11c-4.11e.

Various conditions were explored for the synthesis of the final targets (4.12a-

4.12e). The synthesis of a series of (S)-4-(1-methylheptyloxy)phenyl 4-(5-(alkoxy)-1,3- thiazol-2-yl)benzoates (2.12) through the use of the Steglich esterification (DCC/DMAP) were discussed in Chapter 2.137,138 However, when the same conditions were employed for the preparation of the 2-alkoxy-1,3-thiazole derivative 4.12a, the isolated yield was slightly lower at 63% versus 69% for the analogous 5-alkoxy-1,3-thiazole 2.12a (see

Scheme 4.17).

Scheme 4.17: Synthesis of (S)-4-(1-methylheptyloxy)phenyl 4-(2-(alkoxy)-1,3-thiazol-

5-yl)benzoates 4.12a-4.12e.

Given that the nitrogen of the 2-alkoxy-1,3-thiazole ring is rather nucleophilic, as well as basic, it was postulated that the nitrogen of the 2-alkoxy-1,3-thiazole ring might be interfering with the esterification. Thus, the use of amine additives was investigated as a means to aid in preventing the nitrogen of the 2-alkoxy-1,3-thiazole from becoming protonated. During our initial studies, it was found that the addition of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) (see Table 4.3, entries 2 and 3) prevented any product from forming. In contrast, the use of 1,4-diazabicyclo[2.2.2]octane (DABCO) appeared to make a slight improvement in the progression of the reaction as indicated by the ratio of product to starting material, as determined by 1H NMR analysis of the crude reaction mixture (see Table 4.3, entries 1 versus 5, and 6 versus 7). As a result, a small amount of DABCO (0.50-0.78 equivalents) was added during the formation of compounds 4.12a-4.12e; however, we later found that the use of DABCO had no effect on the final isolated yield of the product after purification. Upon comparison of Table

4.3, entries 11 and 12, the isolated yields of compounds 4.12d and 4.12e were virtually identical despite the absence of DABCO during the synthesis of compound 4.12e as shown in entry 12. The synthesis of compound 4.12a was also attempted by converting compound 4.11a to the corresponding acid chloride (4.13) and then reacting it with phenol 2.11 in triethylamine (see Scheme 4.18). This method was found to be just as efficient for generating compound 4.12a as the Steglich esterification.

Scheme 4.18: Alternate synthesis of (S)-4-(1-methylheptyloxy)phenyl 4-(2-

(octyloxy)-1,3-thiazol-5-yl)benzoate (4.12a).

Interestingly, esterification of carboxylic acids 4.11c-4.11e, which were generated via the Pinnick oxidation, reacted more favorably than carboxylic acids 4.11a-4.11c, which were generated via hydrolysis of the corresponding nitriles (Table 4.3, entries 11-

13 versus entries 6-9). The observed difference in reactivity could be attributed to a small, ethyl-containing impurity that was present in the carboxylic acids generated via hydrolysis. Unfortunately, the identity of this impurity could not be determined. As previously mentioned, the synthesis of compound 4.11c via hydrolysis of compound 4.5c

was very inefficient. Esterification of the resulting carboxylic acid generated from hydrolysis of compound 4.5c gave compound 4.12c in only 53% yield. Although an extra step is required, DIBAl-H reduction of nitriles 4.5c-4.5e to aldehydes 4.9c-4.9e followed by Pinnick oxidation was further justified by the observed enhancement in yield for the synthesis of carboxylic acids 4.11c-4.11e as well as their esterification to final targets 4.12c-4.12e.

Table 4.3: Optimization for conversions of 4.11a-4.11e to 4.12a-4.12e.

Entry # Phenol (mmol) Eq. DMAPa Eq. DCCb Base, Eqc % Completiond Isolatede 1f 1.21 0.26 1.36 --- 97% --- 2f 1.21 0.26 1.36 DBU, 0.55 45% --- 3f 1.21 0.26 1.34 DBU, 0.55g 79% --- 4f 1.21 0.26 1.36 DABCO, 0.52 93% --- 5f 1.21 0.26 1.35 DABCO, 0.51g 99% --- 6h 0.36 0.28 1.46 --- 75% 62% 7h 0.30 0.25 1.37 DABCO, 0.50g 83% 63% 8i 1.24 0.25 1.37 DABCO, 0.74g 81% 63% 9j 0.75 0.30 1.48 DABCO, 0.78g 73% 53%k 10l 0.72 0.31 1.55 DABCO, 0.76g 65% 71% 11m 0.69 0.30 1.64 DABCO, 0.75g 79% 80% 12l 0.26 0.30 1.64 --- 75-76% 79% 13j 0.55 0.31 1.65 --- 82-85% 81%

a Equivalents of DMAP added to the reaction in relation to phenol b Equivalents of DCC added to the reaction in relation to phenol c Base added to the reaction, number of equivalents added in relation to phenol d Progression of the reaction determined from the remaining phenol as indicated by crude 1H NMR analysis e Isolated yield of compounds 4.12a-4.12e after chromatographic separation f Reaction performed on 4-toluic acid and 4-methoxyphenol g Indicated base added after reaction had stirred for 30 minutes h Reaction performed on compound 4.11a and phenol 2.11 i Reaction performed on 4.11b and phenol 2.11 j Reaction performed on 4.11c and phenol 2.11 k Isolated yield likely compromised by trace of EtOH present in starting material 4.11c l Reaction performed on 4.11e and phenol 2.11 m Reaction performed on 4.11d and phenol 2.11

In conclusion, the targeted 2-alkoxy-1,3-thiazoles 4.12 were successfully generated starting from previously synthesized 2,5-dibromo-1,3-thiazole (3.3). The 2- position alkoxy chain was introduced via selective SNAr chemistry of 2,5-dibromo-1,3- thiazole (3.3) with long-chain alkoxides. Synthesis of the long-chain derivatives of carboxylic acids 4.11 was troublesome. However, through the use of a two-step sequence requiring DIBAl-H reduction of nitriles 4.5 followed by the Pinnick oxidation of the resulting aldehydes 4.9 generated the remaining carboxylic acids 4.11c-4.11e. The mesophase properties of these 2-alkoxy-1,3-thiazole targets 4.12a-4.12e are discussed in

Chapter 7.

CHAPTER 5. 4-FLUORO-1,3-THIAZOLE LIQUID CRYSTALS

5.1. Rationale for targeting 4-fluoro-1,3-thiazole-based liquid crystals

The incorporation of fluorine into liquid crystalline materials is quite common and of all the various locations within the liquid crystal structure, placing fluorine into the rigid core is arguably the most widely studied.19 As a lateral substituent on the core, fluorine creates a substantial lateral dipole without greatly increasing the width of the molecule. However, if the lateral substituent is too big, the mesomorphic properties are often significantly reduced.2 As a result of the strong dipole imparted by lateral fluorines, tilted phases such as the smectic C phase are more likely to be observed in such systems since formation of titled phases is favored when the molecule is polar.19 In addition to creating a large lateral dipole, the addition of fluorine into the core of liquid crystals can facilitate lower melting points as well as modify the “mesophase morphology, transition temperatures, and many essential physical properties of liquid crystals, such as optical, dielectric, and visco-elastic properties.”19

Despite the favorable properties imparted by the addition of fluorine, the synthesis of fluorinated heterocycle-based liquid crystal systems is rare outside the work of our group.27 Previously, our group has reported the synthesis of 3- and 4-fluorothiophene- containing liquid crystals, some of which were found to exhibit lower melting points than the non-fluorinated analogs and showed “exceptional promise for use in surface- stabilized ferroelectric liquid crystal (SSFLC) displays and other applications as they showed fast switching times, chevron-free topology and low viscosity.”1 However, the synthesis of other fluorinated heterocycle-based liquid crystals, such as a 4-fluoro-1,3- 73

thiazole, has not been explored despite the ring exhibiting such a strong lateral dipole.

For 1,3-thiazole, placement of fluorine at the 4-position greatly increases its dipole moment from 1.6 debye to almost 2.5 debye and also causes the dipole to adopt a more lateral orientation when compared to the unsubstituted 1,3-thiazole, whose dipole is tilted slightly towards the ring nitrogen (see Figure 5.1).139

Figure 5.1: Strength and orientation of the dipole moment for 1,3-thiazole and 4-

fluoro-1,3-thiazole.

While the synthesis of 2- and 5-fluoro-1,3-thiazoles has been reported by numerous groups,140-142 the synthesis of a 4-fluoro-1,3-thiazole has not been presented in the open literature. Since 5-fluoro-1,3-thiazoles have previously been prepared, incorporating such a structure into a liquid crystal would be less cumbersome, but its expected properties would be inferior to the 4-fluoro-1,3-thiazole. First, the 5-fluoro-1,3- thiazole would have a much smaller lateral dipole moment due to the opposing influences of the ring nitrogen and 5-fluoro substituent. In addition, incorporating a 5-fluoro-1,3- thiazole into a liquid crystal would cause the core of the liquid crystal to adopt a more bent geometry since the mesogenic core would necessarily be based on a 2,4- disubstituted 1,3-thiazole ring (see Chapter 1.3), which makes the structure less likely to exhibit mesogenic properties.

5.2. Literature approaches to 4-fluoro-1,3-thiazoles

As previously mentioned, the 4-position is the least reactive of the 1,3-thiazole ring carbons, which significantly complicates synthesis and limits the available approaches for introducing fluorine into the 1,3-thiazole ring at the 4-position. Several patents claim to have synthesized or used a 4-fluoro-1,3-thiazole; however, only a handful give any experimental detail of how they generated such a moiety. In one of the few patents that cite a yield, a 4-bromo-1,3-thiazole (5.1) was reacted with n-BuLi and the resulting lithio species was quenched with NFSI to generate 4-fluoro-1,3-thiazole 5.2 in 10% yield (see Scheme 5.1).143

Scheme 5.1: Synthesis of 4-fluoro-1,3-thiazole 5.2 via lithiation.

Three other patents introduced the fluorine through electrophilic aromatic substitution by reacting a 1,3-thiazole bearing a hydrogen at the 4-position (compounds 5.3, 5.5, and 5.8) with an electrophilic source of fluorine such as SelectFluor™ or N-fluoro-1,3- dichloropyridinium tetrafluoroborate (5.7; see Scheme 5.2). Of the patents which utilized electrophilic aromatic substitution, two used SelectFluor™ to generate 4-fluoro-1,3- thiazoles 5.4 and 5.6. A good yield was reported for 5.4; however, the 4-position of this ring is strongly activated by the 5-amino substituent (no yield was reported for the synthesis of 5.6).47,144 As a side note, mesogenic properties would be expected for compound 5.6; however, the patent does not report any transition temperatures.47 The

third patent to use electrophilic aromatic substitution utilized N-fluoro-1,3- dichloropyridinium tetrafluoroborate (5.7) to generate 4-fluoro-1,3-thiazole 5.9 which was likely reported to be the wrong regioisomer as they claimed to fluorinate 2-aryl-1,3- thiazole 5.8 at the 4-position but with the more reactive 5-position unsubstituted.145

Unfortunately, no NMR data was provided to support whether they generated a 4- or 5- fluoro-1,3-thiazole.

Scheme 5.2: Synthesis of 4-fluoro-1,3-thiazoles 5.4, 5.6, and 5.9 via electrophilic

aromatic substitution.

A fourth patent generated 4-fluoro-1,3-thiazole 5.11 in 40% yield by utilizing SNAr chemistry for the reaction of 4-chloro-1,3-thiazole 5.10 with KF (see Scheme 5.3).146

While this method gave the desired product in respectable yield, their substrate possessed a strong electron-withdrawing group (CHF2) at the 5-position to facilitate the SNAr reaction at the 4-position. Without such a strong electron-withdrawing group at the 5-

position, the reaction would likely fail, thus greatly limiting the flexibility of this approach.

Scheme 5.3: Synthesis of 4-fluoro-1,3-thiazole 5.11 via SNAr chemistry.

The synthesis of 2-bromo-4-fluoro-1,3-thiazole (5.13) was reported in the patent literature,147 which would serve as an excellent building block for organic synthesis (see

Scheme 5.4). Starting from 2-bromo-4-amino-1,3-thiazole hydrobromide (5.12), the fluoro substituent was introduced via a Balz-Schiemann reaction. Although no yield was reported, a procedure was provided. Unfortunately, our attempts to reproduce their work yielded a mixture of unknown composition and thus we were unable to generate any of the desired 2-bromo-4-fluoro-1,3-thiazole (5.13).

Scheme 5.4: Synthesis of 2-bromo-4-fluoro-1,3-thiazole (5.13) via a Balz-Schiemann

reaction.

The only open literature account for the synthesis of a 4-fluoro-1,3-thiazole was reported by Herkes, who generated 4-fluoro-1,3-thiazole 5.16 as a side-product from the reaction

148 of 2-carboxy-4,5-dichloro-1,3-thiazole (5.14) with SF4, HF, and NaF (see Scheme 5.5).

From this reaction, the major product was 4,5-dichloro-2-trifluoromethyl-1,3-thiazole

(5.15) but the reaction also generated a trace amount of 5-chloro-4-fluoro-2- trifluoromethyl-1,3-thiazole (5.16). In addition to generating 4-fluoro-1,3-thiazole 5.16 in low yield, this approach is quite unattractive given the extreme hazards associated with the use of SF4 and HF.

Scheme 5.5: Synthesis of 4-fluoro-1,3-thiazole 5.16 from a side-reaction of SF4.

In summary, despite lacking a practical approach for the synthesis of 4-fluoro-1,3- thiazoles in the open literature, the incorporation of such a moiety into liquid crystalline targets is attractive given its strong lateral dipole and promise for enhanced physical properties of the resulting liquid crystals. From the patent literature, only one approach, electrophilic aromatic substitution, claimed to generate a 4-fluoro-1,3-thiazole in good yield (Scheme 5.2) and this example employed a highly activated 5-amino-1,3-thiazole substrate. Other reported methods were inconvenient or impractical from the standpoint of low yield or required the use of hazardous reagents.

5.3. De novo approaches to 4-fluoro-1,3-thiazoles

As previously mentioned, the synthesis of 4-fluoro-1,3-thiazoles is severely limited by the unreactive nature of the 1,3-thiazole ring’s 4-position carbon. As a result of the low reactivity of the 4-position, 4-substituted-1,3-thiazoles are often synthesized through ring closing approaches. Thus, the substituent is incorporated into an - acylamino carbonyl compound, which upon reaction with Lawesson’s reagent, is

elaborated to the desired 4-substituted-1,3-thiazole. While this approach is very successful for incorporating carbon-based groups at the 4-position of 1,3-thiazole, the required substrate for the analogous preparation of a 4-fluoro-1,3-thiazole would almost certainly decompose by eliminating HF (see Scheme 5.6).

Scheme 5.6: Required substrate for synthesis of a 4-fluoro-1,3-thiazole via ring

closing.

Since HF elimination was anticipated as a major problem, we envisioned that placing a second group on the amide nitrogen to serve as a protecting group would likely prevent

HF elimination. The work of Sheldrake demonstrated that N,N-diformylaminomethyl aryl ketones (5.17) when reacted with P2S5 and triethylamine would generate a 5-aryl-

1,3-thiazole (5.18) in yields ranging from 47-83% (see Figure 5.7).149

Scheme 5.7: Sheldrake’s synthesis of 5-aryl-1,3-thiazole 5.18.

Since the requisite N,N-diformylaminomethyl ketones are often made from α- bromoketones such as compound 5.16, we attempted to make the difluoro analog of compound 5.17 from ethyl bromodifluoroacetate (5.19; see Scheme 5.8), which is a commercially inexpensive reagent. Additionally, the open literature has shown a handful of examples where a 2,2-difluoro-2-halocarbonyl compound (Hal = Br or Cl) will

undergo a substitution reaction with an amine to yield the desired 2-amino-2,2- difluorocarbonyl compound.150-152 From compound 5.20, reaction with Lawesson’s reagent or P2S5 might generate 5-ethoxy-4-fluoro-1,3-thiazole (5.21) which could serve as an excellent building block for liquid crystals.

Scheme 5.8: Targeted precursor for the synthesis of 5-ethoxy-4-fluoro-1,3-thiazole

(5.21).

Unfortunately, attempts to generate compound 5.20 from ethyl bromodifluoroacetate

(5.19) and sodium diformylamide in refluxing MeCN yielded only unreacted starting material. Since the literature has shown DMF to be an effective solvent for the synthesis of N,N-diformylaminomethyl ketones (5.17), the solvent was switched from MeCN to

DMF.153 By switching the solvent to DMF, ethyl bromodifluoroacetate (5.19) was consumed but again none of the desired product (5.20) was formed. Instead, a mixture of

1 13 ethyl formate, bromoethane, and CHBrF2 resulted, which was confirmed by H, C and

19F NMR analysis. The formation of these compounds was not fully understood, although a radical-based mechanism is a likely explanation given the odd outcome of the reaction; however, no further investigation of the mechanism was performed due to time constraints.

As previously discussed, HF elimination is a major problem when attempting to synthesize a 4-fluoro-1,3-thiazole via ring closing strategies. Another ring closing

approach which avoids HF elimination is through the use of “diazohalo” compounds. As shown below in Scheme 5.9, trisubstituted-1,3-oxazole 5.24 can be generated by the reaction of a nitrile (5.22) and a diazo compound (5.23) in the presence of a transition

154 metal catalyst such as Rh2(OAc)4, or a Lewis acid such as BF3•Et2O (see Scheme 5.9).

Scheme 5.9: Synthesis of trisubstituted-1,3-oxazole 5.24 from diazo compound 5.23.

While this is a well-documented method for the synthesis of 1,3-oxazoles, the literature does not contain an example in which a 4-halo-1,3-oxazole was derived from a diazo compound. The synthesis of ethyl diazobromoacetate (5.26) has been reported in the open literature155 and use of this procedure afforded ethyl diazobromoacetate (5.26) cleanly from commercially available ethyl diazoacetate (5.25). Since diazo compounds are known to be thermally unstable, it was used directly without any purification and was reacted with 4-bromobenzonitrile (5.27) in the presence of BF3•Et2O as a one-pot reaction (see Scheme 5.10).

Scheme 5.10: Synthesis of 4-bromo-1,3-oxazole 5.28 from ethyl diazobromoacetate

(5.26).

Despite generating 4-bromo-1,3-oxazole 5.28 in only 10% yield, the method is still extremely powerful. In what would normally require several steps, a trisubstituted-1,3-

oxazole was generated in a single step from commercially available reagents. Given this groundbreaking result, we attempted to apply this method to the synthesis of a 4-fluoro-

1,3-oxazole, which might have permitted direct access to the 4-fluoro analog of 5.28.

Unfortunately, ethyl diazofluoroacetate could not be generated from ethyl diazoacetate

(5.25) with either SelectFluor™ or NFSI as the source of electrophilic fluorine. As a result, this approach was abandoned.

Fluorinations of enolates and silyl enol ethers are well established, high yielding reactions.156 Although this chemistry has not been utilized as a means for generating a 4- fluoro-1,3-thiazole, a patent does claim to have used a silyl enol ether for generating a 5- fluoro-1,3-thiazol-4-one (5.30) although, unfortunately, no yield was reported for this transformation (see Scheme 5.11).157

Scheme 5.11: Synthesis of 5-fluoro-1,3-thiazol-4-one 5.30.

Since we desired the 4-fluoro derivative, a different substrate was required than reported in the patent literature. Using literature precedents, we were able to obtain the requisite starting material for an enolate fluorination which could lead to a 4-fluoro-1,3-thiazole.

Starting from commercially inexpensive methyl anisate (5.31), O-methyl 4- methoxybenzothioate (5.32) was obtained in 94% yield which was subsequently converted to 2-(4-methoxyphenylthioamido)acetic acid (5.33; see Scheme 5.12) in 95% yield.158

Scheme 5.12: Synthesis of 2-(4-methoxyphenylthioamido)acetic acid (5.33).

2-(4-Methoxyphenylthioamido)acetic acid (5.33) was successfully converted to 1,3- thiazol-5-one 5.34 using DCC,159 but since 1,3-thiazol-5-ones are reported to be unstable,160 it was used immediately with minimal purification. 2-(4-Methoxyphenyl)-

1,3-thiazol-5(4H)-one (5.34) was confirmed to have been formed by 1H NMR, but upon reaction with triethylamine and SelectFluor™, 1H and 19F NMR failed to provide any strong evidence to support the formation of the desired 4-fluoro-2-(4- methoxyphenyl)thiazol-5(4H)-one (5.35; see Scheme 5.13).

Scheme 5.13: Synthesis of 4-fluoro-1,3-thiazol-4-one 5.35.

Attempting the reaction as a one-pot synthesis starting from 2-(4- methoxyphenylthioamido)acetic acid (5.33) and without triethylamine seemed promising as a 48 Hz doublet at 6.28 ppm was observed in the 1H NMR spectrum of the crude reaction product. This is consistent with the presence of the CHF group of 4-fluoro-2-(4- methoxyphenyl)thiazol-5(4H)-one (5.35); however, only a pair of singlets (-63.7 and

-66.6 ppm) was observed in the 19F NMR. The lack of a matching 48 Hz doublet in the

19F NMR demonstrated that the CHF group was in fact not present, so the reaction was determined to have failed. As previously mentioned, 1,3-thiazol-5-ones are reported to

be unstable, thus the reaction temperature was decreased to -40 °C since we anticipated that the 1,3-thiazol-5-one 5.34 would be more stable at this temperature. Unfortunately, changing the reaction temperature also failed to generate the desired 4-fluoro-1,3-thiazol-

5-one 5.35 and by the crude 1H NMR spectrum, a complex mixture of numerous compounds resulted.

5.4. Halogen-metal exchange approaches leading to 4-fluoro-1,3-thiazoles

Due to the lack of success in generating a 4-fluoro-1,3-thiazole via ring closing strategies, halogen-metal exchange approaches were next explored. In recent years, numerous publications have shown various halogen-metal exchange reactions to efficiently yield fluoroaromatic compounds in excellent yield.156,161,162 However, only a few have been used to fluorinate sulfur-based heterocycles such as thiophene162-170 and only a single account has utilized this approach for the fluorination of 1,3-thiazole which was utilized to produce a 5-fluoro-1,3-thiazole.171

The most common and straightforward halogen-metal exchange reaction which leads to formation of fluoroaromatics involves lithiation of the corresponding halooaromatic (bromine or iodine) followed by quenching with a source of electrophilic fluorine such as NFSI. Although this is the most direct pathway for halogen-metal exchange, the yields are often low due to competing reactions from single electron transfer172-174 and nucleophilic attack at the sulfur of NFSI.175

Since the 2- and 5-positions of 1,3-thiazole are known to be acidic and will react with n-BuLi, we desired a simple 2,5-disubstituted-1,3-thiazole which could be used as a test substrate for lithiation but would not create any potential complications from

competing sites of lithiation. At the time when this study was conducted, we had not yet developed our method for the synthesis of 2,5-dibromo-1,3-thiazole (3.3), which would have served as an excellent building block for the synthesis of our desired test substrate

4-bromo-2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.43). Therefore, a Lawesson’s reagent-mediated ring closing strategy was employed for its synthesis (see Scheme 5.14).

Starting from commercially inexpensive 4-methoxyacetophenone (5.36), the methyl ketone was brominated through the use of elemental bromine to generate α-bromo-4- methoxyacetophenone (5.37) in good yield.176 α-Bromo-4-methoxyacetophenone (5.37) was converted to α-azido-4-methoxyacetophenone (5.38)177 and was subsequently reduced to the hydrochloride salt (5.39) in excellent yield. Reaction of α-amino-4- methoxyacetophenone hydrochloride (5.39) with 4-methoxybenzoyl chloride, which was prepared from 4-methoxybenzoic acid (5.40) and SOCl2, in the presence of pyridine and

178 solid NaHCO3 afforded the -acylamino carbonyl compound (5.41) in excellent yield.

The 2,5-disubstituted-1,3-thiazole (5.42) was obtained in quantitative yield from the reaction of Lawesson’s reagent and 4-methoxy-N-2-(4-methoxyphenyl)-2- oxoethylbenzamide (5.41). The conditions for the synthesis of 4-bromo-2,5-bis(4- methoxyphenyl)-1,3-thiazole (5.43) were chosen carefully to avoid bromination of the highly activated 4-methoxyphenyl rings. Fortunately, the literature contained an example of a 1,3-thiazole being selectively brominated at the 4-position of 1,3-thiazole through the use of NBS at low temperature even in the presence of a 4-methoxyphenyl ring.67

Application of this procedure to 2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.42) generated the desired 4-bromo-2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.43) in good yield.

Lithiation of 4-bromo-2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.43) followed by quenching with NFSI afforded the desired 4-fluoro-2,5-bis(4-methoxyphenyl)-1,3- thiazole (5.44) in a moderate yield of 50% which is the first instance for the synthesis of a

4-fluoro-1,3-thiazole outside the patent literature.

Scheme 5.14: Synthesis of 4-fluoro-2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.44).

Since 4-fluoro-2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.44) is not useful in terms of incorporating it into the liquid crystalline materials targeted in this dissertation, we aspired to apply this approach to a more flexible building block such as a 2-alkoxy-4- bromo-1,3-thiazole. As expected, SNAr chemistry with long-chain alkoxides and 2,4- dibromo-1,3-thiazole (3.11) exclusively yielded 4-bromo-2-octyloxy-1,3-thiazole (5.45; see Scheme 5.15), although the yield was significantly lower compared to the analogous reaction with 2,5-dibromo-1,3-thiazole (3.3). Unfortunately, the desired 4-fluoro-2- octyloxy-1,3-thiazole (5.46) could not be generated via lithiation followed by quenching with NFSI. Lithiation of 4-bromo-2-octyloxy-1,3-thiazole (5.45) was found to be an

efficient process; lithiation in Et2O followed by trapping with tributylstannyl chloride afforded 2-octyloxy-4-tributylstannyl-1,3-thiazole (5.51) in nearly quantitative yield (see

Scheme 5.20). However, NFSI was found to be insoluble in Et2O. The use of a 2:1 mixture of Et2O and THF allowed for NFSI to be dissolved, but yielded at most a trace amount of the desired 4-fluoro-2-octyloxy-1,3-thiazole (5.46). Since NFSI was insoluble in Et2O, the solvent was switched to THF; however, the use of THF caused lithiation of

4-bromo-2-octyloxy-1,3-thiazole (5.45) to inexplicably fail and as a result none of the desired 4-fluoro-2-octyloxy-1,3-thiazole (5.46) was generated (see Scheme 5.15).

Scheme 5.15: Attempted synthesis of 4-fluoro-2-octyloxy-1,3-thiazole (5.46).

Another recently developed halogen-metal exchange reaction which leads to the formation of fluoroaromatics involves the use of iPrMgCl to create an arylmagnesium chloride species which is then quenched with NFSI. While n-BuLi is more commonly used for such a transformation, use of iPrMgCl offers several advantages such as functional group tolerance (iPrMgCl will tolerate esters, amides, and nitriles), and the use of higher reaction temperatures is possible (reactions of iPrMgCl are often performed at

0 °C or room temperature),179 and has been used in the synthesis of various fluorothiophenes.162,163 In addition to the advantages of using iPrMgCl, this method is touted to be higher yielding than lithiation approaches due to its ability to minimize single electron transfer,162,163 a reported side reaction of quenching aryl lithium species

with NFSI. As a result of using iPrMgCl, the choice of solvent is not limited to just THF or Et2O. Thus, the authors reported that the use of a mixture of CH2Cl2 and perfluorodecalin would lead to enhanced yields since this solvent system is less susceptible to single electron transfer reactions due to the solvent possessing fewer hydrogens for participation in this side reaction. Since iPrMgCl is tolerant of nitriles, we attempted to incorporate fluorine into a previously synthesized series of targets, the 5- alkoxy-2-(4-cyanophenyl)-1,3-thiazoles (2.8). Bromination of 2-(4-cyanophenyl)-5- octyloxy-1,3-thiazole (2.8a) proceeded smoothly and in high yield with NBS at room temperature (see Scheme 5.16). However, three separate attempts to react 4-bromo-2-(4- cyanophenyl)-5-octyloxy-1,3-thiazole (5.47) with iPrMgCl followed by NFSI failed to generate the desired 2-(4-cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole (5.48a; see

Scheme 5.16). While attempting to apply this approach162 to 4-bromo-2-(4- cyanophenyl)-5-octyloxy-1,3-thiazole (5.47), it was ascertained that several equivalents of iPrMgCl were required to consume all the starting material. Also, NFSI was identified as being insoluble in the reported solvent system of CH2Cl2 and perfluorodecalin.

Furthermore, we recognized that this solvent system was biphasic. Upon addition of this biphasic solvent system containing suspended NFSI to the cold (-78 °C) aryl magnesium chloride species, the mixture was observed to freeze. Upon warming to room temperature, none of the desired 2-(4-cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole

(5.48a) had formed. Given the odd nature of the freezing, biphasic solvent system, the lack of solubility of NFSI in this solvent system, the complications associated with

consuming all the starting material, and the lack of desired product, this approach was abandoned.

Scheme 5.16: Attempted synthesis of 2-(4-cyanophenyl)-4-fluoro-5-octyloxy-1,3-

thiazole (5.48a).

Recently in the open literature, Ritter has shown that phenyl-based boronate esters, boronic acids, and tributylstannyl groups can be converted to fluorophenyls in excellent yield through the use of silver catalysts and SelectFluor™.180-182 While this approach required an additional step for the preparation of boronic acids or tributylstannanes, the functional group tolerance of this approach was shown to be excellent as alkoxy groups, primary alcohols, nitriles, aldehydes, amides, and esters were all demonstrated to be tolerated. Mechanistically, this approach was quite simple. The first step of their proposed mechanism (see Scheme 5.17) was transmetalation of the aryl stannane (or the aryl boronate complex resulting from reaction of the boronic acid with base) to give intermediate I followed by oxidation of the aryl-silver(I) species by

SelectFluor™ to give intermediate II. The final step was reductive elimination to give the desired aryl fluoride and regenerate the silver(I) catalyst.182

Scheme 5.17: Proposed mechanism for silver-catalyzed fluorination.

Due to issues of toxicity associated with organotin compounds, we first explored the conversion of 1,3-thiazole-based boronate esters to 4-fluoro-1,3-thiazoles. Boronate esters are commonly synthesized through lithiation, followed by quenching with a trialkyl borate. However, since a nitrile was present within our starting material (5.47), lithiation would have to be carried out at lower temperatures than -78 °C; thus the requisite boronate ester was targeted through Pd0-catalyzed cross coupling.183,184 As previously discussed, 4-bromo-2-(4-cyanophenyl)-5-octyloxy-1,3-thiazole (5.47) can be prepared in excellent yield from 2-(4-cyanophenyl)-5-octyloxy-1,3-thiazole (2.8a; see Scheme 5.16).

Reaction of 4-bromo-2-(4-cyanophenyl)-5-octyloxy-1,3-thiazole (5.47) with Pd(PPh3)4 and bis(pinacolato)diboron seemed to have formed mostly the desired product (5.49; see

Scheme 5.18) and a trace of the parent 1,3-thiazole (2.8a) according to crude 1H NMR

analysis. However, after the material was subjected to silica gel chromatography, the recovered material was mostly 2-(4-cyanophenyl)-5-octyloxy-1,3-thiazole (2.8a) and none of the desired product was isolated. In retrospect, the instability of 5.49 was not surprising given that other 1,3-thiazole-based boronic acids and esters have been reported to decompose and thus are rarely used in Suzuki coupling.60 In hindsight, conversion of the crude boronate ester 5.49 to the corresponding 1,3-thiazole-based potassium trifluoroborate (BF3K) might have been worth investigating since they are less prone to protodeboronation than boronate esters, especially in the case of heteroaryl-based boronate esters such as 5.49.185 However, due to time constraints conversion to the corresponding 1,3-thiazole-based potassium trifluoroborate (BF3K) was not attempted.

Given the instability of 1,3-thiazole-based boronate esters, the conversion to 2-(4- cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole (5.48a) was never attempted and tributyl tin-based compounds were instead investigated.

Scheme 5.18: Attempted synthesis of 1,3-thiazole-based boronate ester 5.49.

2-(4-Cyanophenyl)-5-octyloxy-4-tributylstannyl-1,3-thiazole (5.50) was targeted

186 through the use of Pd(PPh3)4 and Sn2Bu6 (see Scheme 5.19), again to avoid the use of

n-BuLi. 1H NMR analysis of the crude product showed the presence of mostly the desired product (74%) with smaller amounts of starting material 5.47 (9%), and parent

1,3-thiazole 2.8a (17%). Upon silica gel chromatography, the isolated yield of 5.50 dropped to only 54% and a significant amount of parent 1,3-thiazole 2.8a was recovered

(42%). In hindsight, treatment of the silica gel with triethylamine might have prevented the observed protodestannylation during purification. With 2-(4-cyanophenyl)-5- octyloxy-4-tributylstannyl-1,3-thiazole (5.50) in hand, we subjected 5.50 to the conditions described by Ritter (see Scheme 5.19),180 but none of the desired 2-(4- cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole (5.48a) was present by crude 1H NMR analysis. Instead, only protodestannylation had occurred to yield parent 1,3-thiazole 2.8a as the only product.

Scheme 5.19: Attempted synthesis of 2-(4-cyanophenyl)-4-fluoro-5-octyloxy-1,3-

thiazole (5.48a) via silver-catalyzed fluorination.

Given the lack of success in generating 2-(4-cyanophenyl)-4-fluoro-5-octyloxy-1,3- thiazole (5.48a) through halogen-metal exchange, we postulated that the 5-position alkoxy chain could be destabilizing the resulting analogous silver intermediate I derived from 5.50 which would explain the prevalent protodestannylation observed during the reaction in Scheme 5.19.

With this hypothesis in mind, the synthesis of 2-alkoxy-4-fluoro-1,3-thiazoles were targeted since the alkoxy chain would no longer be donating electron density to the

site of halogen-metal exchange and the required silver intermediate I should be more stable. 2-Octyloxy-4-tributylstannyl-1,3-thiazole (5.51) was obtained from previously synthesized 4-bromo-2-octyloxy-1,3-thiazole (5.45; see Scheme 5.15) in excellent yield

(98%; see Scheme 5.20) using a procedure based on the work of Dondoni.107

Unfortunately, the silver-catalyzed fluorination of 2-octyloxy-4-tributylstannyl-1,3- thiazole (5.51) again failed and yielded only 2-octyloxy-1,3-thiazole (5.53). The crude

19F NMR spectrum showed only a peak corresponding to AgOTf (see Scheme 5.20).

Scheme 5.20: Attempted synthesis of 2-octyloxy-4-fluoro-1,3-thiazole (5.52) via

silver-catalyzed fluorination.

182 Use of alternate conditions reported recently by Ritter (Ag2O, NaHCO3, NaOTf) also failed in three separate attempts to yield the desired 4-fluoro-2-octyloxy-1,3-thiazole

(5.52). Instead, these reactions yielded mostly 2-octyloxy-1,3-thiazole (5.53) with a trace of 5-fluoro-2-(octyloxy)-1,3-thiazol-4(5H)-one (5.54; see Scheme 5.20). The formation of 5.54 can be easily explained from the reaction mechanism of silver-catalyzed fluorination proposed by Ritter (see Scheme 5.17). Within Ritter’s proposed mechanism, reaction of H2O with silver complex II (5.55) leads to the formation of a phenol, which in

the case of 1,3-thiazole (5.56) would not be stable and would react as shown in Scheme

5.21 to form 5-fluoro-2-(octyloxy)-1,3-thiazol-4(5H)-one (5.54).

Scheme 5.21: Mechanism for the formation of 5-fluoro-2-(octyloxy)-1,3-thiazol-

4(5H)-one (5.54).

Although the best available method for removing H2O from acetone was utilized

187 (distillation from B2O3 has been shown to remove all but 18ppm of H2O from acetone ), a trace amount of H2O was still present and led to the formation of 5.54. From this side reaction, we envisioned that through the use of aqueous acetone, we might be able to target the formation of 5-fluoro-2-(octyloxy)-1,3-thiazol-5(4H)-one (5.59; see Scheme

5.22) which we previously investigated as an entry to the synthesis of 4-fluoro-1,3- thiazoles (see Scheme 5.13). However, due to time constraints this pathway was never examined.

Scheme 5.22: Proposed pathway for formation of 4-fluoro-2-(octyloxy)-1,3-thiazol-

5(4H)-one (5.59).

In summary, despite numerous halogen-metal exchange-based approaches being explored, only a single method (Scheme 5.14) led to the formation of a 4-fluoro-1,3- thiazole (5.44). While this method was successful for our test substrate, 4-bromo-2,5-

bis(4-methoxyphenyl)-1,3-thiazole (5.43), we were unsuccessful in applying this approach to more flexible building blocks such as 4-bromo-2-octyloxy-1,3-thiazole

(5.45).

5.5. Fluorination via nucleophilic sources of fluorine

Methods for the synthesis of fluoroaromatic compounds through the use of electrophilic sources of fluorine tend to be much more flexible in terms of their required starting materials (see Sections 5.4 and 5.6). However, the main disadvantage to these approaches is the cost of purchasing expensive sources of electrophilic fluorine such as

SelectFluor™ and NFSI. From a cost standpoint, nucleophilic sources of fluorine are much cheaper; however, the substrates in which nucleophilic sources of fluorine will react are much less flexible and in terms of safety, handling of these sources of fluorine

(for example HF) can be extremely hazardous.

One of the most common methods for generating fluoroaromatic compounds which utilizes a nucleophilic source of fluorine is the Balz-Schiemann reaction, which allows for the conversion of aryl amines to fluoroaromatic compounds through the use of diazotization. The Balz-Schiemann reaction has been successfully employed for the synthesis of fluorothiophenes,27 but in the area of 1,3-thiazoles, it has only been used for the synthesis of 2-fluoro-1,3-thiazoles. The biggest obstacle for using the Balz-

Schiemann reaction in the synthesis of 4-fluoro-1,3-thiazoles is the challenging synthesis of the required precursor, a 4-amino-1,3-thiazole. The most common method for introduction of an amine onto an aromatic ring involves reduction of a nitro group which is itself introduced through electrophilic nitration using nitric acid and acetic anhydride or

nitric acid and sulfuric acid. For phenyl or thiophene-based substrates, these conditions are sufficient for nitration;188 however, under these conditions the nitrogen of a 1,3- thiazole ring becomes protonated and as a result the ring loses its ability to undergo electrophilic aromatic substitution. Thus, ring closing strategies are the best option for the synthesis of a 4-amino-1,3-thiazole for use in the Balz-Schiemann reaction. Through the use of the Hantzsch thiazole synthesis, 2,4-diamino-1,3-thiazole hydrochloride (5.62) was generated in excellent yield (94%) from commercially inexpensive thiourea (5.60) and chloroacetonitrile (5.61; see Scheme 5.23).189

Scheme 5.23: Synthesis of 2,4-diamino-1,3-thiazole hydrochloride (5.62).

Initially this approach appears rather daunting given that two Balz-Schiemann reactions must sequentially occur on the same molecule (5.62) to generate a product (5.63) that is likely to possess a low boiling point. However, in the literature, 1,3- and 1,4- difluorobenzene have been generated in excellent yield (78% and 65%, respectively) from 1,3- and 1,4-diaminobenzene through bis-Balz-Schiemann chemistry using NaNO2,

HF-pyridine, and heat.190 Unfortunately, use of their conditions failed to generate the desired 2,4-difluoro-1,3-thiazole (5.63; see Scheme 5.24). No bubbling was observed during the reaction which would have indicated the release of nitrogen gas and a successful reaction. Additionally, no peaks were observed in the crude 19F NMR spectrum. In hindsight, the failure of this reaction was not surprising as Davies reported

2,4-diamino-1,3-thiazole to be “almost devoid of aromatic character” and, in his hands, could not be diazotized.189

Scheme 5.24: Attempted synthesis of 2,4-difluoro-1,3-thiazole (5.63) via the Balz-

Schiemann reaction.

Fluorodeoxygenation of alcohols and ketones using DAST or DeoxoFluor®191 was another functional group transformation that we envisioned could potentially be utilized for the synthesis of a 4-fluoro-1,3-thiazole. We attempted the fluorodeoxygenation of 1,3-thiazolidine-2,4-dione (3.10), a commercially inexpensive starting material, with one of several outcomes in mind. The reaction of DAST or

DeoxoFluor® with ketones is known to give either a geminal difluoro compound or a vinyl fluoride.191,192 Thus a reaction with DAST or DeoxoFluor® with 1,3-thiazolidine-

2,4-dione (3.10; see Scheme 5.25) could lead to the formation of a compound possessing a pair of geminal difluoro groups (5.64) or a “vinyl fluoride” which would lead directly to

2,4-difluoro-1,3-thiazole (5.63). If the tetrafluoro adduct 5.64 was generated, we anticipated that reaction with base would allow for elimination of two equivalents of HF to generate the desired 2,4-difluoro-1,3-thiazole (5.63).

Scheme 5.25: Attempted synthesis of 2,4-difluoro-1,3-thiazole (5.63) via

fluorodeoxygenation using DAST or DeoxoFluor®.

Unfortunately, neither compound 5.64 or the desired 2,4-difluoro-1,3-thiazole (5.63) were detected in the crude product; only unreacted starting material was detected by 1H

NMR analysis. As previously mentioned, 2,4-difluoro-1,3-thiazole (5.63) would be expected to have a very low boiling point and might therefore be difficult to isolate.

Consequently, we next reacted DAST and DeoxoFluor® with a substrate which upon fluorination would not be volatile. As with the synthesis of 4-amino-1,3-thiazoles, 4- hydroxy-1,3-thiazoles are easily accessible through the Hantzsch thiazole synthesis.

Although our desired 4-hydroxy-1,3-thiazole (5.68a) was not directly accessible from commercially available materials, it was obtained in only two steps. Starting from commercially available 5.65, compound 5.66 was generated via radical bromination,193 which upon reaction of 5.67 underwent a Hantzsch thiazole synthesis194 in excellent yield

(94%) to generate the desired 2,5-bis(4-methoxyphenyl)-1,3-thiazol-4-ol (5.68a; see

Scheme 5.26).

Scheme 5.26: Synthesis of 2,5-bis(4-methoxyphenyl)-1,3-thiazol-4-ol (5.68).

DAST and DeoxoFluor® are not known to react well with phenols; however, 1,3- thiazole-based alcohols such as 2,5-bis(4-methoxyphenyl)-1,3-thiazol-4-ol (5.68a) are known to tautomerize between the enol form (5.68a) and the keto form (5.68b; see

Scheme 5.27), the latter of which is favored in less polar solvents195 and should be reactive towards DAST or DeoxoFluor®. Unfortunately, reaction of 2,5-bis(4- methoxyphenyl)-1,3-thiazol-4-ol (5.68a) with either DAST or DeoxoFluor® gave unreacted starting material and failed to yield any of the desired 4-fluoro-2,5-bis(4- methoxyphenyl)-1,3-thiazole (5.44; see Scheme 5.27).

Scheme 5.27: Attempted synthesis of 4-fluoro-2,5-bis(4-methoxyphenyl)-1,3-thiazole

(5.44) via fluorodeoxygenation.

We have previously shown that 1,3-thiazolidine-2,4-dione (3.10) can be halogenated through the use of P2O5 and Bu4NBr to yield 2,4-dibromo-1,3-thiazole (3.11) in excellent yield (see Scheme 3.11). With this in mind, 1,3-thiazolidine-2,4-dione (3.10) was stirred with P2O5 and Bu4NF with the aim of generating 2,4-difluoro-1,3-thiazole

100

(5.63; see Scheme 5.28); however, by crude 1H NMR analysis, only unreacted starting material was present.

Scheme 5.28: Attempted synthesis of 2,4-difluoro-1,3-thiazole (5.63) from P2O5 and

Bu4NF.

In summary, several approaches were explored for the preparation of 4-fluoro-

1,3-thiazoles which utilized nucleophilic sources of fluorine via the Balz-Schiemann reaction or fluorodeoxygenation. Despite several substrates being subjected to the aforementioned reactions, a 4-fluoro-1,3-thiazole was never obtained from any of these approaches.

5.6. Preparation of 4-fluoro-1,3-thiazole-containing liquid crystal targets via fluorination using electrophilic aromatic substitution

Given the lack of success with the previously discussed approaches to 4-fluoro-

1,3-thiazoles, a more simplistic, straightforward approach to generating 4-fluoro-1,3- thiazoles was explored. Through the use of electrophilic aromatic substitution, fluoroaromatic compounds can be generated in good yield from the reaction of electron- rich substrates with electrophilic sources of fluorine such as SelectFluor™ or NFSI.156

While electron-poor substrates typically do not react well, this approach still offers several advantages over the previously discussed methods. First, it does not require the preparation of intermediate boronate or stannyl groups since an unsubstituted electron-

101

rich aromatic ring will react with SelectFluor™ or NFSI via electrophilic aromatic substitution. Also, the use of toxic or pyrophoric reagents such as HF and n-BuLi are not required. In contrast, SelectFluor™ and NFSI are known to be stable, easy to handle reagents.156 Although the use of SelectFluor™ ($1.06/mmol) and NFSI ($0.50/mmol) offers several advantages, the main disadvantage to these reagents is their relatively high cost on a per mole basis.

The first substrate investigated was 2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.42), whose synthesis was previously discussed (see Scheme 5.14). Reaction of 5.42 with 1.05 equivalents of SelectFluor™ in refluxing MeCN generated the desired 4-fluoro-2,5-bis(4- methoxyphenyl)-1,3-thiazole (5.44), but in only 11% isolated yield (see Scheme 5.29).

Optimization of this reaction was attempted by adding more SelectFluor™ (2.15 equivalents) but no product formation was observed in this case.

Scheme 5.29: Synthesis of 4-fluoro-2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.44)

through electrophilic aromatic substitution.

Despite the low yield from our test substrate, the fact that some fluorinated product formed was an encouraging result; therefore, other 1,3-thiazole-based substrates were subjected to similar conditions. 2,5-Dibromo-1,3-thiazole (3.3) was refluxed with both

SelectFluor™ and NFSI, but in each case only starting material was obtained (see

Scheme 5.30). The failure of these reactions was not surprising given that the 4-position

102

of 2,5-dibromo-1,3-thiazole (3.3) is less electron-rich than the 4-position of 2,5-bis(4- methoxyphenyl)-1,3-thiazole (5.42). However, if the reaction would have succeeded, the resulting product, 2,5-dibromo-4-fluoro-1,3-thiazole (5.69), would have served as an excellent building block for the synthesis of 4-fluoro-1,3-thiazole-based liquid crystals.

Scheme 5.30: Attempted synthesis of 2,5-dibromo-4-fluoro-1,3-thiazole (5.69)

through electrophilic aromatic substitution.

Fluorination of 5-bromo-2-dodecyloxy-1,3-thiazole (4.3e) was also examined, but again reaction with NFSI in refluxing MeCN failed to generate the desired 5-bromo-2- dodecyloxy-4-fluoro-1,3-thiazole (5.70) and yielded only unreacted starting material (see

Scheme 5.31).

Scheme 5.31: Attempted synthesis of 5-bromo-2-dodecyloxy-4-fluoro-1,3-thiazole

(5.70) through electrophilic aromatic substitution.

As a result of the limited success in using electrophilic aromatic substitution for generating a 4-fluoro-1,3-thiazole, a more optimal substrate was then explored. The placement of an alkoxy chain at the 5-position would give ring fluorination its best opportunity for success since the 4-position of the 1,3-thiazole ring would be extremely electron-rich and thus very activated towards electrophilic aromatic substitution. When

103

2-(4-fluorophenyl)-5-octyloxy-1,3-thiazole (5.71) was heated under reflux with 1.06 equivalents of SelectFluor™ in MeCN, GC analysis indicated the product to starting material ratio to be 56:44 (see Scheme 5.32 and Table 5.1 entry 1). As a result of significant starting material remaining, another 1.05 equivalents of SelectFluor™ was added; however, instead of more 4-fluoro-2-(4-fluorophenyl)-5-octyloxy-1,3-thiazole

(5.72) being formed, none of the desired product was then detected by GC. Reactions of

SelectFluor™ leaving significant amounts of unreacted starting material which could not be consumed even with the addition of more SelectFluor™ has previously been reported for other 1,3-thiazole-based substrates.141

Scheme 5.32: Synthesis of 4-fluoro-5-octyloxy-1,3-thiazoles 5.48a, 5.72, and 5.73 via

electrophilic aromatic substitution.

The aforementioned reaction was repeated (see Table 5.1, entry 2) and stopped after the first addition of SelectFluor™ to give a 17% isolated yield of 4-fluoro-2-(4- fluorophenyl)-5-octyloxy-1,3-thiazole (5.72). Different reaction temperatures were explored (see Table 5.1, entries 3 and 4), but modest yields were still obtained, with the reaction at 55 °C giving the best isolated yield (23%). It was considered that

SelectFluor™ could be getting consumed by a side reaction and thus, if the fluorinating agent was added slowly, the isolated yield of 4-fluoro-2-(4-fluorophenyl)-5-octyloxy-1,3- thiazole (5.72) might be enhanced. Unfortunately, addition of SelectFluor™ via syringe

104

pump over a duration of 40 minutes made no difference in the isolated yield of 5.72 (see

Table 5.1, entry 5).

At this stage it was recognized that 4-fluoro-2-(4-fluorophenyl)-5-octyloxy-1,3- thiazole (5.72) was not likely to be synthetically useful for further synthetic elaboration to the corresponding 4-cyanophenyl 5.48a which was required for the synthesis of our liquid crystal targets. Thus, the para-substituent of the phenyl ring in the substrate was switched to bromine. As expected, use of 4-bromo-2-(4-fluorophenyl)-5-octyloxy-1,3- thiazole (2.7a) as the starting material did not negatively alter the isolated yield of the desired 4-fluoro-1,3-thiazole (5.73; see Table 5.1 entry 6). The work of Campbell reported the reaction of SelectFluor™ with 2,4-diaryl-1,3-thiazoles to be quick (usually complete within two to three hours) and the use of extended reaction times produced no change in the progress of the reaction.141 However, for 4-bromo-2-(4-fluorophenyl)-5- octyloxy-1,3-thiazole (2.7), extended reaction times (26 hours) resulted in a considerable increase in the isolated yield from 25% to 34% (see Table 5.1 entry 7).

Ultimately, 2-(4-cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole (5.48a) was required for continuation of our synthesis. As a result, we subjected 2-(4-cyanophenyl)-

5-octyloxy-1,3-thiazole (2.8a) to fluorination. Despite possessing a strong electron- withdrawing group, the isolated yield of 4-fluoro-1,3-thiazole 5.48a was not compromised (see Table 5.1 entry 8). Upon switching substrates, the effect of reaction temperature was again investigated; however, no significant difference in the isolated yield of 5.48a was observed, although the amount of unreacted starting material (2.8a) recovered was higher for the reaction at 55 °C relative to that conducted under reflux

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conditions (see Table 5.1 entries 8 and 9). The impact of substrate concentration in the reaction was next evaluated. However, it was found that both dilute and concentrated reactions at reflux led to virtually the same isolated yield of 5.48a although the amount of unreacted starting material (2.8a) recovered was slightly higher for the dilute reaction

(see Table 5.1 entries 9 and 10). Interestingly, the use of dilute conditions at 55 °C did result in a small enhancement in the isolated yield of 5.48a and recovered unreacted starting material (2.8a; see Table 5.1 entry 11). During the process of optimizing the formation of the 4-fluoro-5-octyloxy-1,3-thiazoles (5.48a, 5.72, and 5.73), the only condition found to be detrimental to the isolated yield was the use of non-anhydrous

MeCN. When the MeCN was not dried, the isolated yields of the desired product dropped dramatically to 4% and 13% for the formation of compounds 5.48a and 5.73, respectively (see Table 5.1 entries 12 and 13).

At this stage, extensive experimentation had delivered only modest improvements in the isolated yield of the desired 4-fluoro-1,3-thiazoles (~35%). Thus, we considered exchanging SelectFluor™ for another electrophilic fluorinating agent, NFSI. The use of

NFSI offers several advantages over SelectFluor™. The cost of SelectFluor™

($1.06/mmol) is more than twice that of NFSI ($0.50/mmol), and SelectFluor™ has limited solubility in most common organic solvents except MeCN, MeOH, and DMF.196

On the other hand, NFSI is soluble in a wide range of solvents and has a fairly low melting point (110 °C) which affords it the potential to be used in solvent-free reactions.197-200 Since NFSI is soluble in a wide range of solvents, we first surveyed the fluorination in several different solvents. Interestingly, refluxing MeCN was found to be

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the optimal solvent studied for NFSI fluorination of 2-(4-cyanophenyl)-5-octyloxy-1,3- thiazole (2.8a; see Table 5.1 entries 14-15). Use of refluxing toluene and CHCl3 afforded either lower yields of the desired product or returned less unreacted starting material. As was observed with SelectFluor™, the reaction with NFSI was also found to stop with a significant percentage of unreacted starting material still present and the use of more

NFSI resulted in none of the desired product being isolated (see Table 5.1 entry 17).

Despite these findings, an experiment was performed in which a total of 1.5 equivalents of NFSI were added sequentially over the course of two days. Unlike the reactions of

SelectFluor™, the reaction continued to consume starting material with each addition of

NFSI; however, the isolated yields of product and unreacted starting material were virtually unaffected (see Table 5.1 entries 15 versus 18). Since the presence of excess

NFSI was found to destroy product, we next studied the effect of using less NFSI.

Interestingly, the use of 1.05 equivalents of NFSI (as opposed to 1.25 equivalents) increased the isolated yield of 2-(4-cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole

(5.48a) by 6% and nearly doubled the amount of unreacted starting material recovered

(see Table 5.1 entries 15 versus 19). Since using less NFSI had a positive effect on the isolated yield of 5.48a, another pair of reactions was performed, one with NFSI (1.05 equivalents) being slowly added over 60 minutes and another with even less NFSI (0.91 equivalents). Unfortunately, through the use of a syringe pump, the isolated yield of

5.48a dropped by 7% but the amount of unreacted starting material recovered was unaffected (see Table 5.1 entries 20 versus 19). As expected, use of sub-stoichiometric

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Table 5.1: Optimization for the synthesis of 4-fluoro-5-octyloxy-1,3-thiazoles 5.48a,

5.72, and 5.73 (Scheme 5.32) via electrophilic aromatic substitution.

Entry Scale (g) Ra Source of F+ Eq. F+ Solvent Molarityb Temp (°C) Time (hrs) product:SMc Yieldd % SMd 1 0.25 F8 SelectFluor 1.06+1.05 MeCN 0.090 reflux 2 56:44, 0:0 ------2 0.25 F8 SelectFluor 1.05 MeCN 0.090 reflux 0.5 55:45 ~17% --- 3 0.25 F8 SelectFluor 1.05 MeCN 0.102 55 0.5 58:42 ~23% --- 4 0.22 F8 SelectFluor 1.05 MeCN 0.102 RT 1 40:60 ~12% --- 5 0.25 F8 SelectFluore 1.05 MeCN 0.068 55 0.5 55:45 ~22% --- 6 2.01 Br8 SelectFluor 1.05 MeCN 0.152 55 2.5 68:32 ~25% --- 7 1.00 Br8 SelectFluor 1.05 MeCN 0.151 55 26 75:25 34% ~17% 8 0.10 CN8 SelectFluor 1.05 MeCN 0.190 55 25 67:33 ~35% ~20% 9 0.10 CN8 SelectFluor 1.05 MeCN 0.191 reflux 25 84:16 ~36% ~11% 10 0.10 CN8 SelectFluor 1.05 MeCN 0.054 reflux 25 72:28 35% ~18% 11 0.10 CN8 SelectFluor 1.05 MeCN 0.106 55 25 72:28 ~38% ~17% 12 1.49 CN8 SelectFluor 1.05 MeCNf 0.158 55 24 4:96 ~4% 47% 13 2.02 Br8 SelectFluor 1.05 MeCNf 0.152 55 3.5 30:70 ~13% ~40% 8 14 0.10 CN NFSI 1.25 CHCl3 0.064 reflux 48 44:56 by NMR ~18% ~32% 15 0.10 CN8 NFSI 1.25 MeCN 0.064 reflux 22 100:0 by NMR 27% ~23% 16 0.10 CN8 NFSI 1.25 toluene 0.064 reflux 48 64:46 by NMR ~16% ~16% 17 0.10 CN8 NFSI 2.5 MeCN 0.053 reflux 26 0:0 ------18 0.10 CN8 NFSI 1.0+0.25+0.25 MeCN 0.080 reflux 4, 20, 44 45:55, 53:47, 58:42 ~28% ~23% 19 0.10 CN8 NFSI 1.05 MeCN 0.053 reflux 26 47:53 33% 41% 20 0.10 CN8 NFSIe 1.05 MeCN 0.106 reflux 26 44:56 ~26% 43% 21 0.20 CN10 SelectFluor 0.91 MeCN 0.090 reflux 25 53:47 24% 28% 22 0.10 CN8 NFSI 1.05 MeCN 0.064 55 26 42:58 ~25% 41% 23 0.10 CN8 NFSI 1.05 MeCN 0.064 110 24 54:46 ~30% ~34% 24 0.10 CN8 NFSI 1.05 neat -- 100 3, 5 59:41, 63:37 ~22% ~15% 25g 0.10 CN8 NFSI 1.25 MeCN 0.046 reflux 46 trace ------26h 0.10 CN8 NFSI 1.05 MeCN 0.064 reflux 21 5:95 ------27i 0.10 CN8 NFSI 1.05 MeCN 0.053 reflux 23 7:93 ------28j 0.10 CN8 NFSI 1.05 MeCN 0.064 reflux 24 4:96 ------29k 0.10 CN8 NFSI 1.25 MeCN 0.064 reflux 48 0:0 0% --- 30l 0.10 CN8 NFSI 1.25 MeCN 0.064 reflux 48 0:0 0% --- 31m 0.10 CN8 NFSI 1.05 MeCN 0.064 reflux 23 42:58 31% 41% 32n 0.10 CN8 NFSI 1.05 MeCN 0.064 reflux 21 44:56 ~31% 37% 33o 0.10 CN8 NFSI 1.05 MeCN 0.106 reflux 25 21:79 ~18% 67% 34p 0.10 CN8 NFSI 1.05 MeCN 0.053 reflux 23 28:72 25% 59% 35p 0.10 CN8 NFSI 1.05+1.05 MeCN 0.064 reflux 5, 22 25:75, 35:65 28% 51% 36q 0.10 CN8 NFSI 1.05 MeCN 0.053 reflux 23 43:57 ~27% 44% 37 0.10 CN8 NFSI 1.05 MeCNr 0.053 reflux 26 48:52 31% 44% 38 0.50 CN12 SelectFluor 1.05 MeCN 0.054 reflux 25 73:27 ~34% ~20% 39 2.74 CN12 SelectFluor 1.05 MeCN 0.123 reflux 25 83:17 37% ~5% 40 3.00 CN8 SelectFluor 1.05 MeCN 0.106 55 25 72:28 43% ~17% 41 3.00 CN9 SelectFluor 1.05 MeCN 0.190 reflux 25 85:15 42% ~9% 42 3.00 CN10 SelectFluor 1.05 MeCN 0.146 reflux 25 83:17 40% ~12% 43 3.00 CN11 SelectFluor 1.05 MeCN 0.210 reflux 25 83:17 42% ~8%

a alkoxy chain length j para -Phenyl substituent NaHCO3 and 0.50mL H2O added b Concentration of 5.71, 2.7a, or 2.8a-2.8e k 1,8-Bis(dimethylamino)naphthalene (proton sponge) added c Ratio of product to SM determined by GC unless otherwise noted l Hunig's base added, which underwent N -fluorination d m Isolated yield of purified product. Yields with ~ in front are estimated due NaHCO3 and 10μL H2O added to the product being impure n 2,6-di-t butylpyridine added e F+ source dissolved in reaction solvent and added via syringe pump o 2,4,6-collidine added f p Non-anhydrous MeCN was used K2CO3 added g KOAc added q BHT added as a radical trap h NaBHT added r Solvent degassed by three cycles of freeze/thaw under i NaH added vacuum

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quantities of NFSI (0.91 equivalents) gave a lower yield of desired product (see Table 5.1 entries 21 versus 19).

Once again, the effects of temperature were investigated and interestingly the use of lower temperatures (55 °C) decreased the yield of 5.48a by 8% while the amount of unreacted starting material recovered remained unchanged (see Table 5.1 entries 22 versus 19). Since higher reaction temperatures seemed to enhance the isolated yield of

5.48a, a reaction was carried out at 110 °C through the use of a glass-pressure vessel.

However, the increase in temperature from reflux (82 °C) to 110 °C lead to small decreases in isolated yield of 5.48a (3%) and unreacted starting material (7%; see Table

5.1 entries 23 versus 19). As previously mentioned, NFSI has a fairly low melting point

(110 °C) which has allowed it to be used in solvent-free reactions.197-200 Use of solvent- free conditions for the synthesis of 2-(4-cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole

(5.48a) provided the best GC ratio of product to starting material of all the trials utilizing

NFSI; however, the isolated yield of 5.48a and the amount of unreacted starting material recovered was much lower (11% and 26% lower, respectively) than the reaction carried out under refluxing MeCN (see Table 5.1 entries 24 versus 19).

One possible limitation of using NFSI for electrophilic aromatic substitution chemistry is the low basicity of the sulfonimide conjugate base (pKa of dibenzenesulfonimide is 1.45)201 which might have hindered the final deprotonation step and / or led to side reactions due to the high acidity of the dibenzenesulfonimide byproduct. Since NFSI-mediated fluorinations had achieved only limited success, various bases were added to NFSI fluorinations in an effort to eliminate these possible

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problems and (hopefully) enhance the yield of the 4-fluoro-1,3-thiazole product.

Unfortunately, most bases added were found to be quite detrimental and resulted in a lower (or no) yield of the desired 2-(4-cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole

(5.48a). These bases included KOAc, NaBHT (sodium 2,6-tert-butyl-4- methylphenoxide), NaH, NaHCO3 (with 0.50 mL of H2O added), proton sponge (1,8- bis(dimethylamino)naphthalene), and Hunig’s base (see Table 5.1 entries 25-30). KOAc,

NaBHT, NaHCO3, and NaH were chosen since they are non-nucleophilic bases which are not nitrogen-based. Nitrogen-based bases were generally avoided due concerns of N- fluorination of the nitrogen, which was observed for Hunig’s base but not for proton sponge. The addition of NaHCO3 (with 10 μL of H2O added; reduced from 0.50 mL to

10 μL since H2O is known to halt the reaction, see Table 5.1 entries 12 and 13, but

NaHCO3 is not soluble in MeCN) and 2,6-di-t-butylpyridine were found to have no effect on the outcome of the reaction (see Table 5.1 entries 31 and 32). Interestingly, the addition of 2,4,6-collidine and K2CO3 had a substantial effect on the amount of unreacted starting material recovered from the reaction without drastically lowering the isolated yield of 5.48a (see Table 5.1 entries 33 and 34). Since K2CO3 gave the best isolated yield of 5.48a but still returned about as much unreacted starting material as 2,4,6-collidine, optimization of the reaction with K2CO3 was attempted. Once the reaction had consumed the initial quantity of NFSI, a second addition of NFSI was made and the reaction was allowed to stir for a total of 24 hours. Unfortunately, the effect of adding more NFSI was minimal as very little starting material was consumed after the initial stage of the reaction

(see Table 5.1 entry 35).

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Radical-mediated side reactions were hypothesized to be a potential contributor to the inexplicably low yields for 4-fluoro-5-octyloxy-1,3-thiazoles (5.48a, 5.72, and 5.73) and to the halting of the reactions even in the presence of unreacted starting material.

However, addition of BHT, a known radical trap, decreased the isolated yield of 2-(4- cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole (5.48a) slightly and the yield of recovered

2-(4-cyanophenyl)-5-octyloxy-1,3-thiazole (2.8a) remained unaffected (see Table 5.1 entry 36). Oxygen being present in the reaction solvent was also eliminated as a potential inhibitor of fluorination as degassing of the solvent also had a minimal impact on the isolated yields of the desired product and unreacted starting material (see Table 5.1 entry

37).

After extensive optimization, isolated yields of 2-(4-cyanophenyl)-4-fluoro-5- octyloxy-1,3-thiazole (5.48a) from the reactions of SelectFluor™ and NFSI with 2-(4- cyanophenyl)-5-octyloxy-1,3-thiazole (2.8a) were virtually identical (35-38% and 33%, respectively). From the standpoint of purity, the reactions using both SelectFluor™ and

NFSI were found to generate byproducts which were difficult to remove. SelectFluor™ was discovered to generate the analogous 5-alkoxy-4-chloro-2-(4-cyanophenyl)-1,3- thiazole in trace quantities, which greatly complicated purification via silica gel chromatography, but the pure 5-alkoxy-2-(4-cyanophenyl)-4-fluoro-1,3-thiazoles 5.48a-

5.48e could still be obtained. Although, no mechanism was available for the formation of

5-dodecyloxy-4-chloro-2-(4-cyanophenyl)-1,3-thiazole (5.48Cl), its presence was confirmed using EI-MS. The formation of similar chlorinated byproducts has previously been reported for electrophilic aromatic substitution reactions utilizing SelectFluor™.141

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On the other hand, the byproduct from reactions of NFSI (which was never fully characterized) could not be removed by either silica gel chromatography or recrystallization. Therefore, despite the advantages associated with using NFSI (see above), SelectFluor™ was chosen for scaling-up of the optimized reaction conditions since the 4-fluoro-1,3-thiazole-based product could be more easily purified. Upon scaling-up the optimized reaction conditions, another increase in isolated yield for the 5- alkoxy-2-(4-cyanophenyl)-4-fluoro-1,3-thiazoles 5.48a-5.48e was observed. For reactions on a scale of less than 3.0 grams, the isolated yield of 5-alkoxy-2-(4- cyanophenyl)-4-fluoro-1,3-thiazoles (5.48) remained less than 40% (see Table 5.1 entries

38 and 39). However, for reactions performed on a scale of 3.0 grams, the isolated yield of 5-alkoxy-2-(4-cyanophenyl)-4-fluoro-1,3-thiazoles 5.48a-5.48e was always 40% or greater (see Scheme 5.33 and Table 5.1 entries 40-43).

Scheme 5.33: Synthesis of 5-alkoxy-2-(4-cyanophenyl)-4-fluoro-1,3-thiazoles 5.48a-

5.48e via electrophilic aromatic substitution.

With the series of 5-alkoxy-2-(4-cyanophenyl)-4-fluoro-1,3-thiazoles 5.48a-5.48e finally in hand, conversion to the corresponding carboxylic acid 5.75e was attempted using NaOH in a 50:50 solution of EtOH and H2O. Unfortunately, we experienced the same issue which was observed during the 2-alkoxy-1,3-thiazole project (Chapter 4), in

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that the reaction would not go to completion and yielded a mixture of the desired carboxylic acid (5.75e) and the corresponding amide. The reaction could be driven to completion by subjecting the mixture to a second hydrolysis reaction under the same conditions. However, the isolated yield of carboxylic acid 5.75e was often low (78%) compared to the yields for the analogous, non-fluorinated carboxylic acids 2.9a-2.9e (93-

100%), which were generated via nitrile hydrolysis (see Chapter 2), or the resulting material would be significantly impure. Taking into consideration the cost and difficulty in synthesizing the 5-alkoxy-2-(4-cyanophenyl)-4-fluoro-1,3-thiazoles 5.48a-5.48e, the reduction-oxidation pathway (see Chapter 4.2) was explored as a means for generating the 4-(5-alkoxy-4-fluoro-1,3-thiazol-2-yl)benzoic acids 5.75a-5.75e. As previously mentioned, this route requires an extra step, but it offers the advantage of being more reliable without significantly sacrificing the overall yield, in addition to providing a product that is more effectively esterified in the subsequent step. The 5-alkoxy-2-(4- cyanophenyl)-4-fluoro-1,3-thiazoles 5.48a-5.48e were successfully reduced with DIBAl-

H to generate the 4-(5-alkoxy-4-fluoro-1,3-thiazol-2-yl)benzaldehydes 5.74a-5.74e in good yield (see Scheme 5.34). Fortunately, no issues of over-reduction, as seen for the reduction of the 2-alkoxy-1,3-thiazoles 4.5c-4.5e, was observed upon reaction of DIBAl-

H with the 5-alkoxy-2-(4-cyanophenyl)-4-fluoro-1,3-thiazoles 5.48a-5.48e.

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Scheme 5.34: Synthesis of 4-(5-alkoxy-4-fluoro-1,3-thiazol-2-yl)benzaldehydes 5.74a-

5.74e via DIBAl-H reduction.

The resulting 4-(5-alkoxy-4-fluoro-1,3-thiazol-2-yl)benzaldehydes 5.74a-5.74e were oxidized to the corresponding carboxylic acids (5.75a-5.75e) in excellent yield via the

Pinnick oxidation (see Scheme 5.35). For a few of the Pinnick oxidations, methyl-2- butene was used in place of 2,3-dimethylbut-2-ene as the HOCl scavenger, but was found to be inferior as it allowed for the generation of trace amounts (at most 6%) of an unknown byproduct. The switch in HOCl scavenger from 2,3-dimethylbut-2-ene to methyl-2-butene was considered since we had depleted our supply of the more commonly used 2,3-dimethylbut-2-ene; however, upon discovering the ineffectiveness of methyl-2- butene, we switched back to 2,3-dimethylbut-2-ene.

Scheme 5.35: Synthesis of 4-(5-alkoxy-4-fluoro-1,3-thiazol-2-yl)benzoic acids 5.75a-

5.75e via the Pinnick oxidation.

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Esterification of 4-(5-alkoxy-4-fluoro-1,3-thiazol-2-yl)benzoic acids 5.75a-5.75e with phenol 2.11 proceeded smoothly via the Steglich esterification to afford the final 4- fluoro-1,3-thiazole-based liquid crystal targets 5.76a-5.76e (see Scheme 5.36).

Scheme 5.36: Synthesis of (S)-4-(1-methylheptyloxy)phenyl 4-(5-alkoxy-4-fluoro-1,3-

thiazol-2-yl)benzoates 5.76a-5.76e.

In conclusion, after numerous attempts and exploring a wide array of approaches for generating 4-fluoro-1,3-thiazoles, electrophilic aromatic substitution using

SelectFluor™ was found to generate the desired 5-alkoxy-2-(4-cyanophenyl)-4-fluoro-

1,3-thiazoles 5.48a-5.48e in moderate yield from 5-alkoxy-2-(4-cyanophenyl)-1,3- thiazoles 2.8a-2.8e (see Scheme 5.33). Although extensive efforts were made to optimize this reaction, the isolated yield for this transformation never exceeded 43%. Nonetheless, we were able to generate the first series of 4-fluoro-1,3-thiazole-based liquid crystals through the use of this electrophilic aromatic substitution strategy. The mesophase properties of these 5-alkoxy-4-fluoro-1,3-thiazole targets 5.76a-5.76e are discussed in

Chapter 7.

CHAPTER 6. 2- AND 5-CARBOXY-1,3-THIAZOLE LIQUID CRYSTALS

6.1. Rationale for targeting 2- and 5-carboxy-1,3-thiazole-based liquid crystals

To this point, the liquid crystalline targets synthesized in these studies have been based on either a 2- or 5-alkoxy-1,3-thiazole ring system (see Structures II and I from

Figure 1.15, respectively). In order to examine the impact of having the 1,3-thiazole ring and the 1,4-disubstituted phenyl ring transposed within the biaryl core, the structural isomers (Structures III and IV from Figure 1.15) were targeted.

Figure 1.15: Four variations of the targeted liquid crystals with the 1,3-thiazole ring

occupying “Ring 1” or “Ring 2.”

6.2. Synthesis of 5-carboxy-1,3-thiazole-based liquid crystals via selective Suzuki coupling of 2,5-dibromo-1,3-thiazole (3.3)

Previously, a 5-carboxy-1,3-thiazole-based liquid crystal was successfully generated by another worker within our group via a route that involved initial Suzuki coupling of 2-bromo-1,3-thiazole (3.2) and 4-(dodecyloxy)phenylboronic acid (6.1), which proceeded in 44% yield.22 The resulting 2-(4-(dodecyloxy)phenyl)-1,3-thiazole

(6.2) was reacted with n-BuLi and quenched with solid CO2 to generate 2-(4-

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(dodecyloxy)phenyl)-1,3-thiazole-5-carboxylic acid (6.3) in 59% yield (see Scheme

6.1).22

Scheme 6.1: Synthesis of 2-(4-(dodecyloxy)phenyl)-1,3-thiazole-5-carboxylic acid

(6.3) via a lithiation-based approach.

2-(4-(Dodecyloxy)phenyl)-1,3-thiazole-5-carboxylic acid (6.3) was also required for the synthesis of our target, but a more synthetically interesting pathway was explored. As previously discussed, a high yielding, convenient approach was developed for the synthesis of 2,5-dibromo-1,3-thiazole (3.3; see Chapter 3.2.2). We had already demonstrated the value of 2,5-dibromo-1,3-thiazole (3.3) as a flexible building block in the synthesis of the 2-alkoxy-1,3-thiazole-based liquid crystals (see Chapter 4.2).

Therefore, we explored a further application of 2,5-dibromo-1,3-thiazole (3.3) in the synthesis of intermediates related to compound 6.3. In the open literature, a few groups have showcased the use of 2,5-dibromo-1,3-thiazole (3.3) as an efficient, selective coupling partner for Suzuki coupling.61,202,203 Initially, Suzuki coupling of 2,5-dibromo-

1,3-thiazole (3.3) and 4-(dodecyloxy)phenylboronic acid (6.1) was attempted using

Pd(PPh3)4 as the catalyst. However, Pd(PPh3)4 was found to have a low turnover number

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for this reaction as nearly 13 mol% of catalyst was required to completely consume the starting 4-(dodecyloxy)phenylboronic acid (6.1). Use of Pd(PPh3)4 did lead to selective reaction at the 2-position of 2,5-dibromo-1,3-thiazole (3.3), but as a result of the high catalyst loading, purification by silica gel chromatography was extremely difficult and the isolated yield of pure Suzuki adduct 6.5 was quite low (13-25%). Based on the crude

1H NMR spectrum and the yield of crude organic material, the yield of compound 6.5 was likely high from this reaction. However, as a result of the high catalyst loading, only a fraction of the generated 6.5 could be separated from the catalyst. Switching to the

61 catalyst system developed by Strotman, Pd(OAc)2 and Xantphos (6.4), allowed for selective formation of 5-bromo-2-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.5; see Scheme

6.2) in excellent yield (75%). Due to the extremely low catalyst load (3 mol%) of this approach, the desired product 6.5 could be easily separated from the Pd / Xantphos (6.4) byproducts.

Scheme 6.2: Synthesis of 5-bromo-2-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.5) via

selective Suzuki coupling of 2,5-dibromo-1,3-thiazole (3.3).

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5-Bromo-2-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.5) was converted to the corresponding 5-cyano-2-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.6; see Scheme 6.3) with the intention of studying its liquid crystalline properties; however, purification by silica gel chromatography (even while pretreating the silica gel with Et3N) caused partial decomposition yielding 2-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.2). Recrystallization of

5-cyano-2-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.6) failed to significantly enhance its purity and thus compound 6.6 had to be used in the subsequent DIBAl-H reduction without being completely pure (see Scheme 6.3). Use of impure 5-cyano-2-(4-

(dodecyloxy)phenyl)-1,3-thiazole (6.6) likely contributed to the isolated yield of 2-(4-

(dodecyloxy)phenyl)-5-formyl-1,3-thiazole (6.7) being lower than typically seen for such a reaction (see Chapters 4.2 and 5.6).

Scheme 6.3: Synthesis of 2-(4-(dodecyloxy)phenyl)-5-formyl-1,3-thiazole (6.7).

Fortunately, no issues in purification of 2-(4-(dodecyloxy)phenyl)-5-formyl-1,3-thiazole

(6.7) were experienced and the subsequent Pinnick oxidation generated 2-(4-

(dodecyloxy)phenyl)-1,3-thiazole-5-carboxylic acid (6.3) in excellent yield (94%).

Esterification of 2-(4-(dodecyloxy)phenyl)-1,3-thiazole-5-carboxylic acid (6.3) with

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phenol 2.11 proceeded smoothly via the Steglich esterification to afford the final target

6.8 (see Scheme 6.4) in good yield.

Scheme 6.4: Synthesis of (S)-4-(1-methylheptyloxy)phenyl 2-(4-(dodecyloxy)phenyl)-

1,3-thiazole-5-carboxylate (6.8).

6.3. Attempted synthesis of 2-carboxy-1,3-thiazole-based liquid crystals

The 2-carboxy-1,3-thiazole-based analog of compound 6.3 was previously targeted by our group, but never synthesized.22 5-(4-(Dodecyloxy)phenyl)-1,3-thiazole-

2-carboxylic acid (6.13) was originally targeted via a series of lithiation reactions starting from 2-bromo-1,3-thiazole (3.2) as shown in Scheme 6.5. However, the synthesis of 2-

(trimethylsilyl)-5-(trimethylstannyl)-1,3-thiazole (3.15) failed for unknown reasons,22 at which point the project was abandoned.

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Scheme 6.5: Previously proposed synthesis of 5-(4-(dodecyloxy)phenyl)-1,3-thiazole-

2-carboxylic acid (6.13) via a lithiation-based approach.

With this in mind, alternate approaches to 5-(4-(dodecyloxy)phenyl)-1,3-thiazole-

2-carboxylic acid (6.13) were explored. As previously discussed in Scheme 4.14, reaction of 2-alkoxy-5-(4-cyanophenyl)-1,3-thiazoles 4.5c-4.5e with excess DIBAl-H cleaves away the 2-position alkoxy-chain to yield a 4-(1,3-thiazol-5-yl)benzaldehyde

(4.10). From this work, we envisioned that alkoxy-chains could be utilized as a chemically robust, yet easily removed protection group for the 2-position of 1,3-thiazole rings. Our desired test substrate, 5-(4-(dodecyloxy)phenyl)-2-octyloxy-1,3-thiazole

(6.15), was generated in excellent yield via Suzuki coupling of previously synthesized 5- bromo-2-octyloxy-1,3-thiazole (4.3a) and potassium 4-(dodecyloxy)phenyltrifluoroborate

(6.14) as shown in Scheme 6.6.

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Scheme 6.6: Synthesis of 5-(4-(dodecyloxy)phenyl)-2-octyloxy-1,3-thiazole (6.15) via

Suzuki coupling.

Disappointingly, reaction of 5-(4-(dodecyloxy)phenyl)-2-octyloxy-1,3-thiazole (6.15) with DIBAl-H failed to yield the desired 5-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.12) and instead returned unreacted starting material (6.15; see Scheme 6.7).

Scheme 6.7: Attempted synthesis of 5-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.12).

Addition of a second equivalent of DIBAl-H while allowing the reaction to warm to room temperature also failed to consume 5-(4-(dodecyloxy)phenyl)-2-octyloxy-1,3-thiazole

(6.15). In hindsight, the failure of this reaction was not surprising considering the addition of an electron-rich phenyl ring at the 5-position of 1,3-thiazole would make the

2-position carbon of the 1,3-thiazole ring slightly more electron-rich compared to the 2- position carbon of 1,3-thiazole ring in compounds 4.5c-4.5e which possessed an electron- poor phenyl ring at the 5-position of 1,3-thiazole. For compounds 4.5c-4.5e the electron- withdrawing nitrile makes the 2-position carbon of the 1,3-thiazole ring more electron- poor (see top of Scheme 6.8), and thus more reactive with DIBAl-H. However, for compound 6.15, the electron-donating alkoxy chain of the phenyl ring makes the 2-

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position carbon of the 1,3-thiazole ring more electron-rich and therefore less susceptible to reaction with DIBAl-H (see bottom of Scheme 6.9).

Scheme 6.8: Resonance structures of compounds 4.5c-4.5e and 6.15.

Considering that 2,5-dibromo-1,3-thiazole (3.3) will undergo selective SNAr chemistry in high yield, we attempted to introduce a cyano-group onto the 2-position of

2,5-dibromo-1,3-thiazole (3.3) through use of SNAr chemistry (see Scheme 6.9).

However, according to the crude 1H NMR spectrum, reaction of 2,5-dibromo-1,3-thiazole

(3.3) with KCN in DMSO (see Scheme 6.10) gave mostly unreacted starting material

(77%) along with what appeared to be the desired 5-bromo-2-cyano-1,3-thiazole (6.17;

11%) and an equal amount of 2-cyano-1,3-thiazole (6.16; 12%). The use of CuCN in refluxing DMF consumed all of the 2,5-dibromo-1,3-thiazole (3.3), but also failed to generate the desired 5-bromo-2-cyano-1,3-thiazole (6.17) and instead yielded 2-cyano-

1,3-thiazole (6.16) as the sole product, albeit in only 23% yield as estimated from the crude 1H NMR spectrum.

Scheme 6.9: Attempted synthesis of 5-bromo-2-cyano-1,3-thiazole (6.17).

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If 5-bromo-2-cyano-1,3-thiazole (6.17) could have been generated in moderate isolated yield, it would have been subjected to Suzuki coupling with 4-

(dodecyloxy)phenylboronic acid (6.1) to yield 2-cyano-5-(4-(dodecyloxy)phenyl)-1,3- thiazole (6.18; see Scheme 6.10) which would have either been hydrolyzed directly to the desired 5-(4-(dodecyloxy)phenyl)-1,3-thiazole-2-carboxylic acid (6.13) or reduced and oxidized using DIBAl-H and the Pinnick oxidation, respectively, to yield compound 6.13.

Scheme 6.10: Proposed synthesis of 2-cyano-5-(4-(dodecyloxy)phenyl)-1,3-thiazole

(6.18).

As previously discussed, selective Pd0-catalyzed cross-coupling of 2,5-dibromo-

1,3-thiazole (3.3) is well documented. The use of Pd0-catalyzed alkoxycarbonylation of halo-1,3-thiazoles has been reported in the literature;204 however, the use of 2,5-dibromo-

1,3-thiazole (3.3) to yield a methyl ester has not been reported in the open literature.

Using conditions described by Buchwald (see Scheme 6.11),205 we attempted the regioselective alkoxycarbonylation of 2,5-dibromo-1,3-thiazole (3.3). However, the crude 1H NMR spectrum showed mostly unreacted starting material along with a trace

(~10%) of the desired methyl 5-bromo-1,3-thiazole-2-carboxylate (6.19). If compound

6.19 could have been generated in moderate yield, it would have been cross-coupled with

4-(dodecyloxy)phenylboronic acid (6.1) in a similar manner to that shown in Scheme

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6.10 and the resulting product hydrolyzed to 5-(4-(dodecyloxy)phenyl)-1,3-thiazole-2- carboxylic acid (6.13).

Scheme 6.11: Attempted synthesis of methyl 5-bromo-1,3-thiazole-2-carboxylate

using carbonylative coupling (6.19).

Lithiation of 2,5-dibromo-1,3-thiazole (3.3) and quenching with solid CO2 would be an attractive pathway towards the synthesis of a 2-carboxy-1,3-thiazole-based building block. However, reaction of 2,5-dibromo-1,3-thiazole (3.3) with n-BuLi was unselective and led to significant amounts of decomposition resulting from ring opening95 along with smaller amounts of lithiation at the 5-position (see Scheme 6.12).

Scheme 6.12: Reaction of 2,5-dibromo-1,3-thiazole (3.3) with n-BuLi followed by

quenching with H2O.

Since lithiation of 2,5-dibromo-1,3-thiazole (3.3) was not a viable approach, 2-bromo-

1,3-thiazole (3.2) was considered for the introduction of a 2-position carboxyl group via lithiation chemistry. The syntheses of several different 2-carboxy-1,3-thiazole-based compounds starting from 2-bromo-1,3-thiazole (3.2) were attempted, but met with little

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success. Although the synthesis of 1,3-thiazole-2-carboxylic acid (6.20) has been reported in the open literature,99,206 our attempts to reproduce this work were unsuccessful. 1,3-Thiazole-2-carboxylic acid (6.20) was targeted via lithiation of 2- bromo-1,3-thiazole (3.2; see Scheme 6.13) and quenching with solid CO2, but unfortunately the crude 1H NMR spectrum provided no signs of the desired product.207

Scheme 6.13: Attempted synthesis of 1,3-thiazole-2-carboxylic acid (6.20).

Synthesis of 2-formyl-1,3-thiazole (6.21) from 2-bromo-1,3-thiazole (3.2) was successful, albeit in only 39% yield (see Scheme 6.14).208

Scheme 6.14: Synthesis of 2-formyl-1,3-thiazole (6.21).

With 2-formyl-1,3-thiazole (6.21) in hand, we then attempted to couple the material with

4-bromododecyloxybenzene (6.10). In the recent literature, ligand-free palladium- catalyzed direct arylation of 2,4-disubstituted-1,3-thiazoles has been documented. In addition to eliminating the need for preparing boronic acids, the reaction was reported to be high yielding and extremely tolerant of functional groups.209 Although coupling of 2- formyl-1,3-thiazole (6.21) was not reported, coupling of ethyl 2-methyl-1,3-thiazole-4- carboxylate was reported with isolated yields ranging from 54-70%.209 Unfortunately, application of this literature procedure to 2-formyl-1,3-thiazole (6.21) failed to generate

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the desired 5-(4-(dodecyloxy)phenyl)-1,3-thiazole-2-carbaldehyde (6.22; see Scheme

6.15) and instead yielded unreacted starting material 6.10 and 1,3-thiazole (3.1). If compound 6.22 could have been generated, it would have been subjected to the Pinnick oxidation to yield the targeted 5-(4-(dodecyloxy)phenyl)-1,3-thiazole-2-carboxylic acid

(6.13).

Scheme 6.15: Attempted synthesis of 5-(4-(dodecyloxy)phenyl)-1,3-thiazole-2-

carbaldehyde (6.22).

Ethyl benzoates have been generated via lithiation of the corresponding aryl- bromide followed by quenching with ethyl chloroformate.210 Using a similar strategy, ethyl 1,3-thiazole-2-carboxylate (6.23) was targeted; however, upon addition of 2-lithio-

1,3-thiazole to 3.1 equivalents of ethyl chloroformate, the crude 1H NMR spectrum showed only 33% of the desired ethyl 1,3-thiazole-2-carboxylate (6.23) and mostly bis(1,3-thiazol-2-yl) ketone (6.24; see Scheme 6.16).

Scheme 6.16: Attempted synthesis of ethyl 1,3-thiazole-2-carboxylate (6.23).

An alternative route to ethyl 1,3-thiazole-2-carboxylate (6.23) was explored, but this also met with failure. As shown in Scheme 6.17, the open literature reports that reaction of 2-

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(trimethylsilyl)-1,3-thiazole (6.9) with ethyl chloroformate generates ethyl 1,3-thiazole-2- carboxylate (6.23) in good yield (62%).211 However, in our hands, preparation of 2-

(trimethylsilyl)-1,3-thiazole (6.9) failed and 1,3-thiazole (3.1) was observed as the only compound present in the crude 1H NMR spectrum. Use of recently purchased TMSCl also failed to alleviate the underlying problem associated with this reaction. However, due to time constraints the reaction was never attempted using freshly redistilled TMSCl.

Scheme 6.17: Attempted synthesis of 2-(trimethylsilyl)-1,3-thiazole (6.9).

If ethyl 1,3-thiazole-2-carboxylate (6.23) could have been generated in moderate isolated yield, it would have been subjected to the previously discussed ligand-free palladium- catalyzed direct arylation conditions209 to yield ethyl 5-(4-(dodecyloxy)phenyl)-1,3- thiazole-2-carboxylate (6.25; see Scheme 6.18). Hydrolysis of compound 6.25 to the corresponding carboxylic acid 6.13 would have then been performed followed by esterification with phenol 2.11 to yield the final desired target 6.14.

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Scheme 6.18: Proposed synthesis of (S)-4-(1-methylheptyloxy)phenyl 5-(4-

(dodecyloxy)phenyl)-1,3-thiazole-2-carboxylate (6.14).

In conclusion, the targeted 5-carboxy-1,3-thiazole-based liquid crystal 6.8 was successfully generated starting from previously synthesized 2,5-dibromo-1,3-thiazole

(3.3). The aryl group at the 2-position of the 1,3-thiazole ring was introduced via selective Pd0-catalyzed cross-coupling using conditions developed by Strotman.61 The 5- carboxyl group of the 1,3-thiazole ring was generated via the reduction of nitrile 6.6 followed by a Pinnick oxidation of aldehyde 6.7. Unfortunately, the analogous 5- carboxy-1,3-thiazole-based liquid crystal 6.14 could not be generated, since numerous attempts to incorporate a carboxyl unit at the 2-position of the 1,3-thiazole ring were met with failure. The mesophase properties of the 5-carboxy-1,3-thiazole-based liquid crystal target 6.8 is discussed in Chapter 7.

CHAPTER 7. TRANSITION TEMPERATURES AND COMPARISON OF

LIQUID CRYSTALLINE TARGETS

7.1.1. Liquid crystalline properties of synthesized alkoxy-4-cyanophenyl-1,3- thiazole-based liquid crystals

Transition temperatures of the targeted 5-alkoxy-2-(4-cyanophenyl)-1,3-thiazoles

(2.8a-2.8e) are shown in Table 7.1 and plotted in Figure 7.1. 5-Alkoxy-1,3-thiazoles with odd numbers of carbon atoms in the chain (2.8b and 2.8d) were found to be non- mesogenic. This trend in mesogenic properties is commonly referred to as the “even-odd effect” in which alkoxy chains with an even number of carbons tend to have higher mesophase stability when compared to the alkoxy chains possessing an odd number of carbons. This phenomenon is a result of the higher polarizability anisotropy associated with the alkoxy-based, even chain mesogens.212 It is interesting to note that both the odd and even chain length 5-alkoxy-1,3-thiazoles exhibited very little supercooling (< 4 °C for odd chain lengths, see experimental details) even at rapid (up to 20 °C min-1) cooling rates. In Table 7.1, no enthalpy is given for the nematic – smectic A phase transition of

2.8a as this was not observable by DSC (recrystallization occurred in tandem with the microscopic observation of smectic A phase formation). As expected, the smectic A mesophase thermal stabilities of these compounds increased with increasing length of the alkoxy chain.

129

130

Table 7.1: Transition temperatures (°C) of compounds 2.8a-2.8e with transition

enthalpies (J/g) given as italicized numbers in parentheses.

n Compound number Cryst SmA N Iso Liq 8 2.8a • 58.5 (• 48.8 • 54.5) • (160.9) (3.305) 9 2.8b • 67.5 ― ― • (197.8) 10 2.8c • 66.6 (• 62.9) ― • (166.5) (10.40) 11 2.8d • 73.8 ― ― • (209.4) 12 2.8e • 60.5 • 68.7 ― • (141.1) (21.07)

Figure 7.1: Plot of transition temperatures (°C) of compounds 2.8a-2.8e.

65 Cryst - Iso Liq SmA - Iso Liq 60 Cryst - SmA 55 N - Iso Liq SmA - N 50

45 8 9 10 11 12

Melting points of 5-alkoxy-2-(4-cyanophenyl)-4-fluoro-1,3-thiazoles (5.48a-

5.48e) are shown in Table 7.2 and plotted in Figure 7.2. Fluorination of compounds 2.8a-

2.8e to generate 4-fluoro-1,3-thiazoles 5.48a-5.48e resulted in a significant and universal

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drop in melting point by an average of 20 °C but no overall trend was observed for the melting points of compounds 5.48a-5.48e. Unfortunately, all mesogenic properties were lost upon introduction of fluorine onto the 1,3-thiazole ring of compounds 2.8a-2.8e which is likely due to the larger width caused by introduction of the slightly larger fluoro substituent.19

Table 7.2: Melting points (°C) of compounds 5.48a-5.48e.

n Compound number Cryst Iso Liq 8 5.48a • 41.9 • 9 5.48b • 40.8 • 10 5.48c • 43.1 • 11 5.48d • 52.0 • 12 5.48e • 49.7 •

Figure 7.2: Plot of transition temperatures (°C) of compounds 5.48a-5.48e.

Cryst - Iso Liq 46

40 8 9 10 11 12

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Transition temperatures of the targeted 2-alkoxy-5-(4-cyanophenyl)-1,3-thiazoles

(4.5a-4.5e) are shown in Table 7.3 and plotted in Figure 7.3. Compounds 4.5a-4.5e had variable melting points and no clear trend appears to exist between the chain length (even or odd) and the melting point of the materials. Compounds 4.5a-4.5e were non- mesogenic except for compound 4.5c which exhibited a monotropic smectic A phase which was observed to be 7.2 °C higher than the analogous 5-alkoxy-1,3-thiazole 2.8c.

In Table 7.3, no enthalpy is given for the isotropic – smectic A transition of 4.5c as this was not observable by DSC as recrystallization occurred in tandem with the microscopic observation of smectic A phase formation.

Table 7.3: Transition temperatures (°C) of compounds 4.5a-4.5e with transition

enthalpies (J/g) given as italicized numbers in parentheses.

n Compound number Cryst SmA Iso Liq 8 4.5a • 84.2 ― • (316.1) 9 4.5b • 87.3 ― • (158.4) 10 4.5c • 81.9 (• 70.1) • (151.9) 11 4.5d • 85.5 ― • (145.5) 12 4.5e • 87.7 ― • (154.7)

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Figure 7.3: Plot of transition temperatures (°C) of compounds 4.5a-4.5e.

Cryst - Iso Liq 78 SmA - Iso Liq

68 8 9 10 11 12

7.1.2. Comparison of alkoxy-4-cyanophenyl-1,3-thiazole-based liquid crystals

Transition temperatures of the analogous 2-alkoxy-5-(4-cyanophenyl)thiophenes are shown in Table 7.4.213 The replacement of thiophene with a 5-alkoxy-1,3-thiazole resulted in a universal increase in the mesophase thermal stabilities. For the octyloxy compounds (2.8a and 7.1a) both mesogens displayed monotropic smectic A and nematic phases. Replacement of thiophene with a 5-alkoxy-1,3-thiazole resulted in a 12.0 °C increase in the smectic A – nematic transition and an 8.8 °C increase in the clearing point.

For the decyloxy derivatives the 1,3-thiazole (2.8c) was found to possess a monotropic smectic A phase at 62.9 °C while the thiophene derivative (7.1c) was non-mesogenic and a virtual nematic phase was recorded at 36 °C. Both dodecyloxy derivatives (2.8e and

7.1e) exhibited smectic A phases although the 1,3-thiazole was enantiotropic and the

134

thiophene was monotropic. In this example, the increase in the smectic A mesophase thermal stability on replacing thiophene with a 5-alkoxy-1,3-thiazole was 7 °C. These increases in the mesophase thermal stabilities are consistent with the increased linearity of the 2,5-disubstituted-1,3-thiazole,24 which leads to an enhanced aspect ratio.

Table 7.4: Transition temperatures (°C) of compounds 7.1a-7.1e.

n Compound number Cryst SmA N Iso Liq 8 7.1a • 54.3 (• 36.8 • 45.7) • 10 7.1c • 70.4 ― [• 36] • 12 7.1e • 69.1 (• 61.7) ― •

Transition temperatures of the analogous 4'-alkoxybiphenyl-4-yl-carbonitriles

(7.2a-7.2e) are shown in Table 7.5.214 When the phenyl ring was replaced by a 5-alkoxy-

1,3-thiazole ring the melting points were seen to increase for all compounds (compare

2.8a and 7.2a [increase of 4.0 °C], 2.8b and 7.2b [increase of 3.5 °C], 2.8c and 7.2c

[increase of 7.1 °C], and 2.8d and 7.2d [increase of 2.3 °C]) except the dodecyloxy derivative (compare 2.8e with 7.2e [decrease of 9.5 °C]). Incorporation of a 5-alkoxy-

1,3-thiazole ring in place of the phenyl ring caused all the observed transition temperatures to decrease. Compounds 2.8a and 7.2a (octyloxy derivatives) both had smectic A and nematic phases (monotropic in the case of the 5-alkoxy-1,3-thiazole and enantiotropic in the case of the phenyl compound). Replacement of the phenyl ring with the 5-alkoxy-1,3-thiazole resulted in a decrease of the smectic A – nematic phase transition temperature and the clearing point by 18.2 °C and 25.5 °C, respectively. The decyloxy (2.8c and 7.2c) and dodecyloxy (2.8e and 7.2e) derivatives all had smectic A

135

phases and once again were monotropic in the case of the 1,3-thiazole derivatives and enantiotropic in the case of the phenyl derivatives. The clearing points again were seen to decrease upon replacement of the phenyl ring by 5-alkoxy-1,3-thiazole (compare compounds 2.8c and 7.2c [decrease of 21.1 °C] and 2.8e and 7.2e [decrease of 21.3 °C]).

Again, these decreases in transition temperatures are consistent with the greater linearity of the biphenyl derivatives.

Table 7.5: Transition temperatures (°C) of compounds 7.2a-7.2e.

n Compound number Cryst SmA N Iso Liq 8 7.2a • 54.5 • 67.0 • 80.0 • 9 7.2b • 64.0 • 77.5 • 79.5 • 10 7.2c • 59.5 • 84.0 ― • 11 7.2d • 71.5 • 87.5 ― • 12 7.2e • 70.0 • 90.0 ― •

Replacement of the thiophene and phenyl rings with a 5-alkoxy-4-fluoro-1,3- thiazole resulted in a universal decrease in melting point. However, the resulting 5- alkoxy-4-fluoro-1,3-thiazoles (5.48a-5.48e) also failed to exhibit any liquid crystalline properties.

Exchanging the thiophene for a 2-alkoxy-1,3-thiazole resulted in a loss of all mesogenic properties for the octyloxy and dodecyloxy derivatives (7.1a and 7.1e) while the decyloxy derivative saw its monotropic nematic phase get replaced by a monotropic smectic A phase. Substitution of the phenyl ring for a 2-alkoxy-1,3-thiazole shows similar trends in that all mesogenic properties were lost except for the decyloxy

136

derivative (4.5c) which again had a monotropic smectic A phase at 70.1 °C while the phenyl decyloxy derivative (7.2c) had an enantiotropic smectic A phase at 59.5 °C.

7.2.1. Liquid crystalline properties of synthesized 1,3-thiazole containing (S)-4-(1- methylheptyloxy)phenyl-based liquid crystals

Transition temperatures of the targeted (S)-4-(1-methylheptyloxy)phenyl 4-(5-

(alkoxy)-1,3-thiazol-2-yl)benzoates (2.12a-2.12e), which were found to be free of chevron defects, are shown in Table 7.6 and plotted in Figure 7.4. No general trend was observed for the melting points or clearing points of compounds 2.12a-2.12e, but all liquid crystal targets 2.12a-2.12e were found to possess at least a smectic A phase.

Compounds 2.12c-2.12e were found to exhibit a smectic C* phase, although compound

2.12c was found to possess only a monotropic smectic C* phase. For compounds containing odd alkoxy chain lengths (2.12b and 2.12d), the mesophase thermal stabilities were noticed to be much higher when compared to the even chain length analogs (2.12a,

2.12c, and 2.12e). In Table 7.6, no enthalpy is given for the smectic A – smectic C* transition of 2.12e as this was not observable by DSC due to the narrow width of the smectic A phase.

137

Table 7.6: Transition temperatures (°C) of compounds 2.12a-2.12e with transition

enthalpies (J/g) given as italicized numbers in parentheses.

n Compound number Cryst SmC* SmA Iso Liq 8 2.12a • 79.4 ― • 95.4 • (62.32) (13.36) 9 2.12b • 65.8 ― • 94.6 • (48.40) (13.44) 10 2.12c • 74.7 (• 74.6) • 96.4 • (55.59) (0.2330) (13.60) 11 2.12d • 74.2 • 85.2 • 95.9 • (62.13) (0.2815) (12.63) 12 2.12e • 82.3 • 88.8 • 96.2 • (57.09) (0.3132) (12.88)

Figure 7.4: Plot of transition temperatures (°C) of compounds 2.12a-2.12e.

100

90 SmA - Iso Liq 85 SmC* - SmA 80 Cryst - SmC*

75 Cryst - SmA

65 8 9 10 11 12

Transition temperatures of the targeted (S)-4-(1-methylheptyloxy)phenyl 4-(5-

(alkoxy)-4-fluoro-1,3-thiazol-2-yl)benzoates (5.76a-5.76e), which were found to be free

138

of chevron defects, are shown in Table 7.7 and plotted in Figure 7.5. The melting points of compounds 5.76a-5.76e decreased with increasing chain length except for the decyloxy derivative 5.76c. The clearing points were found to gradually increase with increasing chain length except for the nonyloxy derivative 5.76b. Compounds 5.76a-

5.76e were all found to exhibit the smectic C* and smectic A phases although they were enantiotropic for only dodecyloxy derivative 5.76e.

Table 7.7: Transition temperatures (°C) of compounds 5.76a-5.76e with transition

enthalpies (J/g) given as italicized numbers in parentheses.

n Compound number Cryst Cryst II SmC* SmA Iso Liq 8 5.76a • 37.1 • 73.1 (• 59.2 65.7) • (15.80) (88.72) (0.491) (7.298) 9 5.76b • 72.5 ― (• 60.7 • 64.9) • (106.8) (1.314) (7.503) 10 5.76c • 73.0 ― (• 64.0 • 67.2) • (80.82) (1.245) (8.957) 11 5.76d • 68.8 ― (• 64.4 • 67.5) • (86.18) (1.234) (7.462) 12 5.76e • 59.2 ― • 65.4 • 68.3 • (82.75) (0.790) (6.909)

139

Figure 7.5: Plot of transition temperatures (°C) of compounds 5.76a-5.76e.

68 Cryst - Iso Liq

66 SmA - Iso Liq SmC* - SmA 64 Cryst - SmC* 62

58 8 9 10 11 12

Transition temperatures of the targeted (S)-4-(1-methylheptyloxy)phenyl 4-(2- alkoxy-1,3-thiazol-5-yl)benzoates (4.12a-4.12e), which were found to be free of chevron defects, are shown in Table 7.8 and plotted in Figure 7.6. The melting points of compounds 4.12a-4.12e appear to exhibit a parabolic trend when compared with the chain lengths possessing the shortest and longest chains (compounds 4.12a and 4.12e) exhibiting the highest melting points and the medium length chain (compound 4.12c) possessing the lowest melting point. The smectic C* mesophase thermal stabilities of compounds 4.12a-4.12e increased as the length of the alkoxy chain increased, but the opposite trend was observed for the smectic A mesophase thermal stabilities.

140

Table 7.8: Transition temperatures (°C) of compounds 4.12a-4.12e with transition

enthalpies (J/g) given as italicized numbers in parentheses.

n Compound number Cryst SmC* SmA Iso Liq 8 4.12a • 80.2 • 90.8 • 109.1 • (61.95) (0.1104) (9.415) 9 4.12b • 79.8 • 101.0 • 109.5 • (65.07) (1.313) (8.469) 10 4.12c • 74.1 • 101.5 • 107.7 • (65.51) (0.8111) (8.113) 11 4.12d • 75.8 • 103.6 • 107.1 • (67.49) (0.2574) (9.009) 12 4.12e • 79.9 • 104.0 • 106.1 • (75.66) (14.75)

Figure 7.6: Plot of transition temperatures (°C) of compounds 4.12a-4.12e.

110

105

100

95 SmA - Iso Liq 90 SmC* - SmA 85 Cryst - SmC*

70 8 9 10 11 12

141

Transition temperatures of the targeted (S)-4-(1-methylheptyloxy)phenyl 2-(4-

(dodecyloxy)phenyl)-1,3-thiazole-5-carboxylate (6.8) are shown in Table 7.9. At this point, studies for chevron defects have not been performed for this material. No enthalpy is given for the smectic A – smectic C* transition of 6.8 as this was not observable by

DSC due to the narrow width of the smectic A phase.

Table 7.9: Transition temperatures (°C) of compound 6.8 with transition enthalpies

(J/g) given as italicized numbers in parentheses.

n Compound number Cryst SmC* SmA Iso Liq 12 6.8 • 70.4 • 98.4 • 100.3 • (49.31) (13.92) 7.2.2. Comparison of (S)-4-(1-methylheptyloxy)phenyl-based liquid crystals

Transition temperatures of the analogous (S)-4-(1-methylheptyloxy)phenyl 4'- alkoxybiphenyl-4-ylcarboxylates (7.3a-7.3e) are shown in Table 7.10 and plotted in

Figure 7.7.53,55

Table 7.10: Transition temperatures (°C) of compounds 7.3a-7.3e.

n Compound number Cryst SmX SmC* SmA Iso Liq 8 7.3a • 65.7 • 84.3 • 107.2 • 151.8 • 9 7.3b • 71.1 • 72.2 • 121.5 • 144.3 • 10 7.3c • 70.0 ― • 125.0 • 143.0 • 12 7.3e • 78.0 ― • 127.0 • 140.0 •

142

Figure 7.7: Plot of transition temperatures (°C) of compounds 7.3a-7.3e.

155

145

135

125 SmA - Iso Liq 115 SmC* - SmA

105 SmX - SmC* Cryst - SmC* 95 Cryst - SmX 85

65 8 9 10 12

Replacement of the phenyl ring with a 5-alkoxy-1,3-thiazole moiety resulted in a loss of chevron defects. Incorporation of a 5-alkoxy-1,3-thiazole moiety generally resulted in an increase in melting point (compare 2.12a and 7.3a [increase of 13.7 °C],

2.12c and 7.3c [increase of 4.7 °C], and 2.12e and 7.3e [increase of 4.3 °C]), except for the nonyloxy derivative which resulted in a decrease in melting point (compare 2.12b and 7.3b [decrease of 5.3 °C]). In switching the phenyl ring for a 5-alkoxy-1,3-thiazole, only the three longer chain derivatives exhibited the smectic C* phase (2.12c-2.12e), one of which was monotropic (2.12c). The smectic C* – smectic A transition temperatures were found to be considerably lower for the 5-alkoxy-1,3-thiazole analogs 2.12c-2.12e when compared to the analogous biphenylcarboxylates 7.3c-7.3e (compare 2.12c and

7.3c [decrease of 50.4 °C] and 2.12e and 7.3e [decrease of 38.2 °C]). The clearing points were found to be significantly lower for the 5-alkoxy-1,3-thiazole analogs 2.12a-2.12e

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when compared to the analogous biphenylcarboxylates 7.3a-7.3e (compare 2.12a and

7.3a [decrease of 56.4 °C], 2.12b and 7.3b [decrease of 49.7 °C], 2.12c and 7.3c

[decrease of 46.6 °C], and 2.12e and 7.3e [decrease of 43.8 °C]). The widths of the smectic C* liquid crystal phases were also found to be narrower upon replacement of the phenyl ring with a 5-alkoxy-1,3-thiazole (compare 2.12e and 7.3e [decrease of 42.5 °C]).

The observed differences in properties between the 5-alkoxy-1,3-thiazoles 2.12a-2.12e and the phenyl-based mesogens 7.3a-7.3e is to be expected due to the more bent nature of the 1,3-thiazole-based mesogen which is imparted by the 1,3-thiazole ring (see Figure

1.11).1

Substitution of the phenyl ring with a 2-alkoxy-1,3-thiazole moiety also resulted in a loss of chevron defects. Use of a 2-alkoxy-1,3-thiazole resulted in a universal increase in melting point (compare 4.12a and 7.3a [increase of 14.5 °C], 4.12b and 7.3b

[increase of 8.7 °C], 4.12c and 7.3c [increase of 4.1 °C], and 4.12e and 7.3e [increase of

1.9 °C]). The smectic C* – smectic A transition temperatures were found to be much lower for the 2-alkoxy-1,3-thiazole analogs 4.12a-4.12e when compared to the analogous biphenylcarboxylates 7.3a-7.3e (compare 4.12a and 7.3a [decrease of 16.4 °C], 4.12b and 7.3b [decrease of 20.5 °C], 4.12c and 7.3c [decrease of 23.5 °C] and 4.12e and 7.3e

[decrease of 23.0 °C]). The clearing points were also found to be significantly lower for the 2-alkoxy-1,3-thiazole analogs 4.12a-4.12e when compared to the analogous biphenylcarboxylates 7.3a-7.3e (compare 4.12a and 7.3a [decrease of 42.7 °C], 4.12b and 7.3b [decrease of 34.8 °C], 4.12c and 7.3c [decrease of 35.3 °C], and 4.12e and 7.3e

[decrease of 33.9 °C]). The widths of the smectic C* liquid crystal phases were also

144

found to be narrower upon replacement of the phenyl ring with a 2-alkoxy-1,3-thiazole

(compare 4.12a and 7.3a [decrease of 12.3 °C], 4.12b and 7.3b [decrease of 28.1 °C],

4.12c and 7.3c [decrease of 27.6 °C], and 4.12e and 7.3e [decrease of 24.9 °C]). As previously mentioned, the observed differences in the 5-alkoxy-1,3-thiazoles 4.12a-4.12e and the phenyl-based mesogens 7.3a-7.3e is a result of the structural bend created by the

1,3-thaizole ring.

Replacement of the right-hand phenyl ring with a 5-carboxy-1,3-thiazole moiety resulted in a decrease in melting point (compare 6.8 and 7.3e [decrease of 7.6 °C]). The smectic C* – smectic A transition temperature was found to be much lower for the 5- carboxy-1,3-thiazole analog 6.8 when compared to the analogous biphenylcarboxylate

7.3e (decrease of 28.6 °C). The clearing point was also found to be significantly lower for the 5-carboxy-1,3-thiazole analog 6.8 when compared to the analogous biphenylcarboxylate 7.3e (decrease of 39.7 °C). The width of the smectic C* liquid crystal phase was also found to be narrower upon replacement of the phenyl ring with a

5-carboxy-1,3-thiazole (compare 6.8 and 7.3e [decrease of 21.0 °C]).

Replacement of the 5-alkoxy-1,3-thiazole ring (2.12a-2.12e) with the 2-alkoxy-

1,3-thiazole (4.12a-4.12e) moiety revealed no obvious trend for the melting points

(compare 4.12a and 2.12a [increase of 0.8 °C], 4.12b and 2.12b [increase of 14.0 °C],

4.12c and 2.12c [decrease of 0.6 °C], 4.12d and 2.12d [increase of 1.6 °C], and 4.12e and

2.12e [decrease of 2.4 °C]). In switching the 5-alkoxy-1,3-thiazole moiety for the 2- alkoxy-1,3-thiazole, all mesogens exhibited an enantiotropic smectic C* instead of just the three longer chain derivatives as seen for the 5-alkoxy-1,3-thiazoles (the decyloxy

145

homolog was monotropic). The 2-alkoxy-1,3-thiazoles 4.12a-4.12e, when compared to the analogous 5-alkoxy-1,3-thiazoles 2.12a-2.12e, universally had higher smectic C* – smectic A transition temperatures (compare 4.12c and 2.12c [increase of 26.9 °C], 4.12d and 2.12d [increase of 18.4 °C], and 4.12e and 2.12e [increase of 15.2 °C]) and clearing points (compare 4.12a and 2.12a [increase of 13.7 °C], 4.12b and 2.12b [increase of 14.9

°C], 4.12c and 2.12c [increase of 11.3 °C], 4.12d and 2.12d [increase of 11.2 °C], and

4.12e and 2.12e [increase of 9.9 °C]). The widths of the smectic C* liquid crystal phases were also found to be much wider upon replacement of the 5-alkoxy-1,3-thiazole with a

2-alkoxy-1,3-thiazole (compare 4.12d and 2.12d [increase of 16.8 °C] and 4.12e and

2.12e [increase of 17.6 °C]).

Introduction of fluorine onto the 5-alkoxy-1,3-thiazoles 2.12a-2.12e to give the 5- alkoxy-4-fluoro-1,3-thiazoles 5.76a-5.76e did not result in chevron defects and generally resulted in a decrease in melting point (compare 5.76a and 2.12a [decrease of 6.3 °C],

5.76c and 2.12c [decrease of 1.7 °C], 5.76d and 2.12d [decrease of 5.4 °C], and 5.76e and

2.12e [decrease of 23.1 °C]), except for the nonyloxy derivative (compare 2.12b and

5.76b [increase of 6.7 °C]). Introduction of fluorine also resulted in all the 5-alkoxy-4- fluoro-1,3-thiazoles 5.76a-5.76e exhibiting a at least a monotropic smectic C* phase

(5.76e showed an enantiotropic smectic C*) while only the three longer chain derivatives of the non-fluorinated analogs 2.12c-2.12e exhibited the smectic C* phase (2.12d and

2.12e showed an enantiotropic smectic C*). The smectic C* – smectic A transition temperatures and clearing points were found to be lower for the 5-alkoxy-4-fluoro-1,3- thiazole analogs 5.76a-5.76e when compared to the analogous 5-alkoxy-1,3-thiazoles

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2.12a-2.12e (for the smectic C* – smectic A transition temperatures compare 5.76c and

2.12c [decrease of 10.6 °C], 5.76d and 2.12d [decrease of 20.8 °C], and 5.76e and 2.12e

[decrease of 23.4 °C]; for the clearing points compare 5.76a and 2.12a [decrease of 29.7

°C], 5.76b and 2.12b [decrease of 29.7 °C], 5.76c and 2.12c [decrease of 29.2 °C], 5.76d and 2.12d [decrease of 28.4 °C], and 5.76e and 2.12e [decrease of 27.9 °C]).

Interestingly, the observed decrease in clearing points was very consistent for each mesogen. The width of the smectic C* phase was found to be slightly more narrow upon introduction of fluorine onto the 5-alkoxy-1,3-thiazole moiety (compare 5.76e and 2.12e

[decrease of 0.3 °C]).

Comparison of the 5-carboxy-1,3-thiazole-based liquid crystal 6.8 with the other non-fluorinated 1,3-thiazole-based liquid crystals reveals compound 6.8 had the lowest melting point (compare 2.12e and 6.8 [decrease of 11.9 °C] and 4.12e and 6.8 [decrease of 9.5 °C]). When comparing the smectic C* – smectic A transition temperatures and clearing points for the 5-carboxy-1,3-thiazole-based liquid crystal 6.8 with analogs 2.12e and 4.12e, both temperatures were lower for the 5-alkoxy-1,3-thiazole analog 2.12e but higher for the 5-alkoxy-1,3-thiazole analog 4.12e (for the smectic C* – smectic A transition temperatures compare 2.12e and 6.8 [increase of 9.6 °C] and 4.12e and 6.8

[decrease of 5.6 °C]; for the clearing points compare 2.12e and 6.8 [increase of 4.1 °C] and 4.12e and 6.8 [decrease of 5.8 °C]). The width of the smectic C* phase was found to be wider for the 5-carboxy-1,3-thiazole-based liquid crystal 6.8 when compared to the other non-fluorinated 1,3-thiazole-based liquid crystals (compare 2.12e and 6.8 [increase of 21.5 °C] and 4.12e and 6.8 [increase of 3.9 °C]).

147

As previously discussed in Chapter 1.4, replacement of one of the phenyl rings with a 1,3-thiazole moiety was expected to lead to an increase in spontaneous polarization. However, the opposite trend was observed upon comparison of the spontaneous polarization of the 2- and 5-alkoxy-1,3-thiazoles 2.12e and 4.12e (see

Chapter 8) with the phenyl-based analog 7.3e.55 At 15 °C below the smectic C* – smectic A phase transition temperature, the spontaneous polarization was determined to be about 30 and 41 nC/cm2 for compounds 2.12e and 4.12e, respectively, while the

2 phenyl-based analog 7.3e was 50 nC/cm . On the other hand, at 15 °C below the smectic

C* – smectic A phase transition temperature, the spontaneous polarization was determined to be 79 nC/cm2 for the 5-alkoxy-4-fluoro-1,3-thiazole 5.76e. Although the phenyl-based analog 7.3e had higher mesophase thermal stabilities and higher values of spontaneous polarization (for the non-fluorinated analogs), compound 7.3e exhibits chevron defects which prevents its use in liquid crystal displays. Conversely, the alkoxy-

1,3-thiazole-based liquid crystals 2.12e, 4.12e, and 5.76e were found to be free of chevron defects, which is a first for liquid crystals containing this particular sulfur-based heterocycle.

In Chapter 1.4, predictions were also made that the 5-alkoxy-1,3-thiazole-based liquid crystals (Structure I from Figure 1.15) would exhibit the best mesogenic properties based on arguments of lateral dipole orientation and interannular torsion angle, while the

2-alkoxy- and the 5- and 2-carboxy-1,3-thiazole-based liquid crystals (Structures II, III, and IV from Figure 1.15, respectively) would be less favorable.

148

Figure 1.15: Four variations of the targeted liquid crystals with the 1,3-thiazole ring

occupying “Ring 1” or “Ring 2.”

However, the opposite trend was discovered upon analysis of 1,3-thiazole-based mesogens I, II and III (as previously discussed in Chapter 6.3, we were unsuccessful in finding a pathway towards the synthesis of the 2-carboxy-1,3-thiazole-based mesogen IV in the time available to complete its synthesis). While most of the 5-alkoxy-1,3-thiazoles

I exhibited the smectic C* phase, the width of the smectic C* phase was quite small. On the other hand, the 2-alkoxy-1,3-thiazoles II and the 5-carboxy-1,3-thiazole III all exhibited the smectic C* phase and the width of these smectic C* phases were much wider (average width of 5.9 °C for I, 22.2 °C for II, and 28.0 °C for III) than for the analogous 5-alkoxy-1,3-thiazoles I. Despite the 5-carboxy-1,3-thiazole III being predicted to be one of the least favorable of the 1,3-thiazole-based mesogens, it exhibited the lowest melting point and the widest smectic C* phase of all the non-fluorinated, 1,3- thiazole-based liquid crystals discussed within this dissertation.

The enhanced mesogenic properties for the 2-alkoxy-1,3-thiazoles II and the 5- carboxy-1,3-thiazole III could be a result of the orientation of the 1,3-thiazole ring with respect to the electron-donating alkoxy chain. For both structures, the 2-position of the

1,3-thiazole ring is nearest to the electron-donating alkoxy chain which could be

149

enhancing the partial charge separation of the molecule through resonance (see Scheme

7.1) which, as discussed in Chapter 1.1, encourages the formation of tilted smectic phases.

Scheme 7.1: Resonance structures for Structures II and III.

CHAPTER 8. ELECTRO-OPTICAL STUDIES

8.1. Determination of pitch in relation to temperature

Helical pitch measurements were made by filling 25 μm cells (purchased from

E.H.C. Inc., Japan) with compounds 2.12e, 4.12e, or 5.76e, none of which exhibited chevron defects during our studies. Upon cooling from the isotropic – smectic A phase at a rate of 1 °C/min, a multi-domain texture with uniform areas in the 10 to 30 μm range formed due to the lack of a nematic phase. In order to obtain the proper alignment required for measuring the pitch, the samples were heated up to the isotropic phase for about 8 to 10 minutes, and then 0.08 V/μm, 200 Hz square wave electric fields were then applied. After slowly cooling to the smectic C* phase, the voltage was removed, and images were taken at every 1 °C. In doing so, larger domains formed which allowed for a more precise determination of the pitch, which is the distance between two adjacent unwinding defect lines (pitch bands). In order to increase the precision of the measurements, the length of ten pitch bands was measured at several different areas and then averaged for each temperature. We found that for all three compounds (2.12e,

4.12e, and 5.76e) the pitch decreased by about 25 to 40% in going from the top of the smectic C* range to the lower end of the phase before it finally crystallized. The largest helical pitch of 4.12e, 2.12e, and 5.76e were 18±2 μm, 32±1 μm and 20±2 μm, respectively. As shown in Figure 8.1, the distribution of pitch bands was not completely uniform, which was due to the comparable size of the film thickness and the pitch which causes the pitch formation to be very slow.

150

151

Figure 8.1: Representative polarizing optical microscope textures of 25 μm thick

films (scale bars represent 200 μm). Left: compound 4.12e at 98.4 °C; Middle:

compound 2.12e at 87.5 °C; Right: compound 5.76e at 64.3 °C.

8.2. Determination of polarization current

Using 5 μm films with planar alignment layers, which were made in the clean room of the Liquid Crystal Institute at Kent State University, the polarization current was determined by applying triangular wave voltages with up to 20 V/μm electric fields at different frequencies: 132 Hz, 42 Hz and 5 Hz. As shown in Figure 8.2, only one peak appears in each half, indicating ferroelectric polarization. In Figure 8.3, the integration of the electric current curve is shown as a function of the applied voltages for compounds

4.12e, 2.12e, and 5.76e. A linear increase was observed for the areas above the threshold voltages which correspond to the point at which the pitch starts to unwind, which were determined to be Vu = 2.5 V, 1.0 V, and 1.3 V for compounds 4.12e, 2.12e, and 5.76e, respectively. Above a second set of threshold voltages, which were determined to be Vs

= 5.7 V, 3.2 V and 4.6 V for compounds 4.12e, 2.12e, and 5.76e, respectively, the slopes decreased and saturated to values of 0.5 nC/(cm2V), 0.4 nC/(cm2V) and 0.8 nC/(cm2V).

These small increases were due to field-induced quenching of the fluctuations and as well as the electroclinic effect.

152

Figure 8.2: Typical time dependence of the electric current for compounds 4.12e,

2.12e, and 5.76e flowing through 5 μm thick films with triangular shaped voltages

applied on the sandwich cells between the ITO electrodes.

) 1 V

( 5

0 2

0 0

r r

u 2.12e : 80oC -5 C -1 4.12e : 80oC 5.76e : 54oC -10 0 2 4 6 8

Time (ms)

Figure 8.3: Integration of the electric current curves from Figure 8.2 as a function of

the applied voltages.

) 100

m c / 80

C 4.12e

n (

2.12e s 5.76e

a 60

a 40

i r

t 20

e l

E 0 0 2 4 6 8 10

Voltage (V)

153

The spontaneous polarization was determined by the peak areas at very high fields of 20 V/μm, which was where the peaks were saturated. A plot of temperature versus spontaneous polarization (Ps) is shown in Figure 8.4 and their relationship can be

described by the function PPTTs o() AC , where Po is the intrinsic polarization (17.4,

2 12.1 and 29 nC/cm for compounds 4.12e, 2.12e, and 5.76e, respectively), TAC is the temperature of the smectic C* – smectic A phase transition, and the exponent α had a value of about 0.33 for all three compounds. The fact that Po was the largest for compound 5.76e is not surprising as it possesses a lateral fluorine, thus giving it the largest lateral dipole moment.

Figure 8.4: Plot of temperature versus spontaneous polarization for compounds

4.12e, 2.12e, and 5.76e.

100 5.76e: P=29(65.5-T)0.37 2.12e: P=12.1(89-T)0.32

80 4.12e: P=17.4(103-T)0.33

) 2

m 60

n (

s 40 P 20

0 40 60 80 100

o Temperature ( C) 8.3. Determination of tilt angle

The tilt angles were determined by applying square wave electric fields (45 Hz, 2

V/μm) and measuring the angle difference between two directions of the optical axis

154

corresponding to the positive and negative voltages. As shown in Figure 8.5, the tilt angles, which were determined at temperatures of 80 °C for compounds 4.12e and 2.12e and 54 °C for compound 5.76e, increased in magnitude with increasing applied voltage, but were found to saturate very quickly, at which point the voltages reached Vs. The slight linear increase (0.13 °/V, 0.15 °/V and 0.024 °/V for compounds 4.12e, 2.12e, and

5.76e, respectively) above Vs was due to the electroclinic effect, and are quite typical for smectic C* materials. It is remarkable that the addition of fluorine greatly suppressed the electroclinic effect which, in part, could be due to the lower range of the transition temperatures for compound 5.76e.

Figure 8.5: Plot of voltage versus the tilt angle measured in 25 μm thick films of

compounds 4.12e, 2.12e, and 5.76e.

) 20

g e

d 15

(

e l 4.12e: T=80oC g o

n 10 2.12e: T=80 C

a 5.76e

l i

T 5

0 0 4 8

Voltage (V)

A plot of the temperature versus the saturated tilt angle is shown in Figure 8.6.

For all three compounds, the tilt angle jumped sharply to an almost constant value of

155

about 20 to 25° which is in agreement with the temperature dependence of the spontaneous polarization which showed a gradual increase as the temperature decreased.

This behavior was very unusual, as typically for compounds with relatively low values of spontaneous polarizations which exhibit smectic C* – smectic A phase sequences, the temperature dependence of the spontaneous polarization and tilt angles are very similar.

This highly unusual behavior may be due to the narrow smectic A ranges (3-5 °C), which could be mimicking a direct isotropic – smectic C* transition where the tilt angles are typically independent of temperature.

Figure 8.6: Plot of temperature versus the tilt angle for compounds 4.12e, 2.12e, and

5.76e. )

e 20

(

e l

g 4.12e

n 10

a 2.12e

t 5.76e

i T

0 50 70 90 110

o Temperature ( C) 8.4. Determination of switching time

The switching times were measured from the peak position of the polarization current under square wave electric fields. A plot of the voltage (V) versus the switching time (τ) is shown in Figure 8.7. The curves above the second threshold voltages were

156

1 fitted by the function 2 , where 1 is the rotational viscosity, E is the Ps E1/ 2 Kq electric field (which is defined as V/d where d is the cell thickness), K is the effective

Frank elastic constant of the material, and q = 2 / ξ, [where ξ is the electric coherence length (the distance from the cell substrate to the border where the molecules switch from adopting a homogenous orientation to a homeotropic orientation when an electric field is applied)].

Figure 8.7: Plot of voltage versus the switching times at 80 °C for compounds 4.12e

and 2.12e and 54 °C for compound 5.76e measured in 5 μm thick films.

0.3

)

(

e 0.2 m

i 4.12e: =5.76/(U+58.7) t

2.12e: =0.566/(U+3.03)

g 5.76e: =2.84/(U=7.35)

i h

c 0.1

w S

0 2 4 6 8 10

Voltage (V)

From the measured polarization values and the numerator from the best fit parameter shown in Figure 8.7, the rotational viscosity can be calculated as 0.57 Pas, 0.023 Pas and

0.4 Pas for compounds 4.12e, 2.12e, and 5.76e, respectively. The very low rotational viscosity of compound 2.12e compared to the other two materials can partially be explained by the fact that its value was measured closest to the smectic C* – smectic A

157

phase transition temperature (10 °C away), and that it has the smallest tilt angle. In addition the molecular structure of 2.12e should be responsible for the observed low rotational viscosity. This is surprising considering 2.12e only differs from that of 4.12e by the position of the nitrogen in the 1,3-thiazole moiety. A plot of temperature versus switching times is shown in Figure 8.8, where again we see that the position of the nitrogen has a great effect (factor of two) on the rotational viscosity of the material.

Figure 8.8: Plot of temperature versus the switching times for compounds 4.12e,

2.12e, and 5.76e measured at 10 V in 5 μm thick films.

1.5

) 2.12e s 1.2

m 4.12e

(

e 5.76e

m 0.9

g n

i 0.6

t i

w 0.3 S

0 40 55 70 85 100 115

o Temperature ( C)

158

CHAPTER 9. CONCLUSIONS

The research described within this dissertation was divided into five main projects. Three of the five projects dealt with the synthesis of alkoxy-1,3-thiazole-based liquid crystals while a fourth project involved the synthesis of a 5-carboxy-1,3-thiazole- based liquid crystal. The fifth project, involving the synthesis of dihalo-1,3-thiazoles, provided access to building blocks which served as starting materials for several of the discussed targets. In the projects dealing with the synthesis of liquid crystals, the underlying goal was to better understand the impact of incorporating a 1,3-thiazole ring into liquid crystalline targets, which to date is not a well explored area.

In the first project (Chapter 2), the synthesis of a series of 5-alkoxy-1,3-thiazole- based liquid crystals 2.12a-2.12e was presented. The 5-alkoxy-1,3-thiazole moiety was efficiently constructed via a Lawesson’s reagent mediated cyclization of an α-benzamido ester 2.5a-2.5e. Although this project required several synthetic steps to reach the final target, only the final step required silica gel chromatography which allowed for the synthetic intermediates to be easily generated and purified on a multi-gram scale. From this project, the first series of 5-alkoxy-1,3-thiazole-based liquid crystals 2.12a-2.12e were produced, which were found to be free of chevron defects. In general, the resulting

5-alkoxy-1,3-thiazole-based liquid crystals exhibited melting points which were higher and smectic C* phases which were more narrow than the analogous phenyl-based derivatives 7.3a-7.3e.

In a second project (Chapter 3), the synthesis of various dihalo-1,3-thiazoles were discussed. Of the various dihalo-1,3-thiazoles explored, only 2,4- (3.11) and 2,5-

159

dibromo-1,3-thiazole (3.3) were successfully generated on a multi-gram scale from commercially inexpensive starting materials. Even though both 2,4- (3.11) and 2,5- dibromo-1,3-thiazole (3.3) are commercially available, they are both quite expensive on a per mole basis ($4858/mol and $5786/mol, respectively). New methods were developed for their synthesis which were higher yielding, more cost-effective, and scalable, than the previously reported methods. 2,4-Dibromo-1,3-thiazole (3.11) was generated from a reaction of ,3-thiazolidine-2,4-dione (3.10) with P2O5 and Bu4NBr while 2,5-dibromo-

1,3-thiazole (3.3) was generated from of a reaction of 2-bromo-1,3-thiazole (3.2) with elemental bromine and NaHCO3 through electrophilic aromatic substitution.

Starting from 2,5-dibromo-1,3-thiazole (3.3), whose synthesis was discussed in

Chapter 3, a third project (Chapter 4) explored the synthesis of a series of 2-alkoxy-1,3- thiazole-based liquid crystals 4.12a-4.12e which were structurally transposed analogs of the 5-alkoxy-1,3-thiazole-based liquid crystals 2.12a-2.12e from Chapter 2. The 2- alkoxy-1,3-thiazole moiety was efficiently constructed via selective SNAr chemistry of

2,5-dibromo-1,3-thiazole (3.3) with the appropriate sodium alkoxides. Synthesis of the final targets 4.12a-4.12e was not straightforward as the hydrolysis of nitriles 4.5c-4.5e failed. Fortunately, a two-step sequence involving DIBAl-H reduction followed by

Pinnick oxidation afforded the required carboxylic acids 4.11c-4.11e, which allowed for the generation of the first series of 2-alkoxy-1,3-thiazole-based liquid crystals 4.12a-

4.12e which were also found to be free of chevron defects. The resulting 2-alkoxy-1,3- thiazole-based liquid crystals 4.12a-4.12e exhibited similar melting points to the analogous 5-alkoxy-1,3-thiazole-based liquid crystals 2.12a-2.12e; however, compounds

160

4.12a-4.12e did exhibit wider smectic C* phase transition temperatures. Like the 5- alkoxy-1,3-thiazole-based liquid crystals 2.12a-2.12e, the 2-alkoxy-1,3-thiazole-based liquid crystals 4.12a-4.12e also exhibited higher melting points and smectic C* phase transition temperatures which were more narrow than the analogous phenyl-based derivatives 7.3a-7.3e.

For the fourth project (Chapter 5), a series of 5-alkoxy-4-fluoro-1,3-thiazole- based liquid crystals 5.76a-5.76e, which were ring fluorinated analogs of the 5-alkoxy-

1,3-thiazole-based liquid crystals 2.12a-2.12e was discussed. Outside the patent literature, no methods exist for synthesizing 4-fluoro-1,3-thiazoles. As a result, numerous strategies were explored as potential pathways for generating 4-fluoro-1,3- thiazoles. Through the use of electrophilic aromatic substitution, the synthesis of the first series of 4-fluoro-1,3-thiazoles to be reported outside the patent literature was accomplished in a moderate yield of about 40%. 5-Alkoxy-4-fluoro-1,3-thiazoles 5.48a-

5.48e were generated from the reaction of 5-alkoxy-2-(4-cyanophenyl)-1,3-thiazoles

(2.8a-2.8e) with SelectFluor™, a commercially available source of electrophilic fluorine.

From this project, the first series of 4-fluoro-1,3-thiazole-based liquid crystals 5.48a-

5.48e were produced which also happened to be free of chevron defects. In comparison to their non-fluorinated analogs 2.12a-2.12e, compounds 5.76a-5.76e exhibited melting points which were generally lower while the width of their smectic C* phase ranges were similar to the non-fluorinated analogs 2.12a-2.12e. When compared to their phenyl- based analogs 7.3a-7.3e, the melting points were generally higher for the 4-fluoro-1,3-

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thiazole-based liquid crystals 5.76a-5.76d, although 5.76e displayed a significantly lower melting point.

As a final project (Chapter 6), the synthesis of a 5-carboxy-1,3-thiazole-based liquid crystal 6.8 was presented. Once again starting from 2,5-dibromo-1,3-thiazole

(3.3), an aryl group was introduced onto the 2-position of the 1,3-thiazole ring via selective Pd0-catalyzed cross-coupling using conditions developed by Strotman.61 The 5- carboxyl group of the 1,3-thiazole ring was generated via the reduction of nitrile 6.6 followed by a Pinnick oxidation of aldehyde 6.7. From this project, the first 5-carboxy-

1,3-thiazole-based liquid crystal 6.8 was produced. Of the non-fluorinated 1,3-thiazole- based liquid crystals, compound 6.8 exhibited the lowest melting point as well as the widest smectic C* phase transition temperature. When compared to its phenyl-based analog, compound 6.8 exhibited a lower melting point, while the observed smectic C* phase was narrower for compound 6.8 than for the phenyl-based analog 7.3e.

Although the synthesized 2-alkoxy, 5-alkoxy, and the 5-alkoxy-4-fluoro-1,3- thiazole-based liquid crystals (compounds 4.12, 2.12, and 5.76, respectively) exhibited phase transition temperatures and spontaneous polarizations (30, 41, and 50 nC/cm2 for compounds 2.12e, 4.12e, 7.3e, respectively at 15 °C below the smectic C* – smectic A phase transition temperature) which were inferior to their phenyl analogs 7.3 (for 5.76e the spontaneous polarization was actually higher, 79 nC/cm2 at 15 °C below the smectic

C* – smectic A phase transition temperature), they were superior in one respect. The synthesized 1,3-thiazole-based liquid crystals were found to be free of chevron defects, meaning they are likely to be de Vries materials and would facilitate their use in liquid

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crystal displays. Previously, only a single sulfur-based heterocyclic liquid crystal has been reported to be free of chevron defects, a fluorothiophene-based compound reported by our group (see Figure 1.9,structure IV).1 With the synthesis of compounds 4.12, 2.12, and 5.76, we have now generated four sulfur-based heterocyclic liquid crystals which are free of chevron defects. The compounds reported within this dissertation are also the first

1,3-thiazole-based compounds reported to be free of chevron defects.

CHAPTER 10. EXPERIMENTAL

Confirmation of the structures of products was obtained by 1H (400 MHz), 13C

(100 MHz), 19F (376.5 MHz), and 119Sn (149 MHz) NMR (Bruker Avance 400 MHz spectrometer using Topspin version 2.1 software) in CDCl3 or DMSO-d6 with

19 tetramethylsilane as internal standard. CFCl3 was used as internal standard for F NMR

119 and Me4Sn was used as internal standard for Sn NMR. EI-MS was obtained at 70 eV using a Finnigan Polaris ion trap MS coupled with a Trace GC instrument. Elemental analyses were performed by Atlantic Microlab, Inc. (Norcross, GA).

Transition temperatures of the final products were determined by polarizing optical microscopy using a Leica Laborlux 12 POLS polarizing microscope combined with a Mettler FP82HT Hot Stage and a Mettler FP90 Central Processor. Differential scanning calorimetry (DSC) measurements were performed using a TA Instruments

Differential Scanning Calorimeter 2920 at heating and cooling rates of 5 °C per minute

(unless otherwise stated) with indium as the internal standard.

Thin Layer Chromatography (TLC) was carried out using Whatman brand aluminum backed plates (250 μm thick layer of 60 Å silica gel with UV 254 nm fluorescence indicator). Column chromatography (flash) was carried out using Silicycle brand 60 Å, 40-63 μm particle size silica.

Triethylamine and MeCN were dried by distilling over CaH2 and CHCl3 was dried by distilling over P2O5. Acetone was dried by distilling over boric anhydride.

THF, Et2O, and toluene were dried by distilling over sodium benzophenone ketyl. DMF

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164

was dried using 4 Å molecular sieves unless otherwise noted. Petroleum ether was redistilled. All other chemicals were used as received.

10.1. Experimental for Chapter 2

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Octyl 2-aminoethanoate hydromethanesulfonate (2.4a)

Octan-1-ol (31.7526 g, 243.819 mmol) and glycine (2.3; 5.3075 g, 70.701 mmol) were stirred in an oil bath (external temperature 130 °C) for a few minutes before methanesulfonic acid (7.4163 g, 77.165 mmol) was added over about 1 minute and the resulting solution was heated at the same temperature for 3 hours 30 minutes. The cooled solution was then diluted with Et2O (100 mL) and cooled on a slurry of dry ice/acetone.

Once a solid had crystallized, it was filtered off and washed with cold Et2O (500 mL, -60

°C) to give a pearly, white solid (19.12 g, 95%) which was dried under vacuum (P2O5) for 3 days and was pure by 1H NMR. Yield 19.12 g (95%). Mp = 72.5-73.5 °C. 1H

NMR: (CDCl3) δ 0.88 (t, J = 6.86 Hz, 3H), 1.20-1.38 (m, 10H), 1.64 (quint., J = 7.02 Hz,

2H), 2.77 (s, 3H), 3.91 (br. q, J = 5.62 Hz, 2H), 4.17 (t, J = 6.84 Hz, 2H), 7.91 (br. s, 3H);

13 C NMR (CDCl3) δ 14.1, 22.6, 25.8, 28.4, 29.19, 29.24, 31.8, 39.0, 40.6, 66.4, 168.0;

Anal. Calcd for C11H25NO5S: C, 46.62; H, 8.89; N, 4.94. Found: C, 46.55; H, 8.85; N,

4.92%.

Nonyl 2-aminoethanoate hydromethanesulfonate (2.4b)

Compound 2.4b was prepared using a similar procedure to that described for the preparation of 2.4a using the quantities stated: Nonan-1-ol (8.8124 g, 61.091 mmol), glycine (2.3; 1.3322 g, 17.746 mmol) methanesulfonic acid (1.8388 g, 19.132 mmol).

A pearly, white solid was obtained which was dried in vacuo (P2O5). Yield 5.08 g (96%).

1 Mp = 69.6-70.7 °C. H NMR: (CDCl3) δ 0.88 (t, J = 6.84 Hz, 3H), 1.20-1.40 (m, 12H),

1.64 (quint., J = 6.97 Hz, 2H), 2.76 (s, 3H), 3.92 (br. q, J = 4.48 Hz, 2H), 4.17 (t, J = 6.85

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13 Hz, 2H), 7.91 (br. s, 3H); C NMR (CDCl3) δ 14.1, 22.7, 25.8, 28.4, 29.3 (2), 29.5, 31.9,

39.0, 40.6, 66.4, 168.0; Anal. Calcd for C12H27NO5S: C, 48.46; H, 9.15; N, 4.71. Found:

C, 48.22; H, 9.01; N, 4.69%.

Decyl 2-aminoethanoate hydromethanesulfonate (2.4c)

Compound 2.4c was prepared using a similar procedure to that described for the preparation of 2.4a (except that the solution was not cooled prior to being filtered) using the quantities stated: Decan-1-ol (0.8889 g, 5.616 mmol), glycine (2.3; 0.1215 g, 1.618 mmol), methanesulfonic acid (0.1972 g, 2.052 mmol). A white solid was obtained which was dried in vacuo (P2O5). Yield 0.4832 g (96%).* Traces of the starting alcohol were

1 removed by recrystallizing from Et2O and a few drops of EtOH. Mp = 67.4-69.2 °C. H

NMR: (CDCl3) δ 0.88 (t, J = 6.83 Hz, 3H), 1.20-1.38 (m, 14H), 1.64 (quint., J = 6.98 Hz,

2H), 2.76 (s, 3H), 3.91 (br. q, J = 4.79 Hz, 2H), 4.17 (t, J = 6.85 Hz, 2H), 7.94 (br. s, 3H);

13 C NMR (CDCl3) 14.0, 22.7, 25.9, 28.6, 29.4 (2), 29.61, 29.64, 32.0, 39.2, 40.8, 66.6,

167.9; Anal. Calcd for C13H29NO5S: C, 50.13; H, 9.39; N, 4.50. Found: C, 49.79; H,

9.23; N, 4.57%. *Using a similar procedure to that described for compound 2.4a gave a lower yield (9.5980 g, 87%).

Undecyl 2-aminoethanoate hydromethanesulfonate (2.4d)

Compound 2.4d was prepared using a similar procedure to that described for the preparation of 2.4a (except that the solution was not cooled prior to being filtered) using the quantities stated: Undecan-1-ol (0.9273 g, 5.382 mmol), glycine (2.3; 0.1167 g, 1.555

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mmol), methanesulfonic acid (0.1879 g, 1.955 mmol). A white solid was obtained which was dried in vacuo (P2O5). Yield 0.4946 g (98%).* Traces of the starting alcohol were

1 removed by recrystallizing from Et2O and a few drops of EtOH. Mp = 77.5-79.1 °C. H

NMR: (CDCl3) δ 0.88 (t, J = 6.84 Hz, 3H), 1.20-1.40 (m, 16H), 1.64 (quint., J = 6.96 Hz,

2H), 2.77 (s, 3H), 3.91 (br. q, J = 5.23 Hz, 2H), 4.17 (t, J = 6.84 Hz, 2H), 7.94 (br. s, 3H);

13 C NMR (CDCl3) δ 14.1, 22.7, 25.8, 28.4, 29.3, 29.4, 29.55, 29.64 (2), 31.9, 39.1, 40.5,

66.4, 168.0; Anal. Calcd for C14H31NO5S: C, 51.66; H, 9.60; N, 4.30. Found: C, 51.50;

H, 9.52; N, 4.30%. *Using a similar procedure to that described for compound 2.4a gave a lower yield (6.2719 g, 56%).

Dodecyl 2-aminoethanoate hydromethanesulfonate (2.4e)

Compound 2.4e was prepared using a similar procedure to that described for the preparation of 2.4a (except that the solution was not cooled prior to being filtered) using the quantities stated: Dodecan-1-ol (23.1476 g, 124.229 mmol), glycine (2.3; 2.6506 g,

35.308 mmol), methanesulfonic acid (3.6721 g, 38.207 mmol). An off-white solid was obtained which was dried in vacuo (P2O5). Yield 11.5367 g (96%). Traces of the starting alcohol were removed by recrystallizing from Et2O and a few drops of EtOH. Mp =

1 78.1-79.6 °C. H NMR: (CDCl3) δ 0.88 (t, J = 6.83 Hz, 3H), 1.20-1.40 (m, 18H), 1.64

(quint., J = 7.03 Hz, 2H), 2.77 (s, 3H), 3.91 (br. q, J = 5.48 Hz, 2H), 4.17 (t, J = 6.84 Hz,

13 2H), 7.96 (br. s, 3H); C NMR (CDCl3) δ 14.1, 22.7, 25.8, 28.4, 29.3, 29.4, 29.56, 29.64,

29.66, 29.69, 31.9, 39.1, 40,5, 66.4, 168.0; Anal. Calcd for C15H33NO5S: C, 53.07; H,

9.80; N, 4.13. Found: C, 53.00; H, 9.87; N, 4.13%.

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Octyl (4-bromobenzoylamino)ethanoate (2.5a)

Octyl 2-aminoethanoate hydromethanesulfonate (2.4a; 12.60 g, 44.46 mmol) and Et3N

(anhydrous, 21.5 mL, 154 mmol, d = 0.726 g/mL) were stirred in CHCl3 (anhydrous, 84 mL) under argon and cooled to 0 °C (internal temperature) before a cooled solution (~5

°C) of 4-bromobenzoyl chloride (9.8620 g, 44.938 mmol) in CHCl3 (anhydrous, 34 mL) was slowly added dropwise over 20 minutes (internal temperature was kept under 8 °C).

The resulting solution was stirred at a temperature range of 0-10 °C for 2 hours before being allowed to warm to room temperature over 1 hour. Once at room temperature, the reaction was stirred with saturated NaHCO3 (150 mL) before the organic layer was drained away. The aqueous layer was extracted with CH2Cl2 (3 x 75 mL) and the combined organic extracts were washed with brine (75 mL), dried over MgSO4 and filtered through a 1 inch silica plug which was subsequently washed with EtOAc (150 mL). The colorless filtrate was then concentrated under reduced pressure to give a white

1 solid that was pure based on H NMR. The product was dried in vacuo (P2O5). Yield

1 16.15 g (98%). Mp = 74.3-75.4 °C. H NMR (CDCl3) δ 0.88 (t, J = 6.70 Hz, 3H), 1.20-

1.40 (m, 10H), 1.67 (quint., J = 6.98 Hz, 2H), 4.19 (t, J = 6.85 Hz, 2H), 4.22 (d, J = 4.95

Hz, 2H), 6.79 (br. t, J = 3.78 Hz, 1H), 7.59 (d, J = 8.49 Hz, 2H), 7.71 (d, J = 8.43 Hz,

13 2H); C NMR (CDCl3) δ 14.1, 22.6, 25.8, 28.5, 29.2 (2), 31.8, 41.9, 66.0, 126.6, 128.7,

131.9, 132.6, 166.4, 170.1; Anal. Calcd for C17H24BrNO3: C, 55.14; H, 6.53; N, 3.78.

Found: C, 55.31; H, 6.55; N, 3.86%.

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Nonyl (4-bromobenzoylamino)ethanoate (2.5b)

Compound 2.5b was prepared using a similar procedure to that described for the preparation of 2.5a using the quantities stated: 2.4b (5.08 g, 17.1 mmol), Et3N

(anhydrous, 8.5 mL, 61 mmol, d = 0.726 g/mL), CHCl3 (anhydrous, 44 mL), 4- bromobenzoyl chloride (in 25 mL of CHCl3, 3.7949 g, 17.292 mmol). Once at room temperature, the reaction was stirred with saturated NaHCO3 (85 mL) before the organic layer was drained away. The aqueous layer was extracted with CH2Cl2 (3 x 30 mL) and the combined organic extracts were washed with brine (30mL), dried over MgSO4 and filtered through a 1 inch silica plug which was subsequently washed with EtOAc (75 mL). The colorless filtrate was then concentrated under reduced pressure. A white solid was obtained which was dried in vacuo (P2O5). Yield 6.4598 g (98%). Mp = 78.7-79.2

1 °C. H NMR (CDCl3) δ 0.88 (t, J = 6.84 Hz, 3H), 1.20-1.40 (m, 12H), 1.67 (quint., J =

6.99 Hz, 2H), 4.19 (t, J = 7.47 Hz, 2H), 4.22 (d, J = 5.09 Hz, 2H), 6.75 (br. t, J = 3.94 Hz,

13 1H), 7.57 (d, J = 8.60 Hz, 2H), 7.68 (d, J = 8.55 Hz, 2H); C NMR (CDCl3) δ 14.1, 22.7,

25.8, 28.5, 29.2 (2), 29.5, 31.9, 41.9, 66.0, 126.6, 128.7, 131.9, 132.5, 166.4, 170.1;

Anal. Calcd for C18H26BrNO3: C, 56.26; H, 6.82; N, 3.64. Found: C, 56.42; H, 6.84; N,

3.69%.

Decyl (4-bromobenzoylamino)ethanoate (2.5c)

Compound 2.5c was prepared using a similar procedure to that described for the preparation of 2.5a using the quantities stated: 2.4c (5.16 g, 16.6 mmol), Et3N

(anhydrous, 8.0 mL, 57 mmol, d = 0.726 g/mL), CHCl3 (anhydrous, 40 mL), 4-

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bromobenzoyl chloride (in 15 mL of CHCl3, 3.6671 g, 16.710 mmol). Once at room temperature, the reaction was stirred with saturated NaHCO3 (90 mL) before the organic layer was drained away. The aqueous layer was extracted with CH2Cl2 (3 x 30 mL) and the combined organic extracts were washed with brine (30 mL), dried over MgSO4 and filtered through a 1 inch silica plug which was subsequently washed with EtOAc (75 mL). The colorless filtrate was then concentrated under reduced pressure. A white solid was obtained which was dried in vacuo (P2O5). Yield 6.4606 g (98%). Mp = 77.1-78.5

1 °C. H NMR (CDCl3) δ 0.88 (t, J = 6.85 Hz, 3H), 1.20-1.40 (m, 14H), 1.67 (quint., J =

6.97 Hz, 2H), 4.19 (t, J = 6.79 Hz, 2H), 4.22 (d, J = 5.02 Hz, 2H), 6.71 (br. t, J = 3.78 Hz

13 1H), 7.57 (d, J = 8.62 Hz, 2H), 7.71 (d, J = 8.59 Hz, 2H); C NMR (CDCl3) δ 14.1, 22.7,

25.8, 28.5, 29.2, 29.3, 29.5 (2), 31.9, 41.9, 66.0, 126.6, 128.7, 131.9, 123.6, 166.4, 170.1;

Anal. Calcd for C19H28BrNO3: C, 57.29; H, 7.09; N, 3.52. Found: C, 57.15; H, 7.27; N,

3.48%.

Undecyl (4-bromobenzoylamino)ethanoate (2.5d)

Compound 2.5d was prepared using a similar procedure to that described for the preparation of 2.5a using the quantities stated: 2.4d (4.92 g, 15.1 mmol), Et3N

(anhydrous, 8.0 mL, 57 mmol, d = 0.726 g/mL), CHCl3 (anhydrous, 42 mL), 4- bromobenzoyl chloride (in 16 mL of CHCl3, 3.3792 g, 15.398 mmol). Once at room temperature, the reaction was stirred with saturated NaHCO3 (75 mL) before the organic layer was drained away. The aqueous layer was extracted with CH2Cl2 (3 x 30 mL) and the combined organic extracts were washed with brine (30 mL), dried over MgSO4 and

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filtered through a 1 inch silica plug which was subsequently washed with EtOAc (75 mL). The colorless filtrate was then concentrated under reduced pressure. A white solid was obtained which was dried in vacuo (P2O5). Yield 6.1654 g (99%). Mp = 81.3-82.0

1 °C. H NMR (CDCl3) δ 0.88 (t, J = 6.85 Hz, 3H), 1.20-1.40 (m, 16H), 1.67 (quint., J =

6.99 Hz, 2H), 4.19 (t, J = 6.79 Hz, 2H), 4.22 (d, J = 5.00 Hz, 2H), 6.70 (br. t, J = 3.88 Hz,

13 1H), 7.58 (d, J = 8.61 Hz, 2H), 7.68 (d, J = 8.61 Hz, 2H); C NMR (CDCl3) δ 14.1, 22.7,

25.8, 28.5, 29.2, 29.3, 29.5, 29.57, 29.60, 31.9, 41.9, 66.0, 126.6, 128.7, 131.9, 132.6,

166.4, 170.1; Anal. Calcd for C20H30BrNO3: C, 58.25; H, 7.33; N, 3.40. Found: C, 58.22;

H, 7.30; N, 3.37%.

Dodecyl (4-bromobenzoylamino)ethanoate (2.5e)

Compound 2.5e was prepared using a similar procedure to that described for the preparation of 2.5a using the quantities stated: 2.4e (10.64 g, 31.34 mmol), Et3N

(anhydrous, 14.8 mL, 106 mmol, d = 0.726 g/mL), CHCl3 (anhydrous, 70 mL), 4- bromobenzoyl chloride (in 35 mL of CHCl3, 6.8956 g, 31.421 mmol). Once at room temperature, the reaction was stirred with saturated NaHCO3 (100 mL) before the organic layer was drained away. The aqueous layer was extracted with CH2Cl2 (2 x 100 mL) and the combined organic extracts were washed with brine (60 mL), dried over MgSO4 and filtered through a 1 inch silica plug which was subsequently washed with EtOAc (135 mL). The colorless filtrate was then concentrated under reduced pressure. A white solid was obtained which was dried in vacuo (P2O5). Yield 12.77 g (96%). Mp = 83.5-84.6

1 °C. H NMR (CDCl3) δ 0.88 (t, J = 6.82 Hz, 3H), 1.20-1.40 (m, 18H), 1.67 (quint., J =

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6.97 Hz, 2H), 4.19 (t, J = 6.80 Hz, 2H), 4.22 (d, J = 4.99 Hz, 2H), 6.69 (br. t, J = 3.86 Hz,

13 1H), 7.58 (d, J = 8.54 Hz, 2H), 7.68 (d, J = 8.54 Hz, 2H); C NMR (CDCl3) δ 14.1, 22.7,

25.8, 28.5, 29.2, 29.4, 29.5, 29.6, 29.7 (2), 31.9, 41.9, 66.0, 126.6, 128.7, 131.9, 132.6,

166.4, 170.1; Anal. Calcd for C21H32BrNO3: C, 59.15; H, 7.56; N, 3.28. Found: C, 59.27;

H, 7.54; N, 3.28%.

Dodecyl (4-bromobenzoylthioamido)ethanoate (2.6)

Dodecyl (4-bromobenzoylamino)ethanoate (2.5e ; 0.9964 g, 2.337 mmol) was dissolved in THF (anhydrous, 30 mL) while under argon at room temperature. Lawesson’s reagent

(1.0466 g, 2.5876 mmol) was added to the solution in one portion and the resulting solution was allowed to stir at room temperature for 48 hours. The solution was concentrated under reduced pressure to give a thick, yellow semi-solid which was dissolved in CH2Cl2 (25 mL) and shaken with a solution of KOH (10% wt./vol., 20 mL).

The aqueous layer was extracted with CH2Cl2 (2 x 20 mL), the organic extracts were combined, washed with brine (35 mL), dried over CaCl2 and concentrated under reduced pressure to give a yellow solid that was found to be relatively pure by 1H NMR (along with a trace of by-products that appear to be related to Lawesson’s reagent). Yield

1 1.2903 g (quant.). H NMR (CDCl3) δ 0.88 (t, J = 6.84 Hz, 3H), 1.20-1.40 (m, 18H),

1.69 (quint., J = 7.01 Hz, 2H), 4.27 (t, J = 6.70 Hz, 2H), 4.56 (d, J = 4.43 Hz, 2H), 7.57

13 (d, J = 8.66 Hz, 2H), 7.73 (d, J = 8.66 Hz, 2H), 8.11 (app. br. s, 1H); C NMR (CDCl3) δ

14.1, 22.7, 25.8, 28.5, 29.2, 29.36, 29.50, 29.56, 29.6 (2), 31.9, 48.1, 66.4, 126.2, 128.3,

131.7, 139.6, 169.1, 197.6.

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2-(4-Bromophenyl)-5-octyloxy-1,3-thiazole (2.7a)

Octyl (4-bromobenzoylamino)ethanoate (2.5a; 8.74 g, 23.6 mmol) and Lawesson’s reagent (10.5071 g, 25.9774 mmol) were dissolved in toluene (anhydrous, dried over 4Å molecular sieves, 230 mL) while under argon and the resulting solution was heated to reflux for 40 hours (1H NMR showed complete consumption of the starting material, solution was a lighter shade of yellow) before being concentrated under reduced pressure.

When all of the toluene was removed, the light yellow solid was dissolved in CH2Cl2

(100 mL) and stirred with KOH (10% wt./vol., 200 mL). However an extremely slow resolving emulsion was observed so the white liquid was strongly rotovapped after which no emulsion was observed. The aqueous layer was then extracted with CH2Cl2 (2 x 100 mL) and the organic extracts were combined then washed with brine (100 mL), dried over CaCl2, filtered through celite, and concentrated under reduced pressure to give an off-white solid. The solid was then recrystallized from EtOH to give very light off-white

1 crystals (7.91 g, 91%) which were dried in vacuo (P2O5). Mp = 81.3-82.6 °C. H NMR

(CDCl3) δ 0.89 (t, J = 6.83 Hz, 3H), 1.20-1.40 (m, 8H), 1.45 (quint., J = 7.15 Hz, 2H),

1.80 (quint., J = 7.02 Hz, 2H), 4.08 (t, J = 6.52 Hz, 2H), 7.12 (s, 1H), 7.52 (d, J = 8.59

13 Hz, 2H), 7.66 (d, J = 8.59 Hz, 2H); C NMR (CDCl3) δ 14.1, 22.7, 25.8, 29.12, 29.19,

29.23, 31.8, 75.5, 123.0, 123.3, 127.0, 132.0, 133.2, 154.0, 162.4; Anal. Calcd for

C17H22BrNOS: C, 55.43; H, 6.02; N, 3.80. Found: C, 55.34; H, 6.01; N, 3.85%.

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2-(4-Bromophenyl)-5-nonyloxy-1,3-thiazole (2.7b)

Compound 2.7b was prepared using a similar procedure to that described for the preparation of 2.7a using the quantities stated: 2.5b (6.4598 g, 16.809 mmol),

Lawesson’s reagent (7.4990 g, 18.540 mmol), toluene (anhydrous, 120 mL). The solution was concentrated under reduced pressure to give a light yellow solid. The resulting solid was dissolved in Et2O/EtOAc (ratio of 25/75, 300mL)* before being stirred in aq. KOH (10% wt./vol., 100 mL) for about 5 minutes. Once the organic layer was drained away, the aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, and filtered through celite. The filtrate was concentrated under reduced pressure to give a yellow solid (~13 g). The resulting solid was dissolved in Et2O (100 mL) and stirred in aq. KOH (10% wt./vol., 100 mL) for about 20 minutes. Once the organic layer was drained away, the aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, and filtered through celite. The filtrate was concentrated under reduced pressure to give a yellow solid (~8 g) which was recrystallized from EtOH. An off-white solid was obtained which was dried

1 in vacuo (P2O5). Yield 5.7482 g (89%). Mp = 63.0-65.6 °C. H NMR (CDCl3) δ 0.89 (t,

J = 6.85 Hz, 3H), 1.20-1.40 (m, 10H), 1.45 (quint., J = 7.14 Hz, 2H), 1.80 (quint., J =

7.02 Hz, 2H), 4.08 (t, J = 6.52 Hz, 2H), 7.12 (s, 1H), 7.52 (d, J = 8.58 Hz, 2H), 7.66 (d, J

13 = 8.59 Hz, 2H); C NMR (CDCl3) δ 14.1, 22.7, 25.8, 29.1, 29.23, 29.25, 29.5, 31.9, 75.5,

123.0, 123.3, 127.0, 132.0, 133.2, 154.0, 162.4; Anal. Calcd for C18H24BrNOS: C, 56.54;

H, 6.33; N, 3.66. Found: C, 56.63; H, 6.32; N, 3.62%. *The extraction solvent was

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switched from CH2Cl2 since it gives a very slow resolving emulsion, but EtOAc was a bad choice of solvent as it extracted nearly all the Lawesson’s reagent byproducts instead of allowing them to remain in the aqueous layer. EtOAc was chosen due to its lower cost and since Et2O was not dissolving all the material, but it was found that the use of Et2O allowed for a quick extraction while the Lawesson’s related milky white suspension remained in the aqueous layer.

2-(4-Bromophenyl)-5-decyloxy-1,3-thiazole (2.7c)

Compound 2.7c was prepared using a similar procedure to that described for the preparation of 2.7b except that after the solvent was removed the material was dissolved in Et2O and the aqueous layer was extracted with Et2O using the quantities stated: 2.5c

(6.4606 g, 16.219 mmol), Lawesson’s reagent (7.2209 g, 17.853 mmol), toluene

(anhydrous, 120 mL). The solution was concentrated under reduced pressure to give a light yellow solid. The resulting solid was partially dissolved in Et2O (100 mL) and stirred in aq. KOH (10% wt./vol., 100 mL) for about 20 minutes. Once the organic layer was drained away, the aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, and filtered through celite. The filtrate was concentrated under reduced pressure to give a yellow solid (~8 g) which was recrystallized from EtOH. Very light, off-white crystals were obtained which were dried in vacuo (P2O5). Yield 5.8672 g (91%). Mp = 73.1-75.4

1 °C. H NMR (CDCl3) δ 0.88 (t, J = 6.82 Hz, 3H), 1.20-1.40 (m, 12H), 1.45 (quint., J =

7.15 Hz, 2H), 1.80 (quint., J = 7.02 Hz, 2H), 4.08 (t, J = 6.51 Hz, 2H), 7.12 (s, 1H), 7.52

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13 (d, J = 8.58 Hz, 2H), 7.66 (d, J = 8.59 Hz, 2H); C NMR (CDCl3) δ 14.1, 22.7, 25.8,

29.1, 29.25, 29.31, 29.5 (2), 31.9, 75.5, 123.0, 123.3, 126.9, 132.0, 133.2, 154.0, 162.4;

Anal. Calcd for C19H26BrNOS: C, 57.57; H, 6.61; N, 3.53. Found: C, 57.41; H, 6.64; N,

3.56%.

2-(4-Bromophenyl)-5-undecyloxy-1,3-thiazole (2.7d)

Compound 2.7d was prepared using a similar procedure to that described for the preparation of 2.7c using the quantities stated: 2.5d (6.1654 g, 14.951 mmol), Lawesson’s reagent (6.6626 g, 16.472 mmol), toluene (anhydrous, 100 mL). The solution was concentrated under reduced pressure to give a light yellow solid. The resulting solid was partially dissolved in Et2O (100 mL) and stirred in aq. KOH (10% wt./vol., 100 mL) for about 20 minutes. Once the organic layer was drained away, the aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic extracts were washed with brine

(50 mL), dried over MgSO4, and filtered through celite. The filtrate was concentrated under reduced pressure to give a yellow solid which was recrystallized from EtOH. A white solid was obtained which was dried in vacuo (P2O5). Yield 5.4464 g (89%). Mp =

1 68.6-69.7 °C. H NMR (CDCl3) δ 0.88 (t, J = 6.82 Hz, 3H), 1.20-1.40 (m, 14H), 1.45

(quint., J = 7.14 Hz, 2H), 1.80 (quint., J = 7.02 Hz, 2H), 4.08 (t, J = 6.52 Hz, 2H), 7.12

13 (s, 1H), 7.52 (d, J = 8.59 Hz, 2H), 7.66 (d, J = 8.59 Hz, 2H); C NMR (CDCl3) δ 14.1,

22.7, 25.8, 29.1, 29.26, 29.35, 29.52, 29.58, 29.61, 31.9, 75.5, 123.0, 123.3, 127.0, 132.0,

133.2, 154.0, 162.4; Anal. Calcd for C20H28BrNOS: C, 58.53; H, 6.88; N, 3.41. Found:

C, 58.10; H, 6.86; N, 3.40%.

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2-(4-Bromophenyl)-5-dodecyloxy-1,3-thiazole (2.7e)

Compound 2.7e was prepared using a similar procedure to that described for the preparation of 2.7a using the quantities stated: 2.5e (9.60 g, 22.5 mmol), Lawesson’s reagent (10.0450 g, 24.8349 mmol), toluene (anhydrous, 225 mL). The solution was concentrated under reduced pressure. The resulting light yellow solid was dissolved in

CH2Cl2 (100 mL) and stirred with KOH (10% wt./vol., 300 mL) before being extracted with CH2Cl2 (2 x 100mL), washed with brine (100 mL), dried over CaCl2, filtered through celite, and concentrated under reduced pressure to give an impure orange solid.

The solid was then recrystallized from EtOH. Very light, off-white crystals were

1 obtained which were dried in vacuo (P2O5). Yield 8.74 g (92%). Mp = 76.7-78.1 °C. H

NMR (CDCl3) δ 0.88 (t, J = 6.84 Hz, 3H), 1.20-1.40 (m, 16H), 1.44 (quint., J = 7.16 Hz,

2H), 1.80 (quint., J = 7.02 Hz, 2H), 4.08 (t, J = 6.52 Hz, 2H), 7.12 (s, 1H), 7.51 (d, J =

13 8.61 Hz, 2H), 7.66 (d, J = 8.59 Hz, 2H); C NMR (CDCl3) δ 14.1, 22.7, 25.8, 29.1, 29.3,

29.4, 29.52, 29.57, 29.65 (2), 31.9, 75.5, 122.9, 123.3, 126.9, 132.0, 133.2, 154.0, 162.4;

Anal. Calcd for C21H30BrNOS: C, 59.43; H, 7.12; N, 3.30. Found: C, 59.52; H, 7.15; N,

3.26%.

2-(4-Cyanophenyl)-5-octyloxy-1,3-thiazole (2.8a)

2-(4-Bromophenyl)-5-octyloxy-1,3-thiazole (2.7a; 4.0005 g, 10.861 mmol), CuCN

(1.9002 g, 21.217 mmol), and DMF (anhydrous, 60 mL) were stirred and heated under reflux under argon for 20 hours (1H NMR showed complete consumption of starting material) before HCl (3.25 M, 65 mL) was slowly added over about 30 minutes. The

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resulting solution was allowed to stir for another 30 minutes. The purple solution was then extracted with Et2O (4 x 50 mL), washed with brine (50 mL), dried over MgSO4 and filtered through a silica plug which was washed with EtOAc (80 mL). The resulting red organic extracts were concentrated under reduced pressure to give a brown solid which was then recrystallized from EtOH to give a tan solid which was dried under vacuum for

~24 hours to remove EtOH and DMF at which point the material was shown to be pure product by 1H NMR. The mother liquor was concentrated and recrystallized to give a second batch of product which was pure by 1H NMR. Combined yield: 3.2003 g, 94%.

Approximately 0.5 g of the crude material was subjected to column chromatography (30 g silica, eluent was 20% Et2O in petroleum ether) to further purify the material for liquid crystal analysis. Transition temperatures (°C): Cryst. 58.5 (SmA 48.8 N 54.5) Iso. Liq.

1 (Rec. 48.6). H NMR (CDCl3) δ 0.89 (t, J = 6.86 Hz, 3H), 1.20-1.40 (m, 8H), 1.46

(quint., J = 7.21 Hz, 2H), 1.82 (quint., J = 7.02 Hz, 2H), 4.12 (t, J = 6.51 Hz, 2H), 7.19

13 (s, 1H), 7.68 (d, J = 8.61 Hz, 2H), 7.89 (d, J = 8.51 Hz, 2H); C NMR (CDCl3) δ 14.1,

22.6, 25.7, 29.09, 29.17, 29.20, 31.8, 75.6, 112.2, 118.6, 123.6, 125.8, 132.7, 138.1,

152.3, 163.8. Anal. Calcd for C18H22N2OS: C, 68.75; H, 7.05; N, 8.91. Found: C, 68.48;

H, 7.04; N, 8.83%.

2-(4-Cyanophenyl)-5-nonyloxy-1,3-thiazole (2.8b)

Compound 2.8b was prepared using a similar procedure to that described for the preparation of 2.8a using the quantities stated: 2.7b (5.7482 g, 15.033 mmol), CuCN

(2.6509 g, 29.599 mmol), DMF (anhydrous, 85 mL). Once at room temperature, HCl

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(3.25 M, 90 mL) was slowly added over about 30 minutes and allowed to stir for an additional 30 minutes. The purple solution was then extracted with Et2O (4 x 60 mL) and the combined organic extracts were washed with brine (50 mL), dried over MgSO4 and filtered through a silica plug which was washed with EtOAc (80 mL). The resulting red organic extracts were concentrated under reduced pressure to give a dark brown solid which was then recrystallized from EtOH. A very light brown solid was obtained which was dried in vacuo (P2O5). Yield 4.4647 g (90%). Transition temperatures (°C): Cryst.

1 67.5 Iso. Liq. (Rec. 63.9). H NMR (CDCl3) δ 0.89 (t, J = 6.86 Hz, 3H), 1.20-1.40 (m,

10H), 1.46 (quint., J = 7.14 Hz, 2H), 1.82 (quint., J = 7.02 Hz, 2H), 4.11 (t, J = 6.51 Hz,

13 2H), 7.19 (s, 1H), 7.68 (d, J = 8.53 Hz, 2H), 7.89 (d, J = 8.53 Hz, 2H); C NMR (CDCl3)

δ 14.1, 22.7, 25.7, 29.1, 29.2 (2), 29.5, 31.9, 75.6, 112.2, 118.6, 123.6, 125.8, 132.7,

138.1, 152.3, 163.8. Anal. Calcd for C19H24N2OS: C, 69.47; H, 7.36; N, 8.53. Found: C,

69.63; H, 7.40; N, 8.47%.

2-(4-Cyanophenyl)-5-decyloxy-1,3-thiazole (2.8c)

Compound 2.8c was prepared using a similar procedure to that described for the preparation of 2.8a using the quantities stated: 2.7c (9.29 g, 23.4 mmol), CuCN (4.0822 g, 45.581 mmol), DMF (anhydrous, 150 mL). Once at room temperature, HCl (3.25 M,

155 mL) was slowly added over about 35 minutes. The resulting solution was allowed to stir for another 25 minutes. The purple solution was then extracted with Et2O (4 x 150 mL), washed with brine (120 mL), dried over MgSO4 and filtered through a silica plug.

The resulting red organic extracts were concentrated under reduced pressure until about

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300 mL of the Et2O remained. Then decolorizing charcoal (powder, 4 small scoops) was added to the solution which was then heated under reflux for about 35 minutes. Once cool, the yellow solution was filtered through celite and concentrated under reduced pressure to give an orange solid which was then recrystallized from EtOH. A very light yellow solid was obtained which was dried in vacuo (P2O5). Yield 7.2822 g (91%).

Transition temperatures (°C): Cryst. 66.6 (SmA 62.9) Iso Liq. (Rec. 61.0). 1H NMR

(CDCl3) δ 0.88 (t, J = 6.83 Hz, 3H), 1.20-1.40 (m, 12H), 1.46 (quint., J = 7.19 Hz, 2H),

1.82 (quint., J = 7.02 Hz, 2H), 4.11 (t, J = 6.52 Hz, 2H), 7.19 (s, 1H), 7.67 (d, J = 8.49

13 Hz, 2H), 7.89 (d, J = 8.51 Hz, 2H); C NMR (CDCl3) δ 14.1, 22.7, 25.7, 29.1, 29.2, 29.3,

29.5 (2), 31.9, 75.6, 112.2, 118.6, 123.6, 125.8, 132.7, 138.1, 152.3, 163.8. Anal. Calcd for C20H26N2OS: C, 70.14; H, 7.65; N, 8.18. Found: C, 70.04; H, 7.61; N, 8.06%.

2-(4-Cyanophenyl)-5-undecyloxy-1,3-thiazole (2.8d)

Compound 2.8d was prepared using a similar procedure to that described for the preparation of 2.8a using the quantities stated: 2.7d (5.4464 g, 13.271 mmol), CuCN

(2.3412 g, 26.141 mmol), DMF (anhydrous, 80 mL). Once at room temperature, HCl

(3.25 M, 80 mL) was slowly added over about 30 minutes and allowed to stir for an additional 30 minutes. The purple solution was then extracted with Et2O (4 x 60 mL) and the combined organic extracts were washed with brine (50 mL), dried over MgSO4 and filtered through a silica plug which was washed with EtOAc (80 mL). The resulting red organic extracts were concentrated under reduced pressure to give a dark brown solid which was then recrystallized from EtOH. A gray / light green solid was obtained which

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was dried in vacuo (P2O5). Yield 4.4051 g (93%). Transition temperatures (°C): Cryst.

1 73.8 Iso Liq. (Rec. 70.2). H NMR (CDCl3) δ 0.88 (t, J = 6.81 Hz, 3H), 1.20-1.40 (m,

14H), 1.46 (quint., J = 7.19 Hz, 2H), 1.82 (quint., J = 7.02 Hz, 2H), 4.11 (t, J = 6.50 Hz,

13 2H), 7.19 (s, 1H), 7.67 (d, J = 8.46 Hz, 2H), 7.89 (d, J = 8.43 Hz, 2H); C NMR (CDCl3)

δ 14.1, 22.7, 25.7, 29.1, 29.2, 29.3, 29.50, 29.56, 29.60, 31.9, 75.6, 112.2, 118.6, 123.6,

125.8, 132.7, 138.1, 152.3, 163.8. Anal. Calcd for C21H28N2OS: C, 70.75; H, 7.92; N,

7.86. Found: C, 70.85; H, 7.97; N, 7.87%.

2-(4-Cyanophenyl)-5-dodecyloxy-1,3-thiazole (2.8e)

Compound 2.8e was prepared using a similar procedure to that described for the preparation of 2.8a using the quantities stated: 2.7e (11.79 g, 27.78 mmol), CuCN

(4.7256 g, 52.765 mmol), DMF (anhydrous, 180 mL). Once at room temperature, HCl

(3.25 M, 180 mL) was slowly added over about 30 minutes. The resulting solution was allowed to stir for another 20 minutes. The purple solution was then extracted with Et2O

(4 x 150 mL), washed with brine (130 mL), dried over MgSO4 and filtered through a silica plug. The resulting red organic extracts were concentrated under reduced pressure until about 300 mL of the Et2O remained. Then decolorizing charcoal (powder, 2 small scoops) was added to the solution which was then heated under reflux for about 25 minutes. Once cool, the orange solution was filtered through celite and concentrated under reduced pressure to give a yellow solid which was then recrystallized from EtOH.

A very light orange solid was obtained which was dried in vacuo (P2O5). Yield 9.3367 g

(91%). Transition temperatures (°C): Cryst. 60.5 SmA 68.7 Iso Liq. (Rec. 49.5). 1H

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NMR (CDCl3) δ 0.88 (t, J = 6.84 Hz, 3H), 1.20-1.40 (m, 16H), 1.46 (quint., J = 7.17 Hz,

2H), 1.82 (quint., J = 7.02 Hz, 2H), 4.11 (t, J = 6.50 Hz, 2H), 7.19 (s, 1H), 7.67 (d, J =

13 8.56 Hz, 2H), 7.89 (d, J = 8.57 Hz, 2H); C NMR (CDCl3) δ 14.1, 22.7, 25.7, 29.1, 29.2,

29.4, 29.50, 29.56, 29.64 (2), 31.9, 75.7, 112.2, 118.6, 123.6, 125.8, 132.7, 138.1, 152.3,

163.8. Anal. Calcd for C22H30N2OS: C, 71.31; H, 8.16; N, 7.56. Found: C, 71.50; H,

8.25; N, 7.58%.

4-(5-Octyloxy-1,3-thiazol-2-yl)benzoic acid (2.9a)

2-(4-Cyanophenyl)-5-octyloxy-1,3-thiazole (2.8a; 5.36 g, 17.0 mmol), sodium hydroxide

(9.0432 g, 226.08 mmol), and a 1:1 mixture of EtOH and H2O (90 mL) were stirred and heated under reflux for about 19 hours before being cooled and the solvent removed in vacuo. The resulting white solid was partially dissolved in H2O (250 mL) and the resulting suspension was acidified to pH 2 with HCl (3.25 M, 150 mL) and allowed to stir at room temperature for about 1 hour. The white precipitate was then filtered off and washed with H2O (300 mL) before being dried in vacuo with heating (P2O5, 60 °C). Yield

= 5.5974 g (99%). Transition temperatures (°C): Cryst I 121.5 Cryst II 136.3 SmX 183.3

1 SmB 186.5 SmC 190.4 Iso Liq (Rec. 123.9). H NMR (DMSO-d6) 0.86 (t, J = 6.80 Hz,

3H), 1.17-1.36 (m, 8H), 1.40 (quint., J = 6.85 Hz, 2H), 1.75 (quint., J = 6.82 Hz, 2H),

4.17 (t, J = 6.38 Hz, 2H), 7.39 (s, 1H), 7.90 (d, J = 8.29 Hz, 2H), 8.00 (d, J = 8.27 Hz,

13 2H), 13.10 (br. s, 1H); C NMR (DMSO-d6) 13.9, 22.0, 25.1, 28.4, 28.5 (2), 31.1, 75.0,

123.5, 125.0, 130.1, 131.0, 137.1, 152.3, 162.6, 166.7. Anal. Calcd for C18H23NO3S: C,

64.84; H, 6.95; N, 4.20. Found: C, 64.59; H, 6.90; N, 4.18%.

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4-(5-Nonyloxy-1,3-thiazol-2-yl)benzoic acid (2.9b)

Compound 2.9b was prepared using a similar procedure to that described for the preparation of 2.9a using the quantities stated: 2.8b (5.24 g, 16.0 mmol), sodium hydroxide (9.28 g, 232 mmol), 1:1 mixture of EtOH and H2O (100 mL). The solution was concentrated under reduced pressure. The white solid obtained was partially dissolved in H2O (165 mL) and the resulting suspension was acidified to pH 2 with HCl

(3.25M, 105 mL) and allowed to stir at room temperature for 2 hours. The white precipitate was then filtered and washed with H2O (300 mL) and heated (90 °C) under vacuum. A white solid was obtained which was dried in vacuo (P2O5, 90 °C). Yield =

5.33 g (96%). Transition temperatures (°C): Cryst I 136.9 Cryst II 153.4 SmB 181.8

1 SmC 192.8 Iso Liq (Rec. 144.1). H NMR (DMSO-d6) 0.86 (t, J = 6.83 Hz, 3H), 1.18-

1.36 (m, 10H), 1.40 (quint., J = 6.75 Hz, 2H), 1.75 (quint., J = 6.93 Hz, 2H), 4.17 (t, J =

6.46 Hz, 2H), 7.39 (s, 1H), 7.90 (d, J = 8.49 Hz, 2H), 8.00 (d, J = 8.45 Hz, 2H), 13.10

13 (br. s, 1H); C NMR (DMSO-d6) 13.9, 22.0, 25.1, 28.4, 28.5 (2), 28.8, 31.2, 75.0,

123.5, 125.0, 130.1, 131.0, 137.1, 152.3, 162.6, 166.7.

4-(5-Decyloxy-1,3-thiazol-2-yl)benzoic acid (2.9c)

Compound 2.9c was prepared using a similar procedure to that described for the preparation of 2.9a using the quantities stated: 2.8c (6.80 g, 19.9 mmol), sodium hydroxide (10.5423 g, 263.558 mmol), 1:1 mixture of EtOH and H2O (110 mL). The solution was concentrated under reduced pressure. The solid was then partially dissolved in H2O (210 mL) and the resulting suspension was then acidified to pH 2 using HCl (3.25

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M, 125 mL) and stirred at room temperature for about 2 hours. The white solid was filtered off and washed with about 300 mL of H2O then heated (80 °C) under vacuum. A white solid was obtained which was dried in vacuo (P2O5, 80 °C). Yield =7.19 g (100%).

Transition temperatures (°C): Cryst I 119.1 Cryst II 135.2 SmB 176.5 SmC 195.7 Iso Liq

1 (Rec. 129.5). H NMR (DMSO-d6) 0.85 (t, J = 6.77 Hz, 3H), 1.16-1.35 (m, 12H), 1.40

(quint., J = 6.69 Hz, 2H), 1.75 (quint., J = 6.92 Hz, 2H), 4.17 (t, J = 6.45 Hz, 2H), 7.39

(s, 1H), 7.90 (d, J = 8.43 Hz, 2H), 8.00 (d, J = 8.43 Hz, 2H), 13.10 (br. s, 1H); 13C NMR

(DMSO-d6) 13.9, 22.0, 25.1, 28.4, 28.5, 28.6, 28.8 (2), 31.2, 75.0, 123.5, 125.0, 130.1,

131.0, 137.1, 152.2, 162.6, 166.7.

4-(5-Undecyloxy-1,3-thiazol-2-yl)benzoic acid (2.9d)

Compound 2.9d was prepared using a similar procedure to that described for the preparation of 2.9a using the quantities stated: 2.8d (4.07 g, 11.4 mmol), sodium hydroxide (6.0680 g, 151.70 mmol), 1:1 mixture of EtOH and H2O (65 mL). The solution was concentrated under reduced pressure. The white solid was partially dissolved in H2O (125 mL) and the resulting suspension was acidified to pH 2 with HCl

(3.25 M, 75 mL) and allowed to stir at room temperature for 2 hours. The white precipitate was then filtered and washed with H2O (300 mL) and the resulting white solid was heated (90°C) under vacuum. A white solid was obtained which was dried in vacuo

(P2O5, 90 °C). Yield = 4.0029 g (93%). Transition temperatures (°C): Cryst I 113.3

1 Cryst II 133.0 SmB 174.1 SmC 195.1 Iso Liq (Rec. 126.6). H NMR (DMSO-d6) 0.85

(t, J = 6.82 Hz, 3H), 1.16-1.35 (m, 14H), 1.40 (quint., J = 6.73 Hz, 2H), 1.75 (quint., J =

185

6.92 Hz, 2H), 4.17 (t, J = 6.44 Hz, 2H), 7.38 (s, 1H), 7.90 (d, J = 8.44 Hz, 2H), 8.00 (d, J

13 = 8.50 Hz, 2H), 13.09 (br. s, 1H); C NMR (DMSO-d6) 13.8, 22.0, 25.1, 28.3, 28.5,

28.6, 28.81, 28.85, 28.87, 31.2, 75.1, 123.5, 125.0, 130.1, 131.0, 137.1, 152.3, 162.6,

166.7.

4-(5-Dodecyloxy-1,3-thiazol-2-yl)benzoic acid (2.9e)

Compound 2.9e was prepared using a similar procedure to that described for the preparation of 2.9a using the quantities stated: 2.8e (9.28 g, 25.0 mmol), sodium hydroxide (12.7268 g, 318.170 mmol), 1:1 mixture of EtOH and H2O (135 mL). The solution was concentrated under reduced pressure. The solid was then partially dissolved in H2O (250 mL) and the resulting suspension was then acidified to pH 2 using HCl (3.25

M, 150 mL) and stirred at room temperature for about 1 hour. The white solid was filtered off, washed with H2O (300 mL), and heated (60 °C) under vacuum. A white solid was obtained which was dried in vacuo (P2O5, 60 °C). Yield = 9.6158 g (99%).

Transition temperatures (°C): Cryst I 122.3 Cryst II 133.6 SmB 171.4 SmC 194.2 Iso Liq

1 (Rec. 129.0). H NMR (DMSO-d6) 0.85 (t, J = 6.83 Hz, 3H), 1.16-1.36 (m, 16H), 1.40

(quint., J = 6.61 Hz, 2H), 1.75 (quint., J = 6.93 Hz, 2H), 4.17 (t, J = 6.45 Hz, 2H), 7.38

(s, 1H), 7.90 (d, J = 8.47 Hz, 2H), 8.00 (d, J = 8.49 Hz, 2H), 13.07 (br. s, 1H); 13C NMR

(DMSO-d6) 13.8, 22.0, 25.1, 28.3, 28.5, 28.6, 28.79, 28.83, 28.9 (2), 31.2, 75.0, 123.5,

125.0, 130.0, 131.1, 137.1, 152.3, 162.6, 166.7.

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(S)-4-(1-methylheptyloxy)phenol (2.11)

Compound 2.11 was prepared using a previously reported procedure.56

1 A light yellow oil was obtained (8.40 g, 97%). H NMR (CDCl3 0.88 (t, J = 6.77 Hz,

3H), 1.25 (d, J = 6.08 Hz, 3H), 1.27-1.60 (m, 9H), 1.65-1.77 (m, 1H), 4.20 (sext., J =

6.07 Hz, 1H), 4.77 (s, 1H), 6.74 (d, J = 9.15 Hz, 2H), 6.78 (d, J = 9.18 Hz, 2H).

(S)-4-(1-Methylheptyloxy)phenyl 4-(5-(octyloxy)-1,3-thiazol-2-yl)benzoate (2.12a)

A mixture of 4-(5-octyl-1,3-thiazol-2-yl)benzoic acid (2.9a; 1.13 g, 3.39 mmol), 4-(N,N- dimethylamino)pyridine (DMAP) (0.1173 g, 0.9601 mmol), compound 2.11 (0.71 g, 3.2 mmol), and CH2Cl2 (anhydrous, 200 mL) was stirred at room temperature for 5 minutes under argon before N,N’-dicyclohexycarbodiimide (DCC) (1.3804 g, 6.6903 mmol) was added in one portion and the mixture was allowed to stir under the same conditions for 60 hours. The reaction mixture was concentrated to ~50 mL under reduced pressure and filtered before being washed with aqueous acetic acid (10% vol./vol., 100 mL) and H2O

(90 mL) added. The resulting mixture was then extracted with CH2Cl2 (3 x 60 mL), washed with brine (70 mL), dried over MgSO4, and partially concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, 5%

EtOAc in petroleum ether] and was recrystallized from EtOH to give a white solid which was dried in vacuo (P2O5). Yield = 1.18 g (69%). The product was recrystallized twice more from EtOH and dried in vacuo (P2O5) to give a sample for liquid crystal analysis.

Yield = 1.18 g (69%). Transition temperatures (°C): Cryst. 79.4 SmA 95.4 Iso Liq. (Rec.

1 49.0). H NMR (CDCl3) 0.89 (t, J = 6.76 Hz, 3H), 0.90 (t, J = 6.78 Hz, 3H), 1.22-1.41

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(m, 15H), 1.31 (d, J = 6.03 Hz, 3H), 1.41-1.52 (m, 3H), 1.52-1.63 (m, 1H), 1.69-1.78 (m,

1H), 1.83 (quint., J = 7.02 Hz, 2H), 4.12 (t, J = 6.51 Hz, 2H), 4.33 (sext., J = 6.07 Hz,

1H), 6.92 (d, J = 9.04 Hz, 2H), 7.11 (d, J = 9.01 Hz, 2H), 7.20 (s, 1H), 7.93 (d, J = 8.56

13 Hz, 2H), 8.21 (d, J = 8.54 Hz, 2H); C NMR (CDCl3) 14.1 (2), 19.8, 22.6, 22.7, 25.6,

25.8, 29.12, 29.18, 29.22, 29.30, 31.78, 31.83, 36.5, 74.5, 75.6, 116.6, 122.4, 123.5,

125.4, 129.8, 130.8, 138.6, 144.1, 153.5, 156.1, 163.4, 165.1. Anal. Calcd for

C32H43NO4S: C, 71.47; H, 8.06; N, 2.60. Found: C, 71.62; H, 8.17; N, 2.65%.

(S)-4-(1-Methylheptyloxy)phenyl 4-(5-(nonyloxy)-1,3-thiazol-2-yl)benzoate (2.12b)

Compound 2.12b was prepared using a similar procedure to that described for the preparation of 2.12a using the quantities stated: Compound 2.9b (1.17 g, 3.37 mmol),

DMAP (0.1220 g, 0.9986 mmol), compound 2.11 (0.70 g, 3.1 mmol), DCC (1.3735 g,

6.6568 mmol) and CH2Cl2 (anhydrous, 210 mL). The reaction mixture was stirred for 65 hours. The crude product was purified by column chromatography [silica gel, 5% EtOAc in petroleum ether] to give a white solid (1.15 g, 66%) which was pure by 1H NMR.

Several impure fractions were combined and recrystallized from EtOH to give a white solid (0.0695 g, 4%) which was pure by 1H NMR. The combined product was recrystallized twice more from EtOH and dried in vacuo (P2O5). Yield = 1.22 g (70%).

Transition temperatures (°C): Cryst. 65.8 SmA 94.6 Iso Liq. (Rec. 42.3). 1H NMR

(CDCl3) 0.89 (app. t, J = 6.76 Hz, 6H), 1.22-1.41 (m, 17H), 1.31 (d, J = 6.00 Hz, 3H),

1.41-1.50 (m, 3H), 1.52-1.62 (m, 1H), 1.70-1.79 (m, 1H), 1.83 (quint., J = 7.01 Hz, 2H),

4.12 (t, J = 6.51 Hz, 2H), 4.33 (sext., J = 6.06 Hz, 1H), 6.92 (d, J = 9.03 Hz, 2H), 7.12 (d,

188

J = 9.01 Hz, 2H), 7.20 (s, 1H), 7.93 (d, J = 8.53 Hz, 2H), 8.21 (d, J = 8.56 Hz, 2H); 13C

NMR (CDCl3) 14.10, 14.12, 19.8, 22.6, 22.7, 25.6, 25.8, 29.1, 29.24, 29.26, 29.31,

29.5, 31.8, 31.9, 36.5, 74.6, 75.6, 116.6, 122.4, 123.5, 125.4 ,129.8, 130.8, 138.7, 144.1,

153.5, 156.1, 163.4, 165.1. Anal. Calcd for C33H45NO4S: C, 71.83; H, 8.22; N, 2.54.

Found: C, 72.10; H, 8.23; N, 2.57%.

(S)-4-(1-Methylheptyloxy)phenyl 4-(5-(decyloxy)-1,3-thiazol-2-yl)benzoate (2.12c)

Compound 2.12c was prepared using a similar procedure to that described for the preparation of 2.12a using the quantities stated: Compound 2.9c (1.22 g, 3.37 mmol),

DMAP (0.1181 g, 0.9601 mmol), compound 2.11 (0.70 g, 3.1 mmol), DCC (1.3472 g,

6.5293 mmol) and CH2Cl2 (anhydrous, 200 mL). The reaction mixture was stirred for 62 hours. The crude product was purified by column chromatography [silica gel, 5% EtOAc in petroleum ether] to give a white solid (1.06 g) which was pure by 1H NMR. Several impure fractions were combined and recrystallized from EtOH to give a white solid

(0.1579 g) which was pure by 1H NMR. The combined pure product was recrystallized twice more from EtOH to give a white solid which was dried in vacuo (P2O5). Yield =

1.22 g (71%). Transition temperatures (°C): Cryst. 74.7 (SmC* 74.6) SmA 96.4 Iso Liq.

1 (Rec. 48.2). H NMR (CDCl3) 0.89 (app. t, J = 6.47 Hz, 6H), 1.21-1.41 (m, 19H), 1.30

(d, J = 6.00 Hz, 3H), 1.42-1.52 (m, 3H), 1.52-1.62 (m, 1H), 1.69-1.79 (m, 1H), 1.83

(quint., J = 7.00 Hz, 2H), 4.12 (t, J = 6.50 Hz, 2H), 4.33 (sext., J = 6.04 Hz, 1H), 6.92 (d,

J = 9.00 Hz, 2H), 7.12 (d, J = 8.98 Hz, 2H), 7.20 (s, 1H), 7.93 (d, J = 8.46 Hz, 2H), 8.21

13 (d, J = 8.45 Hz, 2H); C NMR (CDCl3) 14.10, 14.12, 19.8, 22.6, 22.7, 25.6, 25.8, 29.1,

189

29.26, 29.31 (2), 29.5 (2), 31.8, 31.9, 36.5, 74.6, 75.6, 116.6, 122.4, 123.5, 125.4, 129.8,

130.8, 138.7, 144.1, 153.5, 156.1, 163.4, 165.1. Anal. Calcd for C34H47NO4S: C, 72.17;

H, 8.37; N, 2.48. Found: C, 72.09; H, 8.48; N, 2.50%.

(S)-4-(1-Methylheptyloxy)phenyl 4-(5-(undecyloxy)-1,3-thiazol-2-yl)benzoate (2.12d)

Compound 2.12d was prepared using a similar procedure to that described for the preparation of 2.12a using the quantities stated: Compound 2.9d (1.24 g, 3.30 mmol),

DMAP (0.1227 g, 1.004 mmol), compound 2.11 (0.69 g, 3.1 mmol), DCC (1.3664 g,

6.6224 mmol) and CH2Cl2 (anhydrous, 210 mL). The reaction mixture was stirred for

162 hours (for convenience). The crude product was purified by column chromatography

[silica gel, 5% EtOAc in petroleum ether] to give a white solid (1.01 g, 56%) which was pure by 1HNMR Several impure fractions were combined and recrystallized from EtOH to give a white solid (0.15 g) which contained product and a small amount of an unidentified para-substituted aromatic impurity. The impure fraction was purified by column chromatography [silica gel, 15% diethyl ether in petroleum ether] to give a white solid (0.13 g) which was pure by 1HNMR. The pure combined product was recrystallized twice from EtOH to give a white solid which was dried in vacuo (P2O5). Yield = 1.14 g

(64%). Transition temperatures (°C): Cryst. 74.2 SmC* 85.2 SmA 95.9 Iso Liq. (Rec.

1 49.5). H NMR (CDCl3) 0.88 (t, J = 6.80 Hz, 3H), 0.89 (t, J = 6.79 Hz, 3H), 1.21-1.40

(m, 21H), 1.31 (d, J = 6.01 Hz, 3H), 1.40-1.51 (m, 3H), 1.51-1.62 (m, 1H), 1.70-1.79 (m,

1H), 1.83 (quint., J = 7.02 Hz, 2H), 4.12 (t, J = 6.52 Hz, 2H), 4.33 (sext., J = 6.06 Hz,

1H), 6.92 (d, J = 9.03 Hz, 2H), 7.11 (d, J = 9.00 Hz, 2H), 7.20 (s, 1H), 7.93 (d, J = 8.55

190

13 Hz, 2H), 8.21 (d, J = 8.53 Hz, 2H); C NMR (CDCl3) 14.10, 14.13, 19.8, 22.6, 22.7,

25.6, 25.8, 29.1, 29.26, 29.30, 29.34, 29.51, 29.58, 29.61, 31.8, 31.9, 36.5, 74.5, 75.6,

116.6, 122.4, 123.5, 125.4, 129.8, 130.7, 138.7, 144.1, 153.5, 156.1, 163.4, 165.0. Anal.

Calcd for C35H49NO4S: C, 72.50; H, 8.52; N, 2.42. Found: C, 72.61; H, 8.62; N, 2.43%.

(S)-4-(1-Methylheptyloxy)phenyl 4-(5-(dodecyloxy)-1,3-thiazol-2-yl)benzoate (2.12e)

Compound 2.12e was prepared using a similar procedure to that described for the preparation of 2.12a using the quantities stated: Compound 2.9e (0.1004 g, 0.2577 mmol), DMAP (0.0088 g, 0.072 mmol), compound 2.11 (0.0540 g, 0.243 mmol), DCC

(0.0655 g, 0.317 mmol) and CH2Cl2 (anhydrous, 17 mL). The reaction mixture was stirred for 59 hours. The crude product was purified by column chromatography [silica gel, 5% EtOAc in petroleum ether]. A white solid was obtained (0.0946 g, 66%). The product was recrystallized twice from EtOH to afford a white solid which was dried in vacuo (P2O5). Transition temperatures (°C): Cryst. 82.3 SmC* 88.8 SmA 96.2 Iso Liq.

1 (Rec. 46.6). H NMR (CDCl3) 0.88 (t, J = 6.84 Hz, 3H), 0.89 (t, J = 6.76 Hz, 3H),

1.20-1.41 (m, 23H), 1.31 (d, J = 6.04 Hz, 3H), 1.41-1.51 (m, 3H), 1.51-1.63 (m, 1H),

1.69-1.79 (m, 1H), 1.83 (quint., J = 7.00 Hz, 2H), 4.12 (t, J = 6.52 Hz, 2H), 4.33 (sext., J

= 6.06 Hz, 1H), 6.92 (d, J = 9.04 Hz, 2H), 7.12 (d, J = 9.00 Hz, 2H), 7.20 (s, 1H), 7.93

13 (d, J = 8.48 Hz, 2H), 8.21 (d, J = 8.48 Hz, 2H); C NMR (CDCl3) 14.09, 14.12, 19.8,

22.6, 22.7, 25.6, 25.8, 29.1, 29.25, 29.29, 29.35, 29.51, 29.56, 29.64 (2), 31.8, 31.9, 36.5,

74.6, 75.6, 116.6, 122.4, 123.5, 125.4, 129.8, 130.7, 138.7, 144.1, 153.5, 156.1, 163.4,

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165.1. Anal. Calcd for C36H51NO4S: C, 72.81; H, 8.66; N, 2.36. Found: C, 72.55; H,

8.75; N, 2.35%.

10.2. Experimental for Chapter 3

2-Bromo-1,3-thiazole (3.2)

2-Amino-1,3-thiazole (3.5; 25.01 g, 0.2498 mol) was partially dissolved in H3PO4 (85%,

94 mL). This solution was stirred and cooled to 5 °C before concentrated HNO3 (50 mL) was slowly added over 10 minutes (the internal temperature did not exceed 8 °C). The resulting solution was cooled to 2 °C and a solution of NaNO2 (20.00 g, 0.2899 mol) in

H2O (50 mL) was slowly added over a period of 30 minutes (a brown gas was evolved

(NO2); the internal temperature did not exceed 8 °C). The resulting solution was stirred at 0-5 °C for 1 hour. A stirred solution of CuSO4•5H2O (41.02 g, 0.1643 mol) and NaBr

(73.39 g, 0.7133 mol) in H2O (180 mL) was cooled to 6 °C before the red “diazonium solution” was slowly added over 90 minutes (the internal temperature was kept below 8

°C). The resulting green, bubbling solution was allowed to stir at 0-7 °C for at least 6 hours before being allowed to warm to room temperature overnight. The solution pH was initially adjusted to about pH 7 via the addition of solid KOH to avoid the vigorous effervescence that occurs with the addition of Na2CO3. Final adjustment to pH 9 was completed via the cautious addition of solid Na2CO3. The resulting solution was then

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subjected to steam distillation until the distillate was no longer cloudy (~500 mL collected). The first 200 mL fraction contained a light yellow organic layer which was

1 separated, dried over MgSO4, filtered and found to be pure title compound 3.2 by H

NMR (29.46 g). The filter and MgSO4 were washed with Et2O. The remaining distillate was extracted with Et2O (3 x 50 mL). The combined organic extracts were washed with brine (25 mL), dried over MgSO4 and concentrated to a light yellow oil (5.87 g) which was also found to be pure title compound 3.2 by 1H NMR (matched literature data215).

1 Isolated yield: 35.34 g (86%). H NMR (CDCl3) 7.31 (d, J = 3.56 Hz, 1H), 7.61 (d, J =

13 3.56 Hz, 1H); C NMR (CDCl3) 123.0, 136.1, 143.1.

2-Iodo-1,3-thiazole (3.6)

Compound 3.6 was prepared using a similar procedure to that described for the preparation of 3.2 using the quantities stated: 3.5 (5.00 g, 49.9 mmol), H3PO4 (85%, 19 mL), HNO3 (concentrated, 10 mL) NaNO2 (4.00 g, 58.0 mol) in H2O (10 mL),

CuSO4•5H2O (8.34 g, 33.4 mol) and NaI (anhydrous; 21.39 g, 142.7 mmol) in H2O (40 mL). The title compound was obtained as a yellow solid (6.9129 g, 66%) which was found to be pure title compound 3.6 by 1H NMR (matched literature data215). Mp = 33.3

1 13 - 35.4 °C. H NMR (CDCl3) 7.34 (d, J = 3.48 Hz, 1H), 7.61 (d, J = 3.48 Hz, 1H); C

NMR (CDCl3) 100.7, 125.4, 144.9.

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2,5-Dibromo-1,3-thiazole (3.3)

A mixture of 2-bromo-1,3-thiazole (3.2; 14.29 g, 87.12 mmol), CHCl3 (stabilized with

1% EtOH, 100 mL), and solid NaHCO3 (25.98 g, 309.2 mmol) was stirred at room temperature for a few minutes before Br2 (19 mL, 371 mmol, d = 3.119 g/mL) diluted with CHCl3 (100 mL) was added slowly over 30 minutes via an addition funnel at room temperature. The resulting mixture was allowed to stir for 96 hours (after 48 hours of stirring the reaction was observed to be 98% complete by 1H NMR and after 72 hours the reaction was 98.5% complete: an additional quantity of Br2 (2.5 mL, 0.049 mol) was added at this time) at which point no starting material was present. The mixture was then cooled on ice and allowed to stir with saturated Na2S2O3 (200 mL) for 30 minutes before being filtered to remove elemental sulfur. The yellow solid was washed with CH2Cl2

(100 mL) and the organic filtrate was separated. The aqueous layer was then extracted with CH2Cl2 (4 x 100 mL) and the combined organic extracts were washed with brine

(100 mL), dried (MgSO4). The solvent was removed in vacuo and the resulting oil (22.67 g) was then heated at 55°C under vacuum (1.0 mmHg) which caused a white solid to sublime onto a dry ice/acetone cold finger (the solid was eventually heated up to 90 °C to ensure all of the product was collected). Mp = 43.7-47.8 °C (lit. Mp = 48°C).111 Yield =

1 13 15.79 g (75%). H NMR (CDCl3) s C NMR (CDCl3) 110.7, 135.8,

144.0 (matched that found in the literature57).

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2,5-Dichloro-1,3-thiazole (3.8)

A mixture of 2-chloro-1,3-thiazole (3.9; 0.2516 g, 2.104 mmol) and NCS (0.3118 g,

2.335 mmol) was dissolved in MeCN (anhydrous, distilled over CaH2, 5.5 mL) while under argon. The solution was heated at 60 °C (external temperature) for 44 hours (at 20 hours the reaction was 49% complete with no aromatic other side products, no change at

44 hours) before another addition of NCS (0.3592 g, 2.690 mmol) was made. After stirring for 92 hours another addition of NCS (0.0325 g, 0.243 mmol) was made (reaction was 79% complete after 68 hours and 92% complete after 92 hours). After a total of 116 hours of stirring at 60 °C, no starting material was present so once at room temperature the solution was shaken with H2O (10 mL). The organic layer was drained away and the aqueous layer was extracted with CH2Cl2 (3x10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure to give a yellow solid which by 1H NMR was desired product mixed with NCS and succinimide. The material was chromatographed (35 g silica, eluant was 3% Et2O in petroleum ether) which failed to purify the material despite being a single spot by TLC.

The material was vacuum sublimed at 1.0 mmHg up to a temperature of 90 °C

(temperature at which it sublimed/boiled is unknown) to give a clear liquid (0.1040 g)

1 which was more pure than before, but still not pure enough. H NMR (CDCl3) 7.40 (s,

1H).

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2-Chloro-1,3-thiazole (3.9)

2-Amino-1,3-thiazole (3.5; 5.00 g, 49.9 mmol) was dissolved in H3PO4 (85%, 19.0 mL), stirred and cooled to -2 °C before concentrated HNO3 (10.1 mL) was slowly added over a few minutes followed by a solution of NaNO2 (in 10 mL of H2O, 4.0085 g, 58.094 mmol) which was added over 30 minutes (internal temperature did not exceed 6 °C). After stirring at a temperature range of 0-5 °C for 30 minutes, it was slowly transferred to a cold (2 °C) solution of CuSO4•5H2O (8.33 g, 33.4 mol) and NaCl (8.35 g, 143 mol) in

H2O (36 mL) over 25 minutes (brown gas evolved, internal temperature did not exceed 4

°C). The resulting green (later dark brown), bubbling solution was allowed to stir at a temperature less than 4 °C for 1 hour before being brought to pH 4 with NaOH and

NaHCO3 (some material was lost due to excessive foaming caused by NaHCO3). The black aqueous solution was steam distilled until the distillate was no longer cloudy (~150 mL collected, 1H NMR of the aqueous layer showed a trace amount of product). The distillate was extracted with Et2O (3 x 40 mL) and the combined organic extracts were washed with brine (40 mL), dried over MgSO4 and concentrated under reduced pressure.

The resulting light yellow oil (1.4657 g, 25%) was found to be desired product which was slightly impure (traces of 1,3-thiazole, EtOH, and at least two other 1,3-thiazole based

1 compounds). H NMR (CDCl3) 7.25 (d, J = 3.64 Hz, 1H), 7.58 (d, J = 3.60, 1H).

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2,4-Dibromo-1,3-thiazole (3.11)

1,3-Thiazolidine-2,4-dione (3.10; 2.5018 g, 21.359 mmol), P2O5 (14.35 g, 0.1011 mol), and Bu4NBr (15.9612 g, 49.5121 mmol) were dissolved in toluene (48 mL) and heated under reflux, under argon for 20 hours. The solvent was removed under reduced pressure and the resulting residue was dissolved in Et2O/H2O (25 mL/75 mL) before being adjusted to pH 9 with solid Na2CO3. Once the organic layer was drained away, the aqueous layer was extracted with Et2O (3 x 35 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, and concentrated to give a light brown solid. The impure material was then sublimed under vacuum to give a white solid

(4.9333 g, 95%) which was pure product by 1H NMR and matched that of the literature.57

103 1 13 Mp = 81.1-82.4 °C (lit. Mp = 82°C). H NMR (CDCl3) 7.21 (s, 1H); C NMR

(CDCl3) 120.8, 124.3, 136.3.

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10.3. Experimental for Chapter 4

198

5-Bromo-2-octyloxy-1,3-thiazole (4.3a)

Octan-1-ol (1.6191 g, 12.433 mmol) and Na metal (0.1430 g, 6.220 mmol) were heated under argon until all the metal had dissolved before KI (0.0080 g, 0.048 mmol), CuO

(0.1649 g, 2.073 mmol), and 2,5-dibromo-1,3-thiazole (3.3; 1.0011 g, 4.1211 mmol) were added along with Et2O (anhydrous, 20 mL) to ensure complete transfer. The resulting solution was stirred and heated under reflux for 72 hours before the cooled solution was diluted with CH2Cl2 and filtered through celite. The solvent was removed in vacuo to give an orange oil which was distilled (~1.0 mmHg, 35 °C) to remove about 0.8-0.9 mL of unreacted octan-1-ol. The resulting oil was purified by column chromatography (silica gel / 1% Et2O in petroleum ether) to give a clear, slightly yellow oil (1.10 g, 91%) which was found to be product with a small amount of dioctyl carbonate (estimated to be 0.0279 g or 2.5% by 1H NMR). The impure material was then vigorously stirred (did not completely dissolve) overnight with MeOH/NaOH (2.5% vol./wt., 10 mL) before being concentrated in vacuo. The resulting oil was then extracted with Et2O (2 x 15 mL), washed with brine (15 mL) and the combined organic washings were dried (MgSO4).

The drying agent was filtered off and the solvent was removed in vacuo to give an oil

(0.9379 g) which by 1H NMR was shown to contain product and octan-1-ol, but none of the dioctyl carbonate. The oil was then purified by column chromatography (silica gel /

1 1% Et2O in petroleum ether) to give a clear, colorless oil. Yield = 0.91 g (76%). H

NMR (CDCl3) 0.88 (t, J = 6.88 Hz, 3H), 1.20-1.37 (m, 8H), 1.41 (quint., J = 7.03 Hz,

2H), 1.77 (quint., J = 7.06 Hz, 2H), 4.35 (t, J = 6.64 Hz, 2H), 7.03 (s, 1H); 13C NMR

(CDCl3) 14.1, 22.6, 25.8, 28.7, 29.2 (2), 31.8, 71.7, 98.6, 137.7, 174.5.

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5-Bromo-2-nonyloxy-1,3-thiazole (4.3b)

Compound 4.3b was prepared using a similar procedure to that described for the preparation of 4.3a using the quantities stated: nonan-1-ol (2.0578 g, 14.266 mmol), Na metal (0.1638 g, 7.125 mmol), KI (0.0088 g, 0.053 mmol), CuO (0.1882 g, 2.366 mmol),

3.3 (1.1500 g, 4.7341 mmol), and Et2O (anhydrous, 25 mL). The starting materials were removed by distillation (1.0 mmHg, 42 °C). A clear, light yellow oil was obtained which contained a small amount of dinonyl carbonate (estimated to be 0.0377 g or 3.0% by 1H

NMR). The product was used in the next step without further purification. Yield = 1.25

1 g (86%). H NMR (CDCl3) 0.88 (t, J = 6.84 Hz, 3H), 1.19-1.37 (m, 10H), 1.41 (quint.,

J = 7.09 Hz, 2H), 1.77 (quint., J = 7.05 Hz, 2H), 4.35 (t, J = 6.64 Hz, 2H), 7.03 (s, 1H);

13 C NMR (CDCl3) 14.1, 22.7, 25.7, 28.7, 29.2 (2), 29.5, 31.9, 71.7, 98.6 ,137.7, 174.5.

5-Bromo-2-decyloxy-1,3-thiazole (4.3c)

Compound 4.3c was prepared using a similar procedure to that described for the preparation of 4.3a using the quantities stated: decan-1-ol (2.1702 g, 13.711 mmol), Na metal (0.1575 g, 6.851 mmol), KI (0.0083 g, 0.050 mmol), CuO (0.1828 g, 2.298 mmol),

3.3 (1.1038 g, 4.5439 mmol), and Et2O (anhydrous, 25 mL). The starting materials were removed by distillation (1.0 mmHg, 55 °C). A clear, light yellow oil was obtained which contained a small amount of didecyl carbonate (estimated to be 0.0349 g or 2.9% by 1H

NMR). The product was used in the next step without further purification. Yield = 1.19

1 g (82%). H NMR (CDCl3) 0.88 (t, J = 6.86 Hz, 3H), 1.20-1.37 (m, 12H), 1.41 (quint.,

J = 7.03 Hz, 2H), 1.77 (quint., J = 7.06 Hz, 2H), 4.35 (t, J = 6.66 Hz, 2H), 7.03 (s, 1H);

200

13 C NMR (CDCl3) 14.1, 22.7, 25.8, 28.8, 29.2, 29.3, 29.5 (2), 31.9, 71.8, 98.6, 137.7,

174.5.

5-Bromo-2-undecyloxy-1,3-thiazole (4.3d)

Compound 4.3d was prepared using a similar procedure to that described for the preparation of 4.3a (except that THF was used instead of Et2O) using the quantities stated: undecan-1-ol (2.6758 g, 15.529 mmol), Na metal (0.1784 g, 7.760 mmol), KI

(0.0864 g, 0.520 mmol), CuO (0.2051 g, 2.578 mmol), 3.3 (1.2513 g, 5.1511 mmol) THF

(anhydrous, 30 mL). The starting materials were removed by distillation (1.0 mmHg, 65

°C). A yellow liquid was obtained which contained a small amount of diundecyl carbonate (estimated to be 0.0255 g or 1.5% by 1H NMR). Yield = 1.5085 g (88%). 1H

NMR (CDCl3) 0.88 (t, J = 6.86 Hz, 3H), 1.19-1.37 (m, 14H), 1.41 (quint., J = 7.04 Hz,

2H), 1.77 (quint., J = 7.06 Hz, 2H), 4.35 (t, J = 6.66 Hz, 2H), 7.03 (s, 1H); 13C NMR

(CDCl3) 14.1, 22.7, 25.8, 28.8, 29.2, 29.3, 29.50, 29.57, 29.60, 31.9, 71.8, 98.6, 137.7,

174.5. Anal. Calcd for C14H24BrNOS: C, 50.30; H, 7.24; N, 4.19. Found: C, 50.24; H,

7.49; N, 3.97%.

5-Bromo-2-dodecyloxy-1,3-thiazole (4.3e)

Compound 4.3e was prepared using a similar procedure to that described for the preparation of 4.3a (except that THF was used instead of Et2O) using the quantities stated: dodecan-1-ol (0.5757 g, 3.090 mmol), Na metal (0.0368 g, 1.60 mmol), KI

(0.0017 g, 0.010 mmol), CuO (0.0409 g, 0.514 mmol), 3.3 (0.2515 g, 1.035 mmol), and

201

THF (anhydrous, 15 mL). The starting materials were removed by distillation (1.0 mmHg, 75 °C) to afford a brown solid which contained a small amount of didodecyl carbonate (estimated to be 0.0123 g or 3.6% by 1H NMR). Yield 0.3404 g (94%). For the purposes of elemental analysis, the solid was recrystallized from petroleum ether which removed the didodecyl carbonate and generated pure product as a white solid. Mp =

1 34.8-35.3 °C. H NMR (CDCl3) 0.88 (t, J = 6.84 Hz, 3H), 1.19-1.37 (m, 16H), 1.41

(quint., J = 7.00 Hz, 2H), 1.78 (quint., J = 7.05 Hz, 2H), 4.35 (t, J = 6.66 Hz, 2H), 7.03

13 (s, 1H); C NMR (CDCl3) 14.1, 22.7, 25.7, 28.7, 29.2, 29.4, 29.50, 29.56, 29.63 (2),

31.9, 71.8, 98.6, 137.7, 174.5. Anal. Calcd for C15H26BrNOS: C, 51.72; H, 7.52; N, 4.02.

Found: C, 51.42; H, 7.58; N, 3.98%.

4-Cyanophenylboronic acid (4.4)

Synthesis of compound 4.4 has previously been reported and was obtained as a light yellow solid. 1H NMR of the product matched that found in the literature.216 Yield

0.6562 g (81%).

Pd(PPh3)4

PdCl2 (0.2507 g, 1.414 mmol), PPh3 (1.9530 g, 7.4460 mmol) and DMSO (18 mL) were stirred and heated to 150 °C while under argon. Once the solution turned clear and dark red, the heat was removed and hydrazine hydrate (0.30 mL, 64% hydrazine, d = 1.029 g/mL, 6.2 mmol) was quickly added and the solution was cooled on ice for 3 hours while being shielded from light. The resulting light orange solid was then allowed to warm to

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room temperature over 3 hours while being shielded from light. The solution was then filtered and the resulting green/yellow crystals were washed with EtOH (80 mL) followed by Et2O (80 mL). The crystals were dried under vacuum filtration while shielded from light and while under argon for about 30 minutes (1.3589 g, 83%).

5-(4-Cyanophenyl)-2-octyloxy-1,3-thiazole (4.5a)

5-Bromo-2-octyloxy-1,3-thiazole (4.3a; 1.2804 g, 4.3813 mmol), DME (degassed, 25 mL), and Na2CO3 (4.2 mL, 2.0 M, 8.4 mmol) were stirred for a few minutes under argon before 4.4 (0.7738 g, 5.266 mmol) and Pd(PPh3)4 (0.5089 g, 0.4404 mmol) were all added in one portion. The resulting solution was heated under reflux under argon for 24 hours (the solution turned black after ~6 hours) before the cooled solution was washed with H2O (45 mL), extracted with Et2O (3 x 45 mL), washed with brine (45 mL), and dried (MgSO4). The drying agent was filtered off and the solvent was removed in vacuo to give a black solid. The solid was purified by column chromatography (silica gel/petroleum ether until the black band stopped moving, then the eluant was switched to

20% Et2O in petroleum ether) to give a white solid. Yield 1.0772 g (78%). The solid was then recrystallized twice from EtOH to give an analytically pure sample. Transition

1 temperatures (°C): Cryst. 84.2 Iso Liq. (Rec. 76.2). H NMR (CDCl3) 0.89 (t, J = 6.84

Hz, 3H), 1.20-1.40 (m, 8H), 1.45 (quint., J = 7.17 Hz, 2H), 1.83 (quint., J = 7.08 Hz, 2H),

4.44 (t, J = 6.66 Hz, 2H), 7.44 (s, 1H), 7.52 (d, J = 8.48 Hz, 2H), 7.64 (d, J = 8.44 Hz,

13 2H); C NMR (CDCl3) 14.1, 22.6, 25.8, 28.8, 29.18, 29.20, 31.8, 72.3, 110.6, 118.7,

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125.9, 128.8, 132.8, 134.6, 136.6, 175.1. Anal. Calcd for C18H22N2OS: C, 68.75; H, 7.05;

N, 8.91. Found: C, 68.74; H, 7.12; N, 8.98%.

5-(4-Cyanophenyl)-2-nonyloxy-1,3-thiazole (4.5b)

Compound 4.5b was prepared using a similar procedure to that described for the preparation of 4.5a using the quantities stated: 4.3b (1.1508 g, 3.7576 mmol), DME

(degassed, 25 mL), and Na2CO3 (3.7 mL, 2.0 M, 7.4 mmol), 4.4 (0.6628 g, 4.511 mmol), and Pd(PPh3)4 (0.3473 g, 0.3005 mmol). The crude product was purified by column chromatography (silica gel/petroleum ether- until the black band stopped moving, then the eluant was switched to 20% Et2O in petroleum ether) to give a white solid (0.90 g,

73%). The solid was then recrystallized twice from EtOH to afford an analytically pure sample. Transition temperatures (°C): Cryst. 87.3 Iso Liq. (Rec. 80.8). 1H NMR

(CDCl3) 0.88 (t, J = 6.83 Hz, 3H), 1.20-1.40 (m, 10H), 1.45 (quint., J = 7.11 Hz, 2H),

1.82 (quint., J = 7.07 Hz, 2H), 4.44 (t, J = 6.66 Hz, 2H), 7.44 (s, 1H), 7.52 (d, J = 8.46

13 Hz, 2H), 7.63 (d, J = 8.44 Hz, 2H); C NMR (CDCl3) 14.1, 22.7, 25.8, 28.8, 29.2 (2),

29.5, 31.9, 72.3, 110.6, 118.7, 125.9, 128.8, 132.8, 134.6 ,136.6 ,175.1. Anal. Calcd for

C19H24N2OS: C, 69.47; H, 7.36; N, 8.53. Found: C, 69.60; H, 7.61; N, 8.58%.

5-(4-Cyanophenyl)-2-decyloxy-1,3-thiazole (4.5c)

Compound 4.5c was prepared using a similar procedure to that described for the preparation of 4.5a using the quantities stated: 4.3c (1.1003 g, 3.4353 mmol), DME

(degassed, 20 mL), Na2CO3 (3.4 mL, 2.0 M, 6.9 mmol), 4.4 (0.6068 g, 4.130 mmol),

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Pd(PPh3)4 (0.3189 g, 0.2760 mmol). The crude product was purified by column chromatography (silica gel/petroleum ether- until the black band stopped moving, then the eluant was switched to 20% Et2O in petroleum ether) to give a white solid. Yield

0.85 g (72%). The solid was then recrystallized twice from EtOH to afford an analytically pure sample. Transition temperatures (°C): Cryst. 81.9 (SmA 70.1) Iso Liq.

1 (Rec. 69.6). H NMR (CDCl3) 0.88 (t, J = 6.84 Hz, 3H), 1.20-1.40 (m, 12H), 1.45

(quint., J = 7.14 Hz, 2H), 1.82 (quint., J = 7.07 Hz, 2H), 4.44 (t, J = 6.66 Hz, 2H), 7.44

13 (s, 1H), 7.51 (d, J = 8.54 Hz, 2H), 7.63 (d, J = 8.48 Hz, 2H); C NMR (CDCl3) 14.1,

22.7, 25.8, 28.8, 29.2, 29.3, 29.5 (2), 31.9, 72.3, 110.6, 118.7, 125.9, 128.8, 132.8, 134.6,

136.6, 175.1. Anal. Calcd for C20H26N2OS: C, 70.14; H, 7.65; N, 8.18. Found: C, 69.89;

H, 7.80; N, 8.17%.

5-(4-Cyanophenyl)-2-undecyloxy-1,3-thiazole (4.5d)

Compound 4.5d was prepared using a similar procedure to that described for the preparation of 4.5a using the quantities stated: 4.3d (1.0821 g, 3.2367 mmol), DME

(degassed, 20 mL), Na2CO3 (3.2 mL, 2.0 M, 6.4 mmol), 4.4 (0.5715 g, 3.889 mmol),

Pd(PPh3)4 (0.2614 g, 0.2262 mmol). The crude product was purified by column chromatography (silica gel/petroleum ether- until the black band stopped moving, then the eluant was switched to 20% Et2O in petroleum ether) to give a white solid. Yield

0.84 g (73%). The solid was then recrystallized twice from EtOH to afford an analytically pure sample. Transition temperatures (°C): Cryst. 85.5 Iso Liq. (Rec. 80.6).

1 H NMR (CDCl3) 0.88 (t, J = 6.84 Hz, 3H), 1.20-1.40 (m, 14H), 1.45 (quint., J = 7.14

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Hz, 2H), 1.82 (quint., J = 7.07 Hz, 2H), 4.44 (t, J = 6.66 Hz, 2H), 7.44 (s, 1H), 7.51 (d, J

13 = 8.52 Hz, 2H), 7.64 (d, J = 8.52 Hz, 2H); C NMR (CDCl3) 14.1, 22.7, 25.8, 28.8,

29.2, 29.3, 29.50, 29.57, 29.60, 31.9, 72.3, 110.6, 118.7, 125.9, 128.8, 132.8, 134.6,

136.6, 175.1. Anal. Calcd for C21H28N2OS: C, 70.75; H, 7.92; N, 7.86. Found: C, 70.63;

H, 8.05; N, 7.82%.

5-(4-Cyanophenyl)-2-dodecyloxy-1,3-thiazole (4.5e)

Compound 4.5e was prepared using a similar procedure to that described for the preparation of 4.5a using the quantities stated: 4.3e (1.0146 g, 2.9127 mmol), DME

(degassed, 25 mL), Na2CO3 (2.9 mL, 2.0 M, 5.8 mmol), 4.4 (0.5141 g, 3.499 mmol),

Pd(PPh3)4 (0.2372 g, 0.2053 mmol). The crude product was purified by column chromatography (silica gel/petroleum ether- until the black band stopped moving, then the eluant was switched to 20% Et2O in petroleum ether) to give a white solid. Yield =

0.8200 g (76%). The solid was then recrystallized twice from EtOH to afford an analytically pure sample. Transition temperatures (°C): Cryst. 87.7 Iso Liq. (Rec. 83.2).

1 H NMR (CDCl3) 0.88 (t, J = 6.82 Hz, 3H), 1.20-1.40 (m, 16H), 1.45 (quint., J = 7.17

Hz, 2H), 1.82 (quint., J = 7.07 Hz, 2H), 4.44 (t, J = 6.65 Hz, 2H), 7.44 (s, 1H), 7.52 (d, J

13 = 8.36 Hz, 2H), 7.64 (d, J = 8.42 Hz, 2H); C NMR (CDCl3) 14.1, 22.7, 25.8, 28.8,

29.2, 29.4, 29.52, 29.57, 29.64 (2), 31.9, 72.3, 110.6, 118.7, 125.9, 128.8, 132.8, 134.6,

136.6, 175.1. Anal. Calcd for C22H30N2OS: C, 71.31; H, 8.16; N, 7.56. Found: C, 71.49;

H, 8.18; N, 7.50%.

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2-Dodecyloxy-1,3-thiazol-5-ylboronic acid (4.7)

5-Bromo-2-dodecyloxy-1,3-thiazole (4.3e; 1.0009 g, 2.8733 mmol) was dissolved in THF

(anhydrous; 40 mL) under argon and cooled to -75 °C before n-BuLi (1.50 mL, 2.2 M,

3.3 mmol) was slowly added over a few seconds (internal temperature did not exceed -70

°C, turned light yellow) and after stirring at -75 °C for 30 minutes (GC showed complete consumption of 4.3e), B(OMe)3 (0.50 mL, d = 0.932 g/mL, 4.5 mmol) was slowly added over a few seconds (internal temperature did not exceed -70 °C). The solution was allowed to stir at -74 °C for at least 5 hours before being allowed to warm to room temperature overnight and then stirred with HCl (1 M, 20 mL). After stirring for a few minutes the solution was concentrated under reduced pressure. The remaining residue was shaken with CH2Cl2 (20 mL) and once the organic layer was drained away, the aqueous layer was extracted with CH2Cl2 (4 x 20 mL). The combined organic extracts were washed with brine (25 mL), dried over MgSO4, and concentrated under reduced pressure to give a thick oil (0.8011 g) which by 1H NMR was found to be product (80%)

1 and 2-dodecyloxy-1,3-thiazole (20%). H NMR (DMSO-d6) 0.85 (t, J = 6.76 Hz, 3H),

1.21-1.41 (m, 16H), 1.45 (quint., J = 7.11 Hz, 2H), 1.71 (quint., J = 7.00 Hz, 2H), 4.33 (t,

J = 6.56 Hz, 2H), 7.61 (s, 1H), 8.27 (s, 2H).

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4-Carboxyphenylboronic acid (4.8)

4-Bromotoluene (1.0017 g, 5.8569 mmol) was dissolved in THF (anhydrous; 45 mL) and cooled to -75 °C while under argon before n-BuLi (4.4 mL, 1.58 M, 7.0 mmol) was slowly added over 5 minutes (internal temperature did not exceed -70 °C, no change in color) and the solution was allowed to stir at -75 °C for 30 minutes (GC showed no starting material present). Then B(OMe)3 (1.0 mL, d = 0.932 g/mL, 9.0 mmol) was added over 5 minutes (internal temperature did not exceed -69 °C) and the solution was allowed to stir at an internal temperature range of -70 to -75 °C for at least 6 hours before being allowed to warm to room temperature overnight. The solution was then stirred with HCl (6 M, 3 mL) for 30 minutes before being concentrated under reduced pressure.

The resulting aqueous solution was diluted with H2O (3 mL) and extracted with Et2O (3 x

20 mL). The combined organic extracts were washed with brine (20 mL), dried over

MgSO4, and concentrated under reduced pressure to give a white solid (0.7021 g, 88%)

1 217 1 which was pure product and matched the literature H NMR. H NMR (CDCl3) 1.54

(s, 2H), 2.45 (s, 3H), 7.32 (d, J = 7.56 Hz, 2H), 8.13 (d, J = 7.88 Hz, 2H). The following was based on a literature procedure.131 4-Tolylboronic acid (0.4523 g, 3.327 mmol) was dissolved in a solution of NaOH (0.2719 g, 6.798 mmol) and H2O (50 mL) before

1 KMnO4 (1.9538 g, 12.363 mmol) was added and after stirring for 24 hours H NMR showed the reaction (brown in color) was about 25% complete. More NaOH (0.2800 g,

7.000 mmol) and KMnO4 (1.9513 g, 12.348 mmol) were added and the solution was

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allowed to stir for another 24 hours at which point EtOH (10 mL) was added to the purple solution (1H NMR also showed complete consumption of starting material) and heated at

55 °C for 45 minutes before being concentrated under reduced pressure. The resulting light tan solid was dissolved in H2O (25 mL) and acidified with HCl (6 M, 12 mL) which generated a white precipitate. The solution was then cooled on ice before being filtered and after drying overnight the white solid (0.2228 g, 40%) was found to be pure product

1 1 by H NMR. H NMR (DMSO-d6) 7.88 (d, J = 8.56 Hz, 2H), 7.90 (d, J = 8.52 Hz,

2H), 8.25 (s, 2H), 12.92 (br. s, 1H).

4-(2-Decyloxy-1,3-thiazol-5-yl)benzaldehyde (4.9c)

5-(4-Cyanophenyl)-2-decyloxy-1,3-thiazole (4.5c; 0.6729 g, 1.965 mmol) was dissolved in toluene (44 mL, anhydrous, distilled over Na and benzophenone) and cooled to -40 °C while under argon before DIBAl-H (2.10 mL, 1.5 M, 3.2 mmol) was slowly added dropwise via syringe pump (speed #4, 0.16 mL minutes-1). The resulting red solution was allowed to stir at -40°C for an additional 45 minutes (1H NMR showed mostly product and smaller amounts of 4-(1,3-thiazol-2-yl)benzaldehyde (4.10; 6%) and compound 4.5c (14%)) before a second aliquot of DIBAl-H (0.30 mL, 1.5 M, 0.45 mmol) was added manually over 60 seconds. The solution was allowed to stir at -40 °C for another 30 minutes (1H NMR showed mostly product and smaller amounts of 4-(1,3- thiazol-2-yl)benzaldehyde (4.10; 9%) and compound 4.5c (3%)) before a third aliquot of

DIBAl-H (0.05 mL, 1.5 M, 0.08 mmol) was added. The red solution was allowed to stir at -40 °C for another 30 minutes before being allowed to warm to -15 °C at which point

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the excess of DIBAl-H was neutralized with HCl (1 M, 5 mL). The solvent was removed in vacuo and the yellow solid was dissolved in CH2Cl2 and stirred with HCl (1 M, 55 mL) for 45 minutes. The yellow organic layer was drained away and the aqueous layer was extracted with CH2Cl2 (3x25 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure to give a light yellow solid (0.6242 g) which by 1H NMR was found to be mostly product with a smaller amount of 4-(1,3-thiazol-5-yl)-benzaldehyde (4.10; 10%). The solid was recrystallized from EtOH to give a light yellow solid (0.4745 g) which was pure by 1H

NMR. The mother liquor was concentrated under reduced pressure (0.1490 g) and purified by column chromatography (silica gel, eluant was 20% Et2O in petroleum ether) to give a white solid (0.0411 g). Yield = 0.5156 g (76%). Mp = 75.8 °C. 1H NMR

(CDCl3) 0.88 (t, J = 6.82 Hz, 3H), 1.20-1.40 (m, 12H), 1.45 (quint., J = 7.18 Hz, 2H),

1.83 (quint., J = 7.07 Hz, 2H), 4.44 (t, J = 6.66 Hz, 2H), 7.48 (s, 1H), 7.59 (d, J = 8.28

13 Hz, 2H), 7.87 (d, J = 8.36 Hz, 2H), 9.99 (s, 1H); C NMR (CDCl3) 14.1, 22.7, 25.8,

28.8, 29.25, 29.31, 29.5 (2), 31.9, 72.2, 125.8, 129.4, 130.5, 134.5, 135.1, 138.0, 175.1,

191.2. Anal. Calcd for C20H27NO2S: C, 69.53; H, 7.88; N, 4.05. Found: C, 69.47; H,

8.02; N, 4.07%.

4-(2-Undecyloxy-1,3-thiazol-5-yl)benzaldehyde (4.9d)

Compound 4.9d was prepared using a similar procedure to that described for the preparation of 4.9c using the quantities stated: 4.5d (0.8616 g, 2.417 mmol), toluene

(anhydrous, 52 mL), DIBAl-H (2.60 mL, 1.5 M, 3.9 mmol). Crude 1H NMR showed

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mostly product but also contained 4-(1,3-thiazol-5-yl)benzaldehyde (4.10; 6%) and compound 4.5d (4%) before another aliquot of DIBAl-H (0.10 mL, 1.5 M, 0.15 mmol) was added manually over about 30 seconds. After stirring for another 30 minutes at -40

°C to -55 °C crude 1H NMR showed mostly product with a trace of 4-(1,3-thiazol-5-yl)- benzaldehyde (4.10; 9%)). The crude product was purified by column chromatography

(silica, eluant was 20% Et2O in petroleum ether) to give a white solid. Yield = 0.6514 g

1 (75%). Mp = 77.5 °C. H NMR (CDCl3) 0.88 (t, J = 6.84 Hz, 3H), 1.20-1.40 (m,

14H), 1.45 (quint., J = 7.23 Hz, 2H), 1.83 (quint., J = 7.08 Hz, 2H), 4.44 (t, J = 6.66 Hz,

2H), 7.49 (s, 1H), 7.59 (d, J = 8.24 Hz, 2H), 7.87 (d, J = 8.36 Hz, 2H), 9.99 (s, 1H); 13C

NMR (CDCl3) 14.1, 22.7, 25.8, 28.8, 29.25, 29.34, 29.52, 29.58, 29.61, 31.9, 72.2,

125.8, 129.4, 130.5, 134.5, 135.1, 138.0, 175.1, 191.2. Anal. Calcd for C21H29NO2S: C,

70.15; H, 8.13; N, 3.90. Found: C, 70.32; H, 8.08; N, 3.83%.

4-(2-Dodecyloxy-1,3-thiazol-5-yl)benzaldehyde (4.9e)

Compound 4.9e was prepared using a similar procedure to that described for the preparation of 4.9c using the quantities stated: 4.5e (0.2004 g, 0.5408 mmol), toluene

(anhydrous, 12 mL), DIBAl-H (0.55 mL, 1.5 M, 0.83 mmol). Crude 1H NMR after 1 hour showed mostly product but also contained 4-(1,3-thiazol-5-yl)benzaldehyde (4.10;

5%) and compound 4.5e (7%) so another aliquot of DIBAl-H (0.04 mL, 1.5 M, 0.06 mmol) was added manually over about 30 seconds. After stirring for another 30 minutes crude 1H NMR showed mostly product with a trace of 4-(1,3-thiazol-5-yl)benzaldehyde

(4.10; 7%)). The crude product was purified by column chromatography (silica, eluant

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was 20% Et2O in petroleum ether) to give a light yellow solid. Yield = 0.1674 g (83%).

1 Mp = 81.6 °C. H NMR (CDCl3) 0.88 (t, J = 6.82 Hz, 3H), 1.21-1.40 (m, 16H), 1.45

(quint., J = 7.11 Hz, 2H), 1.83 (quint., J = 7.07 Hz, 2H), 4.44 (t, J = 6.64 Hz, 2H), 7.48

(s, 1H), 7.59 (d, J = 8.28 Hz, 2H), 7.87 (d, J = 8.40 Hz, 2H), 9.99 (s, 1H); 13C NMR

(CDCl3) 14.1, 22.7, 25.8, 28.8, 29.3, 29.4, 29.52, 29.57, 29.65 (2), 31.9, 72.2, 125.8,

129.4, 130.5, 134.5, 135.1, 138.0, 175.1, 191.2. Anal. Calcd for C22H31NO2S: C, 70.74;

H, 8.36; N, 3.75. Found: C, 70.70; H, 8.82; N, 3.81%.

4-(2-Octyloxy-1,3-thiazol-5-yl)benzoic acid (4.11a)

5-(4-Cyanophenyl)-2-octyloxy-1,3-thiazole (4.5a; 0.7141 g, 2.271 mmol), NaOH (1.1287 g, 28.218 mmol), and a 1:1 mixture of EtOH and H2O (26 mL) were stirred and heated under reflux for about 24 hours before being cooled and concentrated under reduced pressure. The resulting yellow solid was then suspended in H2O (45 mL) and acidified to pH 3.5 with AcOH (glacial, 35 mL). The solution was stirred at room temperature for about an hour before being filtered and the resulting solid washed with H2O (50 mL) to give a light yellow solid (0.6253 g). The solid was dried in vacuo (95 °C, P2O5). Yield =

0.6195 g (82%). Transition temperatures (°C): Cryst 168.6 SmA 209.7 Iso Liq/Decomp.

1 H NMR (DMSO-d6) 0.86 (t, J = 6.48 Hz, 3H), 1.18-1.35 (m, 8H), 1.39 (quint., J =

6.60 Hz, 2H), 1.76 (quint., J = 6.87 Hz, 2H), 4.42 (t, J = 6.50 Hz, 2H), 7.65 (d, J = 8.28

13 Hz, 2H), 7.79 (s, 1H), 7.94 (d, J = 8.28 Hz, 2H), 13.00 (br. s, 1H); C NMR (DMSO-d6)

13.9, 22.0, 25.1, 28.1, 28.5 (2), 31.1, 71.8, 125.1, 129.0, 129.5, 130.0, 134.8, 135.3,

166.7, 173.4.

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4-(2-Nonyloxy-1,3-thiazol-5-yl)benzoic acid (4.11b)

Compound 4.11b was prepared using a similar procedure to that described for the preparation of 4.11a using the quantities stated: 4.5b (0.8619 g, 2.624 mmol), NaOH

(1.3302 g, 33.255 mmol), 1:1 mixture of EtOH and H2O (30 mL). An off-white solid was obtained which was dried in vacuo (85 °C, P2O5). Yield = 0.7758 g (85%).

Transition temperatures (°C): Cryst 156.9 SmA 209.8 N 215.1 Iso Liq/Decomp. 1H

NMR (DMSO-d6) 0.86 (t, J = 6.82 Hz, 3H), 1.18-1.35 (m, 10H), 1.39 (quint., J = 6.79

Hz, 2H), 1.76 (quint., J = 6.96 Hz, 2H), 4.42 (t, J = 6.53 Hz, 2H), 7.65 (d, J = 8.42 Hz,

13 2H), 7.78 (s, 1H), 7.94 (d, J = 8.44 Hz, 2H), 13.00 (br. s, 1H); C NMR (DMSO-d6)

13.8, 22.0, 25.1, 28.1, 28.5 (2), 28.8, 31.2, 71.9, 125.1, 129.0, 129.4, 130.0, 134.8, 135.4,

166.7, 173.5.

4-(2-Decyloxy-1,3-thiazol-5-yl)benzoic acid (4.11c)

4-(2-Decyloxy-1,3-thiazol-5-yl)benzaldehyde (4.9c; 0.4745 g, 1.373 mmol) was dissolved in a solution of NaH2PO4•H2O (0.5021 g, 3.639 mmol), 2,3-dimethylbut-2-ene

(1.5 mL, d = 0.708 g/mL, 13 mmol), t-BuOH (48 mL), H2O (10 mL) and THF (24 mL) before NaClO2 (0.7636 g, 8.443 mmol) was added in one portion. The resulting solution was allowed to stir at room temperature for 3 hours (a white precipitate formed after 90 minutes and TLC indicated the absence of starting aldehyde) before being concentrated under reduced pressure. The light yellow solid obtained was stirred with H2O (70 mL) before being acidified with AcOH (glacial, 24 mL) to pH 3. The solution was stirred at room temperature for about 1 hour before being cooled on ice for about 45 minutes. The

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solution was filtered and the resulting light yellow solid was washed with H2O (125 mL) and dried and heated in vacuo (100 °C). Yield = 0.4699 g (95%). Transition temperatures (°C): Cryst I 162.6 Cryst II 212.8 SmA 216.7 Iso Liq/Decomp. 1H NMR

(DMSO-d6) 0.85 (t, J = 6.52 Hz, 3H), 1.15-1.45 (m, 14H), 1.76 (quint., J = 6.85 Hz,

2H), 4.41 (t, J = 6.48 Hz, 2H), 7.65 (d, J = 8.28 Hz, 2H), 7.78 (s, 1H), 7.94 (d, J = 8.32

13 Hz, 2H), 12.99 (br. s, 1H); C NMR (DMSO-d6) 13.9, 22.0, 25.1, 28.1, 28.5, 28.6, 28.8

(2), 31.2, 71.9, 125.1, 129.0, 129.3, 130.1, 134.8, 135.4, 166.7, 173.5.

4-(2-Undecyloxy-1,3-thiazol-5-yl)benzoic acid (4.11d)

Compound 4.11d was prepared using a similar procedure to that described for the preparation of 4.11c using the quantities stated: 4.9d (0.5582 g, 1.553 mmol),

NaH2PO4•H2O (0.5678 g, 4.115 mmol), 2,3-dimethylbut-2-ene (1.8 mL, d = 0.708 g/mL,

15 mmol), t-BuOH (56 mL), H2O (11 mL), THF (non-anhydrous, 28 mL), NaClO2

(0.8509 g, 9.408 mmol). A pale yellow solid was obtained which was dried and heated in vacuo (100 °C). Yield = 0.5461 g (94%). Transition temperatures (°C): Cryst I 157.4

1 Cryst II 215.1 SmA 225.1 Iso Liq/Decomp. H NMR (DMSO-d6) 0.85 (t, J = 6.76 Hz,

3H), 1.17-1.44 (m, 16H), 1.76 (quint., J = 6.92 Hz, 2H), 4.42 (t, J = 6.50 Hz, 2H), 7.66

(d, J = 8.40 Hz, 2H), 7.79 (s, 1H), 7.94 (d, J = 8.42 Hz, 2H), 12.99 (br. s, 1H); 13C NMR

(DMSO-d6) 13.9, 22.0, 25.1, 28.1, 28.5, 28.6, 28.80, 28.85, 28.87, 31.2, 71.9, 125.1,

129.0, 129.3, 130.0, 134.8, 135.4, 166.7, 173.5.

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4-(2-Dodecyloxy-1,3-thiazol-5-yl)benzoic acid (4.11e)

Compound 4.11e was prepared using a similar procedure to that described for the preparation of 4.11c using the quantities stated: 4.9e (1.3189 g, 3.5307 mmol)

NaH2PO4•H2O (1.2743 g, 9.2347 mmol), 2,3-dimethylbut-2-ene (4.0 mL, d = 0.708 g/mL, 34 mmol), t-BuOH (85 mL), H2O (20 mL), THF (non-anhydrous, 45 mL), NaClO2

(1.9164 g, 21.190 mmol). The resulting solution was allowed to stir at room temperature for 3 hours (a white precipitate formed after 10 minutes, TLC indicated the presence of starting material) before more NaClO2 (0.2205 g, 2.438 mmol) and THF (15 mL) were added. After stirring another 1 hour (TLC indicated the presence of starting material), more NaH2PO4•H2O (0.1386 g, 1.004 mmol) was added and the solution was allowed to stir for another 1 hour (TLC again indicated the presence of starting material). Another addition of NaClO2 (0.2507 g, 2.772 mmol) and NaH2PO4•H2O (0.1506 g, 1.091 mmol) was made and the reaction mixture was allowed to stir for an additional 30 minutes (TLC indicated the absence of starting material). A white solid was obtained which was dried and heated in vacuo (100 °C). Yield = 1.2804 g (93%). Transition temperatures (°C):

1 Cryst I 158.1 Cryst II 208.4 SmA 215.0 Iso Liq/Decomp. H NMR (DMSO-d6) 0.85 (t,

J = 6.68 Hz, 3H), 1.17-1.44 (m, 18H), 1.76 (quint., J = 6.90 Hz, 2H), 4.42 (t, J = 6.49 Hz,

2H), 7.66 (d, J = 8.34 Hz, 2H), 7.78 (s, 1H), 7.94 (d, J = 8.34 Hz, 2H), 12.97 (br. s, 1H);

13 C NMR (DMSO-d6) 13.8, 22.0, 25.1, 28.1, 28.5, 28.6, 28.77, 28.81, 28.9 (2), 31.2,

71.9, 125.1, 129.0, 129.3, 130.0, 134.8, 135.4, 166.7, 173.5.

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(S)-4-(1-Methylheptyloxy)phenyl 4-(2-(octyloxy)-1,3-thiazol-5-yl)benzoate (4.12a;

Scheme 4.17)

A mixture of 4-(2-octyloxy-1,3-thiazol-5-yl)benzoic acid (4.11a; 0.1583 g, 0.4747 mmol), DMAP (0.0135 g, 0.111 mmol), 2.11 (0.1009 g, 0.4539 mmol), and CH2Cl2

(anhydrous, 18 mL) was stirred at room temperature for a few minutes under argon before DCC (0.1286 g, 0.6233 mmol) was added in one portion. After stirring at room temperature for about 30 minutes, DABCO (0.0252 g, 0.225 mmol) was added in one portion and the reaction mixture was allowed to stir under the same conditions for 48 hours (at 24 hours, the reaction was 83% complete by 1H NMR and at 48 hours no significant change had occurred). The solution was filtered before being washed with

AcOH (5% vol./vol., 20 mL), extracted with CH2Cl2 (3 x 25 mL), and the combined organic washings were washed with brine (15 mL), and dried over MgSO4. The drying agent was filtered off and the crude product was purified by column chromatography

(silica gel, eluant was 5% EtOAc in petroleum ether) to give an off-white solid (0.1781g) which by 1H NMR was contaminated with starting phenol (~0.0112 g). The solid was recrystallized from EtOH to give a white solid which was pure by 1H NMR and dried in vacuo (P2O5). Yield = 0.1538 g (63%). The product was then recrystallized twice more from EtOH for LC analysis. Transition temperatures (°C): Cryst. 80.2 SmC* 90.8 SmA

1 109.1 Iso Liq. (Rec. 57.8). H NMR (CDCl3) 0.889 (t, J = 5.53 Hz, 3H), 0.892 (t, J =

6.35 Hz, 3H), 1.22-1.41 (m, 15H), 1.30 (d, J = 6.06 Hz, 3H), 1.46 (m, 3H), 1.53-1.62 (m,

1H), 1.69-1.79 (m, 1H), 1.83 (quint., J = 7.08 Hz, 2H), 4.33 (sext., J = 6.07 Hz, 1H), 4.44

(t, J = 6.65 Hz, 2H), 6.92 (d, J = 9.03 Hz, 2H), 7.11 (d, J = 9.00 Hz, 2H), 7.47(s, 1H),

216

13 7.55 (d, J = 8.43 Hz, 2H), 8.17 (d, J = 8.44 Hz, 2H); C NMR (CDCl3) 14.1 (2), 19.7,

22.6, 22.7, 25.6, 25.8, 28.8, 29.19, 29.21, 29.29, 31.79, 31.82, 36.5, 72.2, 74.5, 116.6,

122.4, 125.4, 128.3, 129.6, 130.9, 134.0, 137.0, 144.1, 156.0, 165.1, 174.8. Anal. Calcd for C32H43NO4S: C, 71.47; H, 8.06; N, 2.60. Found: C, 71.52; H, 8.18; N, 2.66%.

(S)-4-(1-Methylheptyloxy)phenyl 4-(2-(octyloxy)-1,3-thiazol-5-yl)benzoate (4.12a;

Scheme 4.18)

4.11a (0.1610 g, 0.4828 mmol), SOCl2 (0.06 mL, 0.8 mmol, d = 1.631 g/mL), and toluene (anhydrous, dried over 4Å molecular sieves and sodium metal, 6 mL) were stirred and heated under reflux while under argon for about 3 hours and once cool the excess SOCl2 and toluene were distilled away under an argon atmosphere (about 5.5 mL collected). The remaining residue was transferred to a cooled solution (3 °C internal temperature) of 2.11 (0.1008 g, 0.4534 mmol), Et3N (anhydrous, distilled from CaH2,

0.30 mL, 2.2 mmol, d = 0.726 g/mL), and toluene (anhydrous, dried over 4 Å molecular sieves, 10 mL) that had been stirred under argon for about 30 minutes at room temperature before being cooled to 3 °C (internal temperature). The resulting solution was stirred under argon at 3 °C for about 30 minutes and then overnight at room temperature (1H NMR of the crude reaction mixture showed the reaction went to about

95% completion with some of the unreacted starting phenol, after 48 hours no significant change in this ratio had occurred). The solution was concentrated under reduced pressure and the remaining solids were dissolved in H2O (30 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted with CH2Cl2 (3 x 25 mL) and the combined organic extracts

217

were washed with brine (25 mL), dried over MgSO4, and concentrated under reduced pressure to give a tan solid (0.3007 g). The solid was dissolved in CH2Cl2 and concentrated onto 4.6 g of silica. The material was then chromatographed (14 g silica, eluant was 5% EtOAc in petroleum ether) to give a white solid (0.1516 g, 62%) which was pure by 1H NMR.

(S)-4-(1-Methylheptyloxy)phenyl 4-(2-(nonyloxy)-1,3-thiazol-5-yl)benzoate (4.12b)

Compound 4.12b was prepared using a similar procedure to that described for the preparation of 4.12a using the quantities stated: 4.11b (0.7073 g, 2.036 mmol), DMAP

(0.0593 g, 0.485 mmol), 2.11 (0.4316 g, 1.941 mmol), CH2Cl2 (anhydrous, 80 mL), DCC

(0.5478 g, 2.655 mmol), DABCO (0.1612 g, 1.437 mmol). The crude product was purified by column chromatography (silica gel, eluant was 5% EtOAc in petroleum ether) to give a white solid and recrystallized from EtOH before being dried in vacuo (P2O5).

Yield 0.68 g, (63%). The product was then recrystallized twice from EtOH for LC analysis. Transition temperatures (°C): Cryst. 79.8 SmC* 101.0 SmA 109.5 Iso Liq.

1 (Rec. 60.7). H NMR (CDCl3) 0.89 (t, J = 6.74 Hz, 6H), 1.20-1.41 (m, 17H), 1.30 (d, J

= 6.00 Hz, 3H), 1.41-1.51 (m, 3H), 1.52-1.63 (m, 1H), 1.69-1.79 (m, 1H), 1.83 (quint., J

= 7.08 Hz, 2H), 4.32 (sext., J = 6.06 Hz, 1H), 4.44 (t, J = 6.64 Hz, 2H), 6.92 (d, J = 9.00

Hz, 2H), 7.11 (d, J = 8.96 Hz, 2H), 7.47(s, 1H), 7.55 (d, J = 8.44 Hz, 2H), 8.17 (d, J =

13 8.44 Hz, 2H); C NMR (CDCl3) 14.10, 14.12, 19.7, 22.6, 22.7, 25.6, 25.8, 28.8, 29.25

(2), 29.29, 29.5, 31.8, 31.9, 36.5, 72.1, 74.5, 116.6, 122.4, 125.4, 128.3, 129.6, 130.9,

218

134.0, 137.0, 144.1, 156.0, 165.1, 174.8. Anal. Calcd for C33H45NO4S: C, 71.83; H, 8.22;

N, 2.54. Found: C, 71.97; H, 8.26; N, 2.65%.

(S)-4-(1-Methylheptyloxy)phenyl 4-(2-(decyloxy)-1,3-thiazol-5-yl)benzoate (4.12c)

Compound 4.12c was prepared using a similar procedure to that described for the preparation of 4.12a using the quantities stated: 4.11c (0.3660 g, 1.012 mmol), DMAP

(0.0347 g, 0.284 mmol), 2.11 (0.2046 g, 0.9203 mmol), CH2Cl2 (anhydrous, 60 mL),

DCC (0.3125 g, 1.515 mmol). The crude product was purified by column chromatography (silica gel, eluant was 5% EtOAc in petroleum ether) to give a white solid. Yield 0.4226 g (81%). Recrystallization from EtOH was attempted and a gel was obtained which solidified to a wax once dried in vacuo (P2O5). Transition temperatures

1 (°C): Cryst. 74.1 SmC* 101.5 SmA 107.7 Iso Liq. (Rec. 63.7). H NMR (CDCl3) 0.88

(t, J = 6.80 Hz, 3H), 0.89 (t, J = 6.14 Hz, 3H), 1.20-1.40 (m, 19H), 1.29 (d, J = 6.04 Hz,

3H), 1.40-1.51 (m, 3H), 1.51-1.62 (m, 1H), 1.69-1.78 (m, 1H), 1.82 (quint., J = 7.05 Hz,

2H), 4.31 (sext., J = 6.04 Hz, 1H), 4.43 (t, J = 6.64 Hz, 2H), 6.91 (d, J = 9.00 Hz, 2H),

7.10 (d, J = 8.96 Hz, 2H), 7.46 (s, 1H), 7.52 (d, J = 8.40 Hz, 2H), 8.15 (d, J = 8.40 Hz,

13 2H); C NMR (CDCl3) 14.10, 14.13, 19.7, 22.6, 22.7, 25.6, 25.8, 28.8, 29.27, 29.32

(2), 29.5 (2), 31.8, 31.9, 36.5, 72.1, 74.5, 116.5, 122.4, 125.4, 128.3, 129.6, 130.9, 134.1,

137.0, 144.2, 156.0, 165.0, 174.8. Anal. Calcd for C34H47NO4S: C, 72.17; H, 8.37; N,

2.48. Found: C, 72.27; H, 8.45; N, 2.54%.

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(S)-4-(1-Methylheptyloxy)phenyl 4-(2-(undecyloxy)-1,3-thiazol-5-yl)benzoate (4.12d)

Compound 4.12d was prepared using a similar procedure to that described for the preparation of 4.12a using the quantities stated: 4.11d (0.4838 g, 1.288 mmol), DMAP

(0.0433 g, 0.354 mmol), 2.11 (0.2606 g, 1.172 mmol), CH2Cl2 (anhydrous, 50 mL), DCC

(0.3960 g, 1.919 mmol), DABCO (0.0982 g, 0.8755 mmol). The crude product was purified by column chromatography (silica gel, eluant was 5% EtOAc in petroleum ether) to give a white solid. Yield 0.5405 g (80%). Attempted recrystallization from EtOH gave a gel which solidified to a wax once dried in vacuo (P2O5). Transition temperatures

1 (°C): Cryst. 75.8 SmC* 103.6 SmA 107.1 Iso Liq. (Rec. 71.1). H NMR (CDCl3) 0.88

(t, J = 6.86 Hz, 3H), 0.89 (t, J = 6.82 Hz, 3H), 1.19-1.41 (m, 21H), 1.30 (d, J = 6.03 Hz,

3H), 1.41-1.51 (m, 3H), 1.52-1.62 (m, 1H), 1.69-1.79 (m, 1H), 1.83 (quint., J = 7.08 Hz,

2H), 4.32 (sext., J = 6.07 Hz, 1H), 4.44 (t, J = 6.65 Hz, 2H), 6.92 (d, J = 9.05 Hz, 2H),

7.11 (d, J = 9.01 Hz, 2H), 7.47 (s, 1H), 7.55 (d, J = 8.53 Hz, 2H), 8.17 (d, J = 8.51 Hz,

13 2H); C NMR (CDCl3) 14.10, 14.13, 19.8, 22.6, 22.7, 25.6, 25.8, 28.8, 29.26, 29.30,

29.34, 29.52, 29.58, 29.61, 31.8, 31.9, 36.5, 72.2, 74.6, 116.6, 122.4, 125.4, 128.3, 129.6,

130.9, 134.1, 137.0, 144.1, 156.0, 165.0, 174.8. Anal. Calcd for C35H49NO4S: C, 72.50;

H, 8.52; N, 2.42. Found: C, 72.86; H, 8.51; N, 2.38%.

(S)-4-(1-Methylheptyloxy)phenyl 4-(2-(dodecyloxy)-1,3-thiazol-5-yl)benzoate (4.12e)

Compound 4.12e was prepared using a similar procedure to that described for the preparation of 4.12a using the quantities stated: 4.11e (0.1927 g, 0.4947 mmol), DMAP

(0.0165 g, 0.135 mmol), 2.11 (0.1005 g, 0.4521 mmol), CH2Cl2 (anhydrous, 20 mL),

220

DCC (0.1526 g, 0.7396 mmol). The crude product was purified by column chromatography (silica gel, eluant was 5% EtOAc in petroleum ether) to give a white solid. Yield 0.2119 g (79%). Attempted recrystallization from EtOH gave a gel which solidified to a wax once dried in vacuo (P2O5). Transition temperatures (°C): Cryst. 79.9

1 SmC* 104.0 SmA 106.1 Iso Liq. (Rec. 73.1). H NMR (CDCl3) 0.88 (t, J = 6.70 Hz,

3H), 0.89 (t, J = 6.76 Hz, 3H), 1.20-1.41 (m, 23H), 1.30 (d, J = 5.92 Hz, 3H), 1.41-1.50

(m, 3H), 1.51-1.63 (m, 1H), 1.69-1.79 (m, 1H), 1.83 (quint., J = 7.07 Hz, 2H), 4.33 (sext.,

J = 6.00 Hz, 1H), 4.44 (t, J = 6.64 Hz, 2H), 6.92 (d, J = 8.92 Hz, 2H), 7.11 (d, J = 8.96

Hz, 2H), 7.47 (s, 1H), 7.55 (d, J = 8.28 Hz, 2H), 8.17 (d, J = 8.28 Hz, 2H); 13C NMR

(CDCl3) 14.10, 14.13, 19.8, 22.6, 22.7, 25.6, 25.8, 28.8, 29.26, 29.3, 29.36, 29.53,

29.58, 29.65 (2), 31.8, 31.9, 36.5, 72.2, 74.6, 116.6, 122.4, 125.4, 128.3, 129.6, 130.9,

134.1, 137.0, 144.1, 156.0, 165.1, 174.9. Anal. Calcd for C36H51NO4S: C, 72.81; H, 8.66;

N, 2.36. Found: C, 72.53; H, 8.78; N, 2.34%.

10.4. Experimental for Chapter 5

4-Bromo-2-(4-bromophenyl)-5-ethoxy-1,3-oxazole (5.28)

1 Ethyl diazoacetate (5.25; 7% CH2Cl2 as determined by H NMR; 0.2520 g, 2.054 mmol) and DBU (0.42 mL, d = 1.018 g/mL, 2.8 mmol) were dissolved in CH2Cl2 (anhydrous,

221

distilled over CaH2, 3 mL) and cooled to 0 °C before NBS (0.4747 g, 2.667 mmol) was added in one portion which caused the solution to turn red. Ethyl diazobromoacetate

(5.26) was verified to be pure by 1H NMR and matched that of the literature.155 1H NMR

(CDCl3) 1.31 (t, J = 7.12 Hz, 3H), 4.29 (quint., J = 7.14 Hz, 2H). After stirring at 0 °C for 7 minutes, the solution was slowly transferred to a cold (3 °C) solution of 4- bromobenzonitrile (5.27; 0.4067 g, 2.234 mmol) and BF3•Et2O (48% BF3, 0.75 mL, d =

1.15 g/mL, 6.1 mmol) in CH2Cl2 (anhydrous, distilled over CaH2, 5 mL) over a period of about 5 minutes (internal temperature did not exceed 6 °C, lots of bubbling). The solution was allowed to stir at 0 °C for 45 minutes (crude 1H NMR showed a ratio of product 5.28 to starting material 5.27 of 1:3.7) before being vigorously stirred/shaken with saturated NaHCO3 (15 mL). Once the organic layer was drained away, the aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure onto silica (2.09 g). The material (1.10 g) was chromatographed (85 g silica, eluant was

5% EtOAc in petroleum ether) to give an off-white solid (0.0778 g, 10%) which by 1H

1 NMR was found to be slightly impure desired product. H NMR (CDCl3) 1.46 (t, J =

7.08 Hz, 3H), 4.38 (q, J = 7.08 Hz, 2H), 7.57 (d, J = 8.64 Hz, 2H), 7.78 (quint., J = 8.64

Hz, 2H).

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O-Methyl 4-methoxybenzothioate (5.32)

Methyl anisate (5.31; 4.0042 g, 24.097 mmol) and Lawesson’s reagent (11.6165 g,

28.720 mmol) were stirred in anhydrous toluene (80mL, anhydrous, distilled over Na and benzophenone) while under argon. The resulting solution was heated under reflux for 72 hours (1H NMR showed starting material was still present) before more Lawesson’s reagent (1.8745 g, 4.6345 mmol) was added. The solution was heated under reflux for another 24 hours (1H NMR did not show any significant improvement in the consumption of starting material) before being concentrated under reduced pressure. A portion of the crude material (1.2293 g) was dissolved in CH2Cl2 (25 mL) and shaken with aqueous

KOH (25 mL, 10% wt./vol.) before the organic layer was drained away. The aqueous layer was then extracted with CH2Cl2 (3 x 15 mL) and the combined organic extracts were washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure. The resulting yellow semi-solid was found to be product which was slightly cleaner, but still contaminated with Lawesson’s reagent related byproducts. The semi- solid was dissolved in CH2Cl2 and run through a silica plug which also failed to remove the Lawesson’s reagent related byproducts. The material was again dissolved in CH2Cl2,

223

washed with KOH (30 mL, 20% wt./vol.) and once the organic layer was drained away the aqueous layer was extracted with CH2Cl2 (3 x 10 mL) and the combined organic extracts were washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure. The yellow oil was found to still contain Lawesson’s reagent related impurities. The small batch of material was recombined with the main batch and the

1 material was partially dissolved in CH2Cl2 and a white solid was filtered away (by H

NMR was found to be Lawesson’s reagent related). Once concentrated under reduced pressure, the yellow semi-solid (12.0153 g) was chromatographed (125 g silica, eluant was 5% Et2O in hexanes; Rf = 0.41 for product, Rf = 0.14 for starting material) to give a yellow solid (4.12 g, 94%) which was found to be pure product by 1H NMR. 1H NMR:

(CDCl3) δ 3.86 (s, 3H), 4.27 (s, 3H), 6.86 (d, J = 9.04 Hz, 2H), 8.19 (d, J = 9.08 Hz, 2H).

2-(4-Methoxyphenylthioamido)acetic acid (5.33)

O-Methyl 4-methoxybenzothioate (5.32; 0.7531 g, 4.132 mmol) and glycine (dried overnight in vacuum oven at 120 °C; 0.3440 g, 4.582 mmol) were stirred in Et2O (3.5 mL, non-anhydrous) before solid NaOH (0.3663 g, 9.158 mmol) was added along with

H2O (3.5 mL). The resulting solution was stirred vigorously for 24 hours at room temperature before being diluted with Et2O (15 mL) which created a white precipitate which dissolved upon the addition of H2O (25 mL) and saturated NaHCO3 (5 mL). The aqueous layer was then extracted with Et2O (2 x 20 mL), and acidified with 6 M HCl (25 mL). The aqueous layer was extracted with Et2O (3 x 20 mL) and the organic extracts were washed with brine (20 mL), dried over MgSO4 and concentrated to give a yellow

224

1 1 (0.8815g, 95%) solid which by H NMR was pure product. H NMR: (DMSO-d6) δ 3.82

(s, 3H), 4.41 (d, 2H, J = 4.0 Hz), 6.99 (d, J = 8.7 Hz, 2H), 7.87 (d, J = 8.7 Hz, 2H), 10.31

(t, 1H, J = 5.44), 12.75 (br. s, 1H).

2-(4-Methoxyphenyl)-1,3-thiazol-5(4H)-one (5.34)

2-(4-Methoxyphenylthioamido)acetic acid (5.33; 0.2003 g, 0.8892 mmol) was partially dissolved in CH2Cl2 (12 mL, anhydrous, distilled over CaH2) while under argon. Then

DCC (0.1855 g, 0.8990 mmol) was added in one portion which caused the solution to turn clear within a few minutes and then cloudy again (sonication at this point did help dissolve the material). After stirring at room temperature for 25 minutes, the solution was concentrated under reduced pressure to about 5 mL and gravity filtered to remove the dicyclohexylurea. The filtrate was concentrated under reduced pressure to give a yellow solid which agreed with 1H NMR data available in the literature.218 Due to instability, the

1 desired product was used crude, in situ without further purification. H NMR (CDCl3)

3.87 (s, 3H), 4.85 (s, 2H), 6.98 (d, J = 8.88 Hz, 2H), 7.77 (d, J = 8.84 Hz, 2H).

225

α-Bromo-4-methoxyacetophenone (5.37)

4-Methoxyacetophenone (5.36; 5.00 g, 33.3 mmol) was dissolved in CHCl3 (23 mL) and stirred at room temperature before a solution of Br2 (1.73 mL, d = 3.119 g/mL, 33.8 mmol) in CHCl3 (17 mL) was slowly added over a period of about 10 minutes. After a few minutes, the solution was diluted with Et2O (100 mL) and neutralized by slowly adding saturated NaHCO3 (40 mL). Once the solution had stirred for about 10 minutes, it was extracted with Et2O (3 x 50 mL). The combined organic extracts were washed with

1 brine (50 mL), dried over CaCl2, and concentrated under reduced pressure. H NMR showed a trace of dibrominated product which was removed through recrystallization from aqueous EtOH to give a white solid which was dried under vacuum under dark conditions. Yield: 6.24 g, 82%. 1H NMR matched that reported in the literature.219 1H

NMR (CDCl3, 300MHz) 3.89 (s, 3H), 4.40 (s, 2H), 6.97 (d, J = 9 Hz, 2H), 7.98 (d, J =

9 Hz, 2H).

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α-Azido-4-methoxyacetophenone (5.38)

α-Bromo-4-methoxyacetophenone (5.37; 19.23 g, 83.95 mmol) was dissolved in acetone

(375 mL) before NaN3 (8.29 g. 128 mmol) was added in one portion and allowed to stir at room temperature for 24 hours. The solution was then diluted with H2O (350 mL) and extracted with CH2Cl2 (3 x 150 mL), washed with brine (100 mL), dried over CaCl2 and concentrated to a yellow solid which was pure by 1H NMR and matched that of the

177 1 literature. Yield: (15.2047 g, 95%). H NMR (CDCl3, 300MHz) 3.89 (s, 3H), 4.51

(s, 2H), 6.97 (d, J = 8 Hz, 2H), 7.90 (d, J = 9 Hz, 2H).

α-Amino-4-methoxyacetophenone hydrochloride (5.39)

α-Azido-4-methoxyacetophenone (5.38; 3.13 g, 16.4 mmol) and Pd (10% on carbon;

0.2668 g) were dissolved in EtOH and HCl (6 M, 7.0 mL) and stirred for a few minutes before being placed under an atmosphere of hydrogen gas. After stirring under a hydrogen atmosphere for about 64 hours (100 mL of H2 was absorbed) the solution was filtered through celite and concentrated under reduced pressure. The resulting off-white solid was dissolved in H2O (100 mL) and extracted with Et2O (75 mL). The aqueous layer was concentrated to a light yellow solid which was dried under vacuum (P2O5) and

1 220 1 matched H NMR data from the literature. Yield: 3.00 g, 91%. H NMR (D2O,

300MHz) 3.91 (s, 3H), 4.62 (s, 2H), 7.11 (d, J = 8.91 Hz, 2H), 7.99 (d, J = 8.94 Hz,

2H).

227

4-Methoxy-N-(2-(4-methoxyphenyl)-2-oxoethyl)benzamide (5.41)

4-Methoxybenzoic acid (5.40; 0.3784 g, 2.487 mmol) was dissolved in toluene

(anhydrous, dried over 4Å molecular sieves; 5 mL) under argon before SOCl2 (2.3 mL, d

= 1.631 g/mL, 32 mmol) was added in one portion and the resulting solution was heated under reflux for 2 hours. The resulting solution was then concentrated under reduced pressure and diluted with THF (anhydrous; 20mL) and pyridine (anhydrous, distilled from CaH2; 0.45 mL, d = 0.978 g/mL, 35 mmol). α-Amino-4-methoxyacetophenone hydrochloride (5.39; 0.5026 g, 2.492 mmol) was suspended in THF (anhydrous; 20 mL) before NaHCO3 (solid; 0.7177 g, 8.543 mmol). The solution of acid chloride was then quickly added to the solution of 5.39 at room temperature. After stirring at room temperature, under argon overnight, the orange solution was diluted with H2O (30 mL) then partially concentrated under reduced pressure until only the H2O remained. The orange solution was then extracted with CH2Cl2 (2 x 20 mL), washed with brine (20 mL), and dried over MgSO4. The solvent was removed in vacuo to give a dark yellow solid

1 221 which was dried under vacuum (P2O5) and matched H NMR data from the literature.

1 Yield: 0.63 g, 85%. H NMR (CDCl3, 300MHz) 3.87 (s, 3H), 3.90 (s, 3H), 4.90 (d, J =

4 Hz, 2H), 6.96 (d, J = 9 Hz, 2H), 6.99 (d, J = 10 Hz, 2H), 7.86 (d, J = 9 Hz, 2H), 8.02 (d,

J = 8 Hz, 2H).

2,5-Bis(4-methoxyphenyl)-1,3-thiazole (5.42)

4-Methoxy-N-(2-(4-methoxyphenyl)-2-oxoethyl)benzamide (5.41; 7.27 g, 24.3 mmol) was dissolved in THF (anhydrous; 240 mL) under nitrogen before Lawesson’s reagent

228

(10.90 g, 26.95 mmol) was added in one portion. The resulting solution was allowed to stir at room temperature for 18 hours at which point the solvent was removed in vacuo to give a red semi-solid which was washed with KOH (20% wt./vol., 300 mL) and extracted with CH2Cl2 (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over CaCl2 and concentrated under reduced pressure to give a red solid which

1 was pure. The material was dried under vacuum (P2O5), found to be pure by H NMR

30 1 and matched that of the literature. Yield: 7.19 g, 100%. H NMR (CDCl3) 3.85 (s,

3H), 3.87 (s, 3H), 6.95 (d, J = 8.36 Hz, 2H), 6.97 (d, J = 8.60 Hz, 2H), 7.52 (d, J = 8.84

Hz, 2H), 7.86 (s, 1H), 7.89 (d, J = 8.92 Hz, 2H).

4-Bromo-2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.43)

2,5-Bis(4-methoxyphenyl)-1,3-thiazole (5.42; 0.2520 g, 0.8474 mmol) was dissolved in

CHCl3 (anhydrous; 5.5 mL) and cooled to -40 °C using a CaCl2/dry ice bath while under argon. NBS (0.1881 g, 1.057 mmol) was added in one portion and the resulting solution was stirred for 2 hours before being allowed to stir at room temperature for another hour.

The solution was then washed with H2O (40 mL) and extracted with CH2Cl2 (3 x 25 mL).

The combined organic extracts were washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure. The impure material (0.31 g) was chromatographed (30 g silica, eluant was 10% EtOAc in petroleum ether)* to give a white solid which was pure by 1H NMR. Yield: 0.25 g, 78%. *The material could also

1 be purified by recrystallizing from EtOH. H NMR (CDCl3) 3.86 (s, 3H), 3.87 (s, 3H),

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6.96 (d, J = 9.00 Hz, 2H), 6.98 (d, J = 8.96 Hz, 2H), 7.61 (d, J = 8.84 Hz, 2H), 7.87 (d, J

= 8.96 Hz, 2H).

4-Fluoro-2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.44)

4-Bromo-2,5-bis(4-methoxyphenyl)-1,3-thiazole (5.43; 0.0503 g, 0.134 mmol) was dissolved in THF (anhydrous; 5 mL) and cooled to -75 °C while under argon. Then n-

BuLi (0.08 mL, 2.2 M in cyclohexane, 0.2 mmol) was slowly added over a few seconds

(internal temperature did not exceed -72 °C, solution turned orange) and then allowed to stir at -78 °C for 2 hours (complete consumption of the starting material was confirmed by GC) before a solution of NFSI (0.0507 g, 0.161 mmol) in THF (anhydrous; 2.5 mL) was slowly added over 30 seconds (internal temperature did not exceed -65 °C, solution turned yellow). The resulting solution was allowed to stir at -78 °C for 3 hours before being allowed to warm to room temperature overnight (crude 19F showed product (-109) and starting NFSI (-38.6); 1H NMR showed mostly the parent 1,3-thiazole (55%) and product (45%)). After warming to room temperature, the solution was concentrated under reduced pressure and the yellow solid was dissolved in CH2Cl2 before the aqueous layer was drained away. The aqueous layer was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure to give a yellow solid (0.0687 g). The material was chromatographed (16 g silica, eluant was 10% EtOAc in petroleum ether; Rf of parent

1,3-thiazole = 0.07, Rf of product = 0.20) to give a white solid (0.0217 g, ~51%) which

1 was pure desired product contaminated with grease. H NMR (CDCl3) 3.84 (s, 3H),

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3.86 (s, 3H), 6.96 (app. d, J = 8.48 Hz, 4H), 7.54 (d, J = 8.80 Hz, 2H), 7.83 (d, J = 8.84

19 Hz, 2H); F NMR (CDCl3, CFCl3) -109.0 (s, 1F).

4-Bromo-2-octyloxy-1,3-thiazole (5.45)

1-Octanol (0.4335 g, 3.329 mmol) and Na metal (0.0447 g, 1.94 mmol) were stirred and heated under reflux, under argon in THF (anhydrous, distilled over Na and benzophenone; 5 mL) overnight to give a white, cloudy solution. Once at room temperature, CuO (0.0508 g, 0.639 mmol), KI (0.0025 g, 0.015 mmol), and 2,4-dibromo-

1,3-thiazole (3.11; 0.3088 g, 1.271 mmol) were added sequentially in one portion each along with more THF (anhydrous; 10 mL). The resulting brown solution was heated under reflux, under argon for 22 hours at which point a crude 1H NMR showed desired product and no signs of starting material. The material was filtered through celite which was washed with EtOAc (25 mL) to give a clear brown solution which was concentrated under reduced pressure to a brown oil. The material (0.6573 g) was chromatographed (16 g silica, eluant was 3% Et2O in petroleum ether; Rf = 0.22) to give a light yellow oil

(0.2415 g) which by 1H NMR was found to be mostly product with a small amount of dioctylcarbonate (~3%). After being vigorously stirred in a solution of methanolic NaOH

(3 mL; 2.5% wt./vol.), the solution was concentrated under reduced pressure, then extracted with Et2O (3 x 5 mL). The combined organic extracts were dried over MgSO4

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and concentrated to an off-white oil which by 1H NMR was found to contain no dioctylcarbonate. The material was chromatographed (15 g silica, eluant was 2% Et2O in petroleum ether) to give a colorless oil (0.2144 g, 58%) which was pure by 1H NMR. 1H

NMR (CDCl3) 0.88 (t, J = 6.84 Hz, 3H), 1.20-1.46 (m, 10H), 1.78 (quint., J = 7.05 Hz,

13 2H), 4.40 (t, J = 6.64 Hz, 2H), 6.56 (s, 1H); C NMR (CDCl3) 14.1, 22.6, 25.7, 28.7,

29.2 (2), 31.8, 72.6, 107.9, 118.5, 174.4.

4-Bromo-2-(4-cyanophenyl)-5-octyloxy-1,3-thiazole (5.47)

2-(4-Cyanophenyl)-5-octyloxy-1,3-thiazole (2.8a; 2.2000 g, 6.9963 mmol) and NBS

(1.5588 g, 8.7583 mmol) were dissolved in CHCl3 (40 mL, stabilized with 1% EtOH) and stirred at room temperature for 20 hours (1H NMR showed no starting material and only a single product) before being washed with H2O (25 mL). Once the organic layer was drained away, the aqueous layer was extracted with CH2Cl2 (3 x 35 mL). The combined organic extracts were washed with brine (35 mL), dried over MgSO4, and concentrated under reduced pressure to give an orange solid which by 1H NMR was product with a small amount of succinimide. The impure material was recrystallized from EtOH to give a light yellow solid (2.1988 g) which was pure by 1H NMR. The mother liquor (0.64 g) was concentrated onto silica (0.98 g) and chromatographed (15 g silica, eluant was 5%

EtOAc) to give a light yellow solid (0.3444 g). Combined yield: 2.5432 g, 92%. 1H

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NMR (CDCl3) 0.89 (t, J = 6.90 Hz, 3H), 1.22-1.41 (m, 8H), 1.49 (quint., J = 7.35 Hz,

2H), 1.85 (quint., J = 7.04 Hz, 2H), 4.17 (t, J = 6.52 Hz, 2H), 7.69 (d, J = 8.64 Hz, 2H),

13 7.91 (d, J = 8.64 Hz, 2H); C NMR (CDCl3) 14.1, 22.6, 25.6, 29.1 (2), 29.2, 31.8, 78.3,

110.5, 112.9, 118.4, 125.6, 132.7, 137.1, 152.3, 155.7.

2-(4-Cyanophenyl)-5-octyloxy-4-tributylstannyl-1,3-thiazole (5.50)

4-Bromo-2-(4-cyanophenyl)-5-octyloxy-1,3-thiazole (5.47; 0.1003 g, 0.2550 mmol), bis(tributyltin) (0.3324 g, 0.5730 mmol), and Pd(PPh3)4 (0.0157 g, 0.0136 mmol) were dissolved in toluene (anhydrous; 5 mL) and heated under reflux, under argon for 24 hours

(1H NMR showed starting material [44%], parent 1,3-thiazole [11%], and desired product

[46%]). A second addition of Pd(PPh3)4 (0.0168 g, 0.0145 mmol) was made and the resulting solution was heated under reflux, under argon for another 24 hours (1H NMR showed starting material [9%], parent 1,3-thiazole [17%], and desired product [74%]).

Once at room temperature, the black solution was filtered through celite and concentrated onto silica (0.97 g). The material (0.4445 g) was chromatographed (16 g silica, eluant was 5% EtOAc in petroleum ether) to give an off-white oil (0.0830 g, 54%) which by 1H

NMR was found to be pure. A significant portion of starting material and parent 1,3- thiazole was also recovered (0.0499 g) which by 1H NMR was 92% parent 1,3-thiazole

1 and 8% starting material.* H NMR (CDCl3) 0.85-0.95 (m, 12H), 1.00-1.71 (m, 28H),

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1.81 (quint., J = 6.99 Hz, 2H), 4.07 (t, J = 6.46 Hz, 2H), 7.64 (d, J = 8.28 Hz, 2H), 7.92

13 (d, J = 8.28 Hz, 2H); C NMR (CDCl3) 10.3, 13.8, 14.1, 22.7, 25.9, 27.3, 29.1, 29.2,

29.3, 29.5, 31.8, 77.4, 111.4, 118.9, 125.9, 132.5, 138.8, 141.1, 154.0, 168.1; 119Sn {1H}

NMR (CDCl3) -52.6 (s, 1Sn). *In some instances the product was contaminated with

Bu3SnBr which was removed by dissolving the impure product in Et2O, stirring with aq.

KF (0.25 g in 1 mL of H2O) for a few minutes and the resulting white precipitate

(Bu3SnF) was gravity filtered away.

2-Octyloxy-4-tributylstannyl-1,3-thiazole (5.51)

A solution of n-BuLi (0.86 mL, 1.8 M in cyclohexane, 1.5 mmol) was diluted with Et2O

(anhydrous, distilled over Na and benzophenone; 12 mL) and cooled to -76 °C while under argon. Then, a solution of 4-bromo-2-octyloxy-1,3-thiazole (0.3003 g, 1.028 mmol) in Et2O (anhydrous, 1.0 mL) was slowly added to the aforementioned n-BuLi over a period of about 15 minutes (internal temperature did not exceed -74 °C). The resulting clear, colorless solution was allowed to stir at -78 °C for 50 minutes (GC showed complete consumption of starting material and no signs of halogen dance) before a solution of Bu3SnCl (0.6119 g, 1.880 mmol) in Et2O (anhydrous, 1.0 mL) was slowly added over a period of about 10 minutes (internal temperature did not exceed -74 °C).

After stirring at -78 °C for 60 minutes, the clear, colorless solution was allowed to warm

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to room temperature over about 60 minutes (turned milky white around 0 °C). The crude material was then washed with aq. KF (1.25 g in 10 mL of H2O) and the aqueous layer was extracted with Et2O (3 x 15mL). The combined organic extracts were washed with brine (12 mL), dried over MgSO4 and concentrated to give a light yellow oil (0.8000 g)

1 119 which was nearly pure by H and Sn NMR except for what appears to be Bu4Sn (-12.7, s). The material was chromatographed (25 g silica, eluant was 3% Et2O in petroleum ether) to give a clear, colorless oil (0.7238 g, 98%*) by 119Sn NMR was 70% desired

1 1 product and 30% Bu4Sn. *Estimated from H NMR ratio. H NMR (CDCl3) 0.84-0.93

(m, 12H), 0.97-1.15 (m, 6H) 1.21-1.67 (m, 22H), 1.79 (quint., J = 7.07 Hz, 2H), 4.35 (t, J

13 = 6.64 Hz, 2H), 6.64 (m, 1H); C NMR (CDCl3) 10.2, 13.7, 14.1, 22.7, 25.9, 27.3, 29.0

119 1 (2), 29.2, 29.3, 31.8, 72.0, 117.4, 154.4, 175.2; Sn { H} NMR (CDCl3) -56.5 (s,

1Sn).

5-Fluoro-2-(octyloxy)-1,3-thiazol-4(5H)-one (5.54)

Impure 2-octyloxy-4-tributylstannyl-1,3-thiazole (0.1432 g, 70% pure with 30% Bu4Sn,

0.1995 mmol), Ag2O (0.0028 g, 0.012 mmol), NaHCO3 (0.0353 g, 0.420 mmol), NaOTf

(0.0341 g, 0.198 mmol) and SelectFluor™ (0.1066 g, 0.3009 mmol) were dissolved in acetone (anhydrous; 7 mL) which was stirred in a glass pressure vessel and heated

(external temperature was 65 °C) for 90 minutes. Crude 1H NMR showed mostly 2-

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octyloxy-1,3-thiazole, starting material and perhaps a trace of the desired product in a ratio of 55:38:7* *(peak is not a clean doublet for the suspected product). The crude reaction mixture was filtered through celite and concentrated to a white solid (0.2049 g) which was then redissolved, and concentrated onto silica (0.51 g). The material was chromatographed (15 g silica, eluant was 6% EtOAc in petroleum ether) to give mostly protodestannylated material (0.0121 g, 28%), 5-fluoro-2-octyloxy-1,3-thiazol-4-one

(0.0022 g, 4%), and another unknown compound which contained a signal in the 19F

1 NMR. 2-Octyloxy-1,3-thiazole (5.53): H NMR (CDCl3) 0.88 (t, J = 6.90 Hz, 3H),

1.20-1.39 (m, 8H), 1.43 (quint., J = 7.15 Hz, 2H), 1.80 (quint., J = 7.08 Hz, 2H), 4.38 (t,

J = 6.66, 2H), 6.65 (d, J = 3.84 Hz, 1H), 7.11 (d, J = 3.84 Hz, 1H). 5-Fluoro-2-

1 (octyloxy)-1,3-thiazol-4(5H)-one (5.54): H NMR (CDCl3) 0.89 (t, J = 6.88 Hz, 3H),

1.20-1.46 (m, 10H), 1.83 (quint., J = 7.08 Hz, 2H), 4.64 (dt, J = 10.48 Hz, 6.68 Hz, 1H),

19 4.68 (dt, J = 10.44 Hz, 6.77 Hz, 1H), 6.44 (d, J = 55.14 Hz, 1H); F NMR (CDCl3,

CFCl3) -164.07 (d, J = 55.16 Hz, 1F).

2,4-Diamino-1,3-thiazole hydrochloride (5.62)

Thiourea (5.60; 0.5007 g, 6.578 mmol) was stirred in acetone (10 mL, non-anhydrous) and chloroacetonitrile (5.61; 0.5010 g, 6.636 mmol) was added in one portion and the resulting solution was refluxed for 7 days before being cooled to -20 °C, filtered and

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washed with cold acetone (30 mL, -20 °C) to give an off-white solid (0.9474 g, 94%)

1 1 which was pure by H NMR. H NMR (DMSO-d6) 4.59 (s, 2H), 9.94 (br. s, 3H).

Methyl α-bromo-4-methoxyphenylacetate (5.66)

Compound 5.66 was prepared using a previously reported procedure.193

A light yellow oil was obtained (2.92 g, 100%) which matched the provided 1H NMR

193 1 data. H NMR (CDCl3, 300MHz) 3.79 (s, 3H), 3.81 (s, 3H), 5.35 (s, 1H), 6.89 (d, J

= 9 Hz, 2H), 7.49 (d, J = 9 Hz, 2H).

2,5-Bis(4-methoxyphenyl)-1,3-thiazol-4-ol (5.68a)

4-Methoxythiobenzamide (5.67; 0.2507 g, 1.499 mmol), pyridine (0.60mL, d = 0.978 g/mL, 7.4 mmol), and toluene (15 mL) were stirred for a few minutes before a solution of methyl α-bromo-4-methoxyphenylacetate (5.66; 0.3950 g, 1.525 mmol) in toluene (5 mL) was added dropwise. The resulting solution was then heated at 82 °C (external temperature) for about 2 hours at which point it was cooled in an ice bath for another hour. The resulting precipitate was filtered and washed with petroleum ether. 1H NMR showed both the isolated solid and filtrate contained product. Separately they were washed with H2O and extracted with Et2O (3 x 20 mL) which failed to purify the material. The solid and filtrate were recombined then chromatographed (40 g silica,

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eluant was 15% EtOAc in petroleum ether) to give a dark yellow solid (0.4410 g, 92%)

1 1 which was pure by H NMR. H NMR (DMSO-d6, 300MHz) 3.77 (s, 3H), 3.82 (s,

3H), 6.97 (d, J = 9.07 Hz, 2H), 7.06 (d, J = 8.93 Hz, 2H), 7.63 (d, J = 8.92 Hz, 2H), 7.81

(d, J = 8.90 Hz, 2H), 10.55 (s, 1H).

2-(4-Fluorophenyl)-5-octyloxy-1,3-thiazole (5.71)

4-Fluorobenzoic acid (3.1701 g, 22.626 mmol) was dissolved in toluene (anhydrous; 24 mL) before SOCl2 (17.0 mL, d = 1.631 g/mL, 233 mmol) was added in one portion. The solution was heated under reflux for 4 hours, whereupon crude 19F NMR showed starting material was still present (10%) and additional SOCl2 (2.5 mL, 34 mmol) was added and the solution was allowed to heat under reflux for another 90 minutes (starting material

19 was consumed according to F NMR). The excess SOCl2 and toluene were boiled away under argon and collected in a Dean-Stark trap (24 mL collected). Once at room temperature, the light tan solution was cooled on ice and added slowly to a cold solution

(2 °C, internal temperature) of octyl 2-aminoethanoate hydromethanesulfonate (2.4a;

6.3167 g, 22.291 mmol), Et3N (anhydrous, distilled from CaH2; 11.0 mL, d = 0.726 g/mL, 78.9 mmol) and CHCl3 (anhydrous; 50 mL) over a period of 25 minutes (internal

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temperature did not exceed 8 °C). The resulting dark solution was allowed to stir at a temperature range of 0-3 °C for at least 90 minutes before being allowed to warm to room temperature overnight. The solution was shaken with saturated NaHCO3 (120 mL) and once the organic layer was drained away, the aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over

MgSO4, and concentrated to give a dark liquid (8.13 g). The material was chromatographed (215 g, eluant was 25% EtOAc in petroleum ether) to give an off-white solid (4.33 g, 63%) which was product with a trace of the some 4-fluorophenyl based

1 compound. H NMR (CDCl3) 0.89 (t, J = 6.86 Hz, 3H), 1.20-1.41 (m, 10H), 1.67

(quint., J = 7.02 Hz, 2H), 4.20 (t, J = 6.74 Hz, 2H), 4.23 (d, J = 4.92 Hz, 2H), 6.60 (br. s,

19 1H), 7.13 (app. t, J = 8.62 Hz, 2H), 7.83 (dd, J = 5.19, 8.82 Hz, 2H); F NMR (CDCl3,

13 CFCl3) -108.2 (app. tt, J = 5.27 Hz, 8.38 Hz, 1F); C NMR (CDCl3) 14.1, 22.6, 25.8,

28.5, 29.2 (2), 31.8, 41.9, 65.9, 115.6 (d, J = 21.84 Hz), 129.5 (d, J = 9.01 Hz), 129.9 (d,

J = 3.03 Hz), 164.9 (d, J = 252.30 Hz), 166.5, 170.3. Octyl (4- fluorobenzoylamino)ethanoate (4.33 g, 14.0 mmol) and Lawesson’s reagent (6.2628 g,

15.484 mmol) were dissolved in toluene (anhydrous, distilled over Na and benzophenone,

120 mL) and heated under reflux, under argon for 24 hours (1H NMR showed absence of starting material) before being concentrated under reduced pressure. The resulting thick liquid was dissolved in CH2Cl2 and stirred with KOH (aq. 20% wt./vol, 80 mL). A slow resolving emulsion resulted so the solution was heated (50 °C) under vacuum. The aqueous layer was then easily extracted (no emulsion) with CH2Cl2 (3 x 50 mL). The combined organic extracts were washed with brine (25 mL), dried over MgSO4, filtered

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through celite, and concentrated to give a red solid which was recrystallized from EtOH

1 to give a tan solid (3.4573 g, 80%). H NMR (CDCl3) 0.89 (t, J = 6.82 Hz, 3H), 1.22-

1.40 (m, 8H), 1.45 (quint., J = 7.24 Hz, 2H), 1.80 (quint., J = 7.03 Hz, 2H), 4.08 (t, J =

6.52 Hz, 2H), 7.09 (app. t, J = 8.68 Hz, 2H), 7.10 (s, 1H), 7.78 (dd, J = 5.26, 8.90 Hz,

13 2H); C NMR (CDCl3) 14.1, 22.7, 25.8, 29.13, 29.18, 29.23, 31.8, 75.5, 115.9 (d, J =

22.05 Hz), 122.8, 127.4 (d, J = 8.34 Hz), 130.6 (d, J = 3.10 Hz), 154.3, 162.15, 163.4 (d,

19 J = 251.08 Hz); F NMR (CDCl3, CFCl3) -112.3 (app. tt, J = 5.26 Hz, 8.45 Hz, 1F).

4-Fluoro-2-(4-fluorophenyl)-5-octyloxy-1,3-thiazole (5.72)

2-(4-Fluorophenyl)-5-octyloxy-1,3-thiazole (5.71; 0.2504 g, 0.8145 mmol) was stirred with MeCN (anhydrous; 8 mL) for a few minutes under argon before SelectFluor™

(0.3024 g, 0.8536 mmol) was added in one portion (solution quickly turned light pink then became dark purple). The resulting solution was heated at 55 °C (external temperature), under argon for 30 minutes (solution was dark red after 30 minutes; by GC the product to starting material ratio was 58:42). Once cool, the solution was concentrated under reduced pressure to give a red/orange solid which was then dissolved in CH2Cl2 and shaken with H2O. Once the organic layer was drained away, the aqueous layer was extracted with CH2Cl2 (3 x 10mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered through celite, and concentrated under reduced pressure onto silica (1.04 g) to give an orange material (~0.3247 g). The material was chromatographed (30 g silica, eluant was 3% Et2O in petroleum ether) to give an impure pink oil (0.0606 g, 23%) which by 1H and 19F NMR was mostly product.

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1 Mp = 28.2°C. H NMR (CDCl3) 0.89 (t, J = 6.88 Hz, 3H), 1.20-1.39 (m, 8H), 1.44

(quint., J = 7.20 Hz, 2H), 1.78 (quint., J = 7.05 Hz, 2H), 4.09 (t, J = 6.56 Hz, 2H), 7.08

13 (app. t, J = 8.64 Hz, 2H), 7.75 (dd, J = 5.20, 8.92 Hz, 2H); C NMR (CDCl3) 14.1,

22.7, 25.6, 29.18, 29.21, 29.28, 31.8, 77.9, 116.1 (d, J = 22.24 Hz), 126.9 (d, J = 8.43

Hz), 129.7 (d, J = 3.13 Hz), 136.7 (d, J = 28.25 Hz; C5 of 1,3-thiazole), 148.3 (d, J =

242.06 Hz; C4 of 1,3-thiazole), 149.9 (d, J = 18.29 Hz; C2 of 1,3-thiazole), 163.8 (d, J =

19 250.65 Hz); F NMR (CDCl3, CFCl3) -111.0 (app. tt, J = 5.21 Hz, 8.39 Hz, 1F), -123.0

(s, 1F). Anal. Calcd for C17H21F2NOS: C, 62.74; H, 6.50; N, 4.30. Found: C, 63.03; H,

6.45; N, 4.43%.

2-(4-Bromophenyl)-4-fluoro-5-octyloxy-1,3-thiazole (5.73)

2-(4-Bromophenyl)-5-octyloxy-1,3-thiazole (2.7a; 1.0004 g, 2.7160 mmol) was stirred with MeCN (anhydrous; 18 mL) and heated (55 °C, external temperature) for a few minutes under argon before SelectFluor™ (1.0109 g, 2.8536 mmol) was added in one portion (solution quickly turned dark purple then red after about 2 hours). The resulting solution was heated at 55 °C (external temperature), under argon for 26 hours (by GC the product to starting material ratio was 70:30 at 5.5 hours, increased to 75:25 after 22 hours, and had not changed after 26 hours) before being concentrated under reduced pressure. The resulting red solid was dissolved in CH2Cl2 and shaken with H2O. Once

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the organic layer was drained away, the aqueous layer was extracted with CH2Cl2 (3 x 25 mL). The combined organic extracts were dried over MgSO4, filtered through celite, and concentrated under reduced pressure onto silica (1.50 g) to give a dark red material which by 1H and 19F NMR did not show any signs of N-fluorination of the 1,3-thiazole ring but did show product. The material was chromatographed (40 g silica, eluant was 1% Et2O in petroleum ether then switched to 10% EtOAc in petroleum ether to recover the starting material) to give a yellow oil (0.3610 g, 34%) which by 1H and 19F NMR was about 99% product. A significant amount of starting material (0.3408 g) was also recovered which

1 1 by H NMR was not very pure. H NMR (CDCl3) 0.89 (t, J = 6.90 Hz, 3H), 1.22-1.39

(m, 8H), 1.44 (quint., J = 7.18 Hz, 2H), 1.78 (quint., J = 7.04 Hz, 2H), 4.10 (t, J = 6.56

13 Hz, 2H), 7.52 (d, J = 8.64 Hz, 2H), 7.63 (d, J = 8.64 Hz, 2H); C NMR (CDCl3) 14.1,

22.6, 25.6, 29.17, 29.19, 29.26, 31.8, 77.9, 124.1, 126.3, 132.1, 132.3, 137.1 (d, J = 28.20

Hz; C5 of 1,3-thiazole), 148.3 (d, J = 242.30 Hz; C4 of 1,3-thiazole), 148.5 (d, J = 18.22

19 Hz; C2 of 1,3-thiazole); F NMR (CDCl3, CFCl3) -122.7 (s, 1F). Anal. Calcd for

C17H21BrFNOS: C, 52.85; H, 5.48; N, 3.63. Found: C, 52.97; H, 5.47; N, 3.72%.

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2-(4-Cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole (5.48a)

2-(4-Cyanophenyl)-5-octyloxy-1,3-thiazole (2.8a; 3.0005 g, 9.5421 mmol) and

SelectFluor™ (3.5589 g, 10.046 mmol) were dissolved in MeCN (anhydrous; 90 mL) and heated at 55 °C (external temperature), under argon for 25 hours at which point (by

GC the product to starting material ratio was 72:28) the cool, dark solution was filtered through celite, which was washed with EtOAc. The filtrate was concentrated under reduced pressure onto silica (8.04 g). The material (6.25 g) was chromatographed (325 g silica, eluant was 69% petroleum ether, 30% CH2Cl2, and 1% Et2O then switched to

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recycled solvent with 10 mL Et2O added per 100 mL of solvent once all the pure product had eluted) to give an off-white crystalline solid (1.2843 g, 40%) which was pure by 1H

NMR. Impure product was recovered (0.20 g) which by 1H NMR was 62% product, 4%

4-chloro-1,3-thiazole, and 34% unknown. Starting material was also recovered (0.6745 g) which by 1H NMR was 79% pure with unknown contaminants. The impure product was chromatographed again (70 g silica, eluant was 69% petroleum ether, 30% CH2Cl2,

1 and 1% Et2O) to give an off-white solid (0.0692 g) which was pure by H NMR. Impure product was recovered (0.0197 g) which by 1H NMR was 58% product, 26% 4-chloro-

1,3-thiazole, and 16% of two unknown contaminants. For the purposes of liquid crystal analysis, about 0.40g of the pure product was twice recrystallized from a 1:1 mixture of light petroleum ether and Et2O (had to be slowly cooled to about 7°C before crystals started forming) to give an off-white solid which was dried under vacuum. Combined

1 isolated yield: 1.3535 g, 43%. Mp = 41.9 °C (rec. 34.5 °C). H NMR (CDCl3) 0.89 (t,

J = 6.86 Hz, 3H), 1.22-1.40 (m, 8H), 1.45 (quint., J = 7.17 Hz, 2H), 1.80 (quint., J = 7.04

Hz, 2H), 4.14 (t, J = 6.54 Hz, 2H), 7.68 (d, J = 8.64 Hz, 2H), 7.86 (d, J = 8.64 Hz, 2H);

13 C NMR (CDCl3) 14.1, 22.6, 25.6, 29.15, 29.17, 29.25, 31.8, 78.0, 112.9, 118.4, 125.1,

132.7, 137.1, 139.0 (d, J = 28.22 Hz; C5 of 1,3-thiazole), 146.4 (d, J = 18.15 Hz; C2 of

19 1,3-thiazole), 148.6 (d, J = 243.09 Hz; C4 of 1,3-thiazole); F NMR (CDCl3, CFCl3) -

122.1 (s, 1F). Anal. Calcd for C18H21FN2OS: C, 65.03; H, 6.37; N, 8.43. Found: C,

65.13; H, 6.34; N, 8.40%.

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2-(4-Cyanophenyl)-4-fluoro-5-nonyloxy-1,3-thiazole (5.48b)

Compound 5.48b was prepared using a similar procedure to that described for the preparation of 5.48a (except the reaction was heated under reflux) using the quantities stated: 2.8b (3.0005 g, 9.1348 mmol), SelectFluor™ (3.4076 g, 9.6189 mmol), MeCN

(anhydrous; 48 mL). By GC the product to starting material ratio was 85:15. The material (4.12 g) was chromatographed (320 g silica, eluant was 69% petroleum ether,

30% CH2Cl2, and 1% Et2O then switched to recycled solvent with 7.5 mL Et2O added per

100 mL of solvent once all the pure product had eluted) to give an off-white crystalline solid (1.1018 g, 35%) which was pure by 1H NMR. Impure product was recovered (0.36 g) which by 1H NMR was 86% product, 6% 4-chloro-1,3-thiazole, and 8% unknown.

Starting material was also recovered (0.54 g) which by 1H NMR was 49% pure with unknown contaminants. The impure product was chromatographed (320 g silica, eluant was 69% petroleum ether, 30% CH2Cl2, and 1% Et2O then switched to recycled solvent with 7.5 mL Et2O added per 100 mL of solvent once all the pure product had eluted) to give an off-white crystalline solid (0.2350 g, 7%) which was pure by 1H NMR. Again, impure product was collected (0.06 g) which by 1H NMR was 53% desired product, 36%

4-chloro-1,3-thiazole and 11% unknown contaminants. For the purposes of liquid crystal analysis, about 0.40g of the pure product was twice recrystallized from a 1:1 mixture of light petroleum ether and Et2O to give a white solid which was dried under vacuum.

Combined isolated yield: 1.3368 g, 42%. Mp = 40.8 °C (rec. 34.2 °C). 1H NMR

(CDCl3) 0.89 (t, J = 6.88 Hz, 3H), 1.21-1.40 (m, 10H), 1.45 (quint., J = 7.15 Hz, 2H),

1.80 (quint., J = 7.04 Hz, 2H), 4.14 (t, J = 6.54 Hz, 2H), 7.68 (d, J = 8.64 Hz, 2H), 7.87

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13 (d, J = 8.68 Hz, 2H); C NMR (CDCl3) 14.1, 22.7, 25.6, 29.21 (2), 29.25, 29.4, 31.8,

78.0, 112.9, 118.4, 125.2, 132.8, 137.1, 139.0 (d, J = 27.88 Hz; C5 of 1,3-thiazole), 146.4

(d, J = 18.15 Hz; C2 of 1,3-thiazole), 148.6 (d, J = 243.19 Hz; C4 of 1,3-thiazole); 19F

NMR (CDCl3, CFCl3) -122.0 (s, 1F). Anal. Calcd for C19H23FN2OS: C, 65.87; H, 6.69;

N, 8.09. Found: C, 65.62; H, 6.68; N, 8.05%.

2-(4-Cyanophenyl)-5-decyloxy-4-fluoro-1,3-thiazole (5.48c)

Compound 5.48c was prepared using a similar procedure to that described for the preparation of 5.48a (except the reaction was heated under reflux) using the quantities stated: 2.8c (3.0001 g, 8.7594 mmol), SelectFluor™ (3.2674 g, 9.2232 mmol), MeCN

(anhydrous; 60 mL). By GC the product to starting material ratio was 83:17. The material (3.85 g) was chromatographed (320 g silica, eluant was 69% petroleum ether,

30% CH2Cl2, and 1% Et2O then switched to recycled solvent with 7.5% Et2O added once all the pure product had eluted) to give an off-white solid (1.0733 g, 34%) which was pure by 1H NMR. Some impure product was recovered (0.23 g) which by 1H NMR was

91% product, and 9% 4-chloro-1,3-thiazole. Starting material was recovered (0.52 g) which by 1H NMR was 70% pure with unknown contaminants. The impure product was chromatographed (80 g silica, eluant was 69% petroleum ether, 30% CH2Cl2, and 1%

Et2O then switched to recycled solvent with 7.5 mL Et2O added per 100 mL of solvent once all the pure product had eluted) to give a light, off-white solid (0.1830 g, 6%) which was pure by 1H NMR. Again, impure product was collected (0.0263 g) which was 52% desired product mixed with the analogous 4-chloro-1,3-thiazole. For the purposes of

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liquid crystal analysis, about 0.40g of the pure product was twice recrystallized from a

1:1 mixture of light petroleum ether and Et2O to give a white solid which was dried under vacuum. Combined isolated yield: 1.2563 g, 40%. Mp = 43.1 °C (rec. 32.8 °C). 1H

NMR (CDCl3) 0.88 (t, J = 6.68 Hz, 3H), 1.17-1.40 (m, 12H), 1.45 (quint., J = 7.08 Hz,

2H), 1.80 (quint., J = 7.01 Hz, 2H), 4.14 (t, J = 6.52 Hz, 2H), 7.68 (d, J = 8.40 Hz, 2H),

13 7.86 (d, J = 8.40 Hz, 2H); C NMR (CDCl3) 14.1, 22.7, 25.6, 29.21, 29.25, 29.29,

29.49, 29.51, 31.9, 78.0, 112.9, 118.4, 125.2, 132.7, 137.1, 139.0 (d, J = 28.00 Hz; C5 of

1,3-thiazole), 146.4 (d, J = 18.25 Hz; C2 of 1,3-thiazole), 148.6 (d, J = 243.10 Hz; C4 of

19 1,3-thiazole); F NMR (CDCl3, CFCl3) -122.0 (s, 1F). Anal. Calcd for C20H25FN2OS:

C, 66.64; H, 6.99; N, 7.77. Found: C, 66.60; H, 7.00; N, 7.82%.

2-(4-Cyanophenyl)- 4-fluoro-5-undecyloxy-1,3-thiazole (5.48d)

Compound 5.48d was prepared using a similar procedure to that described for the preparation of 5.48a (except the reaction was heated under reflux) using the quantities stated: 2.8d (3.0004 g, 8.4158 mmol), SelectFluor™ (3.1400 g, 8.8635 mmol), MeCN

(anhydrous; 40 mL). By GC the product to starting material ratio was 83:17. The material (4.27 g) was chromatographed (320 g silica, eluant was 69% petroleum ether,

30% CH2Cl2, and 1% Et2O then switched to recycled solvent with 7.5 mL Et2O added per

100 mL of solvent once all the pure product had eluted) to give an off-white solid (1.1832 g, 38%) which was pure by 1H NMR. Impure product was recovered (0.20 g) which by

1H NMR was 87% product, 7% 4-chloro-1,3-thiazole, and 6% unknown contaminants (2 compounds). Starting material was recovered (0.61 g) which by 1H NMR was found to

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be 39% pure with unknown contaminants. The impure material was chromatographed

(70 g silica, eluant was 69% petroleum ether, 30% CH2Cl2, and 1% Et2O then switched to recycled solvent with 7.5 mL Et2O added per 100 mL of solvent once all the pure product had eluted) to give an off-white solid (0.1394 g) which was pure by 1H NMR. Impure product was recovered (0.0546 g) which by 1H NMR was 57% product, 34% 4-chloro-

1,3-thiazole, and 10% of two unknown compounds. For the purposes of liquid crystal analysis, about 0.40g of the pure product was twice recrystallized from a 1:1 mixture of light petroleum ether and Et2O to give a white solid which was dried under vacuum.

Combined isolated yield: 1.3226 g, 42%. Mp = 52.0 °C (rec. 45.7 °C). 1H NMR

(CDCl3) 0.88 (t, J = 6.86 Hz, 3H), 1.19-1.40 (m, 14H), 1.45 (quint., J = 7.17 Hz, 2H),

1.80 (quint., J = 7.04 Hz, 2H), 4.14 (t, J = 6.56 Hz, 2H), 7.68 (d, J = 8.60 Hz, 2H), 7.87

13 (d, J = 8.60 Hz, 2H); C NMR (CDCl3) 14.1, 22.7, 25.6, 29.21, 29.25, 29.33, 29.49,

29.55, 29.59, 31.9, 78.0, 112.9, 118.4, 125.2, 132.7, 137.1, 139.0 (d, J = 28.23 Hz; C5 of

1,3-thiazole), 146.4 (d, J = 18.18 Hz; C2 of 1,3-thiazole), 148.6 (d, J = 243.13 Hz; C4 of

19 1,3-thiazole); F NMR (CDCl3, CFCl3) -122.0 (s, 1F). Anal. Calcd for C21H27FN2OS:

C, 67.35; H, 7.27; N, 7.48. Found: C, 67.23; H, 7.24; N, 7.42%.

2-(4-Cyanophenyl)-5-dodecyloxy-4-fluoro-1,3-thiazole (5.48e)

Compound 5.48e was prepared using a similar procedure to that described for the preparation of 5.48a (except the reaction was heated under reflux) using the quantities stated: 2.8e (2.7315 g, 7.3715 mmol), SelectFluor™ (2.7428 g, 7.7423 mmol), MeCN

(anhydrous; 60 mL). By GC the product to starting material ratio was 83:17. The

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material (3.80 g) was chromatographed (310 g silica, eluant was 69% petroleum ether,

30% CH2Cl2, and 1% Et2O and switched to 63% petroleum ether, 27% CH2Cl2 and 10%

Et2O once all the pure product had eluted it was switched to 10% EtOAc in petroleum ether) to give a white solid (0.9338 g, 33%) which was found to be pure product 5.48e by

1H NMR. Impure product was recovered (0.75 g) which by 1H NMR was 70% product and 30% starting material. The mixture was chromatographed (75 g silica, eluant was

69% petroleum ether, 30% CH2Cl2, and 1% Et2O and switched to 63% petroleum ether,

27% CH2Cl2 and 1% Et2O once all the pure product had eluted it was switched to 10%

Et2O in petroleum ether) to give a white solid (0.1148 g, 4%) which was pure product

5.48e by 1H NMR. Impure product was recovered (0.0670 g) which by 1H NMR contained 51% product 5.48e and 49% 4-chloro-1,3-thiazole 5.48Cl. Impure starting material was also recovered (0.4947 g) which by 1H NMR was 30% pure. For the purposes of liquid crystal analysis, about 0.40g of the pure product 5.48e was twice recrystallized from a 1:1 mixture of light petroleum ether and Et2O to give a white solid which was dried under vacuum. Combined isolated yield of 5.48e: 1.0486 g, 37%. 2-(4-

Cyanophenyl)-5-dodecyloxy-4-fluoro-1,3-thiazole (5.48e): Mp = 49.7 °C (rec. 41.0 °C).

1 H NMR (CDCl3) 0.88 (t, J = 6.86 Hz, 3H), 1.20-1.40 (m, 16H), 1.45 (quint., J = 7.19

Hz, 2H), 1.80 (quint., J = 7.03 Hz, 2H), 4.14 (t, J = 6.54 Hz, 2H), 7.68 (d, J = 8.64 Hz,

13 2H), 7.87 (d, J = 8.60 Hz, 2H); C NMR (CDCl3) 14.1, 22.7, 25.6, 29.21, 29.26, 29.36,

29.49, 29.55, 29.64 (2), 31.9, 78.1, 112.9, 118.4, 125.2, 132.8, 137.1, 139.0 (d, J = 28.04

Hz; C5 of 1,3-thiazole), 146.3 (d, J = 18.09 Hz; C2 of 1,3-thiazole), 148.6 (d, J = 243.24

19 Hz; C4 of 1,3-thiazole); F NMR (CDCl3, CFCl3) -122.0 (s, 1F). Anal. Calcd for

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C22H29FN2OS: C, 68.01; H, 7.52; N, 7.21. Found: C, 68.24; H, 7.57; N, 7.10%; EI-MS m/z 388.2 (M+, 6%), 220.1 (100%), 146.1 (15%), 57.2 (23%). 4-Chloro-2-(4-

1 cyanophenyl)-5-dodecyloxy-1,3-thiazole (5.48Cl): H NMR (CDCl3) 0.88 (t, J = 6.86

Hz, 3H), 1.20-1.40 (m, 16H), 1.45 (quint., J = 7.19 Hz, 2H), 1.84 (quint., J = 7.01 Hz,

2H), 4.17 (t, J = 6.54 Hz, 2H), 7.69 (d, J = 8.72 Hz, 2H), 7.90 (d, J = 8.68 Hz, 2H); EI-

MS m/z 406.2 (3%), 404.2 (M+, 7%), 238.1 (33%), 236.1 (100%), 146.1 (25%), 57.1

(30%).

4-(4-Fluoro-5-octyloxy-1,3-thiazol-2-yl)benzaldehyde (5.74a)

2-(4-Cyanophenyl)-4-fluoro-5-octyloxy-1,3-thiazole (5.48a; 1.2532 g, 3.7697 mmol) was dissolved in toluene (anhydrous; 40 mL) and cooled to -72 °C while under argon

(solution became cloudy) DIBAl-H (3.5 mL, 1.2M in toluene, 4.2 mmol) was added dropwise over about 5 minutes causing the solution to turn yellow and clear (internal temperature did not exceed -65 °C). After stirring at -74 °C for 30 minutes (1H NMR showed a trace of starting material, ~1%) another addition of DIBAl-H (0.05 mL, 1.2M in toluene, 0.06 mmol) was made. Given the small amount of starting material remaining before the second addition of DIBAl-H, it was assumed all the starting material was gone so after stirring at -74 °C for 30 minutes the solution was allowed to warm to room temperature over about 20 minutes Once at room temperature, the solvent was removed under reduced pressure and the resulting residue was dissolved in CH2Cl2 (30 mL) and vigorously stirred with HCl (1M, 70 mL) for 15 minutes. After the organic layer was drained away, the aqueous layer was extracted with CH2Cl2 (3x25 mL) and the combined

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organic extracts were dried over MgSO4 and concentrated onto silica (2.70 g). The material (1.31 g) was chromatographed (140 g silica, eluant was 10% EtOAc in petroleum ether) to give a light yellow solid (1.0833 g, 86%) which was found to be pure by 1H NMR. For the purposes of EA, ~0.30 g of the material was recrystallized from a solution of Et2O / light petroleum ether (50:50) to give a light yellow, crystalline solid.

1 Mp = 38.4-39.7 °C. H NMR (CDCl3) 0.89 (t, J = 6.90 Hz, 3H), 1.22-1.40 (m, 8H),

1.46 (quint., J = 7.21 Hz, 2H), 1.80 (quint., J = 7.04 Hz, 2H), 4.15 (t, J = 6.54 Hz, 2H),

13 7.91 (d, J = 8.68 Hz, 2H), 7.94 (d, J = 8.68 Hz, 2H), 10.03 (s, 1H); C NMR (CDCl3)

14.1, 22.6, 25.6, 29.17, 29.18, 29.27, 31.8, 78.0, 125.2, 130.3, 136.8, 138.4, 138.8 (d, J

= 28.11 Hz; C5 of 1,3-thiazole), 147.2 (d, J = 18.24 Hz; C2 of 1,3-thiazole), 148.6 (d, J =

19 242.68 Hz; C4 of 1,3-thiazole), 191.3; F NMR (CDCl3, CFCl3) -122.1 (s, 1F). Anal.

Calcd for C19H24FNO2S: C, 64.45; H, 6.61; N, 4.18. Found: C, 64.36; H, 6.60; N, 4.12%.

4-(4-Fluoro-5-nonyloxy-1,3-thiazol-2-yl)benzaldehyde (5.74b)

Compound 5.74b was prepared using a similar procedure to that described for the preparation of 5.74a using the quantities stated: 5.48b (1.3187 g, 3.8062 mmol), toluene

(anhydrous; 40 mL), DIBAl-H (3.80 mL, 1.5M in toluene, 5.7 mmol). Once at room temperature, the solvent was removed under reduced pressure and the resulting residue was dissolved in CH2Cl2 (30 mL) and vigorously stirred with HCl (1 M, 70 mL) for 15 minutes. After the organic layer was drained away, the aqueous layer was extracted with

CH2Cl2 (3 x 25 mL) and the combined organic extracts were washed with brine (20 mL), dried over MgSO4, and concentrated onto silica (2.75 g). The material (1.47 g) was

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chromatographed (140 g silica, eluant was 10% EtOAc in petroleum ether) to give a light yellow solid (1.1469g, 86%) which was found to be pure by 1H NMR. For the purposes of EA, ~0.30 g of the material was recrystallized from a solution of Et2O / light petroleum ether (50:50) to give a light yellow, crystalline solid. Mp = 54.3-55.3 °C. 1H

NMR (CDCl3) 0.89 (t, J = 6.88 Hz, 3H), 1.22-1.40 (m, 10H), 1.46 (quint., J = 7.15 Hz,

2H), 1.80 (quint., J = 7.04 Hz, 2H), 4.14 (t, J = 6.56 Hz, 2H), 7.90 (d, J = 8.72 Hz, 2H),

13 7.94 (d, J = 8.68 Hz, 2H), 10.03 (s, 1H); C NMR (CDCl3) 14.1, 22.7, 25.6, 29.23 (2),

29.27, 29.47, 31.9, 78.0, 125.2, 130.3, 136.8, 138.4, 138.8 (d, J = 28.15 Hz; C5 of 1,3- thiazole), 147.2 (d, J = 18.20 Hz; C2 of 1,3-thiazole), 148.6 (d, J = 242.77 Hz; C4 of 1,3-

19 thiazole), 191.2; F NMR (CDCl3, CFCl3) -122.1 (s, 1F). Anal. Calcd for

C19H24FNO2S: C, 65.30; H, 6.92; N, 4.01. Found: C, 65.33; H, 6.96; N, 4.00%.

4-(5-Decyloxy-4-fluoro-1,3-thiazol-2-yl)benzaldehyde (5.74c)

Compound 5.74c was prepared using a similar procedure to that described for the preparation of 5.74a using the quantities stated: 5.48c (0.1508 g, 0.4183 mmol), toluene

(anhydrous; 3 mL), DIBAl-H (0.41 mL, 1.5M in toluene, 0.62 mmol). Once at room temperature, the solvent was removed under reduced pressure and the resulting residue was dissolved in CH2Cl2 and vigorously stirred with HCl (1 M, 9 mL) for 20 minutes.

After the organic layer was drained away, the aqueous layer was extracted with CH2Cl2

(3 x 10 mL) and the combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give a yellow solid (0.1448 g) which by 1H NMR was nearly

100% pure except for some DIBAl-H related impurities and a few minor aromatic

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impurities. The material was concentrated onto silica (0.32 g) and chromatographed (30 g silica, eluant was 10% EtOAc in petroleum ether) to give a light yellow solid (0.1319 g,

87%). For the purposes of EA, the material was recrystallized from a solution of Et2O / light petroleum ether (50:50) to give a light yellow, crystalline solid. Mp = 47.7-48.8 °C.

1 H NMR (CDCl3) 0.88 (t, J = 6.82 Hz, 3H), 1.19-1.40 (m, 12H), 1.45 (quint., J = 7.13

Hz, 2H), 1.80 (quint., J = 7.03 Hz, 2H), 4.14 (t, J = 6.56 Hz, 2H), 7.90 (d, J = 8.72 Hz,

13 2H), 7.93 (d, J = 8.68 Hz, 2H), 10.02 (s, 1H); C NMR (CDCl3) 14.1, 22.7, 25.6,

29.22, 29.27, 29.30, 29.50, 29.52, 31.9, 78.0, 125.2, 130.3, 136.8, 138.4, 138.8 (d, J =

28.03 Hz; C5 of 1,3-thiazole), 147.2 (d, J = 18.11 Hz; C2 of 1,3-thiazole), 148.7 (d, J =

19 242.74 Hz; C4 of 1,3-thiazole), 191.3; F NMR (CDCl3, CFCl3) -122.0 (s, 1F). Anal.

Calcd for C20H26FNO2S: C, 66.09; H, 7.21; N, 3.85. Found: C, 65.96; H, 7.21; N, 3.91%.

4-(4-Fluoro-5-undecyloxy-1,3-thiazol-2-yl)benzaldehyde (5.74d)

Compound 5.74d was prepared using a similar procedure to that described for the preparation of 5.74a using the quantities stated: 5.48d (0.3005 g, 0.8024 mmol), toluene

(anhydrous; 10 mL), DIBAl-H (0.80 mL, 1.5M in toluene, 1.2 mmol). Once at room temperature, the solvent was removed under reduced pressure and the resulting residue was dissolved in CH2Cl2 (20 mL) and vigorously stirred with HCl (1 M, 20 mL) for 15 minutes. After the organic layer was drained away, the aqueous layer was extracted with

CH2Cl2 (3 x 12 mL) and the combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give a yellow solid (0.3251 g) which by 1H NMR was nearly 100% pure except for some DIBAl-H related impurities and a few minor

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aromatic impurities. The material was concentrated onto silica (0.65 g) and chromatographed (65 g silica, eluant was 10% EtOAc in petroleum ether) to give a light yellow solid (0.2594 g, 86%). For the purposes of EA, the material was recrystallized from a solution of Et2O / light petroleum ether (50:50) to give a light yellow, crystalline

1 solid. Mp = 64.6-64.9 °C. H NMR (CDCl3) 0.88 (t, J = 6.72 Hz, 3H), 1.20-1.40 (m,

14H), 1.46 (quint., J = 7.13 Hz, 2H), 1.80 (quint., J = 7.03 Hz, 2H), 4.15 (t, J = 6.54 Hz,

2H), 7.91 (d, J = 8.40 Hz, 2H), 7.94 (d, J = 8.52 Hz, 2H), 10.03 (s, 1H); 13C NMR

(CDCl3) 14.1, 22.7, 25.6, 29.24, 29.28, 29.36, 29.52, 29.59, 29.62, 31.9, 78.0, 125.1,

130.3, 136.8, 138.4, 138.8 (d, J = 27.97 Hz; C5 of 1,3-thiazole), 147.1 (d, J = 18.23 Hz;

C2 of 1,3-thiazole), 148.6 (d, J = 242.66 Hz; C4 of 1,3-thiazole), 191.2; 19F NMR

(CDCl3, CFCl3) -122.1 (s, 1F). Anal. Calcd for C21H28FNO2S: C, 66.81; H, 7.48; N,

3.71. Found: C, 66.51; H, 7.46; N, 3.78%.

4-(5-Dodecyloxy-4-fluoro-1,3-thiazol-2-yl)benzaldehyde (5.74e)

Compound 5.74e was prepared using a similar procedure to that described for the preparation of 5.74a using the quantities stated: 5.48e (0.7794 g, 2.006 mmol), toluene

(anhydrous; 30 mL), DIBAl-H (2.00 mL, 1.5M in toluene, 3.0 mmol). Once at room temperature, the solvent was removed under reduced pressure and the resulting residue was dissolved in CH2Cl2 (25 mL) and vigorously stirred with HCl (1 M, 40 mL) for 30 minutes. After the organic layer was drained away, the aqueous layer was extracted with

CH2Cl2 (3 x 15 mL) and the combined organic extracts were dried over MgSO4, and concentrated onto silica (1.45 g). The material (0.71 g) was chromatographed (75 g

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silica, eluant was 10% EtOAc in petroleum ether) to give a light yellow solid (0.6402 g,

82%). For the purposes of EA, ~0.30 g of the material was recrystallized from a solution of Et2O / light petroleum ether (50:50) to give a light yellow, crystalline solid. Mp =

1 55.1-55.9 °C. H NMR (CDCl3) 0.88 (t, J = 6.88 Hz, 3H), 1.21-1.40 (m, 16H), 1.46

(quint., J = 7.40 Hz, 2H), 1.80 (quint., J = 7.03 Hz, 2H), 4.15 (t, J = 6.56 Hz, 2H), 7.91

13 (d, J = 8.68 Hz, 2H), 7.94 (d, J = 8.64 Hz, 2H), 10.03 (s, 1H); C NMR (CDCl3) 14.1,

22.7, 25.6, 29.23, 29.28, 29.37, 29.51, 29.57, 29.65 (2), 31.9, 78.0, 125.2, 130.3, 136.8,

138.4, 138.8 (d, J = 28.08 Hz; C5 of 1,3-thiazole), 147.2 (d, J = 18.17 Hz; C2 of 1,3-

19 thiazole), 148.7 (d, J = 242.83 Hz; C4 of 1,3-thiazole), 191.2; F NMR (CDCl3, CFCl3)

-122.1 (s, 1F). Anal. Calcd for C22H30FNO2S: C, 67.49; H, 7.72; N, 3.58. Found: C,

67.50; H, 7.67; N, 3.57%.

4-(4-Fluoro-5-octyloxy-1,3-thiazol-2-yl)benzoic acid (5.75a)

4-(4-Fluoro-5-octyloxy-1,3-thiazol-2-yl)benzaldehyde (5.74a; 1.0084 g, 3.0062 mmol) was dissolved in a solution of NaH2PO4•H2O (1.0797 g, 7.8245 mmol), 2,3-dimethylbut-

2-ene (3.50 mL, d = 0.708g/mL, 29.4 mmol), t-BuOH (65 mL), H2O (28 mL) and THF

(50 mL) before NaClO2 (1.6326 g, 18.052 mmol) was added in one portion. The resulting solution was allowed to stir at room temperature for 2 hours (TLC showed absence of starting material) before being concentrated under reduced pressure. The resulting white solid was stirred with H2O (70 mL) before being acidified with AcOH

(glacial, 45 mL) to pH 3. The solution was stirred at room temperature for 15 minutes, followed by 60 minutes on ice before being filtered. The resulting white solid was

255

1 washed with cold H2O (300 mL) and heated (90 °C) under vacuum for 18 hours. H

1 NMR showed the material to be 99% pure. Yield: 0.9874 g, 93%. H NMR (DMSO-d6)

0.86 (t, J = 6.74 Hz, 3H), 1.17-1.35 (m, 8H), 1.39 (quint., J = 6.87 Hz, 2H), 1.73

(quint., J = 6.92 Hz, 2H), 4.17 (t, J = 6.42 Hz, 2H), 7.89 (d, J = 8.44 Hz, 2H), 8.02 (d, J =

13 8.48 Hz, 2H), 13.16 (br. s, 1H); C NMR (DMSO-d6) 13.9, 22.0, 25.0, 28.49, 28.52,

28.54, 31.1, 77.7, 124.5, 130.1, 131.8, 136.0, 138.0 (d, J = 28.25 Hz; C5 of 1,3-thiazole),

147.2 (d, J = 18.60 Hz; C2 of 1,3-thiazole), 147.4 (d, J = 239.30 Hz; C4 of 1,3-thiazole),

19 166.6; F NMR (DMSO-d6, CFCl3) -122.9 (s, 1F).

4-(4-Fluoro-5-nonyloxy-1,3-thiazol-2-yl)benzoic acid (5.75b)

Compound 5.75b was prepared using a similar procedure to that described for the preparation of 5.75a using the quantities stated: 5.74b (1.1124 g, 3.1832 mmol),

NaH2PO4•H2O (1.1434 g, 8.2861 mmol), 2,3-dimethylbut-2-ene (3.70 mL, d =

0.708g/mL, 31.1 mmol), t-BuOH (70 mL), H2O (30 mL), THF (54 mL), NaClO2 (1.7281 g, 19.108 mmol). The solution was concentrated under reduced pressure and the resulting white solid was stirred with H2O (80 mL) before being acidified with AcOH

(glacial, 75 mL) to pH 3. The solution was stirred at room temperature for 15 minutes, followed by 60 minutes on ice before being filtered. The resulting white solid was washed with cold H2O (350 mL) and heated (90 °C) under vacuum for 36 hours. A white

1 solid (1.0880 g, 94%) was obtained. H NMR (DMSO-d6) 0.86 (t, J = 6.82 Hz, 3H),

1.17-1.36 (m, 10H), 1.40 (quint., J = 7.03 Hz, 2H), 1.73 (quint., J = 6.92 Hz, 2H), 4.18 (t,

J = 6.42 Hz, 2H), 7.90 (d, J = 8.60 Hz, 2H), 8.02 (d, J = 8.60 Hz, 2H), 13.15 (br. s, 1H);

256

13 C NMR (DMSO-d6) 13.8, 22.0, 24.9, 28.5 (3), 28.8, 31.2, 77.7, 124.5, 130.1, 131.7,

136.0, 138.0 (d, J = 28.14 Hz; C5 of 1,3-thiazole), 147.2 (d, J = 18.73 Hz; C2 of 1,3-

19 thiazole), 147.4 (d, J = 239.31 Hz; C4 of 1,3-thiazole), 166.5; F NMR (DMSO-d6,

CFCl3) -122.9 (s, 1F).

4-(5-Decyloxy-4-fluoro-1,3-thiazol-2-yl)benzoic acid (5.75c)

Compound 5.75c was prepared using a similar procedure to that described for the preparation of 5.75a using the quantities stated: 5.74c (0.7668 g, 2.110 mmol),

NaH2PO4•H2O (0.7574 g, 5.489 mmol), methyl-2-butene (2.10 mL, d = 0.662g/mL, 19.8 mmol), t-BuOH (45 mL), H2O (20 mL), THF (35 mL), NaClO2 (1.1482 g, 12.696 mmol).

The solution was concentrated under reduced pressure and the resulting white solid was stirred with H2O (50 mL) before being acidified with AcOH (glacial, 50 mL) to pH 3.

The solution was stirred at room temperature for 15 minutes, followed by 60 minutes on ice before being filtered. The resulting white solid was washed with cold H2O (250 mL) and heated (85 °C) under vacuum for 24 hours. A white solid (0.6888 g, 86%) was

1 1 obtained which by H NMR was found to be 98% pure. H NMR (DMSO-d6) 0.85 (t, J

= 6.86 Hz, 3H), 1.17-1.36 (m, 12H), 1.40 (quint., J = 7.11 Hz, 2H), 1.73 (quint., J = 6.91

Hz, 2H), 4.18 (t, J = 6.42 Hz, 2H), 7.90 (d, J = 8.60 Hz, 2H), 8.02 (d, J = 8.60 Hz, 2H),

13 13.15 (br. s, 1H); C NMR (DMSO-d6) 13.8, 22.0, 24.9, 28.46, 28.49, 28.58, 28.8,

31.2, 77.7, 124.5, 130.1, 131.7, 136.0, 138.0 (d, J = 28.14 Hz; C5 of 1,3-thiazole), 147.2

(d, J = 18.50 Hz; C2 of 1,3-thiazole), 147.4 (d, J = 239.32 Hz; C4 of 1,3-thiazole), 166.5;

19 F NMR (DMSO-d6, CFCl3) -122.9 (s, 1F).

257

4-(4-Fluoro-5-undecyloxy-1,3-thiazol-2-yl)benzoic acid (5.75d)

Compound 5.75d was prepared using a similar procedure to that described for the preparation of 5.75a using the quantities stated: 5.74d (0.2404 g, 0.6368 mmol),

NaH2PO4•H2O (0.2340 g, 1.696 mmol), 2,3-dimethylbut-2-ene (0.68 mL, d = 0.708g/mL,

5.7 mmol), t-BuOH (16 mL), H2O (6 mL), THF (11 mL), NaClO2 (0.3475 g, 3.842 mmol). The solution was concentrated under reduced pressure and the resulting white solid was stirred with H2O (60 mL) before being acidified with AcOH (glacial, 15 mL) to pH 3. The solution was stirred at room temperature for 15 minutes, followed by 60 minutes on ice before being filtered. The resulting white solid was washed with cold

H2O (150 mL) and heated (90 °C) under vacuum for 36 hours. A white solid (0.2227 g,

1 1 89%) was obtained which by H NMR was found to be 99% pure. H NMR (DMSO-d6)

0.85 (t, J = 7.01 Hz, 3H), 1.15-1.35 (m, 14H), 1.40 (quint., J = 7.11 Hz, 2H), 1.73

(quint., J = 6.91 Hz, 2H), 4.18 (t, J = 6.42 Hz, 2H), 7.90 (d, J = 8.56 Hz, 2H), 8.02 (d, J =

13 8.60 Hz, 2H), 13.15 (br. s, 1H); C NMR (DMSO-d6) 13.8, 22.0, 24.9, 28.45, 28.48,

28.62, 28.79, 28.84, 28.88, 31.2, 77.7, 124.5, 130.1, 131.7, 136.0, 138.0 (d, J = 28.39 Hz;

C5 of 1,3-thiazole), 147.2 (d, J = 18.57 Hz; C2 of 1,3-thiazole), 147.4 (d, J = 239.27 Hz;

19 C4 of 1,3-thiazole), 166.5; F NMR (DMSO-d6, CFCl3) -122.9 (s, 1F).

4-(5-Dodecyloxy-4-fluoro-1,3-thiazol-2-yl)benzoic acid (5.75e)

Compound 5.75e was prepared using a similar procedure to that described for the preparation of 5.75a using the quantities stated: 5.74e (0.6269 g, 1.601 mmol),

NaH2PO4•H2O (0.5772 g, 4.183 mmol), 2,3-dimethylbut-2-ene (1.80 mL, d = 0.708g/mL,

258

15.1 mmol), t-BuOH (35 mL), H2O (15 mL), THF (24 mL), NaClO2 (0.8694 g, 9.613 mmol). The solution was concentrated under reduced pressure and the resulting white solid was stirred with H2O (50 mL) before being acidified with AcOH (glacial, 40 mL) to pH 3. The solution was stirred at room temperature for 15 minutes, followed by 60 minutes on ice before being filtered. The resulting white solid was washed with cold

H2O (200 mL) and heated (85 °C) under vacuum for 24 hours. A white solid (0.6007 g,

1 1 92%) was obtained which by H NMR was found to be 99% pure. H NMR (DMSO-d6)

0.85 (t, J = 6.38 Hz, 3H), 1.16-1.45 (m, 18H), 1.73 (quint., J = 6.77 Hz, 2H), 4.19 (t, J

= 6.38 Hz, 2H), 7.90 (d, J = 8.24 Hz, 2H), 8.02 (d, J = 8.20 Hz, 2H), 13.15 (br. s, 1H);

13 C NMR (DMSO-d6) 13.8, 22.0, 24.9, 28.44, 28.47, 28.62, 28.78, 28.82, 28.92 (2),

31.2, 77.7, 124.5, 130.1, 131.7, 136.0, 138.0 (d, J = 28.27 Hz; C5 of 1,3-thiazole), 147.2

(d, J = 18.62 Hz; C2 of 1,3-thiazole), 147.4 (d, J = 239.42 Hz; C4 of 1,3-thiazole), 166.5;

19 F NMR (DMSO-d6, CFCl3) -122.9 (s, 1F).

(S)-4-(1-Methylheptyloxy)phenyl 4-(4-fluoro-5-(octyloxy)-1,3-thiazol-2-yl)benzoate

(5.76a)

A mixture of 4-(4-fluoro-2-octyloxy-1,3-thiazol-5-yl)benzoic acid (5.75a; 0.2506 g,

0.7131 mmol), DMAP (0.0266 g, 0.218 mmol), (S)-4-(octan-2-yloxy)phenol (2.11;

0.1664 g, 0.7485 mmol), and CH2Cl2 (anhydrous, distilled over CaH2, 35 mL) was stirred at room temperature for a few minutes under argon before DCC (0.2988 g, 1.448mmol) was added in one portion. After stirring at room temperature for 20 hours (1H NMR showed the product to phenol ratio to be 77:23) and after 48 total hours, the ratio had still

259

not changed by 1H NMR so the solution was partially concentrated under reduced pressure and then filtered. The filtrate was stirred with aq. AcOH (3% vol./vol., 20 mL) for about 15 minutes and then shaken vigorously in a separatory funnel. Once the organic layer was drained away, the aqueous layer was extracted with CH2Cl2 (3 x 15 mL). The combined organic extracts were dried over MgSO4, and concentrated onto silica (1.07 g). The material (0.71 g) was chromatographed (70 g silica, eluant was 5%

EtOAc in petroleum ether) to give an off-white solid (0.2253 g, 57%) which was pure by

1H NMR. Impure product was isolated (0.12 g) which by 1H NMR was 67% desired product contaminated with starting phenol. The impure product was recrystallized from a

1 50:50 solution of EtOH/Et2O to give a white solid which was pure by H NMR.

Combined isolated yield: 0.2884 g, 73%. The material was recrystallized three additional times from a 50:50 solution of EtOH/Et2O for the purposes of liquid crystal analysis. Transition temperatures (°C): Cryst I 37.1 Cryst II 73.1 (SmC* 59.2 SmA 65.7)

1 Iso Liq (Rec. 49.8). H NMR (CDCl3) 0.889 (t, J = 6.84 Hz, 3H), 0.895 (t, J = 6.88 Hz,

3H) 1.24-1.41 (m, 15H), 1.31 (d, J = 6.04 Hz, 3H), 1.41-1.50 (m, 3H), 1.52-1.62 (m, 1H),

1.69-1.77 (m, 1H), 1.81 (quint., J = 7.04 Hz, 2H), 4.15 (t, J = 6.56 Hz, 2H), 4.33 (sext., J

= 6.06 Hz, 1H), 6.92 (d, J = 9.04 Hz, 2H), 7.11 (d, J = 9.04 Hz, 2H), 7.90 (d, J = 8.68 Hz,

13 2H), 8.21 (d, J = 8.68 Hz, 2H); C NMR (CDCl3) 14.1 (2), 19.7, 22.62, 22.64, 25.56,

25.59, 29.17, 29.19, 29.27, 29.30, 31.77, 31.82, 36.5, 74.6, 78.0, 116.6, 122.3, 124.8,

130.5, 130.8, 137.6, 138.4 (d, J = 28.19 Hz; C5 of 1,3-thiazole), 144.1, 147.7 (d, J =

18.15 Hz; C2 of 1,3-thiazole), 148.6 (d, J = 242.57 Hz; C4 of 1,3-thiazole), 156.1, 164.9;

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19 F NMR (CDCl3, CFCl3) -122.3 (s, 1F). Anal. Calcd for C32H42FNO4S: C, 69.16; H,

7.62; N, 2.52. Found: C, 69.30; H, 7.76; N, 2.52%.

(S)-4-(1-Methylheptyloxy)phenyl 4-(4-fluoro-5-(nonyloxy)-1,3-thiazol-2-yl)benzoate

(5.76b)

Compound 5.76b was prepared using a similar procedure to that described for the preparation of 5.76a using the quantities stated: 5.75b (0.5655 g, 1.547 mmol), DMAP

(0.0570 g, 0.467 mmol), 2.11 (0.3626 g, 1.631 mmol), DCC (0.6410 g, 3.107 mmol),

1 CH2Cl2 (anhydrous; 100 mL). By H NMR the product to phenol ratio was 73:27 after

42 hours. The material (1.43 g) was chromatographed (140 g silica, eluant was 5%

EtOAc in petroleum ether) to give an off-white solid (0.4512 g, 51%) which was pure by

1H NMR. Impure product was isolated (0.25 g) which by 1H NMR was 67% desired product contaminated with starting phenol. The impure product was recrystallized from a

50:50 solution of EtOH/Et2O to give a white, fluffy solid (0.1865 g) which was pure by

1H NMR. Combined isolated yield: 0.6371 g, 72%. For the purposes of EA and LC analysis, the material was recrystallized three times from a 50:50 solution of EtOH/Et2O to give a white, cotton like solid. Transition temperatures (°C): Cryst 72.5 (SmC* 60.7

1 SmA 64.9) Iso Liq (Rec. 52.3). H NMR (CDCl3) 0.89 (app. t, J = 6.84 Hz, 6H), 1.21-

1.41 (m, 17H), 1.30 (d, J = 6.04 Hz, 3H), 1.41-1.50 (m, 3H), 1.52-1.62 (m, 1H), 1.69-

1.77 (m, 1H), 1.81 (quint., J = 7.04 Hz, 2H), 4.14 (t, J = 6.56 Hz, 2H), 4.33 (sext., J =

6.07 Hz, 1H), 6.92 (d, J = 9.04 Hz, 2H), 7.11 (d, J = 9.00 Hz, 2H), 7.90 (d, J = 8.64 Hz,

13 2H), 8.21 (d, J = 8.64 Hz, 2H); C NMR (CDCl3) 14.09, 14.11, 19.7, 22.62, 22.67,

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25.56, 25.59, 29.23 (2), 29.27, 29.30, 29.46, 31.8, 31.9, 36.5, 74.6, 78.0, 116.6, 122.3,

124.8, 130.5, 130.8, 137.6, 138.4 (d, J = 28.04 Hz; C5 of 1,3-thiazole), 144.1, 147.7 (d, J

= 18.13 Hz; C2 of 1,3-thiazole), 148.6 (d, J = 242.56 Hz; C4 of 1,3-thiazole), 156.1,

19 164.9; F NMR (CDCl3, CFCl3) -122.3 (s, 1F). Anal. Calcd for C33H44FNO4S: C,

69.56; H, 7.78; N, 2.46. Found: C, 69.74; H, 8.01; N, 2.43%.

(S)-4-(1-Methylheptyloxy)phenyl 4-(5-(decyloxy)-4-fluoro-1,3-thiazol-2-yl)benzoate

(5.76c)

Compound 5.76c was prepared using a similar procedure to that described for the preparation of 5.76a using the quantities stated: 5.75c (0.2440 g, 0.6430 mmol), DMAP

(0.0238 g, 0.195 mmol), 2.11 (0.1515 g, 0.6815 mmol), DCC (0.2696 g, 1.307 mmol),

1 CH2Cl2 (anhydrous; 40 mL). By H NMR the product to phenol ratio was 72:28 after 44 hours. The material (0.89 g) was chromatographed (70 g silica, eluant was 5% EtOAc in petroleum ether) to give an off-white solid (0.2129 g, 57%) which was pure by 1H NMR.

Impure product was isolated (0.0631 g) which by 1H NMR was 80% desired product contaminated with starting phenol. The impure product was recrystallized from a 50:50

1 solution of EtOH/Et2O to give a white solid which was pure by H NMR. Combined isolated yield: 0.2574 g, 69%. Transition temperatures (°C): Cryst 73.0 (SmC* 64.0

1 SmA 67.2) Iso Liq (Rec. 49.4). H NMR (CDCl3) 0.886 (app. t, J = 6.54 Hz, 3H),

0.888 (app. t, J = 6.54 Hz, 3H), 1.21-1.41 (m, 19H), 1.30 (d, J = 6.04 Hz, 3H), 1.41-1.50

(m, 3H), 1.52-1.62 (m, 1H), 1.69-1.77 (m, 1H), 1.81 (quint., J = 7.03 Hz, 2H), 4.15 (t, J =

6.54 Hz, 2H), 4.33 (sext., J = 6.07 Hz, 1H), 6.92 (d, J = 9.04 Hz, 2H), 7.11 (d, J = 9.04

262

13 Hz, 2H), 7.90 (d, J = 8.56 Hz, 2H), 8.21 (d, J = 8.60 Hz, 2H); C NMR (CDCl3) 14.09,

14.12, 19.8, 22.62, 22.69, 25.56, 25.59, 29.23, 29.28, 29.30 (2), 29.51 (2), 31.8, 31.9,

36.5, 74.6, 78.0, 116.6, 122.3, 124.8, 130.5, 130.8, 137.7, 138.4 (d, J = 28.28 Hz; C5 of

1,3-thiazole), 144.1, 147.7 (d, J = 18.14 Hz; C2 of 1,3-thiazole), 148.6 (d, J = 242.55 Hz;

19 C4 of 1,3-thiazole), 156.1, 164.9; F NMR (CDCl3, CFCl3) -122.3 (s, 1F). Anal. Calcd for C34H46FNO4S: C, 69.95; H, 7.94; N, 2.40. Found: C, 69.82; H, 7.90; N, 2.51%.

(S)-4-(1-Methylheptyloxy)phenyl 4-(4-fluoro-5-(undecyloxy)-1,3-thiazol-2-yl)benzoate

(5.76d)

Compound 5.76d was prepared using a similar procedure to that described for the preparation of 5.76a using the quantities stated: 5.75d (0.1690 g, 0.4295 mmol), DMAP

(0.0154 g, 0.126 mmol), 2.11 (0.1004 g, 0.4516 mmol), DCC (0.1805 g, 0.8748 mmol),

1 CH2Cl2 (anhydrous; 28 mL). By H NMR the product to phenol ratio was 70:30 after 44 hours. The material (0.46 g) was chromatographed (45 g silica, eluant was 5% EtOAc in petroleum ether) to give an off-white solid (0.1323 g, 52%) which was pure by 1H NMR.

Impure product was isolated (0.06 g) which by 1H NMR was 58% desired product contaminated with starting phenol. The impure product was recrystallized from a 50:50

1 solution of EtOH/Et2O to give a white solid (0.0454 g) which was pure by H NMR.

Combined isolated yield: 0.1777 g, 69%. For the purposes of EA and LC analysis, the material was recrystallized three times from a 50:50 solution of EtOH/Et2O to give a white, cotton like solid. Transition temperatures (°C): Cryst 68.8 (SmC* 64.4 SmA 67.5)

1 Iso Liq (Rec. 48.2). H NMR (CDCl3) 0.88 (t, J = 6.84 Hz, 3H), 0.89 (t, J = 6.88 Hz,

263

3H), 1.20-1.41 (m, 21H), 1.30 (d, J = 6.04 Hz, 3H), 1.41-1.50 (m, 3H), 1.52-1.62 (m,

1H), 1.69-1.77 (m, 1H), 1.81 (quint., J = 7.04 Hz, 2H), 4.15 (t, J = 6.56 Hz, 2H), 4.33

(sext., J = 6.09 Hz, 1H), 6.92 (d, J = 9.08 Hz, 2H), 7.11 (d, J = 9.04 Hz, 2H), 7.90 (d, J =

13 8.64 Hz, 2H), 8.21 (d, J = 8.68 Hz, 2H); C NMR (CDCl3) 14.09, 14.12, 19.8, 22.62,

22.70, 25.56, 25.59, 29.23, 29.28, 29.30, 29.34, 29.50, 29.57, 29.60, 31.8, 31.9, 36.5,

74.6, 78.0, 116.6, 122.3, 124.8, 130.5, 130.8, 137.7, 138.4 (d, J = 28.01 Hz; C5 of 1,3- thiazole), 144.1, 147.7 (d, J = 18.12 Hz; C2 of 1,3-thiazole), 148.6 (d, J = 242.53 Hz; C4

19 of 1,3-thiazole), 156.1, 164.9; F NMR (CDCl3, CFCl3) -122.3 (s, 1F). Anal. Calcd for

C35H48FNO4S: C, 70.32; H, 8.09; N, 2.34. Found: C, 70.02; H, 8.18; N, 2.38%.

(S)-4-(1-Methylheptyloxy)phenyl 4-(5-(dodecyloxy)-4-fluoro-1,3-thiazol-2-yl)benzoate

(5.76e)

Compound 5.76e was prepared using a similar procedure to that described for the preparation of 5.76a using the quantities stated: 5.75e (0.1485 g, 0.3644 mmol), DMAP

(0.0138 g, 0.113 mmol), 2.11 (0.0871 g, 0.392 mmol), DCC (0.1558 g, 0.7551 mmol),

1 CH2Cl2 (anhydrous; 30 mL). By H NMR the product to phenol ratio was 63:37 after 40 hours. The material (0.4438 g) was chromatographed (30 g silica, eluant was 5% EtOAc in petroleum ether) to give an off-white solid (0.1114 g, 50%) which was pure by 1H

NMR. Impure product was isolated (0.0300 g) which by 1H NMR was 65% desired product contaminated with starting phenol. The impure product was recrystallized from a

1 50:50 solution of EtOH/Et2O to give a white solid which was pure by H NMR.

Combined isolated yield: 0.1323 g, 59%. Transition temperatures (°C): Cryst 59.2 SmC*

264

1 65.4 SmA 68.3 Iso Liq (Rec. 46.2). H NMR (CDCl3) 0.88 (t, J = 6.84 Hz, 3H), 0.89 (t,

J = 6.78 Hz, 3H), 1.20-1.41 (m, 23H), 1.31 (d, J = 6.04 Hz, 3H), 1.41-1.51 (m, 3H), 1.52-

1.62 (m, 1H), 1.69-1.77 (m, 1H), 1.80 (quint., J = 7.03 Hz, 2H), 4.15 (t, J = 6.54 Hz, 2H),

4.33 (sext., J = 6.09 Hz, 1H), 6.91 (d, J = 9.12 Hz, 2H), 7.11 (d, J = 9.04 Hz, 2H), 7.90

13 (d, J = 8.60 Hz, 2H), 8.21 (d, J = 8.60 Hz, 2H); C NMR (CDCl3) 14.09, 14.12, 19.8,

22.6, 22.7, 25.56, 25.59, 29.23, 29.27, 29.30, 29.36, 29.50, 29.56, 29.64 (2), 31.8, 31.9,

36.5, 74.6, 78.0, 116.6, 122.3, 124.7, 130.5, 130.8, 137.6, 138.4 (d, J = 27.90 Hz; C5 of

1,3-thiazole), 144.1, 147.7 (d, J = 18.15 Hz; C2 of 1,3-thiazole), 148.6 (d, J = 242.58 Hz;

19 C4 of 1,3-thiazole), 156.1, 164.9; F NMR (CDCl3, CFCl3) -122.3 (s, 1F). Anal. Calcd for C36H50FNO4S: C, 70.67; H, 8.24; N, 2.29. Found: C, 70.77; H, 8.27; N, 2.28%.

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10.5. Experimental for Chapter 6

4-(Dodecyloxy)phenylboronic acid (6.1)

Compound 6.1 was prepared using a previously reported procedure.1

A white solid was obtained (4.49 g, 100%) which matched the provided 1H NMR data.1

2-(4-(Dodecyloxy)phenyl -1,3-thiazole-5-carboxylic acid (6.3)

2-(4-(Dodecyloxy)phenyl)-5-formyl-1,3-thiazole (6.7; 0.2129 g, 0.5699 mmol) was dissolved in a solution of NaH2PO4•H2O (0.2055 g, 1.489 mmol), 2,3-dimethylbut-2-ene

(0.64 mL, d = 0.708 g/mL, 5.4 mmol), t-BuOH (12 mL), H2O (5 mL) and THF (9 mL)

266

before NaClO2 (0.3104 g, 3.432 mmol) was added in one portion. The resulting solution was allowed to stir at room temperature for 2 hours (TLC showed absence of starting material) before being concentrated under reduced pressure. The white solid was stirred with H2O (30 mL) before being acidified with AcOH (glacial, 12 mL) to pH 3. The solution was stirred at room temperature for 15 minutes, followed by 60 minutes on ice before being filtered. The resulting white solid was washed with cold H2O (100 mL) and heated (85 °C) under vacuum for 14 hours. 1H NMR showed the material to be 100%

1 pure. Yield: 0.2082 g, 94%. H NMR (DMSO-d6) 0.85 (t, J = 6.76 Hz, 3H), 1.17-1.37

(m, 16H), 1.41 (quint., J = 7.03 Hz, 2H), 1.73 (quint., J = 6.90 Hz, 2H), 4.05 (t, J = 6.48

Hz, 2H), 7.06 (d, J = 8.88 Hz, 2H), 7.94 (d, J = 8.80 Hz, 2H), 8.34 (s, 1H), 13.49 (br. s,

13 1H); C NMR (DMSO-d6) 13.8, 22.0, 25.3, 28.4, 28.6 (2), 28.86 (2), 28.91 (2), 31.2,

67.7, 115.1, 124.9, 128.2, 129.1, 148.6, 161.2, 162.1, 171.9.

5-Bromo-2-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.5)

While under argon, Pd(OAc)2 (0.0100 g, 0.0445 mmol) was added to Xantphos (0.0259 g, 0.0448 mmol) in THF (degassed by 10 cycles of sonicating under vacuum and backfilling with argon; 1.5 mL) and stirred for 5 minutes at room temperature. The dark orange solution was then transferred to a solution of 2,5-dibromo-1,3-thiazole (3.1;

0.3605 g, 1.484 mmol), 4-(dodecyloxy)phenylboronic acid (6.1; 0.5004 g, 1.634 mmol), and K3PO4 (0.9462 g, 4.458 mmol) in THF (degassed; 6 mL). The resulting orange solution was heated under reflux, under argon for 18 hours at which point crude 1H NMR of the brown solution showed fairly clean product with some 2,5-dibromo-1,3-thiazole

267

(12%) and a trace (1%) of starting boronic acid remaining. Once at room temperature, the crude solution was filtered through celite which was washed with CH2Cl2 and concentrated onto silica (1.14 g). The material (0.7998 g) was chromatographed (65 g silica, eluant was 3% EtOAc in petroleum ether) to give a white solid which by 1H NMR was pure except for some remaining 2,5-dibromo-1,3-thiazole (3.3). The material was placed under vacuum which removed the starting 2,5-dibromo-1,3-thiazole (3.3). Yield:

1 0.4746 g, 75%. Mp = 74.2-75.9 °C. H NMR (CDCl3) 0.88 (t, J = 6.84 Hz, 3H), 1.20-

1.40 (m, 16H), 1.46 (quint., J = 7.16 Hz, 2H), 1.80 (quint., J = 7.05 Hz, 2H), 4.00 (t, J =

6.58 Hz, 2H), 6.93 (d, J = 8.88 Hz, 2H), 7.66 (s, 1H), 7.78 (d, J = 8.88 Hz, 2H); 13C

NMR (CDCl3) 14.1, 22.7, 26.0, 29.2, 29.37, 29.39, 29.58, 29.61, 29.65, 29.67, 31.9,

68.2, 107.2, 114.9, 125.8, 127.7, 144.5, 161.1, 169.6. Anal. Calcd for C21H30BrNOS: C,

59.43; H, 7.12; N, 3.30. Found: C, 59.54; H, 7.14; N, 3.35%.

5-Cyano-2-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.6)

5-Bromo-2-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.5; 0.4717 g, 1.111 mmol) and CuCN

(0.1993 g, 2.225 mmol) were heated under reflux, under argon in DMF (anhydrous; 15 mL) for 24 hours (color changed to light red) at which point 1H NMR showed no starting material. Once at room temperature, the solution was stirred with HCl (1 M, 25 mL) causing the solution to become milky white. The solution was extracted with Et2O (4 x

20 mL) and the combined organic extracts were washed with brine (10 mL), dried over

MgSO4, and concentrated under reduced pressure to give a yellow solid (0.4279 g) which was mostly product with some unknown alkoxyphenyl-based compound. The material

268

was recrystallized from EtOH to give a yellow solid which was more pure than the

1 extracted material (0.3332 g). H NMR (CDCl3) 0.88 (t, J = 6.82 Hz, 3H), 1.21-1.41

(m, 16H), 1.47 (quint., J = 7.52 Hz, 2H), 1.81 (quint., J = 7.03 Hz, 2H), 4.02 (t, J = 6.58

Hz, 2H), 6.98 (d, J = 8.88 Hz, 2H), 7.89 (d, J = 8.88 Hz, 2H), 8.22 (s, 1H).

2-(4-(Dodecyloxy)phenyl)-5-formyl-1,3-thiazole (6.7)

5-Cyano-2-(4-(dodecyloxy)phenyl)-1,3-thiazole (6.6; 0.3332 g, 0.8992 mmol) was dissolved in toluene (anhydrous; 20 mL) and cooled to -72 °C while under argon before

DIBAl-H (0.87 mL, 1.2 M in toluene, 1.0 mmol) was slowly added over about 30 seconds (internal temperature did not exceed -66 °C). After stirring at -72 °C for 30 minutes, 1H NMR showed 15% starting material remaining so another addition of

DIBAl-H (0.23 mL, 1.2 M in toluene, 0.28 mmol) was made. After stirring at -72 °C for another 30 minutes, 1H NMR showed about 4% starting material left so a 3rd addition of

DIBAl-H (0.23 mL, 1.2 M in toluene, 0.28 mmol) was made which consumed all but a trace of starting material. A 4th addition of DIBAl-H (0.15 mL, 1.2 M in toluene, 0.18 mmol) was made and it was assumed to have consumed the remaining starting material.

After warming to room temperature over about 30 minutes, the brown solution was concentrated to a solid which was dissolved in CH2Cl2 and vigorously stirred with HCl (1

M, 25 mL) for 20 minutes. Once the organic layer was drained away, the aqueous layer was extracted with CH2Cl2 (3 x 15mL). The combined organic extracts were dried over

MgSO4, filtered through celite, and concentrated to a brown solid (0.31 g) which was 90-

95% pure by 1H NMR. The material was concentrated onto silica (0.59 g) and

269

chromatographed (30 g silica, eluant was 12% EtOAc in petroleum ether) to give an

1 1 amber solid (0.2385 g, 71%) which was pure by H NMR. H NMR (CDCl3) 0.88 (t, J

= 6.78 Hz, 3H), 1.19-1.41 (m, 16H), 1.46 (quint., J = 7.19 Hz, 2H), 1.80 (quint., J = 7.01

Hz, 2H), 4.02 (t, J = 6.56 Hz, 2H), 6.96 (d, J = 8.84 Hz, 2H), 7.95 (d, J = 8.80 Hz, 2H),

13 8.36 (s, 1H), 10.00 (s, 1H); C NMR (CDCl3) 14.1, 22.7, 26.0, 29.1, 29.37 (2), 29.58,

29.60, 29.65, 29.67, 31.9, 68.3, 115.1, 125.2, 129.0, 138.0, 152.6, 162.3, 175.7, 182.0.

Anal. Calcd for C22H31NO2S: C, 70.74; H, 8.36; N, 3.75. Found: C, 70.73; H, 8.52; N,

3.70%.

(S)-4-(1-methylheptyloxy)phenyl 2-(4-(dodecyloxy)phenyl)-1,3-thiazole-5-carboxylate

(6.8)

A mixture of 2-(4-(dodecyloxy)phenyl)-1,3-thiazole-5-carboxylic acid (6.3; 0.1567 g,

0.4023 mmol), DMAP (0.0151 g, 0.124 mmol), 2.11 (0.0951 g, 0.428 mmol), and CH2Cl2

(anhydrous; 35 mL) was stirred at room temperature for a few minutes under argon before DCC (0.1685 g, 0.8167 mmol) was added in one portion. After stirring at room temperature for 20 hours (1H NMR showed the product to phenol ratio to be 66:34) and after 48 total hours, the ratio had still had changed to only 68:32 so the solution was partially concentrated under reduced pressure and then filtered. The filtrate was stirred with aq. AcOH (3% vol./vol., 10 mL) for about 15 minutes and then shaken vigorously in a separatory funnel. Once the organic layer was drained away, the aqueous layer was extracted with CH2Cl2 (3 x 12 mL). The combined organic extracts were washed with brine (12 mL), dried over MgSO4, and concentrated onto silica (0.78 g). The material

270

(0.4091 g) was chromatographed (40 g silica, eluant was 15% EtOAc in petroleum ether; column solvent optimized for wrong spot) to give a yellow solid (0.2017 g) which by 1H

NMR was mostly product mixed with starting phenol (~18%). The material was recrystallized from EtOH/EtOAc (material was melted and partially dissolved in EtOH then drops of EtOAc were added until the remaining material dissolved, once it cooled to

70 °C, more EtOAc had to be added due to the material oiling out) to give a light yellow solid (0.1733 g, 73%) which was pure by 1H NMR. Transition temperatures (°C): Cryst

1 70.4 SmC* 98.4 SmA 100.3 Iso Liq (34.8 °C). H NMR (CDCl3) 0.88 (t, J = 6.82 Hz,

3H), 0.89 (t, J = 6.82 Hz, 3H), 1.20-1.42 (m, 23H), 1.30 (d, J = 6.04 Hz, 3H), 1.42-1.52

(m, 3H), 1.52-1.62 (m, 1H), 1.69-1.77 (m, 1H), 1.81 (quint., J = 7.07 Hz, 2H), 4.03 (t, J =

6.56 Hz, 2H), 4.32 (sext., J = 6.06 Hz, 1H), 6.91 (d, J = 9.04 Hz, 2H), 6.97 (d, J = 8.88

Hz, 2H), 7.12 (d, J = 9.04 Hz, 2H), 7.95 (d, J = 8.88 Hz, 2H), 8.51 (s, 1H); 13C NMR

13 (CDCl3) C NMR (CDCl3) 14.08, 14.12, 19.7, 22.62, 22.70, 25.5, 26.0, 29.16, 29.30,

29.38 (2), 29.58, 29.60, 29.65, 29.67, 31.8, 31.9, 36.5, 68.4, 74.6, 115.1,116.6, 122.3,

125.6, 127.0, 128.7, 143.7, 150.3, 156.2, 160.3, 162.0, 174.3. Anal. Calcd for

C36H51NO4S: C, 72.81; H, 8.66; N, 2.36. Found: C, 72.78; H, 8.82; N, 2.39%.

271

Potassium 4-(dodecyloxy)phenyltrifluoroborate (6.14)

4-(Dodecyloxy)phenylboronic acid (6.1; 0.48 g, 1.6 mmol) and KHF2 (0.33 g, 4.2 mmol) were stirred for at room temperature for 15 minutes. The resulting solid was partially dissolved in hot acetone and filtered. The solid was washed with boiling acetone and the filtrate was partially concentrated under reduced pressure. A few milliliters of Et2O were added, but no additional precipitate formed, so the white solid was filtered and washed with cold Et2O (-30 °C, 50 mL). The resulting white, pearly solid (0.3662 g, 63%) was

1 1 dried under vacuum (P2O5) and found to be pure product by H NMR. H NMR (DMSO- d6) 0.86 (t, J = 6.84 Hz, 3H), 1.18-1.34 (m, 16H), 1.39 (quint., J = 6.95 Hz, 2H), 1.66

(quint., J = 6.95 Hz, 2H), 3.86 (t, J = 6.52 Hz, 2H), 6.63 (d, J = 7.96 Hz, 2H), 7.19 (d, J =

13 8.36 Hz, 2H); C NMR (DMSO-d6) 13.9, 22.0, 25.5, 28.66, 28.77, 28.83, 28.96 (4),

31.2, 66.8, 112.4, 132.2, 141.3, 156.5.

5-(4-(Dodecyloxy)phenyl)-2-octyloxy-1,3-thiazole (6.15)

5-Bromo-2-octyloxy-1,3-thiazole (4.3a; 0.0770 g, 0.263 mmol), potassium 4-

(dodecyloxy)phenyltrifluoroborate (6.14; 0.1005 g, 0.2729 mmol), and K2CO3 (0.0718 g,

0.519 mmol) were dissolved in a degassed (accomplished by 10 cycles of sonicating under vacuum and backfilling with argon) solution of toluene, acetone, and H2O (ratio of

4:2:1, 14 mL). The solution was stirred under argon for a few minutes before Pd(PPh3)4

272

(0.0219 g, 0.0190 mmol) was added in one portion and the resulting solution was heated under reflux, under argon for 20 hours at which point neither starting material was present by 1H NMR. Once at room temperature, the solvent was removed under reduced pressure and the resulting residue was dissolved in CH2Cl2 (15 mL) and shaken with H2O

(10 mL) in a separatory funnel. Once the organic layer was drained away, the aqueous layer was extracted with CH2Cl2 (3 x 10 mL) and the combined organic extracts were washed with brine (10 mL), dried over MgSO4, and concentrated onto silica (0.32 g) as a black solid. The material (0.1893 g) was chromatographed (16 g silica, eluant was 4%

EtOAc in petroleum ether) to give an off-white white solid (0.1114 g, 89%) which was

1 1 pure by H NMR. H NMR (CDCl3) 0.880 (t, J = 6.52 Hz, 3H), 0.885 (t, J = 6.84 Hz,

3H) 1.18-1.39 (m, 24H), 1.39 (m, 4H), 1.72-1.87 (m, 4H), 3.95 (phenyl alkoxy chain; t, J

= 6.52 Hz, 2H), 4.39 (1,3-thiazole alkoxy chain; t, J = 6.64 Hz, 2H), 6.87 (d, J = 8.68 Hz,

13 2H), 7.17 (s, 1H), 7.34 (d, J = 8.60 Hz, 2H); C NMR (CDCl3) 14.10, 14.13, 22.66,

22.71, 25.8, 26.0, 28.9, 29.21, 29.25 (2), 29.37, 29.41, 29.60, 29.62, 29.66, 29.68, 31.8,

31.9, 68.1, 71.6, 115.0, 124.4, 127.2, 130.8 (2; C4 and C5 of 1,3-thiazole), 158.8, 173.2

(C2 of 1,3-thiazole).

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