Synthesis and Comparison of the Reactivity of Allyl Fluorides and ...

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Starting Substrate Product Yield (%) (64) (65) (66) (67) 50 (68) (69) (70) (71) Table 2.8 Yields obtained of products (68) - (71) 29 74 79 65 Chapter Two (4-(benzyloxy)but-2-enyl)trimethylsilane (68) was prepared by stirring allyl benzyl ether (64) with three equivalents of allyltrimethylsilane in DCM and heating to reflux under an atmosphere of argon for 48 hours. Over the 48 hour time period 5 mol % Grubbs 2 nd generation catalyst was added in small portions. After which, purification by column chromatography [hexane: diethyl ether (97:3)] was meant to afford the desired product. However, the product obtained also contained starting material, due to the close proximity of the starting material and product Rf values. Alteration of the solvent mixture to hexane yielded a small amount of product, but an insufficient quantity to continue with the fluorination step. The reaction was repeated, and monitored closely throughout the reflux by 1 H NMR spectroscopy. After 48 hours the 1 H NMR spectrum still showed half of the reaction mixture to be starting material, therefore a longer reaction time was given, and a small amount of extra Grubbs catalyst added, in an attempt to drive the reaction to
51 Chapter Two completion. This enabled the reaction mixture to form a little more product but the reaction was not found to go to completion even after an extra 72 hours, and the addition of more catalyst. Therefore purification was conducted using column chromatography [hexane: diethyl ether (97:3)], affording the desired product as a cloudy oil, in a 29 % yield. After the disappointing yields obtained in the synthesis of (68), (3-[1,3]dioxalan-2-yl-allyl) trimethylsilane (69) was prepared with relative ease. The reaction was conducted as described by Gouverneur et al., yielding the pure product in 74 % yield as an oil. 2-(4-trimethylsilanyl-but-2-enyl)isindole-1,3-dione (70) was synthesised after firstly preparing 2-allyl-isoindole-1,3-dione (66), following the protocol by Abulikemu et al., [49] and was obtained as white crystals in a moderate 51 % yield. The subsequent reaction with allyltrimethylsilane afforded the desired product as a white solid in 79 % yield. Benzoic acid 4-trimethylsilanyl-but-2-enyl ester (71) was synthesised by firstly forming the starting allyl benzoate (67), which was prepared following the protocol by Yasui et al. [50] Allyl alcohol and benzoyl chloride were stirred in the presence of triethylamine, after workup, the desired product was afforded in 90 % yield. Therefore, allyl benzoate was reacted with 3 equivalents of allyl trimethylsilane in DCM with 5 mol % Grubbs catalyst. The reaction mixture was refluxed for 48 hours under an atmosphere of argon, after which column chromatography [hexane: diethyl ether (95:5)], afforded the product (71) as an oil in 65 % yield (Table 2.8). The fluorination step for (69) proved problematic. The reaction was conducted as described in the literature, (69) was stirred with 1 equivalent of Selectfluor in MeCN, under an atmosphere of argon for 48 hours at room temperature. The crude reaction mixture was then purified via column chromatography [hexane: diethyl ether (96:4)] However, only a single fluorine peak at δF -150 ppm was observed in the 19 F{ 1 H} NMR spectrum, indicative of the Selectfluor BF4 - counter ion. The reaction was repeated, using different solvent combinations for purification by column chromatography, however, the desired product (72) was not formed. In contrast, both (68) and (71) showed excellent conversion to the corresponding allylic fluorides ((73) and (75)) and were isolated by column chromatography [hexane: diethyl ether (95:5)] as oils in 33 % and 55 % yield. The fluorination of (70) also proceeded smoothly and the desired allylic fluoride (74) was afforded as a white solid in 77 % yield
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Synthesis and Comparison of the Rea
Page 3 and 4:
Acknowledgements Firstly, I would l
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2.2.2.1.1 Synthesis of 1-(Benzyloxy
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6.2.12 Preparation of 2-(4-trimethy
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6.4.12 Experimental Data for Dimeth
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AgF ap Bn Bz CsF d DAST dba DCM DME
Page 13 and 14: Chapter one
Page 15 and 16: 2 Chapter One potentially explosive
Page 17 and 18: 4 Chapter One ortho-biphenyl trifla
Page 19 and 20: 6 Chapter One 2,10 (3,3-dichlorocam
Page 21 and 22: 8 Chapter One both enantiomers were
Page 23 and 24: 10 Chapter One poor to moderate ena
Page 25 and 26: Scheme 1.10 Fluorination of (17) 12
Page 27 and 28: 14 Chapter One fluorine donors, Lew
Page 29 and 30: 1.3 Enantioselective Nucleophilic F
Page 31 and 32: Scheme 1.16 Fluorination of (32) 18
Page 33 and 34: 20 Chapter One (iii) SN2’ type su
Page 35 and 36: 22 Chapter One cytotoxicity in the
Page 37 and 38: 24 Chapter One Manabe and Ishikawa
Page 39 and 40: Scheme 1.25 Synthesis of (41)-(44)
Page 41 and 42: Figure 1.12 �-fluorinated NSAIDs
Page 43 and 44: 1.6 Thesis Outline 30 Chapter One T
Page 45 and 46: 32 Chapter One [26] M. Abdul-Ghani,
Page 47 and 48: [79] M. Schlosser, D. Michael, Z.-W
Page 49 and 50: 2.1 Introduction 2 Synthesis of All
Page 51 and 52: 37 Chapter Two In dehydroxyfluorina
Page 53 and 54: Scheme 2.6 Fluorination with IF5/Et
Page 55 and 56: 41 Chapter Two desired allylic fluo
Page 57 and 58: 43 Chapter Two c) Formation of a su
Page 59 and 60: Scheme 2.14 Reaction of cis-3-methy
Page 61 and 62: Substrate (60) (61) (62) (63) R = O
Page 63: Alcohol Product Yield (%) Table 2.7
Page 67 and 68: 53 Chapter Two Chapter Three. Follo
Page 69 and 70: 55 Chapter Two Two allyl alcohols w
Page 71 and 72: 57 Chapter Two The conversion of (8
Page 73 and 74: Starting substrate (88) (89) (90) (
Page 75 and 76: Starting substrate (99) (76) (77) (
Page 77 and 78: 63 Chapter Two Both (105) and (104)
Page 79 and 80: Scheme 2.25 Mechanistic pathway for
Page 81 and 82: 2.3 Conclusions 67 Chapter Two The
Page 83 and 84: [28] D. F. Taber, J. Am. Chem. Soc.
Page 85 and 86: Chapter THRee
Page 87 and 88: 72 Chapter Three Kurosawa reacted a
Page 89 and 90: 74 Chapter Three These results demo
Page 91 and 92: 76 Chapter Three More recently, wor
Page 93 and 94: 3.2 Results and Discussion 3.2.1 Re
Page 95 and 96: 80 Chapter Three Starting substrate
Page 97 and 98: 82 Chapter Three Figure 3.4 Crystal
Page 99 and 100: Scheme 3.12 Oxidative addition of 1
Page 101 and 102: 86 Chapter Three when the reaction
Page 103 and 104: 88 Chapter Three Therefore, from th
Page 105 and 106: -140 -140 -140 -140 -140 -150 -150
Page 107 and 108: 92 Chapter Three monitored for 80 m
Page 109 and 110: 3.4 References [1] W. T. Dent, R. L
Page 111 and 112: Chapter Four
Page 113 and 114: 97 Chapter Four nucleophilic substi
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99 Chapter Four Further reactions w
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Figure 4.3 Structure of co-product
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4.2.2 Reactions of palladium cation
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105 Chapter Four substituents on th
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107 Chapter Four The desired produc
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109 Chapter Four The reaction of (1
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111 Chapter Four were both reacted
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[28] D. Landini, A. Maia, A. Rampol
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5.1 Introduction 5 Synthesis and Re
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116 Chapter Five The first enantios
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118 Chapter Five Gem(difluoroallyl)
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120 Chapter Five benzaldehyde, 3-br
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Starting Substrate (76) (77) (78) (
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Starting Substrate Product Yield (%
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5.2.4 Synthesis of Allylic Difluori
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5.2.5 Metal-mediated synthesis of 3
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130 Chapter Five process. [40] Unfo
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132 Chapter Five compounds were pur
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134 Chapter Five [30] H. L. Sham, N
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6.1 General Experimental Procedures
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6.2 Experimental Details for Chapte
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139 Chapter Six (1 g, 0.75 cm 3 , 6
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6.2.7 Preparation of allyl 4-(trifl
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6.2.10 Preparation of (3-[1,3]Dioxa
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145 Chapter Six reaction mixture wa
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147 Chapter Six mg, 1.1 mmol), ally
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149 Chapter Six 260.3 Hz, ArCF), 16
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6.2.22 Preparation of 2-fluorobut-3
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6.2.25 Preparation of 2-fluorobut-3
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6.2.28 Preparation of 2-hydroxybut-
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157 Chapter Six 1 JCF = 253.5 Hz, A
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159 Chapter Six drying under high v
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6.2.37 Preparation of 2-chlorobut-3
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6.2.40 Preparation of 2-chlorobut-3
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6.3.2 Preparation of Bis[�-chloro
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167 Chapter Six 6.3.5 Preparation o
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169 Chapter Six 4 JHH = 1.2 Hz, ArH
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Time (minutes) 4 11 18 25 Table 6.2
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Time (minutes) 19 F{ 1 H} (ppm) Tim
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175 Chapter Six suspension of sodiu
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177 Chapter Six Hz, Ha), 5.19 (1H,
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6.4.9 Preparation of Dimethyl 2-(4-
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181 Chapter Six 6.4.13 Preparation
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6.5 Experimental Details for Chapte
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185 Chapter Six CHCH2), 133.9 (d, 3
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187 Chapter Six 6.5.6 Preparation o
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189 Chapter Six (5 mg, 0.27 mmol) a
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191 Chapter Six (d, 1 JCF = 255.0 H
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193 Chapter Six layer separated and
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195 Chapter Six Hz, 4 JHF = 3.2 Hz,
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Appendix
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II Appendix Second generation Grubb
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IV Appendix mixture was stirred at
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VI Appendix stirred at room tempera
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VIII Appendix The organic phase was
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X Appendix A6 Crystal data and stru
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XII Appendix A8 Crystal data and st
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XIV Appendix A10 Crystal data and s
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A12 Lecture Courses Attended XVI Ap
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A14 Conferences Attended RSC Organi
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