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

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Scheme 3.4 Attempt toward Pd-mediated allylic fluorination Scheme 3.5 Scheme showing synthesis of allyl complexes 75 Chapter Three A stoichiometric variant of the reaction with attack of fluoride ion on isolated cationic � 3 -palladium (II) and platinum (II) complexes has also been studied. In the first series of experiments allyl complexes, (120)–(122) (Scheme 3.5 for synthesis) were reacted with one of the fluoride sources, TBAT, Me4NF or Schwesinger’s phosphazenium fluoride P2F, then mixed in a deuterated solvent for ease of sample monitoring. 1 H, 19 F and 31 P NMR spectroscopy were used to monitor the reactions. When no change was observed at room temperature samples were warmed to 50 ºC. The only specific reaction pattern was observed with complex (121) and the fluoride sources Me4NF and P2F, where the diene (123) was formed in an elimination reaction (Scheme 3.6). Scheme 3.6 Fluorination mediated elimination of diene (121) from (123)
76 Chapter Three More recently, work by Narumi has shown that selective mono-defluorination of allylic difluorides can be achieved via catalysis with Pd(0). Inspired by the research of Hudlicky, [26] where hydrogenolysis of allyl fluorides in the presence of Pd/C was found to be a convenient route for the replacement of a fluorine atom by hydrogen, Narumi and co- workers [27] reacted gem-difluorides with a Pd catalyst and additives that have an affinity for fluorine in order to promote the elimination of fluorine. This reaction led to the generation of a fluorinated �-allyl Pd intermediate that on reaction with a nucleophile afforded a (Z)- fluoroalkene (Scheme 3.7). These products are an important class of compounds that can be utilised as peptide isosteres, [28-31] enzyme inhibitors [32] and in liquid crystalline materials. [33] Scheme 3.7 Synthesis of fluoroalkene via Pd catalysis The reaction was conducted using readily available allylic difluorides. Initially, in order to optimise and hone reaction conditions, ��-difluoro-��-enoate was used and reacted with dimethyl sodiomalonate in the presence of Pd catalyst and dppe. Several additives were screened including TMSCl, Et4Si, (EtO)4Si and Me3Al, however, none promoted the desired defluorination reaction. However, PhSiH3 was found to promote the formation of the desired product. After optimisation of solvent and temperature, it was found that PhSiH3 with NEt3 in EtOH at 50 ºC yielded the desired product in 96 % yield (Scheme 3.8). These conditions were then used in reactions with different allylic difluorides, all of which were found to be chemoselective with good to excellent yields being obtained of the desired product (64 – 99 %). In addition it was noted that N-Boc amides, esters and substituents such as alkyl and siloxy groups at the � carbon did not affect the reaction and that amides, peptides, (Z)-enoates and lactams could all be used to give the desired fluoroalkene. A mechanistic study demonstrated that the reactive species was formed via the Et3N promoted dehydrogenative coupling of PhSiH3 with EtOH. Scheme 3.8 Pd and Et3N catalysed reductive defluorination
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Synthesis and Comparison of the Rea
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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
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Chapter one
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2 Chapter One potentially explosive
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4 Chapter One ortho-biphenyl trifla
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6 Chapter One 2,10 (3,3-dichlorocam
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8 Chapter One both enantiomers were
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10 Chapter One poor to moderate ena
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Scheme 1.10 Fluorination of (17) 12
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14 Chapter One fluorine donors, Lew
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1.3 Enantioselective Nucleophilic F
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Scheme 1.16 Fluorination of (32) 18
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20 Chapter One (iii) SN2’ type su
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22 Chapter One cytotoxicity in the
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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 and 64: Alcohol Product Yield (%) Table 2.7
Page 65 and 66: 51 Chapter Two completion. This ena
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: 74 Chapter Three These results demo
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
Page 115 and 116: 99 Chapter Four Further reactions w
Page 117 and 118: Figure 4.3 Structure of co-product
Page 119 and 120: 4.2.2 Reactions of palladium cation
Page 121 and 122: 105 Chapter Four substituents on th
Page 123 and 124: 107 Chapter Four The desired produc
Page 125 and 126: 109 Chapter Four The reaction of (1
Page 127 and 128: 111 Chapter Four were both reacted
Page 129 and 130: [28] D. Landini, A. Maia, A. Rampol
Page 131 and 132: 5.1 Introduction 5 Synthesis and Re
Page 133 and 134: 116 Chapter Five The first enantios
Page 135 and 136: 118 Chapter Five Gem(difluoroallyl)
Page 137 and 138: 120 Chapter Five benzaldehyde, 3-br
Page 139 and 140: 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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