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

More documents

Recommendations

Info

Scheme 1.5 N-fluoro sultams (4) and (5) 5 Chapter One Fluorination experiments using the N-fluoro sultams (4) and (5) showed them to react with various metal enolates generated under standard reaction conditions to give the anticipated �-fluoro carbonyl compounds with the ee depending strongly on the structure of the metal enolate (Table 1.1). N-fluoro sultam (4) was found to give greater enantiomeric excesses in comparison with (5); the best result observed with ethyl cyclopentanone-2-carboxylate (70 % ee). However, the main secondary reaction of N-fluoro sultam (4) was HF elimination from the N-fluoro sultam by the metal enolate to give the starting imine and carbonyl compounds. N-fluoro sultam (5), although designed to prevent HF elimination from the fluorinating reagent, gave poor results possibly as a result of steric hindrance. N-fluoro sultam Product Reaction Conditions ee (%) Yield (%) a NaH; Et2O; 0 °C - r.t. 1.5 equiv. (4) LDA; THF; -78 °C - r.t. 1.2 equiv. (4) KH; Toluene/THF (2:1), 0 °C - r.t. 1.3 equiv. (5) LDA; THF; -78 °C - r.t. 1.2 equiv. (5) 70 63 (63) 35 27 (30)
6 Chapter One 2,10 (3,3-dichlorocamphorsultam) (6), N-fluoro-2,10-(3,3-dimethoxycamphorsultam) (7) in addition to N-fluoro-2,10-(camphorsultam) (4). Figure 1.4 N-fluoro-2,10-(3,3-dichlorocamphorsultam) (6) and N-fluoro-2,10-(3,3dimethoxycamphorsultam) (7). N-fluoro-2,10-(3,3-dichlorocamphorsultam) (6) was found to give greater yields and enantioselectivities than N-fluoro-2,10-(camphorsultam) (4) and this was attributed to the greater reactivity of (6) in comparison with that of (4), with fluorinations occurring at lower temperatures (-78 ºC vs. r.t. for (4)). Since the reactions occur at -78 ºC with (6), the rate of HF elimination is decreased, which in turn increases the yield of the fluorinated product. The best result observed for N-fluoro-2,10-(3,3-dichlorocamphorsultam) (6) was the fluorination of the sodium enolate of 2-methyl-1-tetralone, affording the product 2-fluoro-2- methyl-1-tetralone in 53 % yield with 76 % ee. However, with fluorinations of �-ketone ester enolates, enantiomeric excesses were in the range of 34-46 %. The only secondary enolate studied, the enolate of propiophenone, gave a moderate yield but racemic product, due to base-catalysed epimerisation under the reaction conditions, owing to the enhanced acidity of the �-fluoro proton. Fluorination yields for N-fluoro-2,10-(3,3-dimethoxycamphorsultam) (7) were good (55-83 %), however, the enantiomeric excesses were very low (< 5 %). Takeuchi and Shibata synthesised three enantiomeric N-fluorosulfonamides, (8, 9, 10), which comprised of a stable but reactive N-F bond and also steric factors that were expected to favour asymmetric induction (Figure 1.5). [21-23] Figure 1.5 The three N-Fluorosulfonamides synthesised by Takeuchi and Shibata
Page 1 and 2: Synthesis and Comparison of the Rea
Page 3 and 4: Acknowledgements Firstly, I would l
Page 5 and 6: 2.2.2.1.1 Synthesis of 1-(Benzyloxy
Page 7 and 8: 6.2.12 Preparation of 2-(4-trimethy
Page 9 and 10: 6.4.12 Experimental Data for Dimeth
Page 11 and 12: 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: 4 Chapter One ortho-biphenyl trifla
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 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 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
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) (
Page 141 and 142:
Starting Substrate Product Yield (%
Page 143 and 144:
5.2.4 Synthesis of Allylic Difluori
Page 145 and 146:
5.2.5 Metal-mediated synthesis of 3
Page 147 and 148:
130 Chapter Five process. [40] Unfo
Page 149 and 150:
132 Chapter Five compounds were pur
Page 151 and 152:
134 Chapter Five [30] H. L. Sham, N
Page 153 and 154:
6.1 General Experimental Procedures
Page 155 and 156:
6.2 Experimental Details for Chapte
Page 157 and 158:
139 Chapter Six (1 g, 0.75 cm 3 , 6
Page 159 and 160:
6.2.7 Preparation of allyl 4-(trifl
Page 161 and 162:
6.2.10 Preparation of (3-[1,3]Dioxa
Page 163 and 164:
145 Chapter Six reaction mixture wa
Page 165 and 166:
147 Chapter Six mg, 1.1 mmol), ally
Page 167 and 168:
149 Chapter Six 260.3 Hz, ArCF), 16
Page 169 and 170:
6.2.22 Preparation of 2-fluorobut-3
Page 171 and 172:
6.2.25 Preparation of 2-fluorobut-3
Page 173 and 174:
6.2.28 Preparation of 2-hydroxybut-
Page 175 and 176:
157 Chapter Six 1 JCF = 253.5 Hz, A
Page 177 and 178:
159 Chapter Six drying under high v
Page 179 and 180:
6.2.37 Preparation of 2-chlorobut-3
Page 181 and 182:
6.2.40 Preparation of 2-chlorobut-3
Page 183 and 184:
6.3.2 Preparation of Bis[�-chloro
Page 185 and 186:
167 Chapter Six 6.3.5 Preparation o
Page 187 and 188:
169 Chapter Six 4 JHH = 1.2 Hz, ArH
Page 189 and 190:
Time (minutes) 4 11 18 25 Table 6.2
Page 191 and 192:
Time (minutes) 19 F{ 1 H} (ppm) Tim
Page 193 and 194:
175 Chapter Six suspension of sodiu
Page 195 and 196:
177 Chapter Six Hz, Ha), 5.19 (1H,
Page 197 and 198:
6.4.9 Preparation of Dimethyl 2-(4-
Page 199 and 200:
181 Chapter Six 6.4.13 Preparation
Page 201 and 202:
6.5 Experimental Details for Chapte
Page 203 and 204:
185 Chapter Six CHCH2), 133.9 (d, 3
Page 205 and 206:
187 Chapter Six 6.5.6 Preparation o
Page 207 and 208:
189 Chapter Six (5 mg, 0.27 mmol) a
Page 209 and 210:
191 Chapter Six (d, 1 JCF = 255.0 H
Page 211 and 212:
193 Chapter Six layer separated and
Page 213 and 214:
195 Chapter Six Hz, 4 JHF = 3.2 Hz,
Page 215 and 216:
Page 217 and 218:
Page 219 and 220:
Appendix
Page 221 and 222:
II Appendix Second generation Grubb
Page 223 and 224:
IV Appendix mixture was stirred at
Page 225 and 226:
VI Appendix stirred at room tempera
Page 227 and 228:
VIII Appendix The organic phase was
Page 229 and 230:
X Appendix A6 Crystal data and stru
Page 231 and 232:
XII Appendix A8 Crystal data and st
Page 233 and 234:
XIV Appendix A10 Crystal data and s
Page 235 and 236:
A12 Lecture Courses Attended XVI Ap
Page 237 and 238:
A14 Conferences Attended RSC Organi
show all

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

Create successful ePaper yourself

Delete template?

Save as template?