My PhD dissertation - Institut Fresnel

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4.2.2 Racemate Resolution of 6,6’-Dibromobiphenyl-2,2’-dicarboxylic Acid 46 The most reliable procedure to resolve chiral carboxylic acids is the fractional crystallization of a diastereomeric salt which can be easily obtained by treatment of the racemic acid mixture with an enantiomer of a chiral amine such as alkaloids, amino acids, terpene derivatives, etc. methylbenzylamine [5] . A first attempt was made with (S)-(-)-α- [ ] 188 . Its low molecular weight constitutes an advantage for large scale racemate resolution. Moreover, this chiral amine is commercially available in both enantiomeric forms. Unfortunately, crystallization of the resulting diastereomeric salt happened to be very slow and had to be repeated several times to give enantiomerically pure products. In view to the results reported by K. Mislow et al. [ ] 189 and R. Adams et al. [ 190 ] , commercial alkaloids were used. The brucine dihydrate salt was prepared and its crystallization attempted in various solvents. Unfortunately, both diastereomeric salts co-crystallized. Quinine monohydrate finally proved to be a better choice. Crystallization of its biphenol salt in ethanol followed by hydrolysis finally allowed separation both atropisomers in good yield (42% and 39%). Br COOH Br COOH rac-31 O HO H H N (Quinine) Ethanol reflux N H Precipitate Mother liquors Br Br COO Quinine, H COOH Br COO Quinine, H Br COOH 10% aq. HCl Br Br COOH COOH (P)-(-)-37, 42% 10% aq. HCl Br COOH Br COOH (M)-(+)-37, 39%
47 The enantiomeric purity was checked by reduction of each pure isomer (see § 4.2.3) followed by conversion into their corresponding Mosher bisester using (R)-(-)-α-methoxy-α- (trifluoromethyl)-phenylacetyl chloride [ 191 ] . 19 F-NMR analysis of each derivatized atropisomer compared that of the racemic mixture showed an enantiomeric excess of 98 to 99% depending on the enantiomer. Br Br (P)-(-)-37 COOH COOH Br COOH Br COOH (M)-(+)-37 Reduction Br Br Br Br (P)-(-)-39 (M)-(+)-39 OH OH OH OH (R)-(-)-RCOCl (2.0 eq.) CCl4, pyridine, 25 °C Br Br Br Br (P)-40 (M)-40 4.2.3 Derivatization of 6,6’-Dibromobiphenyl-2,2’-dicarboxylic Acid OR * OR * OR * OR * R * = CF 3 OCH Ph3 Enantiomerically pure diacid 37 was finally reduced to (6,6’-dibromobiphenyl-2,2’- diyl)dimethanol (39). The latter was considered to be a versatile intermediate for further derivatization such as conversion to ethers or acetals, cyclization into a benzoxepine-type derivatives or even linkage to a solid support. The diacid 37 was first treated with lithium aluminium hydride in diethyl ether at ambient temperature. Unfortunately, although some reduction did effectively occur to produce the diol 39, thin layer chromatography revealed also the presence of starting material and unidentified by-products. As to be expected, dimethyl 6,6’-dibromobiphenyl-2,2’- dicarboxylate (38) gave a far better result, providing diol 39 in 84% yield. Br Br (P)-(-)-37 COOH COOH CH 3OH, cat. H 2SO 4 60 °C Br Br COOCH 3 COOCH 3 (P)-(-)-38, 88% LiAlH 4, THF, - 10 °C Br Br OH OH (P)-(-)-39, 84%
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Various Facets of Organophosphorus
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III Remerciements Je tiens à remer
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3.3.6 Relevance of the Data Assesse
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VII Literature References 115 Compo
Page 17: IX Version Abrégée Les composés
Page 21 and 22: 1 Introduction 1 The present thesis
Page 23 and 24: 3 research groups in the field are
Page 25 and 26: 5 However, this mechanism suffers f
Page 27: 7 At first, a double bromine/lithiu
Page 30 and 31: 10 Although the most frequently emp
Page 32 and 33: 12 The preparation of the latter ph
Page 34 and 35: protected to its dioxolane derivati
Page 36 and 37: N (S)-14 1) NBS, THF, - 75 °C 2) -
Page 39 and 40: 3 Alkaline Decomposition of Phospho
Page 41 and 42: 3.2 Alkyl Carbanions Stabilities in
Page 43 and 44: 3.3.1 Mechanistic Discussion on the
Page 45 and 46: 25 The assumption reported by these
Page 47 and 48: 27 However, in the eventuality of a
Page 49 and 50: 29 To prepare tertiary phosphines b
Page 51 and 52: 31 Table 4. Mixed tertiary alkylpho
Page 53 and 54: 33 were comparable to those obtaine
Page 55 and 56: 35 led to the formation of di-tert-
Page 57 and 58: 37 depending on the alkyl substitue
Page 59 and 60: 39 4 A Novel Access to Atropisomeri
Page 61 and 62: 41 Since the homocoupling of the ha
Page 63 and 64: 43 Few other attempts to selectivel
Page 65: 45 The second phenol ether 36 was f
Page 69 and 70: 49 A second purpose of this derivat
Page 71 and 72: 51 substrates considered. In conseq
Page 73 and 74: 53 Single-crystal X-ray analysis of
Page 75 and 76: 55 To convert atropisomer Ia into I
Page 77 and 78: 57 This finally allows one to use t
Page 79 and 80: the steric bulk and charge delocali
Page 81 and 82: 61 To check the reproducibility of
Page 83: 63 Figure 9. Full lineshape analysi
Page 86 and 87: 66 suitably substituted dilithiobip
Page 89: Experimental Part
Page 92 and 93: 70 deuterochloroform (CDCl3) unless
Page 94 and 95: 72 1 H NMR: δ = 7.32 (dddd, J = 9,
Page 96 and 97: 1 H NMR: δ = 6.96 (s, 3 H), 6.94 (
Page 98 and 99: 76 C21H21O9P (448.36) calcd. C 56.2
Page 100 and 101: 78 C12H12BrN (250.13) calcd. C 57.6
Page 102 and 103: 80 C13H13NO2 (215.25) calcd. C 72.5
Page 104 and 105: 82 3.1.1 Dialkyl-N,N-diethylaminoph
Page 106 and 107: 84 apparatus. The solution was adde
Page 108 and 109: 86 Di-tert-butylisopropylphosphine
Page 110 and 111: 88 13 C NMR: δ = 32.9 (d, J = 12 H
Page 112 and 113: 90 13 C NMR: δ = 41.5 (d, J = 61 H
Page 114 and 115: 31 P NMR: δ = 53.4 ppm. 92 C16H31O
Page 116 and 117:
94 13 C NMR: δ = 40.8 (d, J = 3 Hz
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96 31 P NMR settings: It is known t
Page 120 and 121:
98 Theoretical ratio: (96.1:3.9) Ex
Page 123 and 124:
101 4 The Preparation and Racemate
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103 extraction protocol with ethyl
Page 127 and 128:
105 extracted with ethyl acetate (2
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107 (+)-(M)-Dimethyl-6,6’-dibromo
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109 (+)-(M)-2,2’-Dibromo-6,6’-b
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111 1 H NMR: δ = 7.2 (m, 20 H), 7.
Page 135 and 136:
113 2,2’-Dilithio-6,6’-bis(meth
Page 137:
References
Page 140 and 141:
116 Conference Proceedings, Naples,
Page 142 and 143:
118 [ 70] J. Drowart, C.E. Myers, R
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120 [117] S.T. Graul, R.R. Squires,
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122 [170] B.H. Lipshutz, F. Kayser,
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124 [212] M. Schlosser, in Organome
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O P 27i: p. 30, 80 C 9H 21OP P 26b:
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P P P O 2: p. 11, 59 3 P O O O 11:
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Nom Maurin Prénom Michaël 129 Cur
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