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Synlett 2007(19): 3022-3026  
DOI: 10.1055/s-2007-992361
LETTER
© Georg Thieme Verlag Stuttgart · New York

Diastereoselective Fluorination of Silylated 1,2-Oxazines to Access Fluorinated N,O-Heterocycles

Yu-hong Lama, Matthew N. Hopkinsona, Steven J. Stanwayb, Véronique Gouverneur*a
a Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
Fax: +44(1865)275644; e-Mail: veronique.gouverneur@chem.ox.ac.uk;
b Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science, Third Avenue, Harlow, Essex CM19 5AW, UK
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Publication History

Received 8 October 2007
Publication Date:
08 November 2007 (online)

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Abstract

The electrophilic fluorination of silylated N,O-heterocycles, prepared from a nitroso-Diels-Alder reaction of silylated dienes, afforded fluorinated 1,2-oxazines with the fluorine substituent on a stereogenic centre in moderate to high diastereoselectivities. The sense and level of diastereocontrol were found to be dependent of the substitution pattern of the heterocycle.

Key words

allylsilanes - fluorine - diastereoselectivity - silicon - oxazines

10

General Nitroso-Diels-Alder Procedure
A solution of the N-protected hydroxylamine 2a-c (1 equiv, 1.1-2.5 mmol) in the minimum amount of MeOH was added dropwise to a stirred solution of the diene 1a-d (1.1 equiv) and tetra-n-butylammonium periodate (1.1 equiv) in CH2Cl2 (0.1 M) at 0 °C. The reaction was followed by TLC and when complete (20-30 min), was warmed to r.t. and quenched with sat. Na2S2O3 solution (10 mL). The reaction mixture was transferred to a separating funnel and the layers separated. The aqueous phase was extracted with CH2Cl2 (3 × 15 mL) and the combined organic phases washed with brine (30 mL). After drying over Na2SO4 and filtration, the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (hexane-Et2O, 5:1) giving the product as an oil.
Compound 3a: yellow oil; R f = 0.33 (hexane-Et2O, 4:1). 1H NMR (400 MHz, CDCl3): δ = 7.42-7.33 (5 H, m, Ph), 5.49 (1 H, s, H6), 5.46 (1 H, s, H5), 4.08 (1 H, d, J = 17.2 Hz, H3), 3.99 (1 H, d, J = 17.2 Hz, H3′), 1.58 (2 H, s, Me3SiCH2) 1.44 [9 H, s, C(CH3)3], 0.11 [9 H, s, Si(CH3)3]. 13C NMR (101 MHz, CDCl3): δ = 154.6 (C=O), 138.5, 133.3 (ipso-Ph, C4), 128.6 (Ph), 128.5 (Ph), 128.4 (Ph), 118.5 (C5), 81.2 [C(CH3)3], 79.1 (C6), 48.4 (C3), 28.2 [C(CH3)3], 24.4 [(CH3)3SiCH2], -1.3 [Si(CH3)3]. IR: 1700, 1367, 1249, 1169, 1083, 856. HRMS (EI+): m/z calcd for C19H29NNaO3Si [M + Na]+: 370.1814; found: 370.1809.

12

General Electrophilic Fluorodesilylation Procedure
Selectfluor® (1.1 equiv) was added to a stirred solution of the cycloadduct (1 equiv, 0.1-0.6 mmol) in MeCN (0.1 M) at r.t. The mixture was left to stir for 2-4 h until complete by TLC. The reaction mixture was then diluted with Et2O (5 mL) and washed with H2O (2 × 5 mL). The organic layer was dried over anhyd MgSO4, filtered, and the solvent evaporated in vacuo. The crude mixture was purified and the diastereomers separated using silica gel chromatography. Compound syn-4a: white solid; mp 47 °C; R f = 0.26 (hexane-Et2O, 4:1). 1H NMR (400 MHz, CDCl3): δ = 7.51-7.46 (2 H, m, Ph), 7.42-7.35 (3 H, m, Ph), 5.34 [1 H, d, J = 5.3 Hz, C=C(H)(H′)], 5.33 [1 H, s, C=C(H)(H′)], 5.06 (1 H, d, J = 48.3 Hz, H5), 4.90 (1 H, d, J = 28.3 Hz, H6), 4.48 (1 H, d, J = 14.4 Hz, H3), 4.29 (1 H, dm, J = 14.7 Hz, H3′), 1.50 [9 H, s, C(CH3)3]. 13C NMR (126 MHz, CDCl3): δ = 155.0 (C=O), 136.4 (d, J = 18.1 Hz, C4), 134.7 (ipso-Ph), 128.6 (Ph), 128.4 (Ph), 127.3 (Ph), 117.2 (d, J = 9.5 Hz, C=CH2), 89.7 (d, J = 180.2 Hz, C5), 83.9 (d, J = 21.0 Hz, C6), 82.2 [C(CH3)3], 48.8 (C3), 28.3 [C(CH3)3]. 19F NMR (377 MHz, CDCl3): δ = -190.8 (dd, J = 48.3, 28.3 Hz). IR: 1722, 1454, 1369, 1239, 1159, 1082, 956, 916, 851. HRMS (EI+): m/z calcd for C16H20FNNaO3 [M + Na]+: 316.1325; found: 316.1318.
Compound anti-4a: colourless oil. R f = 0.38 (hexane-Et2O, 4:1). 1H NMR (400 MHz, CDCl3): δ = 7.51-7.34 (5 H, m, Ph), 5.35 [1 H, m, C=C(H)(H′)], 5.24 [1 H, m, C=C(H)(H′)], 5.21 (1 H, dd, J = 48.8, 9.1, H5), 4.75 (1 H, dd, J = 9.1, 6.1 Hz, H6), 4.64 (1 H, dd, J = 14.7, 3.1 Hz, H3), 4.08 (1 H, d, J = 14.7 Hz, H3′), 1.52 [9 H, s, C(CH3)3]. 13C NMR (126 MHz, CDCl3): δ = 154.8 (C=O), 137.7 (d, J = 14.3 Hz, C4), 135.0 (ipso-Ph), 129.2 (Ph), 128.6 (Ph), 127.7 (Ph), 110.5 (d, J = 11.4 Hz, C=CH2), 89.8 (d, J = 187.9 Hz, C5), 84.6 (d, J = 22.9 Hz, C6), 82.4 [C(CH3)3], 52.2 (C3), 28.3 [C(CH3)3]. 19F NMR (377 MHz, CDCl3): δ = -194.4 (d, J = 48.8 Hz). IR: 1711, 1455, 1369, 1234, 1158, 1083, 979, 914, 852. HRMS (EI+): m/z calcd for C16H20FNNaO3 [M + Na]+: 316.1325; found: 316.1318.