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

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.

allylsilanes - fluorine - diastereoselectivity - silicon - oxazines

References and Notes

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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.

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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.

13 Buckle MJC. Fleming I. Gil S. Pang KLC. Org. Biomol. Chem.  2004,  2:  749