Asymmetric Neber Reaction in the Synthesis of Chiral 2-(Tetrazol-5-yl)-2H-Azirines

Published as part of the ISySyCat2019 Special Issue

Abstract

A successful one-pot methodology for the synthesis of chiral 2-tetrazolyl-2H-azirines has been established, resorting to organocatalysis. The protocol involves the in situ tosylation of β-ketoxime-1H-tetrazoles followed by the Neber reaction, in the presence of chiral organocatalysts. Among the organocatalysts studied a novel thiourea catalyst derived from 6β-aminopenicillanic acid afforded excellent enantioselectivities.

Key words

2H-azirines - asymmetric Neber reaction - organocatalysis - tetrazoles - thiourea - 6β-aminopenicillanic acid

• References and Notes

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• 26 Procedure for the Synthesis of (2S,6R)-Benzhydryl 6β-{3-[3,5-bis(trifluoromethyl)phenyl] thioureido}-aminopenicillanate (12) To a solution of benzhydryl 6β-aminopenicillanate 10b (1.94 mmol, 0.74 g) under inert atmosphere in dry THF (3.5 mL) was added dropwise 3,5-bis(trifluoromethyl)phenyl isothiocyanate (11, 1.94 mmol, 0.35 mL). After stirring for 3 h at room temperature, the solvent was evaporated, and the crude product was purified by flash chromatography (eluting with ethyl acetate/hexane, 1:2) and recrystallized with diethyl ether/hexane; yield 48%; white solid; mp 77.0–78.0 °C. IR (KBr): ν = 682, 697, 1128, 1251, 1175, 1276, 1491, 1735, 2968, 2933, 3032, 3066, 3271, 3291 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.93 (s, 1 H), 7.84 (s, 2 H), 7.50 (s, 1 H), 7.35–7.31 (m, 11 H), 6.96 (s, 1 H), 5.19 (d, J = 2 Hz, 1 H), 4.25 (dd, J = 3.2 Hz and J = 1.2 Hz, 1 H), 3.92 (s, 1 H), 1.64 (s, 3 H), 1.00 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 182.8, 170.6, 167.3, 139.1, 138.9, 133.9, 132.4 (q, J = 34.0 Hz, 2 C), 128.8, 128.9, 128.6, 128.5, 128.2, 127.9, 127.7, 126.9, 126.8, 126.6, 124.1, 122.9 (m, 1 C), 121.4, 78.7, 73.3, 66.5, 65.5, 65.1, 60.6, 26.3, 26.1 ppm. ¹⁹F NMR (376 MHz CDCl₃): δ = 62.8 (s, 6 F). HRMS (ESI): m/z calcd for C₃₀H₂₆F₆N₃O₃S₂ [MH⁺]: 654.1314; found: 654.1301.