Synlett 2016; 27(01): 159-163
DOI: 10.1055/s-0035-1560391
letter
© Georg Thieme Verlag Stuttgart · New York

Continuous-Flow Synthesis of 2H-Azirines and Their Diastereoselective Transformation to Aziridines

Marcus Baumann*
Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK   Email: marcus.baumann@durham.ac.uk
,
Ian R. Baxendale
Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK   Email: marcus.baumann@durham.ac.uk
› Author Affiliations
Further Information

Publication History

Received: 27 November 2015

Accepted after revision: 30 November 2015

Publication Date:
01 December 2015 (eFirst)

We dedicate the star of this paper to Prof. Steven V. Ley on the occasion of his 70th birthday

Abstract

Using continuous-flow techniques, a small collection of 2H-azirines was prepared from oxime precursors via mesylation and base-promoted cyclisation. The 2H-azirines were either isolated after in-line purification or derivatised into a selection of 2-substituted aziridines through a telescoped reaction sequence involving nitrile, trifluoromethyl, or hydride nucleophilic addition. Importantly, these 2-substituted aziridines were produced with high cis diastereoselectivity providing access to small chiral heterocyclic entities that hold promise for medicinal chemistry programs because of their druglike features.

Supporting Information

 
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  • 15 Typical Flow Procedure for the Synthesis of 2H-AzirinesUsing a Vapourtec E-Series flow system, two streams containing the oxime substrate (4, 0.1 M MeCN, 1.0 equiv; stream A) and Et3N (1.2 equiv; 0.3 mL/min; stream A) and MsCl (0.12 M MeCN, 1.2 equiv; 0.3 mL/min; stream B) were mixed in a T-piece prior to entering a tubular flow coil (10 mL volume, 40 °C) in which the mesylation occurred. The exiting flow stream was then directed into an Omnifit glass column (10 mm i.d., 150 mm length) filled with silica supported pyridine10 (2.5 g, 1.39 mmol/g loading) and silica gel (1 g) that was maintained at ambient temperature. After exiting this column the crude reaction mixture passed a backpressure regulator (100 psi) before being collected. Final purification could be achieved via silica column chromatography (20–50% EtOAc–hexanes) yielding the desired 2H-aziridines typically in high yield as yellow oils.4-{3-[4-(Trifluoromethyl)phenyl]-2H-azirin-2-yl}pyridine (5a)Yield 201 mg (0.77 mmol, 77%); yellow oil. 1H NMR (400 MHz, CDCl3): δ = 8.47 (2 H, d, J = 8.0 Hz), 7.97 (2 H, d, J = 8.0 Hz), 7.79 (2 H, d, J = 8.0 Hz), 7.02 (2 H, d, J = 8.0 Hz), 3.29 (1 H, s). 13C NMR (101 MHz, CDCl3): δ = 161.9 (C), 149.5 (2 CH), 149.4 (C), 135.1 (C, q, J = 23 Hz), 130.3 (2 CH), 126.4 (2 CH, q, J = 4 Hz), 126.3 (C), 123.3 (CF3, q, J = 271 Hz), 120.9 (2 CH), 33.6 (CH). 19F NMR (376 MHz, CDCl3): δ = –63.3 . IR (neat): ν = 1602 , 1413 , 1322 , 1168 , 1126 , 1065 , 1017 , 851 cm–1. LC–MS (ESI-TOF): m/z = 263.1 [M + H]. HRMS (ESI-TOF): m/z calcd for C14H10N2F3: 263.0796; found: 263.0792 (Δ 0.4 mDa).