Synlett 2015; 26(10): 1375-1378
DOI: 10.1055/s-0034-1379918
letter
© Georg Thieme Verlag Stuttgart · New York

Expedient Synthesis of Highly Functionalised Cyclic Imines

Thomas A. Moss*
AstraZeneca Mereside, Alderley Park, Cheshire, SK10 4TG, UK   Email: thomas.moss@astrazeneca.com
› Author Affiliations
Further Information

Publication History

Received: 13 February 2015

Accepted after revision: 27 March 2015

Publication Date:
23 April 2015 (online)


Abstract

Aryl- and heteroaryl fused cyclic imines are obtained from the starting acetal via a directed metallation–alkylation–condensation sequence using cyclic sulfamidates as the electrophile. A variety of aromatics and heteroaromatics are demonstrated to be applicable to this methodology, which produces highly versatile cyclic imine building blocks for drug discovery and total synthesis programmes.

 
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  • 14 Representative Procedure – Synthesis of Cyclic Imine 5 To an oven-dried three-necked flask containing acetal 1 (1.0 mmol, 219 mg) in THF (4.31 mL) at –78 °C was added n-BuLi (1.6 M in hexanes, 0.688 mL, 1.1 mmol). The reaction was stirred for 2 h, then sulfamidate 2 (260 mg, 1.1 mmol) was added in one portion. The reaction was stirred for 15 min before being allowed to warm to 0 °C over 30 min. The solvents were evaporated, then the residue was stirred in 4 M HCl–dioxane (4 mL) containing H2O (0.5 mL) at r.t. for 30 min. The reaction mixture was diluted with CH2Cl2 and basified by addition of 1 M Na2CO3 solution. The layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and the solvent evaporated. The crude residue was purified by silica gel chromatography [100% EtOAc] to afford the cyclic imine 5 as a straw-coloured oil (141 mg, 66%). [α]D –10.0 (c 2, CH2Cl2, 24 °C). IR: νmax = 2966 (m), 1628 (s), 1556 (m), 1455 (s), 1407 (m), 1166 (s) cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.42 (d, J = 6.9 Hz, 3 H), 2.51 (dd, J = 11.7, 17.0 Hz, 1 H), 3.06 (dd, J = 6.2, 17.0 Hz, 1 H), 3.68–3.80 (m, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 1 H), 8.24 (d, J = 2.5 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 21.77, 29.99, 52.19, 126.10, 127.64, 128.67, 131.76, 135.50, 136.20, 157.43. MS (EI): m/z (%) = 214 (100) [M + H]+. HRMS (EI): m/z [M + H]+ calcd for C10H9NCl2: 214.0190; found: 214.0197.