Expedient Synthesis of Highly Functionalised Cyclic Imines

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.

Key words

cyclic sulfamidate - metallation - ring opening - alkylation - cyclic imine

• References and Notes


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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: ν_max = 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.