Preparation of 2-Azabicyclo[2.1.1]hexane Hydrochloride

Abstract

A batchwise, multigram preparation of 2-azabicyclo-[2.1.1]hexane hydrochloride (1·HCl) was developed, delivering a total of 195 grams of material. The key synthetic step involves an intramolecular displacement of a primary alkyl chloride with a tert-butylsulfinamide to forge the [2.1.1]-bicyclic ring system.

Key words

amines - alkylation - alkyl halides - bicyclic compounds - heterocycles

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• 14 2-Azabicyclo[2.1.1]hexane Hydrochloride (1·HCl) To a 2 L four-necked round-bottomed flask was added 2-(2-methylpropane-2-sulfinyl)-2-azabicyclo[2.1.1]hexane (6, 75.0 g, 0.400 mol) and EtOH (1000 mL). Hydrogen chloride gas was bubbled through the solution via an inlet, and the resulting solution was stirred at room temperature for 3 h. Following concentration under vacuum, the mixture was diluted with Et₂O (500 mL) and stirred for 1 h. The solid material was collected by filtration, washing with Et₂O (2 × 200 mL). This procedure was conducted 5 times to afford 2-azabicyclo[2.1.1]hexane hydrochloride 1·HCl as a brown solid (195 g, 81%). ¹H NMR (400 MHz, DMSO): δ = 9.46 (s, 2 H), 4.16–4.07 (m, 1 H), 3.21–3.09 (m, 2 H), 2.88–2.79 (m, 1 H), 2.04–1.91 (m, 2 H), 1.47–1.34 (m, 2 H). ¹³C NMR (DMSO, 101 MHz): δ = 59.0, 46.0, 37.7, 36.8. HRMS: m/z calcd for C₅H₁₀N [M + H]⁺: 84.0808; found: 84.0809.
• 15 Protection of 1 as the tert-butoxycarbamate was also possible (76% yield, see Supporting Information).