Synlett 2016; 27(15): 2251-2253
DOI: 10.1055/s-0035-1562380
letter
© Georg Thieme Verlag Stuttgart · New York

Preparation of 2-Azabicyclo[2.1.1]hexane Hydrochloride

Haili Liao
a   Pharmaron Beijing Co. Ltd., No. 6 Taihe Road, BDA, Beijing 100176, P. R. of China
,
Aimin Li
a   Pharmaron Beijing Co. Ltd., No. 6 Taihe Road, BDA, Beijing 100176, P. R. of China
,
Xingsong Chen
a   Pharmaron Beijing Co. Ltd., No. 6 Taihe Road, BDA, Beijing 100176, P. R. of China
,
Kun Liang
a   Pharmaron Beijing Co. Ltd., No. 6 Taihe Road, BDA, Beijing 100176, P. R. of China
,
Yang Shen
a   Pharmaron Beijing Co. Ltd., No. 6 Taihe Road, BDA, Beijing 100176, P. R. of China
,
Qingfeng Liang
a   Pharmaron Beijing Co. Ltd., No. 6 Taihe Road, BDA, Beijing 100176, P. R. of China
,
Kewei Xu
b   Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: siu.michael@gene.com   Email: huestis.malcolm@gene.com
,
Daniel G. M. Shore
b   Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: siu.michael@gene.com   Email: huestis.malcolm@gene.com
,
Elisia Villemure
b   Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: siu.michael@gene.com   Email: huestis.malcolm@gene.com
,
Michael Siu*
b   Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: siu.michael@gene.com   Email: huestis.malcolm@gene.com
,
Malcolm P. Huestis*
b   Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: siu.michael@gene.com   Email: huestis.malcolm@gene.com
› Author Affiliations
Further Information

Publication History

Received: 12 May 2016

Accepted after revision: 04 June 2016

Publication Date:
07 July 2016 (online)


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.

Supporting Information

 
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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).