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Synlett 2010(18): 2805-2807  
DOI: 10.1055/s-0030-1258811
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Tandem Amination/Lactamisation Route to 2-Azabicyclo[2.2.2]octanones

James D. Cuthbertsona, Andrew A. Godfreyb, Richard J. K. Taylor*a
a Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax: +44(1904)434523; e-Mail: rjkt1@york.ac.uk;
b AstraZeneca, Pharmaceutical Development, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, UK
Further Information

Publication History

Received 31 August 2010
Publication Date:
12 October 2010 (online)

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Abstract

An efficient one-pot amination/lactamisation sequence for the preparation of 2-azabicyclo[2.2.2]octanones from 6-carboalkoxycyclohex-2-enones and aqueous ammonia is described. Scope and limitation studies are reported for this tandem procedure and a range of bicyclic compounds have been prepared, two of which were characterised by X-ray crystallography.

Key words

amination - lactamisation - azabicyclo[2.2.2]octanones - bicyclic compounds - 6-carboalkoxycyclohex-2-enones

    References and Notes

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7

All novel compounds were fully characterised by ¹H NMR, ¹³C NMR, IR spectroscopies and by HRMS.

9

Typical Procedure for the Synthesis of 8β-Methyl-2-azabicyclo[2.2.2]octane-3,5-dione (5a): A solution of β-keto ester 3a (46 mg, 0.25 mmol) in 35% aq NH3 (1 mL) was stirred at r.t. until consumption of starting material was observed by TLC analysis (CH2Cl2-MeOH, 9:1), ca. 2 h. The reaction mixture was then concentrated in vacuo and purified by column chromatography (SiO2, CH2Cl2-MeOH, 98:2) to give the title compound 5a as a colourless crystalline sold (36 mg, 93%); mp 135-137 ˚C; R f 0.40 (CH2Cl2-MeOH, 9:1). IR (thin film): 3244, 2961, 1730, 1681, 1335, 1105 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.92 (br s, 1 H, NH), 3.93-3.98 (m, 1 H), 3.03-3.11 (m, 1 H), 2.40-2.49 (m, 2 H), 2.28-2.37 (m, 1 H), 2.20 (dd, J = 18.5, 1.9 Hz, 1 H), 1.31 (ddd, J = 13.0, 4.6, 1.0 Hz, 1 H), 1.06 (d, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 205.1 (CO), 171.8 (CO), 64.4 (CH), 47.0 (CH), 43.8 (CH2), 35.4 (CH2), 29.4 (CH), 20.8 (Me). MS: m/z (ESI) = 154 [MH]+. HRMS (ESI): m/z [M + H+] calcd for C8H12NO2: 154.0863; found: 154.0864 (0.6 ppm error).