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Synlett 2008(17): 2647-2650  
DOI: 10.1055/s-0028-1083525
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Investigation of a Tandem Iminium Ion Allylation Approach to Piperidines

Nicole C. Manceya, Roger J. Butlinb, Joseph P. A. Harrity*a
a Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
Fax: +44(114)2229346; e-Mail: j.harrity@sheffield.ac.uk;
b Department of Medicinal Chemistry, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
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Publication History

Received 1 August 2008
Publication Date:
01 October 2008 (online)

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Investigation of a Tandem Iminium Ion Allylation Approach to PiperidinesSynlett 2008; 2008(17): e6-e6
DOI: 10.1055/s-0028-1083534

Abstract

A [3+3]-annulation approach to piperidines via a tandem iminium ion allylation reaction of bisaminals has been developed. The scope of this process is described as well as preliminary experiments aimed at understanding the mechanism of a competing olefin isomer formation.

Key words

allylsilane - iminium ion - piperidines - annulation - Lewis acid

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    Representative Experimental Procedure for the Preparation of [3+3]-Cycloaddition Adducts; Synthesis of 7-Methylenehexahydroindolizin-3(5 H )-one (7): To a solution of 5 (60 mg, 0.35 mmol, 1 equiv) in CH2Cl2 (1.5 mL) at -78 ˚C was added 1 (69 mg, 0.35 mmol, 1 equiv) in CH2Cl2 (1.5 mL) followed by TMSOTf (0.03 mL, 0.17 mmol, 0.5 equiv). The reaction was left at -78 ˚C for 1 h before being warmed to r.t. After 16 h, the reaction was quenched with aq NaHCO3 solution and extracted with CH2Cl2. The organic layers were washed with brine before drying over MgSO4. The reaction was concentrated in vacuo. Purification by silica gel chromatography provided 7 as a mixture of isomers (44 mg, 84%; exo/endo, 1:4). FTIR: 3055 (m), 2986 (m), 2685 (w), 1686 (s), 1668 (s), 1422 (m), 1266 (s) cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 1.50-1.75 (m, 3.4 H, CH), 1.85-2.51 (m, 5.4 H, CH), 2.66 (td, 0.2 H, J = 13.0, 4.0 Hz, CH exo ), 2.82 (m, 0.2 H, CH endo ), 3.41-3.58 (m, 0.8 H, CH), 3.63 (m, 0.6 H, CH), 4.06-4.28 (m, 1.2 H, CH), 4.83 (m, 0.4 H, C=CH2 exo ), 5.39 (m, 0.8 H, C=CH endo ). ¹³C NMR (69.2 MHz, CDCl3): δ = 23.3, 24.9, 25.4, 26.5, 29.3, 30.0, 30.2, 31.6, 33.3, 36.2, 37.3, 40.0, 40.7, 42.3, 53.3, 55.0, 58.3, 110.6, 117.0, 122.3, 131.8, 132.7, 143.7, 173.6, 174.0. HRMS: m/z [M+] calcd for C9H13NO: 151.0997; found: 151.0999.

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12

The low yields of product appear to be due to competing addition of BSA to 5. Indeed, addition of BSA (1 equiv) to a mixture of 5 and TMSOTf (1 equiv) in the absence of allylsilane 1 resulted in <20% recovery of 5 together with unidentified material.