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Synlett 2007(3): 0497-0499  
DOI: 10.1055/s-2007-967942
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a Highly Functionalised Azepine via a New TBSOTf-Mediated Cyclisation of a Terminal Formamide

Stefan Heuser*
Lilly Forschung GmbH, a Division of Eli Lilly Research Laboratories, Essener Bogen 7, 22419 Hamburg, Germany
Fax: +49(40)52724601; e-Mail: heuser_stefan@lilly.com;
Further Information

Publication History

Received 21 December 2006
Publication Date:
07 February 2007 (online)

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Abstract

The synthesis of a highly functionalised azepine which can be further derivatised by common chemical transformations is described herein. The present synthesis comprises high-yielding reaction steps and features a new method for the synthesis of azepines via TBSOTf-mediated cyclisation of terminal formamides.

Key words

azepines - enamines - cyclisation - condensation - heterocycles

    References and Notes

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Procedure for the Preparation of 9.
To a solution of formamide 8 (353 mg, 912 µmol) in 10 mL anhyd CH2Cl2 were added Et3N (1.39 g, 1 mL, 13.7 mmol) and TBSOTf (1.73 g, 1.5 mL, 6.53 mmol). After stiring at r.t. for 5 d 20 mL CH2Cl2 were added and the solution was washed successively with sat. NaHCO3 solution and sat. NH4Cl solution. The organic phase was then filtered through a hydrophobic filter and concentrated. Purification of the residue via flash chromatography on silica eluting with 1:3 EtOAc in hexane afforded 170 mg (51%) of 9 as a pale yellow oil.
1H NMR: (300 MHz, DMSO-d 6): δ = 0.82 (s, 3 H), 1.01 (br s, 24 H), 1.12 (t, 3 J = 7.1 Hz, 3 H), 2.49 (m, 1 H), 2.61 (m, 2 H), 3.13 (dd, 2 J = 11.9 Hz, 3 J = 3.1 Hz, 1 H), 3.76 (dd, 2 J = 11.9 Hz, 3 J = 2.2 Hz, 1 H), 3.96 (m, 2 H), 6.54 (br s, 1 H), 7.32 (d, 3 J = 6.5 Hz, 1 H). MS (ESI): m/z = 370 [M + H+].

19

Analytical Data for 1.
1H NMR: (300 MHz, DMSO-d 6): δ = 0.80 (s, 3 H), 0.95 (s, 3 H), 1.19 (t, 3 J = 7.1 Hz, 3 H), 1.44 (s, 9 H), 3.09 (d, 2 J = 14.2 Hz, 1 H), 3.31 (m, 1 H), 3.67 (d, 2 J = 14.2 Hz, 1 H), 4.09 (q, 3 J = 7.1 Hz, 2 H), 4.80 (m, 1 H), 7.82 (s, 1 H). MS (ESI): m/z = 336 [M + Na+].