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

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.

azepines - enamines - cyclisation - condensation - heterocycles

References and Notes

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<A NAME="RG33406ST-18">18</A>

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⁺].

<A NAME="RG33406ST-19">19</A>

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⁺].