Concise Synthesis of the Tricyclic Skeleton of Cylindricines Using a Radical Cascade Involving 6-Endo Selective Cyclization

Abstract

On treatment with Bu₃SnH and azobis(cyclohexanecarbonitrile) (ACN), enamide 19 underwent a 6-endo-trig/5-endo-trig radical cascade to afford perhydropyrrolo[2,1-j]quinoline derivative 21, a cylindricine skeleton.

Key words

cyclizations - cylindricine - regioselectivity - radical ­cascade - acyl radical

References

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9

The structure of compound 9 was determined by its ¹³C NMR spectrum, which showed the presence of a quaternary carbon atom (δ = 66.3 ppm).

11

Enamide 10 was synthesized by treatment of the imine, prepared from ethylamine and cyclohexanone, with 3-bromopropionyl chloride in the presence of NaHCO₃.

12

¹³C NMR spectrum of compound 11 showed the presence of a quaternary carbon atom (δ = 64.0 ppm) and the IR spectrum of 11 exhibited absorption at 1665 cm^-1 due to the five-membered lactam.

16

Crystallographic data of 13 and 21 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 262989 (13) and 262990 (21), respectively. Copies of these data may be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone].

19

The structure of compound 20 was confirmed by transforming it to compound 8 by removal of the carbonyl group of the ketone.

20

(7a S *,11a S *)-Octahydro-3 H -pyrrolo[2,1- j ]quinoline-3,7 (7a H )-dione ( 21). To a boiling solution of 19 (530 mg, 1.46 mmol) in toluene (70 mL) was added dropwise a solution of Bu₃SnH (649 mg, 2.20 mmol) and ACN (71.5 mg, 0.292 mmol) in toluene (70 mL) over 3 h using a syringe pump. The reaction mixture was cooled to r.t. and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane-EtOAc, 1:1) to give 21 (113 mg, 37%) as colorless crystals; mp 106-107 °C (hexane). IR (CHCl₃): ν = 1715, 1680 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 1.19-1.79 (m, 9 H), 2.00 (td, J = 8.3, 13.5 Hz, 1 H), 2.16 (ddd, J = 6.6, 8.3, 13.5 Hz, 1 H), 2.25-2.31 (m, 1 H), 2.33-2.53 (m, 3 H), 3.04 (ddd, J = 6.3, 10.2, 13.5 Hz, 1 H), 4.38 (ddd, J = 2.3, 6.3, 13.5 Hz, 1 H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 20.5, 21.7, 22.3, 29.0, 29.4, 32.4, 35.0, 39.7, 55.2, 64.6, 173.1, 207.3. Anal. Calcd for C₁₂H₁₇NO₂: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.31; H, 8.42; N, 6.61.