One-Pot Organocatalytic Asymmetric Synthesis of 1H-Pyrrolo[1,2a]indol-3(2H)-ones via a Michael-Hemiaminalization-Oxidation Sequence

Abstract

An efficient one-pot organocatalytic asymmetric synthesis of 1,2-cis-disubstituted 1H-pyrrolo[1,2a]indol-3(2H)-ones in moderate to good overall yields (49-68%) is presented. The ­Michael-hemiaminalization-oxidation sequence occurs with very high asymmetric induction and, after purification, virtually stereo­isomerically pure products were obtained (>98% de, >99% ee).

Key words

pyrrolo[1,2a]indolones - Michael addition - hemiaminalization - organocatalysis - one-pot reaction

References and Notes

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CCDC-798847 (6f) contains the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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General Procedure
To a solution of aldehydes 1 (3.0 mmol, 3.0 equiv), (E)-2-(2-nitrovinyl)-1H-indoles 2 (1.0 mmol, 1.0 equiv), and AcOH (0.20 mmol, 20 mol%) in CH₂Cl₂ (4.0 mL) was added (R)-diphenylprolinol TMS-ether [(R)-3] (0.15 mmol, 15 mol%). After stirring for 1 d, the reaction mixture was treated with pyridinium chloromate (2.0 mmol, 2.0 equiv) and stirred at r.t. for 1 d. The crude product was purified by flash chromatography on silica gel (pentane-Et₂O mixture) affording the corresponding 1H-pyrrolo[1,2a]indol-3
(2H)-ones 6 as a solid or sirup. (1 S ,2 S )-2-Butyl-7-chloro-1-(nitromethyl)-1 H -pyrrolo[1,2- a ]indol-3 (2 H )-one (6f) Isolated as a yellow solid (186 mg, 58%). The ee (>99%) was determined by HPLC on a chiral stationary phase [Chiralcel OD, n-heptane-EtOH (9:1), 1.0 mL/min), t _R = 11.52 min (major), 13.16 min (minor, based on the racemic mixture)]; mp 108 ˚C; [α]_D ^²0 = 77.2 (c 0.32, CHCl₃). IR (KBr): 3293, 3196, 2955, 2924, 2867, 2160, 2064, 1725, 1662, 1598, 1582, 1554, 1498, 1446, 1391, 1360, 1317, 1264, 1201, 1167, 1146, 1055, 968, 946, 914, 893, 868, 810, 777, 754, 712, 693, 677, 655 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 0.96 (t, J = 7.2 Hz, 3 H), 1.26-1.66 (m, 5 H), 1.88-2.00 (m, 1 H), 3.36-3.44 (m, 1 H), 4.32-4.40 (m, 1 H), 4.48-4.56 (m, 1 H), 4.71-4.77 (m, 1 H), 6.29 (s, 1 H), 7.25-7.29 (m, 1 H), 7.48 (d, J = 2.8 Hz, 1 H), 7.93 (d, J = 8.7 Hz, 1 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 13.8, 22.6, 26.1, 29.7, 34.4, 48.5, 74.8, 101.8, 114.6, 120.9, 124.6, 128.8, 130.0, 135.5, 142.0, 171.1 ppm. MS (EI, 70 eV): m/z (%) = 320 (33) [M⁺], 273 (29), 219 (36), 217 (100). ESI-HRMS: m/z calcd for C₁₆H₁₇O₃N₂ ^³5Cl: 320.0922; found: 320.0923.