Stereoselective Synthesis of Pyrrolo[1,2-a]indoles from Allenes in PEG-400 as the Reaction Medium

Abstract

Base-catalyzed domino cyclization of allenes with 3-chloro-2-formylindoles in PEG-400 was investigated. Pyrroloindoles were formed stereoselectively as single products. The structure of the product depends on the type of allene used. Two compounds have been characterized by single crystal X-ray diffraction.

allenes - 3-chloro-2-formylindole - domino cyclization - pyrroloindoles - PEG-400

References and Notes

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12

Representative procedure for the preparation of pyrrolo-indole 5: To the allene (0.200 g, 0.76 mmol), 3-chloro-2-formylindole⁴ (4; 0.176 g, 98 mmol) and K₂CO₃ (0.021 g, 0.15 mmol) in a 25 mL round-bottomed flask, was added PEG-400 (2 mL) and the contents were heated at 90 ˚C for 4 h. The reaction mixture was quenched with H₂O (5 mL) and extracted with CH₂Cl₂ (3 × 25 mL). The whole organic layer was washed with H₂O (3 × 25 mL), dried (Na₂SO₄), filtered, concentrated, and the products were isolated by column chromatography (hexane-EtOAc, 1:4) on silica gel. Yield: 0.25 g (74%); mp 210-214 ˚C. IR (KBr): 3316, 1634, 1601, 1443, 1327, 1308, 1061 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.68 (s, 3 H), 0.97 (s, 3 H), 3.53-3.56 (m, 1 H), 3.67-3.70 (m, 1 H), 3.95-4.00 (m, 2 H), 4.07-4.16 (m, 2 H), 5.43-5.47 (2 H), 6.64-7.45 (m, 9 H). ^¹³C NMR (100 MHz, CDCl₃ + 5%MeOH): δ = 20.7, 21.3, 32.1, 62.4, 75.7, 76.1, 105.3 (d, J _P-C = 190.4 Hz), 114.5, 118.0, 122.3, 123.5, 128.2, 128.7, 131.0, 131.3, 131.7, 135.6, 142.0, 150.9 (d, J _P-C = 27.3 Hz). ^³¹P NMR (160 MHz, CDCl₃): δ = 15.1. LC/MS:
m/z = 442 [M - 2]⁺, 444 [M]⁺. Anal. Calcd for C₂₃H₂₃ClNO₄P: C, 62.24; H, 5.22; N, 3.16. Found: C, 62.35; H, 5.28; N, 3.22. Spectroscopic and analytical data for the remaining pyrroloindoles 6-14 are given in the Supporting Information

X-ray data for compounds 11 (CCDC 806280) and 12 (CCDC 806281) were collected on OXFORD diffractometer using Mo-K_α (λ = 0.71073 Å) radiation. The structures were solved and refined by standard methods, see:

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14 The requirement for a good electron-withdrawing substituent to increase the reactivity of the indole has been reported, see: Pintori DG. Greaney MF. J. Am. Chem. Soc.  2011,  133:  1209