Novel Synthetic Method of 2-(2-Oxoethyl)-1H-indole-3-carbaldehydes

Abstract

The smooth and regioselective synthesis of 2-(2-oxo­ethyl)-1H-indole-3-carbaldehydes via silver-catalyzed 6-endo-dig acetalization-cyclization reaction followed by immediate hydrolysis of the unstable 1-alkoxypyrano[4,3-b]indole intermediates is described.

2-alkynyl-1H-indole-3-carbaldehydes - 2-(2-oxoethyl)-1H-indole-3-carbaldehydes - acetalization - hydrolysis

References

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Typical Procedure for the Synthesis of 2-(2-Oxoethyl)-1 H -indole-3-carbaldehydes 2
A solution of the requisite 2-alkynyl-1H-indole-3-carbaldehyde 1 (0.3 mmol), MeOH (0.0192 g, 0.6 mmol), AgCF₃CO₂ (3.3 mg, 0.015 mmol) in DCE (3 mL) was irradiated in a closed 15 mL vessel in domestic microwave oven (model DAEWOO KOR6305A) at 600 W for 10-15 min. After heating, the solution was cooled to r.t., filtered through a silica gel pad, the solvent evaporated, and the solid residue purified by column chromatography to give 2a-h.
Typical analytical data are given for compounds 2a,f,h.
2-(2-Oxo-2-phenylethyl)-1 H -indole-3-carbaldehyde (2a)
Yield 84%; mp 156 ˚C. IR (KBr): ν_max = 3313 (NH), 1680, 1645 (C=O) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 5.02 (2 H, s, CH₂CO), 7.30-7.34 (2 H, m, ArH), 7.45-7.47 (1 H, m, ArH), 7.53-7.59 (2 H, m, ArH), 7.65-7.70 (1 H, m, ArH), 8.14-8.17 (3 H, m, ArH), 10.20 (1 H, br s, NH), 10.41 (1 H, s, CHO) ppm. ^¹³C NMR (75 Hz, CDCl₃): δ = 34.9, 111.6, 119.1, 122.6, 123.5, 126.4, 128.6, 128.8, 128.9, 129.1, 134.3, 135.2, 135.8, 184.7, 196.7 ppm. Anal. Calcd for C₁₇H₁₃NO₂: C, 77.55; H, 4.98; N, 5.32. Found: C, 77.62; H, 5.03; N, 5.18.
1-Benzyl-2-(3,3-dimethyl-2-oxobutyl)-1 H -indole-3-carbaldehyde (2f)
Yield 67%; mp 131-131.5 ˚C. IR (KBr): ν_max = 1709, 1651 (C=O) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.28 [9 H, s, C(CH₃)₃], 4.44 (2 H, s, CH₂CO), 5.35 (2 H, s, NCH₂), 6.99-7.03 (2 H, m, ArH), 7.30-7.34 (6 H, m, ArH), 8.19-8.22 (1 H, m, ArH), 10.25 (1 H, s, CHO) ppm. ^¹³C NMR (75 Hz, CDCl₃): δ = 26.4, 33.8, 44.8, 47.1, 110.3, 114.7, 119.5, 122.9, 123.5, 125.9, 126.5, 127.9, 129.1, 135.7, 137.0, 143.1, 184.1, 209.9 ppm. Anal. Calcd for C₂₂H₂₃NO₂: C, 79.25; H, 6.95; N, 4.20. Found: C, 79.40; H, 7.02; N, 4.33.
2-(2,2-Dimethoxyethyl)-1 H -indole-3-carbaldehyde (2h)
Yield 78%(from 1k); mp 145-146 ˚C. IR (KBr): ν_max = 3185 (NH), 1628 (C=O) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 3.47 (2 H, d, J = 4.8 Hz, CH₂CH),3.48 [6 H, s, CH(OCH₃)₂], 4.71 [1 H, t, J = 4.8 Hz, CH(OCH₃)₂], 7.27-7.30 (2 H, m, ArH), 7.40-7.43 (1 H, m, ArH), 8.25-8.28 (1 H, m, ArH), 9.57 (1 H, br s, NH), 10.23 (1 H, s, CHO) ppm. ^¹³C NMR (75 Hz, CDCl₃): δ = 29.9, 54.4, 103.5, 111.2, 114.9, 120.6, 122.6, 123.5, 125.8, 135.2, 145.1, 184.5 ppm. Anal. Calcd for C₁₃H₁₅NO₃: C, 66.94; H, 6.48; N, 6.00. Found: C, 67.00; H, 6.38; N, 6.05.

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The Supporting Information contains experimental procedures and characterization data for compounds 1a-k, 2b,e,g, 5-9.