First Example of C-3 Alkylation of Indoles with Activated Azetidines Catalyzed by Indium(III) Bromide

Abstract

Indoles undergo smooth alkylation with N-tosylazetidines in the presence of indium(III) bromide in dichloroethane under mild conditions to produce the corresponding C-3 substituted indole derivatives in good to high yields and with high selectivity. This is the first report on the alkylation of indoles with activated azetidines.

indoles - indium(III) bromide - activated azetidine - C-3 alkylation

References and Notes

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12

General Procedure To a stirred solution of indole (1 mmol) in DCE (3 mL) were added the N-tosylazetidine (1 mmol) and InBr₃ (0.1 mmol). The resulting mixture was stirred at reflux temperature for the appropriate time (Table  [¹] ).
After complete conversion as indicated by TLC, the solvent was removed by evaporation, and the residue was diluted with H₂O and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhyd Na₂SO₄ and concentrated in vacuo. The resulting product was purified by column chromatography on SiO₂ (Merck, 100-200 mesh) using EtOAc-hexane (3:7) as eluent to afford pure 3-alkenyl indole derivative.
Spectroscopic Data for Selected Products
N -1-[3-(1 H -3-indolyl)propyl]-4-methyl-1-benzenesulfon-amide (3a) Semisolid. IR (KBr): ν_max = 3405, 3054, 2923, 2853, 1598, 1455, 1322, 1156, 1091, 813, 771, 745 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 1.71-1.85 (m, 2 H), 2.38 (s, 3 H), 2.72 (t, J = 6.6 Hz, 2 H), 2.94 (q, J = 6.6 Hz, 2 H), 4.74 (br s, 1 H, NH), 6.85-7.30 (m, 6 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 2 H), 7.88 (br s, 1 H, ArNH). LC-MS: m/z = 351 [M + Na], 169, 139. HRMS: m/z calcd for C₁₈H₂₀N₂O₂NaS: 351.1143; found: 351.1131. N -1-[3-(2-Methyl-1 H -3-indolyl)propyl]-4-methyl-1-benzenesulfonamide (3c) Solid; mp 107-109 ˚C. IR (KBr): ν_max = 3397, 3290, 3054, 2923, 2856, 1596, 1462, 1322, 1156, 1091, 814, 745 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 1.65-1.72 (m, 2 H), 2.25 (s, 3 H), 2.40 (s, 3 H), 2.65 (t, J = 6.6 Hz, 2 H), 2.87 (q, J = 6.6 Hz, 2 H), 4.65 (t, J = 6.6 Hz, 1 H), 6.89-7.07 (m, 2 H), 7.10-7.30 (m, 4 H), 7.60 (d, J = 8.0 Hz, 2 H), 7.73 (br s, 1 H, ArNH): LC-MS: m/z = 381 [M + K], 365 [M + Na], 242, 197, 169, 139. HRMS: m/z calcd for C₁₉H₂₂N₂O₂KS: 381.1039; found: 381.1043. N-1-[3-(2-Methyl-1 H -3-indolyl)-3-phenylpropyl]-4-methyl-1-benzenesulfonamide (3i)
Solid: mp 76-78 ˚C. IR (KBr): ν_max = 3380, 3026, 2924, 2855, 1601, 1457, 1323, 1156, 1092, 813, 753 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 2.30 (s, 3 H), 2.30-2.35 (m, 2 H), 2.38 (s, 3 H), 2.84 (t, J = 5.2 Hz, 2 H), 4.23 (dd, J = 6.4, 9.4 Hz, 1 H), 4.57 (t, J = 6.0 Hz, 1 H), 6.85-7.24 (m, 10 H), 7.28 (d, J = 7.5 Hz, 1 H), 7.54 (d, J = 8.3 Hz, 2 H), 7.84 (br s, 1 H, ArNH). LC-MS: m/z = 441 [M + Na], 139, 111. HRMS: m/z calcd for C₂₅H₂₆N₂O₂NaS: 441.1612; found: 441.1619.