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Synlett 2003(15): 2377-2379  
DOI: 10.1055/s-2003-42105
LETTER
© Georg Thieme Verlag Stuttgart · New York

The Michael Addition of Indole to α,β-Unsaturated Ketones Catalyzed by Iodine at Room Temperature

Shun-Yi Wanga, Shun-Jun Ji*a, Teck-Peng Loh*a,b
a College of Chemistry and Chemical Engineering of Suzhou University, Suzhou, 215006 China
b Department of Chemistry, 3 Science Drive 3, National University of Singapore, 117543 Singapore
Fax: +86(512)65224873; e-Mail: shunjun@suda.edu.cn;
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Publication History

Received 13 September 2003
Publication Date:
22 October 2003 (online)

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Abstract

Indole undergoes conjugate addition with α,β-unsaturated ketones by means of alkylation of indole in the presence of a ­catalytic amount of molecular I2 at room temperature to afford the corresponding adduct in excellent yields (up to 96%). The substitution on the indole nucleus occurred exclusively at the 3-position. N-alkylation products have not been observed.

Key words

molecular iodine - indoles - Michael reaction

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Typical Experimental Procedure: A mixture of indole (0.117 g, 1 mmol), 2c (0.355 g, 1 mmol), I2 (0.025 g, 0.1 mmol) and anhyd EtOH (2 mL) was stirred in an open vessel at r.t. until the disappearance of the starting indole (5 h, checked by TLC). After standing for 2 h, the reaction mixture was washed by cold water (2 Ž 25 mL) and cold EtOH (2 Ž 0.5 mL). The crude mixture recrystallized from hot EtOH to afford the pure product 3c (0.453 g, yield: 96%).
3-(1H-Indol-3-yl)-3-(4-methoxy-phenyl)-1-phenyl-propan-1-one (3c): solid; mp 161-162 °C (Lit. [9] 162 °C). IR (KBr): 1669 (CO), 3420 (NH) cm-1. 1H NMR (400 MHz, CDCl3):
δ = 3.69-3.83 (m, 5 H, CH2, CH3), 5.02 (t, J = 7.2 Hz, 1 H, CH), 6.79-7.63 (m, 12 H), 7.98-8.03 (m, 3 H). HRMS: m/z [M] calcd for C24H21NO2: 355.1572; found: 355.1555 [M+].

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Selected Characterization Data of New Compounds.
3-(1H-Indol-3-yl)-1-phenyl-3-p-tolyl-propan-1-one (3b): solid; mp 140 °C. IR (KBr): 1672 (CO), 3428 (NH) cm-1. 1H NMR (400 MHz, CDCl3): δ = 2.28 (s, 3 H, CH3), 3.68-3.84 (m, 2 H, CH2), 5.04 (t, J = 7.2 Hz, 1 H, CH), 6.97-7.53 (m, 12 H), 7.91-7.96 (m, 3 H). HRMS: m/z [M] calcd for C24H21NO: 339.1623; found: 339.1634 [M+].
3-(4-Chloro-phenyl)-3-(1H-indol-3-yl)-1-phenyl-propan-1-one (3d): solid; mp 127-129 °C. IR (KBr): 1677 (CO), 3401 (NH) cm-1. 1H NMR (400 MHz, CDCl3): δ = 3.66-3.83 (m, 2 H, CH2), 5.04 (t, J = 7.2 Hz, 1 H, CH), 6.70-7.60 (m, 12 H), 7.92-8.00(m, 3 H). HRMS: m/z [M] calcd for C23H18ClNO: 359.0891; found: 359.0855 [M+].
3-(1H-Indol-3-yl)-1-phenyl-3-thiophen-2-yl-propan-1-one (3e): solid; mp 151-153 °C. IR (KBr): 1683 (CO), 3401(NH) cm-1. 1H NMR (400 MHz, CDCl3): δ = 3.83 (d, J = 7.2 Hz, 2 H, CH2), 5.36 (t, J = 7.2 Hz, 1 H, CH), 6.87-7.55 (m, 12 H), 7.92-8.00 (m, 3 H). HRMS: m/z [M] calcd for C21H17NOS: 331.1031; found: 331.0977 [M+].
1-(4-Chloro-phenyl)-3-(1H-indol-3-yl)-3-phenyl-propan-1-one (3f): solid; mp 158-160 °C. IR (KBr): 1680 (CO), 3445 (NH) cm-1. 1H NMR (400 MHz, CDCl3): δ = 3.65-3.80 (m, 2 H, CH2), 5.03 (t, J = 7.2 Hz, 1 H, CH), 6.99-7.43 (m, 12 H), 7.84-7.98 (m, 3 H). HRMS: m/z [M] calcd for C23H18ClNO: 359.0891; found: 359.0891 [M+].
3-(4-Chloro-phenyl)-3-(1H-indol-3-yl)-1-(4-methoxy-phenyl)-propan-1-one (3h): solid; mp 123-125 °C. IR (KBr): 1658 (CO), 3461(NH) cm-1. 1H NMR (400 MHz, CDCl3):
δ = 3.22-3.35 (m, 2 H, CH2), 3.89 (s, 3 H, CH3), 5.30 (t, J = 7.2 Hz, 1 H, CH), 6.93-7.60 (m, 11 H), 7.74-7.95(m, 3 H). HRMS: m/z [M] calcd for C24H20ClNO2: 389.1183; found: 389.1194 [M+].
3-(1H-Indol-3-yl)-1-(4-methoxy-phenyl)-3-thiophen-2-yl-propan-1-one (3i): solid; mp 149-151 °C. IR (KBr): 1670 (CO), 3430 (NH) cm-1. 1H NMR (400 MHz, CDCl3): δ = 3.78 (d, J = 7.2 Hz, 2 H, CH2), 3.86 (s, 3 H, CH3), 5.37 (t,
J = 7.2 Hz, 1 H, CH), 6.87-7.56 (m, 10 H), 7.92-8.00 (m, 3 H). HRMS: m/z [M] calcd for C22H19NO2S: 361.1136; found: 361.1066 [M+].