Base-Catalyzed Conjugate Addition
of Thiols to Indolyl Acrylic Acids and in situ Decarboxylation:
An Expedient Synthesis of Functionalized 3-(1-Thio)ethyl-1H-indoles

Shijay Gao; Chi Tseng; B. Rama Raju; Chen Hsuan Tsai; Ching-Fa Yao

doi:10.1055/s-0029-1218294

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Synlett 2009(19): 3201-3205
DOI: 10.1055/s-0029-1218294

LETTER

Base-Catalyzed Conjugate Addition of Thiols to Indolyl Acrylic Acids and in situ Decarboxylation: An Expedient Synthesis of Functionalized 3-(1-Thio)ethyl-1H-indoles

Shijay Gao, Chi Tseng, B. Rama Raju, Chen Hsuan Tsai, Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University, 88 Tingchow Road, Section 4, Taipei 11677, Taiwan
Fax: +886(2)29324249; e-Mail: cheyaocf@ntnu.edu.tw;

Further Information

Publication History

Received 2 July 2009
Publication Date:
13 October 2009 (online)

Abstract
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Supplementary Material

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Abstract

A one-pot, two-step method for the synthesis of 3-(1-thio)ethyl-1H-indoles is described herein. This simple procedure involves the Michael addition of thiols to 3-indoleacrylic acids followed by in situ decarboxylation of the Michael adduct in the presence of a catalytic amount of K₂CO₃ in DMF at 100 ˚C. The method was found to be fairly general with various thiols and different 3-indoleacrylic acids.

Key words

indole - thiol - conjugate addition - decarboxylation - 3-[1-(thio)ethyl]-1H-indole

Supporting Information

References and Notes

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16

Typical Procedure for the Synthesis of 3-[1-(Phenyl-thio)ethyl]-1 H -indole (3a)
A mixture containing 3-indoleacrylic acid (187 mg, 1 mmol), thiophenol (165 mg, 1.5 mmol), and K₂CO₃ (27 mg, 0.2 mmol) in DMF (1 mL) was stirred at 100 ˚C for 1 h (monitored by TLC). After completion of the reaction, the mixture was poured into an ice-cold dilute HCl (aq) solution and the solution then extracted with CH₂Cl₂ (3 × 25 mL). The CH₂Cl₂ layers were washed with brine and dried over anhyd MgSO₄. After evaporation of the organic solvent, the crude product was purified by flash column chromatog-raphy, to afford 3-[1-(phenylthio)ethyl]-1H-indole (3a, 258 mg, 98% isolated yield). Colorless solid; mp 86-88 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 7.96 (s, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.36-7.33 (m, 3 H), 7.25-7.14 (m, 5 H), 7.03 (d, J = 2.4 Hz, 1 H), 4.71 (q, J = 7.0 Hz, 1 H), 1.75 (d, J = 7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 136.7, 135.9, 132.6, 128.8, 127.0, 126.3, 122.5, 122.0, 119.9, 119.7, 118.2, 111.4, 40.3, 22.1. HRMS: m/z calcd for C₁₆H₁₅NS [M⁺]: 253.0925; found: 253.0919.
3-[1-(4-Methoxyphenylthio)ethyl]-1 H -indole (3b)
Colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.92 (s, 1 H), 7.83 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.25 (d, J = 8.3 Hz, 2 H), 7.21 (t, J = 7.5 Hz, 1 H), 7.15 (t, J = 7.4 Hz, 1 H), 6.91 (d, J = 2.1 Hz, 1 H), 6.76 (d, J = 8.6 Hz, 2 H), 4.53 (q, J = 7.0 Hz, 1 H), 3.77 (s, 3 H) 1.69 (d, J = 7.0 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 159.7, 136.7, 136.3, 126.3, 125.8, 122.4, 121.9, 120.1, 119.7, 118.3, 114.3, 111.4, 55.5, 41.4, 21.8. HRMS: m/z calcd for C₁₇H₁₇NOS [M⁺]: 283.1031; found: 283.1035.
5-Chloro-3-[1-(phenylthio)ethyl]-1 H -indole (4a)
Colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.99 (s, 1 H), 7.76 (d, J = 1.8 Hz, 1 H), 7.34-7.31 (m, 2 H), 7.28-7.21 (m, 4 H), 7.16 (dd, J = 8.6, 1.9 Hz, 1 H), 7.04 (d, J = 2.4 Hz, 1 H), 4.63 (q, J = 7.0 Hz, 1 H), 1.73 (d, J = 7.0 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 135.5, 135.0, 132.9, 128.9, 127.4, 127.3, 125.6, 123.3, 122.9, 119.5, 118.2, 112.4, 40.1, 21.9. HRMS: m/z calcd for C₁₆H₁₄ClNS [M⁺]: 287.0535; found: 287.0533.

Supplementary Material

Supporting Information