Straightforward Synthesis of 2-Acetyl-Substituted Benzo[b]thiophenes

Abstract

Described herein is a green one-step protocol for the preparation of substituted 2-acetylbenzo[b]thiophenes from commercially available aromatic halides. This efficient method has the advantage of using water as the reaction medium, resulting in a high yield of pure cyclized products. Two scaffold types have been prepared using this general procedure: 2-acetylbenzo[b]thiophenes and 2-acetyl-3-aminobenzo[b]thiophenes, both crystallized directly from the reaction mixture, due to their low solubility with water, and without the need for an additional purification step.

Key words

heterocycles - benzo[b]thiophene - nucleophilic aromatic substitution - thiol - cyclization

• References and Notes

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• 19 2-Acetyl-4-chlorobenzo[b]thiophene (1b) White solid; mp 113–115 °C (Et₂O); yield 88%. ¹H NMR (300 MHz, CDCl₃): δ = 8.05 (1 H, s, H_arom), 7.74 (1 H, dd, J = 2.2, 6.6 Hz, H_arom), 7.40–7.34 (2 H, m, H_arom), 2.69 (3 H, s, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 192.2 (C_q), 144.8 (C_q), 143.7 (C_q), 137.7 (C_q), 130.8 (C_q), 128.1 (CH), 127.6 (CH), 125.0 (CH), 121.7 (CH), 26.9 (CH₃). ESI-MS (MeCN): m/z calcd: 210 [M + H]⁺; found: 211. ESI-HMRS: m/z [M + Na]⁺ calcd for C₁₀H₇ClNaOS: 232.9798; found: 232.9801. 2-Acetyl-5-nitrobenzo[b]thiophene (1c) White-brown solid; mp 176–178 °C (from Et₂O); yield 86%. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.86 (1 H, d, J = 1.5 Hz, H_arom), 8.47 (1 H, s, H_arom), 8.29–8.21 (2 H, m, H_arom), 2.66 (3 H, s, CH₃). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 192.4 (C_q), 147.1 (C_q), 146.7 (C_q), 145.4 (C_q), 139.0 (C_q), 131.5 (CH), 124.5 (CH), 121.7 (CH), 121.1 (CH), 26.6 (CH₃). ESI-MS (MeCN): m/z calcd: 221 [M + H]⁺; found: 222. HMRS (CI): m/z [M + H]⁺ calcd for C₁₀H₈NO₃S: 222.0219; found: 222.0218. Acetylnaphtho[1,2-b]thiophene (1d) White solid; mp 128–130 °C (from Et₂O); yield 99%. ¹H NMR (300 MHz, CDCl₃): δ = 8.20–8.17 (1 H, m, H_arom), 8.04 (1 H, s, H_arom), 7.95–7.92 (1 H, m, H_arom), 7.83–7.74 (2 H, m, H_arom), 7.65–7.58 (2 H, m, H_arom), 2.71 (3 H, s, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 191.9 (C_q), 142.9 (C_q), 142.1 (C_q), 137.0 (C_q), 132.1 (C_q), 130.6 (CH), 129.0 (CH), 128.7 (C_q), 127.4 (CH), 127.2 (CH), 126.4 (CH), 124.2 (CH), 122.8 (CH), 26.8 (CH₃). ESI-MS (MeCN): m/z calcd: 226 [M + H]⁺; found: 227. ESI-HMRS: m/z [M + Na]⁺ calcd for C₁₄H₁₀NaOS: 249.0345; found: 249.0349. 2-Acetyl-5,6-methylenedioxybenzo[b]thiophene (1e) Brown solid; mp 170–172 °C (from Et₂O); yield 35%. ¹H NMR (300 MHz, CDCl₃): δ = 7.78 (1 H, s, H_arom), 7.25 (1 H, m, H_arom), 6.06 (2 H, s, CH₂), 2.60 (3 H, s, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 191.7 (C_q), 149.5 (C_q), 147.6 (C_q), 142.5 (C_q), 138.2 (C_q), 133.8 (C_q), 129.5 (CH), 103.6 (CH), 101.9 (CH₂), 101.8 (CH), 26.8 (CH₃). ESI-MS (MeCN): m/z calcd: 220 [M + H]⁺; found: 221. ESI-HMRS: m/z [M + Na]⁺ calcd for C₁₁H₈NaO₃S: 243.0086; found: 234.0079. 2-Acetylpyrido[2,3-b]thiophene (1f) White solid; mp 120–122 °C (from Et₂O); yield 86%. ¹H NMR (300 MHz, CDCl₃): δ = 8.67 (1 H, dd, J = 1.5, 4.5 Hz, H_arom), 8.17 (1 H, dd, J = 1.5, 8.1 Hz, H_arom), 7.87 (1 H, s, H_arom), 7.36 (1 H, dd, J = 4.5, 8.1 Hz, H_arom), 2.66 (3 H, s, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 192.2 (C_q), 163.5 (C_q), 149.7 (CH), 143.8 (C_q), 133.7 (CH), 132.9 (C_q), 127.0 (CH), 120.4 (CH), 26.8 (CH₃). ESI-MS (MeCN): m/z calcd: 177 [M + H]⁺; found: 178. ESI-HMRS: m/z [M + Na]⁺ calcd for C₉H₇NaNOS: 200.0141; found: 200.0138.
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• 21 2-Acetyl-3-aminobenzo[b]thiophene (2a) Yellow solid; mp 146–148 °C (from Et₂O); yield 91%. ¹H NMR (300 MHz, CDCl₃): δ = 7.72 (1 H, d, J = 8.1 Hz, H_arom), 7.67 (1 H, d, J = 8.1 Hz, H_arom), 7.49 (1 H, dd, J = 7.5 Hz, H_arom), 7.36 (1 H, dd, J = 7.5 Hz, H_arom), 6.52 (2 H, br s, NH₂), 2.46 (3 H, s, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 193.3 (C_q), 148.8 (C_q), 139.9 (C_q), 131.3 (C_q), 129.0 (CH), 124.2 (CH), 123.6 (CH), 121.9 (CH), 108.8 (C_q), 29.2 (CH₃). ESI-MS (MeCN): m/z calcd: 191 [M + H]⁺; found: 192. ESI-HMRS: m/z [M + H]⁺ calcd for C₁₀H₁₀NOS: 192.0478; found: 192.0470. 2-Acetyl-3-amino-4-chlorobenzo[b]thiophene (2b) Yellow solid; mp 101–103 °C (from Et₂O); yield 82%. ¹H NMR (300 MHz, CDCl₃): δ = 7.59 (1 H, d, J = 8.0 Hz, H_arom), 7.34 (1 H, dd, J = 7.8 Hz, H_arom), 7.27 (1 H, d, J = 7.5 Hz, H_arom), 2.43 (3 H, s, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 192.7 (C_q), 149.9 (C_q), 142.4 (C_q), 130.7 (C_q), 128.9 (CH), 126.8 (C_q), 125.9 (CH), 122.4 (CH), 107.9 (C_q), 29.3 (CH₃). ESI-MS (MeCN): m/z calcd: 225 [M + H]⁺; found: 226. ESI-HMRS: m/z [M + H]⁺ calcd for C₁₀H₉ClNOS: 226.0088; found: 226.0093. 2-Acetyl-3-amino-7-methylbenzo[b]thiophene (2c) Brown solid; mp 110–111 °C (from Et₂O); yield 90%. ¹H NMR (300 MHz, CDCl₃): δ = 7.54–7.51 (1 H, m, H_arom), 7.35–7.31 (2 H, m, H_arom), 2.50 (3 H, s, CH₃), 2.49 (3 H, s, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 193.3 (C_q), 149.6 (C_q), 140.2 (C_q), 133.0 (C_q), 131.2 (C_q), 129.2 (CH), 124.7 (CH), 119.4 (CH), 108.9 (C_q), 29.1 (CH₃), 19.8 (CH₃). ESI-MS (MeCN): m/z calcd: 205 [M + H]⁺; found: 206. ESI-HMRS: m/z [M + Na]⁺ calcd for C₁₁H₁₁NNaOS: 228.0454; found: 228.0451. 2-Acetyl-3-amino-5-methoxybenzo[b]thiophene (2d) Brown solid; mp 116–117 °C (from Et₂O); yield 15%. ¹H NMR (300 MHz, CDCl₃): δ = 7.59 (1 H, d, J = 8.8 Hz, H_arom), 7.16 (1 H, dd, J = 2.2, 8.8 Hz, H_arom), 7.06 (1 H, d, J = 2.2 Hz, H_arom), 3.89 (3 H, s, CH₃), 2.45 (3 H, s, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 193.4 (C_q), 157.6 (C_q), 148.4 (C_q), 132.4 (C_q), 132.1 (C_q), 124.5 (CH), 119.8 (CH), 110.4 (C_q), 103.5 (CH), 55.8 (CH₃), 29.0 (CH₃). ESI-MS (MeCN): m/z calcd: 221 [M + H]⁺; found: 222. ESI-HMRS: m/z [M + H]⁺ calcd for C₁₁H₁₂NO₂S: 222.0593; found: 22.0589.2-Acetyl-3-amino-5-nitrobenzo[b]thiophene (2e) Orange solid; mp 290–292 °C (from MeOH); yield 99%. ¹H NMR (300 MHz, DMSO-d ₆): δ = 9.23 (1 H, d, J = 2.0 Hz, H_arom), 8.28 (1 H, dd, J = 2.0, 8.8 Hz, H_arom), 8.09 (1 H, d, J = 8.8 Hz, H_arom), 2.37 (3 H, s, CH₃). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 191.7 (C_q), 150.0 (C_q), 145.0 (C_q), 144.9 (C_q), 131.7 (C_q), 124.9 (CH), 122.9 (CH), 120.2 (CH), 107.8 (C_q), 29.2 (CH₃). ESI-MS (MeCN): m/z calcd: 236 [M + H]⁺; found: 237. HMRS (CI): m/z [M + H]⁺ calcd for C₁₀H₉N₂O₃S: 237.0328; found: 237.0327. 2-Acetyl-3-aminopyrido[2,3-b]thiophene (2f) Yellow solid; mp 194–196 °C (from Et₂O); yield 96%. ¹H NMR (300 MHz, CDCl₃): δ = 8.72 (1 H, dd, J = 1.5, 4.7 Hz, H_arom), 7.98 (1 H, dd, J = 1.5, 8.0 Hz, H_arom), 7.33 (1 H, dd, J = 4.7, 8.0 Hz, H_arom), 6.68 (2 H, br s, NH₂), 2.49 (3 H, s, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 193.9 (C_q), 160.8 (C_q), 151.3 (CH), 146.3 (C_q), 130.0 (CH), 125.5 (C_q), 119.2 (CH), 108.0 (C_q), 29.4 (CH₃). ESI-MS(MeCN): m/z calcd: 192 [M + H]⁺; found: 193. ESI-HMRS: m/z [M + H]⁺ calcd for C₉H₉N₂OS: 193.0430; found: 193.0432.