Cross-Dehydrogenative Coupling of Dithiolanes with Ketones and Indoles under Metal-Free Conditions

Abstract

A metal-free cross-dehydrogenative coupling of dithiolanes with ketones and indoles has been developed using DDQ as an oxidant. It provides an economical protocol for the synthesis of β-keto dithiolanes and 3-(1,3-dithiolan-2-yl) indoles.

Key words

cross-dehydrogenative coupling - dithiolane - metal-free coupling - C–C bond - DDQ

• References and Notes

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• 15a Typical Procedure for Coupling of 9 and 2 To a 10 mL two-necked round-bottom flask charged with acetophenone 2 (8 equiv) and DDQ (1.2 equiv) was added dithiolane 9 (1 equiv) under nitrogen atmosphere. The reaction mixture was heated at 100 °C immediately and stirred at this temperature for 3 h. The resultant crude material was directly purified by flash chromatography on silica gel (EtOAc–hexane, 3:97) to afford the pure product 10. Data for Representative Examples 1-Phenyl-2-(2-phenyl-1,3-dithiolan-2-yl)ethanone (10a) ^2a,4a Yield 0.11 g (55%); white solid; mp 129–131 °C (EtOAc–hexane, 5:95). IR: ν = 3064, 2962, 2921, 2855, 1681, 1659, 1603, 1595, 1529, 1446, 1340, 1242, 1207 cm^–1. ¹H NMR [300 MHz, CDCl₃–CCl₄ (1:1)]: δ = 7.81 (d, J = 1.5 Hz, 2 H), 7.67 (d, J = 1.5 Hz, 2 H), 7.43–7.41 (m, 1 H), 7.35–7.30 (m, 2 H), 7.19–7.14 (m, 2 H), 7.08–7.06 (m, 1 H), 4.17 (s, 2 H), 3.29–3.20 (m, 4 H). ¹³C NMR [75 MHz, CDCl₃–CCl₄ (1:1)]: δ = 195.0, 144.6, 136.7, 133.1, 128.5, 128.1, 127.9, 127.1, 126.9, 69.0, 54.2, 39.4. MS (ES⁺): m/z = 323.4 [M + Na]⁺. 2-[2-(4-Methoxyphenyl)-1,3-dithiolan-2-yl]-1-p-tolyl-ethanone (10i) Yield 0.100g (62%); white solid, mp 110–113 °C (EtOAc–hexane = 5:95). IR: ν = 3016, 2835, 1682, 1605, 1576, 1505, 1507, 1463, 1414, 1338, 1291, 1249, 1215 cm^–1. ¹H NMR [300 MHz, CDCl₃–CCl₄ (1:1)]: δ = 7.71 (d, J = 8.0 Hz, 2 H), 7.57 (d, J = 8.8 Hz, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 6.67 (d, J = 8.8 Hz, 2 H), 4.10 (s, 2 H), 3.67 (s, 3 H), 3.24–3.21 (m, 4 H), 2.32 (s, 3 H). ¹³C NMR [75 MHz, CDCl₃–CCl₄ (1:1)]: δ = 194.7, 158.4, 143.6, 136.7, 134.4, 129.2, 128.4, 128.3, 113.1, 68.9, 55.0, 53.9, 39.3, 21.7. HRMS (ES⁺): m/z calcd for C₁₉H₂₀S₂O₂Na [M + Na]⁺: 367.0796; found: 367.0780. 2-[2-(4-Chlorophenyl)-1,3-dithiolan-2-yl]-1-phenyl-ethanone (10j) Yield 0.086 g (56%); viscous oil. IR: ν = 3018, 2924, 2855, 1687, 1596, 1488, 1448, 1397, 1342, 1260, 1213 cm^–1. ¹H NMR [300 MHz, CDCl₃–CCl₄ (1:1)]: δ = 7.81 (t, J = 7.0 Hz, 2 H), 7.64–7.59 (m, 2 H), 7.48 (t, J = 7.0 Hz, 1 H), 7.36–7.31 (m, 2 H), 7.18–7.12 (m, 2 H), 4.16 (s, 2 H), 3.31–3.16 (m, 4 H). ¹³C NMR [75 MHz, CDCl₃–CCl₄ (1:1)]: δ = 195.0, 143.3, 136.4, 133.3, 132.9, 128.6, 128.0, 127.9, 68.4, 54.1, 39.4. HRMS (ES⁺): m/z calcd for C₁₇H₁₅S₂ClONa [M + Na]⁺: 357.0145; found: 357.0146. 2-[2-(4-Chlorophenyl)-1,3-dithiolan-2-yl]-1-p-tolyl-ethanone (10m) Yield 0.096 g (60%); viscous oil. IR: ν = 3016, 2922, 2859, 2055, 1682, 1606, 1571, 1488, 1404, 1337, 1216 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.72 (d, J = 8.1 Hz, 2 H), 7.64 (d, J = 8.7 Hz, 2 H), 7.18–7.12 (m, 4 H), 4.17 (s, 2 H), 3.32–3.18 (m, 4 H), 2.31 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 195.2, 144.3, 143.4, 133.8, 132.7, 129.2, 128.4, 128.1, 127.9, 68.2, 53.8, 39.3, 21.6. HRMS (ES⁺): m/z calcd for C₁₈H₁₇S₂ClONa [M + Na]⁺: 371.0301; found: 371.0378.
• 15b Typical Procedure for Coupling of 9 and 11 To a 10 mL two-necked round-bottom flask charged with indole 11 (2 equiv) and DDQ (1.2 equiv) was added dithiolane 9 (1 equiv) under nitrogen atmosphere. The reaction mixture was heated at 60 °C immediately and stirred at this temperature for 12 h. The resultant crude material was directly purified by flash chromatography on silica gel (EtOAc–hexane, 10:90) to afford the pure product 12. Data for Representative Examples 3-(2-Phenyl-1,3-dithiolan-2-yl)-1H-indole (12a) ^17a Yield 0.070 g (35%); yellow reddish solid, mp 91–93 °C (EtOAc–hexane, 5:95). IR: ν = 3406, 3052, 2921, 1593, 1567, 1517, 1492, 1455, 1443, 1413, 1337, 1241, 1210 cm^–1. ¹H NMR [300 MHz, CDCl₃–CCl₄ (1:1)]: δ = 7.84 (br s, 1 H), 7.64 (d, J = 7.0 Hz, 2 H), 7.35 (d, J = 7.8 Hz, 1 H), 7.21–7.12 (m, 5 H), 7.06 (t, J = 7.0 Hz, 1 H), 6.91 (t, J = 7.2 Hz, 1 H) 3.45–3.30 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃–CCl₄ = 1:1): δ = 143.4, 137.6, 128.2, 127.9, 127.3, 125.6, 124.8, 122.4, 121.9, 120.7, 119.6, 111.1, 71.1, 40.0. MS (ES⁺): m/z = 298.1 [M + H]⁺. 3-[2-(4-Methoxyphenyl)-1,3-dithiolan-2-yl]-1H-indole (12c) Yield 0.069 g (45%); orange solid, mp 125–130 °C (EtOAc–hexane, 5:95). IR: ν = 3334, 2962, 2923, 1708, 1599, 1504, 1419, 1303, 1244, 1213 cm^–1. ¹H NMR [300 MHz, CDCl₃–CCl₄ (1:1)]: δ = 7.78 (br s, 1 H), 7.52 (d, J = 9.0 Hz, 2 H), 7.35 (d, J = 7.4 Hz, 1 H), 7.19–7.14 (m, 2 H), 7.05–7.00 (m, 1 H), 6.91–6.85 (m, 1 H), 6.68 (d, J = 8.7 Hz, 2 H), 3.70 (s, 3 H), 3.41–3.30 (m, 4 H). ¹³C NMR [75 MHz, CDCl₃–CCl₄ (1:1)]: δ = 137.7, 129.6, 124.8, 122.4, 122.3, 119.6, 113.2, 111.0, 71.1, 55.0, 39.9. HRMS (ES⁺): m/z calcd for C₁₈H₁₈S₂NO [M + H]⁺: 328.0824; found: 328.0873. 3-[2-(4-Chlorophenyl)-1,3-dithiolan-2-yl]-1H-indole (12e) Yield 0.053g (35%); yellow oil. IR: ν = 3407, 2923, 1630, 1589, 1540, 1485, 1445, 1413, 1393, 1331, 1241, 788 cm^–1. ¹H NMR [300 MHz, CDCl₃–CCl₄ (1:1)]: δ = 7.80 (br s, 1 H), 7.56 (d, J = 8.7 Hz, 2 H), 7.32 (d, J = 8.1 Hz, 1 H), 7.19–7.11 (m, 4 H), 7.06 (t, J = 7.2 Hz, 1 H), 6.92 (t, J = 7.2 Hz, 1 H), 3.43–3.29 (m, 4 H). ¹³C NMR [75 MHz, CDCl₃–CCl₄ (1:1)]: δ = 142.0, 137.6, 133.3, 129.8, 128.0, 125.5, 124.7, 122.6, 122.0, 120.4, 119.8, 111.1, 70.5, 40.1. HRMS (ES⁺): m/z calcd for C₁₇H₁₅S₂NCl [M + H]⁺: 332.0328; found: 332.0341. 3-[2-(3,4-Dimethoxyphenyl)-1,3-dithiolan-2-yl]-1H-indole (12f) Yield 0.051 g (35%); brown solid, mp 100–103 °C (EtOAc–hexane, 5:95). IR: ν = 3158, 2917, 2848, 1594, 1565, 1510, 1439, 1379, 1334, 1268, 1201 cm^–1. ¹H NMR [300 MHz, CDCl₃–CCl₄ (1:1)]: δ = 7.83 (br s, 1 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.30 (d, J = 2.2 Hz, 1 H), 7.18 (t, J = 3.6 Hz, 1 H), 7.11 (d, J = 2.2 Hz, 1 H), 7.06 (t, J = 7.2 Hz, 2 H), 6.92 (t, J = 7.2 Hz, 1 H), 6.60 (d, J = 8.1 Hz, 1 H), 3.76 (s, 3 H), 3.73 (s, 3 H), 3.41–3.30 (m, 4 H). ¹³C NMR [75 MHz, CDCl₃–CCl₄ (1:1)]: δ = 148.4, 137.6, 135.5, 125.6, 125.0, 122.4, 122.2, 120.9, 119.6, 112.1, 111.0, 110.2, 71.2, 55.8, 55.7, 39.9. HRMS (ES⁺): m/z calcd for C₁₉H₁₉S₂NO₂Na [M + Na]⁺: 380.0749; found: 380.0750.
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