Photocatalytic Oxidative C–H Thiolation: Synthesis of Benzothiazoles and Sulfenylated Indoles

^‡ Both authors contributed equally

Published as part of the Cluster for Organosulfur and Organo­selenium Compounds in Catalysis

Abstract

We report studies on the photocatalytic formation of C–S bonds to form benzothiazoles via an intramolecular cyclization and sulfenylated indoles via an intermolecular reaction. Cyclic voltammetry (CV) and density functional theory studies suggest that benzothiazole formation proceeds via a mechanism that involves an electrophilic sulfur radical, while the indole sulfenylation likely proceeds via a nucleophilic sulfur radical adding into a radical cationic indole. These conditions were successfully extended to several thiobenzamides and indole substrates.

Key words

photoredox catalysis - benzothiazole - indole - thiolation - C–H functionalization

• References and Notes

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• 36 General Procedure for Synthesis of Substituted BenzothiazolesIn a 10 mL scintillation vial, thioabenzamide (1.0 equiv), Ru(bpy)₃Cl₂ (5 mol%), Na₂S₂O₈ (2.0 equiv), and pyridine (2.0 equiv) were added to a solution of 1:1 MeCN/H₂O (25 mg/1 mL). The reaction was stirred under blue LEDs for 12 h at room temperature. The resulting solution was quenched with H₂O, extracted with EtOAc, dried over Na₂SO₄, and concentrated in vacuo. The product was purified via FCC and prep TLC with gradient from hexanes to 8:2 Hex/EtOAc.General Procedure for the Synthesis of Sulfenylated IndolesIn a 10 mL scintillation vial, substituted indole (1.0 equiv), {Ir[dF(CF₃)ppy]₂(dtbpy)}PF₆ photocatalyst (1 mol%), Na₂S₂O₈ (2.0 equiv), KOH (2.0 equiv), and thiophenol (1.2 equiv) were added to a solution of 1:1 MeCN/H₂O (25 mg/1 mL). The reaction was left to stir under blue LEDs for 12 h at room temperature. The resulting solution was quenched with H₂O and extracted with EtOAc, dried over Na₂SO₄, and concentrated in vacuo. The product was purified via FCC and prep TLC (8:2 Hex/EtOAc). Melatonin substrates were purified via FCC with (2:8 Hex/EtOAc).2-(tert-Butyl)benzo[d]thiazole (1b)57% with no pyridine, 79% with pyridine, off-white solid. ¹H NMR (500 MHz, CDCl₃): δ = 8.00 (dt, J = 8.2, 0.9 Hz, 1 H), 7.85 (dd, J = 8.0, 0.45 Hz, 1 H), 7.44 (ddd, J = 8.3, 7.2, 1.3 Hz, 1 H), 7.34 (ddd, J = 8.2, 7.2, 1.2 Hz, 1 H), 1.53 (s, 9 H). The spectral data are in agreement with the reported literature.³⁷ MS-APCI: m/z calcd: C₁₁H₁₃NS [M + H]⁺ 192.3; found: 192.1.2-(tert-Butyl)napthol[1,2-d]thiazole (6b)55% with no pyridine, 54% with pyridine, yellow-green solid. ¹H NMR (500 MHz, CDCl₃): δ = 8.82 (dt, J = 8.0, 0.8 Hz, 1 H), 7.93 (d, J = 8.1 Hz, 1 H), 7.87 (d, J = 8.7 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.65 (ddd, J = 8.2, 6.9, 1.3 Hz, 1 H), 7.55 (ddd, J = 8.2, 6.9, 1.3 Hz, 1 H), 1.59 (s, 9 H). ¹³C NMR (101 Hz, CDCl₃): δ = 180.7, 149.2, 131.8, 131.2, 128.6, 127.9, 126.6, 125.7, 125.0, 124.0, 119.0, 38.4, 31.0. MS-APCI: m/z calcd for C₁₅H₁₅NS [M+H]⁺: 242.4; found: 242.1. N-{2-[5-Methoxy-2-(p-tolylthio)-1H-indol-3- yl]ethyl}acetamide (18b)68%, tan solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.12 (s, 1 H), 7.22 (d, 8.8 Hz, 1 H), 7.02–7.06 (m, 3 H), 6.98 (d, 8.3 Hz, 2 H), 6.91 (dd, J = 8.8, 2.4 Hz, 1 H), 5.50 (s, 1 H), 3.86 (s, 3 H), 3.52 (q, J = 6.4 Hz, 2 H), 3.05 (t, J = 6.5 Hz, 2 H), 2.27 (s, 3 H), 1.78 (s, 3 H). ¹³C NMR (126 Hz, CDCl₃): δ = 170.28, 154.36, 136.17, 133.22, 132.07, 130.04, 128.13, 127.00, 123.50, 119.64, 114.32, 111.93, 100.32, 55.87, 40.01, 24.75, 23.13, 20.89. MS-APCI: m/z calcd for C₂₀H₂₂N₂O₂S [M + H]⁺: 355.5; found: 355.5
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