Copper(I)-Promoted C–N Cross-Coupling of N-Heterocyclic Compounds with 1,2-Di(pyrimidin-2-yl) Disulfides

Abstract

A CuTC-promoted C–N cross-coupling of 1,2-di(pyrimidin-2-yl) disulfides with N-heterocyclic compounds including indoles, triazole benzotriazole, and benzoimidazole by C–S cleavage of the disulfides is reported.

Key words

N-heterocycles - indoles - disulfides - CuTC - C–N cross-coupling

• References and Notes

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Some examples on the C–H thiolation using disulfides:
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• 14 The structure of 3a was determined by X-ray crystallographie. CCDC 1435800 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 15 General Procedure for the Synthesis of 3a Under an atmosphere of nitrogen, disulfide¹ 1a (1 mmol, 0.546 g), indole 2a (3 mmol, 0.351 g), CuTC (1.0 mmol, 0.191 g), and Cs₂CO₃ (3.0 mmol, 0.978 g) were added to an oven-dried Schlenk tube. The tube was stoppered and degassed with nitrogen three times. Water-free dioxane (3 mL) was added by syringe, the mixture was stirred for 12 h at 120 °C, and the reaction was monitored by TLC analysis. Then, diluted HCl (2 mL) was added to the mixture to quench the reaction, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with aq NaHCO₃ and brine, dried over MgSO₄, filtered, and the volatiles were removed in vacuo. The residue was purified by column chromatography on silica gel (EtOAc–PE = 1:30) to give the corresponding products. Ethyl 2-(1H-Indol-1-yl)-4-methyl-6-phenylpyrimidine-5-carboxylate (3a) Yield 80%, colorless crystals, mp 135–137 °C. ¹H NMR (600 MHz, CDCl₃): δ = 8.88 (d, J = 8.4 Hz, 1 H, ArH), 8.37 (d, J = 3.6 Hz, 1 H, ArH), 7.77–7.75 (m, 2 H, ArH), 7.62 (d, J = 7.8 Hz, 1 H, CH), 7.53–7.50 (m, 3 H, ArH), 7.34 (t, J = 7.8 Hz, 1 H, ArH), 7.25 (t, J = 7.2 Hz, 1 H, ArH), 6.71 (d, J = 3.6 Hz, 1 H, CH), 4.20 (q, J = 7.2 Hz, 2 H, OCH₂), 2.70 (s, 3 H, CH₃), 1.07 (t, J = 7.2 Hz, 3 H, CH₂CH₃). ¹³C NMR (150 MHz, CDCl₃): δ = 168.12, 167.31, 165.39, 156.44, 138.06, 135.48, 131.49, 130.13, 128.52 (2 C), 128.36 (2 C), 126.04, 123.74, 122.31, 120.81, 120.57, 116.62, 107.24, 61.69, 22.97, 13.64. HRMS (ESI⁺): m/z calcd for C₂₂H₂₀N₃O₂: 358.1550 [M + H]⁺; found: 358.1553.
• 16 For the reaction of 1,2-di(pyrimidin-2-yl) disulfides with indole achieved the C–S coupling product, see Scheme 5.
• 17 General Procedure for the Synthesis of 4a Under an atmosphere of nitrogen, disulfide^13a (1 mmol, 0.546 g), 2-methylindole (2b, 3 mmol, 0.393 g), CuTC (1.0 mmol, 0.191 g), Ni(dppp)Cl₂ (0.1 mol, 0.054 g), and Cs₂CO₃ (3.0 mmol, 0.978 g) were added to an oven-dried Schlenk tube. The tube was stoppered and degassed with nitrogen three times. Water-free dioxane (3 mL) was added by syringe, the mixture was stirred for 12 h at 120 °C, and the reaction was monitored by TLC analysis. Then, diluted HCl (2 mL) was added to the mixture to quench the reaction, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with aq NaHCO₃ and brine, dried over MgSO₄, filtered, and the volatiles were removed in vacuo. The residue was purified by column chromatography on silica gel (EtOAc–PE = 1:30) to give the corresponding products. Ethyl 4-Methyl-2-(2-methyl-1H-indol-1-yl)-6-phenylpyrimidine-5-carboxylate (4a) Yield 79%, yellow oil. ¹H NMR (600 MHz, CDCl₃): δ = 8.30 (d, J = 8.4 Hz, 1 H, ArH), 7.68–7.66 (m, 2 H, ArH), 7.55–7.54 (m, 3 H, ArH), 7.48 (d, J = 7.8 Hz, 1 H, ArH), 7.16–7.13 (m, 2 H, ArH), 6.51 (s, 1 H, CH), 4.19 (q, J = 7.2 Hz, 2 H, OCH₂), 2.70 (s, 3 H, CH₃), 2.62 (s, 3 H, CH₃), 1.03 (t, J = 7.2 Hz, 3 H, CH₂CH₃). ¹³C NMR (150 MHz, CDCl₃): δ = 168.12, 167.31, 165.39, 156.44, 138.06, 135.48, 131.49, 130.13, 128.52 (2 C), 128.36 (2 C), 126.04, 123.74, 122.31, 120.82, 120.57, 116.62, 107.24, 61.69, 22.97, 13.64, 13.63. HRMS (ESI⁺): m/z calcd for C₂₃H₂₂N₃O₂: 372.1707 [M + H]⁺; found: 372.1710.