Palladium-Catalyzed Direct Arylation of 2,6-Disubstituted Imidazo[2,1-b][1,3,4]thiadiazoles

Abstract

This work reports the original synthesis of trisarylimidazo[2,1-b][1,3,4]thiadiazole derivatives using a C–H arylation process. The scope of the reaction demonstrated the critical importance of the electronic effects of each substituent on the efficiency of the reaction. In addition, a double efficient ‘one-pot’ functionalization at the C-2 and then at the C-5 positions of 2-bromo-6-arylimidazo[2,1-b][1,3,4]thiadiazole derivatives was achieved using a sequential Suzuki–Miyaura–C–H arylation cascade procedure.

Key words

imidazothiadiazole - Suzuki–Miyaura - palladium - C–H arylation - cross-coupling

• References and Notes

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• 13 General Procedure A solution of 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivative (1.0 equiv), Cs₂CO₃ (3.0 equiv) and (het)aryl bromide (1.5 equiv) in dry 1,4-dioxane or toluene (3 mL for 80 mg) was degassed by argon bubbling for 15 min. Xantphos (0.2 equiv) and Pd(OAc)₂ (0.1 equiv) were then added, and the mixture was heated to 150 °C for 60 min under microwave irradiation. After removing the solvent in vacuo, the crude product was purified by flash chromatography on silica gel.
• 14 2-(4-Methylphenyl)-5-phenyl-6-(4-nitrophenyl)imidazo-[2,1-b][1,3,4]thiadiazole (2) The reaction was carried out as described in general procedure using 1 (80 mg, 0.24 mmol, 1.0 equiv) and bromobenzene (37 μL, 0.36 mmol, 1.5 equiv) in dioxane (3 mL). The crude product was purified by flash chromatography on silica gel (PE–CH₂Cl₂, 2:8 to 0:1) to afford 2 as a yellow solid (90 mg, 91%). R_f = 0.36 (PE–CH₂Cl₂, 2:8); mp >260 °C. IR (ATR diamond): ν = 1593, 1505, 1481, 1338, 1324, 1108, 1084, 971, 856, 816, 739, 708, 681 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.16 (d, J = 8.7 Hz, 2 H, 2 × H_Ar), 7.83 (d, J = 8.7 Hz, 2 H, 2 × H_Ar), 7.77 (d, J = 8.1 Hz, 2 H, 2 × H_Ar), 7.65 (dd, J = 7.6, 1.5 Hz, 2 H, 2 × H_Ar), 7.56–7.44 (m, 3 H, 3 × H_Ar), 7.30 (d, J = 8.1 Hz, 2 H, 2 × H_Ar), 2.46 (s, 3 H, CH₃) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 162.6 (Cq), 146.8 (Cq), 145.3 (Cq), 142.8 (Cq), 141.4 (Cq), 140.0 (Cq), 130.1 (2 × CH_Ar), 129.6 (2 × CH_Ar), 129.3 (CH_Ar), 129.2 (2 × CH_Ar), 128.5 (Cq), 128.0 (2 × CH_Ar), 127.5 (Cq), 127.0 (2 × CH_Ar), 126.0 (Cq), 124.0 (2 × CH_Ar), 21.8 (CH₃) ppm. HRMS (EI-MS): m/z calcd for C₂₃H₁₆N₄O₂S: 413.10667 [M + H]⁺; found: 413.10692.