Direct C-2 Acylation of Thiazoles with Aldehydes via Metal- and Solvent-Free C–H Activation in the Presence of tert-Butyl Hydroperoxide

Abstract

A novel and efficient methodology for the synthesis of heteroaryl ketones by C–H activation of aldehydes and thiazoles is developed. The reaction occurs smoothly, under metal-, acid- and solvent-free conditions using tert-butyl hydroperoxide as the oxidant under an air atmosphere, to afford a wide range of heteroaryl ketones in moderate to good yields. The sp² C–H bonds in the aldehyde and thiazole undergo direct oxidative cross-coupling, resulting in C-2 acylation of the azole.

Key words

acylation - C–H activation - oxidative cross-coupling - metal-free - solvent-free

• References and Notes

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• 21 (4,5-Dimethylthiazol-2-yl)(phenyl)methanone (3a); Typical Procedure An oven-dried 15 mL glass vial containing a magnetic stir bar was charged with 4,5-dimethylthiazole (1a) (1 mmol) and benzaldehyde (2a) (4 mmol). The vial was then flushed with air and sealed with a cap. Next, TBHP (4 mmol, 5–6 M in decane) was added dropwise with stirring and the mixture was further stirred at 100 °C for 16 h under an air atm. After cooling the mixture to r.t., it was washed with sat. NaHCO₃ solution (1 × 30 mL). The product was extracted with EtOAc (3 × 10 mL) and dried over Na₂SO₄. The solvent was removed under vacuum and the crude residue was purified by column chromatography (silica gel, 60–100 mesh; PE–EtOAc) to afford pure coupled product 3a. ¹H NMR (300 MHz, CDCl₃): δ = 8.44–8.41 (m, 2 H), 7.56–7.51 (m, 3 H), 2.47 (s, 3 H), 2.45 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 184.08, 162.58, 151.77, 135.92, 133.25, 131.10, 128.68, 124.02, 15.14, 12.02. GC–MS (EI, 70 eV): m/z (%) = 217 (20) [M]⁺, 188 (52), 105 (100), 85 (37), 77 (87), 53 (10), 51 (31). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₂NOS: 218.0640; found: 218.0634. (4,5-Dimethylthiazol-2-yl)(p-tolyl)methanone (3b) ¹H NMR (300 MHz, CDCl₃): δ = 8.34 (d, J = 8.05 Hz, 2 H), 7.29 (d, J = 8.05 Hz, 2 H), 2.46 (s, 3 H), 2.44 (s, 3 H), 2.42 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 183.69, 162.89, 151.60, 144.15, 135.57, 133.01, 131.23, 129.07, 21.80, 15.14, 12.00. GC–MS (EI, 70 eV): m/z (%) = 231 (23) [M]⁺, 202 (55), 119 (100), 91 (55), 89 (13), 86 (27), 65 (29), 45 (30), 44 (23), 39 (11). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₄NOS: 232.0796; found: 232.0791. (2,6-Dimethylphenyl)(4,5-dimethylthiazol-2-yl)methanone (3c) ¹H NMR (300 MHz, CDCl₃): δ = 7.52 (t, J = 7.6 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 2 H), 2.45 (s, 3 H), 2.35 (s, 3 H), 2.19 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 191.94, 161.71, 152.86, 138.78, 130.63, 129.32, 127.62, 119.38, 19.70, 15.06, 12.22. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₆NOS: 246.0953; found: 246.0947. GC–MS (EI, 70 eV): m/z (%) = 245 (38) [M]⁺, 228 (16), 218 (18), 217 (100), 216 (63), 202 (18), 133 (37), 105 (56), 103 (24), 86 (60), 79 (32), 78 (14), 77 (41), 71 (22), 53 16), 39 (13).