Palladium-catalyzed 3-Thiomethyltriazine-boronic Acid Cross Coupling: Easy Access to 3-Substituted-1,2,4-triazines

Abstract

The palladium-catalyzed coupling reaction of 3-thiomethyl-1,2,4-triazine 1 with different organoboron compounds in the presence of copper(I) 3-methylsalicylate proceeds to afford the corresponding 3-substituted-1,2,4-triazines in good yield. This approach leads very easily to a large range of C-5 and C-6 unsubstituted as-triazines.

Key words

as-triazine - copper - boron - thioethers - palladium cross-coupling

References

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  During the very late stages of the production of this letter, Liebeskind and Srogl have disclosed to the authors a prior art manuscript describing a general heteroaromatic thioether-boronic acid cross-coupling.

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12

The related nickel- and palladium-catalyzed cross coupling of Grignard and benzylzinc reagents with methylthio-substituted heterocycles is known. [16]

13

Experimental Procedure: The following procedure for the synthesis of 3-(p-methoxyphenyl)-1,2,4-triazine is representative. To a mixture of 3-methylthio-1,2,4-triazine 1 (50 mg, 0.393 mmol, 1.0 equiv), CuMeSal (186 mg, 0.867 mmol, 2.2 equiv), p-methoxyphenylboronic acid (132 mg, 0.867 mmol, 2.2 equiv) in dry THF (3 mL) under argon, was added Pd(PPh₃)₄ (23 mg, 0.02 mmol, 5% mol). The reaction was stirred for 5 h at 50 °C. The mixture was quenched with a Na₂CO₃ solution (2 N) and extracted with dichloromethane. The combined organic phases were washed with a Na₂CO₃ solution (2 N) and water, dried over MgSO₄ and concentrated in vacuo. After purification by column chromatography on silica gel (petroleum ether-ethyl acetate, 70:30), the desired 3-(p-methoxyphenyl)-1.2.4-triazine 2 was obtained as yellow powder (63 mg, 85%); mp 90-91 °C; (M + H)⁺ (IS) 188; ¹H NMR (250 MHz, CDCl₃) δ 9.08 (d, 1 H_triazine, J = 2.1 Hz); 8.61 (d, 1 H_triazine, J = 2.1 Hz); 8.51 (d, 2 H_Ar, J = 7 Hz); 7.03 (d, 2 H_Ar, J = 7Hz); 3.90 (s, 3 H_OMe); ¹³C NMR (62.5 MHz, CDCl₃) δ 164.3, 163.1, 149.0, 147.4, 130.0, 127.6, 114.7, 55.8. Spectroscopic data for 3: tan solid; mp 75 °C; (M + H)⁺ (IS) 148; ¹H NMR (250 MHz, CDCl₃) δ 9.09 (d, 1 H_triazine, J = 2.5 Hz), 8.62 (d, 1 H_triazine, J = 2.5 Hz), 7.72 (dd, 1 H_furyl, J = 0.9, 1.6 Hz), 7.54 (dd, 1 H_furyl, J = 0.9, 3.5 Hz), 6.65 (dd, 1 H_furyl, J = 1.6, 3.5 Hz); ¹³C NMR (62.5 MHz, CDCl₃) δ 158.1, 149.5, 148.8, 147.2, 146.6, 115.7, 112.3.