Warming Up to Oxazole: Noncryogenic Oxazole Metalation and Negishi Coupling Development

Abstract

This report details the development of several suitable noncryogenic metalation conditions for the synthesis of oxazole zincate. Subsequent rounds of high-throughput catalyst screening ultimately led to the identification of several suitable Pd sources that can be used for the Negishi coupling of unsubstituted oxazole. The scope and generality for one of the reported conditions is also presented.

Key words

Negishi coupling - catalysis - cross-coupling - organozinc - oxazole - high-throughput screening

• References and Notes

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• 15 Typical Procedure for the Synthesis of tert-Butyl 2-Methyl-2-{5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl}propanoate (2)A stock solution was prepared by addition of i-PrMgCl (60 mL, 120 mmol) to oxazole (7.3 mL, 112 mmol) in THF (120 mL) at –15 °C, followed by addition of a solution of ZnCl₂ (30.5 g, 224 mmol) in MeTHF (105 mL) and warming to 22 °C. To a reaction vial, under nitrogen, was added the aryl halide 1 (2.50 mmol), followed by the oxazole zincate solution (20 mL, 7.50 mmol, 3.0 equiv) and t-BuXPhos Pd G3 (105 mg, 5 mol%). The vial was warmed to 65 °C for 18 hours under nitrogen. The reaction was then cooled and quenched by addition of 1 M HCl (20 mL). Compound 2 was obtained by filtration. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.36 (s, 9 H), 1.64 (s, 6 H), 2.72 (s, 3 H), 8.20 (s, 1 H), 7.36 (s, 1 H), 12.31 (s, 1 H) ppm. ¹³C NMR (100 MHz DMSO-d ₆): δ = 14.2, 24.2, 27.4, 62.5, 79.9, 113.6, 114.2, 128.2, 136.2, 139.4, 150.1, 151.6, 156.7, 159.9, 171.2 ppm. Compounds 6–15 were obtained following the general procedure above, using the appropriate aryl halide starting material, however, following the addition of 1 M HCl (20 mL), ethyl acetate (20 mL) was added, and the layers separated. The aqueous layer was again extracted with ethyl acetate (20 mL), and the combined ethyl acetate layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 4:1 heptanes/ethyl acetate (compounds 7–10) or dichloromethane (compounds 6, 11–15). The characterization data for examples 8 and 10 below was found to be in agreement with that previously reported.¹¹ 2-(4-Methoxyphenyl)oxazole (8) ¹H NMR (400 MHz, CDCl₃): δ = 7.98–7.96 (m, 2 H), 7.64 (s, 1 H), 7.18 (s, 1 H), 6.97–6.95 (m, 2 H), 3.84 (s, 3 H) ppm. ¹³C NMR (100 MHz CDCl₃): δ = 162.0, 161.3, 138.0, 128.2, 128.0, 120.3, 114.2, 55.3 ppm.4-(Oxazol-2-yl)benzonitrile (10) ¹H NMR (400 MHz, CDCl₃): δ = 8.16 (d, J = 8.0 Hz, 2 H), 7.78 (d, J = 8.0 Hz, 2 H), 7.75 (s, 1 H), 7.32 (s, 1 H) ppm. ¹³C NMR (100 MHz CDCl₃): δ = 160.1, 139.8, 132.7, 131.2, 129.2, 126.8, 118.3, 113.7 ppm.