Base-Promoted Reaction between N-Acyl Benzotriazoles and p-Toluenesulfonylmethyl Isocyanide (TosMIC): A Facile Synthesis of 4,5-Disubstituted Oxazoles

Abstract

We herein developed a base-promoted cyclization reaction between N-acyl benzotriazoles and p-toluenesulfonylmethyl isocyanide (TosMIC) to afford 4,5-disubstituted oxazoles. In the presence of 3 equiv of K₃PO₄, the two readily available starting materials reacted in N,N-dimethylformamide at 80 °C to give 28 examples of 4-tosyl-5-aryl, -alkyl, or -alkenyl-substituted oxazoles in moderate to high yields.

Key words

oxazole synthesis - N-acyl benzotriazole - p-toluenesulfonylmethyl isocyanide

Publication History

Received: 08 June 2024

Accepted after revision: 25 June 2024

Accepted Manuscript online:
25 June 2024

Article published online:
15 July 2024

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• 18 General Procedure for the K₃PO₄-Promoted Cyclization between N-Acyl Benzotriazoles and TosMIC An oven-dried Schlenk tube was sequentially charged with N-acyl benzotriazole (0.2 mmol), TosMIC (46.9 mg, 0.24 mmol), and K₃PO₄ (55.3 mg, 0.6 mmol) under N₂. Then the Schlenk tube was capped with a rubber septum before connecting to Schlenk line. Then DMF (2 mL) was added with an injector. The perimeter of the septum was carefully sealed with parafilm. Then the mixture was allowed for stirring at 80 °C for 12 h. After cooling to room temperature, the mixture was diluted with 5 mL water and extracted with EtOAc (3 × 3 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄, and concentrated by rotoevaporation. The desired product was purified by flash column chromatography (petroleum ether (PE)/EtOAc). 5-(Thiophen-2-yl)-4-tosyloxazole (3r) The compound was isolated as a white solid (49.1 mg, 80%) by flash column chromatography (PE/EtOAc, 10:1). ¹H NMR (500 MHz, CDCl₃): δ = 8.09 (d, J = 2.6 Hz, 1 H), 7.92 (d, J = 8.3 Hz, 2 H), 7.76 (s, 1 H), 7.56 (d, J = 3.9 Hz, 1 H), 7.31 (d, J = 8.1 Hz, 2 H), 7.20–7.15 (m, 1 H), 2.40 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 148.4, 148.0, 145.0, 137.1, 133.2, 131.4, 130.3, 129.8, 128.2, 127.9, 126.4, 21.6. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₄H₁₁NO₃S₂Na: 328.0078; found: 328.0078. 5-(Furan-2-yl)-4-tosyloxazole (3s) The compound was isolated as a white solid (41.6 mg, 72%) by flash column chromatography (PE/EtOAc, 10:1). ¹H NMR (500 MHz, CDCl₃): δ = 7.92 (d, J = 8.4 Hz, 2 H), 7.80 (s, 1 H), 7.62 (d, J = 1.0 Hz, 1 H), 7.57 (d, J = 3.5 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 6.61 (dd, J = 3.6, 1.8 Hz, 1 H), 2.41 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 148.8, 145.2, 145.1, 144.0, 140.4, 137.1, 133.5, 129.8, 128.0, 116.1, 112.5, 21.6. 5-(4-Ethylthiazol-5-yl)-4-tosyloxazole (3t) The compound was isolated as a white solid (39.0 mg, 64%) by flash column chromatography (PE/EtOAc, 10:1). ¹H NMR (500 MHz, CDCl₃): δ = 8.93 (s, 1 H), 7.95 (s, 1 H), 7.87 (d, J = 8.3 Hz, 2 H), 7.41 (dt, J = 6.3, 3.4 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 2 H), 2.55 (s, 3 H), 2.41 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 156.7, 155.3, 150.5, 145.4, 145.0, 137.9, 136.5, 129.9, 128.2, 125.7, 114.6, 21.6, 17.0. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₄H₁₂N₂O₃S₂Na: 343.0187; found: 343.0185.
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