A One-Pot Tandem Approach for the Synthesis of 5-(Het)aryloxazoles from Substituted (Het)aryl Methyl Alcohols and Benzyl Bromides

Abstract

A new modified van Leusen strategy has been developed for the synthesis of biologically significant 5-substituted oxazoles by the reaction of (het)aryl methyl alcohols or benzyl bromides as precursors with tosylmethylisocyanide (TosMIC) under basic conditions. This method is efficient, takes place under mild reaction conditions, and is tolerant of various functional groups with high yield.

Key words

oxazole - TosMIC - T3P^® - DMSO - NaHCO₃

• References and Notes

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• 26 To a solution of benzyl alcohol (4.6 mmol) in DMSO (2 mL), T3P^® (5.5 mmol, 50% solution in EtOAc) was added at 0 °C followed by Et₃N (9.2 mmol) under nitrogen atmosphere. The mixture was stirred at r.t. for 1.5 h. After completion of the reaction (monitored by TLC), KOH (69.0–92.0 mmol) in H₂O–EtOH mixture (3 mL, 1:1, v/v) was added dropwise to the reaction mixture at 0 °C and stirred for 5 min followed by TosMIC (5.0 mmol) addition. The reaction was monitored by TLC and evaporated the EtOH from reaction mixture under reduced pressure, followed by dilution with EtOAc (2 × 25 mL). The organic layer was washed with H₂O (2 × 20 mL) and brine solution (2 × 20 mL). Then, the organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuum to afford crude product. The crude was purified by column chromatography over silica gel (60–120 mesh) using hexane–EtOAc mixture as eluent (8:2) and obtained 3a (83% yield) as pale yellow solid; mp 37–39 °C. FTIR: 3013, 3006, 2988, 2251, 1661, 1052, 1024, 1005, 658 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.89 (s, 1 H, ArH), 7.65-7.62 (m, 2 H, ArH), 7.43–7.38 (m, 2 H, ArH), 7.34–7.30 (m, 2 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 151.5, 150.3, 128.9, 128.6, 127.7, 124.3, 121.4. HRMS: m/z calcd: 145.158; found: 146.703 [M + H]⁺. Anal. Calcd for C₉H₇NO: C, 74.47; H, 4.86; N, 9.65; O, 11.02. Found: C, 74.48; H, 4.89; N, 9.66.
• 27 CCDC 1429231 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 28 The mixture of benzyl bromide (2.9 mmol) and NaHCO₃ (4.3 mmol) was stirred for 5 min followed by the addition of DMSO (1 mL) at r.t., and the reaction was monitored by TLC, followed by dropwise addition of KOH (4.3–5.8 mmol) in H₂O–EtOH mixture (3 mL, 1:1, v/v) at 0 °C. The reaction mixture was stirred for 5 min followed by the addition of TosMIC (5.0 mmol), then continued the stirring for 2–3 h. After completion of the reaction, EtOH was removed under reduced pressure; extracted and purified the crude product 3a as mentioned the above procedure. The characterisation data were identical with the products isolated in the earlier protocol.
• 29 Bratulescu G. Synth. Commun. 2008; 38: 2748