Facile Synthesis of 2,4-Disubstituted Thiooxazoles and 2,4-Disubstituted Oxazole Sulfonyl Chlorides via Acyl Isothiocyanates and TMS-Diazomethane

Abstract

An expedient method for the direct conversion of acyl isothiocyanates to 2,4-disubstitued thiooxazoles and 2,4-disubstituted oxazole sulfonyl chlorides is described. The method takes advantage of an early observation by Sheehan and the reaction of diazomethane with isocyanates to form oxazolones. However, in this case an acyl isothiocyanate is utilized as well as the readily available TMS-diazomethane to provide access to the desired 4-substituted sulfur derivatives. The 2,4-disubstituted oxazole systems synthesized represent novel thiooxazoles and oxazole sulfonyl chlorides not previously described.

Key words

medicinal chemistry - heterocycles - sulfonamides - diazo compounds - sulfur

• References and Notes

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• 17 General Procedure for Preparation of SBn Derivatives To a solution of benzoylisothiocyanate (500 mg, 3.06 mmol) in CH₂Cl₂ (15.0 mL, 0.12 M) cooled to 0 °C (ice-water bath) for 15 min was added TMSCHN₂ (2 M in hexanes, 2.30 mL, 4.60 mmol, 1.5 equiv) slowly. The mixture became orange upon addition. After stirring for 1 h at 0 °C a yellow suspension was evident. To the mixture was slowly added DBU (0.92 mL, 6.13 mmol, 2.0 equiv), followed by the addition of BnBr (0.36 mL, 3.06 mmol) at which time the color dissipated. The reaction allowed to warm to ambient temperature and stirred overnight. The reaction was diluted with CH₂Cl₂ (10 mL) and then washed with brine, dried (Na₂SO₄), and the solvent removed to give a residue. The residue was diluted with CH₂Cl₂ (10 mL) and HCl in Et₂O (2 M) was added (5 mL). Note: This was done to ensure removal of TMS group at the 5-position, which was approximately 20% by GC–MS. Alternatively, use of TBAF (2 M in THF was also used). The mixture was stirred for 3 h and then portioned between brine and CH₂Cl₂. The layers were separated and organic phase washed with brine, dried (Na₂SO₄), and the solvent removed to give a residue, which was purified by chromatography (silica, 12 g RediSep Column Gold, EtOAc–heptane, 0–40%, 15 CVs) to give the desired product 4-(benzylthio)-2-phenyloxazole (362 mg, 44%) as an oil and N-(1,2,3-thiadiazol-5-yl)benzamide (138 mg, 22%). 4-(Benzylthio)-2-phenyloxazole (12, Table 1 and 14a, Table 2, entry 1) ¹H NMR (400 MHz, CDCl₃): δ = 8.02–8.09 (m, 2 H), 7.44–7.52 (m, 3 H), 7.43 (s, 1 H), 7.20–7.33 (m, 5 H), 4.12 (s, 2 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 162.2, 139.4, 137.7, 134.3, 130.7, 130.2, 129.1, 128.9, 128.8, 128.4, 127.2, 127.1, 126.5, 38.6 ppm. ESI-HRMS: m/z calcd for C₁₆H₁₃NOS [M + H]⁺: 268.0791; found: 268.0791 N-(1,2,3-thiadiazol-5-yl)benzamide (13) ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.76 (br s, 1 H) 8.85 (s, 1 H) 8.08 (d, J = 7.81 Hz, 2 H) 7.50–7.81 (m, 3 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 164.7, 151.1, 136.2, 133.2, 130.9, 128.9, 128.1 ppm. ESI-HRMS: m/z calcd for C₉H₇N₃OS [M + H]⁺: 206.0388; found: 206.0382.
• 18 General Procedure for Preparation of SO₂Cl Derivatives To a solution of 4-(benzylthio)-2-phenyloxazole (347.2 mg, 1.3 mmol) in AcOH (2 mL) was added H₂O (0.5 mL). The reaction was cooled with an ice-water bath. After 10 min, NCS (538 mg, 4.03 mmol) was added in three portions. The reaction was stirred for 15 min at 0 °C and then allowed to stir at ambient temperature for 2 h. Solids were present when the flask was removed from the cooling bath, which subsequently dissolved upon warming. The yellow homogeneous solution was partitioned between brine and EtOAc. The layers were separated, and the organic phase washed with brine, dried (Na₂SO₄), and the solvent removed to give a residue. The residue was purified by chromatography (silica, 4 g Redisep Gold, EtOAc–heptane, 0–55%, 48 CVs) to give the desired product 2-phenyloxazole-4-sulfonyl chloride (240 mg, 76%) as a solid. 2-Phenyloxazole-4-sulfonyl Chloride (14b, Table 2, entry 1) ¹H NMR (400 MHz, CDCl₃): δ = 8.40 (s, 1 H), 8.12–8.19 (m, 2 H), 7.52–7.65 (m, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 163.5, 144.8, 141.7, 133.7, 132.4, 130.2, 129.1, 128.5, 128.2, 127.3, 125.1. ESI-HRMS: m/z calcd for C₉H₆ClNO₃S [M + H]⁺: 243.983; found: 243.9829.