Expedient Syntheses of Sulfonylhydantoins and Two Six-Membered Analogues

Abstract

A range of α-amino esters can be turned into sulfonyl­hydantoins 2 in a single, atom-economic step using sulfamide and DBU. This procedure obviates the need for a three- or four-step sequence utilised by traditional procedures. Two new six-membered analogues 3 and 4 have also been prepared utilising novel synthetic protocols.

Key words

amino acids - sulfonamides - heterocycles - medicinal chemistry - phosphates

References

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11

Sulfamide (159 mg, 1.65 mmol) was added to methyl N-(2-methoxybenzyl)glycinate (345 mg, 1.65 mmol) followed by addition of DBU (0.25 mL, 1.65 mmol) in a 10 mL pyrex tube under an argon stream. The reaction was then heated to 160 °C at which point the reaction became homogeneous and bubbling was observed. After 15 min, the reaction was cooled to r.t. and diluted with 1 M NaOH (40 mL) and Et₂O (20 mL) and shaken until all the gum dissolved. The aqueous layer was separated, acidified with 6 M HCl until pH 1 and then extracted with EtOAc (2 × 20 mL). The combined EtOAc layers were dried (MgSO₄), filtered and evaporated to form a beige solid. Trituration with Et₂O-hexanes (1:5, 5 mL) followed by filtration afforded the sulfonylhydantoin product (Table [1] entry 4, 190 mg, 0.742 mmol, 45%) as an off-white solid. ¹H NMR (300 MHz, DMSO): δ = 3.80 (s, 3 H), 4.00 (s, 2 H), 4.24 (s, 2 H), 6.93 (t, J = 7.5 Hz, 1 H), 7.01 (d, J = 8.0 Hz, 1 H), 7.29-7.37 (m, 2 H), 8.60 (br s, 1 H). ¹³C NMR (75 MHz, DMSO): δ = 45.1, 55.3, 55.8, 111.3, 120.7, 123.7, 129.7, 129.9, 157.5, 168.6. HRMS (TOF MS EI⁺): m/z calcd for C₁₀H₁₂N₂O₄S: 256.0518; found: 256.0521.