A Convenient One-Pot Synthesis of Both Enantiomers of 1,3,5-Trisubstituted Hydantoins

Abstract

A novel one-pot asymmetric synthetic method for the direct conversion of bromoacetates into highly substituted hydantoins has been developed. Both enantiomers of 1,3,5-trisubstituted hydantoins were conveniently synthesized through a dynamic kinetic resolution of bromoacetates derived from either ethyl l-lactate or diacetone-d-glucose. The sequential three-component reaction permitted the preparation of (R)- or (S)-1,3,5-trisubstituted hydantoins in yields of 77–51% with enantiomeric ratios of up to 95:5.

Key words

hydantoins - one-pot reaction - asymmetric synthesis - kinetic resolution - chiral auxiliaries - bromoacetates

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• 8 1,3,5-Trisubstituted Hydantoins 3–10: General Procedure The appropriate amine (1.0 equiv) and TBAI (1.0 equiv) were added to a stirred solution of a 1:1 diastereomeric mixture of bromoacetate 1a–d in CH₂Cl₂ at r.t. After the disappearance of 1 (TLC; 15–20 h), the appropriate isocyanate (1.2 equiv) and pyridine (1.2 equiv) were added, and the mixture was allowed to stand at r.t. for 0.5–1 h. The resulting mixture was washed with sat. aq NH₄Cl, dried (MgSO₄), filtered, concentrated, and purified by column chromatography. 1-Benzyl-3,5-diphenylhydantoin (4) Colorless oil; yield: yield: 109 mg (64%, R/S er 93:7) from 1a; 111 mg (64%, S/R er 92:8) from 1c. HPLC (Chiralpak AD-H; 40% i-PrOH–hexane, 0.5 mL/min): t _R (R)-4: 24.0 min; t _R (S)-4: 33.9 min. ¹H NMR (CDCl₃, 400 MHz): δ = 7.47–7.18 (m, 15 H), 5.24 (d, J = 15.2 Hz, 1 H), 4.82 (s, 1 H), 3.81 (d, J = 15.2 Hz, 1 H). ¹³C NMR (CDCl₃, 100 MHz): δ = 170.1, 155.5, 135.2, 132.5, 131.8, 129.5, 129.4, 129.1, 129.0, 128.7, 128.3, 128.2, 127.7, 126.1, 62.9, 44.8. HRMS: m/z [M + H]⁺ Calcd for C₂₂H₁₉N₂O₂: 343.1447; found: 343.1445.