Synlett 2017; 28(17): 2285-2290
DOI: 10.1055/s-0036-1588468
letter
© Georg Thieme Verlag Stuttgart · New York

Facile One-Pot Synthesis of Substituted Hydantoins from Carbamates

Dinesh Kumar Tanwar, Anjali Ratan, Manjinder Singh Gill*
  • Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab-160062, India   Email: msingh@niper.ac.in
Further Information

Publication History

Received: 13 April 2017

Accepted after revision: 21 May 2017

Publication Date:
03 August 2017 (eFirst)

Abstract

A novel and simple approach for the preparation of 3-substituted, 5-substituted, or 3,5-disubstituted hydantoins is reported. It involves the reaction of α-amino methyl ester hydrochlorides with carbamates to yield the corresponding ureido derivatives, which subsequently cyclize under basic conditions to produce substituted ­hydantoins in good yields. By applying this method, the bioactive anticonvulsant drug ethotoin was synthesized in good yield. The process avoids conventional multistep protocols and does not use the hazardous, irritant, toxic, or moisture-sensitive reagents, such as isocyanates or chloroformates, that are commonly used for the synthesis of these important compounds.

Supporting Information

 
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  • 37 Substituted Hydantoins 3aw; General Procedure The appropriate methyl α-amino ester hydrochloride 1 (2 mmol) and carbamate 2 (2.2 mmol) were dissolved in a mixture of MeCN (12 mL) and Et3N (6 mL), and reaction mixture was refluxed for 10 h. NaOH (5 mmol) was then added, and the reaction was continued for another 8 h. When the reaction was complete, the solvents were distilled off and the residue was partitioned between EtOAc (70 mL) and 0.1 M aq HCl (20 mL). The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to give a crude product that was purified by either crystallization (hexane–EtOAc) or by column chromatography (silica gel, hexane–EtOAc). 5-Benzyl-3-propylimidazolidine-2,4-dione (3a) This compound was prepared by the general procedure, and purified by crystallization (hexane–EtOAc) to give a white solid; yield: 0.350 g (75%); mp 147–149 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 8.21 (br s, 1 H), 7.25–7.13 (m, 5 H), 4.35 (t, J = 4.4 Hz, 1 H), 3.17–3.00 (m, 2 H), 2.96 (d, J = 4.5 Hz, 2 H), 1.24–1.10 (m, 2 H), 0.50 (t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 174.0, 157.1, 135.3, 130.2, 128.4, 127.2, 57.3, 39.4, 36.5, 21.0, 11.1. HRMS (ESI): m/z Calcd [M + Na]+ for C13H16N2NaO2: 255.1109; found: 255.1102. 3-Benzylimidazolidine-2,4-dione (3t) Purified by crystallization from hexane–EtOAc as white solid; yield: 255 mg (67%); mp 140–142 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 8.12 (br s, 1 H), 7.35–7.26 (m, 5 H), 4.53 (s, 2 H), 3.98 (s, 2 H). 13C NMR (100 MHz, DMSO-d 6): δ = 172.4, 157.8, 137.2, 128.9, 127.9, 127.8, 46.4, 41.4. HRMS (ESI): m/z Calcd [M + Na]+ for C10H10N2NaO2: 213.0640; found: 213.0625. 5-Benzylimidazolidine-2,4-dione (3v) Purified by crystallization from hexane–EtOAc as white solid; yield: 278 mg (73%); mp 187–189 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 10.44 (br s, 1 H), 7.92 (br s, 1 H), 7.29–7.17 (m, 5 H), 4.33 (t, J = 4.8 Hz, 1 H), 2.97–2.88 (m, 2 H). 13C NMR (100 MHz, DMSO-d 6): δ = 175.7, 157.6, 136.0, 130.2, 128.5, 127.1, 58.8, 36.8. HRMS (ESI): m/z Calcd [M + Na]+ for C10H10N2NaO2: 213.0640; found: 213.0637.
  • 38 Gram-Scale Synthesis of Ethotoin (3-Ethyl-5-phenylimidazolidine-2,4-dione; 3q) Methyl phenylglycinate hydrochloride (10 mmol, 2.017 g) and phenyl ethylcarbamate (11 mmol, 1.817 g) were dissolved in a mixture of MeCN (60 mL) and Et3N (30 mL), and the mixture was refluxed for 10 h. NaOH (25 mmol, 1.0 g) was then added and reaction was continued for another 8 h. When the reaction was complete, the solvents were distilled off and the residue was partitioned between EtOAc (350 mL) and 0.1 M aq HCl (100 mL). The organic layer was washed with brine (2 × 100 mL), dried (Na2SO4), filtered, and concentrated to give the crude product, which was purified by column chromatography [silica gel, hexane–EtOAc (28%)] to give a white solid; yield: 1.595 g (78%); mp 85–87 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 8.70 (br s, 1 H), 7.43–7.31 (m, 5 H), 5.20 (s, 1 H), 3.43 (q, J = 3.7 Hz, 2 H), 1.08 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 172.8, 157.2, 136.2, 129.1, 128.8, 127.2, 60.2, 33.2, 13.7. HRMS (ESI): m/z Calcd [M + Na]+ for C11H12N2NaO2: 227.0796; found: 227.0782.