Facile One-Pot Synthesis of Substituted Hydantoins from Carbamates

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.

Key words

hydantoins - aminocarboxylate hydrochlorides - carbamates - ureido compounds - ethotoin - medicinal chemistry

• References and Notes

• 1 Meusel M. Gütschow M. Org. Prep. Proced. Int. 2004; 36: 391
• 2a Shorvon SD. Epilepsia 2009; 50: 69
• 2b Hill DS. Wlodarczyk BJ. Palacios AM. Finnell RH. Expert Rev. Neurother. 2010; 10: 943
• 2c Etemad L. Moshiri M. Moallem SA. J. Res. Med. Sci. 2012; 17: 876
• 3a Corey AE. Agnew JR. Valentine SN. Nesbitt JD. Wagner DL. Powell JH. Thompson GA. Br. J. Clin. Pharmacol. 2000; 49: 279
• 3b Riley P. Figary PC. Entwisle JR. Roe AL. Thompson GA. Ohashi R. Ohashi N. Moorehead TJ. J. Pharm. Sci. 2005; 94: 2084
• 4 Krause T. Gerbershagen MU. Fiege M. Weißhorn R. Wappler F. Anaesthesia 2004; 59: 364
• 5 Ask K. Dijols S. Giroud C. Casse L. Frapart Y.-M. Sari M.-A. Kim K.-S. Stuehr DJ. Mansuy D. Camus P. Boucher J.-L. Chem. Res. Toxicol. 2003; 16: 1547
• 6a Foulds G. O’Brien MM. Bianchine JR. Gabbay KH. Clin. Pharmacol. Ther. 1981; 30: 693
• 6b Sarges R. Bordner J. Dominy BW. Peterson MJ. Whipple EB. J. Med. Chem. 1985; 28: 1716
• 7a Cherukuvada S. Babu NJ. Nangia A. J. Pharm. Sci. 2011; 100: 3233
• 7b Cunha BA. Schoch PE. Hage JR. Mayo Clin. Proc. 2011; 86: 1243
• 8 Leonard MJ. Lingham AR. Niere JO. Jackson NC. R. McKay PG. Hugel HM. RSC Adv. 2014; 4: 14143
• 9 Edmunds JJ. Klutchko S. Hamby JM. Bunker AM. Connolly CJ. C. Winters RT. Quin JIII. Sircar I. Hodges JC. J. Med. Chem. 1995; 38: 3759
• 10 Bezzera de Queiroz R. Léles de Carvalho F. Vilar da Fonsêca D. Barbosa-Filho JM. Salgado PR. R. Paulo LL. Maroja de Queiroz AB. de Moaris Pordeus LC. Araújo de Souza S. da Silva Souza H. Lira BF. Filgueras de Athayde-Filho P. Molecules 2015; 20: 974
• 11 Somsák L. Kovács L. Tóth M. Ősz E. Szilágyi L. Györgydeák Z. Dinya Z. Docsa T. Tóth B. Gergely P. J. Med. Chem. 2001; 44: 2843
• 12 Marton J. Enisz J. Hosztafi S. Timar T. J. Agric. Food Chem. 1993; 41: 148
• 13a Kim D. Wang L. Caldwell CG. Chen P. Finke PE. Oates B. MacCoss M. Mills SG. Malkowitz L. Gould SL. DeMartino JA. Springer MS. Hazuda D. Miller M. Kessler J. Danzeisen R. Carver G. Carella A. Holmes K. Lineberger J. Schleif WA. Emini EA. Bioorg. Med. Chem. Lett. 2001; 11: 3099
• 13b Verlinden Y. Cuconati A. Wimmer E. Rombaut B. Antiviral Res. 2000; 48: 61
• 14 Zhang Q.-l. Song L.-q. Wang E.-s. Chem. Res. Chin. Univ. 2013; 29: 76
• 15 Zarghi A. Javid FS. Ghodsi R. Dadrass OG. Daraei B. Hedayati M. Sci. Pharm. 2011; 79: 449
• 16a Cachet N. Genta-Jouve G. Regalado EL. Mokrini R. Amade P. Culioli G. Thomas OP. J. Nat. Prod. 2009; 72: 1612
• 16b Schumacher M. Kelkel M. Dicato M. Diederich M. Molecules 2011; 16: 5629
• 16c Youssef DT. A. Shaala LA. Alshali KZ. Mar. Drugs 2015; 13: 6609
• 17a Chen F. Lu C. Nie J. Chen Z. Yang G. Chem. Res. Chin. Univ. 2016; 32: 219
• 17b Chen F. Lu C.-F. Nie J.-Q. Yang G-C. Chen Z.-X. Dong N.-G. Tetrahedron: Asymmetry 2015; 26: 180
• 18a Abdollahi-Alibeik M. Zaghaghi Z. Chem. Pap. 2008; 63: 97
• 18b Khazaei A. Zolfigol MA. Rostami A. Synthesis 2004; 2959
• 19 Hernández-Torres G. Tan B. Barbas CF. III. Org. Lett. 2012; 14: 1858
• 20a Martinez A. Alonso M. Castro A. Dorronsoro I. Gelpi JL. Luque FJ. Pérez C. Moreno FJ. J. Med. Chem. 2005; 48: 7103
• 20b Pedregal C. Trigo GG. Espada M. Elguero J. Vincent E.-J. Faure R. J. Heterocycl. Chem. 1984; 21: 477
• 21 Hulme C. Ma L. Romano JJ. Morton G. Tang S.-Y. Cherrier MP. Choi S. Salvino J. Labaudiniere R. Tetrahedron Lett. 2000; 41: 1889
• 22 Wallberg H. Xu MH. Lin GQ. Lei XS. Sun P. Parkes K. Johnson T. Samuelsson B. WO 2007068474, 2007
• 23a Sanders ML. Donkor IO. Synth. Commun. 2002; 32: 1015
• 23b Dieltiens N. Claeys DD. Zhdankin VV. Nemykin VN. Allaert B. Verpoort F. Stevens CV. Eur. J. Org. Chem. 2006; 2006: 2649
• 23c Park K.-H. Kurth MJ. Tetrahedron Lett. 2000; 41: 7409
• 23d Zhai Z. Chen J. Wang H. Zhang Q. Synth. Commun. 2003; 33: 1873
• 23e Zhang D. Xing X. Cuny GD. J. Org. Chem. 2006; 71: 1750
• 23f Teng X. Degterev A. Jagtap P. Xing X. Choi S. Denu R. Yuan J. Cuny GD. Bioorg. Med. Chem. Lett. 2005; 15: 5039
• 24 Duan M. Kazmierski WM. Tallant M. Jun JH. Edelstein M. Ferris R. Todd D. Wheelan P. Xiong Z. Bioorg. Med. Chem. Lett. 2011; 21: 6381
• 25 Buntain IG. Suckling CJ. Wood HC. S. J. Chem. Soc., Perkin Trans. 1 1988; 3175
• 26 Phadte M. Sonawane R. Morris JA. Boehmer JE. Desson TR. Russell SE. Ling K. Hennessy AJ. Hotson MB. Longstaff A. Russell CJ. Goodwin-Tindall J. WO2015052076, 2015
• 27 Gilbert K. Williams PD. Evans BE. Hobbs DW. Veber DF. US 5693643, 1997
• 28a Blanco-Ania D. Hermkens PH. H. Sliedregt LA. J. M. Scheeren HW. Rutjes FP. J. T. J. Comb. Chem. 2009; 11: 527
• 28b Fraile JM. Lafuente G. Mayoral JA. Pallarés A. Tetrahedron 2011; 67: 8639
• 28c Colacino E. Lamaty F. Martinez J. Parrot I. Tetrahedron Lett. 2007; 48: 5317
• 29a Fresneda PM. Molina P. Sanz MA. Tetrahedron Lett. 2001; 42: 851
• 29b Bolognese A. Correale G. Manfra M. Esposito A. Novellino E. Lavecchia A. J. Med. Chem. 2008; 51: 8148
• 30a Smith RJ. Bratovanov S. Bienz S. Tetrahedron 1997; 53: 13695
• 30b Kapadia SR. Spero DM. Eriksson M. J. Org. Chem. 2001; 66: 1903
• 31a Vázquez J. Royo M. Albericio F. Lett. Org. Chem. 2004; 1: 224
• 31b Matthews J. Rivero RA. J. Org. Chem. 1997; 62: 6090
• 32 Konnert L. Reneaud B. de Figueiredo RM. Campagne JM. Lamaty F. Martinez J. Colacino E. J. Org. Chem. 2014; 79: 10132
• 33 Konnert L. Dimassi M. Gonnet L. Lamaty F. Martinez J. Colacino E. RSC Adv. 2016; 6: 36978
• 34 Mascitti A. Lupacchini M. Guerra R. Taydakov I. Tonucci L. d’Alessandro N. Lamaty F. Martinez J. Colacino E. Beilstein J. Org. Chem. 2017; 13: 19
• 35 Kreye O. Mutlu H. Meier MA. R. Green Chem. 2013; 15: 1431
• 36 Tanwar DK. Ratan A. Burman RP. Suresh S. Gill MS. IN 3386/DEL/2015, 2015
• 37 Substituted Hydantoins 3a–w; 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.