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DOI: 10.1055/a-2217-6821
New Synthesis of 3-Aminohydantoins via Condensation of Hydrazines with Isocyanates Derived from α-Amino Esters
This work was financially supported by the Ministère de l'Enseignement Supérieur et de la Recherche Scientifique Tunisien, the Fonds de recherche du Québec – Nature et technologies (FRQNT) Centre in Green Chemistry and Catalysis (CGCC) Strategic Cluster (FRQNT-2020-RS4-265155-CCVC), and Université Laval.
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Abstract
A new, simple, and efficient method for the synthesis of 3-aminohydantoins was reported in two steps, starting from the corresponding l -amino esters. Commercially available α-amino esters were converted into the corresponding isocyanate derivatives, which were then subjected to the condensation reaction with hydrazine hydrate and arylhydrazines, in the presence of DMAP and DIPEA. This method provides the corresponding 3-aminohydantoins in moderate and good yields under a simple and practical protocol.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2217-6821.
- Supporting Information
Publication History
Received: 17 October 2023
Accepted after revision: 22 November 2023
Accepted Manuscript online:
24 November 2023
Article published online:
11 December 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)
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References and Notes
- 1 Meusel M, Gutschow M. Org. Prep. Proced. Int. 2004; 36: 391
- 2 Caldwell AG, Harris CJ, Stepney R, Whittaker N. J. Chem. Soc., Perkin Trans. 1 1980; 495
- 3 Wessels FL, Schwan TJ, Pong SF. J. Pharm. Sci. 1980; 69: 1102
- 4 Thenmozhiyal JC, Wong PT.-H, Chui W.-K. J. Med. Chem. 2004; 47: 1527
- 5 Konnert L, Lamaty F, Martinez J, Colacino E. Chem. Rev. 2017; 117: 13757
- 6 Tung JS, Guinn AC, Thorsett G, Pleiss MA. WO03/064396 A1, 2003
- 7 Beard RL, Vu T, Donello JE, Viswanath V, Garst ME. WO2013/071203 A1, 2013
- 8 Nakamura T, Takagi M, Ueda N. WO2003/037864, 2003
- 9 Todorov PT, Naydenova ED, Troev KD. Heteroat. Chem. 2009; 20: 87
- 10 Vincent-Rocan J.-F, Clavette C, Leckett K, Beauchemin AM. Chem. Eur. J. 2015; 21: 3886
- 11 Mani S, Bouchnak H, Pradeloux S, Kraiem J, Soulet D, Messaoudi I. Clin. Exp. Pharmacol. Physiol. 2023; 50: 728
- 12 Lalezari I. J. Heterocycl. Chem. 1985; 22: 741
- 13 Yousong N, Min Z, Yangguang G, Fei D, Hang L, Yongmin Z, Xianran H. Bull. Korean Chem. Soc. 2002; 23: 1836
- 14 Myung-Sook P, Eun-Sung C, Myung-Sook L, Soon-Kyoung K. Med. Chem. Res. 2015; 24: 4207
- 15 Hamuro Y, Marshall WJ, Scialdone MA. J. Comb. Chem. 1999; 1: 163
- 16 Yoon J, Cho C-W, Han H, Janda KD. Chem. Commun. 1998; 2703
- 17 Tsai JH, Takaoka LR, Powell NA, Nowick JS. Org. Synth. 2002; 78: 220
- 18 Typical Procedure for the Synthesis of Isocyanates 2a–f A mixture of phenylalanine methyl ester hydrochloride (1a, 4.30 g, 20 mmol) and triphosgene (BTC) (1.98 g, 6.66 mmol) in saturated aqueous sodium bicarbonate (100 mL) and dichloromethane (100 mL) was stirred in an ice bath for 0.5 h and then poured into a 500 mL separatory funnel. The organic layer was collected, and the aqueous layer was extracted with dichloromethane (3 × 50 mL). The combined organic layers were dried (MgSO4), and the solvent was evaporated under reduced pressure to afford quantitatively the corresponding isocyanate 2a. The isocyanate was used in the next step without further purification.Methyl 2-Isocyanato-3-phenylpropanoate (2a)The product was isolated as colorless oil (3.88 g, 19.0 mmol, 95%). IR (KBr): 2257, 1747 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.30 (m, 3 H), 7.23 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 2 H), 4.29 (dd, J1 =7.6 Hz, J2 = 4.4 Hz, 1 H), 3.80 (s, 3 H), 3.17 (dd, J1 = 13.6 Hz, J2 = 4.4 Hz, 2 H), 3.05 (dd, J1 = 13.6 Hz, J2 = 7.6 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 171.0, 135.6, 129.3, 128.6, 127.4, 126.5, 58.5, 53.1, 39.8.
- 19 Nowick JS, Holmes DL, Noronha G, Smith EM, Nguyen TM, Huang S.-L. J. Org. Chem. 1996; 61: 3929
- 20 Castellano RK, Nuckolls C, Rebek J. J. Am. Chem. Soc. 1999; 121: 11156
- 21 Ulatowski F, Jurczak J. Tetrahedron: Asymmetry 2014; 25: 962
- 22 Experimental Procedure and Characterization DataIsocyanate 2 (5 mmol), hydrazine hydrate (0.25 mL, 5 mmol), DIPEA (2.55 mL, 15 mmol), and DMAP (0.122 g, 1 mmol) were dissolved in anhydrous dimethyl sulfoxide (2 mL). The mixture was stirred for 0.5 h at 0 °C and then heated for 0.5 h at 100 °C in a pressure tube. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to room temperature, the product was precipitated by adding diethyl ether (5 mL). The precipitate was then filtered and purified by flash chromatography using CH2Cl2/MeOH (90:10) as the eluent. 5-[2-(Methylthio)ethyl]-3-(phenylamino)imidazolidine-2,4-dione (4f)According to the general procedure, the product was isolated as white solid (0.966 g, 3.6 mmol, 73%); Rf = 0.44 (CH2Cl2/CH3OH, 95:5); mp 164–166 °C. IR (KBr): 3359, 3108, 1778, 1732 cm–1. 1H NMR (500 MHz, DMSO-d 6): δ = 8.52 (s, 1 H, Ph–NH), 8.34 (s, 1 H, NH–CO), 7.22–6.67 (m, 5 H, Ph), 4.37 (dd, J1 = 6.8 Hz, J2 = 5.0 Hz, 1 H, CH–CH2), 2.62 (m, 2 H, S–CH2), 2.07 (s, 3 H, CH3–S), 1.90 (m, 2 H, CH2–CH). 13C NMR (125 MHz, DMSO-d 6): δ = 173.0, 155.6, 147.2, 129.3, 120.0, 112.5, 54.3, 31.6, 29.1, 15.0. HRMS: m/z calcd for C12H15N3O2S [M+]: 266.0959; found [M + H+]: 266.0958.
- 23 Beauchemin AM, Clavette C, Gan W, Markiewicz T, Toderian AB. WO2013/067646 A1, 2013