Mechanochemical Preparation of Hydantoins from Amino Esters: Application to the Synthesis of the Antiepileptic Drug Phenytoin Laure Konnert, Benjamin Reneaud, Renata Marcia de Figueiredo, Jean-Marc Campagne, Frédéric Lamaty, Jean Martinez, Evelina Colacino To cite this version: Laure Konnert, Benjamin Reneaud, Renata Marcia de Figueiredo, Jean-Marc Campagne, Frédéric Lamaty, et al.. Mechanochemical Preparation of Hydantoins from Amino Esters: Application to the Synthesis of the Antiepileptic Drug Phenytoin. Journal of Organic Chemistry, American Chemical Society, 2014, 79 (21), pp.10132-10142. 10.1021/jo5017629. hal-01082359 HAL Id: hal-01082359 https://hal.archives-ouvertes.fr/hal-01082359 Submitted on 12 Feb 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Article pubs.acs.org/joc Mechanochemical Preparation of Hydantoins from Amino Esters: Application to the Synthesis of the Antiepileptic Drug Phenytoin † † ‡ ‡ Laure Konnert, Benjamin Reneaud, Renata Marcia de Figueiredo, Jean-Marc Campagne, † † † Fredérić Lamaty, Jean Martinez, and Evelina Colacino*, † UniversitéMontpellier II, Institut des Biomoleculeś Max Mousseron UMR 5247 CNRS − Universiteś Montpellier I & II − ENSCM, Place E. Bataillon, cc 1703, 34095 Montpellier, France ‡ Institut Charles Gerhardt Montpellier (ICGM), UMR 5253 CNRS-UM2-UM1-ENSCM, Ecole Nationale Superieuré de Chimie, 8 Rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France *S Supporting Information ABSTRACT: The eco-friendly preparation of 5- and 5,5- disubstituted hydantoins from various amino ester hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-step protocol consisted in the formation of ureido ester intermediates, followed by a base-catalyzed cyclization to hydantoins. This easy-handling mechanochemical methodology was applied to a large variety of α- and β-amino esters, in smooth conditions, leading to hydantoins in good yields and with no need of purification steps. As an example, the methodology was applied to the “green” synthesis of the antiepileptic drug Phenytoin, with no use of any harmful organic solvent. ■ INTRODUCTION preparation of spirohydantoins.26 Trimethylsilyl-isocyanate 2,4-Imidazolidinediones, also known as hydantoins, are a class (TMS-NCO) and chlorosulfonyl-isocyanate are alternatives to cyanate salts for the preparation of 1,3-unsubstituted of well-known molecules that have demonstrated a wide 27,28 therapeutic interest,1 including antiepileptic,2 anticonvulsant,3 hydantoins. Recently, our group has described the solid- 4 5 6 phase synthesis of 5-substituted hydantoins under microwave- antiandrogenic, antidiabetic or antifungal activities. From the 29 synthetic point of view, hydantoins are precursors of choice of irradiation from supported amino acids and isocyanates. The α 7 8 condensation of benzil and urea in excess according to Biltz -amino acids, or provide access to optically active polymers 7,30,31 or metal complexes.9,10 A particular hydantoin, 1,3-dibromo- reaction remains the main pathway to the obtention of ′ 5,5-disubstituted hydantoins and was historically used for the 5,5 -dimethylhydantoin (DBDMH), is used for bromination 2,31 reactions11,12 and acts as a catalyst in a number of organic synthesis of the antiepileptic drug phenytoin. Several 13−15 improvements were described using enabling technologies transformations. There are three main pathways to access 32,33 1,7,16 such as ultrasonication, heating via microwave irradiation 1,3-unsubstituted hydantoins, the choice of which depends − (in solution or neat34 37), in polar solvents [water,2 poly- not only on the synthetic easiness to access the precursors, but 38 34 fi (ethylene glycol) or DMSO ] or grinding the reactants (with also on the nal target that includes 5-substituted or 5,5- 39 disubstituted hydantoins (Scheme 1). mortar and pestle). In view of the REACH (Registration, − 17,18 Evaluation, Authorisation and Restriction of Chemicals) Under Bucherer Bergs conditions involving a carbonyl 40 compound, toxic potassium cyanide and ammonium carbonate, legislation, regulating chemical substances and directed to mainly 5-substituted hydantoins were obtained. A few examples both the protection of the human health and the environment 8 from the risks of potentially toxic chemicals, the use of certain exploited this approach to access 5,5-disubstituted derivatives, ff and very recently a variant methodology, starting from a chemicals will be phased out, a ecting industries throughout methylene aziridine instead of a carbonyl compound, was also the world. Thus, the use of possible alternative substances and/ reported for the synthesis of this class of compounds.19 or technologies, including present and future research and Reactions were mainly performed in solution under reflux or development processes, will enhance innovation and com- microwaves20 (MW). Neat conditions21 were also reported, petitiveness. In this perspective, reduction or elimination of involving Fe O nanoparticles as catalyst.22 The second major harmful chemicals includes the possibility to perform organic 3 4 synthesis in the absence of solvents, in neat conditions41 or via pathway to obtain 1,3-unsubstituted hydantoins is the reaction 42,43 6 7,23 mechanochemistry. Ball-milling technology has been, for of cyanate salts with either amino acids or their ester, amide fi or nitrile24 derivatives, known as the Read synthesis. The the past decade, more and more used in the eld of organic corresponding ureido derivative was cyclized under acidic conditions, although the base catalyzed-cyclization has also Received: July 31, 2014 been reported.25 This reaction has been notably used for the Published: October 3, 2014 © 2014 American Chemical Society 10132 dx.doi.org/10.1021/jo5017629 | J. Org. Chem. 2014, 79, 10132−10142 The Journal of Organic Chemistry Article Scheme 1. Main Retrosynthetic Pathways to the Synthesis of 1,3-Unsubstituted Hydantoins Table 1. Screening of the Conditions for the Synthesis of 5-Benzyl-hydantoin 2 conversion (HPLC %) ball-milling apparatusb/jar materialb/rotation speed (rpm) entry basea or frequency (Hz) time (h) 12 1K2CO3 VM/SS/30 Hz 2 0 0 2 NaHCO3 VM/SS/30 Hz 4 70 0 3 NaHCO3 PM/SS/500 rpm 4 70 0 c 4 NaHCO3 PM/SS/500 rpm 6 90 traces c 5 NaHCO3 PM/WC/500 rpm 6 84 traces c 6K2CO3 PM/SS/500 rpm 4 00 c 7Et3N (excess) PM/SS/500 rpm 4 00 d,e e 8 Et3N/H2O/ 24090 f c 9 Et3N/H2O PM/SS/500 rpm 6 37 21 g c h 10 NaHCO3 (step 1) PM/SS/300 rpm 3 91 n.d. c h Et3N/H2O (step 2) PM/SS/500 rpm 6 n.a. 31 a b 2 equiv of base were used. Typical procedure: L-phenylalanine methyl ester hydrochloride (1 equiv), KNCO (1 equiv) and the base (2 equiv) were milled in a vibrational ball-mill (VM), 10 mL stainless steel (SS) jar, 2 stainless steel balls (5 mm diameter) at 30 Hz or in a planetary ball-mill (PM), 12 mL stainless steel or 50 mL tungsten carbide (WC) jar, 25 stainless steel balls (or 50 tungsten carbide balls, 5 mm diameter) at 500 (or 300 rpm) for the specified time. cCycled milling of 10 min cycles followed by 5 min of standby in between, with reverse rotation, for the specified time. dThe e f phenylalanyl-urea 1 was the starting material. The reaction was performed under stirring at room temperature. The reaction was carried out using L- μ g phenylalanine methyl ester hydrochloride (3.48 mmol), Et3N (6.96 mmol) and H2O (200 L). Step 1: NaHCO3 (6.96 mmol); Step 2:Et3N (6.96 h mmol) and H2O (1 mL). n.d. = not determined; n.a. = not attributed. − chemistry.44 46 The mechanosynthesis of heterocyclic com- methyl esters and potassium cyanate (Scheme 1). The ureido pounds has been notably explored.47,48 However, as far as we intermediate could be either isolated, or cyclized in the know, no mechanochemical procedure for the preparation of presence of base, to afford pure hydantoins in good to excellent hydantoins has ever been developed. In our ongoing work on yields without purification. The methodology was also applied − organic mechanochemistry,49 56 investigation of a solvent-free to the synthesis of the 5,5-disubstituted antiepileptic drug, methodology for the synthesis of hydantoins starting from phenytoin. Compared to solution synthesis, simpler reaction amino ester derivatives in a ball-mill seemed promising. It is conditions, better yields and easier workup are the major fi worth noting that the use of mechanochemistry for the bene ts of this environmentally friendly procedure. synthesis of heterocycles from amino acid derivatives remains a quite unexplored field, with only one example describing the ■ RESULTS AND DISCUSSION 57 synthesis of (R)-thiazolidine from L-cysteine. 5-Benzyl-hydantoin 2 (Table 1) served for the optimization of Herein we describe a systematic investigation and a general the reaction conditions. Several ball-milling parameters (type of method for the eco-friendly mechanochemical synthesis of 5- ball-mill apparatus, material of the jars, speed) were tested, as substituted hydantoins from a large variety of amino acid well as the nature of the base used in the reaction (Table 1). 10133 dx.doi.org/10.1021/jo5017629 | J. Org. Chem. 2014, 79, 10132−10142 The Journal of Organic Chemistry Article The classical conditions of Read synthesis involved a two-step step 2). After ball-milling, the corresponding hydantoin 2 was reaction. The hydantoic ester, formed in the first step was obtained in a moderate conversion (31%), which could be cyclized by the addition of an acid in the second step (Scheme explained, in comparison with the solution-synthesis in water, 1).