Categories: Synthesis of N-Heterocycles >
Synthesis of hydantoins
A simple reaction of α-amino methyl ester hydrochlorides with carbamates provides 3-substituted, 5-substituted, or 3,5-disubstituted hydantoins in good yields via ureido derivatives, which subsequently cyclize under basic conditions. The process avoids conventional multistep protocols and does not use hazardous, irritant, toxic, or moisture-sensitive reagents, such as isocyanates or chloroformates.
D. K. Tanwar, A. Ratan, M. S. Gill, Synlett, 2017, 28, 2285-2290.
The synthesis of highly substituted chiral hydantoins from simple dipeptides proceeded through the dual activation of an amide and a tert-butyloxycarbonyl (Boc) protecting group by Tf2O-pyridine under mild conditions in a single step. This method was successfully applied in the preparation of various biologically active compounds, including drug analogs and natural products.
H. Liu, Z. Yang, Z. Pan, Org. Lett., 2014, 16, 5902-5905.
The use of a hypervalent iodine cyanation reagent as a source of electrophilic carbon enables the synthesis of enantiopure 1,5-substituted hydantoins from inexpensive commercially available enantiopure protected amino acids without epimerization.
N. Declas, F. Le Vaillant, J. Waser, Org. Lett., 2019, 21, 524-528.
A chiral diarylketone catalyzes a photochemical deracemization of 5-substituted 3-phenylimidazolidine-2,4-diones. Mechanistic evidence suggests the reaction to occur by selective hydrogen atom transfer (HAT). The product enantiomer is not processed by the catalyst and is thus enriched in the photostationary state.
J. Großkopf, M. Plaza, A. Seitz, S. Breitenlechner, G. Storch, T. Bach, J. Am. Chem. Soc., 2021, 143, 21241-21245.
An efficient two-step Ugi/cyclization reaction sequence provides hydantoins. This microwave-assisted one-pot cyclization strategy, in which an alkyne group acts as a leaving group under basic conditions, could be applicable to other multicomponent reactions (MCRs) for synthesizing bioactive and drug-like hydantoins.
Z.-G. Xu, Y. Ding, J.-P. Meng, D.-Y. Tang, Y. Li, J. Lei, C. Xu, Z.-Z. Chen, Synlett, 2018, 29, 2199-2202.
Chiral lewis base/copper(I) cooperative catalysis enables an enantioselective α-amination of esters with N,N-di-t-butyldiaziridinone to provide hydantoins in good yields with excellent enantioselectivities.
J. Song, J.-Z. Zhang, S.-S. Chen, T. Fan, L.-Z. Gong, J. Am. Chem. Soc., 2018, 140, 3177-3180.
Reaction of carbodiimides with α-Br(Cl)-aryl acetic acids produces N,N′-substituted 5-arylhydantoins under very mild conditions and high yields. When the carbodiimides are generated in situ by Staudinger reaction, the process becomes a one-pot, three-component sequential synthesis of libraries of differently substituted 5-arylhydantoins.
F. Olimpieri, A. Volonterio, M. Zanda, Synlett, 2008, 3016-3020.
1,5-Disubstituted hydantoins/thiohydantoins have been synthesized in good yield by a microwave-promoted solvent-free condensation of arylglyoxals and phenylurea/thiourea using polyphosphoric ester (PPE) as a reaction mediator. The workup is simple and involves treatment with ice-cold water.
S. Paul, M. Gupta, R. Gupta, A. Loupy, Synthesis, 2002, 75-78.
Enantiomerically pure hydantoins are prepared from optically pure α-amino amides utilizing triphosgene. A mechanism for the racemization observed with 1,1'-carbonyldiimidazole (CDI) for this type of reaction is proposed.
D. Zhang, X. Xing, G. D. Cuny, J. Org. Chem., 2006, 71, 1750-1753.
A novel intermolecular α-amination process of esters using CuCl as catalyst and di-tert-butyldiaziridinone as nitrogen source forms hydantoins effectively under mild reaction conditions.
B. Zhao, H. Du, Y. Shi, J. Am. Chem. Soc., 2008, 130, 7220-7221.
Copper acetate promoted N-arylation of imides with boronic acids can be employed as a major method for the synthesis of N3-aryl hydantoins.
H. M. Hügel, C. J. Rix, K. Fleck, Synlett, 2006, 2290-2292.
F. Fernández-Nieto, J. M. Roselló, S. Lenoir, S. Hardy, J. Clayden, Org. Lett., 2015, 17, 3838-3841.
Palladium(II) trifluoroacetate catalyzes the C-arylation of N,N-disubstituted hydantoins by aryl iodides in good yield. The reaction is successful with various hydantoins and a range of electron-rich and electron-poor aryl iodides.
A cascade [3 + 2] cycloaddition between organo-cyanamides and α-haloamides provided N2-unprotected five-membered cyclic guanidines under mild conditions in very good yields. The corresponding cyclic guanidines could be easily transformed into hydantoins via hydrolysis.
C.-C. Wang, Y.-L. Qu, X.-H. Liu, Z.-W. Ma, B. Yang, Z.-J. Liu, X.-P. Chen, Y.-J. Chen, J. Org. Chem., 2021, 86, 3546-3554.
In the presence of trichloroisocyanuric acid, triphenylphosphine, and sodium cyanamide, readily available carboxylic acids were converted into N-acylcyanamides in very good yields within some minutes at room temperature under ultrasound irradiation. In addition, N-acyl-substituted imidazolones were readily accessible through guanylation-cyclization of in situ generated N-acylcyanamides.
W. Phakhodee, D. Yamano, M. Pattarawarapan, Synlett, 2020, 31, 703-707.
Formation of iminophosphoranes in a Staudinger reaction and condensation with carbon disulfide followed by condensation with α-amino esters provides N-3-substituted 2-thiohydantoins.
S. Gosling, C. El Amri, A. Tatibouët, Synthesis, 2014, 46, 1079-1084.