Meusel Manuela, Ambrozak Agnieszka, Hecker Thomas K, Gütschow Michael
Pharmaceutical Institute, Poppelsdorf, University of Bonn, D-53115 Bonn, Germany.
J Org Chem. 2003 Jun 13;68(12):4684-92. doi: 10.1021/jo020761f.
A general synthesis protocol for the generation of tri- and tetrasubstituted 5-carbamoylhydantoins is described. Starting from barbituric acids and following bromination and reaction with primary amines, 5-aminobarbituric acids 3a-s and 8 were prepared. Compounds 3 and 8 were subjected to different conditions of a base-catalyzed rearrangement reaction to yield the 1,5,5-trisubstituted hydantoins 4a-s and the 1,3,5,5-tetrasubstituted hydantoin 5c, respectively. Alkylation of 4a-s afforded 1,3,5,5-tetrasubstituted hydantoins 5a-h. Mechanisms that explain the transformation of corresponding aminobarbituric acids to hydantoins 4a-s and 5c were discussed in terms of the formation of ring-opened intermediates. Aminobarbituric acids 3a-s unsubstituted at position 3 underwent a ring contraction via intermediate isocyanates which were trapped by the amino function. A different mechanism involving a carbamate intermediate was concluded for conversion of the 1,3,5,5-tetrasubstituted aminobarbituric acid 8.
描述了一种用于生成三取代和四取代5-氨基甲酰基乙内酰脲的通用合成方案。从巴比妥酸开始，经过溴化反应并与伯胺反应，制备了5-氨基巴比妥酸3a-s和8。化合物3和8分别在碱催化的重排反应的不同条件下反应，生成1,5,5-三取代乙内酰脲4a-s和1,3,5,5-四取代乙内酰脲5c。4a-s的烷基化反应得到1,3,5,5-四取代乙内酰脲5a-h。从开环中间体的形成角度讨论了解释相应氨基巴比妥酸转化为乙内酰脲4a-s和5c的反应机理。3位未被取代的氨基巴比妥酸3a-s通过异氰酸酯中间体进行环收缩反应，异氰酸酯被氨基官能团捕获。对于1,3,5,5-四取代氨基巴比妥酸8的转化，得出了一种涉及氨基甲酸酯中间体的不同反应机理。
