Novel multicomponent reactions of primary amines and alkyl propiolates with alloxan derivatives in water Mohammad Bagher Teimouri a, * , Tayyebeh Abbasi b , Houri Mivehchi c a Petrochemical Department, Iran Polymer and Petrochemical Institute, PO Box 14965-115, Tehran, Iran b Department of Chemistry, University of Zanjan, PO Box 45195-313, Zanjan, Iran c Novel Drug Delivery Systems Department, Iran Polymer and Petrochemical Institute, PO Box 14965-115, Tehran, Iran article info Article history: Received 15 June 2008 Received in revised form 28 July 2008 Accepted 14 August 2008 Available online 16 August 2008 Keywords: Amine Alkyl propiolate Alloxan Barbiturate Multicomponent reaction abstract A water-accelerated multicomponent synthesis of organic target molecules has been used as a key method for the preparation of novel barbiturate derivatives. The three-component condensation re- actions of primary amines with alkyl propiolates in the presence of alloxan derivatives in water are developed as efficient and clean green synthetic procedures for the high-yielding preparation of alkyl 2-(5-hydroxy-2,4,6-trioxohexahydro-5-pyrimidinyl)-3-(alkyl or arylamino)-2-propenoates. The above synthetic protocol provides rapid access to novel and diversely substituted barbiturate derivatives. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Barbiturates have attracted the attention of pharmaceutical community for more than a century due to their therapeutic value. 1 Barbiturate derivatives are widely used as sedative hypnotic drugs under a variety of conditions and are also employed for anaesthe- sia. 2 For example, barbiturates like phenobarbital (Luminal) 1 and pentobarbital (Nembutal) 2 were long used as anxiolytics and hypnotics (Fig. 1). Moreover, phenobarbital is the most widely used anticonvulsant worldwide and the oldest still in use. Slight struc- tural modifications in many depressant barbiturates produce compounds with excitatory or convulsant activity, e.g., 5-benzyl-5- ethylbarbituric acid 3, a homologue of phenobarbital. The structure and conformation of the C-5 side chains of the barbiturates have been suggested to be determinants of the different biological activities. Many 5,5-disubstituted barbituric acid derivatives have been synthesized in an effort to develop a structure–activity relationship for these compounds. For instance, Ro 28-2653 4 3 belongs to a new barbiturate class of matrix metalloproteinase (MMP) inhibitors with high selectivity for the gelatinases A and B (MMP-2 and MMP-9), which have been implicated in tumour growth and metastasis. 3,4 Preclinically, Ro 28-2653 has been shown to reduce tumour growth and extend survival time of tumour- bearing animals 5 and, more recently, to induce apoptosis in the tumour cells. 6,7 One of the powerful tools used to combine economic aspects with the environmental concerns is performing organic reactions in water; this strategy consists of two or more synthetic steps, which are carried out in water as a cheap, nontoxic, environmentally friendly solvent, in a one-step reaction, without isolation of any intermediate thus reducing time, saving money, energy and raw materials. 8 Although, production of a contaminated aqueous waste stream can have significant economic impacts, for example, con- centration of contaminated water streams by distillation is very energy intensive compared to say concentration of propanol waste stream. 9 However, the development and implementation of pro- cesses using water as solvent may serve as one avenue for lowering 1 2 3 4 N N O O H H O N O O H O N O O H O N N NO 2 N O O H O H N H N N H Figure 1. Selected examples of biologically active barbiturates. * Corresponding author. Tel.: þ98 21 44580000; fax: þ98 21 44580032. E-mail address: m.teimouri@ippi.ac.ir (M.B. Teimouri). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.08.039 Tetrahedron 64 (2008) 10425–10430