Regioisomeric synthesis of dihydrofuro[2,3-d]pyrimidines in a diastereoselective manner involving nitrogen ylides in one-pot three-component reaction Leema Dutta a , Meenakshi Sharma b , Pulak J. Bhuyan a, * a Medicinal Chemistry Division, CSIR-North-East Institute of Science & Technology, Jorhat 785006, Assam, India b AcSIR, New Delhi, India article info Article history: Received 23 April 2016 Received in revised form 29 August 2016 Accepted 30 August 2016 Available online 31 August 2016 Keywords: Pyrimidine Furo[2,3-d]pyrimidines Aldehyde Pyridinium bromide Pyridinium ylide abstract Synthesized some novel regioisomers of furo[2,3-d]pyrimidines in a diastereoselective manner via one- pot three-component reaction of barbituric acids, aryl aldehydes and pyridinium bromides in the presence of triethylamine as base. Both the isomers were obtained in comparable ratio with excellent overall yield. Ó 2016 Elsevier Ltd. All rights reserved. 1. Introduction Furopyrimidines, particularly furo[2,3-d]pyrimidines represent a very important class of compounds that possess wide range of biological activities such as antibacterial, 1 antifungal, 2 antitumour, 3 antiviral, 4 antifolate 5 and anti-human cytomegalovirus activity. 6 Compounds with this molecular motif are also active on blood circulatory system 7 and stimulate the skin preparative re- generation. 8 In view of the vast biological activities and importance to pharmaceutical discovery research, considerable attention has been diverted towards the synthesis and molecular manipulation of furo[2,3-d]pyrimidines. Furo[2,3-d]pyrimidines are usually pre- pared either from suitably functionalized furan ring 9 by generating the pyrimidine ring on the parent furan ring or from a pyrimidine derivative by constructing a furan ring on the parent pyrimidine ring. 10 Very recently, an excellent review was published describing various synthetic routes for furopyrimidines, particularly furo[2,3- d]pyrimidines. 11 Nitrogen ylides represent an important class of nucleophilic or bifunctional reagents which can undergo cyclization, olefination, rearrangement reactions etc., and hence have wide application for the construction of diverse carbocyclic and heterocyclic compounds of synthetic and biological significance. 12 In this regard, pyridinium ylides have extensive application for the synthesis of dihydrofuran and its annelated derivatives which produced the desired compounds in a diastereoselective manner. 13 In continuation of our work on pyrimidines, 14 in the present paper, we report an unprecedented regioisomeric synthesis of some highly functionalized dihydrofuro[2,3-d]pyrimidines 4 and 5 in diastereoselective manner from one-pot three-components re- action of barbituric acids 1 , aryl aldehydes 2 and pyridinium bro- mides 3 in the presence of triethylamine as base (Scheme 1). During the reaction, nitrogen ylides were formed and involved in [4þ1] annulation as well as [2þ1] annulation processes which after intramolecular ring transformation produced the two regioiso- meric products. 2. Results and discussion The study was initiated by performing the three-component reaction of N,N-dimethylbarbituric acid 1 (R 1 ¼Me), benzaldehyde 2 (Ar¼Ph) and benzylpyridinium bromide 3 (R 2 ¼COPh) in various solvents and base to determine the optimal condition for the model reaction. Among the solvents viz water, ethanol, DMSO, dichloro- methane and acetonitrile, the acetonitrile was found to be most effective. The reaction did not proceed in water as barbituric acid derivative 1 (R 1 ¼Me) was not soluble in the solvent. The model * Corresponding author. E-mail address: pulak_jyoti@yahoo.com (P.J. Bhuyan). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet Tetrahedron 72 (2016) 6654e6660 http://dx.doi.org/10.1016/j.tet.2016.08.084 0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.