A novel reaction of 6-amino-uracils and isatins Minoo Dabiri, Seyyedeh Cobra Azimi, Hamid Reza Khavasi, Ayoob Bazgir * Department of Chemistry, Shahid Beheshti University, Tehran 1983963113, Iran article info Article history: Received 4 March 2008 Received in revised form 26 April 2008 Accepted 15 May 2008 Available online 18 May 2008 Keywords: Uracil Isatine Spiro compound Spiro[pyrimidoquinoline-5,5 0 - pyrrolopyrimidine] abstract A simple and novel cyclo-condensation reaction of 6-amino-uracils and isatins for the synthesis of spiro[pyrimido[4,5-b]quinoline-5,5 0 -pyrrolo[2,3-d]pyrimidine] derivatives is reported. Ó 2008 Published by Elsevier Ltd. 1. Introduction 6-Amino-uracil derivatives represent very important classes of functionalized uracils. 6-Amino-uracils are key intermediates in the synthesis of purines, 1 which constitute the basic nucleus of a number of drugs, for example, caffeine, penciclovir, theobromine, and theophylline. Moreover, 6-amino-uracils find wide applica- tions as starting materials for the synthesis of a number of fused uracils of biological significance, for example, pyrano-, pyrido-, pyrazolo-, pyrimido-, pyridazino-pyrimidines. 2,3 Spirocyclic systems containing one carbon atom common to two rings are structurally interesting. 4,5 The presence of the sterically constrained spiro structure in various natural products also adds to the interest in the investigations of spiro compounds. 6 Spiro com- pounds represent an important class of naturally occurring sub- stances characteristic of their highly pronounced biological properties. 7,8 Considering the above reports, the development of new and simple synthetic methods for the efficient preparation of spiro heterocycles containing uracil ring fragments is therefore an in- teresting challenge. Due to the biological activity of fused pyrimi- dines, 9–12 and our interest in the synthesis of heterocyclic compounds, 13–19 herein, we report a novel and efficient method for the preparation of spiro[pyrimido[4,5-b]quinoline-5,5 0 -pyr- rolo[2,3-d]pyrimidine] derivatives. To the best of our knowledge, this is the first report on the synthesis of spiro[pyrimido[4,5- b]quinoline-5,5 0 -pyrrolo[2,3-d]pyrimidine]s. 2. Results and discussion After some preliminary experimentation, it was found that a mixture of 6-amino-1-methyluracil 1a and isatin 2a in the pres- ence of catalytic p-toluene sulfonic acid (p-TSA) afforded 1,1 0 -di- methyl-1H-spiro[pyrimido[4,5-b]quinoline-5,5 0 -pyrrolo[2,3-d]pyr- imidine]-2,2 0 ,4,4 0 ,6 0 (1 0 H,3H,3 0 H,7 0 H,10H)-pentaone 3a in 76% yield in refluxing ethanol for 6 h (Scheme 1). In order to find a catalyst effective for the synthesis of the spi- ro[pyrimido[4,5-b]quinoline-5,5 0 -pyrrolo[2,3-d]pyrimidine]-pen- taone derivatives in refluxing ethanol, we examined this condensation reaction in the absence and the presence of several catalysts. The best results were obtained when p-TSA was used (Table 1). It should be mentioned that when the reaction was car- ried out in the absence of catalyst and for long period of time (15 h) HN N NH 2 O Me O + N H O O EtOH/Reflux N H N NH O O Me NH N HN O Me O O p-TSA 2 1a 2a 3a 76% Scheme 1. * Corresponding author. Fax þ98 21 2403041. E-mail address: a_bazgir@sbu.ac.ir (A. Bazgir). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd. doi:10.1016/j.tet.2008.05.063 Tetrahedron 64 (2008) 7307–7311