1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 z Organic & Supramolecular Chemistry PTSA-Catalyzed Cyclization of 6-Aminouracils with Diimines: Efficient Synthesis of Functionalized Tetrahydropyrimido[4,5-d]pyrimidine-2,4-diones Mohammad R. Khodabakhshi, [a] Mostafa Kiamehr,* [b] Firouz M. Moghaddam, [c] Alexander Villinger, [d] and Peter Langer* [d, e] A new and efficient method has been developed for the synthesis of 5,7-diaryl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimi- dine-2,4-dione derivatives by cyclization of 6-aminouracils with N,N’-bis(arylmethylidene)arylmethanes (diimines). The products were formed in good yields and with very good anti- diastereoselectivity. The best yields were obtained when p- toluenesulfonic acid (PTSA) was used as the catalyst. The solvent also played an important role in the optimization. An amino-substituted 6-aminouracil and a corresponding sulfur analog could be successfully employed. In addition, various diimines, electron rich and neutral, could be successfully employed. The products are of relevance as analogs of biologically active drugs and natural products. Introduction The chemistry of heterocyclic compounds is important for the discovery of new drugs. Among all heterocyclic compounds, pyrimidines are one of the most important heterocycles exhibiting remarkable pharmacological activities. [1] Pyrimidines and their analogs tetrahydropyrimidines are considered as important heterocyclic systems which were widely explored in the past decade for their interesting biological activities. [2] In particular, they were screened for anti-inflammatory, antiviral and muscarinic agonist activities. [3] Tetrahydropyrimidines are also responsible for salt and heat sensitivity of protein–DNA interactions. [4] Pyrimidopyrimidines are annulated uracils that have attracted considerable interest in recent years. [5] Deriva- tives of pyrimidines and fused heterocyclic pyrimidines are known to display a wide range of pharmacological activities. They act as corticotropin releasing factor (CRF) antagonists, [6] dopamine D4 receptor antagonists, [7] HIV-1 reverse transcrip- tase inhibitors, [8] thymidylate synthase inhibitors, [9] dihydrofo- late reductase inhibitors, [10] anticonvulsant agents, [11] anti- cancer agents, [12] antiviral, [13] antibacterial, [14] antitumor, [15] anti- inflammatory, [16] antifungal, [17] and antileishmanial agents. [18] In addition, their potent binding affinity towards the tyrosine kinase domain of epidermal growth factor receptor [19] has been demonstrated. Examples of biologically active tetrahydropyr- imido[4,5-d]pyrimidine-2,4-diones include compound 1 that possesses significant antidepressant activity (Figure 1). [20] In addition, a new class of Wee-1 inhibitor containing an imino- dihydropyrimidinone pyrimidine core (2) has appeared in the patent literature. [21] On the other hand, p-toluenesulfonic acid (PTSA) is an environmentally benign, economically friendly, and inexpensive catalyst that offers a lot of advantages. [22] Therefore, organic reactions that are based on the use of PTSA as a catalyst could prove ideal for industrial applications provided that the catalyst shows a high catalytic activity. [23] There are only very few methods available in the literature for the synthesis of the [a] Dr. M. R. Khodabakhshi Applied Biotechnology Research Center, Baqiyatallah University of Medi- cal Sciences, Vanak Square, Mollasadra Ave. P.O. Box 1435915371, Tehran, Iran [b] Dr. M. Kiamehr Department of Chemistry, Faculty of Science, University of Qom, Ghadir Blvd, P.O. Box 3716146611, Qom, Iran E-mail: mkiamehr@yahoo.com m.kiamehr@qom.ac.ir [c] Prof. F. M. Moghaddam Laboratory of Organic Synthesis and Natural Products, Department of Chemistry, Sharif University of Technology, PO Box 11155-9516, Tehran, Iran [d] Dr. A. Villinger, Prof. P. Langer Institut für Chemie der Universität Rostock, Albert-Einstein-Straße 3a, D- 18059 Rostock, Germany E-mail: peter.langer@uni-rostock.de [e] Prof. P. Langer Leibniz Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein- Straße 29a, D-18059 Rostock, Germany Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.201801869 Figure 1. Representative pharmacologically interesting pyrimidopyrimidine derivatives. Full Papers DOI: 10.1002/slct.201801869 11671 ChemistrySelect 2018, 3, 11671–11676 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim