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 Multi-Component Reaction of 6-Aminouracils, Aldehydes and Secondary Amines: Conversion of the Products into Pyrimido[4,5-d]pyrimidines through C-H Amination/Cyclization Paran J. Borpatra, [a] Gaurav K. Rastogi, [a, b] Ms. B-S. Saikia, [a] Mohit L. Deb,* [a] and Pranjal K. Baruah* [a] Reaction of 6-aminouracils with aldehydes and secondary amines catalyzed by acetic acid is reported here. This is in fact a domino aza-Michael reaction. 6-Aminouracil reacts first with aldehyde and then amine attacks the newly formed C =C bond, which is established from the mass spectral analysis of the reaction mixture. The products of the reaction are cyclized to pyrimido[4,5-d]-pyrimidines via intramolecular α-C À H function- alization of tertiary amine promoted by I 2 -TBHP at room temperature in ethanol solvent. I 2 (10 mol%) and TBHP (1.5 eq.) are used for the cyclization reactions. Based on few controlled experiments a tentative radical mechanism is proposed for the cyclization step. Introduction Multi-component reactions (MCRs) are powerful tools for the efficient synthesis of large and complex molecules. They have several advantages such as step and atom economy, simple mode of operation, cost and energy savings. [1] Many recent literature shows that there is a resurgence of interest in the chemistry and bioactivity of 6-aminouracil derivatives. 6-Amino- uracils are used as starting materials for the synthesis of several heterocyclic scaffolds such as pyrido-, pyrrolo- and pyrimidopyrimidines. [2] Pyrimidopyrimidines have attracted considerable attention in medicinal chemistry due to their potential and diverse biological activities such as antiviral, [3] antitumor, [4] antimicrobial, [5] and anti-allergic effects. [6] Few bioactive pyrimido[4,5-d]pyrimidines are shown in Figure 1. [7] Pyrimido[4,5-d]pyrimidines were synthesized earlier by several research groups using amines other than cyclic one. [2i–j,8] C À H functionalizations have recently been the hottest area of organic research and is utilized for natural product synthesis, drug discovery and preparation of fine chemicals. [9] The strategy is atom and step-economical, directive, and environ- mentally benign than other cross-coupling reactions which require additional steps for the prefunctionalization of substrates. [10] In particular, α-C À H activation of tertiary amine has attracted more attention lately because the insitu generated iminium ion could participate in various transformations. [11] In recent times, metal-free approaches have become very popular due to their many advantages compared to metal catalyzed reactions. Iodine source catalyzed C À H functionalization with various stoichiometric oxidants has gained interest because of their low toxicity and are inexpensive. [12] Ishihara et al., [13a–c] Prabhu, [13d–f] our group, [13g–h] and others [13i–t] have reported many C À H functionalizations using iodine or its salt as catalyst. Here, we develop a two step process for synthesizing pyrimido[4,5-d]pyrimidines by the reaction of 6-aminouracils with aldehydes and secondary amines and subsequently C À H amination/cyclization of the synthesized domino aza-Michael products (Scheme 1). Results and Discussion Usually reaction of 6-aminouracil with aldehyde in presence of various catalysts give bis(6-aminouracil-5-yl)methanes. [14] There- fore, in the present reaction there is a possibility of formation of bis-compound. We optimized the condition for the 3- component reaction of 1,3-dimethyl-6-aminouracil, benzalde- hyde and tetrahydroisoquinoline (THIQ). Lewis acid catalysts gave bis-compound along with the desired product at room [a] Mr.P.J.Borpatra,Mr.G.K.Rastogi,Ms.B-ShriyaSaikia,Dr.M.L.Deb, Dr.P.K.Baruah Department of Applied Sciences, GUIST, Gauhati University, Guwahati- 781014, Assam, India E-mail: mohitdd.deb@gmail.com baruah.pranjal@gmail.com [b] Mr.G.K.Rastogi Applied Organic Chemistry, CSIR-NEIST, Jorhat-785006, Assam Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.201900210 Figure 1. Bioactive pyrimido[4,5-d]pyrimidines Full Papers DOI: 10.1002/slct.201900210 3381 ChemistrySelect 2019, 4,3381–3386 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim