Synthesis of nitrogen bicyclic scaffolds: pyrimido[1,2-a]pyrimidine-2,6-diones Sylvain Grosjean a , Smail Triki b , Jean-Claude Meslin a , Karine Julienne a , David Deniaud a, * a Laboratoire Chimie Et Interdisciplinarit e: Synth ese, Analyse, Mati ere (CEISAM), UMR CNRS 6230, UFR des Sciences et des Techniques, Universit e de Nantes, 2, rue de la Houssini ere, BP 92208, 44322 Nantes Cedex 3, France b Laboratoire de Chimie Electrochimie Mol eculaires et Chimie Analytique (CEMCA), UMR 6521, Universit e de Bretagne Occidentale, 6, avenue Victor Le Gorgeu, CS 93837, 29238 Brest Cedex 3, France article info Article history: Received 4 August 2010 Received in revised form 19 October 2010 Accepted 21 October 2010 Available online 28 October 2010 Keywords: 1,3-Diazabutadienes [4þ2] Cycloaddition Nitrogen heterocycles Dihydropyrimidinones Methylsulfanyl group abstract The multi-step synthesis of 1,3,7-trisubstituted pyrimido[1,2-a]pyrimidinediones starting from iso- thiocyanates is described. These nitrogen bicycles were prepared by an iterative sequence of function- alization/cyclocondensation reactions. [4þ2] Cycloaddition reactions took place between diazadienic chains and various acyl chlorides providing sophisticated heterobicycles. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Pyrimidopyrimidine moieties are widely represented both in natural and synthetic compounds, and usually display a broad range of biological properties. 1e3 Surprisingly, literature on general access to [1,2-a]-analoguesdin which one of the three nitrogen atoms is at the junction of the two cyclesdis rather limited, with the exception of some examples of specific one-pot or microwave assisted reac- tions. 4e7 In addition to the potential therapeutic applications, the pyrimido[1,2-a]pyrimidine compounds containing a guanidine-like moiety in the structure are also studied as ligands for catalytic activities. 8e10 In this paper we describe an original and general method for the synthesis of pyrimido[1,2-a]pyrimidine-2,6-diones with an iso- thiocyanate starting material. Both heterocycles of the bicyclic structure are obtained through a cyclocondensation reaction between a diazadiene moiety and an acyl chloride. The synthesis is based on an iterative sequence (diazadiene formation followed by cyclization re- action) and consists of four parts (Scheme 1): functionalization of an isothiocyanate into a diazadienic chain; first cycloaddition reaction providing a pyrimidinone; introduction of a second diazadienic chain onto the structure; and second cycloaddition reaction providing a pyrimidopyrimidinedione. 2. Results and discussion 2.1. Pyrimidinone synthesis The first step of the synthesis involved the conversion of com- mercially available isothiocyanates into the corresponding thio- ureas 1 . Reactions were performed in a solution of ammonia in methanol (7 M) in a sealed tube affording thioureas 1 , which then reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) in dichloromethane to give thiazadienes 2. The thiocarbonyl groups were then alkylated with methyl iodide in tetrahydrofuran to afford 2-methylsulfanyl diazadienium iodides 3 in good yields (Scheme 2). N N SMe R 2 R 1 O functionnalization functionnalization cyclization R 1 N N SMe N C R 1 S N N N R 2 R 1 O NMe 2 N N N O R 2 R 1 O R 3 Me 2 N R 3 CH 2 COCl cyclization R 2 CH 2 COCl Scheme 1. * Corresponding author. E-mail address: david.deniaud@univ-nantes.fr (D. Deniaud). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2010.10.059 Tetrahedron 66 (2010) 9912e9924