L. Aguado, M. Camarasa, M. Pérez-Pérez
Jan 29, 2009
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Influential Citations
14
Citations
Journal
Journal of combinatorial chemistry
Abstract
Purine derivatives are a continuous source of biologically active compounds and are thoroughly investigated as chemical biology tools and therapeutic agents. Their reported pharmacological activities involve protein kinases, adenosine receptors, microtubule assembly, etc., as exhaustively described in a recent review article. Other purine applications that have also been recently reviewed include their properties as Hsp90 inhibitors, their central role in neurotransmission and neuromodulation, or their potential for the treatment of infectious diseases (i.e tuberculosis or malaria). N9 in purines is a critical substitution site for pharmacologically active compounds because in natural nucleosides that is the attachment point for (2-deoxy)ribose. Interestingly, 9-arylpurines and therefore their biological activities have been poorly investigated. Some recent examples where the biological activities of 9-arylpurines have been explored include agonists of the A2B adenosine receptors, 6 ligands for the corticotropin-releasing factor receptor, or substrates of the enzyme adenosine deaminase. Moreover, 9-arylpurines are scarcely represented in some recently described purine libraries. At least three methods have been described in the literature for the synthesis of 9-arylpurines. The direct nucleophilic aromatic substitution on purine rings is limited to activated aryl halides. A broader application has been shown for the cross-coupling reaction of the purine base with arylboronic acid catalyzed by copper salts, initially described by Ding and further studied by Gundersen by adapting the general procedure of Chan, Lam, and Evans, and recently reported by other laboratories. Still there are several problems associated with this methodology, including difficulties in the isolation of the compounds, the long reaction time required, or the need of protection of some nucleobases to improve the fate of the reaction, and, more significantly, in some cases, the poor yields reported. As a third alternative, 9-arylpurines can be synthesized through the classical method that involves reaction of 5-amino-4,6-dihalopyrimidines with anilines, followed by a ring closing reaction. This methodology is the most suitable to incorporate diversity at several points of the purine scaffold, as shown in Scheme 1. However, this strategy requires prolonged heating with the corresponding waste of time and energy, and the yields are variable. Therefore we consider that microwave assisted synthesis (MAOS) could constitute an interesting alternative to the classical heating step to perform the two-step synthesis described in Scheme 1. The advantages of MAOS in drug discovery have recently been reviewed. A motivating precedent for our goal was found in the reaction between 4,6-dichloro-5-aminopyrimidine and a few anilines described by Hudson, as the first step in their microwave-assisted synthesis toward pyrimidooxazepines. As shown in Table 1, 4,6-dichloro-5-aminopyrimidine (1, R1 ) H) and its 2-methyl analogue (1, R1 ) CH3) were microwave-irradiated in a Biotage Initiator 2.0 with an equimolar amount of different anilines (2, R5 ) H) in isobutanol in the presence of HCl at 150 °C for 10 min, to afford the 4-chloro-5,6-diaminopyrimidines 3a-3g in good to excellent yields (entries 1-7). This short reaction time