A series of new, 2-substituted 3-aryl-8,9,10,11-tetrahydro-5-methyl[1]benzothieno [3',2' : 5,6]pyrido [4,3-d]pyrimidin-4(3H)-ones, compounds 5a -q, were designed and synthesized via the aza-Wittig reaction as the key step. The iminophosphorane 1 reacted with phenyl isocyanate (or 4-chlorophenyl isocyanate) to the carbodiimide 4, which was cyclized to 5 upon addition of different amines, EtOH, or phenols in the presence of a catalytic amount of EtONa or K 2 CO 3 (Schemes 1 and 2). The structures of compounds 5 were confirmed by IR, 1 H-and 13 C-NMR, EI-MS, elemental analyses, and, in the case of 5l, by single-crystal X-ray diffraction (Figure).
Introduction. -The derivatives of pyridopyrimidines have attracted the interest of pharmaceutical companies recently. This is due, in part, to the wide range of biological activities associated with this heterocyclic scaffold. For example, some related 4-(phen- [d]pyrimidines have been reported as selective inhibitors of tyrosine phosphorylation by the epidermal growth-factor receptor (EGFR), and have become an important class of potential anticancer drugs [1] [2]. The methods described so far for the preparation of some representative derivatives of this ring system involve two general routes: a) formation of the pyridine ring by cyclization of suitable substituents of a pyrimidine [3] [4]; b) formation of the pyrimidine ring by cyclization of a suitable pyridine derivative [5]. Unfortunately, these methods often require forcing conditions, long reaction times, and complex synthetic pathways.
The aza-Wittig reactions of iminophosphoranes have received increasing attention in view of their utility in the synthesis of N-heterocyclic compounds [6]. Recently, we have become interested in the synthesis of pyrazolopyrimidinones, thienopyrimidinones, and pyridopyrimidinones from various iminophosphoranes, with the aim of evaluating their biological activities [7]. Here, we wish to report a facile synthesis of fused pyridopyrimidine derivatives from the easily accessible iminophosphorane 1.
Results and Discussion. -The 5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine 2, easily obtained from 2-amino-4,5,6,7-tetrahydro[1]benzothiophene-3-carbonitrile (3) and ethyl acetoacetate (= ethyl 3-oxobutanoate) in the presence of SnCl 4 , was converted to the iminophosphorane 1 via reaction with Ph 3