A highly concise one-pot synthesis of 6-arylpyrrolo [3,2-d]pyrimidines via conjugative addition reaction of secondary amines to 6-arylethynyl-5-nitropyrimidines and subsequent reduction is described.The pyrrolo [3,2-d]pyrimidine heterosystem is an important class of compounds, possessing notable biological activities, in particular purine nucleoside phosphorylase 1 and thymidylate synthase 2 inhibitory, neuropeptide Y5 receptor 3 and A 1 , A 2 -adenoside receptor 4 antagonistic properties. A literature survey revealed that 5-aminopyrimidines with suitable substituents are the most often used starting compound for this purpose. 5 Also there are only few examples of straightforward synthesis of pyrrolo[3,2-d]pyrimidines from 5-nitropyrimidines 6 and 4-alkynylpyrimidines. 7 The latter method includes classic formation of the pyrrole ring from the neighboring amino group and alkynyl moiety. Normally, the addition of heteroatomic nucleophiles to triple bonds requires high activation energy, so use of harsh reaction conditions, strong bases, or transition-metal catalysts are in practice. 8Previous work in our group showed that the triple bond of some 6-arylethynylpyrimidines is electron-deficient, therefore it is extremely reactive towards nucleophilic reagents, and for that reason the formation of addition products as well as various pyrimidine condensed derivatives are favorable. 9 Moreover, we showed that primary and secondary amines and thiols take part in a regio-and stereoselective addition reaction to the triple bond of 5-nitro-6-phenylethynylpyrimidines to form the corresponding syn addition (in the case of secondary amines) or anti addition (in the case of primary amines or thiols) products (Scheme 1). 10As the latter reaction of starting compounds with secondary amines were fast and high-yielding, we decide to study the possibility of straightforward one-pot synthesis of the pyrrolo[3,2-d]pyrimidine framework from 6-arylethynyl-5-nitropyrimidines via reductive cyclization of intermediate enamines.Our initial studies were aimed at finding optimal conditions for the amine-mediated reductive cyclization of the 6-arylethynyl-5-nitropyrimidines. Our investigation began with 4-amino-5-nitro-6-phenylethynylpyrimidine (1a), the corresponding amine (1 equiv) in different solvents under the reductive conditions (Table 1). The best results were obtained using secondary amines, such as diethylamine, pyrrolidine, or piperidine in methanol and performing reduction by hydrogen in the presence of 10% palladium on charcoal (entries 4, 6, 7). Scheme 1 Our previous work. Reagents and conditions: i) secondary amine (1 equiv), CH 2 Cl 2 , r.t., 20 min; ii) primary amine (1 equiv), CH 2 Cl 2 , r.t., 48 h; iii) R 2 SNa (1 equiv), MeOH, r.t., 30 min.Other solvents (dichloromethane, ethylacetate) under the same reductive conditions were also investigated and proved to be far less effective (entries 1-3, 10, 11). Moreover, using of primary amines (benzylamine, propylamine) resulted in longer reaction times (entries 3, 8, 9). The latte...
