Efficient Synthesis of Pyrido[2,3- d ]pyrimidines by Recyclization of N -Arylitaconimides with Aminopyrimidinones
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cient Synthesis of Pyrido[2,3-d]pyrimidines by Recyclization of N-Arylitaconimides with Aminopyrimidinones Y. U. Shmoylovaa, Yu. A. Kovygina, D. Yu. Vandysheva, I. V. Ledenyovaa, E. A. Koshelevaa, and Kh. S. Shikhalieva,* a
Voronezh State University, Voronezh, 394018 Russia *e-mail: [email protected]
Received February 16, 2020; revised February 22, 2020; accepted February 28, 2020
Abstract—A convenient method has been proposed for the synthesis of 2-(4,7-dioxopyrido[2,3-d]pyrimidin-6yl)acetanilides and 2-(2,4,7-trioxopyrido[2,3-d]pyrimidin-6-yl)acetanilides via reaction of N-arylitaconimides with 6-aminopyrimidin-4(3H)-ones and 6-aminopyrimidine-2,4(1H,3H)-diones, respectively, in boiling acetic acid. Keywords: cascade reactions, N-arylitaconimides, aminopyrimidinones, aminouracils, pyrido[2,3-d]pyrimidines, recyclization
DOI: 10.1134/S107042802009002X Pyridopyrimidine system is the basic structural fragment of numerous biologically active compounds. In particular, some pyrido[2,3-d]pyrimidine derivatives were found to inhibit tyrosine kinases [1], which is responsible for their antitumor activity [2, 3]. Structural similarity of pyrido[2,3-d]pyrimidines to pteridines is likely to explain competitive inhibition of dihydrofolate reductase [4, 5], which is related to their antibacterial [6, 7] and antifungal activities [8]. In addition, pyridopyrimidine derivatives are used in the treatment of HIV-induced pneumonia and other bacterial infections [9]. Several approaches to the synthesis of pyrido[2,3-d]pyrimidine derivatives have been reported. Both rings can be formed by a multicomponent reaction [10] of an α,β-unsaturated ester, malononitrile, and guanidine. The reaction mechanism proposed by the authors involved fusion of pyrimidine ring to initially formed pyridine ring. The same stepwise scheme for the construction of fused pyrido[2,3-d]pyrimidine system was utilized in the condensation of 2-aminonicotinonitriles with thiourea [11], guanidine [12], or formamide [13], as well as in the cyclization of 2-aminonicotinamide with various aldehydes [3]. However, the main synthetic approach to the pyrido[2,3-d]pyrimidine system is based on fusion of a pyridine ring to pyrimidine, in particular conjugate addition of aminouracils to enones [7, 14], including those generated in situ, in a threecomponent synthesis [15], coupling of aminouracils
with β-diketones [16], and cycloaddition of α-aminoaldehydes of the pyrimidine series to activated unsaturated compounds [17]. Among the latest methods, recyclizations of maleimides with aminouracils should be noted [18], which make it possible to obtain polysubstituted hydrogenated systems. Maleimides have been reported to undergo various recyclizations by the action of thioamides [19, 20], guanidines [21], and aminoazoles [22, 23]. On the other hand, the reactivity of their structural analogs, itaconimides, has been poorly explored despite availability of these reagents opens wide possibilities for creating combinatorial libraries based thereon. For instance, their reactions w
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