Photo- and stereochemistry of 5,6-methylenepyrimidine nucleosides, bicyclic isomers of thymidine, and 5-methyluridine

Electron-rich &vinyl-and 6-(azavinyl)pyrimidinediones, such as 6-{ [(dimethylamino)methylene]amino)-(1) and 6-[2-(dimethyl~ho)vinyl]-l,3-dimethyl-2,4(lH,3H)-pyrimidin~iones (8), undergo cycloaddition reactions with electron deficient olefins to give pyrido[2,3-d]pyrimidines (3a -e) and quinazolines (9a -c), respectively, after elimination of dimethylamine from the 1 : 1 cycloadducts and oxidative aromatization. With dimethyl acetylenedicarboxylate, pyrrolo [3,4c]pyridines 5,11, and 15 were obtained due to an initial Michael addition and subsequent ring transformation reaction. Stable Michael adducts were also obtained from reactions of 1 with azodicarboxylates. The stable adducts 6a -c were thermally converted into 8-(dimethylamino)theophylline (7).Quinazolines and pyrido [2,3-d]pyrimidines represent a broad class of compounds which have received considerable attention over the past years due to their wide range of biological activities2a,b). As such, these fused heterocycles have been extensively investigated, and their synthetic preparations are well documented2"*'). Most of these preparations rely on cyclocondensation reactions from pyrimidine or pyridine intermediates. However, this type of stepwise synthetic strategy limits the synthetic flexibility. We now describe a new synthetic route to these heterocycles based on [4 + 2) cycloaddition reactions, which allow access to a range of structural variations by modification of the reacting components.In the past a cycloaddition approach has had little appeal since the dienophilic nature of the pyrimidine ring is rather limited, and the diene properties of vinylpyrimidines had not yet been established3). It was postulated that if a vinylpyrimidine system were appropriately substituted with strong electron donating groups, cycloaddition might occur with electron deficient dienophiles. Recent work in which the diene character of furan was enhanced by incorporation of a dimethylhydrazono group4) as well as the abilities of methacrolein dimethylhydrazone" and 1-(dimethylamino)- 3-met h yl-2-azabutadiene 6, to function as azadienes suggests that the dienic character of vinylpyrimidines would be increased by similar substituents. This is further supported by HOMO calculations7) which show an increase in the HOMO energies of the 6-aminovinyl-, 6-aminomethyleneamino-, and 6-hydrazonomethyl derivatives of 2,4-pyrimidinedione relative to 6-vinyl-2,4-pyrimidinedione (see Scheme 1).

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Photo- and stereochemistry of 5,6-methylenepyrimidine nucleosides, bicyclic isomers of thymidine, and 5-methyluridine

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Reactions of uracils, 16: Substituted 6‐ vinyl‐2,4(1H,3H)‐pyrimidinediones in cycloaddition and Michael‐type reactions: Pyrido[2,3‐d]pyrimidines, pyrrolo[3,4‐c]pyridines, and quinazolines

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