Pyrimidine with electron-donating groups

A green approach for the synthesis of polyfimctionalized pyrazolo[4, 3 5,6]pyrido [2,3-rfl-pyrimidines 60 was elaborated by Tu and co workers [104] via a MCR of an aromatic aldehyde, a 3-methyl-1-phenyl-l//-pyrazol-5-amine and 1-methylbarbituric acid in water under microwave irradiation without catalyst. The yield of this reaction was affected by the volume of water. This protocol could be applied to aromatic aldehydes with either electron-withdrawing or electron-donating groups and also to heterocychc aldehydes giving excellent yields (Scheme 44). 

Tetrazolo[l,5-c]pyrimidines can also exist in equilibrium with 4-azidopyrimidines although, in the solid state, the parent compound (54) is predominantly in the tetrazolo form (73S123). The effect of substituents on this equilibrium can be correlated with that reported in the [1,5-a] system, that is, the azido tautomer is preferred when electron-withdrawing groups are in positions 5 and 7 of the tetrazolo[l,5-c]pyrimidine and electron-donating groups at C-8 favor the tetrazole product (70X4969,738123). 

Nitrosation takes place in the benzenoid 5-position in pyrimidines with three strongly electron-donating groups, e.g., 0x0, thioxo, or amino groups. In disubstituted pyrimidines, the relative positions of the substituents are decisive for any reaction 4,6-diamino- and 4,6-dihydroxy-pyrimidines are 5-nitrosated whereas their 2,4-isomers fail to react. Nitrosation is brought about by nitrous acid or by nitrite esters. When the reaction is slow, an alkyl substituent may be nitrosated on the a-carbon the product is an oxime. An extensive review on nitrosopyrimidines is available [Pg.120]

Complementary substitution of the pyrimidine nucleus with two (or three) strong electron-donating groups at C-2 and C-4 (and C-6) is sufficient to permit the 4v participation of the pyrimidine in apparent normal (HOMO-diene controlled) Diels-Alder reactions with dimethyl acetylenedicarboxy-late [Eq. (19)79-80 and Table 10-V]. 

Pyrimidines with two or more complementary electron-donating groups, e.g., 242, are capable of undergoing normal DA reaction with activated dienophiles although the yields are often only moderate. 

Electron-withdrawing and electron-donating groups on the pyridine moiety were compatible. It is worth noting that ster-ics and electronics play an inportant role in governing C2- vs. C6-selectivity for C3-substituted pyridines sterically hindered substrates, such as C3-pivalamido, phenyl, and ester substrates, preferred C6-arylation, whereas, due to electronic effects, C3-chloro- and fluoro-substrates favored C2-arylation. Other azines could also be cross-coupled with 2-methylthiophene including pyrimidine, quinoline, quinoxaline, pyridine, and pytidazine. 

Besides chlorine, another living group can be involved into nucleophilic fluori-nation. Preliminary transformation of chloropyrimidines 41 to trimethylammonium salts 42 facilitate further ftuorination. In this case the reaction proceeds in very mild conditions - under 5 °C (Scheme 11) [72, 73], This approach allows to fluorinate pyrimidines deactivated by electron-donated groups. When heated with potassium fluoride in ethylene glycol 2,6-dimethoxy-4-trimethylammoniopyrimidine salts were converted into the 4-fluoroderivatives in 42 % yield [74] Analogously fluorination can be accomplished in 2-d position, which was illustrated by preparation of 2-fluoro-4-phenyl-pyrimidine [75],... 

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