2-Chloropyrimidines, reaction with nucleophiles

The majority of pyrimido[4,5-c]pyridazines have been prepared from pyrimidine precursors. The chloropyrimidines (176) give the desired heterocyclic ring (177) on reaction with hydrazine (72BSF1483). Hydrazine also reacts with ethyl a-diazo-/3-oxo-5-(4-chloro-2-methylthiopyrimidine)propionate (178) to give the pyrimido[4,5-c]pyridazine-3-carboxamide (78). A mechanism for this interesting reaction has been proposed as shown, on the basis of the detection of hydrogen azide in the reaction mixture. There is no precedent for the reaction of the a-carbon of a-diazo-/3-oxopropionates with nucleophiles under basic conditions (76CPB2637). 

This trend is also observed in palladium chemistry where the general order for oxidative addition often correlates with that of nucleophilic substitution. Not only are 2-, 4- and 6-chloropyrimidines viable substrates for Pd-catalyzed reactions, but 4- and 6-chloropyrimidines react more readily than 2-chloropyrimidines. 

Palladium(O) exhibits a degree of nucleophilic character, thus electron-with-drawing substituents increase the reactivity of aryl halides in oxidative additions. This is exemplified in the heterocyclic context the inductive effect of C=N units allows 2-chloropyrimidine (it is slightly less reactive than bromobenzene), and even 3-chloropyridine to react (even the moderate inductive effect at the P-position gives rise to a significantly higher rate of reaction relative to chlorobenzene) although a more reactive catalyst is required for the latter case (cf. section 2.7.2.2). 

The use of liquid ammonia as a solvent for Ar reactions has been explored. With 4-fluoronitrobenzene and chloropyrimidines, solvolysis occurs although substitution by added nucleophiles such as phenoxide or triazolate ions can compete successfully. Kinetic studies of the reactions of 2-chloro- and 2-ethoxy-3,5-dinitropyridine with substituted anilines in DMSO in the presence of DABCO indicate a base-catalysed pathway, which is likely to involve rate-limiting proton transfer from the zwitterionic intermediate to base." ° In the reaction of 2,6-bis(trifluoromethanesulfonyl)-4-nitroanisole, (26), with substituted anilines in DMSO/methanol mixtures, nucleophilic attack is rate-limiting. Rate constants have higher values in DMSO than in methanol, and in DMSO-rich mixtures, there is evidence, from changes in slope of Brpnsted and Hammett plots, that formation of the zwitterionic intermediate involves an SET process." ... 

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],... 

Acid catalysis in nucleophilic aromatic displacements with amines has been observed only with heterocyclic substrates. Banks (86) has shown that the reaction rates of 2-chloro-4,6-diamino-s-triazene and of 2-amino-4-chloropyrimidine with aniline and with ring-substituted anilines in aqueous solution or suspension are accelerated by an increase in the hydrogen ion concentration. This catalysis is due to conversion of the substrate to its conjugate acid, since the heterocyclic nitrogen is a better activating group for the displacement reaction in the ammonium form than in the amino form. 

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