2.6- Dimethyl-4-iodopyrimidine

Substituted uracils 1 are of much interest due to their possible use as anti-cancer and anti-AIDS drugs, and both 2,4-dimethoxy-6-iodopyrimidine and l,3-dimethyl-6-iodouracil (1, R = Me, X = I) were required as starting materials for the synthesis of a variety of uracils 1 by palladium-catalysed C-C bond formation. It was reported in 1961 that treatment of 6-chloro-2,4-dimethoxypyrimidine with sodium iodide in refluxing DMF gave a 42% yield of the corresponding 2,4-dimethoxy-6-iodopyrimidine, but repetition of the reaction recently clearly established that the product was in fact the isomeric l,3-dimethyl-6-iodouracil (1, R = Me, X = I). 

A mixture of 2,6-dimethyl-5-iodopyrimidin-4-amine (1.24 g, 5 mmol), ethyl methacrylate (0.68 g, 6 mmol), PdCl2 (30 mg, 0.17 mmol), F.t3N (0.6 g, 6 mmol), and McCN (2 mL) was heated at 120"C in a sealed tube for 24 h. After removal of the solvent, the residue was diluted with H20. The mixture was made alkaline with K,COj and extracted with CHCI3. The CHCI3 extracts were purified by column chromatography (silica gel, benzene/EtOAc 9 1). Recrystallization (benzene) gave the product as needles yield 0.74 g (65%) imp 144-145 "C. 

The relatively vigorous reaction conditions required to effect vinyl substitution by heteroaryl halides under the influence of Pd-catalysis may lead to homo-coupling. The dominating reaction path in attempted alkenyl-ations of 4-iodopyrimidines was the formation of 4,4 -bipyrimidines (19) (Scheme 4 Section II.A.2). In reactions of 4-iodopyrimidines with a Pd-catalyst at 160°C, near-quantitative yields of the 4,4 -bipyrimidine were obtained (79CPB193). Also, in the reaction of 2-iodo-4-methylquinoline with Pd(OAc)2 as added catalyst, a major reaction path led to 4,4 -dimethyl-2,2 -biquinoline (Scheme 2 Section II.A.2.) (82CPB3647). 

Further investigations into the palladium(ll)-catalysed cross-couphng of olefins with iodopyrimidines have been published. As previously reported,2-iodo-4,6-dimethylpyrimidine and its 4-iodo-2,6-dimethyl isomer do not couple with ethyl acrylate if a reagent mixture of Pd(OAc)2, PhaP, and EtaN is used however, omission of the triphenylphosphine permits the coupling to proceed in reasonable yields. Palladium black can also be used as the catalyst. ... 

This reaction type also has been used to prepare C-inethyl 5-pyrimidine-carboxylic acids l94H(38)1375l. Pyrimidinylzinc halides obtained upon oxidative addition of active zinc to 2- or 4-iodopyrimidines have been shown to be transformed into aiylated pyrimidines by palladium-catalysed reaction [93T(49)9713]. Covalent hydration at the 2- and 4-position of monomethyl- and dimethyl-S-pyrimidinecaiboxylic acids has been investigated [94H(38)137S]. 

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