Pyrimidines difluoromethyl

Reaction of 2 equiv of 2-aminopyridines with 2-hydropolyfluoroalk-2-anoates 351 in MeCN in the presence of NEts at 90 °C for 50 h afforded a mixture of the isomeric 2-oxo-2H- and 4-oxo-4//-pyrido[l,2-n]pyrimidines 110 and 111. Reaction of 3 equiv of 2-amino-pyridines and 2-hydropoly-fluoroalk-2-enoates 351 in MeCN in the presence K2CO3 could be accelerated by ultrasonic irradiation (125W). 2-Amino-6-methylpyridine yielded only 2-substituted 6-methyl-4//-pyrido[l,2-n]pyrimidin-4-ones 111 (R = 6-Me), whereas 2-amino-5-bromopyridine gave a mixture of 7-bromo-4//-pyrido[l,2-n]pyrimidin-4-one (111, R = 7-Br, R = CF2C1) and 2-(chlor-o,difluoromethyl)-6-bromoimidazo[l, 2-n]pyrimidine-3-carboxylate in 44 and 8% yields, respectively (97JCS(P 1)981). Reactions in the presence of K2CO3 in MeCN at 90°C for 60h afforded only imidazo[l,2-n]pyrimidine-3-carboxylates. 

The Lewis acid-mediated A -glycosylation of 2,3-dideoxyribofuranosides having a (diethoxyphosphorothioyl)difluoromethyl group at the 3a-position with silylated nucleobases has been reported to be successful for the diastereo-selective synthesis of (3-A -pyrimidine-nucleotide analogues, (56-59). ... 

P-Alkoxy-substituted enones 700 were used as the starting materials in nearly quarter of all the principal syntheses of pyrimidines with fluorinated alkyl at C-4. The structures of the compounds of general formula 700 are summarized in Fig. 25. Quite expectedly, most of them contain trifluoromelhyl substituent, although compounds with difluoromethyl (727 [239], 749 [437,438]), chlorodifluoromethyl (728 [413]), 1,1,2,2-tetrafluoroethyl (750 [437, 439, 4406]), pentafluoroethyl (729 [441]),... 

Another type of reactivity was disclosed for difluorochloro group in pyrimidine series. Recently Iaroshenko, Langer and co-workers shown that difluorochloro substituted pyrimidines 1227 can be converted into corresponding difluoromethyl pyrimidines 1228 by radical reduction with tributyltin hydride in the presence of AIBN in moderate yields. In addition, CFaCl-substituted pyrimidines 1227 were transformed to the corresponding l,l-difluorobut-3-enyl pyrimidines 1129 by reaction with aUyltributyltin and AIBN. In this case the yields of transformation are lower in comparison with tributyltin hydride reduction (Schane 269) [412]. 

Bannwarth P, Gree D, Gree R, Valleix A (2009) Flexible synthesis of pyrimidines with chiral monofluorinated and difluoromethyl side chains. J Org Chem 74 4646-4649... 

The synthesis of Primisulfuron-methyl (299) started from reaction of diethyl malonate and thiourea (Scheme 77) [284]. The resulting pyrimidine derivative 348 was methylated, difluoromethylated and then oxidized to give sulfone 351. Reaction of 351 with aqueous ammonia gave heteroaromatic amine 352, which was transformed to Primisulfuron-methyl (299) upon treatment with isocyanate 353. 

The Baran laboratory described the invention and subsequent use of zinc difluoromethanesulfinate (DFMS) in the direct difluoromethylation of heterocycles (Scheme 15.91). The now commercially available DFMS can be prepared from treatment of difluoromethanesulfonyl chloride with zinc dust on multigram scale (35 Difluoromethylation of heterocyclic C-H bonds with this reagent is carried out at ambient temperature. As is inherent to the nature of a non-programmed approach, regioselectivily issues can arise nonetheless, this C-H difluoromethylation process is suitable to provide access to materials for subsequent testing. Notably, an indole and furan example did not participate in the reaction process, whereas pyridines, pyridinones, pyrimidines, xanthines, pyrroles, pyrazines, purines, quino-lones, quinoxalines and thiadiazoles were all successful. Moreover, difluoromethylation of thiols and enones was effective under similar reaction conditions. 

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