Pyrimidines 4-methoxy-, nucleophilic displacement

Methoxy[l,2,3]triazolo[4,5-4 pyrimidine nucleosides are susceptible to nucleophilic displacement by hydroxide ions, as represented by the example in Scheme 22 <2005HCA751>. 

Halogen atoms in pyrones and pyridones e.g. 902) are unreactive toward SAE nucleophilic displacement. 3-Halopyridines are less reactive than the a- and 7-isomers but distinctly more reactive than unactivated phenyl halides. Thus, a bromine atom in the 3-position of pyridine or quinoline can be replaced by methoxy (NaOMe-MeOH, 150°C), amino (NH3-H20-CuS04, 160°C) or cyano (CuCN, 165°C). 5-Halogens in pyrimidines are also relatively unreactive. 

A 2-methylthio group on 4-pyrimidinones and on 6-amino-4-pyrimidinones (135) is displaced by methylamine acetate and by various salts of ammonia and other amines. Similarly, substitution by hydroxy groups occurs in hot aqueous acid with 2-arylthio- or -alkylthio-pyrimidines. Methylthio appears to be a better leaving group than a methoxy group on pyrimidine but not on -triazine. A 2-methylthio group on pyrimidine is stable to many nucleophiles (NH3, OCHs, CHsNH2) but can be displaced by... 

This gives the 4-pyrimidone ring, which is converted into the 4,5-dichloro-6-(l-fluoroethyl)pyrimidine by the action of sulfuryl chloride in the presence of dimethylformamide (DMF) [68]. The chlorine on the 4-position of the pyrimidine ring is substituted with the side chain 2-[4-(trifluoromethyl)phenyl]ethylamine through a nucleophilic substitution reaction [63]. The side chain 2-[4-(trifluoro-methoxy)phenyl]ethylamine is prepared by chloromethylation of trifluorome-thoxybenzene followed by displacement of the chlorine atom with cyanide and reduction of the nitrile with Raney nickel [69]. 

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