Bromination pyrimidone

Chlorination of 2-hydroxy-4//-pyrido[l,2-n]pyrimidin-4-one with NCS in a mixture of AcOH and TFA at room temperature for 72 h yielded a 3-chloro-2-hydroxy derivative (95JMC4687). Bromination of 2-chloro-4//-pyrido[l, 2-n]pyrimidone with Br2 in a mixture of CH2CI2 and pyridine at room temperature for 15 min gave a 3-bromo derivative (00BMC751). 

One such compound, bropirimine (112), is described as an agent which has both antineo-plastic and antiviral activity. The first step in the preparation involves formation of the dianion 108 from the half ester of malonic acid by treatment with butyllithium. Acylation of the anion with benzoyl chloride proceeds at the more nucleophilic carbon anion to give 109. This tricarbonyl compound decarboxylates on acidification to give the beta ketoester 110. Condensation with guanidine leads to the pyrimidone 111. Bromination with N-bromosuccinimide gives bropirimine (112) [24]. 

The pyrimidone ring system is not fully aromatic, since such compounds exist as amides, rather than hydroxypyrimidines, and the rr-system does not extend fully around the ring. In the case of the uracils, the 5,6-double bond possesses allylic character, and various relatively stable adducts can be obtained, for example, with bromine or chlorine water [210, 486—488]. Catalytic reduction across the 5,6-double bond is also readily accomplished [441, 489—491]. 

A relatively simple pyrimidone, bropirimine (64-3), has been extensively studied as an antitumor agent and immune modulator as a consequence of its unusual activity as an interferon inducer. Condensation of ethyl benzoylacetate (64-1) with guanidine leads to the pyrimidone (64-2) by a sequence quite analogous to those outlined above. Treatment of that product with bromine leads to bromination at the sole open position on the heterocyclic ring to afford bropirimine (64-3) [66]. 

Uracils undergo a range of electrophilic substitution reactions such as halogena-tion, phenylsulfenylation, mercuration, and hydroxy- and chloromethylation. Bromination of uracils has been shown to proceed via the bromohydrin adduct, and similarly of 2-pyrimidone, via the bromohydrin-hydrate iodine with tetrabutyl-ammonium peroxydisulfate allows iodination. ... 

Nitriles condense with malonyl chloride to give 2-chloro4,6-dihydroxypyii-dines (MI-174) in 23 to 63% yield and/or the pyrimidones (XII-17S) or chloropyranooxazines (Section I.5.C.) depending on conditions. 5-Bromo-3-carbethoxy-2-chloro-4,6-dihydroxypyridine (XII-176, R = CO2C2H5) is prepared either by bromination of MI-174 (R = C02Et) or by cyclization of bromomalonyl chloride and ethyl cyanoacetate. Methylmalonyl chloride did not react with propionitrile. The product from acetonitrile and malonyl chloride, first described as 2-chloro-4,6-dihydroxypyridine (MI-174,R = H), is6-chloro-2-methyl-4-pyrimidone (XI-175, R = H). ... 

Electrophilic substitution at the aromatic ring of chain-fluorinated diazines is rather unfavourable due to their electron-deficient nature. It is possible however when electron-donating substituents are also present in the diazine ring. For example, Shlosser reported successful bromination of pyrimidone 1237 with molecular bromine (Scheme 272) [715]. Halogenation of chain-fluorinated pyrimidine 1239 with S02Cl2-FeCl3 was also reported (Scheme 273) [759]. 

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