Halogenation, of pyrimidines

Halogenation of pyrimidine bases may be done with bromine or iodine. Bromination occurs at the C-5 of cytosine, yielding a reactive derivative, which can be used to couple diamine spacer molecules by nucleophilic substitution (Figure 1.48) (Traincard et al., 1983 Sakamoto et al., 1987 Keller et al., 1988). Other pyrimidine derivatives also are reactive to bromine compounds... 

Itahara T, Ide N (1987) Chloroperoxidase catalyzed halogenation of pyrimidine bases. Chem Lett 12 2311-2312... 

Chlorination of 2-methylpyrazine occurs under such mild conditions that it is almost certain that an addition/elimination sequence is involved, rather than a classical aromatic electrophilic substitution. Halogenation of pyrimidines may well also involve such processes. ... 

HOCl Acid-Mediated Halogenation of Pyrimidine and Purine Bases... 

The versatility of pyrimidine substituted chloroquinazolines as intermediates is due to the ready replacement of the halogen atoms by hydrogen, alkyl, alkoxyl, amino, and mercapto groups (see Section VI, A). 

Dehydroxy-halogenation of 89 using POCU led to dihalopyrimidine 92, which was subsequently coupled with phenylacetylene to give 4-chIoro-5-alkynyIpyrimidine 93 [63, 64], Subsequent treatment of 93 with sodium hydrosulfide in refluxing ethanol gave 2,4-dimethyl-6-phenylthieno[2,3-d]pyrimidine (94). 

In a study of the catabolic pathway of pyrimidines, it was found that the reduction of uracil was blocked almost completely by 5-cyanouracil (XXXV) in an in vitro test with the rat enzyme dihydropyrimidine dehydrogenase [303]. 5-Halogenated uracils and thymine are weakly active in this regard, and 5-acetyluracil and 5-trifluoromethyluracil are completely inert. 

Reductive removal of halogen substituents has been of value in the synthesis of pyrimidines and purines since the time of Fisher (1899). Natural purines were de-oxygenated in a sequence of reactions involving the replacement of hydroxyl by chlorine through the reaction with phosphorus pentachloride and the reduction using zinc dust and water [152], 2-Chloropurines 45 are not reduced under these conditions. The 2-iodopurines are however reduced by zinc and water [152]. The elec-... 

The protons of pyrimidines, pyrazines and pyridazines are relatively acidic even without halogen activation, and the three simple heterocycles 240-242 have been lithiated (with varying success) with LiTMP (Scheme 120). ... 

CPB801 75PHA134). In position 6 reactivity of halogens is as low as that in position 5 of pyrimidines even when activated by two adjacent groups they react with only a few reagents (61CPB814). 

Methyl groups in the 2-, 4- or 6-position of pyrimidine are also more reactive. In addition to typical reactions such as condensation with benzaldehyde, selenium dioxide oxidation and halogenation, they can be converted into oximino groups by nitrous acid, and undergo Claisen condensation with (C02Et)2. In the reaction of 2,5-dimethylpyrimidine with benzaldehyde, only the electrophilic 2-methyl group reacts preferentially to yield the 2-styryl derivative (631). In quinazolines partial double bond fixation makes a methyl group in the 4-position more reactive than that in the 2-position. 

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. 

The C-3 atom of 4-oxo-4/f-pyrido[l,2-a]pyrimidines readily takes part in electrophilic substitutions. 4-Oxo-4//-pyrido[ 1,2-a]pyrimidines unsubstituted at position 3 may be transformed by nitrating agents to the 3-nitro derivatives37 42,52 96,1 16,293 and by halogenating agents to the 3-halo derivatives.18,34 108 253,255,294 Nitration of 2-benzyloxy-4-oxo-4H-pyrido-[ 1,2-a] pyrimidine was accompanied by debenzylation.116 Halogenation of the pyrido[l,2-a]pyrimidine (63 R = H) under forced conditions afforded the 2,3-dichloro derivatives.253,255... 

Depending on the molar ratio, halogenation of 4-oxo-6,7,8,9-tetra-hydro-4//-pyrido[l,2-n]pyrimidines gave 9-halo or 9,9-dihalo compounds.75,133,316-319 9-Bromo- or 9-chloro-6-methyl-4-oxo-6,7,8,9-tetra-hydro-4if-pyrido[l,2-a]pyrimidine-3-carboxylic acids were obtained as 4 1 mixtures of the thermodynamically more stable 6,9-diaxial and the 6-axial, 9-equatorial-substituted diastereoisomers.317... 

A similar reaction occurs with 2-pivaloylamino-4-oxopyrrolo[2,3-<7]pyrimidine. In this case the ratio of the 6-mercuri derivative to the 5-mercuri derivative was 10 1 <93H(36)1897>. Subsequent conversion of the mercuri compounds to the corresponding iodo derivatives provides the actual substrates for the palladium-catalyzed coupling reactions. Direct halogenation of the pyrrole ring has also been effected. In the only position available both chlorination (sulfuryl chloride) and bromination (NBS) have been achieved on the C-nucleoside (17 R = benzoylated ribose) (Equation (3)) <90JMC2750>. 

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