2- Aminopyrimidine, bromination

Pyrimidinyl halides are not only precursors for Pd-catalyzed reactions, but also important pharmaceuticals in their own right. One of the most frequently employed approaches for halopyrimidine synthesis is direct halogenation. When pyrimidinium hydrochloride and 2-aminopyrimidine were treated with bromine, 5-bromopyrimidine and 2-amino-5-bromopyrimidine were obtained, respectively, via an addition-elimination process instead of an aromatic electrophilic substitution [4, 5], Analogously, 2-chloro-5-bromopyrimidine (1) was generated from direct halogenation of 2-hydroxypyrimidine [6], Treating 1 with HI then gave to 2-iodo-5-bromopyrimidine (2). In the preparation of 5-bromo-4,6-dimethoxypyrimidine (4), N-bromosuccinimide was found to be superior to bromine for the bromination of 4,6-dimethoxypyrimidine (3) [7]. 

In order to overcome the difficulties associated with the covalent hydrates, anhydrous reagent systems have been investigated, including ionic liquids <2004S2809> and NBS in tetrabutylammonium bromide <200581103>. For example, the bromination of 2-aminopyrimidine 61 with the ionic liquid l-butyl-3-methylimidazolium tribromide [(bmim)Br3] gave 2-amino-5-bromopyrimidine 62 in 96% yield after 5 min at — 10°C <2004S2809>. 

A compound that includes an aminopyrimidine ring as well as the quaternary salt present in thiamine shows preferential inhibition of absorption of that co-factor by coccidia parasites over uptake by vertebrates. The compound is thus used in poultry where coccidiosis is an economically important disease. Condensation of ethoxymethylenemalononitrile (42-1) with the amidine (42-2) leads to the aminopyrimidine (42-4), probably via the intermediate addition-elimination intermediate (42-3). The nitrile group is then reduced to the methylamino derivative (42-5) by means of hthium aluminum hydride. Exhaustive methylation, for example by reaction with formaldehyde and formic acid, followed by methyl iodide leads to the quaternary methiodide (42-6). The quaternary salt is then displaced by bromine, and the resulting benzyhc-like cylic halide (42-7) is displaced by 2-picoline (42-8). There is thus obtained amprolium (42-9) [43]. 

Aminopyrazines, like aminopyridines and aminopyrimidines, form p-aminobenzenesulfonyl derivatives, and one of these, 2-sulfanilamido-3-methoxypyrazine (11), is clinically used as an antibacterial agent.320 Bromination of compound 11 in methanol gives a product (114)321,322 which was originally incorrectly formulated as a hydrate.323 The correct structure follows from spectroscopic evidence and alkaline... 

Similar reactions have been carried out with amidines (67NEP6610627). Thus tri-chloroacetamidine (309) reacts with chlorothioformate esters to produce thioacyl products (310) which are readily oxidized to 5-alkoxy-3-trichloromethyl-l,2,4-thiadiazoles (311). The yields in both steps are about 80% (Scheme 111). The bromine oxidation of N-thiocarbamyl derivatives (312) of cyclic amidines (2-aminopyridine, 2-aminothiazole, 2-aminopyrimidine) yields thiadiazolium salts (313) (71JPR1148). In the 2-aminopyridine series, products of type (230 Scheme 81) are obtained in 20-73% yield when R is an ethoxycar-bonyl group (750PP55). 

Much more is known about substitutions on pyrimidines bearing the common electron-releasing groups, for just as with pyridine these substituents greatly activate the ring. Thus, 2-aminopyrimidine can be brominated in water at 80°C and can react with diazonium ions in cold media (Scheme 9.59). This order of reactivity can be likened to that of a phenol. Because amino and hydroxyl derivatives are easily prepared directly by ring synthesis and indeed are found in natural products, much more work has been done with these derivatives than with pyrimidine itself. 

Meridianins A-G are brominated indole derivatives containing a 2-aminopyrimidine. They were found in Aplidium meridianum harvested by dredging at 100 m in South Georgia. These derivatives are only moderately cytotoxic but some of them are good inhibitors of protein kinases CDKl and CDK5, the most active being... 

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