Halogenated Pyrimidines and Purines

Halogenated pyrimidines. There is a considerable interest in the reactions of 5-halourucils, notably 5BrUra. The latter can substitute Thy in DNA without 

Upon photolysis, there are two reactive species formed side by side, the vinylic uracilyl radical and Br The latter has oxidizing properties (E7 = 1.66 V Ward-man 1989), and in DNA it can oxidize neighboring G and A moieties (Wojcik et al. 2003). The quantum yield of photodecomposition of 5BrUra is only 1.8 x 10 3, but increases dramatically upon deprotonation (Campbell et al. 1974). In the presence of MeOH as an H-donor, it also increases substantially above 2 mol/1 MeOH. It has been speculated that above this concentration cage reactions come into play. Reported rate constants for the reaction of Br- with MeOH are 5 x 104 dm3 mol-1 s 1 in water and 1 x 106 dm3 mol-1 s 1 in acetonitrile (Neta et al. 1988). 

5CIUra 1.4 x 10s 9 x 104 Rivera and Schuler (1983) Wagner and Schulte-Frohlinde (1975) 

It is discussed above that the nucleobase radical anions can be proton-ated at a heteroatom and/or carbon. Only the heteroatom-protonated species retains reducing properties, and thus the rate of protonation at carbon determines whether or not an ET to 5BrUra is observed under the given condition. Protonation at carbon is especially fast in the case of Guo, and for this reason an ET to 5BrUra was not observed (Nese et al. 1992). A compilation of the rate constants for such ET reactions is found in Table 10.26. As can be seen from this table, the radical anions transfer an electron to 5BrUra at practically diffusion-controlled rates, while the heteroatom-protonated species react two orders of magnitude more slowly. 

The Ura-5-yl radical is a vinyl-type radical. It readily adds to, e.g., its parent, 5BrUra (k = 2.7 x 108 dm3 mol-1 s 1 Rivera and Schuler 1983), but vinyl radicals are also good H-abstractors [cf. reaction (234)] and typically react with, e.g., 2-PrOH in the rage of 2 x 10s to 2.4 x 107 dm3 mol-1 s 1, depending on the substituent (Mertens 1994 Mertens and von Sonntag 1994a). 

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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-... 

Scharn, D., Germeroth, L., Schneider-Mergener J. and Wenschuh, H., Sequential nucleophilic substitution on halogenated triazines, pyrimidines, and purines a novel approach to cyclic peptidomimetics, /. Org. Chem., 2001,66, 507-513. 

Many other pyrimidine and purine nucleosides having halogenated ribose moieties have also been prepared. Halogen has been substituted on every available position of the ribose ring. This substitution has been combined with other structural variations in the sugar as well as in the base portion of the molecule. 

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

Halopurines are valuable intermediates for conversion to other purines. The halogen substituents show selectivity for positions 2, 6 and 8. The chloropurines are usually obtained by displacement reactions on hydroxy- or sulfanylpurines (see Sections 7.1.1.3.4.5.2. and 7.1.1.3.4.5.3.). However, they are also accessible by Traube synthesis care must be taken that the reactive halogen substituents are not displaced during the condensation reaction. 2-Chloro-purine (la), 6-chloropurine (lb), and 2,6-dichloropurine (Ic) are obtained from appropriately halogenated pyrimidine-4,5-diamines and ethyl orthoformate. ... 

TABLE 12.4 Experimental and Theoretical Electron Affinities (in eV) of Purines and Pyrimidines and Halogenated Uracils... 

Nucleophilic substitution with heteroaryl halides is a particularly useful and important reaction. Due to higher reactivity of heteroaryl halides (e.g. 35, equation 24) in nucleophilic substitution these reactions are widely employed for synthesis of Al-heteroaryl hydroxylamines such as 36. Nucleophilic substitution of halogen or sulfonate functions has been performed at positions 2 and 4 of pyridine , quinoline, pyrimidine , pyridazine, pyrazine, purine and 1,3,5-triazine systems. In highly activated positions nucleophilic substitutions of other than halogen functional groups such as amino or methoxy are also common. 

There are only a few recorded reactions of N-alkylpurines which result in preservation of the purine ring system, since ring opening generally occurs and pyrimidines or imidazoles are produced. Halogenation may, however, lead to iV-chloromethyl derivatives as with 2,7-dimethylpurine which can be chlorinated to form 7-chloromethyl-2-methylpurine. Details of reaction products derived from some alkylpurines are collected in Table 25. 

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