Alkylpurines

Comparatively little information is available concerning any special reactivity associated with purine alkyl groups, but what is available suggests that their reactivity is comparable to pyridine a-alkyl substituents. 

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With a few notable exceptions—such as puromycin and its relatives, psicofuranine and decoynine, and certain 9-alkylpurines-which will be discussed later, purines and their nucleosides must be anabolized to nucleoside phosphates in order to exert their biological effects. This type of metabolic event has been called a lethal synthesis , because it results in the death of cells that carry it out. 

Peculiarly little attention was aimed at the investiga tion of other 6-alkylpurine derivatives. Recently, cyto kinin activity was reported in some 6-(arylalkynyl), 6-(arylalkenyl)-, and 6-(atylalkyl)purines.21 We have recently described the cytostatic activity of 6-(trifluo-romethyl)purine riboside.22 The corticotropin-releasing hormone antagonist activity of some 2,8,9-trisubsti-tuted-6-arylpurines has been also reported.23... 

With the development of the cross coupling methodology, many 6-C-substituted purines have been prepared in the past decade. Thus, 6 halopurine derivatives react with arylmagnesium halides,25 alkyl(aryl)zinc or tin reagents,26 trialkylaluminum,27 or alkylcuprates28 to give the 6-alkylpurine derivatives. Also a reverse approach based on the reaction of purine-6-zinc iodide with aryl or vinyl halides has recently been described.29 For the synthesis of 6-arylpurines, an alternative approach makes use of radical photochemical reactions of adenine derivatives with aromatic compounds,30 but this method is very unselective and for substituted benzenes, mixtures of ortho-, meta-, and para substituted derivatives were obtained. 

Reagents A Convenient Route to sec- and tert- 6-Alkylpurines. Tetrahedron Lett. 1996, 37, 1285-1288. (c) Dvorakova, H. Dvorak, D. Holy, A. Synthesis of Acyclic Nucleotide Analogues Derived from 6-(sec- or tert-Alkyl) purines via Coupling of 6-Chloropurine Derivatives with Organocuprates. Collect. Czech. Chem. Commun. 1998, 63, 2065-2074. (d) Hocek, M. Holy, A. Perfluoroalkylation of 6-Iodopurines by Trimethyl(perfluoro-alkyl)silanes. Synthesis of 6-(Perfluoroalkyl)purine Bases, Nucleosides and Acyclic Nucleotide Analogues. Collect. Czech. Chem. Commun. 1999, 64, 229-241. 

Sugimura, H. Takei, H. Synthesis of 6-Alkylpurine Derivatives by Nickel Complex Catalyzed Coupling Reaction of 6-(Meth-ylthio)purine derivatives with Grignard Reagents. Bull. Chem. Soc. Jpn. 1985, 58, 664-666. 

The isomeric 3-alkylpurines, in contrast to the parent compounds, are highly reactive at the 2- and 6-carbon atoms. The susceptibility of the 2-carbon to nucleophilic attack is shown by the facility with which 6-oxo-3-methyl-2-methylmercaptopurine (28) is converted by ammonia into the 2-amino (29) and then with alkali into the 2-oxo (30) derivative.75 This reaction sequence explains why the action of aqueous ammonia on the 2-methylmercaptopurine (28) resulted in the isolation of 3-methylxanthine (30) rather than the required... 

Free radical alkylation procedures have proved a useful route to alkylpurines which are not readily available by other methods. Thus 6-substituted purines including adenine and hypoxanthine may be converted into 8-methyl derivatives with t-butyl hydroperoxide in the presence of iron(II) ions and acid (74T2677), although small amounts of 2-methyl and 2,8-dimethyl derivatives were formed simultaneously. Adenosine and guanosine similarly furnished the corresponding 8-methyl derivatives with diacetyl peroxide (as a source of methyl radicals) and iron(II) ions (76T337). 

Free radical reactions of purines with amines gave similar products to those produced in alcohol solution although deamination may also occur, probably at the post- rather than the pre-adduct stage. Whereas purine and n-propylamine afforded 6-n-propylpurine (71MI40907), adenine and caffeine produced both the 8-aminoalkyl and corresponding 9-alkyl derivatives (74MI40904). Also irradiation of 8-aminoalkylpurines in methanol furnished the 8-alkyl derivatives. Amino acids as an amine source are of special biochemical interest. They also tend to produce 8-alkylpurines by concomitant deamination and decarboxylation (69CC905). 

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. 

Alkylation of thiopurines may produce both S- and iV-alkyl derivatives in contrast to oxopurines where O-alkylation is rare (Section 4.09.5.2.2). The 5-alkyl derivatives are favoured by carrying out the reaction below 40 °C in aqueous or aqueous alcoholic solutions with equimolar equivalents of sodium hydroxide and either an alkyl halide or sulfate. At higher temperatures the A/ -alkylpurine tends to be produced normally by S-N rearrangement of the first formed S-alkyl derivative (65MI40906). 

Ortho esters have also been used to prepare 8-alkylpurines, especially triethyl orthoacetate or orthopropionate (60JOC395), but frequently, as with 4,5-diamino-6-chloropyrimidine, only the intermediate alkoxyalkylene pyrimidine derivatives are obtained. These require further treatment to produce the 8-alkyl-6-chloropurine (Scheme 81). 

C-Alkylpurines are usually best obtained by Traube syntheses as in the preparation of 6-methylpurine (65JCS623) and 8-methylpurine <54JCS2060), or by dehydrohalogenation of a halogenoalkylpurine as in the preparation of 2-methylpurine from 2-methyl-6-chloropurine (59JA193). 

Higher acids or anhydrides give on heating the (acylamino)pyr midines, which may be cyclized to 8-alkylpurines. Thus, 8-butyladenine (2) is formed upon reaction with pentanoic anhydride via cyclization of the intermediate 5-(pentanoylamino)pyrimidine-4,6-diamine. ... 

Several C-alkylpurines have been prepared by the Traube protocol. However, metalation and cross-coupling reactions are now also used for the synthesis of C-alkylpurines. 8-Alkyl- and 8-arylpurines are, generally, prepared by the same methods used for unsubstituted derivatives. Acetic or benzoic acid derivatives, such as triethyl orthoacetate, are used as condensation reagents and cyclization normally requires prolonged heating of the reaction mixture. Fusion of the components is also employed. 

The preparation of N-alkylpurines and derivatives encounters problems. When electrophilic alkylation reactions are employed, e.g. methylation, regioisomers are formed. However, in several cases, the Traube synthesis offers a regiospecific or a regioselective route for the synthesis of N-alkylpurines and of related natural products, such as nucleosides. 

The synthesis of several other Af-alkylpurines is summarized in Table 25. 

Methylation is an important biochemical event and all the common purines as well as their nucleosides occur naturally in either mono- or polymethylated forms. The common naturally occurring Af-alkylpurines are summarized in Table 43. 

The fluorine atom at C6 is more readily displaced than the chlorine atom in 9-alkylpurines. Thus, 6-fluoro-9-methylpurine reacts slowly in aqueous solution over a period of one week to give 9-methylhypoxanthine (3). ... 

Several dihydrothiazolopurines have been prepared by cyclization of thioxopurines. Such compounds, by dethiation, offer a useful route to alkylpurines. In this way 1-, 3-, 7-, and 9-ethyl-purines are produced from the thiazolopurines followed by reduction with Raney nickel/hydro-gen. 

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