N-Alkylation purines

Purines, N-alkyl-N-phenyl-synthesis, 5, 576 Purines, alkylthio-hydrolysis, 5, 560 Mannich reaction, 5, 536 Michael addition reactions, 5, 536 Purines, S-alkylthio-hydrolysis, 5, 560 Purines, amino-alkylation, 5, 530, 551 IR spectra, 5, 518 reactions, 5, 551-553 with diazonium ions, 5, 538 reduction, 5, 541 UV spectra, 5, 517 Purines, N-amino-synthesis, 5, 595 Purines, aminohydroxy-hydrogenation, 5, 555 reactions, 5, 555 Purines, aminooxo-reactions, 5, 557 thiation, 5, 557 Purines, bromo-synthesis, 5, 557 Purines, chloro-synthesis, 5, 573 Purines, cyano-reactions, 5, 550 Purines, dialkoxy-rearrangement, 5, 558 Purines, diazoreactions, 5, 96 Purines, dioxo-alkylation, 5, 532 Purines, N-glycosyl-, 5, 536 Purines, halo-N-alkylation, 5, 529 hydrogenolysis, 5, 562 reactions, 5, 561-562, 564 with alkoxides, 5, 563 synthesis, 5, 556 Purines, hydrazino-reactions, 5, 553 Purines, hydroxyamino-reactions, 5, 556 Purines, 8-lithiotrimethylsilyl-nucleosides alkylation, 5, 537 Purines, N-methyl-magnetic circular dichroism, 5, 523 Purines, methylthio-bromination, 5, 559 Purines, nitro-reactions, 5, 550, 551 Purines, oxo-alkylation, 5, 532 amination, 5, 557 dipole moments, 5, 522 H NMR, 5, 512 pJfa, 5, 524 reactions, 5, 556-557 with diazonium ions, 5, 538 reduction, 5, 541 thiation, 5, 557 Purines, oxohydro-IR spectra, 5, 518 Purines, selenoxo-synthesis, 5, 597 Purines, thio-acylation, 5, 559 alkylation, 5, 559 Purines, thioxo-acetylation, 5, 559... 

There has been considerable interest recently in the quatemization of purine compounds, although most of those examined have contained hydroxyl or amino substituents and therefore products may be regarded as the acid salts of N-alkylated derivatives. 

Predictably, 1,2,4-triazole is alkylated preferentially at the 1-position [36, 38,39]. Specific alkylation at the 4-position can be achieved by the initial reaction with dibromomethane to form the bis-triazol-l-ylmethane (see below), followed by quat-emization of the triazole system at the 4-position and subsequent C-N cleavage of the 1,1 -methylenebistriazolium salts [40]. 1,2,3-Benztriazole yields a mixture of the isomeric 1- and 2-alkylated derivatives [41]. The 1-isomer predominates, but the ratio depends on whether the reactions are conducted in the presence, or absence, of a nonpolar organic solvent (Table 5.33). Higher ratios of the 1-isomer are obtained under solidrliquid two-phase conditions. Thus, alkylation of 1,2,3-benztriazole with benzyl chloride produces an overall yield of 95% with the l- 2-isomer ratio of ca. 5.7 1 similar reactions with diphenylmethyl and triphenylmethyl chlorides gives overall yields of 95% (9 1 ratio) and 70% (100% 1-isomer), respectively [38], 6-Substituted purines are alkylated at the N9-atom and reaction with 1-bromo-3-chloropropane yields exclusively the 9-chloropropyl derivative (cf. reaction wi phenols) [42]. 

Substitution of halopurines at C-2 and C-6 has become a well-developed synthetic process, with a wide variety of nucleophilic aromatic substitution and palladium-catalyzed C-N or C-O hond formations exemplified in the literature. The use of selective, sequential substitution reactions on polyhalopurine scaffolds is the basis of an increasing number of combinatorial syntheses of polysubstituted purines, both in solution and on solid phase. The introduction of N-, 0-, or S-substituents has often been combined with transition metal-catalyzed C-C bond-forming reactions (see Section 10.11.7.4.2) and selective N-alkylation (see Section 10.11.5.2.1) to provide versatile routes to purines with multiple, diverse substituents. 

A more pronounced effect on the 77-electron structure is produced by N-alkylation than by C-substitution, replacing the ring nitrogen proton by alkyl groups restricts the number of anionic forms and of tautomeric structures. The alkylated purines can be stabilized toward base attack by anion formation, but if no proton is available then fission of one of the rings is likely. 

N-Alkylated purines, especially compounds such as quaternized caffeine with a positive charge in the imidazole ring, are readily reduced by sodium borohydride to produce dihydro derivatives, reduction occurring in the charged imidazole ring (76TL1199, 76joc2303). 

The synthesis of IV-ribofuranosyltriazoles, for use as metabolite analogs of the purine-forming imidazoles, provides a different aspect of N-alkylation in the triazole series. Acid-catalyzed fusion of 4-nitrotriazole with tetra-O-acetyl-/3-D-ribofuranose gave 2-/5-D-ribofuranosyl-4-nitrotriazole (175°C, 45 min, 58%), accompanied by 24% yield of the 1-ribofuranosyl isomer. The acetyl groups were removed with cold methanolic sodium methoxide (85% yield), and the nitro group reduced to a primary amine with hydrazine hydrate over palladium in methanol (25°C, 93%) (72JHC1195). 

Bredereck used formamidine acetate for the synthesis of purines from N-alkyl and N-acyl derivatives of arainoacetonitrile. 

The introduction of A -glycosyl residues into IPs is a special type of N-alkylation providing new powerful medicines of these purine derivatives. The synthesis of 1-and 3-deazapurine nucleosides was reviewed in (81KG147). 

The tautomeric character of the imidazole system is involved in the synthesis of the related dmg dimetridazole (9.52, 1,2-dimethyl-5-nitroimidazole), which is an effective agent against trichomonal infections in veterinary medicine (Scheme 9.28). The synthesis involves the nitration of 2-methylimidazole to form 2-methyl-5-nitroimidazole (9.50), followed by N-methylation. However, compound 9.50 is involved in tautomeric equilibrium with compound 9.51 (2-methyl-4-nitroimidazole), which would give an isomer (9.53) on methylation. This can be avoided by the proper choice of solvent. Using a nonpolar solvent for methylation with dimethyl sulfate, the desired 9.52 is the predominant product. Tautomerism is a complicating factor in imidazole chemistry where an NH unit is present, and N-alkyl derivatives are more commonly encountered. We will see this factor again with the purines. 

DNA contains two purine bases, guanine and adenine, and two pyrimidine bases, cytosine and thymine. In RNA, thymine is replaced by uracil and in another form, t-RNA, other bases including small amounts of N-alkylated derivatives are present. 

Structural characterization, recognition patterns, and theoretical calculations of long-chain N-alkyl substituted purine and pyrimidine bases as ligands On the importance of anion—tt interactions 13CCR2705. Structure, functionalization, and apphcations of giant hollow spher-... 

N -Dialky1- and N -alkyl, N -aryl-9H-purin-6-amines were... 

Purine analogs and imidazoles can be Af-allylated (Scheme 2). CarbocycUc analogs of nucleosides can be synthesized by the regio- and stereoselective N-alkylation of allylic substrates such as cyclopentenyl acetate or cyclopentadiene monoepoxide with purine... 

---