9-Aryl-6- purines

Intermediate arylguanidinopyrimidines (285) produced from diphenylcarbodiimide and 5-alkyl(or aryl)amino-4-aminopyrimidines furnished 8-anilino-7-alkyl(or aryl)purines (286) in hot DMF (Scheme 101). 

Conversion into 2-alkyl- or -aryl-purines requires the insertion of one carbon to create the six-membered ring, and this is usually effected by condensation with esters in the presence of base," although amides" are occasionally utilised. The use of an isothiocyanate leads to a 2-thiopurine. ... 

Purines are important building blocks and scaffolds of biologically active compounds. The copper-promoted N-arylation methodology is applicable to the synthesis of novel N-9-arylated purines. Gray, Schultz and co-workers were the first to report this application (Scheme 5.18) [36]. Reaction of 2,6-dichloropurine with boronic acids in the presence of Cu(OAc)2 and triethylamine resulted in the desired N-9-arylated product as the major regioisomer (>9 1), with the N-7 regioisomer produced in much lower yield. 

Direct C-Harylation of purines in position 8 by diverse aryl iodides has been achieved with Pd catalysis in the presence of Cul and CS2CO3. The methodology is general and efficient and was applied in the consecutive regioselective synthesis of 2,6,8-trisubstituted purines bearing three different C-substituents in combination with two cross-coupling reactions... 

The N-adducts derived by reaction of 1,5-diaminoimidazoles (96 R = NHPh, R2 = aryl, /Pr) with the /V-acylimidates (140) and (141) were cyclized smoothly in hot xylene solution to give the corresponding purines (168) and (169) in good yield (85MI1). 

Acid and base extractions from this material have been shown to form spontaneous structures in solution termed coercevates that could easily form the basis for protypical membranes (more of this in Chapter 9). Hydrocarbons with chain lengths C15-C30 (both straight and branched chains) and of course PAHs, predominantly pyrene and fluoranthrene, polar hydrocarbons such as aromatic ketones, alkyl and aryl ketones, nitrogen and sulphur heterocycles and most intriguingly purine and pyrimidine analogues have all been observed from this rich carbonaceous cocktail of compounds. Why ... 

That electrophilic aryl nitrenium ions form C-8-purine adducts is inconsistent with the reactivity of other electrophiles that prefer to react at the heteroatoms of DNA. The close proximity of the endocyclic N-7 atom, which is the most nucleophilic site within the heterocyclic bases of DNA, led to the proposal for initial attachment of aryl nitrenium ions to the nucleophilic N-7 atom of As outlined in Scheme 2a,... 

As noted for heteroatom attachment in 8-oxo-dG and C8-arylamine adducts, attachment of the Ph moiety to the C-8 site of dG enhances the one-electron donor characteristics of the purine nucleoside. The redox properties of 8-/>-X-Ph-dG (X = OH, OCH3, CH3, H, CN, CHO) adducts have been studied by cyclic voltammetry in anhydrous DMF. The C8-aryl adducts exhibited irreversible one-electron oxidation peaks with half-peak potentials ( p/2) ranging from 0.85 V versus saturated calomel electrode (SCE) for 8-/>-PhOH-dG (X = OH) up to 1.11 V/SCE for 8- -CHO-Ph-dG. All adducts were oxidized more readily than dG, which gave p/2= 1.14 V/SCE in DMF (Table 2). 

In general, reactive carbon electrophiles have been shown to react preferentially at the nitrogen atoms of the purine bicycle (see Section 10.11.5.2.1). However, 9-(2,3,5-tris-0-/r /T-butyldimethylsilyl)-a-D-ribofuranosyl-6-chloro-2-(tri-butylstannyOpurine reacted with benzoyl chloride to substitute the 2-tributylstannyl group (PhCOCl, pyridine, toluene, 60% yield) <1997JOC6833>. Indirect C-alkylations have been achieved through deprotonation and alkylation see Section 10.11.5.3.4. The major routes to (7-alkyl and (7-aryl substitution are through nucleophilic displacement or transition metal-catalyzed reactions of halopurines see Sections 10.11.7.4.1 and 10.11.7.4.2. 

As an alternative to addition of anionic nucleophiles followed by reoxidation, rhodium(l)-catalyzed C-H activation allowed the nucleophilic addition of alkenes to the intermediate Rh(i) carbene complex <2002JA13964, 2004JOC7329>. Purine behaved anomalously compared to other heterocycles, for which selective monoalkylation was observed, and underwent sequential substitution first at C-8 and then at C-6 (Equation 8). Caffeine was monoalkylated at C-8 in low yield (15%). Selectivity for C-8-arylation was also observed in the palladium-catalyzed C-H activation of 6-phenyl-9-benzylpurine (aryl iodides, 0.05 equiv Pd(OAc)2, 3 equiv Cul, 2.5 equiv CS2CO3, DMF, 160 °C, 60 h, 48-95% yields) <2006OL5389>. 

Trifluoromethylation is the most important perfluoroalkylation reaction. Kobayashi and co-workers reported the trifluoromethylation of aryl, vinyl, alkyl halides with trifluoromethyl iodide in the presence of copper powder in aprotic solvents such as HMPA at 120-150 °C [83,84], and this methodology has been applied to the preparation of fluorinated pyrimidine and purine nucleosides [85,86] (Scheme 27). 

N-Arylations of amines have also been realized with support-bound heteroaromatic halides (Entries 9-11, Table 10.4). Several examples of the synthesis of substituted 1,3,5-triazines [83-85], purines [78,85-93], and pyrimidines [77,85,94—96] have been reported. The reactivity of these arylating agents depends strongly on their precise substitution pattern, and generally increases with decreasing electron density of the het-eroarene. Illustrative examples are given in Table 10.4. The arylation of amines with simultaneous cleavage of the product from the support is discussed in Section 3.8. 

Purine, 8-amino-6-thioxo-1,6-dihydro-synthesis, 5, 579 Purine, 8-anilino-7-aryl-synthesis, 5, 579 Purine, 2-aryl-... 

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