Reactions of C-metallated Purines

Preparative lithiation of purines requires the protection of the 7/9-position lithiation 

After selective lithiation at C-8 in a 6-chloropurine riboside, quench with a stannyl or silyl chloride leads to the isolation of the 2-substituted compound, via rearrangement of a 2-anion formed by a second lithiation of the initial 8-substituted product, as illustrated below.  

Stille couplings with 2,6-dichloropurine occur selectively at C-6, however the selectivity is reversed when chlorine is replaced by bromine or iodine at C-2. A similar pattern is seen for 6,8-dichloropurine, the 6-chlorine again being the more reactive. 8-Bromo-diaminopurines, after prior masking by silylation, undergo normal coupling with heteroaryl stannanes.  

Preparative lithiation of purines requires the protection of the 7/9-position lithi-ation then takes place at C-8. Purines lithiated at C-2 or C-6 can be generated by way of halogen exchange with alkyllithiums, but it is important to maintain a very low temperature in order to avoid subsequent equilibration to the more stable 8-lithiated species.  

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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. 

Heteroaromatic purine and pyrimidine nucleobases and their model compounds exhibit a wide variety of potential binding sites for metal ions [6]. The distribution of metal ions between various donor atoms depends on the basicity of the donor atom, steric factors, interligand interactions, and on the nature of the metal. Under appropriate reaction conditions most of the heteroatoms in purine and pyrimidine moieties are capable to coordinate Pt11 [6]. In addition, platinum-binding also to the carbon atoms (e.g., to C(5) in 1,3-dimethyluracil) has been established [8]. 

Most commonly, palladium-catalysed substitutions on pnrines are carried ont on the halo-purine, bnt some metallated pnrines are useful. 2-Stannyl-6-chloropurines can be prepared via direct (C-H) lithiation, without protection of C-8 (27.7.1). 6-Pnrinyl zinc componnds can be prepared by reaction of the iodide with activated zinc metal." ... 

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. 

Direct condensation of 2,3,5-tri-0-benzoyI-/3-D-ribofuranosyl bromide with adenine in acetonitrile at 50 °C leads after deblocking to the 3-/3-D-ribofuranosyladenine (132) (B-68MI40901). Metal derivatives of purines tend to produce 7- or 9-glycosyl derivatives thus the silver salt of 2,8-dichloroadenine with 2,3,5-tri-O-acetylribofuranosyl chloride produces the 9-/3-D-ribofuranosyl derivative (133) (48JCS967, 48JCS1685). However similar reactions with theobromine produce O-glycosides and with theophylline N-7 derivatives (34JCS1639). 

A halogen - metal exchange reaction between butyllithium and an appropriately A-protected halopurine has been applied for C-C bond formation of intact purines. Operation at low temperature is required in order to avoid diversionary attacks on the heterocyclic ring, e.g. formation of 17. ... 

Syntheses of purines bearing carbon substituents in positions 2, 6, or 8 by metal-or organometal-mediated C-C bond-forming reactions 03EJO245. 

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