Purine nucleophilic substitution

One of the most important reactions of purines is the bromination of guanine or adenine at the C-8 position. It is this site that is the most common point of modification for bioconjugate techniques using purine bases (Figure 1.53). Either an aqueous solution of bromine or the compound N-bromosuccinimide can be used for this reaction. The brominated derivatives then can be used to couple amine-containing compounds to the pyrimidine ring structure by nucleophilic substitution (Chapter 27, Section 2.1). 

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. 

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. 

Thiazolo[5,4-d]pyrimidine, 2,5,7-trichloro-nucleophilic substitution, 6, 686 Thiazolo[3,2-a]pyrimidine-5,7-diones IR spectra, 6, 672 Thiazolopyrimidines synthesis, 5, 572, 574, 578 Thiazolopyrimidines, amino-purine synthesis from, 5, 591 Thiazolo[3,2-a]pyrimidines synthesis... 

Various examples of 2-fold sequential nucleophilic substitutions on insoluble supports have been reported in the literature. Suitable polyelectro-philes are polyhalo triazines, pyrimidines, and purines, and the most common nucleophiles are amines, thiols, and phenols. The use of 2,3-dichloropropionic acid18 and 4,5-difluoro-2-nitrobenzoic acid19 is discussed below to illustrate the scope and limitations of this strategy for the preparation of lead-like compound arrays. 

Synthesis of 2 -Deoxy-2 -a-fluoro Purine Nucleosides via Nucleophilic Substitutions at the Carbon-2 Position... 

The purine base also disturbs nucleophilic substitution at the sugar moiety, but the degree of this disruption is controllable. The nucleophilicity of the N-3 atom was reduced by the... 

A device that is also used in pyridine and purine chemistry is the initial replacement of halogen with a tertiary amine the resulting salt, now having a better leaving group, undergoes nucleophilic substitution... 

Nitration of 6-substituted purines at C-2, using a mixture of tetra-n-butylammonium nitrate and trifluo-roacetic anhydride, is an exceptionally useful functionalisation of the purine ring system. The reaction works for both electron-rich (adenosine), 6-alkoxypurines and electron-poor (6-chloropurine) substrates, but full protection of all OH and NH groups is required. This is not a simple electrophihc substitution - the mechanism has been shown, using 6-chloro-9-Boc purine, to involve sequential nitration of N-7, addition of trifluoroacetoxy at C-8 and then migration of the nitro group to C-2. The final, re-aromatisation, step involves elimination of trifluoroacetic acid. Displacement of a 2-nitro group, thus introduced, by fluoride as nucleophile (see 27.5 for nucleophilic substitutions) can be made the means to synthesise 2-fluoroadenosine. ... 

Nucleophilic substitution (S Ar) can be carried out on purine itself as well as on halo-, alkoxy- and alkylsulfanylpurines. The Chichibabin reaction (see p 278) of purine with KNH2 in liquid ammonia leads to 6-aminopurine (adenine) 3 ... 

Microwave-assisted solid-phase synthesis of purines on an acid-sensitive meth-oxybenzaldehyde (AMEBA)-linked polystyrene has been reported [50]. The heterocyclic scaffold was first attached to the polymer support via an aromatic nucleophilic substitution reaction by conventional heating in l-methyl-2-pyrrolidinone (NMP) in the presence of N,N-diisopropylethylamine. The key aromatic nucleophilic substitution of the iodine with primary and secondary amines was conducted by microwave heating for 30 min at 200 °C in l-methyl-2-pyrrolidone (Scheme 16.28). After reaction the products were cleaved from the solid support by use of trifluoroacetic acid-water at 60 °C. 

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