The Suzuki-Miyaura Cross-Coupling Reactions of 6-Halopurines with Boronic Acids Leading to 6-Aryl- and 6-Alkenylpurines

Abstract

The Suzuki-Myiaura cross-coupling reactions of 9-benzyl-6-chloropurine with boronic acids gave 6-alkylated purines in moderate to excellent yields. The best results with electron rich arylboronic acids were obtained in toluene in the presence of anhydrous K 2 CO 3 as a base, while electron poor boronic acids and alkenyl boronic acids gave better results using aqueous K 2 CO 3 in DME. The reaction was successfully applied for the synthesis of 6-phenylpurine bases and nucleosides.Purine bases modified in the 6-position and their nucleoside and nucleotide derivatives and analogues possess a broad spectrum of biological activity. The cytotoxicity of 6-methylpurine and its nucleosides is well known, 1 while a promising cytostatic activity of 6-(aminoalkyl)purine derivatives (as cytokinines analogues) has been recently discovered. 2 Many 6-alkylaminopurine nucleosides are important adenosine receptors antagonists 3 and acyclic nucleotide analogues derived from 6-(di)alkylaminopurines are strong antivirals, antineoplastic agents and immunomodulators. 4 Recently, several 6-(arylalkynyl)-, 6-(arylalkenyl)-and 6-(arylalkyl)purines were reported 5 to exhibit cytokinine activity.In the last decade, with the development of the cross-coupling methodology, many 6-C-substituted purines have been prepared. 6 Thus 6-halopurine derivatives react with alkyl(aryl)zinc or tin reagents, 6a-e trialkylaluminum 6f or alkylcuprates 6g-i to give the 6-alkylpurine derivatives. Also another approach based on the reaction of purine-6-zinc iodide with aryl or vinyl halides has recently been described. 7 For the synthesis of 6-arylpurines, an alternative based on radical photochemical reactions of adenine derivatives with aromatic compounds was used, 8 but this method is very unselective and for substituted benzenes, mixtures of all ortho-, meta-and para-substituted derivatives were obtained. To the best of our knowledge, no successful Suzuki-Myiaura type of cross-coupling 9 of 6-halopurines with alkyl-or arylboronic acid has been described. The advantage of this reaction compared to the above mentioned methods would be the high stability of boronic acids, the low toxicity of boron compounds, easy work-up and isolation of the product along with availability of starting boronic acids (a number of boronic acids, especially the aromatic ones, is commercially available).In this communication we wish to report our results in this field.To test the Suzuki-Myiaura coupling reaction of purine derivatives we chose 6-halo-9-benzylpurines as model compounds. Thus Pd(PPh 3 ) 4 catalysed reaction of 9-benzyl-6-chloropurine (1) with phenylboronic acid in the presence of K 2 CO 3 in toluene at 100°C afforded after 24 h 9-benzyl-6-phenylpurine (2a) in excellent yield (95%) (Scheme 1). Scheme 19-Benzyl-6-iodopurine reacted faster giving similarly high yield (92%) of 2a, however, the reaction mixture was not as clean as in the case of 1. Also 9-benzyl-7-chloropurine (3) reacted smoothly with phenylboronic acid giving 70% isolated yield of 7-benzyl-6-phenylpurin...

Rapid Evolution of 6-Phenylpurine Inhibitors of Protein Kinase B through Structure-Based Design

“…A limited range of simple benzylamine and phenethylamine substituents were added to the purine core, aiming to access acidic residues in the ribose binding pocket. Suzuki couplings to the protected 6-chloropurine 3 17 attached either benzaldehyde (4,5) or (cyanomethyl)phenyl (8,9) groups, which were elaborated by reductive amination and reduction, respectively (Scheme 1). The increase in PKB enzyme inhibition seen for compounds such as 6 (pdb code 2UVY), 7, and 11 (Table 1) indicated that additional binding interactions were present, which was confirmed by crystallography with the chimera (Figure 1b).…”

Suzuki–Miyaura Cross‐Coupling Reactions of Alkylboronic Acid Derivatives or Alkyltrifluoroborates with Aryl, Alkenyl or Alkyl Halides and Triflates

“…[11] A similar reaction using n-butylboronic acid was described by Hocek and co-workers and by Echavarren and coworkers. [12][13][14] However, the coupling products were obtained in low yields. In order to enhance the yields of these reactions, Falck and co-workers examined other reaction conditions.…”

The Suzuki Reaction with Arylboron Compounds in Arene Chemistry

“…Suzuki crosscoupling reactions of 9-benzyl-6-chloropurine with boronic acids have recently been reported to provide 6-substituted purines in moderate to excellent yields (Eq. (46)) [77]. …”