Direct Synthesis of 6-Arylpurines by Reaction of 6-Chloropurines with Activated Aromatics

Abstract

Highly functionalized C6-aryl-substituted purine analogues were synthesized through direct arylation of 6-chloropurine with aromatics promoted by anhydrous AlCl(3) in a single step. The reactions, which were conducted using a 3-fold excess of AlCl(3) in refluxing 1,2-dichloroethane, gave moderate to excellent product yields in 0.5 h. This work is complementary to the classical coupling reactions for the synthesis of C6-aryl-substituted purine analogues.

Nucleophilic Arylation of Halopurines Facilitated by Brønsted Acid in Fluoroalcohol

“…We subjected 9 H -chloropurine 1d and aniline 4 to our optimized conditions at 60 °C, obtaining selective N -arylation that smoothly provided N -(4-methoxyphenyl)-9 H -purine-6-amine 5 in 79% yield, without the formation of the C-arylated purine coupling product 5′ . On the other hand, Guo’s group previously reported the reaction of purines and anilines or naphthylamines in the presence of a three-fold excess of AlCl 3 in DCE, which alternatively gave the C-arylated coupling products and likewise the biaryl 5′ [21]. Therefore, our reaction system is complementary to the AlCl 3 -mediated coupling reaction [21] for the syntheses of C6-aryl-substituted purine derivatives in view of product selectivity.…”

“…On the other hand, Guo’s group previously reported the reaction of purines and anilines or naphthylamines in the presence of a three-fold excess of AlCl 3 in DCE, which alternatively gave the C-arylated coupling products and likewise the biaryl 5′ [21]. Therefore, our reaction system is complementary to the AlCl 3 -mediated coupling reaction [21] for the syntheses of C6-aryl-substituted purine derivatives in view of product selectivity.…”

“…Compound 6-(1-methyl-1H-indol-3-yl)-9-phenylmethyl)-9H-purine ( 3ba ) [21]. A yellow powder, mp 163–166 °C.…”

“…Compound 4-(9-phenylmethyl-9H-purin-6-yl)-benzene-1,3-diol ( 3bj ) [21]. A yellow solid, mp 250–253 °C.…”

“…Indeed, these approaches represent versatile and reliable synthetic methods; however, these coupling reactions require stoichiometric amounts of metallic reagents and the protection of the nucleophilic functional groups—such as the hydroxyl and amino groups—in the substrates. Hence, direct arylation of 6-chloropurines by electron-rich arenes using a three-fold excess of aluminum chloride (AlCl 3 ) was reported by Guo’s group as an alternative method for preparing aryl purines in a short synthetic step (Scheme 1B) [21].…”