General Approach to N6,C5′-Difunctionalization of Adenosine

Among the C6-halo purine ribonucleosides, the readily accessible 6-chloro derivative has been known to undergo slow SNAr reactions with amines, particularly aryl amines. In this work, we show that in 0.1 M AcOH in EtOH, aryl amines react quite efficiently at the C6-position of 2',3',5'-tri-O-(t-BuMe2Si)-protected 6-chloropurine riboside (6-ClP-riboside), with concomitant cleavage of the 5'-silyl group. These two-step processes proceeded in generally good yields, and notably, reactions in the absence of AcOH were much slower and/or lower yielding. Corresponding reactions of 2',3',5'-tri-O-(t-BuMe2Si)-protected 6-ClP-riboside with alkyl amines proceeded well but without desilylation at the primary hydroxyl terminus. These differences are likely due to the acidities of the ammonium chlorides formed in these reactions, and the role of AcOH was not desilylation but possibly only purine activation. With 50% aqueous TFA in THF at 0 degrees C, cleavage of the 5'-silyl group from 2',3',5'tri-O-(t-BuMe2Si)-protected N-6-alkyl adenosine derivatives and from 6-ClP-riboside was readily achieved. Reactions of the 5'-deprotected 6-ClP-riboside with alkyl amines proceeded in high yields and under mild conditions. Because these complementary methodologies yielded N-6-aryl and -alkyl adenosine derivatives containing a free 5'-hydroxyl group, a variety of product functionalizations were undertaken to yield N-6,C5'-doubly modified nucleoside analogues.

Automated summary

This study demonstrates efficient reactions of aryl amines with 6-chloropurine riboside under specific conditions, leading to C6-position modification and cleavage of the 5'-silyl group. Acetic acid was found to play a crucial role in promoting these processes.