1245630-99-2Relevant academic research and scientific papers
General Approach to N6,C5′-Difunctionalization of Adenosine
Lakshman, Mahesh K.,Pradhan, Padmanava,Satishkumar, Sakilam,Sebastian, Dellamol,Yang, Lijia
, p. 18 - 39 (2021/12/27)
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 °C, cleavage of the 5′-silyl group from 2′,3′,5′-tri-O-(t-BuMe2Si)-protected N6-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 N6-aryl and -alkyl adenosine derivatives containing a free 5′-hydroxyl group, a variety of product functionalizations were undertaken to yield N6,C5′-doubly modified nucleoside analogues.
Palladium-catalyzed aryl amination reactions of 6-bromo- and 6-chloropurine nucleosides
Thomson, Paul F.,Lagisetty, Pallavi,Balzarini, Jan,De Clercq, Erik,Lakshman, Mahesh K.
experimental part, p. 1728 - 1735 (2010/10/21)
Palladium-catalyzed C-N bond forming reactions of 6-bromo- as well as 6-chloropurine ribonucleosides and the 2′-deoxy analogues with arylamines are described. Efficient conversions were observed with palladium(II) acetate/Xantphos/cesium carbonate, in toluene at 100°C. Reactions of the bromonucleoside derivatives could be conducted at a lowered catalytic loading [5 mol% Pd(OAc)2/7.5 mol% Xantphos], whereas good product yields were obtained with a higher catalyst load [10mol% Pd(OAc)2/ 15 mol% Xantphos] when the chloro analogue was employed. Among the examples evaluated, silyl protection for the hydroxy groups appears better as compared to acetyl. The methodology has been evaluated via reactions with a variety of arylamines and by synthesis of biologically relevant deoxyadenosine and adenosine dimers. This is the first detailed analysis of aryl amination reactions of 6-chloropurine nucleosides, and comparison of the two halogenated nucleoside substrates.
