Catalyst controlled N6 versus Cvinyl arylation of 8-vinyl adenine nucleosides, sequential Cvinyl, N6-diarylation, fluorescence properties, and computational evaluations

Palladium-catalyzed C–N bond forming reactions and Heck arylations involve reaction of an aryl halide at either a nitrogen or carbon atom, respectively. A suitable catalyst-ligand combination and a base are generally employed in both. With substrates containing both an amino group and a vinyl moiety, control of C–N versus C–C reactivity will provide a method to regiodivergent functionalization. With such a focus, reactions of 8-vinyl adenosine and 2’-deoxyadenosine with aryl bromides and iodides have been probed herein. Pd(OAc)2, Pd2(dba)3, and preformed dichloro[1,1’-bis(di-t-butylphosphino)ferrocene]palladium (II) (Pd-118) were tested as metal sources. Supporting ligands analyzed were Xantphos, DPEphos, BIPHEP, and DPPF, while Cs2CO3, and K3PO4 were tested as bases. In toluene as solvent, the Pd(OAc)2/Xantphos/Cs2CO3 combination was uniquely capable of promoting N6 arylation predominantly. Aryl bromides and iodides gave comparable product yields. However, replacement of Cs2CO3 with K3PO4 switches reactivity from N6 arylation to predominant Cvinyl arylation, as did all other combinations of catalyst, ligand, and bases that were tested. Changing the Pd source from Pd(OAc)2 to Pd2(dba)3 resulted in loss of chemoselectivity. Two structurally similar catalytic systems that gave selective Cvinyl and N6 arylation reactions were then used to accomplish sequential arylation of the nucleosides at the 8-vinyl and N6 moieties. To demonstrate further applications, products from these reactions were converted to other novel nucleoside analogues. The photophysical properties of fluorescent compounds were experimentally and computationally assessed.