Pd-Catalyzed Regiodivergent N6 versus Cvinyl Arylation of 8-Vinyl Adenine Nucleosides, Sequential Diarylation, Fluorescence Properties, and Computational Evaluations*.

Palladium-catalyzed aryl amination and Heck arylation reactions are complementary transformations, generally requiring a suitable catalyst combination and a base. With substrates containing both an amino group and a vinyl moiety, control of C─N versus C─C reactivity can lead to regiodivergent functionalizations. With this focus, reactions of silyl-protected 8-vinyl 2'-deoxyadenosine and adenosine with aryl bromides and iodides have been studied. Pd(OAc)2, Pd2(dba)3, and preformed dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium (II) (Pd-118) were evaluated as metal sources. Ligands tested were Xantphos, DPEphos, BIPHEP, and DPPF, with Cs2CO3 and K3PO4 as bases. In toluene as solvent, the Pd(OAc)2/Xantphos/Cs2CO3 combination was uniquely capable of predominant N6 arylation. Aryl bromides and iodides gave comparable product yields. Replacement of Cs2CO3 with K3PO4 redirected arylation from the nitrogen atom to the vinyl carbon atom, and all other catalyst, ligand, and base combinations gave Cvinyl arylation as well. Simply switching from Pd(OAc)2 to Pd2(dba)3 resulted in loss of the N6-selectivity and Cvinyl arylation was favored. Based upon these results, using two structurally similar catalytic systems sequential Cvinyl and N6 arylations of the nucleosides were accomplished. Some of the products were converted to other novel nucleoside analogues. Because some compounds were fluorescent, their photophysical properties were assessed experimentally and computationally.