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

Abstract

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 C^vinyl arylation as well. Simply switching from Pd(OAc)₂ to Pd₂(dba)₃ resulted in loss of the N⁶-selectivity and C^vinyl arylation was favored. Based upon these results, using two structurally similar catalytic systems sequential C^vinyl 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.