Pd‐Catalyzed versus Uncatalyzed, PhI(OAc) 2 ‐Mediated Cyclization Reactions of N 6 ‐([1,1′‐Biaryl]‐2‐yl)Adenine Nucleosides

In this work we have assessed reactions of N 6 ‐([1,1′‐biaryl]‐2‐yl)adenine nucleosides with Pd(OAc) 2 and PhI(OAc) 2 , via a Pd II /Pd IV redox cycle. The substrates are readily obtained by Pd/Xantphos‐catalyzed reaction of adenine nucleosides with 2‐bromo‐1,1′‐biaryls. In PhMe, the N 6 ‐biarylyl nucleosides gave C6‐carbazolyl nucleoside analogues by C−N bond formation with the exocyclic N 6 nitrogen atom. In the solvent screening for the Pd‐catalyzed reactions, an uncatalyzed process was found to be operational. It was observed that the carbazolyl products could also be obtained in the absence of a metal catalyst by reaction with PhI(OAc) 2 in 1,1,1,3,3,3‐hexafluoroisopropanol (HFIP). Thus, under Pd catalysis and in HFIP, reactions proceed to provide carbazolyl nucleoside analogues, with some differences. If reactions of N 6 ‐biarylyl nucleoside substrates were conducted in MeCN, formation of aryl benzimidazopurinyl nucleoside derivatives was observed in many cases by C−N bond formation with the N 1 ring nitrogen atom of the purine (carbazole and benzimidazole isomers are readily separated by chromatography). Whereas Pd II /Pd IV redox is responsible for carbazole formation under the metal‐catalyzed conditions, in HFIP and MeCN radical cations and/or nitrenium ions can be intermediates. An extensive set of radical inhibition experiments was conducted and the data are presented.