Benzimidazopurine nucleosides from N⁶-aryl adenosine derivatives by PhI(OAc)₂-mediated C–N bond formation, no metal needed

Abstract

The reaction of a variety N6-aryl 2’-deoxyadenosine and adenosine derivatives with PhI(OAc)2 in 1,1,1,3,3,3-hexafluoro-2-propanol provides facile access to benzimidazopurine nucleoside analogues by metal-free C–N bond formation with a purinyl nitrogen atom. These reactions likely proceed via radical-cation/radical processes as indicated by radical inhibition experiments.

Pd‐Catalyzed versus Uncatalyzed, PhI(OAc)2‐Mediated Cyclization Reactions of N6‐([1,1′‐Biaryl]‐2‐yl)Adenine Nucleosides

“…In our previous work, MeNO 2 promoted benzimidazopurine nucleoside formation from N 6 -aryl adenosine in a modest yield. [14] But here, in MeNO 2 both 14 and 22 were obtained in ~1 : 1 ratio (combined 39%, entry 4). Also, in our previous work, TFE proved to be a reasonably good solvent for cyclization to the benzimidazole derivatives.…”

“…We have observed a similar product in our previously reported work. 14 With ribosyl precursors 10 and 11 , complete conversion was observed with 10 mol% Pd(OAc) 2 . In contrast to the successful reactions, substrates 12 and 13 , with strongly electron-depleting groups, underwent only degradation under these conditions (compare with the low yield of 19 from a precursor with an electron-withdrawing group).…”

“…This was partially prompted by our observation that even catalytic amounts of Cu(OTf) 2 are detrimental to nucleosides. [14] These results are summarized in Table 2. NaBO 3 •4H 2 O, Cu(OAc) 2 , and t -BuOOH proved to be generally ineffective for the conversion (entries 1–4).…”

“…[13] In agreement with these data, in recent work, we observed extensive degradation of a 3’,5’-di- O -silyl N 6 -phenyl 2’-deoxyribosyl substrate under the reported conditions. [14] …”

When nucleoside chemistry met hypervalent iodine reagents

“…These data indicate that these reactions may proceed via radical cations or radicals (Scheme 26). Fluorinated solvents such as TFE and HFIP are known to stabilize radical cations 43,44 that can be formed in reactions involving hypervalent iodine reagents.…”