Late-stage C-H bond arylation of spirocyclic σ ₁ ligands for analysis of complementary σ ₁ receptor surface

Direct C-H bond arylation in the α- and β-positions of spirocyclic thiophenes containing various functional groups (amine, ether, acetal, lactone) was accomplished. Selective phenylation in the α-position of the thiophene ring was achieved by using the catalytic system PdCl ₂/bipy/Ag ₂CO ₃. The introduction of phenyl moieties to the β-position was performed with the catalytic system PdCl ₂/P[OCH(CF ₃) ₂] ₃/Ag ₂CO ₃. Even the five-membered lactone 10 with an electron-withdrawing carbonyl moiety directly attached to the thiophene ring was arylated. Spirocyclic thiophenes substituted with a phenyl moiety in position A (top position) or B (left position) display low nanomolar Ï ₁ affinities (e.g., 4a: K _i = 1.6 nM; 5a: K _i = 2.4 nM), indicating an additional hydrophobic pocket on the complementary Ï ₁ receptor protein. A phenyl moiety in position C (at the bottom position) is not tolerated by the Ï ₁ receptor (e.g., 12: K _i = 483 nM). However, an additional phenyl moiety in position A is able to compensate at least partially the unfavorable effects of the phenyl moiety in position C. Diverse spirocyclic thiophenes were synthesized regioselectively by direct C-H bond arylation using the catalytic systems PdCl ₂/bipy/Ag ₂CO ₃ and PdCl ₂/ P[OCH(CF ₃) ₂] ₃/Ag ₂CO ₃. Compounds bearing the phenyl moiety at the top position and the sulfur atom in left position show the highest Ï ₁ affinity.