Late-Stage C-H Bond Arylation of Spirocyclic σ1 Ligands for Analysis of Complementary σ1 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 PdCl2/bipy/Ag2CO3. The introduction of phenyl moieties to the β‐position was performed with the catalytic system PdCl2/P[OCH(CF3)2]3/Ag2CO3. 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 σ1 affinities (e.g., 4a: Ki = 1.6 nM; 5a: Ki = 2.4 nM), indicating an additional hydrophobic pocket on the complementary σ1 receptor protein. A phenyl moiety in position C (at the bottom position) is not tolerated by the σ1 receptor (e.g., 12: Ki = 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 PdCl2/bipy/Ag2CO3 and PdCl2/P[OCH(CF3)2]3/Ag2CO3. Compounds bearing the phenyl moiety at the top position and the sulfur atom in left position show the highest σ1 affinity.