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Late-Stage C-H Bond Arylation of Spirocyclic s1 Ligands for Analysis of Complementary s1 Receptor Surface

Christina Meyer, Dirk Schepmann, Shuichi Yanagisawa, Junichiro Yamaguchi, Bernhard Wünsch, and Kenichiro Itami

Eur. J. Org. Chem. 2012, Early View. DOI: 10.1002/ejoc.201200837


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.

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