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Late‐Stage C–H Bond Arylation of Spirocyclic σ 1 Ligands for Analysis of Complementary σ 1 Receptor Surface
Author(s) -
Meyer Christina,
Schepmann Dirk,
Yanagisawa Shuichi,
Yamaguchi Junichiro,
Itami Kenichiro,
Wünsch Bernhard
Publication year - 2012
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201200837
Subject(s) - moiety , chemistry , thiophene , stereochemistry , ring (chemistry) , amine gas treating , ether , organic chemistry
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 2 CO 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 2 CO 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 σ 1 affinities (e.g., 4a : K i = 1.6 nM; 5a : K i = 2.4 nM), indicating an additional hydrophobic pocket on the complementary σ 1 receptor protein. A phenyl moiety in position C (at the bottom position) is not tolerated by the σ 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 .