Late‐Stage C–H Bond Arylation of Spirocyclic σ1 Ligands for Analysis of Complementary σ1 Receptor Surface

European Journal of Organic Chemistry - Tập 2012 Số 30 - Trang 5972-5979 - 2012
Christina Meyer1, Dirk Schepmann1, Shuichi Yanagisawa2, Junichiro Yamaguchi2, Kenichiro Itami2, Bernhard Wünsch1
1Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms‐Universität Münster, Hittorfstraße 58–62, 48149 Münster, Germany, Fax: +49‐251‐8332144, http://www.uni‐muenster.de/Chemie.pz/forschen/ag/wuensch/
2Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464‐8602, Japan, Fax: +81‐52‐788 6098, http://synth.chem.nagoya‐u.ac.jp/wordpress/?cat=13&lang=en

Tóm tắt

AbstractDirect 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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European Journal of Organic Chemistry

Tập 2012 Số 30

5972-5979

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