A novel class of AMPA receptor allosteric modulators. Part 1: Design, synthesis, and SAR of 3-aryl-4-cyano-5-substituted-heteroaryl-2-carboxylic acid derivatives

SNAr and Palladium‐Catalyzed Reactions of Deactivated Thiophene: Application to the Synthesis of Protein Farnesyltransferase Inhibitors

“…The replacement of the 5-thioether by an analogous all carbon moiety was first carried out under previously reported conditions [6] with commercially available diethylzinc which provided 5-ethylthiophene 8 in a reasonable yield (Scheme 2). Based on this encouraging result, we performed the same reaction in which di-isobutylzinc was generated in situ by mixing zinc dichloride and isobutylmagnesium chloride.…”

“…[6][7] However, we wished to find a common precursor allowing for facile modification of this part of compound 1 by various groups, especially through the application of S N Ar reactions. Therefore, we decided to activate thioether 1 by oxidation since oxidized thioethers are better leaving groups than are thioethers themselves.…”

“…Direct substitution of thioethers on electron-deficient thiophene rings has only been achieved either by palladiumcatalyzed coupling with alkyl or aryl thiols [6] or by aromatic nucleophilic substitutions with morpholine. [6][7] However, we wished to find a common precursor allowing for facile modification of this part of compound 1 by various groups, especially through the application of S N Ar reactions.…”

“…Additionally, successful substitutions of thienyl sulfoxides or sulfones by amines or alcohols have been previously described. [6,[8][9][10][11] Because we thought that the presence of a free carboxylic acid could be troublesome during the course of our synthesis, we used ethyl 3-(4-chlorophenyl)-4-cyano-5-(isopropylthio)thiophene-2-carboxylate 2 as the starting point for the construction of new esters which would ultimately be saponified to afford the desired acids. In order to oxidize thiophene 2, we used 1 or 2.5 equiv.…”

New protein farnesyltransferase inhibitors in the 3-arylthiophene 2-carboxylic acid series: diversification of the aryl moiety by solid-phase synthesis

“…Suzuki-Miyaura cross-coupling 13,14 fulfilled our requirements because of its common use in arylation of halogenothiophene [15][16][17][18][19] , though less frequently described in solid phase than in homogenous synthesis [20][21][22] . This palladium-catalyzed reaction could afford the desired compounds from the corresponding 3-bromothiophene derivative obtained by a Sandmeyer reaction on a 3-amino thiophene 23 itself synthesized according to previously described Fiesselmann-type reaction on a ketene dithioacetal prepared from commercially available malononitrile (Scheme 1) 24 . This pathway was applied to the synthesis of our hit compound, 3-(4-chlorophenyl)-4--cyano-5-(isopropylthio)thiophene-2-carboxylic acid 1a and proceeded in a very efficient 48% overall yield from malononitrile (Scheme 2).…”