Sequential Regioselective C–H Functionalization of Thiophenes

Abstract

Herein, the sequential functionalization of 5-membered ring heterocycles is disclosed. By employing a pH sensitive directing group both directed and nondirected C-H activation pathways are available, providing access to 2,3,4- and 2,4,5-substituted thiophenes. The C-H arylation was performed in water, and using a surfactant greatly improved the yield and mass recovery. The use of a directing group with an on/off switch offers a potentially powerful means of generating diversity around medicinally relevant cores.

The Hydrophobic Effect Applied to Organic Synthesis: Recent Synthetic Chemistry “in Water”

“…A method for C−H functionalization of thiophenes has been reported by Daniels and Tan at Novartis to provide regioselective substitutions of medicinally relevant building blocks (Scheme ) . Due to its inherent reactivity, the 2‐position of a model 3‐perfluorotoluimide thiophene was arylated in the presence of Pd(OAc) 2 .…”

“…Am ethod for CÀHf unctionalization of thiophenes has been reported by Daniels andT an at Novartis to provide regioselective substitutions of medicinally relevant building blocks (Scheme 15). [33] Due to its inherentr eactivity,t he 2-positiono famodel3 -perfluorotoluimide thiophene was arylated in the presence of Pd(OAc) 2 .T he ligand tri-tert-butylphosphine afforded better control of selectivity toward monosubstitution and limited the over-functionalization at the 4-position. While water outperformedo rganic solvents in terms of substrate and product stability, as well as reaction rates, the use of added surfactants improved the efficiency of the reactions leading to higher yields.…”

An Epoxide-Mediated Deprotection Method for Acidic Amide Auxiliary

“…4 This versatile auxiliary has also been adopted by both academic and industrial efforts. 5 Currently, three main methods are used to remove this directing group: methanolysis promoted by a Lewis acid (BF 3 •Et 2 O); installing an electron-withdrawing group onto the nitrogen atom of the amide to promote methanolysis; hydrolysis by treating with CF 3 SO 3 H. 5 However, many substrates are not compatible with these strongly acidic or basic conditions in synthetic applications. We report a convenient protocol for facile alcoholysis of amides using a mild base (KOAc).…”

A Convergent Synthesis of Functionalized Alkenyl Halides through Cobalt(III)‐Catalyzed Three‐Component C−H Bond Addition

“…Direct CÀHi odination was not observed, thus suggesting that under the reaction conditions, alkenylation completely outcompetes iodination. [12][13][14] Acetic acid has previously been found to be an effective additive for facilitating Co III -catalyzed C À Hb ond additions to p-bonds and was crucial to achieving effective alkyne coupling. However,o nly sub-stoichiometric amounts of acetic acid relative to catalyst loading could be used to minimize undesired proto-demetallation of the alkenyl cobalt intermediate.Itisalso noteworthy that Rh III catalysts,which often show parallel reactivity to Co III ,w ere ineffective for this transformation.…”