Regioselective synthesis of C3 alkylated and arylated benzothiophenes

Abstract

Benzothiophenes are heterocyclic constituents of important molecules relevant to society, including those with the potential to meet modern medical challenges. The construction of molecules would be vastly more efficient if carbon–hydrogen bonds, found in all organic molecules, can be directly converted into carbon–carbon bonds. In the case of elaborating benzothiophenes, functionalization of carbon–hydrogen bonds at carbon-number 3 (C3) is markedly more demanding than at C2 due to issues of regioselectivity (C3 versus C2), and the requirement of high temperatures, precious metals and the installation of superfluous directing groups. Herein, we demonstrate that synthetically unexplored but readily accessible benzothiophene S-oxides serve as novel precursors for C3-functionalized benzothiophenes. Employing an interrupted Pummerer reaction to capture and then deliver phenol and silane coupling partners, we have discovered a directing group-free method that delivers C3-arylated and -alkylated benzothiophenes with complete regioselectivity, under metal-free and mild conditions.

Synthesis of C2 Substituted Benzothiophenes via an Interrupted Pummerer/[3,3]‐Sigmatropic/1,2‐Migration Cascade of Benzothiophene S‐Oxides

“…We have recently reported the use of benzothiophene Soxides in the synthesis of C3-arylated and -alkylated benzothiophenes via an interrupted Pummerer [19] / [3,3]-sigmatropic rearrangement [16,20] cascade. [21] Herein we report ametal-free synthesis of C2 functionalized benzothiophenes (Scheme 1B). Using readily available,y et synthetically underutilized benzothiophene S-oxides as novel starting materials,w e engage phenol, and allyl and propargyl silanes in as trategy that delivers C2 substituted benzothiophenes in aregioselective manner under mild conditions.T he C2 C À Ha lkylation and arylation processes operate via an interrupted Pummerer/ [3,3]-sigmatropic rearrangement sequence to generate 3,3disubstituted benzothiophenium salts II,t hat subsequently undergo apreviously unexplored 1,2-migration.…”

“…[21] We proposed that salts I would be predisposed to facile [3,3]-sigmatropic rearrangement, and that the 3,3disubstituted benzothiophenium intermediates (cf. I)via an interrupted Pummerer reaction with suitable nucleophilic coupling partners.…”

Regioselektive metall‐ und reagenzfreie Arylierung von Benzothiophenen durch dehydrierende Elektrosynthese

“…B. auf Palladiumbasis) eingesetzt. [8][9][10] [*] S. Lips [12] oder Nheterocyclischen Carbenen [13] (NHCs) entwickelt, die zumindest eine einfache C,H-Aktivierung ermçglichen. [10,11] Diese Verfahren liefern die gewünschten Produkte in hoher Selektivitätu nd guten Ausbeuten.…”

“…[10,11] Diese Verfahren liefern die gewünschten Produkte in hoher Selektivitätu nd guten Ausbeuten. [9] Eine [3,3]sigmatrope Umlagerung ermçglicht dann die Bildung des Produkts.A llerdings ist eine vorangestellte aufwendige Synthese der Ausgangsstoffe unumgänglich. Beispiele wichtigera rylierter Benzo[b]thiophene.…”

A bioinspired and biocompatible ortho-sulfiliminyl phenol synthesis

“…These methods mainly include three kinds of strategies: (a) rearrangement of aromatic O–X bonds151617181920; (b) directing group-assisted ortho C–H hydroxylation of arenes21222324252627; and (c) ortho C–H functionalization of phenols2829303132. Although these results have promoted the development of the phenol chemistry, the more efficient, economical and biocompatible methods are still in demand.…”