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.

Functionalized benzothiophenes are important scaffolds found in molecules with wide ranging biological activity and in organic materials. We describe an efficient, metal-free synthesis of C2 arylated, allylated, and propargylated benzothiophenes. The reaction utilizes synthetically unexplored yet readily accessible benzothiophene S-oxides and phenols, allyl-, or propargyl silanes in a unique cascade sequence. An interrupted Pummerer reaction between benzothiophene S-oxides and the coupling partners yields sulfonium salts that lack aromaticity and therefore allow facile [3,3]-sigmatropic rearrangement. The subsequently generated benzothiophenium salts undergo a previously unexplored 1,2-migration to access C2 functionalized benzothiophenes.

A metal-free approach combining sulfoxide-directed metal-free C–H cross-couplings with tuneable heterocyclizations and dimerizations allows expedient access to important organic materials.

A sulfoxide-directed, metal-free ortho-propargylation of aromatics and heteroaromatics exploits intermolecular delivery of a propargyl nucleophile to sulfur followed by an intramolecular relay to carbon. The operationally simple cross-coupling procedure is general, regiospecific with regard to the propargyl nucleophile, and shows complete selectivity for products of ortho-propargylation over allenylation. The use of secondary propargyl silanes allows metal-free ortho-coupling to form carbon–carbon bonds between aromatic and heteroaromatic rings and secondary propargylic centres. The ‘safety-catch’ nature of the sulfoxide directing group is illustrated in a selective, iterative double cross-coupling process. The products of propargylation are versatile intermediates and they have been readily converted into substituted benzothiophenes.

Functionalized benzothiophenes are important scaffolds found in molecules with wide ranging biological activity and in organic materials.W ed escribe an efficient, metal-free synthesis of C2 arylated, allylated, and propargylated benzothiophenes.T he reaction utilizes synthetically unexplored yet readily accessible benzothiophene S-oxides and phenols,a llyl-, or propargyl silanes in au nique cascade sequence.A ni nterrupted Pummerer reaction between benzothiophene S-oxides and the coupling partners yields sulfonium salts that lacka romaticity and therefore allowf acile [3,3]sigmatropic rearrangement. The subsequently generated benzothiophenium salts undergo ap reviously unexplored 1,2migration to access C2 functionalized benzothiophenes.

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What prompted you to investigate this topic/problem?Selective carbon-carbon bond formation to aromatic and heteroaromatic systems is ac rucial synthetic goal. The majority of "classical" and "cutting-edge" cross-couplings have one thing in common:t hey are mediated by platinium group metals (e.g.,R u, Rh, Pd and Pt). Unfortunately,t he supply of these metals is at risk and their use may become unsustainable. An important future course, therefore, involves the development of coupling reactions that do not involve the use of am etal. Such an approach has additional benefits as trace metal contamination in products arising from metal-catalysed processes is am ajor problem in industry.W e thus set out to develop innovative coupling processes that operate under metal-free conditions and that complement existing metalcatalysed cross-coupling technologies and may ultimately lead to their replacement.What is the most significant result of this study?Drawing inspiration from classical sulfoxide Pummerer chemistry, we have developed as trategy for metal-free cross-coupling that exploits as ulfoxide directing group on an aromatic ring. The sulfur atom of the directing group catches the nucleophilic coupling partner before delivering it to the aromatic ring. Thus, intermolecular carbon-sulfur bond formation is used to trigger intramolecular formation of the challenging carbon-carbon bond. Importantly, the directing effect of the sulfoxide is switched off after the coupling so over reaction cannot occur.U pon reoxidation, the directing group effect is restored. The "safety-catch" nature of the sulfoxide directing group has been illustrated in as elective, iterative double cross-coupling process.What future opportunities do you see (in the light of the results presented in this paper)?We are developing ap ortfolio of sulfoxide-directed, metal-free cross-couplings that exploit our strategy.Inparticular,werecognise the potential of developing metal-free couplings that correspond to dehydrogenative CÀH/CÀH-type couplings-arguably the most desirable class of cross-coupling process. The new technology can be used in the synthesis and modification of organic materials, chemosensors and bioactive targets.What other topics are you working on at the moment?We introduce and exploit new synthetic concepts for the efficient construction of molecules with important properties. For example, in addition to developing metal-free coupling technology,w ea re harnessing electron-transfer in new transformations, synthesising natural product-inspired antibacterial agents to address the global problem of resistance to antibiotics, exploring new catalytic processes using copper and iron, using chemical tools to interrogate biological systems, and synthesising new organic materials for applications in organic electronics and energy industries.Invited for the cover of this issue is the group of David J. Procter at the University of Manchester (UK). The image illustrates an ew,m etal-free direction for cross-coupling technology by taking signage from ...