Regioselective synthesis of C3 alkylated and arylated benzothiophenes

ARTICLE Received 8 Nov 2016 | Accepted 2 Feb 2017 | Published 20 Mar 2017 DOI: 10.1038/ncomms14801 OPEN Regioselective synthesis of C3 alkylated and arylated benzothiophenes Harry J. Shrives1, José A. Fernández-Salas1, Christin Hedtke1, Alexander P. Pulis1 & David J. Procter1 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. 1 School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK. Correspondence and requests for materials should be addressed to D.J.P. (email: ). NATURE COMMUNICATIONS | 8:14801 | DOI: 10.1038/ncomms14801 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms14801 B organic materials where performance can be adversely affected by trace metals26. In contrast to C3 C–H arylation of benzothiophenes, C3 C–H alkylation is significantly more challenging and methods are in drastically short supply as reported procedures are severely limited and often described in isolation: Friedel–Crafts alkylation at C3 is restricted to benzylation and suffers from poor regioselectivity27, and C–H metallation at C3, whether stoichiometric28 or catalytic with palladium29 (at 100 °C with primary alkyl boronic acids) or iridium30 (at 90 °C with a diazomalonate), requires an ancillary directing group at C2 to selectively activate the C–H bond at C3 (Fig. 1bii). Herein, we report a method for the completely regioselective, metal-free C3 C–H functionalization of benzothiophenes that utilizes synthetically unexplored benzothiophene S-oxides 1, readily available from straightforward oxidation of benzothiophenes, and phenol, propargyl silane and allyl silane coupling partners, that does not require a conventional directing group (Fig. 1c). This umpolung strategy couples two carbon sites that are inherently nucleophilic and delivers C3-arylated and the more challenging C3-alkylated benzothiophenes under mild conditions, with broad scope. The reaction operates via activation of the S–O bond in benzothiophene S-oxides 1 for an interrupted Pummerer reaction31 with phenol, or allyl- or propargyl-silanes to form intermediates I and II, which are predisposed for charge enzothiophenes are sulfur containing heterocyclic molecules that when functionalized, are often incorporated into important molecular scaffolds which have found utility in materials science1 and in particular in biology and medicine2–8. For example, sertaconazole2 is an antifungal medicine and raloxifene3 is used in the prevention of osteoporosis, and other benzothiophenes have promising biological activity in the areas of diabetes4, antibacterials5 and water regulation6 among others7,8 (Fig. 1a). The synthesis of these important molecules can be achieved by construction of one or both rings, or via direct functionalization of the benzothiophene core9–11. Due to the ubiquity of C–H bonds, the most efficient methods of C–C bond construction are based on C–H functionalization12,13. Functionalization at C2 of readily available benzothiophenes14 is generally well established due to the increased acidity of the C–H bond15. However, C3 C–H functionalization is underdeveloped. In the absence of a directing group, direct C–H arylation at C3 of benzothiophenes is traditionally accomplished with palladium catalysts and coupling partners such as aryl-halides16–19, -borons20,21, silanes22, -sulfonyl chlorides23 and-iodoniums24 (Fig. 1bi). While recent disclosures address the problems associated with harsh conditions, expensive ligands and regioselectivity issues, the risk of metal contamination remains, particularly when the products are intended for human consumption25 or to be used in a b Importance of C3 functionalized benzothiophenes O O Cl N Traditional methods of C3 C−H functionalization of benzothiophenes Ar H Cl O i. Arylation OH S S HO N S Benzothiophene Raloxifene−osteoporosis3 N Cl Sertaconazole−antifungal2 Ph ii. Alkylation Me O S O O NO2 OH Transition metals Alkyl N O MeO S Me Me O HO Ar–X X = Halide, BR2, SiR3, SO2Cl, I+R2 Alkyl-B(OH)2 w. Pd (2 examples) DG (RO2C)2CN2 w. Ir (1 example) S OMe Directing groups required Poor regioselectivity in Friedel-Crafts alkylation, limited to BnX 5 Antibacterial S S Insulin receptor activator4 Vasopressin antagonist6 c A metal-free approach to C3 C − H functionalization of benzothiophenes (this work) H TFAA S+ O– HO Synthetically unexplored Readily accessible No need for isolation 1 [3,3] S+ SiMe3 H OH S+ or O or I S II C3 arylation C-H Functionalization C-C Bond formation Metal-free Umpolung Directing group-free Total regioselectivity or S C3 alkylation Broad scope Mild conditions Figure 1 | C3-functionalized benzothiophenes. (a) Prevalence of C3 functionalized benzothiophene motifs in biologically active molecules including commercial drugs and others with potential in diverse target areas. (b) Traditional methods of C3 C–H arylation of benzothiophenes rely on transition metals and alkylation at C3 is limited in scope and either requires a directing group or exhibits poor regioselectivity. (c) A metal-free approach to benzothiophene C3 C–H arylation and alkylation employing synthetically unexplored benzothiophene S-oxides does not require a directing group and is completely regioselective by virtue of the interrupted Pummerer reaction mechanism which allows the coupling partner to be delivered in a site-selective manner (this work). DG, directing group. 2 NATURE COMMUNICATIONS | 8:14801 | DOI: 10.1038/ncomms14801 | www.nature.com/naturecommunications ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms14801 accelerated [3,3]-sigmatropic rearrangement32, resulting in C–C bond formation, therefore delivering the coupling partner in a perfectly site-selective manner. Results Metal-free C3 C–H arylation. Metal-free methods complement synthetic procedures traditionally based upon the use of transition metals33. Recently, we34–40 and (...truncated)