The first C2-selective alkynylation of indoles using the hypervalent iodine reagent triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) with Pd(II) as a catalyst is described. This convenient and robust method gives a single-step access to substituted alkynyl indoles with very high C2 selectivity. The reaction is orthogonal to classical Pd(0) cross-coupling reactions as it is tolerant to bromide and iodide substituents. The used silyl protecting group can be easily removed to give terminal acetylenes.Since the first synthesis of indole by Baeyer almost 150 years ago, 1 interest in the preparation and functionalization of this privileged heterocycle has constantly grown.2 Indoles can indeed be found in numerous important molecules such as pharmaceuticals, dyes and natural products. Consequently, methods to synthesize and modify this heterocycle are of utmost importance in organic chemistry. † New Address: Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität, Freiburg, Germany.(1 This document is the Accepted Manuscript version of a Published Work that appeared in final form in Organic Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/full/10.1021/ol3031389 groups among others. 8 In several cases, the C2/C3 regioselectivity of these functionalizations could be controlled by the reaction conditions or using directing groups. 4,9 Despite the important applications of acetylenes in synthetic chemistry, biochemistry, and material sciences, 10 there are only a few methods for the direct alkynylation of the indole core.11 In 2009, Gu and Wang first introduced the C3-selective alkynylation of indoles using bromoacetylenes and a Pd catalyst.11a C2-selective alkynylation is especially challenging and only two examples have been reported so far. Li and co-workers described an oxidative Heck-Cassar-Sonogashira type method for the alkynylation of 1,3-dimethylindole.11f This reaction could be applied to a broad scope of acetylenes, but only 3-methylindoles were reported. More recently, a method for the alkynylation of lithiated indoles using ethynylsulfonates as reagents was reported by Garcia Ruano and co-workers.11g,h Depending of the sterical hinderance of the substituent on the indole nitrogen, C2 or C3 alkynylation could be obtained. Nevertheless, the requirement for a strong base such as butyl lithium limited the scope of this transformation. Consequently, the most frequently used methods to access 2-alkynylated indoles are often based on the formation of the heterocycles via cyclisation reactions. 3(1H)-one (TIPS-EBX, 2)13 as an efficient reagent for the gold-catalyzed C3 alkynylation of indoles (Scheme 1). During our first investigation, palladium catalysts gave only traces of product, albeit with very high C2 selectivity. 11b We later demonstrated that efficient acetylene transfer with Pd catalysts was possible for the amino-and oxy-alkynylation o...
A novel highly C3 selective metal free trifluoroethylation of indoles using 2,2,2-trifuoroethyl(mesityl)-iodonium triflate was developed. The methodology enables the introduction of a trifluoroethyl group in a fast and efficient reaction under mild conditions with high functional group tolerance. Beyond the synthetic developments, quantum chemical calculations provide a deeper understanding of the transformation.
Novel methodology for O‐functionalization of carbohydrate derivatives has been established using bench‐stable and easily prepared iodonium(III) reagents. Both electron‐withdrawing and electron‐donating aryl groups were introduced under ambient conditions and without precautions to exclude air or moisture. Furthermore, the approach was extended both to full arylation of cyclodextrin, and to trifluoroethylation of carbohydrate derivatives. This is the first general approach to introduce traditionally non‐electrophilic groups into any of the OH groups around the sugar backbone. The methodology will be useful both in synthetic organic chemistry and biochemistry, as important functional groups can be incorporated under simple and robust reaction conditions in a fast and efficient manner.
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