CuBr‐Promoted Tandem Cyclization/Trifluoromethylation of 2‐Alkynylanilines: Efficient Synthesis of 3‐Trifluoromethylindoles

Abstract

A new efficient strategy for the synthesis of 3‐trifluoromethyl‐indoles was developed through tandem cyclization/trifluoromethylation of 2‐alkynylanilines and Umemoto's reagent under effect of CuBr. The reaction features the use of cheap copper salt, mild reaction conditions and high yield of products. The preliminary mechanism study indicates the solvent dimethylacetamide acts as the role of dealkylation.

Evolution and Future of Hetero‐ and Hydro‐Trifluoromethylations of Unsaturated C−C Bonds

“…In 2014, Ding, Hou and coworkers reported a copper‐catalyzed 2,3‐dihydropyrrolium‐forming amino‐trifluoromethylation of homopropargyl amines with Umemoto reagent (Scheme 104a) [120] . In the same year, the authors developed a copper‐mediated amino‐trifluoromethylation of 2‐alkynylanilines with Umemoto reagent for the synthesis of 3‐trifluoromethylated indoles (Scheme 104b) [121] . A stoichiometric amount of CuBr was necessary for this transformation, as the solvent‐derived dimethylamine generated as a by‐product deactivated CuBr by forming a complex.…”

“…[120] In the same year, the authors developed a coppermediated amino-trifluoromethylation of 2-alkynylanilines with Umemoto reagent for the synthesis of 3trifluoromethylated indoles (Scheme 104b). [121] A stoichiometric amount of CuBr was necessary for this transformation, as the solvent-derived dimethylamine generated as a by-product deactivated CuBr by forming a complex. Both reactions were proposed to proceed via a unique pathway, namely copperpromoted alkyne cyclization followed by trifluoromethylation with Umemoto reagent, which is in contrast to the more commonly proposed mechanism of amino-trifluoromethylations triggered by CF 3 radical addition.…”

“…Intramolecular amino-trifluoromethylation with Umemoto reagent. [120,121] Scheme 105. Photocatalytic intramolecular aminotrifluoromethylation with Umemoto reagent.…”

Synthesis of 2,3-Bis(trifluoromethylseleno) Indoles through an Oxidative Copper-Mediated Domino Reaction

“…Although the intramolecular cyclization of 2-alkynylanilines with the incorporation of functional groups has proven to be an efficient protocol for constructing functionalized indoles, the use of this strategy to access a perfluoroalkylated indole skeleton remains sporadic. The Hou group and then the Tsui group independently reported a tandem cyclization/trifluoromethylation of 2-alkynylanilines for the synthesis of 3-trifluoromethylindoles (Scheme a). A simultaneous study by Tsui and co-workers of the trifluoromethylation/cyclization of terminal 2-alkynylanilines using a fluoroform-derived CuCF 3 reagent affording 2-trifluoromethylindoles was also reported (Scheme b) …”

Synthesis of 3-trifluoromethylindoles via Rh-catalyzed regioselective oxidative coupling of acetanilides with trifluoromethylated alkynes

“…7 Hou and co-workers described a tandem cyclization/trifluoromethylation of 2-alkynylanilines with Umemoto's reagent to generate 3-trifluoromethylindoles. 8 Cao group also successfully rendered the assembly of a series of 2-(perfluoroalkyl)indole-3-carboxylic esters via a one-pot sequential Michael addition and intramolecular cross coupling. 9 Bearing Stuart, Fagnou 4 and Konno's work 7 in mind, we reasonably envisioned that the trifluoromethylated internal alkynes 11 could be used as appropriate fluorine-containing building blocks to participate the oxidative cross-coupling with acetanilides to furnish 3-trifluoromethyl functionalized indoles.…”