B(C₆F₅)₃-Catalyzed Direct C3 Alkylation of Indoles and Oxindoles

Abstract

The direct C3 alkylation of indoles and oxindoles is a challenging transformation, and only a few direct methods exist. Utilizing the underexplored ability of triaryl boranes to mediate the heterolytic cleavage of α-nitrogen C−H bonds in amines, we have developed a catalytic approach for the direct C3 alkylation of a wide range of indoles and oxindoles using amine-based alkylating agents. We also employed this borane-catalyzed strategy in an alkylationring opening cascade.

Electron deficient borane-mediated hydride abstraction in amines: stoichiometric and catalytic processes

“…In the same report, we also reported the use of boranemediated hydride abstraction in a ring-opening cascade process between indoles 170 and pyrrolidines 178 to form 4-(3-indolyl)butylamines 179, a privileged motif found in several serotonergic/ dopaminergic drug molecules (Scheme 33). 44 The mechanism was proposed to proceed in a similar fashion to the previously described alkylation process (cf. Scheme 32), except the cyclic nature of amine 178 allowed for the amine portion to be retained in product 179 after elimination (Scheme 33).…”

“…In 2020, we reported the application of borane-mediated a-amino hydride abstraction in a B(C 6 F 5 ) 3 -catalysed C3 alkylation of indoles and oxindoles that utilised amine based alkylating agents (Scheme 32). 44 The mechanism was proposed to begin with the generation of iminium hydridoborate 175 after B(C 6 F 5 ) 3mediated hydride abstraction of the alkylating agent 172. In the same report, we also reported the use of boranemediated hydride abstraction in a ring-opening cascade process between indoles 170 and pyrrolidines 178 to form 4-(3-indolyl)butylamines 179, a privileged motif found in several serotonergic/ dopaminergic drug molecules (Scheme 33).…”

A Photoredox-Catalyzed Approach for Formal Hydride Abstraction to Enable Csp3–H Functionalization with Nucleophilic Partners

“…Excitingly, benzylic sites adjacent to electron-withdrawing groups successfully provided a-fluoro products in one step (14,15). Lastly, isopropylsubstituted heteroarenes, including pyridine, pyrimidine, and pyrazole worked modestly well in the formal hydride abstraction platform (16)(17)(18). Precursors containing aliphatic tertiary C-H sites were evaluated next.…”

“…1 The abundance of unactivated Csp 3 -H bonds in small molecules makes them the ideal precursors for LSF, but direct C-H functionalization transformations remain a challenging feat. 2 Current well-established mechanistic designs for derivatizing C-H bonds include: 1) deprotonation 3 , 2) oxidative addition into a C-H bond via a metal catalyst [4][5][6] , 3) insertion via a carbene or nitrene species 7-9 , 4) HAT to access nucleophilic carboncentered radicals [10][11][12] , and lastly, 5) hydride abstraction [13][14][15][16][17][18] . While the first four strategies are widespread and fairly general ( Fig.…”

One-pot, three-component Fischer indolisation–N-alkylation for rapid synthesis of 1,2,3-trisubstituted indoles

“…gave 5-methoxy-1,2,3-trimethylindole 4e (94 mg, 72%) as an amorphous blue solid, spectroscopically identical to that previously reported. 49 7-Fluoro-1,2,3-trimethylindole, 4f. By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.…”