A nickel-catalyzed direct C-2 alkylation of indoles through monodentate-chelation assistance has been described. This reaction proceeds via an unusual strategy by the use of a well-designed and defined (quinolinyl)­amido–nickel catalyst, [{κN,κN,κN-Et2NCH2C­(O)­(μ-N)­C9H6N}­Ni­(OAc)], providing a solution to the limitations associated with bidentate-chelate auxiliaries. The method allows coupling of indoles with various unactivated primary and secondary alkyl halides with ample substrate scope. This uniquely strategized alkylation proceeded through crucial C–H activation and via an alkyl radical intermediate. The reaction by this approach represents a rare example of Ni-catalyzed monodentate-chelate-assisted C–H functionalization.

Over the past decade, the use of 3d transition metal for the regioselective C−H bond functionalization of indoles has significantly increased. Particularly, advances in manganese, iron, cobalt, nickel and copper catalysis have demonstrated the selective C(2)−H and C(3)−H arylation, alkenylation, alkynylation and alkylation to a greater extent. Similarly, the C−O and C−N bond‐forming reactions are manifested via direct C−H bond activation by these earth‐abundant metals. The emergence of 3d metals in selective functionalization of the biologically relevant indoles and related heteroarenes would make this protocol more attractive for practical applications. Herein, we provide a brief overview of 3d transition metal‐catalyzed (mostly Mn, Fe, Co, Ni and Cu) C−H functionalization of indoles and related heteroarenes.

Nickel-catalyzed regioselective C–H bond alkenylation of indoles and related heteroarenes with alkenyl bromides is accomplished under relatively mild conditions. This method allows the straightforward synthesis of C-2 alkenylated indoles employing an air-stable and well-defined nickel catalyst, (bpy)­NiBr2, providing a solution to the limitations associated with hydroindolation and oxidative alkenylation. The reaction conceded the coupling of indole derivatives with various alkenyl bromides, such as aromatic and heteroaromatics, α- and β-substituted as well as exo- and endo-cyclic alkenyl compounds. An extensive mechanistic investigation, including controlled study, reactivity experiments, kinetics and labeling studies, and EPR and XPS analyses, highlights that the alkenylation proceeds through a single-electron transfer process comprising an odd-electron oxidative addition of alkenyl bromide. Furthermore, the alkenylation operates via a probable Ni­(I)/Ni­(III) pathway involving the rate-limiting C–H nickelation of indole.

An efficient solvent-free nickel-catalyzed method for C-H bond arylation of arenes and indoles has been developed, which proceeds expeditiously through chelation assistance. The reaction is highly selective for mono-arylation and tolerates sensitive and structurally diverse functionalities, such as halides, ethers, amines, indole, pyrrole and carbazole. This reaction represents the first example of a nickel-catalyzed C-H arylation by monochelate assistance and symbolizes a rare precedent in solvent-free C-H arylation. Mechanistic investigations by various controlled reactions, kinetic studies, and deuterium labeling experiments suggest that the arylation follows a single electron transfer (SET) pathway involving the turnover-limiting C-H nickelation process.

Regioselective C–H bond alkylation of indolines and benzo­[h]­quinoline with a wide range of unactivated and highly demanded primary and secondary alkyl chlorides is accomplished using a low-cost iron catalyst. This reaction tolerates diverse functionalities, such as C­(sp2)–Cl, fluoro, alkenyl, silyl, ether, thioether, pyrrolyl, and carbazolyl groups including cyclic and acyclic alkyls as well as alkyl-bearing fatty-alcohol and polycyclic-steroid moieties. The demonstrated iron-catalyzed protocol proceeded via either a five-membered or a six-membered metallacycle. Intriguingly, the C-7-alkylated indolines can be readily functionalized into free-NH indolines/indoles and tryptamine derivatives. A detailed mechanistic investigation highlights the participation of an active Fe­(I) catalyst and the involvement of a halogen-atom transfer process via a single-electron-based mechanism. Deuterium labeling and kinetics analysis indicate that the C–H metalation of indoline is the probable turnover-limiting step. Overall, the experimental and theoretical studies supported an Fe­(I)/Fe­(III) pathway for the alkylation reaction comprising the two-step, one-electron oxidative addition of alkyl chloride.

Pincer-based ( R2 POCN R ′ 2 )PdCl complexes along with CuI cocatalyst catalyze the arylation of azoles with aryl iodides to give the 2-arylated azole products. Herein, we report an extensive mechanistic investigation for the direct arylation of azoles involving a well-defined and highly efficient ( iPr2 POCN Et2 )PdCl (2a) catalyst, which emphasizes a rare Pd II −Pd IV −Pd II redox catalytic pathway. Kinetic studies and deuterium labeling experiments indicate that the C−H bond cleavage on azoles occurs via two distinct routes in a reversible manner. Controlled reactivity of the catalyst 2a underlines the iodo derivative ( iPr2 POCN Et2 )PdI (3a) to be the resting state of the catalyst. The intermediate species ( iPr2 POCN Et2 )Pd-benzothiazolyl (4a) has been isolated and structurally characterized. A determination of reaction rates of compound 4a with electronically different aryl iodides has revealed the kinetic significance of the oxidative addition of the C(sp 2 )−X electrophile, aryl iodide, to complex 4a. Furthermore, the reactivity behavior of 4a suggests that the arylation of benzothiazole proceeds via an oxidative addition/ reductive elimination pathway involving a ( iPr2 POCN Et2 )Pd IV (benzothiazolyl)(Ar)I species, which is strongly supported by DFT calculations.

Manganese-catalyzed regioselective C−H alkylation of indoles and benzo[h]quinoline with a variety of unactivated alkyl iodides is reported. Unlike other Mn-catalyzed C−H functionalization, this protocol does not require a Grignard reagent base and employs a simple and inexpensive MnBr 2 as a catalyst. This method tolerates diverse functionalities, including fluoro, chloro, bromo, iodo, alkenyl, alkynyl, pyrrolyl, and carbazolyl groups. The alkylation proceeds through a single-electron transfer pathway comprising reversible C−H manganesation and involving an alkyl radical intermediate.

Direct CÀ H functionalization of privileged and biologically relevant azoles and indoles represents an important chemical transformation in molecular science. Despite significant progress in the palladium-catalyzed regioselective CÀ H functionalization of azoles and indoles, the use of abundant and less expensive nickel catalyst is underdeveloped. In the recent past, the nickel-catalyzed regioselective CÀ H alkylation, arylation, alkenylation and alkynylation of azoles and indoles have been substantially explored, which can be applied to the complex organic molecule synthesis. In this Account, we summarize the developments in nickel-catalyzed regioselective functionalization of azoles and indoles with a considerable focus on the reaction mechanism.