Expanding the Scope of Alkynes in C-H Activation: Weak Chelation-Assisted Cobalt-Catalyzed Synthesis of Indole C(4)-Acrylophenone via C-O Bond Cleavage of Propargylic Ethers.

Herein, we report the facile synthesis of indole C(4)-acrylophenone using a C-H bond activation strategy. For this conversion, an unsymmetrical alkyne (phenylethynyl ether) in the presence of cobalt(III)-catalyst works efficiently. In this process, alkyne gets oxidized in the presence of in situ generated water, which is the key step for this method, for which trifluoroethanol is the water source. The pivaloyl directing group chelates effectively to generate the cobaltacycle intermediate, which was detected through high-resolution mass spectrometry (HRMS). Also, the formation of bis(2,2,2-trifluoroethyl) ether has been confirmed and quantified using 19F NMR. In addition, the applicability of obtained indole C(4)-acrylophenone product has been demonstrated by performing the Nazarov cyclization and conjugate addition to the α,ß-unsaturated ketone moiety.

Carboamination and olefination: ortho C-H functionalization of phenoxyacetamide.

Herein, we have demonstrated a rhodium-catalyzed carboamination of olefin with the double bond intact. For the first time, deacylative carboamination of the maleimide has been achieved wherein phenoxyacetamide has behaved as the aminating source. In addition to carboamination, we have also disclosed the C-H olefination protocol where the maleimide group has been installed successfully in the ortho-position of phenoxyacetamide. In this protocol, phenoxyacetamide behaved as a traceless directing group with the in situ release of acetamide. The base-assisted E2-elimination is the key to the success of the olefination reaction.

Rhodium-Catalyzed Synthesis of 2-Methylindoles via C-N Bond Cleavage of N-Allylbenzimidazole.

A rhodium-catalyzed oxidative C-H/N-H dehydrogenative [3 + 2] annulation strategy has been reported between anilines and N-allylbenzimidazole for the synthesis of 2-methylindole scaffolds. An N-allylbenzimidazole has been used as a 2C synthon for the synthesis of indole, and more importantly, this transformation involves the cleavage of the thermodynamically stable C-N bond of allylamine. Detailed mechanistic studies have been performed and a key intermediate was detected in HRMS. This transformation proceeds through a cascade of C(sp2)-H allylation followed by intramolecular cyclization.

Transition metal-catalyzed C-H/C-C activation and coupling with 1,3-diyne.

This review provides a broad overview of the recent developments in the field of transition metal-catalyzed C-H/C-C bond activation and coupling with 1,3-diyne for assembling alkynylated heterocycles, bis-heterocycles, and 1,3-enynes. Transition metal-catalyzed inert bond (C-H/C-C) activation has been the focus of attention among synthetic chemists in recent times. Enormous developments have taken place in C-H/C-C bond activation chemistry in the last two decades. In recent years the use of 2π-unsaturated units as coupling partners for the synthesis of heterocycles through C-H/C-C bond activation and annulation sequence has received immense attention. Among the unsaturated units employed for assembling heterocycles, the use of 1,3-diynes has garnered significant attention due to its ability to render bis-heterocycles in a straightforward manner. The C-H bond activation and coupling with 1,3-diyne has been very much explored in recent years. However, the development of strategies for the use of 1,3-diynes in the analogous C-C bond activation chemistry is less explored. Earlier methods employed to assemble bis-heterocycle used heterocycles that were preformed and pre-functionalized via transition metal-catalyzed coupling reactions. The expensive pre-functionalized halo-heterocycles and sensitive and expensive heterocyclic metal reagents limit its broad application. However, the transition metal-catalyzed C-H activation obviates the need for expensive heterocyclic metal reagents and pre-functionalized halo-heterocycles. The C-H bond activation strategy makes use of C-H bonds as functional groups for effecting the transformation. This renders the overall synthetic sequence both step and cost economic. Hence, this strategy of C-H activation and subsequent reaction with 1,3-diyne could be used for the larger-scale synthesis of chemicals in the pharmaceutical industry. Despite these advances, there is still the possibility of exploration of earth-abundant and cost-effective first-row transition metals (Ni, Cu, Mn. Fe, etc.) for the synthesis of bis-heterocycles. Moreover, the Cp*-ligand-free, simple metal-salt-mediated synthesis of bis-heterocycles is also less explored. Thus, more exploration of reaction conditions for the Cp*-free synthesis of bis-heterocycles is called for. We hope this review will inspire scientists to investigate these unexplored domains.

Annulation of Indole-2-Carboxamides with Bicycloalkenes Catalyzed by Ru(II) at Room Temperature: An Easy Access to ß-Carboline-1-one Derivatives under Mild Conditions.

Herein, we report the annulation of indole-2-carboxamides with bicycloalkenes, to synthesize ß-carboline-1-one derivatives under mild conditions. The commercially available ruthenium catalyst was used for the reaction. This reaction tolerates a wide range of functional groups and affords a good yield of ß-carboline-1-one derivatives. A reversible cyclometalation pathway was found to be operative in the mechanistic study.

Weak-Chelation Assisted Cobalt-Catalyzed C-H Bond Activation: An Approach Toward Regioselective Ethynylation of N-Aryl γ-Lactam.

The sustainable C-H bond ethynylation of N-aryl γ-lactam has been achieved in a highly regioselective manner. In this protocol, earth-abundant cobalt(III)-catalyst was found to be effective, triggering the C-H metalation using a weakly coordinating lactam group. Herein, the ortho-(sp2)-H ethynylation has been obtained regioselectively. The mechanistic studies reveal the non-involvement of the radical pathway for this conversion. However, the parallel kinetic isotope experiment suggests that the C-H bond activation is involved in the rate-determining step. In addition, the synthetic utility of ethynylated N-aryl γ-lactam has been demonstrated for many useful transformations.

N-Allylbenzimidazole as a strategic surrogate in Rh-catalyzed stereoselective trans-propenylation of aryl C(sp2)-H bond.

A Rh-catalyzed C(sp2)-H propenylation has been reported by taking N-allyl benzimidazole as an allylamine congener. This transformation has been observed for the first time, where a tandem process of C-H allylation followed by alkene isomerization delivers a highly stereoselective trans-propenylated product. Detailed mechanistic studies including the characterization of rhodacycle-intermediates have been conducted to understand the mechanism.

Diverse reactivity of alkynes in C-H activation reactions.

Alkynes occupy a prominent role as a coupling partner in the transition metal-catalysed directed C-H activation reactions. Due to low steric requirements and linear geometry, alkynes can effectively coordinate with metal d-orbitals. This makes alkynes one of the most successful coupling partners in terms of the number of useful transformations. Remarkably, by changing the reaction conditions and transition-metals from 5d to 3d, the pattern of reactivity of alkynes also changes. Due to the varied reactivity of alkynes, such as alkenylation, annulation, alkylation, and alkynylation, they have been extensively used for the synthesis of valuable organic molecules. Despite enormous explorations with alkynes, there are still a lot more possible ways by which they can be made to react with M-C bonds generated through C-H activation. Practically there is no limit for the creative use of this approach. In particular with the development of new high and low valent first-row metal catalysts, there is plenty of scope for this chemistry to evolve as one of the most explored areas of research in the coming years. Therefore, a highlight article about alkynes is both timely and useful for synthetic chemists working in this area. Herein, we have highlighted the diverse reactivity of alkynes with various transition metals (Ir, Rh, Ru, Pd, Mn, Fe, Co, Ni, Cu) and their applications, along with some of our thoughts on future prospects.

Rhodium-Catalyzed Selective C(sp2)-H Activation/Annulation of tert-Butyl Benzoyloxycarbamates with 1,3-Diynes: A One Step Access to Alkynylated Isocoumarins and Bis-Isocoumarins.

We report here a Rh(III) catalyzed regio- and stereoselective synthesis of alkynylated and bis-isocoumarin from 1,3-dialkyne. Exclusive one-pot formation of 3,3-bis-isocoumarin isomers has been achieved by eliminating several other possibilities. This is the first example of transition metal catalyzed synthesis of alkynylated and bis-isocoumarin scaffolds. The protocol is compatible with a wide range of functional groups affording good to excellent yields. Several mechanistic investigations, including deuterium labeling experiments and kinetic isotope effect studies, have been carried out.

Switching the Reactivity of the Nickel-Catalyzed Reaction of 2-Pyridones with Alkynes: Easy Access to Polyaryl/Polyalkyl Quinolinones.

A Ni-catalyzed C6 followed by C5 cascade C-H activation/[2 + 2 + 2] annulation of 2-pyridone with alkynes has been achieved. A change in the reaction pathway was achieved by tuning the reaction conditions and incorporating a directing group. A wide variety of substrates and alkynes are amenable to this transformation. The key to success for this transformation is the use of sodium iodide as an additive. More importantly, we detected the five-membered metallacycle intermediate through HRMS wherein iodide is ligated to the metal.

Pyridone Directed Ru-Catalyzed Olefination of sp2(C-H) Bond Using Michael Acceptors: Creation of Drug Analogues.

Herein, the ruthenium-catalyzed regioselective sp2(C-H) monoalkenylation of N-arylpyridones has been demonstrated, where the pyridone was utilized as a weakly coordinating directing group. Importantly, the current methodology has been effectively applied to the synthesis of many drug analogues such as pirfenidone, naproxen, ibuprofen, geraniol, umbelliferone, pregnenolone, and estrone. This methodology tolerates a wide range of functional groups and yields up to 93% yield. A six-membered ruthenium complex was also detected by HRMS.

Palladium-catalyzed selective C-C bond cleavage and stereoselective alkenylation between cyclopropanol and 1,3-diyne: one-step synthesis of diverse conjugated enynes.

The stereoselective synthesis of 1,3-enynes from 1,3-diynes is demonstrated by palladium-catalyzed selective C-C bond cleavage of cyclopropanol. Exclusive formation of mono-alkenylated adducts was achieved by eliminating the possibility of di-functionalization with high stereoselectivity. Indeed, this protocol worked very well with electronically and sterically diverse substrates. Several studies, including deuterium labeling experiments and intermolecular competitive experiments, were carried out to understand the mechanistic details. The atomic-level mechanism followed in the catalytic process was also validated using DFT calculations, and the rate-controlling states in the catalytic cycle were identified. Furthermore, preliminary mechanistic investigations with radical scavengers revealed the non-involvement of the radical pathway in this transformation.

Co(II)-Catalyzed C-H/N-H Annulation of Cyclic Alkenes with Indole-2-carboxamides at Room Temperature: One-Step Access to ß-Carboline-1-one Derivatives.

We report herein a cobalt-catalyzed 8-aminoquinoline-directed highly regio- and stereoselective C-H/N-H activation annulation of indole-2-carboxamides with 1,2-dihydronaphthalene for the synthesis of ß-carboline-1-one derivatives at room temperature. A cheaper and commercially available cobalt catalyst has been used for this transformation. The protocol tolerates a wide range of functionalities, affording ß-carboline-1-one derivatives in good yields. An initial mechanistic study revealed a reversible cyclometalation to be operative.

Overcoming the Challenges toward Selective C(6)-H Functionalization of 2-Pyridone with Maleimide through Mn(I)-Catalyst: Easy Access to All-Carbon Quaternary Center.

An earth-abundant and inexpensive Mn(I)-catalyzed alkylation of 2-pyridone with maleimide has been reported for the first time, in contrast to previously reported Diels-Alder products. Notably, an unexpected rearrangement has been discovered in the presence of acetic acid, which also provides a unique class of compounds bearing three different N-heterocycles with an all-carbon quaternary center. Furthermore, single crystal X-ray and HRMS revealed a five-membered manganacycle intermediate. This methodology tolerates a wide variety of functional groups delivering the alkylated products in moderate to excellent yields.

Synthesis and Photophysical Study of Heteropolycyclic and Carbazole Motif: Nickel-Catalyzed Chelate-Assisted Cascade C-H Activations/Annulations.

Herein, nickel-catalyzed synthesis of polyarylcarbazole through sequential C-H bond activations has been described. Regioselective indole C2/C3 functionalization has been achieved in the presence of indole C7-H, which is quite challenging. In addition, this approach also gives easy access to building a heteropolycyclic motif through C6/C7 C-H functionalization of indoline. This methodology is not limited to aromatic internal alkynes as coupling partners; aliphatic alkynes have also shown good tolerance. Notably, during the optimization the catalytic enhancement with sodium iodide as an additive has been observed. We have also studied the photophysical properties of these highly conjugated molecules.