Hydroxy Group-Enabled Regio- and Stereoselective Hydroalkylation of Alkynyl Cyclobutanol via Palladium-Catalyzed C-C Bond Activation of Cyclopropanol: A One-Step Access to Vinyl Cyclobutanols.

The regio-/stereoselective synthesis of vinyl cyclobutanols from alkynyl cyclobutanols is demonstrated. Here, selective C-C bond activation of the cyclopropyl alcohol ring has been achieved in the presence of the cyclobutanol ring. The KIE experiments indicated the noninvolvement of the O-H oxidative addition step in the rate-determining step. Further, the applicability of these vinyl cyclobutanols for the synthesis of 1,4-diketones and 1,6-diketone is demonstrated.

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.

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.

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.

Ruthenium-Catalyzed Regioselective C(sp2)-H Activation/Annulation of N-(7-Azaindole)amides with 1,3-Diynes Using N-Amino-7-azaindole as the N,N-Bidentate Directing Group.

The ruthenium(II)-catalyzed regioselective annulation of N-(7-azaindole)amides with 1,3-diynes has been demonstrated. Bioactive N-amino-7-azaindole has been used as a new bidentate directing group to furnish an array of 3-alkynylated isoquinolones. Furthermore, the developed protocol works efficiently for both aryl- and heteroaryl-substituted amides producing a range of pharmacologically useful 7-azaindole-based isoquinolones with a wide range of functionality.

O-Directed C-H functionalization via cobaltacycles: a sustainable approach for C-C and C-heteroatom bond formations.

This review focuses on providing comprehensive highlights of the recent advances in the field of cobalt-catalysed C-H functionalization and related synthetic concepts, relying on these through oxygen atom coordination. In recent years, 3d transition metal (Fe, Co, Cu & Ni) catalysed C-H functionalization reactions have received immense attention on account of its higher abundance and low cost, as compared to noble metals such as Ir, Rh, Ru and Pd. Among the first-row transition metals, cobalt is one of the extensively used metals for sustainable synthesis due to its unique reactivity towards the functionalization of inert C-H bonds. The functionalization of the inert C-H bond necessitates a proximal directing group. In this context, strongly coordinating nitrogen atom directed C-H functionalizations have been well explored. Nevertheless, strongly coordinating nitrogen-containing scaffolds, such as pyridine, pyrimidine, and 8-aminoquinoline, have to be installed and removed in a separate process. In contrast, C-H functionalizations through weakly coordinating atoms, such as oxygen, are largely underdeveloped. Since the oxygen atom is a part of many readily available functional groups, such as aldehydes, ketones, carboxylic acids, and esters, it could be used as directing groups for selective C-H functionalization reactions without any modification. Thus, the use of 3d transition metals, such as cobalt, along with weakly coordinating (oxygen) directing groups for C-H functionalization reactions are more sustainable, especially for the large-scale production of pharmaceuticals in industries. During the last decade, notable progress has been made using this concept. Nonetheless, almost all the reports are restricted to the formation of C-C and C-N bond. Therefore, there is a wide scope for developing this area for the formation of other bonds, such as C-X (halogens), C-B, C-S, and C-Se.

Ruthenium-Catalyzed Cross Dehydrogenative Annulation of N-(7-Azaindole)benzamides with Maleimides: One-Step Access to Highly Functionalized Pyrroloisoquinoline.

A ruthenium(II)-catalyzed cross dehydrogenative annulation of N-(7-azaindole)benzamides with maleimides has been demonstrated. Herein, we have explored the use of N-amino-7-azaindole as a new bidentate directing group for dehydrogenative [4 + 2] annulation. This method works efficiently, affording a variety of pharmacologically useful 7-azaindole-based isoquinolones and showing a wide functional group tolerance.

Palladium-Catalyzed C-C Bond Activation of Cyclopropenone: Modular Access to Trisubstituted α,ß-Unsaturated Esters and Amides.

Strain-driven palladium/N-heterocyclic carbene-catalyzed C-C bond activation of diphenylcyclopropenone (DPC) has been explored for one-step access to trisubstituted α,ß-unsaturated esters and amides. The designed transformation works under mild conditions providing exclusively a single stereoisomer. Mechanistic studies support the oxidative addition of the C-C bond of cyclopropenone to in-situ-generated Pd(0) intermediate. We have proved that vinylic hydrogen in the product is coming from phenol/aniline through deuterium-labeling studies. Late-stage functionalization of bioactive molecules such as procaine, estrone, and hymecromone demonstrates the robustness of this protocol.

Redox-Neutral Cobalt(III)-Catalyzed C-H Activation/Annulation of α,ß-Unsaturated Oxime Ether with Alkyne: One-Step Access to Multisubstituted Pyridine.

A redox neutral Co(III)-catalyzed annulation of α,ß-unsaturated oxime ether with alkyne has been reported. Multisubstituted pyridines were synthesized in good yields without the use of any heavy metal oxidants. The developed methodology tolerates a variety of functional groups. Notably, this transformation has been applied to the late-stage modification of the bioactive molecule dehydropregnenolone.

Rhodium-Catalyzed One-Pot Access to N-Polycyclic Aromatic Hydrocarbons from Aryl Ketones through Triple C-H Bond Activations.

A Rh-catalyzed pot and step economic synthesis of aza-polycyclic aromatic hydrocarbons (N-PAHs) from readily available aryl ketones and alkynes has been disclosed. Additionally, a novel synthetic application of the well-known aminating reagent hydroxylamine-O-sulfonic acid (HOSA) has been explored as an in situ redox-neutral directing group for the formation of N-PAHs via isoquinoline. Multiple bond formation in a single operation through a cascade of triple C-H bond activations is the beauty of this protocol. The challenging annulations of two different alkynes in a regioselective fashion have been demonstrated effectively. Mechanistic studies reveal that 3,4-diphenyl-1-methylisoquinoline is an active intermediate for this one-pot transformation.

Rhodium-Catalyzed Room Temperature C-C Activation of Cyclopropanol for One-Step Access to Diverse 1,6-Diketones.

A rhodium-catalyzed room temperature C-C activation of cyclopropanol has been demonstrated for the single-step synthesis of a range of electronically and sterically distinct 1,6-diketones. This reaction proceeds efficiently in shorter reaction time following a highly atom-economical pathway. To illustrate the synthetic potential of 1,6-diketones, aldol and macrocyclization reactions have been successfully demonstrated. Preliminary mechanistic studies revealed the involvement of nonradical pathways.