Metallaelectro-catalyzed alkyne annulations via C-H activations for sustainable heterocycle syntheses.

Alkyne annulation represents a versatile and powerful strategy for the assembly of structurally complex compounds. Recent advances successfully enabled electrocatalytic alkyne annulations, significantly expanding the potential applications of this promising technique towards sustainable synthesis. The metallaelectro-catalyzed C-H activation/annulation stands out as a highly efficient approach that leverages electricity, combining the benefits of electrosynthesis with the power of transition-metal catalyzed C-H activation. Particularly attractive is the pairing of the electro-oxidative C-H activation with the valuable hydrogen evolution reaction (HER), thereby addressing the growing demand for green energy solutions. Herein, we provide an overview of the evolution of electrochemical C-H annulations with alkynes for the construction of heterocycles, with a topical focus on the underlying mechanism manifolds.

Electrochemical Late-Stage Functionalization.

Late-stage functionalization (LSF) constitutes a powerful strategy for the assembly or diversification of novel molecular entities with improved physicochemical or biological activities. LSF can thus greatly accelerate the development of medicinally relevant compounds, crop protecting agents, and functional materials. Electrochemical molecular synthesis has emerged as an environmentally friendly platform for the transformation of organic compounds. Over the past decade, electrochemical late-stage functionalization (eLSF) has gained major momentum, which is summarized herein up to February 2023.

The crucial role of silver(I)-salts as additives in C-H activation reactions: overall analysis of their versatility and applicability.

Transition-metal catalyzed C-H activation reactions have been proven to be useful methodologies for the assembly of synthetically meaningful molecules. This approach bears intrinsic peculiarities that are important to be studied and comprehended in order to achieve its best performance. One example is the use of additives for the in situ generation of catalytically active species. This strategy varies according to the type of additive and the nature of the pre-catalyst that is being used. Thus, silver(I)-salts have proven to play an important role, due to the resulting high reactivity derived from the pre-catalysts of the main transition metals used so far. While being powerful and versatile, the use of silver-based additives can raise concerns, since superstoichiometric amounts of silver(I)-salts are typically required. Therefore, it is crucial to first understand the role of silver(I) salts as additives, in order to wisely overcome this barrier and shift towards silver-free systems.

Enantioselective electrochemical cobalt-catalyzed aryl C-H activation reactions.

Enantioselective redox transformations typically rely on costly transition metals as catalysts and often stoichiometric amounts of chemical redox agents as well. Electrocatalysis represents a more sustainable alternative, in particular through the use of the hydrogen evolution reaction (HER) in place of a chemical oxidant. In this work, we describe strategies for HER-coupled enantioselective aryl carbon-hydrogen bond (C-H) activation reactions using cobalt in place of a precious metal catalyst for the asymmetric oxidation. Thus, highly enantioselective carbon-hydrogen and nitrogen-hydrogen (C-H and N-H) annulations of carboxylic amides were achieved, which gave access to point and axially chiral compounds. Furthermore, the cobalt-mediated electrocatalysis enabled the preparation of various phosphorus (P)-stereogenic compounds by selective desymmetrization through dehydrogenative C-H activation reactions.

Redox-Neutral Ruthenium(II)-Catalyzed Enol-Directed Arene C-H Alkylation with Maleimides.

An enol-assisted regioselective arene C-H alkylation with maleimides is developed under redox-neutral ruthenium(II) catalysis, offering a wide variety of valuable 3-aryl succinimides including amino acid embedded frameworks in good to excellent yields. The products were also aromatized to produce synthetically useful resorcinol-based biaryls. Mechanistic studies support an organometallic pathway with a reversible C-H metalation step for this reaction.

Palladium(II)-Catalyzed Regioselective Hydrocarbofunctionalization of N-Alkenyl Amides: Synthesis of Tryptamine Derivatives.

The hydrocarbofunctionalization of allyl amines connected to the picolinamide directing group is developed under Pd(II) catalysis. The strategy is grounded on a nucleopalladation concept, and a wide range of indoles effectively participated to produce valuable tryptamine derivatives in high yields. Synthetic utilities were showcased through the substrate diversification bearing bioactive core, Pictet-Spengler cyclization, and ß-carboline synthesis. A mechanistic study suggested an irreversible nucleopalladation step, while protodepalladation follows a reversible pathway.

Ruthenium(II)-Catalyzed (4+2) Annulative Difunctionalization of Non-conjugated Alkenyl Amides with Hydroxamic Acid Esters.

Ru(II)-catalyzed C-H bond activation strategy has been capitalized through a (4+2) annulative difunctionalization of non-conjugated alkenyl amides. Under mild conditions, a broad range of (hetero)aromatic amides embedded with NH-OMe unit as an internal oxidant produced high-value dihydroisoquinolinone scaffolds in good to excellent yields. This heteroannulation is also effective with acrylamides to dispense dihydro-2-pyridones and accommodates bioactive scaffolds such as tocopherol, estrone, and amino acids.

Ruthenium(II)-catalyzed C-H activation and (4+2) annulation of aromatic hydroxamic acid esters with allylic amides.

A (4+2) annulation under Ru(II)-catalysis is reported using aromatic hydroxamic acid esters as the oxidizing directing group and allylic amides as unactivated olefin coupling partners, delivering a wide variety of aminomethyl isoquinolinones in good to excellent yields. This annulation is distinctive as allylic congeners typically result in allylation and not the annulation. Late-stage derivatization of a bioactive synthetic bile acid has been showcased.

Ruthenium(II)-Catalyzed Regioselective C-H Olefination of Aromatic Ketones and Amides with Allyl Sulfones.

A Ru(II)-catalyzed cross-dehydrogenative Heck-type olefination of arenes with allyl sulfones leveraging the assistance of weakly coordinating ketone and amide functional groups is reported. It features a distinct reactivity profile in comparison to other allylic congeners, where ß-sulfonyl elimination was not detected. The ambiphilic nature of the allyl sulfone side chain has also been demonstrated through intramolecular aza-Michael addition and aldol condensation. Mechanistic studies indicated the involvement of a reversible metalation step, where ß-hydride elimination takes place selectively from the benzylic position.

Transition Metal Catalyzed Free-Amine (-NH2 ) Directed C-H Bond Activation and Functionalization for Biaryl Frameworks.

Transition-metal-catalyzed direct transformation of inert C-H bond has revolutionized the arsenal of main-stream organic synthesis, providing a new upfront to forge structurally enriched and biologically relevant scaffolds in a step- and atom-economical way. Past decades have accounted for the major developments in this realm, proclaiming excellent site-selectivity by exploiting a variety of coordinating directing groups (DGs). Consideration of versatile, abundant, sp3 -hybridized free-amine (-NH2 ) functionality for the same purpose has always been a formidable task owing to its innate reactivity. In recent years, free-amine functionality has emerged as a potent DG for a wide range of C-C and C-heteroatom bonds formations and annulation cascades. In this review article, we have discussed the advancements of free-amine directed C-H activation/functionalization reactions towards biaryl frameworks made within a decade (2012 to 2021).

Cross-Dehydrogenative Coupling/Annulation of Arene Carboxylic Acids and Alkenes in Water with Ruthenium(II) Catalyst and Air.

A cross-dehydrogenative coupling of arene carboxylic acids with olefins is reported with ruthenium(II) catalyst employing air and water as green oxidant and solvent, respectively. It offers a robust synthesis of valuable phthalide molecules. A one-pot sequential strategy is also disclosed to access Heck-type products that are apparently difficult to make directly from arene carboxylic acids.

Ruthenium(II)-catalyzed amide directed spiroannulation with naphthoquinones: access to spiro-isoindolinone frameworks.

A mild ruthenium(ii)-catalyzed spiroannulation between benzamides and naphthoquinones is developed for the succinct synthesis of biologically relevant spiro-isoindolinone scaffolds. A base promoted transannulation of spirocyclic products en route to valuable benzo[b]phenanthridinetriones in good yields has also been accomplished.

Ruthenium-Catalyzed Site-Selective C-H Bond Activation/Annulation Cascade toward Dibenzoazepinone Skeletons.

A free amine-directed ruthenium(II)-catalyzed hydroarylation and concomitant regioselective transamidation cascade between 2-aminobiphenyls and diversely substituted maleimides is reported, furnishing biologically relevant dibenzo[b,d]azepinone scaffolds in high yields. The protocol accommodates a range of functional groups and showcases synthesis of dibenzoazepinones bearing amino acid side chains through substrate design.

Copper-Catalyzed 8-Aminoquinoline-Directed Oxidative C-H/N-H Coupling for N-Arylation of Sulfoximines.

A copper-catalyzed cross-dehydrogenative C-H/N-H coupling has been devised to access a series of N-arylated sulfoximines in high yield from 8-aminoquinoline-derived benzamides and sulfoximines. The reaction is scalable, and mechanistic studies favor the involvement of an organometallic pathway, where C-H bond cleavage is presumed to be the kinetically relevant step. The utility of sulfoximine-coupled benzamides was displayed through the nickel-catalyzed acceptorless dehydrogenative olefination of benzyl alcohols.

Enhancing Ru(II)-Catalysis with Visible-Light-Mediated Dye-Sensitized TiO2 Photocatalysis for Oxidative C-H Olefination of Arene Carboxylic Acids at Room Temperature.

Erythrosine B sensitized TiO2 photocatalysis has been combined with Ru(II)-catalysis to accomplish an oxidative olefination/annulation of benzoic acids with activated olefins under mild conditions that tolerates useful functionalities, such as halides, free hydroxy, acetamido, etc. The morphology of the photocatalyst is unaffected during the reaction and it can be reused. Mechanistic studies favor the involvement of a photo-induced single electron transfer process.

Recent Advancements in Transition-Metal-Catalyzed One-Pot Twofold Unsymmetrical Difunctionalization of Arenes.

Transition-metal-catalyzed direct C-H bond activation reactions have been embraced as a powerful synthetic tool to access diverse functionalized arenes. However, site-selective incorporation of multiple distinct functionalities in an arene has always been a formidable challenge. Recent efforts from the synthetic community have disclosed a few dynamic synthetic approaches to fabricate multifunctionalized arenes in one-pot using a single catalytic system. These reports manifested the immense potential of such approaches to expedite contemporary organic synthesis towards building molecular complexity. In this minireview, we have illustrated the recent progress in this area, highlighting the contribution from several synthetic chemists including our group.

A ruthenium-catalyzed free amine directed (5+1) annulation of anilines with olefins: diverse synthesis of phenanthridine derivatives.

A ruthenium(ii)-catalyzed cross-ring (5+1) annulation between 2-aminobiphenyls and activated olefins is disclosed for succinct synthesis of valuable phenanthridine scaffolds. The protocol avails a common organic functional group, free amine, as a directing group and represents a unique combination of C-H activation/annulation/C-C bond cleavage cascade that bodes well in the production of bioactive alkaloids including trisphaeridine and bicolorine.

Streamlined Ruthenium(II) Catalysis for One-Pot 2-fold Unsymmetrical C-H Olefination of (Hetero)Arenes.

The potential of carboxylate-directed Ru(II)-catalyzed C-H bond activation has been exploited in the first example of challenging 2-fold unsymmetrical cross-dehydrogenative olefination of (hetero)aromatic carboxylic acids. This highly regioselective protocol operates in one pot under a single catalytic system and tolerates a wide spectrum of carboxylic acids as well as activated olefins. A rare example of an unsymmetrical meta-bis-olefination approach has also been successfully engineered via a tailored unsymmetrical double C-H functionalization and concomitant decarboxylation process.

Directed C-H Bond Functionalization: A Unified Approach to Formal Syntheses of Amorfrutin A, Cajaninstilbene Acid, Hydrangenol, and Macrophyllol.

Formal syntheses of natural products amorfrutin A, cajaninstilbene acid, hydrangenol, and macrophyllol have been accomplished on the basis of successive C-H bond functionalization of ready-stock benzoic acids. This concise strategy involves transition-metal-catalyzed directed C-H olefination, C-H hydroxylation, and acid-mediated C-H prenylation as key steps.

A Cross-Dehydrogenative Annulation Strategy towards Synthesis of Polyfluorinated Phenanthridinones with Copper.

The first cross-dehydrogenative annulation of (hetero)aromatic amides with polyfluoro(hetero)arenes is presented. This operationally simple oxidative annulation process is mediated by inexpensive copper salt, accommodates a wide range of substrates with exquisite chemo- and regioselectivity profile, and produces demanding polyfluorinated phenanthridinones in high yields (up to 92 %). Using alkenyl amides under identical conditions, the synthesis of polyfluorinated 2-quinolones has also been accomplished. Given the importance of fluorinated heterocycles in the pharmaceutical industry and drug discovery, this work is highly significant.