A highly diastereoselective one-pot Ugi/radical spirocyclization/aza-Michael addition sequence.

We hereby report a highly diastereoselective synthesis of chalcogenated azaspirotricycles via a one-pot Ugi/spirocyclization/aza-Michael addition sequence. The reaction proceeds via a key visible light mediated spirocyclization step under mild, metal-free and energy efficient conditions. A variety of complex sulfenylated and selenylated azaspirotricycles were obtained in good yields. The reaction was found to be scalable and preliminary mechanistic studies indicated that the spirocyclization step proceeds via radical intermediates.

α-Carbonyl sulfoxonium ylides in transition metal-catalyzed C-H activation: a safe carbene precursor and a weak directing group.

Transition metal-catalyzed cross-coupling of sp2 C-H bonds with diazo compounds via carbene migratory insertion represents an efficient strategy for the construction of C-C and C-heteroatom bonds in organic synthesis. Despite the popularity of diazo compounds as coupling partners in C-H activation, they pose serious safety and stability issues due to potential exothermic reactions linked with the release of N2 gas. However, compared with diazo compounds, sulfoxonium ylides are generally crystalline solids, more stable, widely used in industrial scales, and easier/safer to prepare. Therefore, recent years have witnessed an upsurge in employing α-carbonyl sulfoxonium ylides as an alternative carbene surrogate in transition metal-catalyzed C-H activation. Unlike diazo compounds, α-carbonyl sulfoxonium ylides contain inherent potential to serve as a coupling partner as well as a weak directing group. This review will summarize the progress made in both categories of reactions.

Visible-Light Mediated Arbuzov-Like Reaction with Thiophenols.

We hereby disclose, a visible light mediated addition of sulfenyl radicals to trialkyl phosphites to access functionalized phosphorothioates. The use of cheap and readily available Eosin Y as a photocatalyst under mild energy efficient conditions bypassing the use of external oxidants forms the chief highlight of the work. The protocol is scalable and mechanistic studies indicate that the reaction proceeds through an ionic-Arbuzov like pathway from phosphoranyl radicals.

Regioselective Dichotomy in Ru(II)-Catalyzed C-H Annulation of Aryl Pyrazolidinones with 1,3-Diynes.

Herein, we present a substrate-controlled regiodivergent strategy for the selective synthesis of C3 or C2-alkynylated indoles via ruthenium-catalyzed [3 + 2]-annulation of readily available pyrazolidinones and 1,3-diynes. Remarkably, C3-alkynylated indoles were obtained in good yields when 1,4-diarylbuta-1,3-diynes were employed as the coupling partners. On the other hand, dialkyl-1,3-diynes led to the selective formation of C2-alkynylated indoles. The key features of the strategy are the operationally simple conditions and external-oxidant-free, broad-scope, and substrate-switchable indole synthesis. Scale-up reactions and further transformations expanded the synthetic utility of the protocol.

Catalytic Insertion Reactions of α-Imino Carbenoids.

Over the past decade, α-imino carbenoids generated via transition metal (such as rhodium, nickel, copper, palladium, silver) catalyzed denitrogenative ring-opening of N-sulfonyl-1,2,3-triazoles have found an extensive account of applications in synthetic organic chemistry. Particularly, they have been widely utilized as a donor/acceptor carbene complex in a range of transformations leading to diverse nitrogen containing compounds and heterocycles. Along the same direction, 3-diazoindolin-2-imines were successfully applied as an alternative source of α-imino carbenoid precursors for the development of a number of methodologies to access diverse indole derivatives. This review summarizes the insertion reactions of α-imino metal carbenes derived from N-sulfonyl-1,2,3-triazoles and 3-diazoindolin-2-imines.

Rh(III)-Catalyzed Stereoselective C-C Bond Cleavage of ACPs with N-Phenoxyacetamides: The Critical Role of the Nucleophilic Directing Group.

Rh(III)-catalyzed redox-neutral chemodivergent coupling of N-phenoxyacetamides and alkylidenecyclopropanes (ACPs) has been documented. The reaction proceeds via C-H activation, regioselective migratory insertion and stereoselective ß-carbon elimination followed by ß-hydride elimination, resulting in o-dienylation of phenols in nonpolar solvents, whereas [3 + 2]-annulation leading to dihydrobenzofurans was realized in polar fluorinated solvents. It was observed that the nucleophilic directing group controls the elimination of ß-carbon and so plays a vital role for achieving high stereoselectivities. The synthetic utility of the dienylation and annulation was demonstrated by carrying out gram scale reactions and further derivatization.

Deoxygenative C2-heteroarylation of quinoline N-oxides: facile access to α-triazolylquinolines.

A metal- and additive-free, highly efficient, step-economical deoxygenative C2-heteroarylation of quinolines and isoquinolines was achieved from readily available N-oxides and N-sulfonyl-1,2,3-triazoles. A variety of α-triazolylquinoline derivatives were synthesized with good regioselectivity and in excellent yields under mild reaction conditions. Further, a gram-scale and one-pot synthesis illustrated the efficacy and simplicity of the developed protocol. The current transformation was also found to be compatible for the late-stage modification of natural products.

Cobalt-Catalyzed C8-Dienylation of Quinoline-N-Oxides.

An efficient Cp*CoIII -catalyzed C8-dienylation of quinoline-N-oxides was achieved by employing allenes bearing leaving groups at the α-position as the dienylating agents. The reaction proceeds by CoIII -catalyzed C-H activation of quinoline-N-oxides and regioselective migratory insertion of the allene followed by a ß-oxy elimination, leading to overall dienylation. Site-selective C-H activation was achieved with excellent selectivity under mild reaction conditions, and 30 mol % of a NaF additive was found to be crucial for the efficient dienylation. The methodology features high stereoselectivity, mild reaction conditions, and good functional-group tolerance. C8-alkenylation of quinoline-N-oxides was achieved in the case of allenes devoid of leaving groups as coupling partners. Furthermore, gram-scale preparation and preliminary mechanistic experiments were carried out to gain insights into the reaction mechanism.

Rh(II)-Catalyzed Denitrogenative Transannulation of N-Sulfonyl-1,2,3-triazolyl Cyclohexadienones for the Synthesis of Benzofurans and Cyclopropa[cd]indole-carbaldehydes.

A rhodium-catalyzed intramolecular denitrogenative transannulation of N-sulfonyl-1,2,3-triazole-tethered cyclohexadienones has been achieved for the synthesis of benzofurans and cyclopropa[cd]indole-carbaldehydes in an operationally simple procedure. Remarkably, the reaction pathway is fully dependent on the linker heteroatom (O or N) present between the cyclohexadienone unit and triazole moiety. In the case of O-linked triazoles, a cascade sequence consisting of intramolecular cyclopropanation and rearrangement takes place, leading to the formation of benzofurans, while, in the case of N-linked triazoles, cyclopropa[cd]indole-carbaldehydes were isolated exclusively.

Visible-light mediated sulfonylation of thiols via insertion of sulfur dioxide.

A simple and efficient visible-light mediated synthesis of thiosulfonates via a radical-radical coupling of sulfenyl radicals and arylsulfonyl radicals was developed. The reaction of thiols, aryldiazonium tetrafluoroborates and DABSO proceeded at room temperature using 5 mol% eosin Y. The reaction displayed wide functional group tolerance and delivered the unsymmetrical thiosulfonates in good to excellent yields.

Rh-Catalyzed Denitrogenative Reaction of N-Sulfonyl-1,2,3-triazoles with Isatoic Anhydrides and Oxadiazolones.

A convenient and simple, RhII -catalyzed denitrogenative method for the synthesis of biologically interesting 2-amino-benzoxazinones and 5-amino-oxadiazoles from readily available isatoic anhydrides and oxadiazolones has been developed. These reactions proceed via an O-H insertion onto α-imino RhII -carbenoid species followed by a rearrangement. The scope of the reaction can also be extended to benzoxazinones to access amino-substituted benzoxazines.

Cu-catalyzed Cascade Cyclization of Isothiocyanates, Alkynes, and Diaryliodonium Salts: Access to Diversely Functionalized Quinolines.

Herein, we report a copper-catalyzed novel, highly efficient, and modular cascade annulation reaction for the synthesis of quinoline derivatives starting from easily available alkynes, isothiocyanates, and diaryliodonium salts. The reaction displayed excellent regioselectivities, when unsymmetrical alkynes were employed as partners, giving access to diversely functionalized quinolines in good to excellent yields for a wide range of functional groups.

Selective Cascade Reaction of Bisallenes via Palladium-Catalyzed Aerobic Oxidative Carbocyclization-Borylation and Aldehyde Trapping.

A cascade reaction, consisting of a palladium-catalyzed regioselective aerobic oxidative carbocyclization-borylation of bisallenes and a final aldehyde trapping, afforded triene alcohols with high diastereoselectivity. The cascade reaction occurs under mild reaction conditions and proceeds via an allylboron intermediate that is trapped by the aldehyde in a stereoselective manner.

Cobalt-Catalyzed sp(2) -C-H Activation: Intermolecular Heterocyclization with Allenes at Room Temperature.

The reactivity of allenes in transition-metal-catalyzed C-H activation chemistry is governed by the formation of either alkenyl-metal (M-alkenyl) or metal-π-allyl intermediates. Although either protonation or a ß-hydride elimination is feasible with a M-alkenyl intermediate, cyclization has remained unexplored to date. Furthermore, due to the increased steric hindrance, the regioselectivity for the intramolecular cyclization of the metal-π-allyl intermediate was hampered towards the more substituted side. To address these issues, a unified approach to synthesize a diverse array of biologically and pharmaceutically relevant heterocyclic moieties by cobalt-catalyzed directed C-H functionalization was envisioned. Upon successful implementation, the present strategy led to the regioselective formation of dihydroisoquinolin-1(2H)-ones, isoquinolin-1(2H)-ones, dihydropyridones, and pyridones.

Palladium-catalyzed oxidative carbocyclization-carbonylation of allenynes and enallenes.

A highly efficient oxidative carbocyclization-carbonylation reaction cascade of allenynes and enallenes has been developed using a Pd(II) salt in low catalytic amounts under ambient temperature and pressure (1 atm of carbon monoxide). The use of DMSO as an additive was found to be important for an efficient reaction. A wide range of alcohols as trapping reagents were used to give the corresponding esters in good yields.

Rh(III)-catalyzed aldehydic and aryl C-H alkylation with cyclopropanols via C-H/C-C bond activation.

Herein, we report Rh(III) catalyzed aldehydic or aryl C-H alkylation via C-C bond activation of cyclopropanols, facilitating the synthesis of ß-functionalized ketones. The protocol employs cyclopropanol as the alkylating agent with 2-aminobenzaldehyde or aniline derivatives to access a variety of unsymmetrical 1,4-diketones or ß-aryl ketones, respectively. The practicality of these transformations is showcased through the modification of natural products, gram-scale synthesis, broad substrate scope and postfunctionalizations.

Ru(II)-Catalyzed Decarboxylative (4 + 2)-Annulation of Benzoic Acids and Benzamides with Propargyl Cyclic Carbonates.

Propargyl cyclic carbonates have emerged as versatile precursors in synthetic chemistry. However, their reactivity has so far been limited to transition metal-catalyzed substitution and cyclization reactions. Herein, we illustrate the successful employment of propargyl cyclic carbonates as coupling partners in Ru(II)-catalyzed C-H annulation of benzoic acids and benzamides. This approach allowed us to access a broad range of biologically relevant isocoumarin and isoquinolinone derivatives in good to excellent yields, utilizing bench-stable and easily accessible precursors. Preliminary mechanistic studies indicated that the C-H metalation step is both reversible and rate-determining in the reaction pathway. Furthermore, the utility of the developed methodology has been illustrated by scale-up and postfunctionalization experiments.

Expedient radical phosphonylations via ligand to metal charge transfer on bismuth.

Bismuth, in spite of its low cost and low toxicity, has found limited application in organic synthesis. Although the photoactivity of Bi(iii) salts has been well studied, this has not been effectively exploited in photocatalysis. To date, only a single report exists for the Bi-based photocatalysis, wherein carbon centered radicals were generated using ligand to metal charge transfer (LMCT) on bismuth. In this regard, expanding the horizon of bismuth LMCT catalysis for the generation of heteroatom centered radicals, we hereby report an efficient radical phosphonylation using BiCl3 as the LMCT catalyst. Phosphonyl radicals generated via visible-light induced LMCT of BiCl3 were subjected to a variety of transformations like alkylation, amination, alkynylation and cascade cyclizations. The catalytic system tolerated a wide range of substrate classes, delivering excellent yields of the scaffolds. The reactions were scalable and required low catalytic loading of bismuth. Detailed mechanistic studies were carried out to probe the reaction mechanism. Diverse radical phosphonylations leading to the formation of sp3-C-P, sp2-C-P, sp-C-P, and P-N bonds in the current work present the candidacy of bismuth as a versatile photocatalyst for small molecule activation.

Dual Copper Photoredox C-H Alkynylation with Arylacetylenes.

In the realm of organic synthesis, direct C-H alkynylation with arylacetylenes has remained a daunting challenge due to competing annulations or alkenylation. Addressing this long-standing issue, herein we demonstrate the merging of copper and photocatalysis to achieve the elusive C-H alkynylation of benzamides using arylacetylenes or arylpropiolic acids. Unlike conventional copper-mediated C-H activations, our protocol circumvents the need for high temperatures and stoichiometric amounts of copper salts or metal/non-metal oxidants. The versatility of the developed dual copper photoredox system is underscored by performing other diverse C-H functionalizations such as amination, selenylation, arylation, sulfonylation, and nitration under slightly modified conditions.

Pyrazolidinone-Aided Ru(II)-Catalyzed Regioselective C-H Annulation with Allenes.

Regioselective annulation of allenes via C-H activation represents an elegant synthetic approach toward the construction of valuable scaffolds. Considering the importance of allenes, herein we developed an unprecedented Ru(II)-catalyzed highly regioselective redox-neutral C-H activation/(4 + 1)-annulation of 1-arylpyrazolidinones employing allenyl acetates to access pyrazolo[1,2-a]indazol-1-one derivatives. Additionally, allenyl cyclic carbonates, which were never tested in C-H activation, were utilized to construct a similar class of heterocycles having a pendent alcohol functionality. Notably, double C-H functionalization was achieved by a simple modification of reaction conditions. The synthetic significance of this methodology is underscored by late-stage modification of natural products, broad substrate scope, gram-scale synthesis, and postfunctionalizations.