Denitrogenative Transannulation Research Articles

Enantioselective Nickel‐Catalyzed Denitrogenative Transannulation En Route to N−N Atropisomers

AbstractNickel‐catalyzed transannulation reactions triggered by the extrusion of small gaseous molecules have emerged as a powerful strategy for the efficient construction of heterocyclic compounds. However, their use in asymmetric synthesis remains challenging because of the difficulty in controlling stereo‐ and regioselectivity. Herein, we report the first nickel‐catalyzed asymmetric synthesis of N−N atropisomers by the denitrogenative transannulation of benzotriazones with alkynes. A broad range of N−N atropisomers was obtained with excellent regio‐ and enantioselectivity under mild conditions. Moreover, density functional theory (DFT) calculations provided insights into the nickel‐catalyzed reaction mechanism and enantioselectivity control.

Enantioselective Nickel-Catalyzed Denitrogenative Transannulation En Route to N-N Atropisomers.

Nickel-catalyzed transannulation reactions triggered by the extrusion of small gaseous molecules have emerged as a powerful strategy for the efficient construction of heterocyclic compounds. However, their use in asymmetric synthesis remains challenging because of the difficulty in controlling stereo- and regioselectivity. Herein, we report the first nickel-catalyzed asymmetric synthesis of N-N atropisomers by the denitrogenative transannulation of benzotriazones with alkynes. A broad range of N-N atropisomers was obtained with excellent regio- and enantioselectivity under mild conditions. Moreover, density functional theory (DFT) calculations provided insights into the nickel-catalyzed reaction mechanism and enantioselectivity control.

Recent Advances in the Denitrogenative Annulation Reactions of 1,2,3‐Thiadiazoles

Abstract1,2,3‐Thiadiazoles exhibit versatile reactivity due to their ability to undergo ring cleavage, forming α‐diazothione species through a Dimroth‐type equilibrium. Denitrogenation of the α‐diazothione, induced by high temperature, irradiation, or strong bases, allows generation of a wide range of reactive intermediates. Since 2016, the transition‐metal‐catalyzed denitrogenative transannulation of 1,2,3‐thiadiazoles has garnered significant attention as a promising approach to constructing diverse heterocyclic scaffolds. This review focuses on the denitrogenative reactions of 1,2,3‐thiadiazoles, particularly highlighting the novel rhodium‐catalyzed denitrogenative transannulation transformations along with their mechanisms.

Regioselectivity for the Rh(I)‐catalyzed Annulation of 1,2,3‐Thiadiazoles with Alkynes: Experimental and Computational Analysis Reveal the Surprising Role of the Alkyne Substituent

AbstractThe Rh(I)‐catalyzed denitrogenative annulation reactions of 1,2,3‐thiadiazoles are a new direct approach to synthesizing densely functionalized heterocycles. The synthesis of multisubstituted thiophenes is possible using this methodology, however the difficulty to predict which regioisomer will form is a current limitation. In this current work, systematic computational and experimental studies were performed addressing how the terminal alkyne substituent effects regioselectivity. The data revealed that the electronic and steric properties of the alkyne substituent effects regioselectivity, including whether the group is aryl or alkyl. The insight gained from this study has allowed the development of a framework for predicting regioselectivity for the Rh(I)‐catalyzed denitrogenative transannulation of 1,2,3‐thiadiazoles with terminal alkynes.

Regioselective Synthesis of 3-Substituted Isocoumarin-1-imines via Palladium-Catalyzed Denitrogenative Transannulation of 1,2,3-Benzotriazin-4(3H)-ones and Terminal Alkynes.

A palladium-catalyzed denitrogenative transannulation strategy to access various 3-substituted isocoumarin-1-imine frameworks using 1,2,3-benzotriazin-4(3H)-ones and terminal alkynes is described. The reaction is highly regioselective and tolerates a wide range of functional groups. The reaction is believed to proceed via a five-membered palladacycle intermediate extruding environmentally benign molecular nitrogen as a by-product. The utility of this method was showcased through the one-pot synthesis of biologically relevant 3-substituted isocoumarin scaffolds.

Rhodium‐Catalyzed Transannulation of 1,2,3‐Thiazoles with Alkynes for the Direct Synthesis of Thiochromenones

Comprehensive SummaryA rhodium‐catalyzed denitrogenative carbonylation of 1,2,3‐thiadiazole with alkynes to construct (benzo)thiochromenones is developed. Both terminal and internal alkynes were compatible in this [3+2+1] cycloaddition, affording a broad range of poly‐substituted thiochromenones. Unsymmetrical alkyne substrates exhibited good regioselectivity. It is noteworthy that the present strategy could be used to construct both monocyclic and benzo‐thiochromenones, and it is a novel example of denitrogenative transannulation with CO insertion.

Assembly of Benzo[c][1,2]dithiol-3-ones via Acid-Promoted Denitrogenative Transannulation of Benzotriazinones.

An expedient synthesis of benzo[c][1,2]dithiol-3-ones via metal-free denitrogenative transannulation of benzotriazinones is developed, which represents the first example of acid-mediated heteroannulation of benzotriazinones. This newly discovered reactivity of benzotriazinones enables the streamline synthesis of diverse benzo[c][1,2]dithiol-3-ones in decent yields by using sodium sulfide as the sulfur source under simple reaction conditions.

Recent advances in 3-aminoindazoles as versatile synthons for the synthesis of nitrogen heterocycles.

Nitrogen-based heterocycles are an important class of structural scaffolds distributed in biologically active natural products, medicinal chemistry, and agrochemicals. Hence, there is increasing interest in the development of novel synthetic strategies for the construction of these privileged structural motifs. Recently, 3-aminoindazoles have emerged as versatile synthons participating in a variety of condensation annulation, denitrogenative transannulation and rearrangement ring expansion reactions, which provide efficient synthetic routes for the formation of nitrogen heterocycles. This review systematically highlights for the first time the most recent advances in 3-aminoindazoles to provide a deep understanding of using 3-aminoindazoles as versatile synthons in organic transformations for synthetic and medicinal chemists.

Transannulation of Pyridotriazoles with Naphthoquinones and Indoles: Synthesis of Benzo[f]Pyrido[1,2‐a]Indoles and Indolizino[3,2‐b]indoles

AbstractRuthenium catalysed denitrogenative transannulation of pyridotriazoles with naphthoquinones provided the transannulated benzo[f]pyrido[1,2‐a]indoles derivatives in good to excellent yields. While pyridotriazoles with indoles in presence of PivOH and oxone yield indolizino[3,2‐b]indoles under metal‐free conditions. Quinone annulation proceeds through ruthenium‐carbenoid intermediate while indole annulation may proceed via a diazo‐pyridinium intermediate. Control experiments suggest that both the transformations follow the ionic mechanism.magnified image

Rhodium-Catalyzed Denitrogenative Transannulation of N-Sulfonyl-1,2,3-triazoles with Glycals Giving Pyrroline-Fused N-Glycosides.

Described here is a selective synthesis of 2,3-dihydropyrrole-fused N-glycosides through rhodium-catalyzed denitrogenative transannulation of N-sulfonyl-1,2,3-triazoles with glycals. A series of pyrroline-fused N-glycosides are afforded in moderate to excellent yields with exclusive regioselectivity and stereoselectivity. Functional application of such a resultant product by oxidative addition and epoxidation is also explored. Notably, the treatment of a pyrroline-fused N-glycoside (3a) with TMSOTf efficiently leads to an interesting unexpected C-nucleoside (9) via a TMSOTf-inducing ring opening/acetyl migration/ring closing reaction sequence.

BF3·Et2O catalyzed transannulation of pyridotriazoles with isothiocyanates: synthesis of thiazolo[3,4-a]pyridin-3-imines

The synthesis of thiazolo[3,4-a]pyridin-3-imines, through denitrogenative transannulation of pyridotriazoles, under transition metal-free conditions is described.

Synthesis of benzothiazonine by rhodium-catalyzed denitrogenative transannulation of 1-sulfonyl-1,2,3-triazole and thiochromone.

A facile synthesis of multi-functionalized benzothiazonine was achieved by the rhodium-catalyzed denitrogenative annulation of 1-sulfonyl-1,2,3-triazole and thiochromone. In view of the excellent atom economy, broad substrate scope and easy availability of starting materials, the protocol provided an efficient strategy for the construction of medium N,S-heterocycles.

Synthesis of 3-Alkoxy-4-Pyrrolin-2-ones via Rhodium(II)-Catalyzed Denitrogenative Transannulation of 1H-1,2,3-Triazoles with Diazo Esters.

A method for the synthesis of densely substituted 4-pyrrolin-2-ones by Rh(II)-catalyzed denitrogenative transannulation of 1-alkyl-4-aryl-1H-1,2,3-triazoles with diazo esters has been developed. The reaction proceeds via an attack of the rhodium-bound carbene at the N2 atom of the triazole and the formation of unstable 3,4-dihydro-1,2,4-triazine, which further undergoes ring contraction to a 4-pyrrolin-2-one under rhodium catalysis. The method is inapplicable to 1,2,3-triazoles with primary alkyl substituent at C4, which afford stable 1,2,3-triazol-3-ium ylides as the main products.

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.

Metal-free synthesis of imidazole by BF3·Et2O promoted denitrogenative transannulation of N-sulfonyl-1,2,3-triazole.

BF3·Et2O promoted metal-free denitrogenative transannulation of N-sulfonyl-1,2,3-triazole was reported. Rather than transition metals, BF3·Et2O was employed for the first time to promote the formation of α-diazoimines from N-sulfonyl-1,2,3-triazoles in nitriles, leading to the synthesis of various imidazoles. The protocol tolerates a broad range of functional groups and could also be applied to the late-stage modification of bioactive molecules, demonstrating the potential of this protocol in organic synthesis. A plausible mechanism was proposed.

Rhodium-catalyzed denitrogenative transannulation of 1,2,3-triazolyl-carbamates: efficient access to 4-aminooxazolidinones

The rhodium(ii)-catalyzed denitrogenative transannulation reaction of 1,2,3-triazolyl-carbamates was described providing an efficient access to biologically interesting 4-aminooxazolidinones in excellent yields and selectivities.

Lewis Acid-Catalyzed Denitrogenative Transannulation of Pyridotriazoles with Nitriles: Synthesis of Imidazopyridines

The synthesis of imidazo[1,5-a]pyridines through denitrogenative transannulation of pyridotriazoles with nitriles using BF3·Et2O as catalyst has been described. The combination of solvents (dichlorobenzene-dichloroethane) plays a crucial role in achieving quantitative yields of desired products under metal-free conditions.

ChemInform Abstract: Copper‐Catalyzed Denitrogenative Transannulation Reaction of Pyridotriazoles: Synthesis of Imidazo[1,5‐a]pyridines with Amines and Amino Acids.

The copper-catalyzed aerobic oxidative synthesis of imidazo[1,5-a]pyridines via cascade denitrogenative transannulation reaction of pyridotriazoles with benzylamines with good functional group tolerance is developed. The present methodology is also applicable to amino acids to obtain imidazo[1,5-a]pyridines via decarboxylative oxidative cyclization.

Nickel(0)-Catalyzed Denitrogenative Transannulation of Benzotriazinones with Alkynes: Mechanistic Insights of Chemical Reactivity and Regio- and Enantioselectivity from Density Functional Theory and Experiment

The mechanism of Ni(0)-catalyzed denitrogenative transannulation of 1,2,3-benzotriazin-4(3H)-ones with alkynes to access isoquinolones has been comprehensively studied by a density functional theory (DFT) calculation and control experimental investigation. The results indicate that the transformations proceed via a sequential nitrogen extrusion, carbometalation, Ni–C bond insertion, and reductive elimination process. A frontier molecular orbital (FMO) theory and natural bond orbital (NBO) analysis reveals that the advantages of substituents on chemical reactivity and regioselectivity exist for multiple reasons: (1) Phenyl groups on the N atom of benzotriazinone and/or unsymmetrical alkynes mainly account for the high reactivity and regioselectivity via its electronic effect. (2) The π···π interaction between the phenyl substituent on the alkyne and triazole ring might partially contribute to the high regioselectivity when unsymmetrical alkynes were employed as the substrates. Furthermore, DFT calculations...

Copper-Catalyzed Denitrogenative Transannulation Reaction of Pyridotriazoles: Synthesis of Imidazo[1,5-a]pyridines with Amines and Amino Acids.

The copper-catalyzed aerobic oxidative synthesis of imidazo[1,5-a]pyridines via cascade denitrogenative transannulation reaction of pyridotriazoles with benzylamines with good functional group tolerance is developed. The present methodology is also applicable to amino acids to obtain imidazo[1,5-a]pyridines via decarboxylative oxidative cyclization.