Nickel-Catalyzed Cycloaddition Research Articles

Improved Total Synthesis of Indolizidine and Quinolizidine Alkaloids via Nickel-Catalyzed (4 + 2) Cycloaddition.

A Ni-catalyzed (4 + 2) cycloaddition of bicyclic 3-azetidinones and alkynes was developed to access indolizidine and quinolizidine alkaloids. A key element was the development of a diazomethylation procedure that allows the efficient synthesis of bicyclic azetidinones from pyroglutamic and 6-oxopiperidine-2-carboxylic acid. A ligand screening led to improved regioselectivity and enantiopurity during the Ni-catalyzed (4 + 2) cycloaddition. This straightforward methodology was leveraged to synthesize (+)-ipalbidine, (+)-septicine, (+)-seco-antofine, and (+)-7-methoxy-julandine.

Ni-catalyzed enantioselective [2 + 2 + 2] cycloaddition of malononitriles with alkynes

Summary Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The α-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes from feedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step.

A Novel Fluorescent Skeleton from Disubstituted Thiochromenones via Nickel-Catalyzed Cycloaddition of Sulfobenzoic Anhydrides with Alkynes

Nickel-catalyzed cycloaddition of alkynes and 2-sulfobenzoic anhydrides gives highly functionalized thiochromenones. The reaction undergoes a deoxygenative rather than decarbonylative pathway and shows advantages of an excellent isolated yield (up to 95%), high reaction efficiency, and high regioselectivity. As one of the resulted products, 2,3-di(triphenylamine)-thiolchromenone possesses a typical aggregation-induced emission property and emits efficient near-infrared fluorescence.

Computational Studies on Reaction Mechanism and Origins of Selectivities in Nickel-Catalyzed (2 + 2 + 2) Cycloadditions and Alkenylative Cyclizations of 1,6-Ene-Allenes and Alkenes.

The reaction mechanism and origins of ligand-controlled selectivity, regioselectivity, and stereoselectivity of Ni-catalyzed (2 + 2 + 2) cycloadditions and alkenylative cyclizations of 1,6-ene-allenes and alkenes were studied by using density functional theory. The catalytic cycle involves intermolecular oxidative coupling and an intramolecular concerted 1,4-addition step to afford a stable metallacycloheptane intermediate; these steps determine both the regioselectivity and stereoselectivity. Subsequent C-C reductive elimination leads to the cyclohexane product, whereas the β-hydride elimination leads to the trans-diene product. The selectivity between (2 + 2 + 2) cycloadditions and alkenylative cyclizations is controlled by the ligand. Irrespective of the nature of the terminal substituents on the ene-allene and alkene, the P(o-tol)3 ligand always favors the C-C reductive elimination, resulting in the cyclohexane product. On the other hand, the flexibility of the PBu3 ligand means that electronic and steric factors play important roles. Electron-withdrawing groups such as CO2Me in the ene-allene terminal substituent induce obvious substrate-ligand repulsion and destabilize the C-C reductive elimination, giving rise to the trans-diene product.

DFT Study on Rhodium-Catalyzed Intermolecular [2 + 2] Cycloaddition of Terminal Alkynes with Electron-Deficient Alkenes

Density functional theory (DFT) calculations with the B3LYP functionals elucidated the reactivity, selectivity, and mechanisms of a rhodium-catalyzed intermolecular [2 + 2] cycloaddition of terminal alkynes with electron-deficient alkenes. The most plausible reaction pathway was discussed as three distinct processes in full catalytic cycles, including (1) substrate exchange, (2) nucleophilic addition and cyclization, and (3) separation of product and recycling of catalyst; the formal [2 + 2] cycloaddition indeed proceeded through a rate-determining and stepwise addition–cyclization process. We then compared the outer-sphere and inner-sphere mechanisms for the formation of cyclobutene intermediates and reported that the former pathway is more accessible kinetically and thus more competitive, being contrary to the proposed mechanism for some nickel-catalyzed cycloaddition reactions in the literature. Furthermore, the substituent effect has been investigated using various alkenes CH2═CHR (R = COOMe, CN, H, C...

Advances in nickel-catalyzed cycloaddition reactions to construct carbocycles and heterocycles.

Transition-metal catalysis has revolutionized the field of organic synthesis by facilitating the construction of complex organic molecules in a highly efficient manner. Although these catalysts are typically based on precious metals, researchers have made great strides in discovering new base metal catalysts over the past decade. This Account describes our efforts in this area and details the development of versatile Ni complexes that catalyze a variety of cycloaddition reactions to afford interesting carbocycles and heterocycles. First, we describe our early work in investigating the efficacy of N-heterocyclic carbene (NHC) ligands in Ni-catalyzed cycloaddition reactions with carbon dioxide and isocyanate. The use of sterically hindered, electron donating NHC ligands in these reactions significantly improved the substrate scope as well as reaction conditions in the syntheses of a variety of pyrones and pyridones. The high reactivity and versatility of these unique Ni(NHC) catalytic systems allowed us to develop unprecedented Ni-catalyzed cycloadditions that were unexplored due to the inefficacy of early Ni catalysts to promote hetero-oxidative coupling steps. We describe the development and mechanistic analysis of Ni/NHC catalysts that couple diynes and nitriles to form pyridines. Kinetic studies and stoichiometric reactions confirmed a hetero-oxidative coupling pathway associated with this Ni-catalyzed cycloaddition. We then describe a series of new substrates for Ni-catalyzed cycloaddition reactions such as vinylcyclopropanes, aldehydes, ketones, tropones, 3-azetidinones, and 3-oxetanones. In reactions with vinycyclopropanes and tropones, DFT calculations reveal noteworthy mechanistic steps such as a C-C σ-bond activation and an 8π-insertion of vinylcyclopropane and tropone, respectively. Similarly, the cycloaddition of 3-azetidinones and 3-oxetanones also requires Ni-catalyzed C-C σ-bond activation to form N- and O-containing heterocycles.

Nickel-catalyzed cycloaddition of methyleneaziridines with diynes to synthesize fused anilines

Methyleneaziridines reacted with diynes to generate fused anilines. This reaction involved a C2–C3 bond cleavage of methyleneaziridine. This work provides a new reaction pattern of methyleneaziridine.

ChemInform Abstract: Nickel‐Catalyzed Intramolecular [3 + 2 + 2] Cycloadditions of Alkylidenecyclopropanes. A Straightforward Entry to Fused 6,7,5‐Tricyclic Systems.

AbstractSmall amounts of cyclooctatetraene are formed as by‐product in the cyclization of (IIIb).

3,5-Disubstituted 2-Aminopyridines via Nickel-Catalyzed Cycloaddition of Terminal Alkynes and Cyanamides

The regioselectivity of the Ni/SIPr-catalyzed cycloaddition of terminal alkynes and cyanamides was explored. In general, 3,5-disubstituted 2-aminopyridines were formed as the major product.

Nickel-catalyzed intramolecular [3 + 2 + 2] cycloadditions of alkylidenecyclopropanes. A straightforward entry to fused 6,7,5-tricyclic systems.

A highly diastereo- and chemoselective intramolecular nickel-catalyzed cycloaddition of alkene- and alkyne-tethered alkynylidenecyclopropanes is reported. The method constitutes the first fully intramolecular [3 + 2 + 2] alkylidenecyclopropropane cycloaddition occurring via a proximal cleavage of the cyclopropane and makes it possible to build relevant 6,7,5-tricyclic frameworks in a single-pot reaction. Importantly, the reaction outcome is highly dependent on the characteristics of the nickel ligands.

Regio- and Diastereoselective Nickel-Catalyzed Cycloaddition of Activated Cyclopropanes with Allenes

Nickel-catalyzed intermolecular [3+2] cycloaddition of activated cyclopropanes with allenes has been developed. This transformation generates highly substituted five-membered carbocyclic compounds with good regio- and diastereoselectivity under mild reaction conditions. This reaction can be extended to a broad variety of allenes to obtain the corresponding adducts.

Nickel-catalyzed Decarbonylative and Decarboxylative Cycloaddition of Isatoic Anhydrides with Alkynes

Abstract We have developed a nickel-catalyzed cycloaddition of isatoic anhydrides with alkynes to afford 2,3-disubstituted indoles. The reaction proceeds via the elimination of carbon monoxide and carbon dioxide and the insertion of alkynes.

Theoretical Studies on Nickel-Catalyzed Cycloaddition of 3-Azetidinone with Alkynes

With the aid of DFT calculations, we have examined the mechanism of the Ni-catalyzed cycloaddition of 3-azetidinone with alkynes. Our DFT results did not support the originally proposed mechanism, which involves a ring expansion through β-carbon elimination. Instead, our calculations supported a mechanism which involves oxidative addition of 1-Boc-3-azetidinone to a Ni(0) center to form an intermediate having both Ni–C(O) and Ni–C(sp3) bonds, then alkyne insertion into either the Ni–C(O) or Ni–C(sp3) bond depending on the alkyne substrates being studied, and finally reductive elimination to give the cycloaddition products. The nature of insertion of alkynes into a Ni–C bond was also discussed. When an alkyne substrate inserts into the Ni–C(O) bond, we found that the alkyne acts as a nucleophile to attack the electron-deficient, metal-bonded C═O carbon center. When an alkyne substrate inserts into the Ni–C(sp3) bond, the alkyne acts as an electrophile to interact with the Ni–C(sp3) bond.

Nickel-Catalyzed Cycloaddition of Vinylcyclopropanes to Imines

Nickel-catalyzed intermolecular [3 + 2] cycloaddition of vinylcyclopropanes to imines has been developed. This transformation generates substituted pyrrolidines in high yields, with good regio- and diastereo- selectivity under mild reaction conditions. A variety of imines can be used in this reaction. An asymmetric variant of the reaction has also been demonstrated.

Synthesis of Quinolones by Nickel-Catalyzed Cycloaddition via Elimination of Nitrile

Substituted quinolones were efficiently synthesized via the nickel-catalyzed cycloaddition of o-cyanophenylbenzamide derivatives with alkynes. The reaction involves elimination of a nitrile group by cleavage of the two independent aryl-cyano and aryl-carbonyl C-C bonds of the amides.

Progress in Nickel-Catalyzed Cycloaddition Reactions

Progress in Nickel-Catalyzed Cycloaddition Reactions

Nickel-catalyzed Cycloaddition of α,β-Unsaturated Oximes with Alkynes: Synthesis of Highly Substituted Pyridine Derivatives

Abstract A nickel-catalyzed cycloaddition of α,β-unsaturated oximes with alkynes to afford 2,3,4,6-tetrasubstituted pyridine derivatives has been developed. The reaction involves oxidative addition of the N–O bond of α,β-unsaturated oximes to Ni(0) and subsequent alkyne insertion to an N–Ni bond, followed by intramolecular cyclization. It was also found that β,γ-unsaturated oximes participate in the nickel-catalyzed reaction with alkynes to furnish pyridine derivatives.

Nickel-catalyzed Cycloaddition of Aromatic (O-Benzyl)ketoximes with Alkynes to Produce Isoquinoline and Isoquinoline N-Oxide Derivatives

Abstract A nickel-catalyzed cycloaddition of aromatic (O-benzyl)ketoximes with alkynes to afford 3,4-disubstituted isoquinoline derivatives has been developed. The reaction involves oxidative addition of N–O bond of O-benzylketoxime to Ni(0) and subsequent intermolecular C–H bond activation via elimination of benzyl alcohol. It was also found that ketoximes participate in the nickel-catalyzed reaction with alkynes to furnish isoquinoline N-oxide derivatives.

ChemInform Abstract: Nickel‐Catalyzed Cycloadditions of Benzoxazinones with Alkynes: Synthesis of Quinolines and Quinolones.

AbstractThe reaction outcome is determined by the C‐2 substituent of the benzoxazinone.

Nickel‐Catalyzed Cycloaddition of α,β,γ,δ‐Unsaturated Ketones with Alkynes

Überraschend führt die Titelreaktion hoch stereoselektiv zu Bicyclo[3.1.0]hexenen (siehe Schema). Die hohe Stereoselektivität wird mit einem Mechanismus erklärt, der eine oxidative Cyclisierung von Nickel(0) mit α,β,γ,δ-ungesättigten Ketonen und Alkinen mit anschließender intramolekularer Carbonickelierung vorsieht.