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.

Trends in the Usage of Bidentate Phosphines as Ligands in Nickel Catalysis.

A critically important process in catalysis is the formation of an active catalyst from the combination of a metal precursor and a ligand, as the efficacy of this reaction governs the amount of active catalyst. This Review is a comprehensive overview of reactions catalyzed by nickel and an added bidentate phosphine, focusing on the steps transforming the combination of precatalyst and ligand into an active catalyst and the potential effects of this transformation on nickel catalysis. Reactions covered include common cross-coupling reactions, such as Suzuki, Heck, Kumada, and Negishi couplings, addition reactions, cycloadditions, C-H functionalizations, polymerizations, hydrogenations, and reductive couplings, among others. Overall, the most widely used nickel precatalyst with free bidentate phosphines is Ni(cod)2, which accounts for ∼50% of the reports surveyed, distantly followed by Ni(acac)2 and Ni(OAc)2, which account for ∼10% each. By compiling the reports of these reactions, we have calculated statistics of the usage and efficacy of each ligand with Ni(cod)2 and other nickel sources. The most common bidentate phosphines are simple, relatively inexpensive ligands, such as DPPE, DCPE, DPPP, and DPPB, along with others with more complex backbones, such as DPPF and Xantphos. The use of expensive chiral phosphines is more scattered, but the most common ligands include BINAP, Me-Duphos, Josiphos, and related analogs.

Orthogonal self-assembly of an organoplatinum(II) metallacycle and cucurbit[8]uril that delivers curcumin to cancer cells.

Curcumin (Cur) is a naturally occurring anticancer drug isolated from the Curcuma longa plant. It is known to exhibit anticancer properties via inhibiting the STAT3 phosphorylation process. However, its poor water solubility and low bioavailability impede its clinical application. Herein, we used organoplatinum(II) ← pyridyl coordination-driven self-assembly and a cucurbit[8]uril (CB[8])-mediated heteroternary host-guest complex formation in concert to produce an effective delivery system that transports Cur into the cancer cells. Specifically, a hexagon 1, containing hydrophilic methyl viologen (MV) units and 3,4,5-Tris[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]benzoyl groups alternatively at the vertices, has been synthesized and characterized by several spectroscopic techniques. The MV units of 1 underwent noncovalent complexation with CB[8] to yield a host-guest complex 4. Cur can be encapsulated in 4, via a 1:1:1 heteroternary complex formation, resulting in a water-soluble host-guest complex 5. The host-guest complex 5 exhibited ca 100-fold improved IC50 values relative to free Cur against human melanoma (C32), melanoma of rodents (B16F10), and hormone-responsive (MCF-7) and triple-negative (MDA-MB231) breast cancer cells. Moreover, strong synergisms of Cur with 1 and 4 with combinatorial indexes of <1 across all of the cell lines were observed. An induced apoptosis with fragmented DNA pattern and inhibited expression of phosphor-STAT3 supported the improved therapeutic potential of Cur in heteroternary complex 5.

Hexaaminobenzene as a building block for a Family of 2D Coordination Polymers.

A family of 2D coordination polymers were successfully synthesized through "bottom-up" techniques using Ni2+, Cu2+, Co2+, and hexaaminobenzene. Liquid-liquid and air-liquid interfacial reactions were used to realize thick (∼1-2 µm) and thin (<10 nm) stacked layers of nanosheet, respectively. Atomic-force microscopy and scanning electron microscopy both revealed the smooth and flat nature of the nanosheets. Selected area diffraction was used to elucidate the hexagonal crystal structure of the framework. Electronic devices were fabricated on thin samples of the Ni analogue and they were found to be mildly conducting and also showed back gate dependent conductance.

Regioselective Iron-Catalyzed [2 + 2 + 2] Cycloaddition Reaction Forming 4,6-Disubstituted 2-Aminopyridines from Terminal Alkynes and Cyanamides.

Iron complexes bound by redox-active pyridine dialdimine (PDAI) ligands catalyze the cycloaddition of two terminal alkynes and one cyanamide. The reaction is both chemo- and regioselective, as only 4,6-disubstituted 2-aminopyridine products are formed in moderate to high yields. Isolation of an iron azametallacycle (4) suggests that catalyst deactivation occurs with a large excess of cyanamide over longer reaction times. Fe-catalyzed cycloaddition allowed for a straightforward synthesis of a variety of aminopyridines, including known estrogen receptor ligands.

Synergy between Experimental and Computational Chemistry Reveals the Mechanism of Decomposition of Nickel-Ketene Complexes.

A series of (dppf)Ni(ketene) complexes were synthesized and fully characterized. In the solid state, the complexes possess η2-(C,O) coordination of the ketene in an overall planar configuration. They display similar structure in solution, except in some cases, the η2-(C,C) coordination mode is also detected. A combination of kinetic analysis and DFT calculations reveals the complexes undergo thermal decomposition by isomerization from η2-(C,O) to η2-(C,C) followed by scission of the C═C bond, which is usually rate limiting and results in an intermediate carbonyl carbene complex. Subsequent rearrangement of the carbene ligand is rate limiting for electron poor and sterically large ketenes, and results in a carbonyl alkene complex. The alkene readily dissociates, affording alkenes and (dppf)Ni(CO)2. Computational modeling of the decarbonylation pathway with partial phosphine dissociation reveals the barrier is reduced significantly, explaining the instability of ketene complexes with monodentate phosphines.

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.

An in Situ Approach to Nickel-Catalyzed Cycloaddition of Alkynes and 3-Azetidinones.

An efficient and convenient procedure that generates the active Ni(0) catalyst in situ from cheap, air stable Ni(II) precursors is developed for the [4 + 2]-cycloaddition of alkynes and 3-azetidinones. The reaction affords useful 3-dehydropiperidinones in comparable yields to the reported Ni(0) procedure. Additionally, the cycloaddition with 3-oxetanone afforded the 3-dehydropyranone product. Chiral 2-substituted azetidinones were also tolerated to form substituted dehydropiperidinones in high yield and enantiomeric excess.

Ni(NHC)]-catalyzed cycloaddition of diynes and tropone: apparent enone cycloaddition involving an 8π insertion.

A Ni/N-heterocyclic carbene catalyst couples diynes to the C(α)-C(ß) double bond of tropone, a type of reaction that is unprecedented for metal-catalyzed cycloadditions with aromatic tropone. Many different diynes were efficiently coupled to afford [5-6-7] fused tricyclic products, while [5-7-6] fused tricyclic compounds were obtained as minor byproducts in a few cases. The reaction has broad substrate scope and tolerates a wide range of functional groups, and excellent regioselectivity is found with unsymmetrical diynes. Theoretical calculations show that the apparent enone cycloaddition occurs through a distinctive 8π insertion of tropone. The initial intramolecular oxidative cyclization of diyne produces the nickelacyclopentadiene intermediate. This intermediate undergoes an 8π insertion of tropone, and subsequent reductive elimination generates the [5-6-7] fused tricyclic product. This initial product undergoes two competing isomerizations, leading to the observed [5-6-7] and [5-7-6] fused tricyclic products.

The discovery of [Ni(NHC)RCN]2 species and their role as cycloaddition catalysts for the formation of pyridines.

The reaction of Ni(COD)(2), IPr, and nitrile affords dimeric [Ni(IPr)RCN](2) in high yields. X-ray analysis revealed these species display simultaneous η(1)- and η(2)-nitrile binding modes. These dimers are catalytically competent in the formation of pyridines from the cycloaddition of diynes and nitriles. Kinetic analysis showed the reaction to be first order in [Ni(IPr)RCN](2), zeroth order in added IPr, zeroth order in nitrile, and zeroth order in diyne. Extensive stoichiometric competition studies were performed, and selective incorporation of the exogenous, not dimer bound, nitrile was observed. Post cycloaddition, the dimeric state was found to be largely preserved. Nitrile and ligand exchange experiments were performed and found to be inoperative in the catalytic cycle. These observations suggest a mechanism whereby the catalyst is activated by partial dimer-opening followed by binding of exogenous nitrile and subsequent oxidative heterocoupling.

Iron-catalyzed formation of 2-aminopyridines from diynes and cyanamides.

Diynes and cyanamides undergo an iron-catalyzed [2 + 2 + 2] cycloaddition to form highly substituted 2-aminopyridines in an atom-efficient manner that is both high yielding and regioselective. This system was also used to cyclize two terminal alkynes and a cyanamide to afford a 2,4,6-trisubstituted pyridine product regioselectively.

An expeditious route to eight-membered heterocycles by nickel-catalyzed cycloaddition: low-temperature C(sp)2-C(sp)3 bond cleavage.

A cool break: 3-Azetidinone and a variety of diynes undergo a cycloaddition reaction catalyzed by Ni/IPr to give dihydroazocine compounds (see scheme; IPr=1,3-bis(2,6-diisopropylphenyl)imidazolidene). The reaction involves a challenging C(sp)2-C(sp)3 bond cleavage step, yet, surprisingly, proceeds at low temperature.

Ni-catalyzed ketene cycloaddition: a system that resists the formation of decarbonylation side products.

Ni-phosphine complexes were used as catalysts for the cycloaddition of various ketenes and diynes. In general, 2,4-cyclohexadienones were formed instead of products arising from decarbonylation of the ketenes.

Rhodium-catalyzed decarboxylative cycloaddition route to substituted anilines.

A convenient method for preparing substituted anilines via a Rh-catalyzed [2 + 2 + 2] cycloaddition reaction of diynes and 2-oxazolone was discovered. The initial cycloaddition adducts undergo facile decarboxylation of carbon dioxide to afford aniline products. Reaction conditions are mild, and only 3 mol % Rh catalyst is required. High regioselectivity was observed when an unsymmetrical diyne was used as a starting material.

Imidazolidene carboxylate bound MBPh4 complexes (M = Li, Na) and their relevance in transcarboxylation reactions.

Combination of 1,3-bis(2,6-diisopropylphenyl)imidazolum-2-carboxylate (IPrCO(2)) with the Lewis acids MBPh(4), where M = Li or Na, provided two separate complexes. The crystal structures of these complexes revealed that coordination to NaBPh(4) yielded a dimeric species, yet coordination of IPrCO(2) with LiBPh(4) yielded a monomeric species. Combination of 1,3-bis(2,4,6-trimethylphenyl)imidazolum-2-carboxylate (IMesCO(2)) with LiBPh(4) also afforded a dimeric species that was similar in global structure to that of the IPrCO(2)+NaBPh(4) dimer. In all three cases, the cation of the organic salt was coordinated to the oxyanion of the zwitterionic carboxylate. Thermogravimetric analysis of the crystals demonstrated that decarboxylation occurred at lower temperatures than the decarboxylation temperature of the parent NHC·CO(2) (NHC = N-heterocyclic carbene). Kinetic analysis of the transcarboxylation of IPrCO(2) to acetophenone with NaBPh(4) to yield sodium benzoylacetate was performed. First-order dependences were observed for IPrCO(2) and acetophenone, whereas zero -order dependence was observed for NaBPh(4). Direct dicarboxylation was observed when I(t)BuCO(2) was added to MeCN in the absence of added MBPh(4).

Nickel-Catalyzed [2+2+2] Cycloaddition of Diynes and Cyanamides.

A variety of bicyclic N,N-disubstituted 2-aminopyridines have been prepared from diynes and cyanamides by nickel-catalyzed [2+2+2] cycloaddition reactions. The reactions proceeded at room temperature with low catalyst loading to afford 2-aminopyridines in good to excellent yields. The method is amenable to both internal and terminal diynes and proceeds in a regioselective manner. A number of cyanamides with diverse functional group tolerance were used. The intermolecular version employing 3-hexyne and N-cyanopyrrolidine also afforded the desired N,N-disubstituted 2-aminopyridine in good yield.

Total Synthesis of Indolizidine Alkaloids via Nickel-Catalyzed (4 + 2) Cyclization.

A Ni-catalyzed (4 + 2) cycloaddition of alkynes and azetidinones toward piperidinones was used as key reaction in the enantioselective synthesis of naturally occurring indolizidine alkaloids. The reaction benefits from the use of an easily accessible azetidinone as an advanced and divergent intermediate to build the indolizidine core. This methodology has been applied in the total syntheses of (+)-septicine, (+)-ipalbidine, and (+)-seco-antofine to illustrate the applicability of the general approach.

A systematic investigation of factors influencing the decarboxylation of imidazolium carboxylates.

A series of 1,3-disubstituted-2-imidazolium carboxylates, an adduct of CO(2) and N-heterocyclic carbenes, were synthesized and characterized using single crystal X-ray, thermogravimetric, IR, and NMR analysis. The TGA analysis of the NHC-CO(2)'s shows that as steric bulk on the N-substituent increases, the ability of the NHC-CO(2) to decarboxylate increases. The comparison of NHC-CO(2)'s with and without methyls at the 4,5-position indicate that extra electron density in the imidazolium ring enhances the stability of an NHC-CO(2) thereby making it less prone to decarboxylation. Single crystal X-ray analysis shows that the torsional angle of the carboxylate group and the C-CO(2) bond length with respect to the imidazolium ring is dependent on the steric bulk of the N-substituent. Rotamers in the unit cell of a single crystal of I(t)BuPrCO(2) (2f) indicate that the C-CO(2) bond length increases as the N-substituents rotate toward the carboxylate moiety, which suggests that rotation of the N-substituents through the plane of the C-CO(2) bond may be involved in the bond breaking event to release CO(2).

Mechanism of the Ni(0)-catalyzed vinylcyclopropane-cyclopentene rearrangement.

A combination of physical organic experiments and quantum chemical calculations were used to construct a detailed mechanistic model for the Ni(0)-N-heterocyclic carbene-catalyzed vinylcyclopropane-cyclopentene rearrangement that involves a mutistep oxidative addition/haptotropic shift/reductive elimination pathway. No evidence for the intermediacy of radicals or zwitterions was found. The roles of substituents on the vinylcyclopropane substrate and variations in the ligands on Ni were evaluated. It is postulated that bulky carbene ligands facilitate formation of the active catalyst species.