Isolation of Cationic η3-Allenylnickel(II) Key Intermediate Complexes: Origins of Enantioselectivity and Regioselectivity in Nickel(0)-Catalyzed Asymmetric Propargylic Substitutions.

Herein, we report the synthesis and isolation of cationic η3-allenylnickel(II) complexes that bear rac-BINAP as a bidentate ligand for the first time via Me3SiOTf-promoted C-O bond cleavage of propargylic tert-butyl carbonate. In contrast, in the presence of the monodentate phosphine ligand PEt3, treatment of propargylic tert-butyl carbonate with Ni(cod)2 resulted in a gradual C-O bond cleavage leading to η1-allenylnickel(II) complexes, i.e., trans-(PEt3)2Ni(η1-CPh═C═CHR)(OBoc). X-ray diffraction and NMR spectroscopy studies of [(η3-RCH-CCPh)Ni(rac-BINAP)](OTf) revealed that the complex adopts an η3-allenyl coordination mode both in the crystal lattice and in solution. A thorough structural comparison between [(η3-RCH-CCPh)Ni(rac-BINAP)](OTf) and palladium and platinum analogues revealed that the η3-allenyl moiety in the nickel complex is similar to that observed in palladium and platinum complexes, albeit that each Ni-C bond is shorter than the corresponding Pd-C and Pt-C bonds due to the smaller ionic radius of nickel to that of Pd or Pt. The reactions of either N-methylaniline or sodium N-methylanilide with [(η3-RCH-CCPh)Ni((R)-BINAP)](OTf) furnished (R)-PhC≡CCH(NMePh)Me as an asymmetric propargylic substitution (APS) product with excellent enantioselectivity. Furthermore, when the nickel-catalyzed APS reaction of propargylic tert-butyl carbonate with N-methylaniline was conducted in DMSO at 60 °C in the presence of 5 mol % of [(η3-RCH-CCPh)Ni((R)-BINAP)](OTf) and 7.5 mol % of sodium N-methylanilide as a catalytic precursor and an additive, respectively, (R)-PhC≡CCH(NMePh)Me was obtained in 79% yield with 90% ee. The experimental results and computational calculations strongly suggest that the nickel-catalyzed APS reaction might proceed via a cationic η3-allenylnickel(II) species as the key reaction intermediate.

N-Heterocyclic Carbenes with Polyfluorinated Groups at the 4- and 5-Positions from [3 + 2] Cycloadditions between Formamidinates and cis-1,2-Difluoroalkene Derivatives.

We herein report the formation of fluorinated N-heterocyclic carbenes (NHCFs) that bear fluorine atoms at the 4- and 5-positions of the imidazol-2-ylidene ring. Treatment of sodium N,N'-bis(aryl)formamidinates with tetrafluoroethylene followed by the addition of LiBF4 induced a [3 + 2] cycloaddition to afford 4,5-difluorinated imidazolium salts, which served as the precursors for 4,5-difluorinated NHCs. A key feature of this procedure is its applicability to other perfluorinated compounds, which enabled us to incorporate polyfluorinated functional groups at 4- and 5-positions on the imidazol-2-ylidene skeleton. Thus, employing octafluorocyclopentene and hexafluorobenzene led to the formation of 4,4,5,5,6,6-hexafluoro-1,3-diaryl-3,4,5,6-tetrahydrocyclopenta[d]imidazolium (CypIPrF·HBF4) and 4,5,6,7-tetrafluoro-1,3-diarylbenzimidazolium (BIPrF·HBF4) salts, respectively. A thorough NMR analysis of these NHCFs, their selenium adducts, and their tricarbonyl nickel complexes, (NHCF)Ni(CO)3, demonstrated that the fluorine substituents, contrary to expectations, tend to act as electron donors owing to the considerable positive mesomeric effect, while the perfluorocyclopentene-fused and tetrafluorobenzo-fused rings are pure electron acceptors due to their strong negative inductive effect. The unique and increased π-accepting character of the perfluorocyclopentene-fused and tetrafluorobenzo-fused NHCFs in both stoichiometric and catalytic reactions is further demonstrated by employing (NHCF)Ni(CO)3 and (NHCF)AuCl species, respectively. Moreover, an analysis of the % buried volume (%Vbur) values clearly suggests that the modification of the NHC backbone with polyfluorinated groups can drastically alter the electronic properties of the NHC ligand without substantially changing its steric properties. Our experimental results were further corroborated by a series of computational calculations.

Synthesis of Fluoroalkyl Sulfides via Additive-Free Hydrothiolation and Sequential Functionalization Reactions.

A modular synthetic method, involving a hydrothiolation, silylation, and fluoroalkylation, for the construction of highly functionalized fluoroalkyl sulfides has been developed. The use of aprotic polar solvents enables the additive-free chemoselective hydrothiolation of tetrafluoroethylene, trifluorochloroethylene, and hexafluoropropene with various thiols. The stepwise functionalization reactions convert the hydrothiolated intermediates into the tetrafluoroethyl sulfides in high efficiency. The method avoids the use of the environmental pollutant Halon-2402, which was employed as a building block in a reported synthetic route.

Cleavage of C(sp3)-F Bonds in Trifluoromethylarenes Using a Bis(NHC)nickel(0) Complex.

The first example of the oxidative addition of a C(sp3)-F bond in trifluoromethylarenes to a nickel(0) complex is described. A nickel(0) complex that bears two N-heterocyclic carbene (NHC) ligands of low steric demand is able to cleave C(sp3)-F bonds of trifluoromethylarenes to afford the corresponding trans-difluorobenzyl nickel(II) fluoride complexes. Isolation and characterization studies suggested that the cleavage of the C(sp3)-F bond proceeds via an η2-arene nickel(0) complex. Taking advantage of the reactivity of these nickel(II) fluoride complexes, we developed a catalytic hydrodefluorination of trifluoromethylarenes using hydrosilanes. A computational study indicated that the electron-rich nickel(0) center supported by two relatively small NHC ligands cleaves the C(sp3)-F bond via a syn-SN2' mechanism.

Enantioselective Synthesis of Polycyclic γ-Lactams with Multiple Chiral Carbon Centers via Ni(0)-Catalyzed Asymmetric Carbonylative Cycloadditions without Stirring.

γ-Lactam derivatives with multiple contiguous stereogenic carbon centers are ubiquitous in physiologically active compounds. The development of straightforward and reliable synthetic routes to such chiral structural motifs in a stereocontrolled manner should thus be of importance. Herein, we report a strategy to construct polycyclic γ-lactam derivatives that contain more than two contiguous stereogenic centers in an enantioselective as well as atom-economic manner. Moreover, we have achieved the first enantioselective synthesis of strigolactam derivative GR-24, a racemic variant of which is a potential seed germination stimulator and plant-growth regulator. A key of the procedure presented here is a nickel(0)/chiral phosphoramidite-catalyzed asymmetric [2+2+1] carbonylative cycloaddition between readily accessible ene-imines and carbon monoxide, which proceeded enantioselectively to furnish up to 90% ee (>99% ee after recrystallization). The results of mechanistic studies, including the isolation of a chiral heteronickelacycle, support that the enantioselectivity on the two contiguous carbon atoms of the γ-lactams is determined during the oxidative cyclization on nickel(0).

Selective Catalytic Formation of Cross-Tetramers from Tetrafluoroethylene, Ethylene, Alkynes, and Aldehydes via Nickelacycles as Key Reaction Intermediates.

In the presence of a catalytic amount of Ni(cod)2 (cod = 1,5-cyclooctadiene) and PCy3 (Cy = cyclohexyl), the cross-tetramerization of tetrafluoroethylene (TFE), ethylene, alkynes, and aldehydes leads to a variety of fluorine-containing enone derivatives. This reaction is the first example of a highly selective cross-tetramerization between four different unsaturated compounds. Stoichiometric reactions revealed that the present reaction involves partially fluorinated five- and seven-membered nickelacycles as key reaction intermediates.

Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted Amines with Aldehydes Using H2.

Given the growing demand for green and sustainable chemical processes, the catalytic reductive alkylation of amines with main-group catalysts of low toxicity and molecular hydrogen as the reductant would be an ideal method to functionalize amines. However, such a process remains challenging. Herein, a novel reductive alkylation system using H2 is presented, which proceeds via a tandem reaction that involves the B(2,6-Cl2C6H3)( p-HC6F4)2-catalyzed formation of an imine and the subsequent hydrogenation of this imine catalyzed by a frustrated Lewis pair (FLP). This reductive alkylation reaction generates H2O as the sole byproduct and directly functionalizes amines that bear a remarkably wide range of substituents including carboxyl, hydroxyl, additional amino, primary amide, and primary sulfonamide groups. The synthesis of isoindolinones and aminophthalic anhydrides has also been achieved by a one-pot process that consists of a combination of the present reductive alkylation with an intramolecular amidation and intramolecular dehydration reactions, respectively. The reaction showed a zeroth-order and a first-order dependence on the concentration of an imine intermediate and B(2,6-Cl2C6H3)( p-HC6F4)2, respectively. In addition, the reaction progress was significantly affected by the concentration of H2. These results suggest a possible mechanism in which the heterolysis of H2 is facilitated by the FLP comprising THF and B(2,6-Cl2C6H3)( p-HC6F4)2.

CuI -Catalyzed Pentafluoroethylation of Aryl Iodides in the Presence of Tetrafluoroethylene and Cesium Fluoride: Determining the Route to the Key Pentafluoroethyl CuI Intermediate.

The Cu(I)-catalyzed pentafluoroethylation of iodoarenes via the fluorocupration of tetrafluoroethylene (TFE) is disclosed. The active species, (phen)CuC2 F5 , was isolated and its molecular structure confirmed by a single-crystal X-ray diffraction analysis. The key to the successful suppression of the competing oligomerization of TFE is to refrain from stirring the reaction mixture. A mechanistic study clearly discarded the possibility that the catalytic reaction proceeds via a radical pathway.

Fluorinated Vinylsilanes from the Copper-Catalyzed Defluorosilylation of Fluoroalkene Feedstocks.

Herein, a copper-catalyzed C-F bond defluorosilylation reaction of tetrafluoroethylene and other polyfluoroalkenes is described. Mechanistic studies, based on a series of stoichiometric reactions with copper complexes, revealed that the key steps of this defluorosilylation reaction are 1) the 1,2-addition of a silylcopper intermediate to the polyfluoroalkene and 2) a subsequent selective ß-fluorine elimination, which generates a Cu-F species. The ß-fluorine elimination is facilitated by Lewis acidic F-Bpin, which is generated in situ during the defluorosilylation.

Nickel-Catalyzed Formation of 1,3-Dienes via a Highly Selective Cross-Tetramerization of Tetrafluoroethylene, Styrenes, Alkynes, and Ethylene.

In the presence of a catalytic amount of Ni(cod)2 (cod = 1,5-cyclooctadiene) and PCy3 (Cy = cyclohexyl), the cross-tetramerization of tetrafluoroethylene (TFE), alkynes, and ethylene occurred in a highly selective manner to afford a variety of 1,3-dienes with a 3,3,4,4-tetrafluorobutyl chain. In addition, a Ni(0)-catalyzed cross-tetramerization of TFE, alkynes, ethylene, and styrenes was developed. These catalytic reactions might proceed via partially fluorinated five- and seven-membered nickelacycle key intermediates.

Copper-Catalyzed Regioselective Monodefluoroborylation of Polyfluoroalkenes en Route to Diverse Fluoroalkenes.

Monodefluoroborylation of polyfluoroalkenes has been achieved in a regioselective manner under mild conditions via copper catalysis. The method has shown an extremely broad scope of substrates, including (difluorovinyl)arenes, tetrafluoroethylene (TFE), (trifluorovinyl)arenes, and trifluoromethylated monofluoroalkenes. The choice of boron source was important for the efficient transformation of (difluorovinyl)arenes; (Bpin)2 was suitable for substrates with an electron-deficient aryl group and (Bnep)2 for those with an electron-rich aryl group. Derivatization of the (fluoroalkenyl)boronic acid esters to the corresponding potassium trifluoroborate salts has rendered the products easily isolable, which greatly improved the synthetic practicality of the monodefluoroborylation reaction. Stoichiometric experiments indicate that the fate of the regioselectivity depends on the mode of ß-fluorine elimination, which depends on the substrate. Further transformation of the boryl group has allowed facile preparation of fluoroalkene derivatives as exemplified by the synthesis of a fluoroalkene mimic of atorvastatin, which potently inhibited the enzyme activity of HMG-CoA reductase.

Nickel(0)-Mediated Transformation of Tetrafluoroethylene and Vinylarenes into Fluorinated Cyclobutyl Compounds.

In the presence of Ni0 /PCy3 , styrene was found to participate in oxidative cyclization with tetrafluoroethylene, thus leading to the corresponding nickelacycle with a unique η3 -π-benzyl structure. In addition, the flexibility of the coordination mode in the η3 -benzyl moiety allowed the partially fluorinated nickelacycle to undergo unprecedented amine-induced α-fluorine elimination, thus leading to the construction of a fluorinated cyclobutyl skeleton.

Transition-Metal-Free Catalytic Hydrodefluorination of Polyfluoroarenes by Concerted Nucleophilic Aromatic Substitution with a Hydrosilicate.

A transition-metal-free catalytic hydrodefluorination (HDF) reaction of polyfluoroarenes is described. The reaction involves direct hydride transfer from a hydrosilicate as the key intermediate, which is generated from a hydrosilane and a fluoride salt. The eliminated fluoride regenerates the hydrosilicate to complete the catalytic cycle. Dispersion-corrected DFT calculations indicated that the HDF reaction proceeds through a concerted nucleophilic aromatic substitution (CSN Ar) process.

Synthesis and Reactivity of Fluoroalkyl Copper Complexes by the Oxycupration of Tetrafluoroethylene.

The copper(I)-mediated generation of -OCF2 CF2 - moieties by the oxycupration of tetrafluoroethylene (TFE) using either copper aryloxides or alkoxides is disclosed. The key intermediates, 2-aryloxy-1,1,2,2-tetrafluoroethyl and 2-alkoxy-1,1,2,2-tetrafluoroethyl copper complexes, were obtained from the reaction of the corresponding aryloxy and alkoxy copper complexes with TFE, and their structures in solution and in the solid state were unambiguously determined by multinuclear NMR spectroscopy and X-ray diffraction analysis. These copper complexes subsequently reacted with aryl iodides (ArI) to afford ROCF2 CF2 Ar (R=aryl or alkyl) in high yields.

Efficient Synthesis of Polycyclic γ-Lactams by Catalytic Carbonylation of Ene-Imines via Nickelacycle Intermediates.

The nickel(0)-catalyzed carbonylative cycloaddition of 1,5- and 1,6-ene-imines with carbon monoxide (CO) is reported. Key to this reaction is the efficient regeneration of the catalytically active nickel(0) species from nickel carbonyl complexes such as [Ni(CO)3 L]. A variety of tri- and tetracyclic γ-lactams were thus prepared in excellent yields with 100 % atom efficiency. Preliminary results on asymmetric derivatives promise potential in the synthesis of enantioenriched polycyclic γ-lactams.

Catalytic Transformation of Aldehydes with Nickel Complexes through η(2) Coordination and Oxidative Cyclization.

Chemists no longer doubt the importance of a methodology that could activate and utilize aldehydes in organic syntheses since many products prepared from them support our daily life. Tremendous effort has been devoted to the development of these methods using main-group elements and transition metals. Thus, many organic chemists have used an activator-(aldehyde oxygen) interaction, namely, η(1) coordination, whereby a Lewis or Brønsted acid activates an aldehyde. In the field of coordination chemistry, η(2) coordination of aldehydes to transition metals by coordination of a carbon-oxygen double bond has been well-studied; this activation mode, however, is rarely found in transition-metal catalysis. In view of the distinctive reactivity of an η(2)-aldehyde complex, unprecedented reactions via this intermediate are a distinct possibility. In this Account, we summarize our recent results dealing with nickel(0)-catalyzed transformations of aldehydes via η(2)-aldehyde nickel and oxanickelacycle intermediates. The combination of electron-rich nickel(0) and strong electron-donating N-heterocyclic carbene (NHC) ligands adequately form η(2)-aldehyde complexes in which the aldehyde is highly activated by back-bonding. With Ni(0)/NHC catalysts, processes involving intramolecular hydroacylation of alkenes and homo/cross-dimerization of aldehydes (the Tishchenko reaction) have been developed, and both proceed via the simultaneous η(2) coordination of aldehydes and other π components (alkenes or aldehydes). The results of the mechanistic studies are consistent with a reaction pathway that proceeds via an oxanickelacycle intermediate generated by the oxidative cyclization with a nickel(0) complex. In addition, we have used the η(2)-aldehyde nickel complex as an effective activator for an organosilane in order to generate a silicate reactant. These reactions show 100% atom efficiency, generate no wastes, and are conducted under mild conditions.

Copper-Catalyzed Reaction of Trifluoromethylketones with Aldehydes via a Copper Difluoroenolate.

A copper-catalyzed reaction of easily accessible α,α,α-trifluoromethylketones with various aldehydes affords difluoro-methylene compounds in the presence of diboron and NaOtBu. The key process of the reaction is the formation of a copper difluoroenolate by 1,2-addition of a borylcopper intermediate to α,α,α-trifluoromethylketones and subsequent ß-fluoride elimination. Mechanistic studies including the isolation and characterization of a possible anionic copper alkoxide intermediate are also described.

Strategic Utilization of Multifunctional Carbene for Direct Synthesis of Carboxylic-Phosphinic Mixed Anhydride from CO2.

Direct synthesis of carboxylic-phosphinic mixed anhydrides has been achieved by treating carbon dioxide with N-phosphine oxide-substituted imidazolylidenes (PoxIms) that contain both nucleophilic carbene and electrophilic phosphorus moieties. This novel mixed anhydride was efficiently derivatized into an ester, an amide, and an unsymmetrical ketone via transformation into its corresponding imidazolium salt followed by a dual substitution reaction. The presented work used well-designed multifunctional carbene reagents to establish a novel utility for carbon dioxide in organic synthesis.

Nickel-Catalyzed Formation of Fluorine-Containing Ketones via the Selective Cross-Trimerization Reaction of Tetrafluoroethylene, Ethylene, and Aldehydes.

In the presence of a catalytic amount of Ni(cod)2 and IPr (1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), a cross-trimerization reaction of tetrafluoroethylene (TFE), ethylene, and aldehydes proceeded in a selective manner to afford a variety of 4,4,5,5-tetrafluoro-1-pentanone derivatives in good to excellent yields. The present system involves a five-membered nickelacycle key intermediate generated via the oxidative cyclization of TFE and ethylene.

Synthesis, characterization, and unique catalytic activities of a fluorinated nickel enolate.

We have synthesized a new nickel enolate [(PhCOCF2)Ni(dcpe)][FB(C6F5)3] featuring fluorine atoms on the enolate moiety via B(C6F5)3-promoted C-F bond activation of α,α,α-trifluoroacetophenone. X-ray diffraction study of [(PhCOCF2)Ni(dcpe)][FB(C6F5)3] revealed that the complex had adopted an η(3)-oxallyl coordination mode in the crystal lattice. The reaction of (t)BuNC with [(PhCOCF2)Ni(dcpe)][FB(C6F5)3] resulted in the coordination of isocyanide to the nickel center to form a C-bound enolate complex. The reactions of [(PhCOCF2)Ni(dcpe)][FB(C6F5)3] with aldehydes gave insertion products quantitatively which were fully characterized by NMR spectroscopy. Furthermore, we established unique catalytic applications for [(PhCOCF2)Ni(dcpe)][FB(C6F5)3] toward a Tishchenko reaction, along with a highly selective crossed-esterification of α,α,α-trifluoroacetophenones with aldehydes.