Ligand Acceleration Effect Research Articles

Enantioselective Synthesis of Spiro[cyclopentane-1,3'-oxindole] Scaffolds with Five Consecutive Stereocenters.

A highly diastereo- and enantioselective cascade annulation reaction of Morita-Baylis-Hillman (MBH) maleimides of isatins with ortho-hydroxychalcones was achieved by a chiral N,N'-dioxide/Mg(II) complex Lewis acid catalyst. This strategy provides a concise and efficient route to densely functionalized spiro[cyclopentane-1,3'-oxindole] compounds with five consecutive stereocenters. The reaction itself features mild conditions, good functional group compatibility, and broad substrate scope (62 examples, up to 99% yield, up to >20:1 dr, 97% ee). In addition, an obvious ligand acceleration effect and chiral amplification effect were observed. DFT calculations were performed to elucidate the stereoselectivity observed. The gram-scale synthesis and the inhibitory effect of two products on the viability of A549 cells demonstrate the potential utility of the current method.

Cu-mediated enantioselective C–H alkynylation of ferrocenes with chiral BINOL ligands

A wide range of Cu(II)-catalyzed C–H activation reactions have been realized since 2006, however, whether a C–H metalation mechanism similar to Pd(II)-catalyzed C–H activation reaction is operating remains an open question. To address this question and ultimately develop ligand accelerated Cu(II)-catalyzed C–H activation reactions, realizing the enantioselective version and investigating the mechanism is critically important. With a modified chiral BINOL ligand, we report the first example of Cu-mediated enantioselective C–H activation reaction for the construction of planar chiral ferrocenes with high yields and stereoinduction. The key to the success of this reaction is the discovery of a ligand acceleration effect with the BINOL-based diol ligand in the directed Cu-catalyzed C–H alkynylation of ferrocene derivatives bearing an oxazoline-aniline directing group. This transformation is compatible with terminal aryl and alkyl alkynes, which are incompatible with Pd-catalyzed C–H activation reactions. This finding provides an invaluable mechanistic information in determining whether Cu(II) cleaves C–H bonds via CMD pathway in analogous manner to Pd(II) catalysts.

Asymmetric Catalytic Rearrangements with α-Diazocarbonyl Compounds.

α-Diazocarbonyl compounds serve as nucleophiles, dipoles, carbene precursors, and rare electrophiles, enabling a vast array of organic transformations under the influence of metal catalysts. Among them, rearrangement processes are attractive and provide straightforward and efficient accesses to one-carbon extension adducts or heteroatom-containing molecules. The reactions occur upon the release of dinitrogen after nucleophilic addition or before ylide formation. Although significant progress has been made for these two types of rearrangement reactions, the issue of enantiocontrol is challenging because the final optically enriched products are generated via multistep transformations and the inherent spacial arrangement of the intermediates has more or less influence on the regio- and enantioselectivity.In this Account, we collected several rearrangements of α-diazocarbonyl compounds, showcasing the efficient catalysts and tailored strategies for tackling enantioselective varieties of these two types of rearrangement reactions. Our research group initiated the catalytic asymmetric reactions of α-diazocarbonyl compounds during the development of chiral Feng N,N'-dioxide-metal complex catalysts and others. As a kind of useful chiral Lewis acid catalyst chiral N,N'-dioxide-metal complexes are favorable for the activation of various carbonyl compounds, accelerating the diastereo- and enantioselective nucleophilic addition of α-diazoesters and the sequential rearrangements in either an intermolecular or intramolecular manner. Aldehydes, acyclic and cyclic ketone derivatives, and α,β-unsaturated ketones could participate in efficient asymmetric homologation reactions, and an obvious ligand-acceleration effect is observed in these processes. For example, the Roskamp-Feng reaction of aldehydes gives optically active β-ketoesters through a H-shift, overwhelming the aryl group shift or oxygen attack. The shift preference and enantiocontrol in the homologation of acyclic and cyclic ketone derivatives could be under excellent control of the chiral catalysts. An unusual electrophilic α-amination of aryl/alkyl ketones and even a complicated homologation/dyotropic rearrangement/interconversion/[3 + 2] cycloaddition cascade used to construct dimeric polycyclic compounds were discovered as a result of the selection of chiral ligands and additives. On the basis of the understanding of the interaction of the functional group with N,N'-dioxide-metal complexes in catalysis and the key enantio-determining issues in ylide-based rearrangements, we designed new α-diazocarbonyl compounds by introducing a pyrazole-1-carboxyl group as the acceptor unit, which could benefit the formation of both carbenoid species and the chiral catalyst-bound ylides to deliver stereoselectivity. Taking advantage of Ni(II) or Co(II) complexes of Feng N,N'-dioxide ligands, we realized several kinds of enantioselective [2,3]-sigmatropic rearrangements, such as the Doyle-Kirmse reaction with allylic sulfides or selenides, [2,3]-Stevens rearrangements of vinyl-substituted α-diazo pyrazoleamides with thioacetates, Sommelet-Hauser rearrangements of aryl-substituted α-diazo pyrazoleamides with thioamides, and thio-Claisen rearrangements of 2-thio-indoles as well. Moreover, this strategy was shown to be applicable to highly γ-selective and enantioselective insertion into N-H bonds of secondary amines with vinyl-substituted α-diazo pyrazoleamides.

α-Cationic Phosphines: from Curiosities to Powerful Ancillary Ligands

AbstractThe distinguishing feature of α-cationic phosphines is the presence of at least one substituent, normally (hetero)cyclic and positively charged, which is directly attached to the phosphorus atom. As result from this unique substitution pattern, the thus designed ligands depict significantly diminished donor properties if compared with their neutral counterparts. Thus, if in a hypothetical catalytic cycle, the step that determines the rate is facilitated by an increase of the electrophilicity at the metal center; then, the use of α-cationic ancillary phosphines can be highly beneficial. This fact, combined with their easy syntheses and stability, which allows an easy handling, make α-cationic phosphines a useful tool for the synthetic practitioner. Our research on the topic demonstrates that generally a remarkable ligand acceleration effect is observed when α-cationic phosphines are employed in Au(I)- and Pt(II)-promoted cycloisomerizations; moreover, in some cases even otherwise not operative transformations can be promoted. This Account describes how we entered into the topic, our efforts, and those of others to understand the coordination behavior of α-cationic phosphines and further develop their range of applications in catalysis; but it also identifies the drawbacks associated with their use, which limit their range of application.1 Introduction2 Polycationic Phosphines: Stronger Acceptors than Phosphites3 Inconveniences Derived from the Use of (Poly)cationic phosphines4 A Second Generation of Cationic Ligands: α-Pyridiniophosphines5 Chiral α-Cationic Phosphines6 α-Radical Phosphines and (Poly)cationic Phosphine Oxides7 Conclusions and Outlook

Moderately Flexible Trans-Chelating Diphosphine Ligands Consisting of a Triazine Unit Showing High Ligand Acceleration Effect for Heck Reaction

Abstract Originally designed trans-chelating diphosphine ligands with moderate flexibility that allows trans- to cis-isomerization and bidentate to monodentate complex form were developed. The novel ligand shows high ligand acceleration effect (LAE) for Heck reaction. The catalyst loading was decreased to 0.0001 mol%, and the turnover number (TON) reached 970,000. The catalytic cycle was evaluated by DFT calculations. The calculations revealed the following: 1) the insertion step in monodentate pathway was the rate-determining step, 2) the high LAE effect of the novel ligand was due to a facile change of conformation from trans to cis form and flexibility to avoid steric repulsion between substrate and catalyst in the insertion step as well.

Development of Homogeneous Hydrogenation of Carbon Dioxide to Formate Catalyzed by Copper Complexes

Hydrogenation of CO2 promoted by heterogeneous metal catalysts has found commercial applications. Furthermore, homogeneous catalysts based on transition metal complexes have also been demonstrated to be useful in the CO2 conversion to formate under relatively mild reaction conditions. In the course of our study aimed to uncover the availability of copper complexes, we focused on the ligand acceleration effect on the hydrogenation reaction. Improved formate yield and catalytic activity were obtained by adding selected bisoxazoline ligands to a copper catalyst system. The results presented here open up the possibility to develop efficient copper catalysts based on appropriate ligand design.

Ligand effect on direct arylation by CMD process

The ligand effect of electron-poor phosphines in the concerted metalation-deprotonation (CMD) process for intramolecular direct arylation was experimentally and theoretically demonstrated. The ligand acceleration effect (LAE) for the intramolecular direct arylation of 1-bromo-2-(phenoxymethyl)benzene increased in the following order: P(BFPy)3 > P{3,5-(CF3)2-C6H3}3 > PCy3 > P(3,4,5-F3-C6H2)3 > P(4-F-C6H4)3 = PPh3 ≫ P(C6F5)3. The use of highly electron-poor P(BFPy)3 allowed the catalyst loading to be decreased up to 0.01 mol%. The LAE is roughly proportional to the electronic effect of the phosphine ligand. The LAE was not observed in the case of P(C6F5)3 because of its lack of coordination ability for Pd(OAc)2, as confirmed by 31P NMR spectroscopy. The donating PCy3 ligand showed a higher LAE than PPh3. The relative activation free energies (ΔG≠) of the CMD process calculated by the density functional theory (DFT) at the M06-2X/6-31G(d) level with LANL2DZ showed the same trend as the experimental results. The LAE in CMD was further evaluated by DFT calculations using two approaches: (1) fragment energy analysis and (2) evaluation of NBO deletion energy in transition states in CMD. The results of the first technique indicated that the conformational change in PCy3 results in increase of activation energy (ΔE≠) in compared with PAr3 systems. The use of the second technique clarified that the highly electron-poor P(BFPy)3 ligand stabilized the CAr→Pd interaction and the electron-donating PCy3 stabilized the O→H⋯CAr interaction in the transition state in CMD.

ChemInform Abstract: Synthesis of 5‐Iodo‐1,2,3‐triazoles from Organic Azides and Terminal Alkynes: Ligand Acceleration Effect, Substrate Scope, and Mechanistic Insights.

AbstractThe improved method for the selective formation of 5‐iodo‐1,2,3‐triazoles proceeds via an iodoalkyne intermediate under mild conditions.

Chiral‐Zn(NTf2)2‐Complex‐Catalyzed Diastereo‐ and Enantioselective Direct Conjugate Addition of Arylacetonitriles to Alkylidene Malonates

Chiral N,N'-dioxide/Zn(NTf2)2 complexes were demonstrated to be highly effective in the direct asymmetric conjugate addition of arylacetonitriles to alkylidene malonates under mild conditions. A wide range of substrates were tolerated to afford their corresponding products in moderate-to-good yields with high diastereoselectivities (82:18->99:1 d.r.) and enantioselectivities (81-99% ee). The reactions performed well, owing to the high Lewis acidity of the metal triflimidate and a ligand-acceleration effect. The N,N'-dioxide also benefited the deprotonation process as a Brønsted base. The catalytic reaction could be performed on the gram-scale with retention of yield, diastereoselectivity, and enantioselectivity. The products that contained functional groups were ready for further manipulation. In addition, a possible catalytic model was proposed to explain the origin of the asymmetric induction.

Synthesis of 5-Iodo-1,2,3-triazoles from Organic Azides and Terminal Alkynes­: Ligand Acceleration Effect, Substrate Scope, and Mechanistic Insights

An improved method has been developed for the preparation of 5-iodo-1,2,3-triazoles directly from organic azides and terminal alkynes by a reaction mediated by copper(I) and iodinating agents generated in situ. The major methodological advance of the current procedure is that it provides a high conversion and good iodo/proto selectivity with a broad range of substrates without using an excess of the alkyne, which was required in the previous method. The use of an accelerating ligand is essential to the success of reactions involving unreactive azides or alkynes. New mechanistic insights are provided, including the confirmation that a 1-iodoalkyne is formed as a key intermediate under the established conditions for the reaction.

Ligand-accelerating low-loading copper-catalyzed effective synthesis of (E)-1,3-enynes by coupling between vinyl halides and alkynes performed in water

The useful conjugated enynes could be easily prepared via low-loading (0.0001 mol %) copper-catalyzed coupling between vinyl halides and terminal alkynes. It is noteworthy that this reaction could be preformed in water without using any co-solvents and the desired 1,3-enynes could be obtained with good yields. In the catalytic reaction, ligand-acceleration effect was markable.

Anomalous Ligand Acceleration on Cinchona-modified Pd/C during Asymmetric Hydrogenation of Properly Substituted Phenylcinnamic Acid

Abstract The hydrogenation of 4,4′-dimethoxy-α-phenylcinnamic acid over Pd/C showed a large ligand acceleration effect when a cinchonidine modifier was used; the hydrogen rate increased to 370% relative to the reaction rate on unmodified Pd/C and resulted in a 91% enantiomeric excess (ee). Another good substrate, 4-fluoro-2′-methoxyphenylcinnamic acid, also resulted in a high ee value of 92%; however, the rate increased only to 230% when this modifier was used. On the basis of the difference in the degree to which the reaction rate was accelerated, the eemax for each substrate was analyzed.

Synthesis and Application of 2,6‐Bis(trifluoromethyl)‐4‐pyridyl Phosphanes: The Most Electron‐Poor Aryl Phosphanes with Moderate Bulkiness

The poor will be rich: BFPy phosphanes (see scheme) mimic the electronic and steric characters of P(C6F5)3 and PPh3, respectively. These novel ligands showed a large ligand acceleration effect on Stille coupling, the Rh-catalyzed 1,2-addition of aryl boronic acid to unactivated ketones and the asymmetric arylation of N-tosylimine using phenylboronic acid.

N-Heterocyclic Carbene Ligands in Copper-Catalyzed Addition of Diethylzinc to N-Sulfonylimines

N-Heterocyclic carbenes (NHCs) were generated in-situ from imidazolium and imidazolinium salts by deprotonation of C-2 hydrogen and were used as ligands in the copper-catalyzed addition of diethylzinc to N-sulfonylimines. The copper-NHC complexes were shown to possess an efficient ligand acceleration effect (LAE).

Aqueous Asymmetric Mukaiyama Aldol Reaction Catalyzed by Chiral Gallium Lewis Acid with Trost‐Type Semi‐Crown Ligands

AbstractThe combination of Ga(OTf)3 with chiral semi‐crown ligands (1a–e) generates highly effective chiral gallium Lewis acid catalysts for aqueous asymmetric aldol reactions of aromatic silyl enol ethers with aldehydes. A ligand‐acceleration effect was observed. Water is essential for obtaining high diastereoselectivity and enantioselectivity. The p‐phenyl substituent in aromatic silyl enol ether (2 h) plays an important role and increases the enantioselectivity up to 95% ee. Although aliphatic silyl enol ethers provided low enantioselectivities and silylketene acetal is easily hydrolyzed in aqueous alcohol, the aldol reactions of silylketene thioacetal (12) with aldehydes in the presence of gallium‐Lewis acid catalysts give the β‐hydroxy thioester with reasonable yields and high diastereo‐ (up to 99 : 1) and enantioselectivities (up to 96% ee).

Meerwein–Ponndorf–Verley alkynylation of aldehydes: Essential modification of aluminium alkoxides for rate acceleration and asymmetric synthesis

A novel carbonyl alkynylation has been accomplished based on utilization of the Meerwein-Ponndorf-Verley (MPV) reaction system. The success of the MPV alkynylation crucially depends on the discovery of the remarkable ligand acceleration effect of 2,2'-biphenol. For example, the alkynylation of chloral (2c) with the aluminium alkoxide 6(R = Ph), prepared in situ from Me(3)Al, 2,2'-biphenol and 2-methyl-4-phenyl-3-butyn-2-ol (1a) as an alkynyl source, proceeded smoothly in CH(2)Cl(2) at room temperature to give the desired propargyl alcohol 3ca in almost quantitative yield after 5 h stirring. The characteristic feature of this new transformation involving no metal alkynides can be visualized by the fact that the alkynyl group bearing keto carbonyl was transferred successfully to aldehyde carbonyl without any side reactions on keto carbonyl. Although the use of (S)-1,1[prime or minute]-bi-2-naphthol and its simple analogues was found to be unsuitable for inducing asymmetry in this reaction, design of new chiral biphenols bearing a certain flexibility of the biphenyl axis led to satisfactory results in terms of enantioselectivity as well as reactivity.

The First Enantioselective Intramolecular Aminocarbonylation of Alkenes Promoted by Pd(II)‐Spiro Bis(isoxazoline) Catalyst.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The first enantioselective intramolecular aminocarbonylation of alkenes promoted by Pd(II)-spiro bis(isoxazoline) catalyst

The highly ligand acceleration effect of spiro bis(isoxazoline) ligand (SPRIX) on the Pd(II)-catalyzed intramolecular aminocarbonylation of alkenyl amine derivatives was realized. Furthermore, the chiral Pd(II)–SPRIX catalyst accomplished the first enantioselective intramolecular aminocarbonylation. The reaction of N-(2,2-dimethyl-pent-4-enyl)- p-toluenesulfonamide in the presence of Pd(II)–SPRIX catalyst and p-benzoquinone in methanol under a carbon monoxide atmosphere afforded [4,4-dimethyl-1-( p-toluene-sulfonyl)-pyrrolidin-2-yl]-acetic acid methyl ester in good yield with moderate enantioselectivity.

Hydrogenation of Aromatic Ketones Catalyzed by (η5-C5(CH3)5)Ru Complexes Bearing Primary Amines

The rapid hydrogenation of simple aromatic ketones is accomplished by using a combination of (η5-C5(CH3)5)Ru complexes and primary amines as a catalyst in 2-propanol. In particular, 1,2-diamines with primary and tertiary amino groups at both ends exhibit a significant ligand acceleration effect. Isotope-labeling experiments using D2 and 2-propanol-dn reveal that 2-propanol participates in the activation of H2 based on a metal/NH bifunctional effect to facilitate the hydrogenation. Asymmetric hydrogenation of prochiral simple ketones with the chiral version of the catalysts provides optically active secondary alcohols with up to 95% ee.

Catalytic efficiency, ligand acceleration, and concentration effect in magnesium ion mediated 1,3-dipolar cycloadditions of mesitonitrile oxide to allylic alcohols

Catalytic cycle, ligand acceleration, and concentration effect in magnesium ion catalyzed nitrile oxide cycloaddition reactions to allylic alcohols are discussed.