Optically Pure C₁-Symmetric Cyclic(alkyl)(amino)carbene Ruthenium Complexes for Asymmetric Olefin Metathesis

Jazzar R., Soleilhavoup M., Bertrand G.

Cyclic (alkyl)- and (aryl)-(amino)carbenes (CAACs and CAArCs) are stronger σ-donors and π-acceptors than imidazol-2-ylidenes and imidazolidin-2-ylidenes, the well-known N-heterocyclic carbenes (NHCs). Consequently, they form strong bonds with coinage metals and stabilize both low and high oxidation states. This Review shows that CAACs and CAArCs have allowed for the isolation of copper and gold complexes that were believed to be only transient intermediates. This has not only allowed for a better understanding of the mechanism of known processes but has also led to the development of novel coinage metal-catalyzed reactions. In addition to their role in homogeneous catalysis, CAAC and CAArC coinage metal complexes have recently found applications in medicinal chemistry, as well as in materials science. When possible, the performance of CAAC and CAArC ligands are compared with those of classical NHCs.

Samkian A.E., Xu Y., Virgil S.C., Yoon K., Grubbs R.H.

Ru–cyclic alkyl amino carbene (Ru–CAAC) olefin metathesis catalysts perform extraordinarily in metathesis macrocyclization and ethenolysis, but previous studies have been limited to the use of five-membered CAAC (CAAC-5) ligands. In this work, we synthesized a different group of ruthenium catalysts with more σ-donating and π-accepting six-membered CAAC (CAAC-6) ligands, and their metathesis activity was probed through initiation studies, ring-closing metathesis (RCM), cross-metathesis, and ethenolysis. These catalysts display higher initiation rates than analogous Ru–CAAC-5 complexes but demonstrate lower activity in RCM and ethenolysis.

Kong L., Morvan J., Pichon D., Jean M., Albalat M., Vives T., Colombel-Rouen S., Giorgi M., Dorcet V., Roisnel T., Crévisy C., Nuel D., Nava P., Humbel S., Vanthuyne N., et. al.

Well-defined optically pure transition metal (TM) complexes bearing C1- and C2-symmetric N-heterocyclic carbene (NHC) ligands were prepared from prochiral NHC precursors. As predicted by DFT calculations, our strategy capitalizes on the formation of a metal-carbene bond which induces an axis of chirality. Configurationally stable atropisomers of various NHC-containing TM complexes were isolated by preparative HPLC on a chiral stationary phase in good yields and excellent optical purities (up to 99.5% ee). The carbene transfer from an optically pure Cu complex to a gold or palladium center reveals, for the first time, a full stereoretentivity, supporting the hypothesis of an associative mechanism for the transmetalation. The potential of these new chiral TM complexes was illustrated in asymmetric catalysis with up to 98% ee.

Nascimento D.L., Fogg D.E.

Examined herein is the basis for the outstanding metathesis productivity of leading cyclic alkyl amino carbene (CAAC) catalysts relative to their important N-heterocyclic carbene (NHC) predecessors, as recently demonstrated in the topical contexts of metathesis macrocyclization and the ethenolysis of renewable oils. The difference is traced to the stability to decomposition of the metallacyclobutane (MCB) intermediate. The CAAC catalysts are shown to undergo little to no β-H elimination of the MCB ring, a pathway to which the H2IMes catalysts are highly susceptible. Unexpectedly, however, the CAAC catalysts are found to be more susceptible to bimolecular coupling of the key intermediate RuCl2(CAAC)(═CH2), a reaction that culminates in elimination of the methylidene ligand as ethylene. Thus, an NMR study of transiently stabilized RuCl2(L)(py)(═CH2) complexes (L = CAAC or H2IMes) revealed bimolecular decomposition of the CAAC derivative within 5 min at RT, as compared to a time scale of hours for the H2IMes analogue. The remarkable productivity of the CAAC catalysts is thus due to their resistance to β-elimination, which enables their use at part per million loadings, and to the retarding effect of these low catalyst concentrations on bimolecular decomposition.

Ton S.J., Fogg D.E.

The impact of O2 on olefin metathesis promoted by Ru-NHC and Ru-CAAC catalysts is examined (NHC = N-heterocyclic carbene; CAAC = cyclic alkyl amino carbene). An atmosphere of 8% O2 in Ar is found t...

Pichon D., Soleilhavoup M., Morvan J., Junor G.P., Vives T., Crévisy C., Lavallo V., Campagne J., Mauduit M., Jazzar R., Bertrand G.

Cyclic (alkyl)(amino)carbene (CAAC) metal complexes can also engage in asymmetric transformations, thereby expanding the toolbox of available chiral carbene ligands.

Nascimento D.L., Gawin A., Gawin R., Guńka P.A., Zachara J., Skowerski K., Fogg D.E.

Access to leading olefin metathesis catalysts, including the Grubbs, Hoveyda, and Grela catalysts, ultimately rests on the nonscaleable transfer of a benzylidene ligand from an unstable, impure aryldiazomethane. The indenylidene ligand can be reliably installed, but to date yields much less reactive catalysts. A fast-initiating, dimeric indenylidene complex (Ru-1) is reported, which reconciles high activity with scaleable synthesis. Each Ru center in Ru-1 is stabilized by a state-of-the-art cyclic alkyl amino carbene (CAAC, C1) and a bridging chloride donor: the lability of the latter elevates the reactivity of Ru-1 to a level previously attainable only with benzylidene derivatives. Evaluation of initiation rate constants reveals that Ru-1 initiates >250× faster than indenylidene catalyst M2 (RuCl2(H2IMes)(PCy3)(Ind)), and 65× faster than UC (RuCl2(C1)2(Ind)). The slow initiation previously regarded as characteristic of indenylidene catalysts is hence due to low ligand lability, not inherently slow cycloaddition at the Ru=CRR' site. In macrocyclization and "ethenolysis" of methyl oleate (i.e., transformation into α-olefins via cross-metathesis with C2H4), Ru-1 is comparable or superior to the corresponding, breakthrough CAAC-benzylidene catalyst. In ethenolysis, Ru-1 is 5× more robust to standard-grade (99.9%) C2H4 than the top-performing catalyst, probably reflecting steric protection at the quaternary CAAC carbon.

Karras M., Dąbrowski M., Pohl R., Rybáček J., Vacek J., Bednárová L., Grela K., Starý I., Stará I.G., Schmidt B.

Helical chirality is a novel enantioselectivity-inducing property in transition-metal-catalyzed transformations. The principle is illustrated herein for the example of asymmetric olefin metathesis. This work reports the synthesis of the first helically chiral Ru-NHC alkylidene complex from an aminohelicene-derived imidazolium salt, which was ligated to the first generation Hoveyda-Grubbs catalyst. Kinetic data were acquired for benchmark test reactions and compared to an achiral catalyst. The helically chiral Ru-catalyst was evaluated in asymmetric ring-closing metathesis (RCM) and ring-opening metathesis-cross-metathesis (ROM/CM) reactions, which proceeded with promising levels of enantioselectivity. Extensive NMR-spectroscopic investigations and a DFT geometry optimization were performed. These results led to a topographic steric map and calculation of percent-buried-volume values for each quadrant around the metal center.

Ogba O.M., Warner N.C., O’Leary D.J., Grubbs R.H.

Ruthenium-based olefin metathesis catalysts, known for their functional group tolerance and broad applicability in organic synthesis and polymer science, continue to evolve as an enabling technology in these areas. A discussion of recent mechanistic investigations is followed by an overview of selected applications.

Zhao M., Zhang Y., Chen J., Zhou L.

Enantioselective organocatalysis by N-heterocyclic carbenes (NHCs) has emerged as a powerful strategy to construct complex chiral molecules. Recent enantioselective NHC-catalyzed reactions have remarkable advances, involving dis-tinct activation intermediates. Which mainly include Breslow intermediate, homoenolate intermediate, α,β-unsaturated acyla-zolium, azolium enolate, and azolium dienolate, generated by the nucleophilic addition of NHC to aldehydes. Meanwhile, NHC-catalyzed reactions through non-covalent bonding interactions have also been developed. Principally, this review focuses on recent advances in enantioselective NHC catalysis.

Paradiso V., Bertolasi V., Costabile C., Caruso T., Dąbrowski M., Grela K., Grisi F.

A series of Hoveyda–Grubbs second-generation catalysts containing N-alkyl/N′-aryl N-heterocyclic carbene (NHC) ligands were synthesized and investigated in representative olefin metathesis reactions. Steric perturbations of unsymmetrical NHCs were achieved through modulation of the hindrance of alkyl (neopentyl, neophyl, cyclohexyl) and aryl (2-isopropylphenyl, mesityl) substituents at the nitrogen atoms in combination with different backbone configurations (syn and anti). The NHC substitution patterns strongly influence the stability and reactivity of the corresponding complexes. In general, complexes bearing an anti NHC backbone are more stable and more active than their corresponding syn isomers. In both the series, the presence of bulky, highly branched N-alkyl groups tends to give reduced catalytic differences between syn and anti isomers, whereas the nature of the N′-aryl substituent (2-isopropylphenyl or mesityl) gives rise to different activity and/or selectivity. Of note, an N′-mesityl catalyst w...

Gawin R., Tracz A., Chwalba M., Kozakiewicz A., Trzaskowski B., Skowerski K.

The active species generated from ruthenium complexes bearing N-heterocyclic carbene (NHC) ligands exhibit limited stability under certain conditions (high dilution, high temperature) and in the presence of nitrile functionality. As a consequence, industrial implementation of metathesis for the production of important materials such as macrocyclic musks and polyamide 11 is uneconomical. Over the past decade, hundreds of ruthenium complexes bearing NHC ligands have been obtained. However, to this date, they have brought rather limited improvements in efficiency. In this paper, we report on cyclic alkyl amino carbene (CAAC) ruthenium complexes that promote highly challenging macrocyclization and cross metathesis (CM) with acrylonitrile reactions at loadings as low as 10–20 ppm.

Paul U.S., Radius U.

The first synthesis of cyclic (alkyl)(amino)carbenes (cAACs) was reported in 2005, and since then this class of carbenes has been on a victory tour in main‐group‐element and transition‐metal chemistry. CAACs are easy to synthesize and among the most nucleophilic (σ‐donating) and simultaneously most electrophilic (π‐accepting) carbenes known to date. These properties have led to a vast number of applications of cAACs in main‐group‐element chemistry in, for example, the activation of small‐molecule compounds and enthalpically strong bonds, as well as in the stabilization of highly reactive main‐group‐element compounds. They also proved to possess outstanding ligand properties in transition‐metal chemistry in, for example, the stabilization of unusual low‐valent transition‐metal complexes, leading to enormously highly active but robust catalysts. Here a brief overview of cAAC‐ligated transition‐metal compounds, mainly in low oxidation states, with an emphasis on nickel complexes, is provided, and a personal account of some of the recent developments in the use of cAACs in coordination chemistry and catalysis is given.

Janssen-Müller D., Schlepphorst C., Glorius F.

Chiral ligands play a central role in enantioselective transition-metal catalysis. The success of achiral N-heterocyclic carbenes (NHCs) as stable electron-rich neutral ligands in homogeneous catalysis led to the development of a manifold of chiral NHCs as stereodirecting ancillary ligands for various enantioselective transformations. Due to the modular design of NHCs and the ease of access to their azolium salt precursors, tailor-made NHCs are readily available. Many chiral NHC scaffolds have been synthesised and tested in catalysis. Herein, we highlight only those NHC structures which have enabled high degrees of enantioselectivity in transition-metal catalysis. Following a brief introduction to the field of chiral NHCs, this tutorial review introduces different categories of chiral NHCs and provides a guide to the structural fine-tuning of ligand requirements and stereochemical models.

Hellou N., Srebro‐Hooper M., Favereau L., Zinna F., Caytan E., Toupet L., Dorcet V., Jean M., Vanthuyne N., Williams J.A., Di Bari L., Autschbach J., Crassous J.

A fused π-helical N-heterocyclic system was prepared and examined through its enantiomerically and diastereoisomerically pure cycloiridiated complexes. The systems display long-lived circularly polarized phosphorescence, which is attributed to extended π conjugation within the helical carbenic ligand efficiently interacting with the IrIII center.

Mandal I., Kilbinger A.F.

Boisvert E.Y., Castellanos R.R., Ferguson M.J., Fogg D.E.

AbstractThe small, lipophilic tetrafluoroborate anion is ubiquitous in the imidazol(in)ium and iminium precursors to N‐heterocyclic carbenes (NHCs), including cyclic (alkyl)(amino)carbenes (CAACs). Its symmetrical distribution of charge over four highly electronegative fluorine atoms confers high stability, attenuating basicity while shielding the boron center. Here we report that this inertness does not withstand the nucleophilicity of free carbenes, when combined with a polarizing lithium cation. Reaction of CAAC ⋅ HBF4 salts with LiN(SiMe3)2, a protocol widely used to liberate free CAACs, generates zwitterionic CAAC‐BF3 adducts within minutes at 80 °C, or hours at room temperature, even for bulky N‐diisopropylphenyl (DIPP) CAACs. Imidazol(in)ium tetrafluoroborates likewise form NHC‐BF3 adducts in excellent yields.

Madron du Vigné A., Cramer N.

A streamlined strategy to diastereo- and enantiomerically pure α,β-chiral CAAC salts and their corresponding transition metal complexes is reported, displaying high enantioselectivities in benchmark asymmetric transformations.

Dočekal V., Mohand M., Petrželová S., Veselý J., Yan X., Bertrand G.

Chiral NHCs have found numerous applications as ligands for transition metals and in their own right for asymmetric catalysis. We report a synthetic route from l-malic acid to enantiopure 1,2,3-triazoliums with the chiral center in a fused ring.

Liu M., Pearson-Long M., Bertus P., Boeda F.

AbstractThe first studies on [Ru]‐catalyzed Asymmetric Ring‐Closing Ene‐Yne Metathesis (ARCEYM) are disclosed in this communication. The desymmetrization of achiral ene‐diyne substrates afforded the corresponding exo cyclic compounds in good yields and enantioselectivities (up to 69 % ee). The methodology provided a straightforward access to functionalized scaffolds displaying alkyne and diene useful for further functionalization such as [4+2] cycloaddition reaction.

Cheng-Sánchez I., Moya-Utrera F., Sarabia F.

Gawin R., Tracz A., Krajczy P., Kozakiewicz-Piekarz A., Martínez J.P., Trzaskowski B.

Morvan J., Del Vecchio A., Talcik J., Bouëtard D., Mauduit M.

AbstractAsymmetric Olefin Metathesis (AOM) represents a highly versatile synthetic tool to lead to relevant chiral building blocks with excellent enantiopurity. As the Z‐alkene moiety is ubiquitous in a wide range of natural products, the development of catalysts which are able to control both the Z‐selectivity and the enantioselectivity of metathesis transformations is in high demands. This review aims to provide a comprehensive overview covering all the breakthroughs accomplished in the field of challenging Z‐enantioselective olefin metathesis, which is of interest in the total synthesis of complex molecules.

Li S., Feng S., Zhou Y., Liu C., Chen B., Xing X.

Sytniczuk A., Struzik F., Grela K., Kajetanowicz A.

A tunable family of ibuprofen intermediate-derived CAAC-base complexes for different applications, dependent from the size of the N-aryl substituent.

Lorkowski J., Bouetard D., Yorkgitis P., Gembicky M., Roisnel T., Vanthuyne N., Munz D., Favereau L., Bertrand G., Mauduit M., Jazzar R.

AbstractOrganic circularly polarized luminescence (CPL)‐active molecular emitters featuring dynamic propeller‐like luminophores were prepared in one step from cyclic(alkyl)(amino) carbenes (CAACs). These molecules exhibit through‐space arene‐arene π‐delocalization and rapid intramolecular inter‐system crossing (ISC) in line with their helical character.

Lorkowski J., Bouetard D., Yorkgitis P., Gembicky M., Roisnel T., Vanthuyne N., Munz D., Favereau L., Bertrand G., Mauduit M., Jazzar R.

AbstractOrganic circularly polarized luminescence (CPL)‐active molecular emitters featuring dynamic propeller‐like luminophores were prepared in one step from cyclic(alkyl)(amino) carbenes (CAACs). These molecules exhibit through‐space arene‐arene π‐delocalization and rapid intramolecular inter‐system crossing (ISC) in line with their helical character.

Kong L., Chou Y., ALBALAT M., Jean M., Vanthuyne N., Nava P., Humbel S., Clavier H.

The concept of atropisomeric N-heterocyclic carbene (NHC)-metal complexes was extended to NHCs possessing a C2-symmetry and implemented to prepare of palladium-based complexes. An in-depth study of the NHC precursors and...

Del Vecchio A., Talcik J., Colombel-Rouen S., Lorkowski J., Serrato M.R., Roisnel T., Vanthuyne N., Bertrand G., Jazzar R., Mauduit M.

Morvan J., Bouëtard D., Kong L., Chou Y., Vives T., Albalat M., Roisnel T., Crévisy C., Nava P., Humbel S., Vanthuyne N., Clavier H., Mauduit M.