The successful isolation and characterization of an N-heterocyclic carbene in 1991 opened up a new class of organic compounds for investigation. From these beginnings as academic curiosities, N-heterocyclic carbenes today rank among the most powerful tools in organic chemistry, with numerous applications in commercially important processes. Here we provide a concise overview of N-heterocyclic carbenes in modern chemistry, summarizing their general properties and uses and highlighting how these features are being exploited in a selection of pioneering recent studies.

An overview of N-heterocyclic carbenes

N-Heterocyclic Carbenes in Late Transition Metal Catalysis

The chemistry of heterocyclic carbenes has experienced a rapid development over the last years. In addition to the imidazolin-2-ylidenes, a large number of cyclic diaminocarbenes with different ring sizes have been described. Aside from diaminocarbenes, P-heterocyclic carbenes, and derivatives with only one, or even no heteroatom within the carbene ring are known. New methods for the synthesis of complexes with N-heterocyclic carbene ligands such as the oxidative addition or the metal atom template controlled cyclization of β-functionalized isocyanides have been developed recently. This review summarizes the new developments regarding the synthesis of N-heterocyclic carbenes and their metal complexes.

Heterocyclic Carbenes: Synthesis and Coordination Chemistry

1.1. Context and Meta-Review
Despite the ubiquity of metallic gold (Au) in popular culture, its deployment in homogeneous catalysis has only recently undergone widespread investigation. In the past decade, and especially since 2004, great progress has been made in developing efficient and selective Au-catalyzed transformations, as evidenced by the prodigious number of reviews available on various aspects of this growing field. Hashmi has written a series of comprehensive reviews outlining the progression of Au-catalyzed reaction development,1 and a number of more focused reviews provide further insight into particular aspects of Au catalysis. A brief meta-review of the available range of perspectives published on Au catalysis helps to put this Chemical Reviews article in context.

The vast majority of reactions developed with homogeneous Au catalysts have exploited the propensity of Au to activate carbon-carbon π-bonds as electrophiles. Gold has come to be regarded as an exceedingly mild, relatively carbophilic Lewis acid, and the broad array of newly developed reactions proceeding by activation of unsaturated carbon-carbon bonds has been expertly reviewed.2

Further reviews and highlights on Au catalysis focus on particular classes of synthetic reactions. An excellent comprehensive review of Au-catalyzed enyne cycloisomerizations is available.3 Even more focused highlights on hydroarylation of alkynes,4 hydroamination of C-C multiple bonds,5 and reactions of oxo-alkynes6 and propargylic esters7 provide valuable perspectives on progress and future directions in the development of homogeneous Au catalysis.

Most of the reviews on Au catalysis emphasize broad or specific advances in synthetic utility. Recently, we have invoked relativistic effects to provide a framework for understanding the observed reactivity of Au catalysts, in order to complement empirical advancements.8 In this Chemical Reviews article, we attempt to enumerate the ways in which selectivity can be controlled in homogeneous Au catalysis. It is our hope that lessons to guide catalyst selection and the design of new catalysts may be distilled from a thorough evaluation of ligand, counterion, and oxidation state effects as they influence chemo-, regio-, and stereoselectivity in homogeneous Au catalysis.

http://www.cchem.berkeley.edu/toste/publications/cr068430g.pdf

Ligand effects in homogeneous Au catalysis.

Gold salts and complexes have emerged in the past few years as the most powerful catalysts for electrophilic activation of alkynes toward a variety of nucleophiles under homogeneous conditions. In a simplified form, nucleophilic attack on the [AuL]-activated alkyne proceeds via π complexes 1 to give trans-alkenyl gold complexes of type 2 as intermediates (Scheme 1). This type of coordination is also a common theme in gold-catalyzed cycloisomerizations of enynes, in which the alkene function acts as the nucleophile. In the reaction of enynes with complexes of other transition metals, an Alder-ene cycloisomerization can take place by simultaneous coordination of the alkyne and the alkene to the metal followed by an oxidative cyclometalation. In contrast, this process does not occur for gold(I) since oxidative addition processes are not facile for this metal. 6 In addition, the [AuL] fragment, which is isolobal to H and HgL, adopts a linear coordination and binds to either the alkene or the alkyne. Thus, cycloisomerizations of enynes catalyzed by gold proceed by an initial coordination of the metal to the alkyne, and as illustrated in Scheme 2, the resulting complex 3 reacts with the alkene by either the 5-exo-dig or 6-endo-dig pathway to form the exoor endocyclopropyl gold carbene 4 or 5, respectively, as has been established with other electrophilic transition-metal complexes or halides MXn as catalysts. The proposed involvement of cyclopropyl metal carbenes of type 4 in the electrophilic activation of enynes by transition metals was first substantiated in reactions catalyzed by Pd(II), in which the initially formed cyclopropyl palladium carbenes undergo [4 + 2] cycloaddition with the double bond of the conjugate enyne. Strong evidence for the existence of cyclopropyl metal carbenes as intermediates was also obtained in the reaction of enynes bearing additional double bonds at the alkenyl chain with Ru(II) and Pt(II) catalysts. In these reactions, the cyclopropyl metal carbenes are trapped intramolecularly by the terminal alkene to give tetracycles containing two cyclopropanes. Gold(I) complexes usually surpass the reactivity shown by Pt(II) and other electrophilic metal salts and complexes for the activation of enynes. They are highly reactive yet uniquely selective Lewis acids that have a high affinity for π bonds. This high π-acidity is linked to relativistic effects, which reach a maximum in the periodic table with gold. However, on occasion, the stronger Lewis acidity of gold complexes can be detrimental in terms of selectivity and because of their low tolerance to certain functional groups. In these instances, the less-strongly Lewis acidic Pt(II) complexes could be the catalysts of choice. * To whom correspondence should be addressed. E-mail: aechavarren@ iciq.es. † Additional affiliation: Departamento de Quı́mica Orgánica, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. Scheme 1 Chem. Rev. 2008, 108, 3326–3350 3326

Gold-catalyzed cycloisomerizations of enynes: a mechanistic perspective.

The availability of catalysts to perform specific transformations is critical for both industry and academia. Over the years, the success of homogeneous catalysis can be attributed largely to the development of a diverse range of ligand frameworks that have been used to tune the behavior of a variety of metal-containing systems. Advances in ligand design have allowed not only for improvements of known processes in terms of scope, mildness, and catalyst loadings, but also for the discovery of new selective reactions. A good illustration is given by palladium-catalyzed coupling reactions, which are applied to a wide area of endeavors ranging from synthetic organic chemistry to materials science.[1] For these catalytic processes, which represent some of the most powerful and versatile tools available for synthetic chemists, major advances have recently been reported thanks to the use of bulky, electron-rich, phosphines A and cyclic diaminocarbenes (N-heterocyclic carbenes (NHCs)) B (Figure 1).[2] These ligands stabilize the active catalytic species, and accelerate the important catalytic steps, namely oxidative addition, transmetallation, and reductive elimination. On the other hand, excessive steric hindrance can present some drawbacks for the coupling of bulky reactants.[3] To overcome this problem Glorius and co-workers have successfully developed ligands with “flexible steric bulk” using the conformational flexibility of cyclohexane.[4]

Stable Cyclic (Alkyl)(Amino)Carbenes as Rigid or Flexible, Bulky, Electron-Rich Ligands for Transition-Metal Catalysts: A Quaternary Carbon Atom Makes the Difference

In possessing a lone pair of electrons and an accessible vacant orbital, singlet carbenes resemble transition metal centers and thus could potentially mimic their chemical behavior. Although singlet di(amino)carbenes are inert toward dihydrogen, it is shown that more nucleophilic and electrophilic (alkyl)(amino)carbenes can activate H2 under mild conditions, a reaction that has long been known for transition metals. However, in contrast to transition metals that act as electrophiles toward dihydrogen, these carbenes primarily behave as nucleophiles, creating a hydride-like hydrogen, which then attacks the positively polarized carbon center. This nucleophilic behavior allows these carbenes to activate NH3 as well, a difficult task for transition metals because of the formation of Lewis acid-base adducts.

https://science.sciencemag.org/content/sci/316/5823/439.full.pdf

Facile splitting of hydrogen and ammonia by nucleophilic activation at a single carbon center.

still today the most severely bent acyclic allene known, with a C=C=C bond angle of 170.18. They demonstrated that the nonlinearity was due to packing effects in the crystal. To induce greater bending in an allene it is necessary to constrain the C=C=C p system into a ring, but this eventually leads to very unstable compounds. So far, the diphosphoruscontaining six-membered ring A3 is the most severely bent allene that has been isolated and characterized by crystallography; it has a C=C=C angle of 155.88. In marked contrast with all-carbon allene fragments (C= C=C), crystallographic and computational studies of allenes that are based on heavier Group 14 elements (E=E=E where E= Si, Ge; B1 and B2, respectively) demonstrate that they are highly flexibile, and exhibit a bent structure (136.58 and 122.68, respectively). The striking differences between the geometry between acyclic all-carbon allenes A1 and their heavier element congeners B1 and B2 is mainly due to the “first long-row anomaly”, as described byGr7tzmacher. The first long-row elements tend to form hybrids from s and p orbitals that lead to the familiar linear, trigonal, and tetragonal bonding geometries of the carbon compounds. Second long-row elements largely avoid hybridization. Among the consequences is that second and higher row elements are generally reluctant to form multiple bonds, and therefore heavier element–heavier element p bonds are weak. From this analysis, we reasoned that weakening the p bonds of all-carbon allenes A1 should make them more flexible, and ultimately lead to a bending of the otherwise rigid and linear C=C=C skeleton. It has been demonstrated that the carbon–carbon p bond of alkenes can be weakened by inducing either a diradical or zwitterionic character, as evidenced in each case by the twisting from planarity and lengthening of the C=C bond. The former option can be effected by steric congestion, as in the symmetrical compound C1 (twist angle= 668 ; dC=C = 1.39 :), whereas the latter is a result of p-bond polarization, as in C2 (twist angle= 868 ; dC=C = 1.47 :). [12] The steric approach cannot be extended to allenes because the termini are too remote for significant interactions. Therefore, the only possible way to weaken the p bonds of allenes is by polarization, which can be accomplished by either a push–pull or a push–push substitution pattern. Push–pull allenesD have a carbene character as inD’ (& = empty orbital), and they are prone to dimerization. Consequently, the best choice for preparing bent allenes is a push–push substitution pattern as in E, which should promote the dicarbanionic resonance form E’. Herein we report the isolation of an acyclic allene featuring a C=C=C bond angle of 134.88. Importantly, we show that bent allenes should not be considered as laboratory curiosities, but instead a novel class of strong h-donor ligands for transition-metal centers. [*] Dr. C. A. Dyker, V. Lavallo, B. Donnadieu, Prof. G. Bertrand UCR-CNRS Joint Research Chemistry Laboratory (UMI 2957) Department of Chemistry, University of California Riverside, CA 92521-0403 (USA) Fax: (+1)951-827-2725 E-mail: guy.bertrand@ucr.edu Homepage: http://research.chem.ucr.edu/groups/bertrand/guybertrandwebpage/

Synthesis of an Extremely Bent Acyclic Allene (A “Carbodicarbene”): A Strong Donor Ligand

Nitrogen–carbon bonds are ubiquitous in products ranging from chemical feedstock to pharmaceuticals. As ammonia is among the least expensive bulk chemicals produced in the largest volume, one of the greatest challenges of synthetic chemistry is to develop atom-efficient processes for the combination of NH3 with simple organic molecules to create nitrogen–carbon bonds. Transition-metal complexes can readily render a variety of N–H bonds reactive enough to undergo functionalization, including those of primary and secondary amines. However, with a few exceptions,[1,2] metals react with ammonia to afford supposedly inert Lewis acid–base complexes, as first recognized in the late 19th century by Werner.[3] Consequently, the homogeneous catalytic functionalization of NH3 remained elusive[4] until the recent discovery by Shen and Hartwig[5] and Surry and Buchwald[6] of the palladium-catalyzed coupling of aryl halides with ammonia in the presence of a stoichiometric amount of a base. An even more appealing process would be the addition of NH3 to carbon–carbon multiple bonds, a process that would occur ideally with 100% atom economy.[7] Although various homogeneous catalysts, including alkali metals,[8] early[9] and late transition metals,[10] and d-[11] and f-block elements,[12] have been used to effect the so-called hydroamination reaction, none of them were reported to be effective when NH3 is used as the amine partner.[13] Herein we report that cationic gold(I) complexes supported by a cyclic (alkyl)(amino)carbene (CAAC)[14] ligand readily catalyze the addition of ammonia to a variety of unactivated alkynes and allenes to provide a diverse array of linear and cyclic nitrogen-containing compounds.

We showed recently that the cationic CAAC–gold complex A was very robust and exhibited unusual catalytic reactivity towards alkynes.[15] This discovery prompted us to investigate whether such a complex could activate alkynes sufficiently to enable the addition of NH3.[16] Thus, excess ammonia was condensed into a sealable NMR tube containing A (5 mol%), 3-hexyne, and deuterated benzene. Upon heating to 160 °C for 3.5 h, the clean addition of NH3 afforded the primary imine 2a, the expected tautomer of the corresponding enamine (Table 1).[17]



Table 1

Catalytic hydroamination of 3-hexyne with ammonia.[a]



Complex A does not have to be isolated; when it was prepared in situ from an equimolar mixture of [(CAAC)AuCl]/KB(C6F5)4 (A1), identical results were obtained. When the related silver complex [(CAAC)AgCl]/KB(C6F5)4 or NH4B(C6F5)4 was used as the catalyst, no reaction was observed, which shows the importance of gold and rules out a Bronsted acid mediated reaction.[18] Finally, as AuCl, AuCl/ KB(C6F5)4, and even [(CAAC)AuCl] do not induce the hydroamination, it is clear that the gold center can only catalyze the addition of NH3 if it is coordinated by the CAAC ligand and rendered cationic by Cl abstraction.

To gain insight into the catalytic process, we performed a number of experiments: The addition of excess NH3 to complex A gave the Werner complex B instantaneously; the addition of 3-hexyne (1a; 1 equiv) to complex A gave the η2-bound alkyne complex C instantaneously (Scheme 1). Upon the exposure of a solution of C in benzene to excess NH3, 3-hexyne was immediately displaced from the gold center, and the Werner complex B was isolated in quantitative yield. This result suggests that NH3 does not add to the alkyne through an outer-sphere mechanism. Importantly, when a solution of complex B in benzene was treated at room temperature for 24 h with a large excess of 3-hexyne, the imine complex D was obtained quantitatively, even when the reaction vessel was open to a glovebox atmosphere. This experiment implies that NH3 does not dissociate from the metal by a simple ligand exchange with the alkyne. Therefore, an insertion mechanism, similar to that proposed by Tanaka and co-workers[19] and Nishina and Yamamoto[20] for gold-catalyzed hydroamination with aryl amines, is quite likely. Finally, the addition of excess NH3 to D liberated the imine 2a and regenerated complex B. From the results of these experiments, it can be concluded that the Werner complex B is the resting state of the catalyst. Indeed, B exhibits identical catalytic activity to that of A/A1. Consequently, the robust and readily available complex B (Figure 1)[21] was used in subsequent experiments.



Scheme 1

Experiments to probe the reaction mechanism. The results suggest that an insertion process is involved, and that B is the resting state of the catalyst.





Figure 1

Molecular structure of complex B in the solid state. (Hydrogen atoms, except those at N1, and the (C6F5)4B anion are omitted for clarity; ellipsoids are drawn at 50% probability).



To test the scope of the reaction, the terminal alkyne 1b and the diaryl alkyne 1c were treated with NH3 in the presence of a catalytic amount of complex B (Scheme 2). With 1b, the reaction took place even at 110 °C to afford the Markovnikov imine 2b exclusively in 60% yield. When diphenyl acetylene (1c) was used, the 2-aza-1,3-diene 3c was formed cleanly in 95% yield. The different outcome of the reaction of 1c with respect to the results with substrates 1a,b can be rationalized by the presence of acidic benzylic hydrogen atoms in the imine. These acidic hydrogen atoms favor the formation of the enamine tautomer, which can then react further with a second molecule of the alkyne to afford 3c.



Scheme 2

Catalytic hydroamination of various alkynes with ammonia.



Nitrogen heterocycles are an important class of compounds that occur widely in natural products and often display potent biological activity. On the basis of the results described above, we attempted the direct synthesis of hetero-cycles from diynes and NH3. When 1,4-diphenylbuta-1,3-diyne (1d) and hexa-1,5-diyne (1e) were used, the corresponding 2,5-disubstituted pyrroles 4d and 4e were produced in 87 and 96% yield, respectively. Both products result from the Markovnikov addition of NH3, followed by ring-closing hydroamination.[22,23] The treatment of the 1,4-diyne 1f with NH3 under similar conditions led to a 3:2 mixture of the five- and six-membered heterocycles 5f and 6f in 88% yield. The six-membered ring 6f arises from two consecutive Markovnikov hydroamination reactions, whereas the formation of 5f involves an anti-Markovnikov addition of NH3 or ring-closing step.

To expand the scope of the hydroamination reaction with NH3, we next tested allenes as substrates. When 1,2-propadiene (7a) was used, a mixture of mono- (8a), di- (9a) and triallylamine (10a) was obtained in excellent yield. Allyl amines are among the most versatile intermediates in synthesis and are of industrial importance. For example, the parent compound 8a, which is produced commercially from ammonia and allyl chloride, is used in antifungal preparations and the synthesis of polymers. By varying the NH3/allene ratio it is possible to control the selectivity of this reaction significantly (Table 2). In particular, the parent allylamine (8a) and triallylamine (10a) can be obtained with 86 and 91% selectivity, respectively, and further optimization of the conditions should be possible. The addition of NH3 to 1,2-dienes is not restricted to the parent allene 7a. The dialkyl-substituted derivative 7b was also converted into the corresponding allyl amines 8b–10b, with exclusive addition of the NH2 group at the less-hindered terminus; however the selectivity of this reaction for the mono-, di-, or trisubstituted amine product needs some improvement. Interestingly, even the tetrasubstituted allene 7c underwent hydroamination with ammonia. Probably because of steric factors, a different regioselectivity was observed, and only the monohydroamination product 11C was formed.[24]



Table 2

Catalytic hydroamination of allenes with ammonia.



The results outlined herein demonstrate that (CAAC)-gold(I) cations readily catalyze the addition of NH3 to non-activated alkynes and allenes. This reaction leads to reactive nitrogen-containing compounds, such as imines, enamines, and allyl amines, and is therefore an ideal initial step for the preparation of simple bulk chemicals, as well as rather complex molecules, as illustrated by the preparation of heterocycles 4–6. This study paves the way for the discovery of catalysts that mediate the addition of ammonia to simple alkenes, a process considered to be one of the ten greatest challenges for catalytic chemistry.[25]

Homogeneous Catalytic Hydroamination of Alkynes and Allenes with Ammonia

Addition of a sterically demanding cyclic (alkyl)(amino)carbene (CAAC) to AuCl(SMe2) followed by treatment with [Et3Si(Tol)]+[B(C6F5)4]− in toluene affords the isolable [(CAAC)Au(η2-toluene)]+[B(C6F5)4]− complex. This cationic Au(I) complex efficiently mediates the catalytic coupling of enamines and terminal alkynes to yield allenes and not propargyl amines as observed with other catalysts. Mono-, di-, and tri-substituted enamines can be used, as well as aryl-, alkyl-, and trimethylsilyl-substituted terminal alkynes. The reaction tolerates sterically hindered substrates and is diastereoselective. This general catalytic protocol directly couples two unsaturated carbon centers to form the three-carbon allenic core. The reaction most probably proceeds through an unprecedented “carbene/vinylidene cross-coupling.”

https://www.pnas.org/content/pnas/104/34/13569.full.pdf

Vincent Lavallo

Papers

Stable Cyclic (Alkyl)(Amino)Carbenes as Rigid or Flexible, Bulky, Electron-Rich Ligands for Transition-Metal Catalysts: A Quaternary Carbon Atom Makes the Difference

Facile splitting of hydrogen and ammonia by nucleophilic activation at a single carbon center.

Synthesis of an Extremely Bent Acyclic Allene (A “Carbodicarbene”): A Strong Donor Ligand

Homogeneous Catalytic Hydroamination of Alkynes and Allenes with Ammonia

Allene formation by gold catalyzed cross-coupling of masked carbenes and vinylidenes.