Nucleophilic heterocyclic carbene

Some of these approaches were attempted by Grubbs et al. 143 171. In later studies [45, 46], the phenoxyimine ligands used in their initial study were replaced with nucleophilic heterocyclic carbene (NHC) ligands with the objective of pushing more electrons into the metal center to reduce the tendency of a last-inserted acrylate... 

Fig. 6 Grubbs nickel complex bearing sterically encumbered nucleophilic heterocyclic carbene ligand...

Nielsen, D.J., CaveU, K.J., Skelton, B.W. and White, A.H. (2006) Methyl-palladium(U) complexes of pyridine-bridged bis(nucleophilic heterocyclic carbene) ligands substituent effects on structure, stabUity, and catalytic performance. Inorg. Chim. Acta, 359, 1855-69. 

V. Nair, C. R. Sinu, B. P. Babu, V. Varghese, A. Jose, E. Suresh, Org. Lett. 2009, 11, 5570-5573. Novel nucleophilic heterocyclic carbene mediated stereoselective conjugate addition of enals to nitrostyrenes via homoenolate. 

The similar three-component reaction of (3-cyanoacetyl)indoles 135, urea and benzaldehydes was found to proceed well in PEG 400 resulting in good yields of pyrimidinones 136 (Scheme 78) [109]. TTiiamine hydrochloride played a role of a nucleophilic heterocyclic carbene efficiently catalyzing this reaction. 

S. Fatma, D. Singh, P Mishra, P.K. Singh, P. Ankit, M. Singh, J. Singh, Nucleophilic heterocyclic carbene promoted one pot multicomponent synthesis of new 6-(lH-indol-3-yl)-2-oxo-4-aryl-l,2,3,4-tetrahydropyrimidine-5-carbonitriles an eco-compatible approach with PEG as a biodegradable medium, RSC Adv. 3 (2013) 22527-22531. 

The ease of formation of the carbene depends on the nucleophilicity of the anion associated with the imidazolium. For example, when Pd(OAc)2 is heated in the presence of [BMIM][Br], the formation of a mixture of Pd imidazolylidene complexes occurs. Palladium complexes have been shown to be active and stable catalysts for Heck and other C-C coupling reactions [34]. The highest activity and stability of palladium is observed in the ionic liquid [BMIM][Brj. Carbene complexes can be formed not only by deprotonation of the imidazolium cation but also by direct oxidative addition to metal(O) (Scheme 5.3-3). These heterocyclic carbene ligands can be functionalized with polar groups in order to increase their affinity for ionic liquids. While their donor properties can be compared to those of donor phosphines, they have the advantage over phosphines of being stable toward oxidation. 

The surprising stability of N-heterocyclic carbenes was of interest to organometallic chemists who started to explore the metal complexes of these new ligands. The first examples of this class had been synthesized as early as 1968 by Wanzlick [9] and Ofele [10], only 4 years after the first Fischer-type carbene complex was synthesized [2,3] and 6 years before the first report of a Schrock-type carbene complex [11]. Once the N-heterocyclic ligands are attached to a metal they show a completely different reaction pattern compared to the electrophilic Fischer- and nucleophilic Schrock-type carbene complexes. 

AT-heterocyclic carbenes show a pure donor nature. Comparing them to other monodentate ligands such as phosphines and amines on several metal-carbonyl complexes showed the significantly increased donor capacity relative to phosphines, even to trialkylphosphines, while the 7r-acceptor capability of the NHCs is in the order of those of nitriles and pyridine [29]. This was used to synthesize the metathesis catalysts discussed in the next section. Experimental evidence comes from the fact that it has been shown for several metals that an exchange of phosphines versus NHCs proceeds rapidly and without the need of an excess quantity of the NHC. X-ray structures of the NHC complexes show exceptionally long metal-carbon bonds indicating a different type of bond compared to the Schrock-type carbene double bond. As a result, the reactivity of these NHC complexes is also unique. They are relatively resistant towards an attack by nucleophiles and electrophiles at the divalent carbon atom. 

The protocol of the allylic alkylation, which proceeds most likely via a c-allyl-Fe-intermediate, could be further improved by replacing the phosphine ligand with an M-heterocyclic carbene (NHC) (Scheme 21) [66]. The addition of a ferf-butyl-substituted NHC ligand 86 allowed for full conversion in the exact stoichiometric reaction between allyl carbonate and pronucleophile. Various C-nucleophiles were allylated in good to excellent regioselectivities conserving the 71 bond geometry of enantiomerically enriched ( )- and (Z)-carbonates 87. Even chirality and prochirality transfer was observed (Scheme 21) [67]. 

Through the use of arenediazonium salts, the straightforward transformation of amines into cross-coupling products can be realized. Whenever the diazonium salts do not tolerate bases and strong nucleophiles (e.g., phosphines), base- and phosphine-free protocols have to be used. Heterocyclic carbene ligands serve well in cross-coupling of Aryl- and vinylboronic acids, or alkylboronates with arenediazonium salts.369,370 Several convenient phosphine-free protocols have been developed for the same purpose.371-373... 

Carbonyl complexes also react with non-carbon nucleophiles. The resulting carbonic acid derivatives can serve as starting material for the preparation of bis-heteroatom-substituted carbene complexes [93]. Heterocyclic carbene complexes can be obtained from nucleophiles with a leaving group in -position (Table 2.2). 

Terminal alkynes readily react with coordinatively unsaturated transition metal complexes to yield vinylidene complexes. If the vinylidene complex is sufficiently electrophilic, nucleophiles such as amides, alcohols or water can add to the a-carbon atom to yield heteroatom-substituted carbene complexes (Figure 2.10) [129 -135]. If the nucleophile is bound to the alkyne, intramolecular addition to the intermediate vinylidene will lead to the formation of heterocyclic carbene complexes [136-141]. Vinylidene complexes can further undergo [2 -i- 2] cycloadditions with imines, forming azetidin-2-ylidene complexes [142,143]. Cycloaddition to azines leads to the formation of pyrazolidin-3-ylidene complexes [143] (Table 2.7). 

The use of functionalized isocyanides containing both the isocyanide function and the nucleophile in the same molecule leads to complexes with heterocyclic carbene ligands via a 1,2-addition across the C=N triple bond. Complexes with functionalized isocyanide ligands can be generated in template reactions or a nucleophile functionalized isocyanide can be reacted directly with a suitable metal complex. 

The addition of other bifunctional nucleophiles also allowed the preparation, in moderate to high yields, of the five-, seven-, and eight-membered heterocyclic carbene species 55-58 (Fig. 9) which, in some cases, were formed along with minor amounts of other derivatives [63]. Related 1,2,3-diheterocyclizations involving (ethoxy)allenylidene complexes have been described, ethanol instead of HNMe2 being released in this case [62],... 

Abstract The use of iV-heterocychc carbenes as catalysts for organic transformations has received increased attention in the past 10 years. A discussion of catalyst development and nucleophilic characteristics precedes a description of recent advancements and new reactions using A-heterocyclic carbenes in catalysis. 

This review will focus on the use of chiral nucleophilic A-heterocyclic carbenes, commonly termed NHCs, as catalysts in organic transformations. Although other examples are known, by far the most common NHCs are thiazolylidene, imida-zolinylidene, imidazolylidene and triazolylidene, I-IV. Rather than simply presenting a laundry list of results, the focus of the current review will be to summarize and place in context the key advances made, with particular attention paid to recent and conceptual breakthroughs. These aspects, by definition, will include a heavy emphasis on mechanism. In a number of instances, the asymmetric version of the reaction has yet to be reported in those cases, we include the state-of-the-art in order to further illustrate the broad utility and reactivity of nucleophilic carbenes. 

The catalytic preparation of esters and amides under mild and waste free reaction conditions using readily available starting materials is a desirable goal. The first redox process of this type using heterocyclic carbenes was reported by Castells and co-workers in 1977 in which aldehydes were oxidized to esters in one-pot in the presence of nitrobenzene [104], Furfural 169 is converted into methyl 2-furoate 170 in 79% yield Eq. 15. Nitrobenzene is the presumed stoichiometric oxidant for the oxidation of the nucleophilic alkene XXX to the acyl azolium XXXI by successive electron transfer events. The authors observe nitrosobenzene as a stoichiometric byproduct. This type of reactivity is also observed when cyanide is used as the catalyst. Miyashita has expanded the scope of this transformation using imida-zolylidene carbenes [105-107]. 

It should be noted that asymmetric acyl transfer can also be catalyzed by chiral nucleophilic A-heterocyclic carbenes [27-32] and by certain chiral Lewis acid complexes [33-37] but these methods are outside the scope of this review. Additionally, although Type I and Type II tr-face selective acyl transfer processes have been reported to be catalyzed by some of the catalysts described in this review, these also lie outside the scope of this review. 

N-Heterocyclic carbenes are an example of a family of nucleophilic catalysts [84-87]. For instance, the polymerization of p-butyrolactone was catalyzed by l,3,4-triphenyl-4,5-dihydro-l//,l,2-triazol-5-ylidene in the presence of methanol as an initiator [86]. This reaction was carried out in toluene at 80 °C. Nevertheless, an undesired elimination (Fig. 4) reaction was observed and control of the polymerization was lost. This issue was overcome by using ferf-butanol as a co-solvent, which reacts reversibly with the free carbene to form a new adduct. Owing to the decrease in the concentration of the free carbene, the elimination is disfavored and the polymerization is then under control provided that a degree of polymerization below 200 is targeted. As a rule, the reactivity of N-heterocyclic carbenes depends on their substituents. Hindered N-heterocyclic carbenes turned out to be not nucleophilic enough for the ROP of sCL. Recently, it was shown that unencumbered N-heterocyclic carbenes were more efficient catalysts [87]. 

Scheme 61, yielded thiazole 200 as the major product, along with minor amounts of carbinol 201 [152]. On the other hand, treatment of the imine formed from 199 and p-methoxyphenylamine with catalytic tetrabutylammonium cyanide, produced suc-cinimide derivative 202. In both cases, the process is initiated by nucleophilic attack to the carbaldehyde C=0 (or azomethine s C=N) group, which is followed up by an anionic rearrangement. A variation of the above process using as catalysts /V-heterocyclic carbenes (NHC) derived from base treatment of azolium, imidazo-lium, or triazolium salts, has also been developed to access gem-disubstituted succinimides [153, 154]. Unfortunately, an attempt of kinetic resolution of racemic 4-formyl (3-lactams by using chiral NHC resulted in moderate selectivities only [154]. 

The chemistry of A-heterocyclic carbenes (NHCs) features strongly in the section on nucleophilic carbenes. In keeping with this interest, the chemistry and reactivity of these species have been reviewed.7 Their reactivity towards small molecules and... 

An IV-heterocyclic carbene (similar to that in Scheme 15) has proved to be an effective catalyst for the nucleophilic ring opening of IV-tosylaziridines by silylated nucleophiles (MesSiX, X = N3, Cl, I).45 Yields range from 89 to 99% for reaction at the least substituted carbon, except when a phenyl group on one of the carbons of the aziridine ring induces predominant attack at the benzyl carbon. The stereochemistry is consistent with the SN2 mechanism and THF was found to be the best solvent for the reaction. 

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