Alkylations Catalyzed by NHCs

To date, there have been no reports of C-alkylations of the homoenolates or enolates catalytically generated with NHCs. Fischer and Fu, however, reported an interesting example of an NHC-catalyzed cyclization that proceeds via the 

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Scheme 11.3 Asymmetric allylic alkylations catalyzed by NHC-Cu complexes.

It is interesting that the Mukaiyama aldol reaction could also be catalyzed by NHCs. In the presence of only 0.5 mol% of imidazolium NHC 69a, a variety of aldehydes reacted well with trimethylsilyl ketene acetal to afford corresponding products in good yield. It is proposed that the NHCs could activate the Si-O bonds in enoxysilanes. The catalytic reaction worked for aromatic aldehydes with electron-donating or electron-withdrawing groups, or even alkyl aldehydes (Scheme 7.50). 

Bode, et al. developed a highly enantioselective azadiene Diels-Alder reactions catalyzed by chiral A-heterocyclic carbenes. Scheme 3.28 [43]. Reactions of alkyl fra -4-oxo-2-butenoate 80 with A-sulfonyl imines 81 and catalyst 82 (10-15 mol%), DIPEA (10 mol%) in toluene-THF (10 1) at room temperature afforded the dihydopyridinones 83 in excellent diastereo- and enantioselectivity (>50 1 cw-diastereoselectivity, 99% ee). The LUMO -controUed inverse electron demand Diels-Alder cycloaddition was facilitated by NHC-carbene catalyst 82. Similar reactions without the catalyst would require high pressure (12 bar) or high temperature. The high cw-diastereoselectivity which would arise from (Z)-enolate reacting with the dienophile is rationalized as depicted in Scheme 3.28. 

Although the NHC-catalyzed reaction of aldehdyes is well established, the activation of carbon-carbon unsaturated by NHC is rarely reported. In 2006, when exploring the Heck reaction with alkyl halide, Fu and co-workers [8] unexpectedly found fliat NHC 80 could catalyze the intramolecular 3-alkylation of Michael acceptors (Scheme 7.57). A range of substrates proceed smoothly under the standard reaction conditions, giving corresponding products in up to 94% yield, the leaving group included bromides, tosylates, and even chlorides. 

Hydrosilylation reactions catalyzed by achiral NHC-Rh complexes were first reported by Lappert and Maskell in 1984, who found 96 and 97 effective for ketones and alkynes (Figure 13.16). In recent studies by Ozdemir and coworkers, different NHC-Rh complexes were applied to the hydrosilylation of acetophenone derivatives with triethylsilane and bimetallic complex 98 was particularly efficient. Also, Rh complexes 99, bearing a hydrophilic tetra-ethylene glycol and/or hydrophobic long-chain alkyl-functionalized NHC, were active catalyst for the hydrosilylation of ketones with Ph2SiH2. ... 

The coordination of NHC ligands greatly enhances the copper-catalyzed asymmetric addition of diethylzinc to cyclohexenone [45]. Employing imi-dazolinylidene ligands with chiral centers in the heterocycle, the alkylation of a-enones [46,47] was systematically studied by the groups of Mangeney and Alexakis [10,48-50]. A summary of the results obtained is presented in Table 1. 

When Ni(II) - NHC complexes contain an alkyl, aryl, or acyl group, reductive elimination can occur, affording Ni(0) compounds and 2-mediated organoim-idazolium salts (Eq. 16). This pathway results in catalyst decomposition for reactions by Ni - NHC systems [45]. In Ni - NHC-catalyzed olefin dimerization, Cavell and Wasserscheid showed that this decomposition is inhibited when reactions are run in ionic liquids rather than more classical solvents such as toluene [46]. 

In 2013, the Chi group realized an NHC-catalyzed asymmetric p-functional-ization reaction of aldehydes via the transformation of saturated aldehydes to formal Michael acceptors via double oxidation. By using the catalyst derived from the chiral amino indanol triazolium salt in combination with quinone as the oxidant, the p-aryl substituted saturated aldehydes were converted to the o,p-unsaturated acyl azolium intermediates which further reacted with 1,3-dicarbonyl compounds or p-keto esters to generate the corresponding 5-lactones. It was found the use of LiCl and 4 A MS as additives was beneficial to improve the ee s of the products. Notably, the p-alkyl substituted saturated aldehydes were not viable substrates, probably due to the reduced acidity of the p-C—H bonds (Scheme 7.118). 

Stabilized Cu(I) in the form of its iV-heterocyclic carbene (NHC) complex, e.g., (SIMes)CuBr (SIMes = iV,7V -f>is(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene), and the eyclohexyl analog [(ICy)2Cu]PF6, catalyzes click reactions very well in aqueous /-butanol, and even better in water alone. Low conversions were noted in nonaqueous solvents such as tetrahydrofuran (THF), /-BuOH, and dichloromethane (DCM). Starting from an alkyl bromide, triazoles could be smoothly generated by m situ conversion to the corresponding azide (aqueous NaNs) followed by copper-catalyzed cycloaddition. This is but one example of the potential for combining several steps in a single flask that culminates with a click reaction vide infra). The... 

A wide range of ligands, including monodentate or bidentate phosphines, phosphites, arsines and NHCs, have been examined by Bedford in iron-catalyzed cross-couphngs between alkyl halides and aryl Grignard reagents. Notably, various of these Hgands exerted a beneficial effect on selectivity and chemical yield (Equation 5.31) [38]. 

Furthermore, an N-heteroqrclic carbene (NHC) complex formed by stoichiometric reaction of a benzimidazole substrate with [RhCl(coe)2]2 in the presence of PCyj was characterized by X-ray crystallography and was proposed to be the catalyst resting state [123]. Similar intermediates have been characterized in the rhodium-catalyzed alkylation of N-methylbenzimidazoles [124], 3,4-dihydroquinazolines [125], and l,4-benzodiazepine-2-ones [126]. This methodology was later extended to the synthesis ofc-Jun N-terminal kinase inhibitors [127]. 

In 2010, Dorta and coworkers [83] reported a new synthetic strategy to access functionalizable 3-allyl oxindoles bearing a chiral quaternary carbon stereocenter via a direct palladium-catalyzed a-arylation protocol. This elegant methodology, previously accessible only via a two-step procedure involving a Pd-catalyzed intramolecular a-arylation followed by an asymmetric Pd-catalyzed allylic alkylation [84], afforded impressive reactivities, and high chemoselectivities and enantioselectivities were also achieved in the synthesis of oxindoles using a new chiral Pd-NHC catalyst (Scheme 8.45). 

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