Chiral NHCs

Herrmann et al. reported for the first time in 1996 the use of chiral NHC complexes in asymmetric hydrosilylation [12]. An achiral version of this reaction with diaminocarbene rhodium complexes was previously reported by Lappert et al. in 1984 [40]. The Rh(I) complexes 53a-b were obtained in 71-79% yield by reaction of the free chiral carbene with 0.5 equiv of [Rh(cod)Cl]2 in THF (Scheme 30). The carbene was not isolated but generated in solution by deprotonation of the corresponding imidazolium salt by sodium hydride in liquid ammonia and THF at - 33 °C. The rhodium complexes 53 are stable in air both as a solid and in solution, and their thermal stability is also remarkable. The hydrosilylation of acetophenone in the presence of 1% mol of catalyst 53b gave almost quantitative conversions and optical inductions up to 32%. These complexes are active in hydrosilylation without an induction period even at low temperatures (- 34 °C). The optical induction is clearly temperature-dependent it decreases at higher temperatures. No significant solvent dependence could be observed. In spite of moderate ee values, this first report on asymmetric hydrosilylation demonstrated the advantage of such rhodium carbene complexes in terms of stability. No dissociation of the ligand was observed in the course of the reaction. 

Fig. 2.1 Chiral NHC ligand designs used in the Rh-catalysed enantioselective hydrogenation of...

This regioselectivity is opposite to the one observed by the non-catalysed additions of BH3 THF or 9-BBN to the same alkene, or those catalysed by Rh and Ir catalysts. Chiral NHC ligands (generated from 84) on Cu under the same conditions proceed with high enantioselectivity (enantiomeric ratio 99 1) [71] (Scheme 2.12). 

Asymmetric versions of this transformation were also developed by using chiral imidazolium pro-ligands as NHC precursors, or silver transmetallation methodology with chiral NHC ligands (Fig. 2.23) [106]. Imidazolium salts with chiral A-substituents (132) or imidazolidinium salts with chirality at the backbone of the heterocycle (133) gave quantitative conversions at -78°C with good ee (58% and 70% respectively). 

Fig. 2.23 Chiral NHC ligand precursors and complexes used in the asymmetric alkylation of conjugated enones...

Fig. 2.24 Chiral NHC pro-ligands used in copper-catalysed asymmetric conjugate additions...

Fig. 3.26 Catalysts 65-67 bearing chiral NHCs with alkyl side chains 3.1.3.2 Chiral Bidentate NHCs...

A chiral NHC-Ru complex 158 was used in the Diels-Alder reaction between methacrolein 156 and cyclopentadiene 157 (Scheme 5.41) [47]. The adduct 159 was obtained in an excellent yield under mild conditions, albeit with low enantioselectivity. 

Some other enantioselective approaches have been attempted, still with moderate enantioselectivities, by making use of in situ systems containing a chiral NHC precursor. Luo and co-workers reported on the use of the bidentate chiral imidazo-lium salt 16, derived from L-proUne, in combination with [RhCia-COCcod)], leading to an enantiometic excess of around 20% [30]. The use of chiral imidazolium salt 17 in combination with [RhCl(CH2=CHj)j]j by Aoyama afforded slightly better ee (Fig. 7.3) [31 ]. So far, Bohn and co-workers have obtained the best enantioselectivities (up to 38% ee) for the catalytic addition of phenylboronic acid to aromatic aldehydes by using planar chiral imidazolium salts 18, derived from paracyclophane, in combination with [Rh(OAc)2]2 [32]. 

So far, there is only one report describing the use of chiral NHC-metal complexes in catalytic asymmetric arylation of imines. This was achieved by using C -symmetric cationic NHC-Pd diaquo complex 20 (Scheme 7.6) [38]. The arylation of a variety of A-tosylimines with different arylboronic acids was carried out under mild conditions. The presence of electron-withdrawing or electron-donating substituents on both partners did not seem to affect the reaction and the corresponding chiral diarylamines were obtained in good to excellent yields and high enantiomeric excess. 

Table 7.2 Chiral NHC-Pd(II) complexes in asymmetric oxidative Heck reaction...

In Section 12.3 stereoselective reactions involving chiral NHCs have been classified in the same manner. Reactions that proceed through a number of these intermediates have been categorised according to the first asymmetric step in the transformation, with a miscellaneous section covering other reaction types. 

Scheme 12.43 Asymmetric 3-lactam synthesis using chiral NHCs...

Whilst the addition of a chiral NHC to a ketene generates a chiral azolium enolate directly, a number of alternative strategies have been developed that allow asymmetric reactions to proceed via an enol or enolate intermediate. For example, Rovis and co-workers have shown that chiral azolium enolate species 225 can be generated from a,a-dihaloaldehydes 222, with enantioselective protonation and subsequent esterification generating a-chloroesters 224 in excellent ee (84-93% ee). Notably, in this process a bulky acidic phenol 223 is used as a buffer alongside an excess of an altemativephenoliccomponentto minimise productepimerisation (Scheme 12.48). An extension of this approach allows the synthesis of enantiomericaUy emiched a-chloro-amides (80% ee) [87]. 

You and co-workers have demonstrated a further application of NHCs in the kinetic resolution of formyl p-lactams ( )-265 [103]. Upon treatment with a chiral NHC, the Breslow-type intermediate is formed, followed by ring-opening of the P-lactam moiety, with subsequent trapping of the acylazolium intermediate leading to the enantio-enriched succinimide product 266 and resolved formyl P-lactam (which is reduced to its alcohol 267). The authors note that when R" = H, the products undergo racemisation readily, and this is a possible explanation for the lower levels of enantioselectivity observed in the succinimide products 266 (Scheme 12.60). 

Major advances in the application of NHCs in organocatalysis have been achieved, and this arena has become a focus of considerable research. The use of chiral NHCs has allowed access to highly enantioselective organocatalytic transformations and the breadth and depth of reactivity that can be accessed is ever expanding. 

Asymmetric homogeneous catalysis generally requires chiral ligands. Approaches to chiral NHCs have focused on the generation of chiral centers either in the 4- and 5-position of imidazolidinium salts 71 or in the a-position of the nitrogen substituents for imidazolium salts 72. 

FIGURE 4. Chiral NHC ligands for the enantioselective copper-catalyzed conjugate addition of Grignard reagents... 

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]. 

Chiral NHCs formed adducts with aldehydes that underwent enantioselective oxo-diene Diels-Alder reactions with enones.98 The NHC only needed to be added at 0.5 mol% to achieve yields >70% and ees in the high 90s. ... 

The strategy that was pursued at first in the design of chiral NHCs was based on the introduction of N-substituents containing a chiral center located on the C-atoms adjacent to the nitrogen atoms in 1 and 3 position within the ring. Their general formula and structure are as represented in Fig. 1 ... 

The first chiral NHCs of this type were developed by Herrmann and En-ders in 1996. Herrmann s group [6] synthesized a symmetric imidazolium salt 1 (as carbene precursor), starting from an enantiopure chiral amine which was readily converted to the heterocycle using a multi-component reaction previously developed by Arduengo [7]. After coordination to a rhodium(I) complex precursor (Scheme 1), this ligand was tested in the hydrosilylation of acetophenone. 

In a interesting example of organocatalysis, Suzuki et al. studied the enantioselective acylation of secondary alcohols using chiral NHCs [11,12]. The approach was partly based on the work of Nolan and Hedrick who had independently reported NHC-catalyzed transesterifications [13,14]. The enantioselective acylation was subsequently improved by using more sterically hindered acylating agents such as diphenylacetate derivatives (Scheme 4), leading to selectivity factors (s = kn, ) of up to 80 [15,16]. 

Chung et al. reported the enantioselective synthesis of chiral NHCs, such as 6, using a chiral ferrocene derivative (Scheme 8) [28]. The nucleophilic substitution of the hydroxy function by an imidazole in an acidic medium gives the imidazolium salt with retention of the configuration at the chiral C-atom. 

Imidazolinylidenes contain sp3-carbon atoms in the 4- and 5-position of the heterocycle and thus provide the possibility of a second strategy for the generation of chiral NHCs. By an appropriate choice of substituent (R) at the 4- and 5-position two (homo)chiral centers may be obtained and the chiral information then transmitted to the active space at the metal center of a catalyst by means of the two N-substituents R (Fig. 8). 

In 2000, Rajanbabu et al. published the synthesis and coordination chemistry of the first chiral NHC containing a l.T-binaphthyl unit as the chiral element (Scheme 24) [69]. It contains two imidazolium rings linked to the l,T-binaphlhyl backbone in the 2 and 2 position through methylene bridges. This linkage was achieved by nucleophilic substitution and the imidazolium salts subsequently generated in an N-quaternization step with methyl iodide. 

Bolm et al. reported the first planar chiral NHC at the beginning of 2002 [87]. The synthetic strategy is based on an oriented ortho-metallation starting from a chiral sulfoxide, followed by the conversion of the sulfoxy group to a hydroxymethyl unit. The imidazole ring is then linked to this intermediate with the aid of W,AT-carbonyl diimidazole and subsequently quarter nized with methyl iodide to give the imidazolium ligand precursor of the carbene 41 (Scheme 31). 

Inspired by the chiral phosphine/oxazoline ligands developed by Helmchen and Pfaltz [131], Crudden and coworkers, have prepared a chiral NHC-oxazoline possessing a rigid backbone (Fig. 14) [ 132 ]. The rhodium complex 74 has been used in the catalytic hydroboration of olefins and the hydrosilylation of prochiral ketones with enantiomeric excesses that did not exceed 10%. 

In a field that is growing as rapidly as that of stereoselective catalysis with chiral NHCs, it is difficult to lay out general guidelines for successful research... 

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