Imine enantioselective arylation

Saito has recently reported high yields and enantioselectivities in aziridine synthesis through reactions between aryl- or vinyl-substituted N-sulfonyl imines and aryl bromides in the presence of base and mediated by a chiral sulfide 122 (Scheme 1.41) [66]. Aryl substituents with electron-withdrawing and -donating groups gave modest transxis selectivities (around 3 1) with high enantioselectiv-... 

Excellent enantioselectivity has also been obtained using 3,3 -6 s-(l-naphthyl) BINOL-phosphoric acids [311]. A -Tosyl imines of aryl aldehydes were also examined using a binaphthyl Pd(II) carbene complex as the catalyst. Enantioselectivity in the 50-75% range was obtained [312]. Imines formed from ot-phenylethylamine and ethyl 3,3,3-trifluoropyruvate give adducts with 85-97% de in the presence of TEA [313]. The chiral auxiliary can be removed by hydrogenolysis. 

Pioneering studies of the catalytic, enantioselective arylation of imines date back to 2000, when Hayashi disclosed a rhodium/phosphine-catalyzed addition of arylstannanes to N-tosylarylimines (31). Whereas, the method gave rise to highly enantioenriched diarylmethylamines, five equivalents of the stannane were required to obtain high yields. 

Scheme 8.14 Rhodium-catalyzed enantioselective arylation of imines 42.

Imines of benzaldehyde that have been protected (or activated) with diarylphosphinyl groups, Ph-CH=N-P(=0)Ar2, are enantioselectively arylated by aryl boronic acids, using rhodium(l) liganded with a chiral amldophosphane. The effects of varying the bulk of the aryl substituents on the phosphorus of the substrate are complex ee is not severely impacted (indeed, it is sometimes improved), but reactivity falls, but so also does competing hydrolysis of the imine. 

Direct additions of aryl groups to the C=N bond has been a popular method in the past [2a], although the poor electrophilicity of the azomethine carbon severely complicated this transformation, due to a tendency for the imine substrates and derivatives to undergo enolization. To circumscribe this problem, several arylating agents were studied, and it was in fact the pioneering studies of the catalytic enantioselective arylation of imines reported by Hayashi and coworkers that have led to the application of rhodium catalysts in this particular catalytic transformation. Their work dates back... 

This methodology has been extended to kinetic resolution of azomethine imines (364) bearing a chiral center at the 5-position of the pyrazolidinone ring (Scheme 17.81) [111]. Modification of the chiral ligand to phosphaferrocene-oxazoline (366) proved optimal for kinetic resolution and allowed the catalyst loading to be lowered to 1 mol%. A number of aldehydes used to prepare azomethine imines are well tolerated, and azomethine imines with aryl, heteroaryl, and branched aliphatic substituents in the 5-position are resolved with high enantioselectivity. Unfortunately, kinetic resolution of C4-substituted azomethine imines is not efficient (s < 2). 

For the catalytic version, addition of MgBr2 was again effective to realize the enhanced enantioselectivities. Aryl-substituted azomethine imines 1 la-1 Ic realized excellent enantioselectivities (Table 11.6, entries 1-3). The cycloaddition of pentyl- and cyclohexyl-substimted azomethine imines llg and llh proceeded with moderate enantioselectivities (entries 4 and 5), while the t-butyl-substituted azomethine imine Hi stiU resulted in high enantioselection (entry 6) [17]. 

As shown in Scheme 1.95, the chiral titanocene catalyst 34 (see Scheme 1.10) prepared from 33, n-C4H9Li, and C5HjSiH3 shows a moderate-to-good enantioselectivity in the hydrogenation of Mbenzyl imines of aryl methyl ketones, whereas the catalytic activity is rather low even at 137 atm [346]. The ketimine with R = 4-CH3OC5H4 is hydrogenated with (R)-34 to give the R amine with 86% ee. The E Z of the imine substrate affects the enantioselection. The optical... 

Preliminary experiments prove that the substitution pattern of the /V-aryl moiety of imine 1 is crucial for the stereoselectivity of this reaction. The 2-substituent on the aryl group is of special importance. Namely, introduction of a methoxy group leads to a considerable decrease of enantioselectivity compared to the corresponding 2-H derivative, probably due to disfavor-able coordination with the organolithium complex. In contrast, alkyl groups show the reverse effect along with increased bulkiness (e.g., Tabic 1, entries l-3a) but 2,6-dimethyl substitution provides lower ee values. Furthermore, the 4-substituent of the TV-aryl moiety is of minor importance for the stereoselectivity of the reaction [the Ar-phcnyl and the /V-(4-methoxyphenyl) derivatives give similar results], whereas a substituent in the 3-position results in lower stereoselectivities (e.g., Et, Cl, OCHj)41. 

Scott et al. [45] prepared diimine derivatives of 2,2 -diamino-6,6 -dimethyl-biphenyl (as structure 37 in Scheme 19) as copper chelates for the catalyzed cyclopropanation reaction. All catalysts were active in this reaction but enan-tioselectivities varied importantly according to the substitution pattern of the imine aryl group only ortho-substituted ligands (by chloride or methyl groups) led to products with measurable enantioselectivity for the model test reaction (up to 57% ee with 37). 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

Optically active /3-ketoiminato cobalt(III) compounds based on chiral substituted ethylenedi-amine find use as efficient catalysts for the enatioselective hetero Diels Alder reaction of both aryl and alkyl aldehydes with l-methoxy-(3-(t-butyldimethylsilyl)oxy)-1,3-butadiene.1381 Cobalt(II) compounds of the same class of ligands promote enantioselective borohydride reduction of ketones, imines, and a,/3-unsaturated carboxylates.1382... 

In hydrogenation, early transition-metal catalysts are mainly based on metallocene complexes, and particularly the Group IV metallocenes. Nonetheless, Group III, lanthanide and even actinide complexes as well as later metals (Groups V-VII) have also been used. The active species can be stabilized by other bulky ligands such as those derived from 2,6-disubstituted phenols (aryl-oxy) or silica (siloxy) (vide infra). Moreover, the catalytic activity of these systems is not limited to the hydrogenation of alkenes, but can be used for the hydrogenation of aromatics, alkynes and imines. These systems have also been developed very successfully into their enantioselective versions. 

Table 34.2 Selected results for the enantioselective hydrogenation of N-aryl imines 1 and 2 (for structures, see Fig. 34.4) Catalytic system, reaction conditions, enantioselectivity, productivity and activity.

F. Spindler, B. Pugin, H.-P. Jalett, H.-P. Buser, U. Pittelkow, H.-U Blaser, A Technically Useful Catalyst for the Homogeneous Enantioselective Hydrogenation of N-Aryl Imines A Case Study, in Catalysis of Organic Reactions (Ed. R. E. Maltz), Dekker, New York, 1996, pp. 153-168. 

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