Enantioselective Arylation of Imines

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. 

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Scheme 8.14 Rhodium-catalyzed enantioselective arylation of imines 42.

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... 

Synthesis of diarylmethylamine derivatives, Ar1 -CH( Ar2 )-NHS02-C(dl4-p-N02, has been achieved enantioselectively using rhodium-catalysed arylation of imines with arylboroxines.56... 

In 2002 the Nguyen lab demonstrated that Al(0/-Pr)((7 )-BINOL) was an effective catalyst for the asymmetric reduction of aryl ketones (20).20 This methodology was recently extended to include the enantioselective reduction of imines (22) to the corresponding amine (23). ... 

In this chapter that highlights the synthesis of arylamines, we will discuss the most recent and relevant developments in the catalytic arylations of imine substrates, which incidentally are mostly enantioselective. The application of organomet2Jlic cat2dysts bearing Pd, Rh, Ru, and other metal catalysts will be considered, as well as the recent multicomponent Petasis reaction. 

A variety of electrophiles are employed for carbonyl alkenylation and arylation that proceed through transmetalation from silicon to transition metal catalysts. For example, addition of alkenylsilanes and aryl(trimethoxy)si lanes to aldehydes is catalyzed by copper/DTBM-SEGPHOS, which mediates transmetalation from silicon to copper to give a wide variety of chiral alcohols with high degree of % ee (Scheme 3-144). The enantioselective alkenylation of imines using 2-(hydroxylmethyl)phenyl-substituted propen-2-ylsilane is catalyzed by a rhodium/chiral diene complex. ... 

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. 

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. 

Substituents on imino nitrogen influence both reactivity and enantioselectivity in hydrogenation of imino compounds. Figure 1.32 shows two successful examples. An f-BINAPHANE-Ir complex effects asymmetric hydrogenation of A-aryl aromatic imines.On the other hand, an Et-DuPHOS-Rh complex (see Figure 1.2) is effective for hydrogenation of A-acyUiydrazones. ... 

Akiyama et al. disclosed an asymmetric hydrophosphonylation in 2005 (Scheme 32) [55], Addition of diisopropyl phosphite (85a) to A-arylated aldimines 86 in the presence of BINOL phosphate (R)-M (10 mol%, R = 3,5-(CF3)j-C Hj) afforded a-amino phosphonates 87 in good yields (72-97%). The enantioselectivities were satisfactory (81-90% ee) in the case of imines derived from a,(3-unsaturated aldehydes and moderate (52-77% ee) for aromatic substrates. 

Highly enantioselective hydrosilylation of N-aryl imines derived from aliphatic ketones was achieved by the use of (S)-ll as a chiral catalyst (Scheme 10)... 

Quite recently, there has been significant expansion and development in the alkylation of imines with organozinc reagents using chiral Lewis acid catalysts. In 2000, Tomioka and co-workers reported a copper(II)-chiral amidophos-phine 4-catalyzed asymmetric process for the addition of diethylzinc to N-sul-fonylimines (Scheme 2) [8]. Excellent enantioselectivities (90-94%) and yields (83-99%) were obtained in reactions of N-sulfonylimines derived from arylal-dehydes. 

Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and a-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enan- tioselective reaction of indoles with iV-sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)] 45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and /V-PhS02-phenyli mines in 90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions. 

Spindler, F., Pugin, B., Jalett, H.-P., Buser, H.-P., Pittelkow, U. and Blaser, H.-U. (1996) A technically useful catalyst for the homogeneous enantioselective hydrogenation of N-aryl imines A case study. Chem. Ind. (Dekker) Catal. Org. React., 68, 153. 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

Under similar conditions, the same authors were able to control two stereogenic centers in an asymmetric vinylogous Mannich reaction. Indeed, treatment of imines derived from aryl a-ketoesters with siloxyfuran under related conditions gave functionalized y-butenolides with high diastereo- and enantioselectivities (Scheme 10.21 ).40... 

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