Reactions of imines with silyl enolates

The Mannich and related reactions provide one of the most fundamental and useful methods for the synthesis of P-aminoketones or p-aminoesters. Although the classical protocols include some severe side-reactions, new modifications using preformed iminium salts and imines have been developed [46]. Among them, reactions of imines with enolate components, especially silyl enolates, provide useful and promising methods leading to p-amino-ketones or p-aminoesters. The first report using a stoichiometric amount of TiCU as a promoter appeared in 1977 [47] and, since then, some efficient catalysts have been developed [48]. 

In aqueous media, water coordinates rare-earth triflates under equilibrium conditions, and thus activation of carbonyl compounds using a catalytic amoxmt of the Lewis acid has been performed. It was expected that, based on the same consideration, the catalytic activation of imines would be possible by using rare-earth triflates. 

We tested the reactions of imines with silyl enolates in the presence of 5 mol% of lanthanide triflates (Ln(OTf)3) and scandium triflate (Sc(OTf)3), and selected examples are shown in Table 8.10 [49]. In most cases, the reactions proceeded smoothly in the presence of 5mol% of Yb(OTf)3 (a representative lanthanide triflate) to afford the corresponding p-aminoester derivatives in good to high yields. Yttrium triflate (Y(OTf)3) was also effective, and the yield was improved when Sc(OTf)3 was used as a catalyst instead of Yb(OTf)3. Not only silyl enolates derived from esters, but also 

2 One-pot synthesis of P-aminoesters from aldehydes using Ln(OTf)3 as catalyst 

While the Lewis-acid-catalyzed reactions of imines with silyl enolates are one of the most efficient methods for the preparation of p-aminoesters, many imines are hygroscopic, unstable at high temperatures and difficult to purify by distillation or column chromatography. It is desirable from a synthetic point of view that imines, generated in situ from aldehydes and amines, immediately react with silyl enolates and provide p-aminoesters in a one-pot reaction. However, most Lewis acids cannot be used in this reaction because they decompose or deactivate in the presence of the amines and water that exist during imine formation. Judging from the unique properties of rare-earth trifiates, we planned to use them as catalysts for the above one-pot preparation of P-aminoesters from aldehydes. 

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Y(03SCF3)3 to afford a monoaminoalkylation product in good yield in aqueous media.40 Zinc tetrafluoroborate is also highly effective for such couplings in aqueous THF.41 Kobayashi also reported a Mannich-type reaction of imines with silyl enolates catalyzed by neutral salts such as sodium triflate in water as a suspension medium. Unusual kinetic behavior indicates that the presence of the Mannich adduct facilitates the rate of its formation.42... 

Kobayashi, S., Araki, M., Ishitani, H., Nagayama, S. and Hachiya, I., Activation of imines by rare earth metal triflates. Ln(OTf)3- or Sc(OTf)3-catalyzed reactions of imines with silyl enolates and Diels-Alder reactions of imines, Synlett, 1995, 233-234. 

Studies in the nineteen-eighties revealed that some Maimich-type reactions of imines with silyl enolates can be controlled with high diastereoselectivity, and that use of a chiral auxiliary enables highly enantioselective synthesis of -aminocarbo-nyl compounds [186]. Some Lewis acids, for example TMSOTf and zinc halides, were also found to be effective in catalytic quantities [187-190] although the original method requires a stoichiometric amount of TiCU [185]. In the last decade, further progress has been made by development of new acid catalysts. 

Table 12. Reactions of imines with silyl enolates...

Lectka has shown that (l )-BlNAP-Pd(C104)2, is effective for enantioselective reaction of imines with silyl enol ethers such as 15. While Sodeoka used the aquo complexes, Lectka carried out the reaction under anhydrous conditions [5]. 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Aldol reactions.2 This combination of catalysts is effective for promoting reaction of acetals with silyl enol ethers and ketene silyl acetals. It can also promote reaction of aldehydes or imines with ketene silyl acetals. The reactions occur in high yield at 25° either CH3CN or THF can be used as the solvent. 

In recent years, catalytic asymmetric Mukaiyama aldol reactions have emerged as one of the most important C—C bond-forming reactions [35]. Among the various types of chiral Lewis acid catalysts used for the Mukaiyama aldol reactions, chirally modified boron derived from N-sulfonyl-fS)-tryptophan was effective for the reaction between aldehyde and silyl enol ether [36, 37]. By using polymer-supported N-sulfonyl-fS)-tryptophan synthesized by polymerization of the chiral monomer, the polymeric version of Yamamoto s oxazaborohdinone catalyst was prepared by treatment with 3,5-bis(trifluoromethyl)phenyl boron dichloride ]38]. The polymeric chiral Lewis acid catalyst 55 worked well in the asymmetric aldol reaction of benzaldehyde with silyl enol ether derived from acetophenone to give [i-hydroxyketone with up to 95% ee, as shown in Scheme 3.16. In addition to the Mukaiyama aldol reaction, a Mannich-type reaction and an allylation reaction of imine 58 were also asymmetrically catalyzed by the same polymeric catalyst ]38]. 

Catalyst for Reactions of Acetals with Silyl Enol Ethers and Allylsilanes. TMS-I catalyzes the condensation of silyl enol ethers with various acetals (eq 30) and imines, and of allylsilanes with acetals. ... 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

The Hf(OTf)4-catalyzed Mannich-type reaction of imine with enol silyl ethers has been used as a means of access to 8-amino carbonyl compounds (Eq. 21) [23] this also was extended to a three-component reaction (Eq. 22). 

Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched P-amino ketones or esters [48a, 48b]. For the most part, these methods involve the use of chirally modified enolates or imines. Only a handful of examples has been reported on the reaction of imines with enolates of carboxylic acid derivatives or silyl ketene acetals in the presence of a stoichiometric amount of a chiral controller [49a, 49b, 49c]. Reports describing the use of a substoichiometric amount of the chiral agent are even more scarce. This section contains some of the most recent advances in the field of catalytic enantioselective additions of lithium enolates and silyl enol ethers of esters and ketones to imines. 

Mannich-type Reactions. The reactions of imines with ketene silyl acetals proceed smoothly in the presence of Sc(OTf)3 to afford the corresponding /3-amino ester derivative in moderate yield (eq 6). Sc(OTf)3 shows higher activity than Yb(OTf>3 does in this case. The catalyst can be recovered after the reaction is complete and reused. A Mannich-type reaction of IV-(/3-aminoalkyl)benzotriazoles with sUyl enolates has also been developed. Mannich-type reactions of polymer-supported sUyl enol ethers with imines or of polymer-supported a-iminoaceta-tes with silyl enolates are also catalyzed by Sc(OTf)3. 

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

In 1997, Kobayashi and colleagues reported the first truly catalytic enantioselective Mannich-type reactions of aldimines 24 with silyl enolates 37 using a novel chiral zirconium catalyst 38 prepared from zirconium (IV) fert-butoxide, 2 equivalents of (R)-6,6 -dibromo-l,l -bi-2-naphthol, and N-methylimidazole (Scheme 13) [27, 28], In addition to imines derived from aromatic aldehydes, those derived from heterocyclic aldehydes also worked well in this reaction, and good to high yields and enantiomeric excess were obtained. The hydroxy group of the 2-hydroxyphenylimine moiety, which coordinates to the zirconium as a bidentate ligand, is essential to obtain high selectivity in this method. 

An approach based on samarium diiodide-promoted reactions of the iminoketone 279 with aldehydes provides access to a series of substituted or fused pyrroles bearing at least two phenyl groups, for instance, the system 280 (Equation 86) <2001T4881>. In an alternative lanthanide-catalyzed route, a series of pyrroles were constructed from imines and nitroalkenes in the presence of Sm(fPrO)3 <1999T13957>. A set of 1-dimethylaminopyrroles have also been obtained by TiCU-induced reactions between 2-acetoxypropanal hydrazones with silyl enol ethers <1995TL8007>. 

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