Imines, reactions with silyl enolates

The properties of the /7-benzyloxybenzylamine (BOBA) resin 7e have been reported. Support 7e forms imines that undergo aldol reactions with silyl enol ethers and the resulting y-ketoamines can be cleaved oxidatively using 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ). In contrast, treatment of the support with triflic acid (TfOH) or trimethylsilyltriflate (TMSOTf) resulted in cleavage at the benzylic ether group of 7e affording... 

Allylation and Mannich-type Reactions. The catalytic ally-lation of imines with allyltributylstannane and catalytic Mannich-t)q)e reactions with silyl enol ethers were successfully carried out in the presence of Hf(OTf)4 to afford the corresponding adducts in high yields (eqs 30 and 31). A one-pot procedure was also developed and furnished the corresponding adducts in high yields. 

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... 

Hagiwara et al.107 reported the chiral Pd(II) complex-catalyzed asymmetric addition of enol silyl ethers to imines, based on the belief that Pd(II) enolate was involved in the reaction. They found that with compound 171a as the catalyst, very low enantioselectivity was obtained in the asymmetric reactions between silyl enol ether and imine compounds (Scheme 3-58). However, in the... 

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). ° ... 

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. 

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. 

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. 

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>. 

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds —activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Man-nich-type reaction of A-(a-aminoalkyl)benzotriazoles with silyl enol ethers, the 1,3-dipolar cycloaddition of nitrones to alkenes, the 1,2-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24], These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky s diene to give the dihydropyridones (Eq. 14) [25,26], The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tet-rahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thio-esters reacted with N-(a-aminoalkyl)benzotriazoles to give the /5-amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazoli-dines (Eq. 17) [28]. Addition of diazoesters to imines afforded CK-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot. 

Another type of pre-formed reagent (28) has been used to carry out diastereose-lective Mannich reactions. The lithium salts 27 are treated with TiCU to give 28, which is then treated with the enolate of a ketone." ° The palladium catalyzed Mannich reaction of enol ethers to imines is also known." ° The reaction of silyl enol ethers and imines is catalyzed by HBF4 in aqueous methanol." ° Similarly, silyl enol ethers react with aldehydes and aniline in the presence of InCla to give the p-amino ketone." ° Imines react on Montmorillonite KIO clay and microwave irra-... 

Further extension of the reaction pool of Schilf bases 138 was achieved by their reaction with tran -l-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky s diene) to give 2-substituted 5,6-didehydro-piperidin-4-ones 164 [135,136] (Scheme 10.54). The reaction is considered to be a sequence of an initial Mannich reaction between the imine and the silyl enol ether, followed by an intramolecular Michael addition and subsequent elimination of methanol. If the reaction was terminated by dilute ammonium chloride solution, then the Mannich bases 163 could be isolated and further transformed to the dehydropiperidinones 164 by treatment with dilute hydrochloric acid. This result proved that the reaction pathway is not a concerted hetero Diels-Alder type process between the electron-rich diene and the activated imine. The use of hydrogen chloride as a terminating agent resulted in exclusive isolation of the piperidine derivatives 164 formed with... 

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. 

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]. 

Aldol reactions also occur with these intermediates 38 though admixtures are often formed.16 Silylation of r-butyl imines occurs reliably in the y-position and this is one of the best ways to control aldol reactions with extended enolates.17... 

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

The reactions of imines with silyl enolates were tested in the presence of 5 mol% of Ln(OTf)3, and selected examples are shown in Table 12 [41]. In most cases the reactions proceeded smoothly in the presence of 5 mol% of Yb(OTf)3 (a representative lanthanide triflate) to afford the corresponding b-amino ester 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 instead of Yb(OTf)3 as a catalyst. Not only silyl enolates derived from esters, but also that derived from a thioester, worked well to give the desired b-amino esters and thioester in high yields. In the reactions of the silyl enolate derived from benzyl propionate, anti adducts were obtained in good selectivities. In addition, the catalyst could be recovered after the reaction was completed and could be reused. 

While the Lewis acid-catalyzed reactions of imines with silyl enolates are one of the most efficient methods for the preparation of b-amino esters, 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 b-amino esters 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. Due to the unique properties of Ln(OTf)3, their use as catalysts for the above one-pot preparation of b-amino esters from aldehydes was planned. 

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. ... 

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. 

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