Nucleophilic imino Ester

An interesting bifunctional system with a combination of In(OTf)3 and benzoyl-quinine 65 was developed in p-lactam formation reaction from ketenes and an imino ester by Lectka [Eq. (13.40)]. High diastrereo- and enantioselectivity as well as high chemical yield were produced with the bifunctional catalysis. In the absence of the Lewis acid, polymerization of the acid chloride and imino ester occurred, and product yield was moderate. It was proposed that quinine activates ketenes (generated from acyl chloride in the presence of proton sponge) as a nucleophile to generate an enolate, while indium activates the imino ester, which favors the desired addition reaction (66) ... 

Rueping has recently reported an interesting alknylation reaction of a-imino esters employing both phosphoric acid Ip and AgOAc as orthogonal cocatalysts [35]. As seen in the catalytic cycle in Scheme 5.21, generation of chiral iminium ion pair I nucleophilic and alkynyl-silver species II proceeds simultaneously. Subsequent nucelophilic addition completes both parallel cycles [36]. 

The synthesis of quaternary amino acids 86 have been shown using azlac-tones 85 as nucleophiles and the Trost ligand 39 under palladium [179] or molybdenum catalysis (Scheme 8) [180]. The allylic alkylation of glycine imino esters under biphasic conditions has also been achieved using a chiral phase-transfer catalyst in combination with an achiral Pd catalyst producing the unnatural amino acid derivatives [181]. 

Chiral Auxiliary for Asymmetric Induction. Numerous derivatives of (—)-8-phenylmenthol have been utilized for asymmetric induction studies. These include inter- and intramolecular Diels-Alder reactions, dihydroxylations, and intramolecular ene reactions of a,p-unsaturated 8-phenylmenthol esters. These reactions usually proceed in moderate to good yield with high diastereofacial selectivity. a-Keto esters of 8-phenylmenthol (see 8-Phenylmenthyl Pyruvate) have been used for asymmetric addition to the keto group, as well as for asymmetric [2 -F 2] photoadditions and nucleophilic alkylation. Ene reactions of a-imino esters of 8-phenylmenthol with alkenes provide a direct route to a-amino acids of high optical purity. Vinyl and butadienyl ethers of 8-phenylmenthol have been prepared and the diastereofacial selectivity of nitrone and Diels-Alder cycloadditions, respectively, have been evaluated. a-Anions of 8-phenylmenthol esters also show significant diastereofacial selectivity in aldol condensations and enantiose-lective alkene formation by reaction of achiral ketones with 8-phenylmenthyl phosphonoacetate gives de up to 90%. ... 

Activation of C=N double bonds by copper Lewis acids for nucleophilic addition has also been reported (Sch. 37) [73]. The a-imino ester 157 undergoes alkylation at the imine carbon with a variety of nucleophiles when catalyzed by copper Lewis acids. The presence of the electron-withdrawing ester group increases the reactivity of the imine and also assists in the formation of a stable five-membered chelate with the Lewis acid. Evidence for Cu(I) Lewis-acid catalysis and a tetrahedral chelate was obtained by FTIR spectroscopy, from the crystal structure of the catalyst, and from several control experiments. The authors rule out the intermediacy of a copper enol-ate in these transformations. The asymmetric alkylation of A,0-acetals with enol silanes mediated by a copper Lewis acid proceeding with high selectivity has been reported [74],... 

Alkylation and acylation of imino esters proceeds at the nitrogen of the imino ester function. In many cases it is not advisable to use alkyl halides or acyl halides for such reactions because the iminium salts (89) or (90 Scheme 8) are readily dealkylated by the halide anions. This can be prevented by the use of stronger alkylating reagents, e.g. tertiary oxonium salts, dialkyl sulfates or alkyl triflates, which produce in the course of the alkylation only anions with low nucleophilicity. Heterocycles containing... 

Lectka and co-workers have simultaneously developed similar phosphine-transition metal catalysts for the same transformation [54a, 54b, 54c, 54d]. These researchers were interested in testing the reactivity of a-imino esters toward enol silane nucleophiles upon chelation with a late transition metal (Ag(I), Cu(I), Ni(II), and Pd(II)) as a means of substrate activation. This ultimately led to the development of a catalytic, enantioselective alkylation of a-imino esters with enol silanes in up to 98% ee and in high chemical yields (Scheme 28). 

Nucleophiles potentially can attack a-imino-esters at three sites the ester group, the imine carbon, or the imine nitrogen. 

Scheme 6.35 Cu(l)-catalyzed enantioselective addition of electron-rich aromatic nucleophiles to imino esters, as described by Johannsen [48].

Lectka developed a series of enantioselective addition reactions of various nucleophiles to N-tosyl imino ester 110 mediated by Cu-complex 216 (Equation 17) [31, 152, 153]. In Mannich additions of enol silanes such as 215, high optical purity and yield were obtained with catalyst loadings as low as 2mol%. The reaction is notable for its convenience of execution and... 

An interesting case of the addition of ketone hydrazone is observed in the reaction of acetone dimethylhydrazone with DMAD, wherein the initial nucleophilic attack is through the imino nitrogen, leading to products such as dimethyl A-isopropylidine-lV-dimethylamino-2-aminomaleate (132) and the dihydropyridine derivative (133). A small amount of the dimethylhydrazone of oxaloacetic ester (134) has also been observed in this reaction (Scheme 20). ... 

Lithium ester enolate-imine condensation has been used for the preparation of / -lactam rings via addition at the imine moiety <1996H(43)1057>. But treatment of imino derivatives of the pyridazine 293 with the lithium enolate of ethyl a,a-dimethylacetate 294 in THE led to the formation of the pyrido[3,4-r/ pyridazine 295 and its oxidized form 296. Compound 295 was obtained by nucleophilic attack of the carbanion species at C-5 of the pyridazine ring followed by cyclization (Equation 24) <1996JHC1731>. 

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