Imines esters

The reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

Titanium ylides are generated from imine esters with titanium isopropoxide chlorides and amines or by transmetalation of the N-lithiated ylides (90,91). The regioselectivity of their reactions with methyl acrylate is opposite to that normally observed (90). A transition state is proposed in Scheme 11.13 to explain this alternative regioselectivity. Intramolecular cycloadditions of the titanium ylides offer a synthetic application of this regioselectivity. 

A biphenyl and ct-methylnaphthylamine-derived chiral quaternary ammonium salt 23d, which was shown by Lygo to be effective for the asymmetric alkylation of Schiffs base 20, was also effective in the Michael reaction (Scheme 7.12) [43]. Notably, the enantioselectivity was highly dependent on the reaction conditions and substrates used. The Michael reaction of imine esters such as benzhydryl and benzyl esters with a,p-unsaturated ketones under solid-liquid phase-transfer catalysis conditions afforded the Michael adduct in up to 94% ee and 91% ee, respectively, while the tert-butyl ester showed moderate enantioselectivity (Scheme 7.12). Interestingly, in contrast to earlier reports, acrylate [42] and acrylamides failed to undergo the Michael reaction under these optimized conditions. 

Glycine imine esters, Ph2C=N-CH2-C02R, undergo asymmetric Michael addition to enones using an ether-water phase-transfer system.218 A chiral ammonium salt, in conjunction with cesium carbonate, gives high ees. 

The introduction of alkyl groups at the a-carbon of amino acids has been accomplished most efficiently by formation of imine esters. For example, the benzaldehyde imine of ethyl glycinate can be deproton-ated and alkylated (equation 39)." Other imines also have been used." Optical activity has been introduced by using chiral palla um ligands during the alkylation step, ° chiral alcohols to form the ester, and chiral ketones to form the imine." Alkylation of 2-pyrrole acetate esters has been accomplished in a similar fashion." ... 

The first evidence for the existence of acyclic N-unsubstituted azomethine ylides as tautomers of imines was reported by Grigg (77CC125 78CC109). When the imines of a-amino esters are heated in benzene or toluene in the presence of a variety of dipolarophiles, pyrrolidine- or 3-pyrroline-2-carboxylates are isolated in high yields. These heterocycles correspond to the products produced by the 1,3-dipolar cycloadditions of N-unsubstituted azomethine ylides, indicating the thermal equilibrium between the imine esters... 

Alkylation of imino or amidine nitrogen and subsequent hydrolysis give rise to amines. For instance, alkylation of imine esters (104a) or amidine esters (104b) with dimethyl sulfate or methyl triflate, fol-... 

Plaquevent and coworkers re-examined and sharply improved this method for a rapid access to enantioenriched P-trifluoromethyl-P-amino acid [47]. Nine cinchona-based catalysts were screened, and the best result was obtained using (DHQ)2PHAL 80. The reaction was performed starting with the p-nitrobenzyl enaminoester 81 at 80 °C and afforded the expected imine ester 82 in 90% isolated yield and 71% ee (Scheme 7.36). The authors put a special emphasis on the mechanistic aspect of the reaction using a deuterated substrate. According to the results, the deprotonation is both rate and asymmetric determining step. 

KOH/kaolin combined with a chiral catalyst was used for asymmetric alkylation of glycine imine esters, and recycled for subsequent reactions without loss of activity over three times [55, 56]. 

Ethylene imines Esters of methane sulfonic acid... 

Selective reduction of lactone 51 afforded intermediate imine lactol 53, which was esterified with 3,5-bis(trifluromethyl)benzoic acid (54) to give imine ester 55 (Scheme 17). Alternatively, the intermediate alkoxide could be directly acetylated with 3,5-bis(trifluromethyl)benzoyl chloride... 

Chiral cychc and acyclic allylsulfoxonium ylides are generated from sulfoxonium-substi-tuted y,8-unsaturated a-amino acids (method A) and 1-alkenylsulfoxonium salts (method B) upon treatment with DBU (1) [51] (Scheme 3.31). Their apphcation to the asymmetric aziridination of A-ferf-butylsulfonyl imine ester, generated either in situ (method A) or externally added (method B), affords the corresponding alkenylaziridinecarboxylate with medium to high diastereoselectivity and enantioselectivity. 

FIG. 7 Asymmetric phase transfer catalysis alkylation of glycine imine esters. 

A chiral selenophosphoramide catalyst was employed for the intramolecular cyclization of an alkenyl sulfonamide to achieve the enantioselective formation of N-heterocycles including an azepane derivative via a mechanism proposed to include formation of a three-membered sulfur-containing ring (14JA8915). A [4 + 3]-cycloaddition reaction of methyl coumalate 12 with an azomethine ylide, formed from imine esters 13 yielded functionalized azepine derivatives 14 (14OL4508). 

Scheme 16.10 Enantioselective phase-transfer catalytic diallq lation using polymer-supported glycine imine esters 15 and 17.

Recently, Sirit and co-workers [45] developed calixarene-based chiral phase-transfer catalysts derived from cinchona alkaloids successfully used for alkylation of glycine-imine esters. In 2010, Itsuno et al. [46] published quartemary ammonium sulfonate polymers used for a-alkylation reaction of a glycine imine ester with high yields and enantioselectivity. 

Based on the catalyst design limitation arising from their synthesis, other chiral quaternary ammonium salts were developed, such as Ca-symmetrical PTC catalysts XXVIII [53], spermidine- and spermine-based catalysts XXIX [54], bis-biphenyl quaternary ammonium salts XXX [55], and other chiral quaternary ammonium salts of types XXXI and XXXII [56]. V-spiro chiral ammonium salt XXXI and XXXII (the later, readily available from gallic acid) possessing flexible alkyl chains showed high catalytic efficiency in alkylations of glycine-imine esters even in the presence of 0.01-0.05 mol% of XXXI or XXXII (Scheme 8.6) [57]. 

In comparison to abundant examples of noncovalent supramolecular assemblies,relatively few structures have been built with strong covalent bonds. This is due to the fact that normal covalent bonds are not easily broken and reformed. One can manipulate the temperature and conditions so that the formation of stable imines, esters, disulfides, hydrazones, and boronate esters is reversible. Some examples of these covalent self-assembled systems include disulfide hosts and covalent organic frameworks. ... 

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