Imines, reaction with conjugated esters

A direct asymmetric reductive Mannich-type reaction that allows for the formation of three contiguous stereocentres with high chemo-, diastereo-, and enantio-selectivity (10 1 to 50 1 dr, 96-99% ee ) has been presented (Scheme 4). The reaction commences with the formation of the corresponding iminium ion from aldehyde (122) and prolinol (g) catalyst (125), followed by conjugate reduction with Hantzsch ester (123) to generate an enamine, which then undergoes Mannich reaction with imine (124) to produce (126).179... 

Aldehydes, ketones, carboxylic esters, carboxylic amides, imines and N,A-disubstiluted hydrazones react as electrophiles at their s/ 2-hybridized carbon atoms. These compounds also become nucleophiles, if they contain an H atom in the a-position relative to their C=0 or C=N bonds. This is because they can undergo tautomerization to the corresponding enol as seen in Chapter 12. They are also C,H-acidic at this position, i.e., the H atom in the a-position can be removed with a base (Figure 13.1). The deprotonation forms the conjugate bases of these substrates, which are called enolates. The conjugate bases of imines and hydrazones are called aza enolates. The reactions discussed in this chapter all proceed via enolates. 

Radical cyclization is not limited to reaction with a C=C unit (see 15-29 and 15-30), and reactions with both C=N and C=0 moieties are known. Reaction of MeON=CH(CH2)3CHO with Bu3SnH and AIBN, for example, led to trans-2-(methoxyamino)cyclopentanol in good yield.Conjugated ketones add to aldehyde via the p-carbon under radical conditions (2 equivalents of Bu3SnH and 0.1 equivalent of CuCl) to give a p-hydroxy ketone.Addition of radical to the C=N unit of R C=N SPh ° or R—C=N—led to cyclic imines. Radical addition to simple imines leads to aminocycloalkenes. Radical also add to the carbonyl unit of phenylthio esters to give cyclic ketones. 

The second reaction starts with nucleophilic attack by the amine on the more electrophilic carbonyl group - the ketone. Imine formation is followed by cyclization and this second step is i normal nucleophilic substitution at the carbonyl group of an ester (Chapter 12). The imine double bond moves into the ring to secure conjugation with the ester. 

Thus, the asymmetric catalysis of cyanoethoxycarbonylation, cyanophosphoryla-tion, epoxidation of electron-deficient olefins, Michael reactions of malonates and (3-keto-esters, Strecker reaction of keto-imines, conjugate addition of cyanide to a, (3-unsaturated pyrrole amides, ring opening of meso aziridines with TMSCN and cyanosilylation of ketones (example shown below) have been successfully carried out using these complexes as asymmetric catalysts. 

With respect to cupreidine, C9 0-benzoyl esters of this cinchona derivative were demonstrated to be the best catalysts for the nitroaldol reaction of a-ketoesters [55], the conjugate addition of anthrone to nitroalkenes [56], the Henry reaction with fluoromethyl ketones (Scheme 6.25) [57], and an aza-Friedel-Crafts reaction of naphthols with N-sulfonyl imines [58]. 

A dihydroquinidine-derived chiral thiourea (DHQD-30), which demonstrated significantly better stereocontrol than other cinchona alkaloids, was utilized in the aza-Henry reaction with nitroalkanes and aldimines by Schaus and coworkers (Scheme 13.8) [26]. The utility of the nitroethane pronucleophile conveniently offers a tertiary stereogenic center in the P-nitroamine product 32. The methodology is also conveniently applicable to novel a,P-unsaturated aliphatic imines 29, which are difficult substrates in asymmetric conjugate addition reactions. Similar reaction conditions can be appHed towards to the use of dimethyl malonates as pronucleophiles that generate adducts in high enantioselectivity, which then convert smoothly into P-amino esters under the Nef conditions. 

The scope of this reaction was expanded with the development of the asymmetric transfer hydrogenation of P-y-alkynyl a-imino esters. In this reaction, both imine and aUcyne undergo reduction to yield synthetically challenging franx-alkenyl amino acid derivatives [65]. It was shown that conjugate hydride transfer to the alkyne takes place first, as propargyl a-amino esters failed to undergo reduction under the reaction conditions. 

Allenylsilanes undergo intramolecular additions to appropriately positioned aldehydes, imines, conjugated esters and alkenes to afford various alkynylcyclopentane and cyclohexane derivatives (Eqs. 9.66-9.70) [66]. The reactions are promoted by SnCl4 or by thermolysis. The stereochemistry of these cyclization reactions is consistent with a concerted sigmatropic process as illustrated in Scheme 9.17. 

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