Enamine related substrates

Aza-Annulation of Enamine Related Substrates with a,b-Unsaturated Carboxylate Derivatives as a Route to the Selective Synthesis of d-Lactams and Pyridones... 

One of the landmark achievements in the area of enantioselective catalysis has been the development of a large-scale commercial application of the Rh(I)/BINAP-catalyzed asymmetric isomerization of allylic amines to enamines. Unfortunately, methods for the isomerization of other families of olefins have not yet reached a comparable level of sophistication. However, since the early 1990s promising catalyst systems have been described for enantioselective isomerizations of allylic alcohols and aUylic ethers. In view of the utility of catalytic asymmetric olefin isomerization reactions, I have no doubt that the coming years will witness additional exciting progress in the development of highly effective catalysts for these and related substrates. 

Modification of the products that resulted from the aza-annulation of tetrasubstituted enamine substrates with acrylate derivatives was very limited. The aza-annulation of benzyl ester 496 with the mixed anhydride, a mixture (497) preformed from EtC CCl and sodium acrylate, provided a route to 498 in >98 2 diastereoselectivity (eq. 100), which allowed access to the carboxylic acid derivative 499 through catalytic hydrogenation.1 Further elaboration of either the ester or the acid derivative was unsuccessful, possibly due to the steric congestion around the reactive functionality. Extended hydrogenation did not reduce the enamine functionality, as observed in related substrates, and 498 was relatively stable to acidic hydrolysis conditions. In addition, DCC (N,N -dicyclohexylcarbodiimide) coupling of acid 499 with either benzyl amine or glycine ethyl ester was unsuccessful. 

Hydrogen bond-promoted asymmetric aldol reactions and related processes represent an emerging facet of asymmetric proton-catalyzed reactions, with the first examples appearing in 2005. Nonetheless, given their importance, these reactions have been the subject of investigation in several laboratories, and numerous advances have already been recorded. The substrate scope of such reactions already encompasses the use of enamines, silyl ketene acetals and vinylogous silyl ketene acetals as nucleophiles, and nitrosobenzene and aldehydes as electrophiles. 

Several reactions have been examined in which the substrates, though not enamines in the strict sense, are nonetheless related to enamines in their reliance on the powerful p—7T donor ability of nitrogen to activate an unsaturated carbon toward electrophilic attack. Rate constants, and in some cases equilibrium constants, for C-protonation of these modified enamines are known. The substrates include p-amino- and/7-dimethyla-minostyrene (41, 42)", seven 1,3,5-triaminobenzenes (43-49)100-1 °2, six enamides (N-vinyl- or A-styrylamides 50-55)103 and three trialkylated/pyrroles (56104, and 57 and 58105). 

To understand the carbanion mechanism in flavocytochrome 62 it is useful to first consider work carried out on related flavoenzymes. An investigation into o-amino acid oxidase by Walsh et al. 107), revealed that pyruvate was produced as a by-product of the oxidation of )8-chloroalanine to chloropyruvate. This observation was interpreted as evidence for a mechanism in which the initial step was C -H abstraction to form a carbanion intermediate. This intermediate would then be oxidized to form chloropyruvate or would undergo halogen elimination to form an enamine with subsequent ketonization to yield pyruvate. The analogous reaction of lactate oxidase with jS-chlorolactate gave similar results 108) and it was proposed that these flavoenzymes worked by a common mechanism. Further evidence consistent with these proposals was obtained by inactivation studies of flavin oxidases with acetylenic substrates, wherein the carbanion intermediate can lead to an allenic carbanion, which can then form a stable covalent adduct with the flavin group 109). Finally, it was noted that preformed nitroalkane carbanions, such as ethane nitronate, acted as substrates of D-amino acid oxidase 110). Thus three lines of experimental evidence were consistent with a carbanion mechanism in flavoenzymes such as D-amino acid oxidase. 

The efficiency of secondary amine catalysts is often eroded when moving from aldehydes to ketones as the donor carbonyl substrates, a trend that can be explained in terms of either the greater difficulty in the generation of the intermediate enamine species or their attenuated reactivity. To alleviate this situation, primary amines have emerged as a complementary family of amine catalysts. For instance, proline and related chiral secondary amines are not useful catalysts for the a-amination of aromatic enolizable ketones. As in other similar situations involving ketones as substrates, primary amines proved to be superior catalysts, although in these cases the presence of an acid co-catalyst seems to be crucial for reactivity. For instance (Scheme 11.4), primary amines derived from cinchona alkaloids can efficiently... 

In recent years a lot of information related to the use of ionic Uquids as media for organocatalytic reactions catalyzed by chiral amine derivatives has been reported [11,13, 24]. ILs specifically solvate polar enamine or iminium intermediates generated from a carbonyl substrate and a catalyst and significantly polarize nucleophilic or electrophilic compounds that enantioselectively interact with these intermediates (Figure 22.1), leading to a rise in reaction rates, sometimes at the expense of a slight drop in the enantiomeric enrichment of products as compared with similar reactions in organic solvents [12]. 

While palladium-catalyzed alkenylation reactions involving amines as nucleophiles have been extensively explored, the related copper-catalyzed processes are rare and only few examples have been reported in the literature. The first example was described in 2001 and implied the particular use of l,3-dibenzyl-5-iodouracil as electrophilic counterpart for the access of enamine-type products with potential pharmacological activity (Scheme 20) [87]. The authors demonstrated that the conditions previously reported by Buchwald for the arylation of imidazoles [88] were suitable for the vinylation of numerous amines (including primary heteroaromatic substrates and both primary and secondary aliphatic ones) to yield thus the corresponding 5-aminouracil derivatives in yields up to 78%. 

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