Enamine nucleophilicity

This approach to the five-membered pyrrole ring reacts an a-aminoketone with a P-ketoester. The mechanism will probably involve imine formation then cyclization via an aldol-type reaction using the enamine nucleophile. Dehydration leads to the pyrrole. Only the key parts of this sequence are shown below. 

Among the electrophilic reaction parmers of the enamine nucleophiles, aldehydes and ketones are arguably the most important class. The addidon of an enamine to a carbonyl compound affords aldol products after hydrolysis (Scheme 13). In this process, one or two new stereogenic centers and one carbon-carbon bond are formed. 

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

Kinetic template effects have been postulated in more typical organic aldol condensations, where metals such as lithium and zinc are likely to coordinate both the enolate or enamine nucleophile and the aldehyde in the transition state. The examples shown in Schemes 58184 and 59185 are illustrative of these reactions and the degree of selectivity obtained. The carboxylation of ketones and nitroalkanes by methyl magnesium carbonate to produce P-keto acids and a-nitro acids respectively provides early examples of similar reactions (Scheme 60).186 187 See also Section 61.1.4.4. 

The available evidence indicates a nonconcerted mechanism which is depicted in Scheme 14. Oxidation of a Pd(0) species by the carbon-nitrogen bond of the allyle-nammonium ion gives cleavage to the 7r-allylpalladium complex and an enamine. Nucleophilic reaction by the enamine on the Pd salt then forms resultant imines after a loss of a proton. The role of co-catalyst CF3C02H is to form the N-allylenammonium ion, which reacts readily with the Pd(0) species. 

SCHEME 13.7 (a) Type I aldolases form enamine nucleophiles (donor) (b) type II aldolases use Zn as a cofactor activating the aldehyde (acceptor). 

Ester-substituted fulvenes of the type 67 (equation 12) were found to undergo ready cycloadditions to enamines. Nucleophilic addition of 68 to the electrophilic 6-position of the fulvene, and cyclization of the resulting zwitterionic intermediate 69 with loss of diethylamine resulted in the formation of the tricyclic fulvene 70 (equation 12). 

Hydroindole derivatives can be obtained by photocyclization of N-aryl enamines. Nucleophilic attack by enamines, e.g. 248, on dichlorophenylphosphine gives an intermediate 249, which can react with a second mole of enamine to give 250. Further amine elimination from 250 and cyclization yield 2-amino-l-phenylphospholes 251 (equation 52). ... 

The foundations of this concept (enamine activation) lie in the fundamental studies by Stork and Robinson covering the stoichiometric use of enamine nucleophiles for the formation of C-C bonds. The Hajos-Parrish-Eder-Sauer-Wiechert reaction reported in 1971 (Scheme 2.2), which consisted of a... 

As has already been mentioned, the low reactivity of enamine nucleophiles needs a highly electrophilic Michael acceptor for the reaction to proceed with good conversions in an acceptable time. In this context, the Michael reaction of aldehydes and ketones with nitroalkenes can be regarded as one of the most studied transformations in which the enamine activation concept has been applied. This reaction furnishes highly functionalized adducts with remarkable potential in organic synthesis, due to the synthetic versatility of the nitro group and the presence of the carbonyl moiety from the donor reagent. 

Lakhdar, S., Maji, B., Mayr, H. (2012). Imidazolidinone-Derived Enamines Nucleophiles with Low Reactivity. Angew. Chem. Int. Ed., 51(23), 5739-5742. 

The use of chiral diols as co-catalyst in aldol reaction led to an improvanent of the achieved results [41]. Thus, when acetone (3a, 8.18 equiv.) was reacted with benzaldehyde (2 h) in DMSO at 0°C catalyzed by (5)-proline (30 mol%) the expected product 4 was obtained in 72% ee, while a 96% ee was achieved in the presence of (R)-BINOL (0.5 mol%). A hypothetical explanation from the authors for this effect is the possible template effect of the chiral diol which may activate and ordered the aldehyde and enamine nucleophile. The same reason was claimed for the beneficial effect achieved by addition of a 10 mol% of (3,5-bistrifluoromethylphenyl)thiourea in the aldol reaction between cyclohexanone (3b) and several aromatic aldehydes catalyzed by proline (1,10 mol%) in hexane a 25°C [42], In this case, reaction times, yields as well as diastereo- and enantioselectivities were improved (75-98%, 76-88% de, 98-99% ee), with these results being also attributed to the enhancement of the proline solubility by the formation of a host-guest proline-thiourea complex. 

A year later, based on the same principle by using primary amine-catalyzed iminium ion activation in combination with external Brpnsted acid additives, Chen et al. [129] were able to achieve the asymmetric 1,3-dipolar cycloaddition of cyclic enones and a variety of azomethine imines in excellent yields and selectivities (Scheme 11.48). In this case, to scavenge the generated H2O during the formation of the enamine nucleophile intermediate, and to overcome the expected hydrogenbonding interaction, a stoichiometric amount of molecular sieves (4 A) was added. Interestingly, when the pseudoenantiomer catalyst 61 was employed, an opposite enantiomer of the product was formed in good yields and selectivities. 

An 5 n2 allylic substitution of l,3-diphenyl-2-propenyl acetate by the enamine nucleophile produced from ketones and aldehydes gives C -substituted aldehydes and ketones in moderate to high yields (60-95%) and high enantioselectivities (79-98% ee). The reaction requires the presence of a palladium catalyst, pyrrolidine, and water. The palladium catalyst was prepared from a chiral ferrocene P,N ligand when a ketone was used, but with a ruthenium-based P,P ligand when an aldehyde was used in the reaction. 

Some of the classic studies of nucleophilic, attack on coordinated olefins were conducted with iron(II) species. Rosenblum reported the reactions of (ti -cyclopentadienyl) iron-olefin complexes with a wide range of carbanion and enamine nucleophiles. These reactions produce stable o-alkyliron complexes (Equation 11.22). The stereochemistry is cleanly trans. However, the regioselectivity of reactions of complexes of imsymmetrical olefins depended on the nucleophile. 

The first step in the catalytic cycle is nucleophilic addition of the anion of the cofactor thiamine diphosphate (ThDP) to the aldehyde. Deprotonation yields an enamine carbanion that serves as the nucleophile for the subsequent C—C bond-forming step. Alternatively, for the decarboxylase type ThDP-lyases, the carbonyl group of a 2-ketoacid donor substrate reacts with the anion of ThDP to yield the corresponding 2-hydroxy acid adduct. After CO is released, the enamine nucleophile is formed. Subsequently, the carbonyl acceptor reacts with the enamine to form the 2-hydroxy ketone. The stereoselectivity is governed by the enzyme that specifically discriminates between the two possible enantio-topic faces of the acceptor [14,48,49]. 

---