Enamine carbonyls electrophilic compound

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]. 

Another advantage of this method is that no catalyst is needed for the addition reaction this means that the base-catalyzed polymerization of the electrophilic olefin (i.e., a,j8-unsaturated ketones, esters, etc.) is not normally a factor to contend with, as it is in the usual base-catalyzed reactions of the Michael typCi It also means that the carbonyl compound is not subject to aldol condensation which often is the predominant reaction in base-catalyzed reactions. An unsaturated aldehyde can be used only in a Michael addition reaction when the enamine method is employed. 

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) ... 

A range of nitrogen, phosphorus, chalcogen (O, S, Se) and halogen electrophiles react with enamines, resulting in a net a-functionalization of the carbonyl compound. In the past five years, all of these reaction variants have been subjected to asymmetric enamine catalysis, with excellent results. 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

Application of 7r-allylpalladium chemistry to organic synthesis has made remarkable progress[l]. As described in Chapter 3, Section 3,7r-allylpalladium complexes react with soft carbon nucleophiles such as malonates, /3-keto esters, and enamines in DMSO to form carbon-carbon bonds[2, 3], The characteristic feature of this reaction is that whereas organometallic reagents are considered to be nucleophilic and react with electrophiles, typically carbonyl compounds, 7r-allylpalladium complexes are electrophilic and react with nucleophiles such as active methylene compounds, and Pd(0) is formed after the reaction. 

An important pyrrole synthesis, known as the Knorr synthesis, is of the cyclizative condensation type. An a -amino ketone furnishes a nucleophilic nitrogen and an electrophilic carbonyl, while the second component, a /3-keto ester or similar /3-dicarbonyl compound, furnishes an electrophilic carbonyl and a nucleophilic carbon. The initial combination involves enamine formation between the primary amine and the dicarbonyl compound. Subsequent cyclization occurs as a result of the nucleophilic jg-carbon of the enamine adding to the electrophilic carbonyl group of the a-amino ketone (equation 76). Since a-amino... 

In origin, the Mannich reaction is a three-component reaction between an eno-lizable CH-acidic carbonyl compound, an amine, and an aldehyde producing / -aminocarbonyl compounds. Such direct Mannich reactions can encompass severe selectivity problems since both the aldehyde and the CH-acidic substrate can often act as either nucleophile or electrophile. Aldol addition and condensation reactions can be additional competing processes. Therefore preformed electrophiles (imines, iminium salts, hydrazones) or nucleophiles (enolates, enamines, enol ethers), or both, are often used, which allows the assignment of a specific role to each car-... 

Figure 6-17. The formation of a C-C bond using a Claisen-type condensation. A nucleophilic enol, enolate or enamine reacts with the electrophilic carbon of a carbonyl compound or an imine.

Enamines are highly valued intermediates in organic synthesis. Almost invariably they are prepared by reaction of a carbonyl compound with a secondary amine. In principle, another attractive route to enamines could be based on construction of the double bond by a Wittig- or Horner-Wittig reaction. The enamines J thus obtained could be easily converted into the corresponding homologous aldehydes, if desired fitted with an extra electrophilic substituent at the original carbonyl carbon atom. 

The direct activation and transformation of a C-H bond adjacent to a carbonyl group into a C-Het bond can take place via a variety of mechanisms, depending on the organocatalyst applied. When secondary amines are used as the catalyst, the first step is the formation of an enamine intermediate, as presented in the mechanism as outlined in Scheme 2.25. The enamine is formed by reaction of the carbonyl compound with the amine, leading to an iminium intermediate, which is then converted to the enamine intermediate by cleavage of the C-H bond. This enamine has a nucleophilic carbon atom which reacts with the electrophilic heteroatom, leading to formation of the new C-Het bond. The optically active product and the chiral amine are released after hydrolysis. 

Fig. 12.16. Electrophilic functionalization of carbonyl compounds A, whose enol tautomer is unsuitable or unavailable at sufficient concentration, via the related enamines D a survey of mechanistic details and important intermediate products.

Oxazolones are attacked by a variety of electrophiles at C(4) these reactions, which require the presence of bases, proceed through the enolate anions (197). This type of anion adds to carbonyl compounds, a key step in the Erlenmeyer synthesis of unsaturated azlactones (equation 35) (see Section 4.18.4.3.4). The anions are intermediates in the formation of the amides (198) when oxazolones are treated with enamines (Scheme 15) (71JCS(C)598>. 

The simplest synthesis for a heterocycle emerges when we remove the heteroatom and see what electrophile we need. We shall use pyrroles as examples. The nitrogen forms an enamine on each side of the ring and we know that enamines are made from carbonyl compounds and amines. 

Enamine catalysis using proline or related catalysts has now been applied to both intermolecular and intramolecular nucleophilic addition reactions with a variety of electrophiles. In addition to carbonyl compounds (C = O), these include imines (C = N) in Mannich reactions (List 2000 List et al. 2002 Hayashi et al. 2003a Cordova et al. 2002c ... 

Two representative organocatalytic reaction systems can be considered for nucleophilic a-substitution of carbonyl compounds, the issue of this chapter. One involves the in situ formation of a chiral enamine through covalent bond between organo-catalyst (mainly a chiral secondary amine such as proline) and substrate (mainly an aldehyde), followed by asymmetric formation of new bond between the a-carbon of carbonyl compound and electrophile. Detachment of organocatalyst provides optically active a-substituted carbonyl compound, and the free organocatalyst then participates in another catalytic cycle (Figure 6.1a) [2]. 

Generation of a cyclopropyl enolate 4 in situ was reported on reaction of 6-cyclopropylidene-5-oxaspiro[2.3]hexan-4-one (3) in dichloromethane at room temperature with nucleophiles such as alcohols, phenols, fluoride, and enamines. The enolate 4 was subsequently treated with an electrophile, such as a proton, iminium salt or carbonyl compound. " ... 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

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