Aldehydes enamine formation secondary

Mechanism of enamine formation by reaction of an aldehyde or ketone with a secondary amine, R2NH. The iminium ion intermediate has no hydrogen attached to N and so must lose H+ from the carbon two atoms away. 

There is a distinct relationship between keto-enol tautomerism and the iminium-enamine interconversion it can be seen from the above scheme that enamines are actually nitrogen analogues of enols. Their chemical properties reflect this relationship. It also leads us to another reason why enamine formation is a property of secondary amines, whereas primary amines give imines with aldehydes and ketones (see Section 7.7.1). Enamines from primary amines would undergo rapid conversion into the more stable imine tautomers (compare enol and keto tautomers) this isomerization cannot occur with enamines from secondary amines, and such enamines are, therefore, stable. 

The reaction is exactly analogous to the chemical aldol reaction (also shown), but it utilizes an enamine as the nucleophile, and it can thus be achieved under typical enzymic conditions, i.e. around neutrality and at room temperature. There is one subtle difference though, in that the enzyme produces an enamine from a primary amine. We have indicated that enamine formation is a property of secondary amines, whereas primary amines react with aldehydes and ketones to form imines (see Section 7.7.1). Thus, a further property of the enzyme is to help stabilize the enamine tautomer relative to the imine. 

Stork Enamine Reaction Aldehydes and ketones react with secondary amines to form compounds called enamines. The general reaction for enamine formation can be written as... 

Secondary amine reacts with aldehyde and ketone to produce enamine. An enamine is an a,P-unsaturated tertiary amine. Enamine formation is a reversihle reaction, and the mechanism is exactly the same as the mechanism for imine formation, except the last step of the reaction. 

The same authors have also reported the synthesis of 2-amino quinolines46, Scheme 5.28. Secondary amines were reacted with aldehydes to form enamines subsequent addition of 2-azidobenzophenones initially forms triazoline intermediates, which undergo a thermal rearrangement and intermolecular base-catalysed cyclocondensation to produce 2-amino quinolines. The reactions were run at 180°C for 10 min (the time includes 3 min required for enamine formation) to give the products in 57-100% yields. 

This explanation confirms the usual findings that primary amines give Schiff bases without further complications, while secondary amines (piperidine) and some aromatic aldehydes easily form the gew-diamino derivatives214 (160), probably through the immo-nium cation (159) that is usually accepted in enamine formation (equation 31). 

Condensation of aldehydes and ketones with secondary amines in the presence of dehydrating agents (often potassium carbonate69-71) represents a general method of enamine preparation. By this procedure ketones afford the enamines directly, whereas aldehydes are converted in the first step into diamino derivatives which decompose on distillation to give the enamine and a molecule of the secondary amine. In the case of ketones and disubstituted acetaldehydes, the water formed by the reaction can be removed by azeotropic distillation with benzene, toluene, or xylene.27,31,72-75 In the case of derivatives of aromatic aldehydes, the formation of intermediary carbinolamines 76 is sometimes observed. 

The reaction of an aldehyde or a ketone with a secondary amine follows exactly the same mechanism as the reaction with a primary amine (see Figure 18.3) until the final step. Unlike the case with a primary amine, the nitrogen of the iminium ion does not have a proton that can be removed to produce a stable imine. Therefore, a proton is removed from an adjacent carbon, resulting in the formation of an enamine. Enamine formation is illustrated in the following equations. In each case the equilibrium is driven toward the products by removal of water. 

The mechanism for enamine formation is exactly the same as that for imine formation, until the last step of the reaction. When a primary amine reacts with an aldehyde or a ketone, the protonated imine loses a proton from nitrogen in the last step of the reaction, forming a neutral imine. However, when the amine is secondary, the positively charged nitrogen is not bonded to a hydrogen. A stable neutral molecule is obtained by removing a proton from the a-carbon of the compound derived from the carbonyl compound. An enamine is the result. 

Aldehydes and ketones react with primary amines to form imines and with secondary amines to form enamines. The mechanisms are the same, except for the site from which a proton is lost in the last step of the reaction. Imine and enamine formation are reversible imines and enamines are hydrolyzed under acidic conditions back to the carbonyl compound and amine. A pH-rate profile is a plot of the observed rate constant as a function of the pH of the reaction mixture. Hydroxide ion and heat differentiate the Wolff-Kishner reduction from ordinary hydrazone formation. 

Microwave-expedited condensation reactions using montmorillonite KIO clay or Envirocat reagent, EPZG , have yielded a rapid synthesis of imines and enamines via the reactions of primary and secondary amines with aldehydes and ketones, respectively (Scheme 2.2-32) [97,98]. In these reactions, the generation of polar transition-state intermediates that readily couple to microwaves is probably responsible for the rapid imine or enamine formation. The use of a MW oven at lower power levels or intermittent heating has been used to prevent the loss of low-boi-Hng reactants. 

In the previons section, secondary chiral amines were employed that give rise to enamine formation npon reaction with ketones or aldehydes. Chiral tertiary amines, unable to form enamines, are nevertheless capable of inducing enantioselectivity in case substrates are used that contain sufficiently acidic protons such as aldehydes, ketones or active methylene compounds [33]. The cinchona alkaloids, by far the most versatile source of Brpnsted base catalysts, have played a prominent role in various types of asymmetric organocatalytic reactions [34], which is also true for the Mannich reaction. 

Secondary amines react with aldehydes and ketones to form enamines. The name enamine is derived from -en- to indicate the presence of a carbon-carbon double bond and -amine to indicate the presence of an amino group. An example is enamine formation between cyclohexanone and piperidine, a cyclic secondary amine. Water is removed by a Dean-Stark trap (Figure 16.1), which forces fhe equilibrium to the right. 

Briefly, the mechanism for formation of an enamine is very similar to that for the formation of an imine. In the first step, nucleophilic addition of the secondary amine to the carbonyl carbon of the aldehyde or ketone followed by proton transfer from nitrogen to oxygen gives a tetrahedral carbonyl addition compound. Acid-catalyzed dehydration gives the enamine. At this stage, enamine formation differs from imine formation. The nitrogen has no proton to lose. Instead, a proton is lost from the a-carbon of the ketone or aldehyde portion of fhe molecule in an elimination reaction. 

The simple chiral secondary amine (S)-70 activates the linear aldehyde 139 by enamine formation, which selectively attacks the nitroalkenes 140 in a Michael-type reaction without any interference by the a,p-unsaturated aldehyde 95. Indeed, the latter prefers to be activated as iminium ion by the catalyst (5)-70 and to undergo the subsequent conjugate addition to form the Michael adduct B (Scheme 2.41). 

Chiral imidazolidin-4-ones operate as chiral secondary amines to activate aldehydes by enamine formation. Enamines of imidazolidin-4-one and hydrocinnamaldehyde... 

Primary amines undergo nucleo philic addition to the carbonyl group of aldehydes and ketones to form carbinol amines These carbinolamines dehydrate under the conditions of their formation to give N substituted imines Secondary amines yield enamines... 

Enamines derived from aldehydes can usually be obtained by the reaction of 2 equivalents of a secondary amine with the carbonyl compound, in the presence of anhydrous potassium carbonate, followed by pyrolytic distillation of the aminal with elimination of one of the amine groups (10,15, 30-36). Ketones are directly converted to enamines under the conditions of aminal formation. The azeotropic removal of water with excess aldehyde has also been described (32,37). 

Reaction of an aldehyde or ketone with a secondary amine, R2NH, rather than a primary amine yields an enamine. The process is identical to imine formation up to the iminium ion stage, but at this point there is no proton on nitrogen that can be lost to form a neutral imine product. Instead, a proton is lost from the neighboring carbon (the a carbon), yielding an enamine (Figure 19.10). 

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