Ketones enamine formation secondary

C. Secondary Reactions in Enamine Formation from Ketones and Amines. ... 

This innovation was exploited by Stork and his co-workers (6-8) for a study of enamine formation from a variety of ketones and secondary amines. 

While enamines can usually be obtained directly from ketones and secondary amines their formation by an indirect route may bo advantageous. The previously mentioned condensation of rnethyl ketones during azeotropic enamine formation has prompted the alklyation (J) or acylation and reduction (59) of Schiff s bases. A parallel method uses the formation and desulfurization of N-acylthiazolines followed by hydride reduetion (60,61). 

The long known catalyses of some ketone condensation reactions by secondary amines, can be postulated to have their basis in the reactions of enamine intermediates with ketones. The unsuitability of methyl ketones for azeotropic enamine formation is based on this phenomenon. Recent studies in cyclization reactions have added further support to this concept (354). 

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). 

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. 

For the general condensation reaction of secondary amines with ketones to yield enamines, pyrrolidine, piperidine, or morpholine is generally used. The rate of enamine formation depends on the basicity of the secondary amine and the steric environment of the carbonyl group [12a, b, 29], Pyrrolidine, which is more basic, usually reacts faster than morpholine. The investigation of piperazine, a disecondary amine, has only been reported recently by Benzing [45, 46] and Sandler [41]. Surprisingly, the reaction of excess -butyraldehyde with piperazine in tetrahydrofuran at — 20°C to 0°C gave mainly AM-butenyl-piperazine [41] (see Eq. 13). 

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. 

Enamine derivatives of steroidal ketones have found most use as protecting groups [220], but also undergo a few useful reactions. Enamine formation involves addition of a secondary amine to the carbonyl group to give a carbinolamine intermediate (5), which then loses a molecule of water. Both steps appear to be involved in determining the over-all rate of reaction [221]. Steroidal A -3-ketones react spontaneously... 

A procedure was studied by which enamines are produced by the condensation of the parent ketones and a secondary amine in the presence of molecular sieves. The molecular sieves are used to trap the water which is formed.[6] The enamine formation is acid catalyzed both BrOnsted adds and Lewis adds can be used as catalysts.[7]... 

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. 

An alternative and useful method for intramolecular conjugate addition when the Michael donor is a ketone is the formation of an enamine and its reaction with a Michael acceptor. This can be advantageous as enamine formation occurs under reversible conditions to allow the formation of the product of greatest thermodynamic stability. Treatment of the ketone 40 with pyrrolidine and acetic acid leads to the bicyclic product 41, formed by reaction of only one of the two possible regio-isomeric enamines (1.51). Such reactions can be carried out with less than one equivalent of the secondary amine and have recently been termed organo-catalysis (as opposed to Lewis acid catalysis with a metal salt). The use of chiral secondary amines can promote asymmetric induction (see Section 1.1.4). 

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. 

---