Mechanisms enamine formation

Antibody 72D4, generated by immunization with 91, catalyzed the aldol reaction of acetone and aldehyde 92 and the retro-aldol reaction of 93, with some enantioselectivity, in the presence of a primary amine cofactor 94 (Scheme 6.18) [54]. The antibody did not catalyze the reactions in the absence amine 94, and evidence supported an enamine mechanism (enamine formation with 94) for this cofactor amine-mediated antibody-catalyzed reaction. 

The primary objectives of this chapter are to detail the methods by which enamines (a,/3-unsaturated amines) (I) can be synthesized and the mechanisms of enamine formation. The enamines discussed are those in which the nitrogen is tertiary and, with the exception of a few selected examples, Contain no other functional groups. The term simple enamines might be used to describe the majority of enamines noted in this chapter. 

Although the emphasis in this chapter has been on tbe synthesis and mechanism of formation of simple enamines, brief mention will be made of the addition of amines to activated acetylenes to indicate the interest and activity in this area of substituted enamines. Since such additions tend to be stereospecific, inclusion in this section seems apropos. The addition of amines to acetylenes has been much studied 130), but the assigning of the stereochemistry about the newly formed double bond could not be done unequivocally until the techniques of NMR spectroscopy were well developed. In the research efforts described below, NMR spectroscopy was used to determine isomer content and to follow the progress of some of the reactions. 

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. 

Due to mechanistic requirements, most of these enzymes are quite specific for the nucleophilic component, which most often is dihydroxyacetone phosphate (DHAP, 3-hydroxy-2-ox-opropyl phosphate) or pyruvate (2-oxopropanoate), while they allow a reasonable variation of the electrophile, which usually is an aldehyde. Activation of the donor substrate by stereospecific deprotonation is either achieved via imine/enamine formation (type 1 aldolases) or via transition metal ion induced enolization (type 2 aldolases mostly Zn2 )2. The approach of the aldol acceptor occurs stereospecifically following an overall retention mechanism, while facial differentiation of the aldehyde is responsible for the relative stereoselectivity. 

The mechanism for the release of the substituted ketone is essentially the reverse of enamine formation. 

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. 

A reaction that is related to that of transketolase but is likely to function via acetyl-TDP is phosphoketolase, whose action is required in the energy metabolism of some bacteria (Eq. 14-23). A product of phosphoketolase is acetyl phosphate, whose cleavage can be coupled to synthesis of ATP. Phosphoketolase presumably catalyzes an a cleavage to the thiamin-containing enamine shown in Fig. 14-3. A possible mechanism of formation of acetyl phosphate is elimination of HzO from this enamine, tautomerization to 2-acetylthiamin, and reaction of the latter with inorganic phosphate. 

In Mechanism 1, Scheme (2), protonation takes place at C-7 (the 6-position of indole) and is then followed by enamine formation via proton abstraction at C-3. The change of configuration at C-3 is completed by enamine protonation and subsequent proton cleavage at C-7. 

Scheme 18 A plausible mechanism for formation of pyridone and enamine...

Whereas the examples discussed so far proceed according to the iminium ion mechanism (A), amine-catalyzed additions of, e.g., ketones to nitroolefins are effected by intermediate enamine formation (B). List et al. were the first to report that L-proline catalyzes the addition of several ketones to nitroolefins (Scheme 4.23). Whereas both the yields and diastereoselectivity were high in DMSO as solvent, the ee did not exceed 23% [38]. A related study of this process by Enders and Seki resulted in identification of methanol as a superior solvent, and enantioselec-tivity up to 76% was achieved (Scheme 4.23) [39]. 

With regard to the mechanism of this new type of reaction, the Jorgensen group postulated enamine formation, by addition of the catalyst to the nitrone, followed by hydroxylamine elimination [132], Subsequent aldol-type reaction of this enamine with the carbonyl component and release of the proline catalyst by exchange... 

For the proline- and proline congener-catalyzed aldol reaction [23, 24], a mechanism based on enamine formation is proposed [25], Scheme 7. The catalytic process starts with condensation of the secondary amino group of proline with a carbonyl substrate leading to a nucleophilic enamine intermediate, which mimics the condensation of the active-site lysine residue with a carbonyl substrate in type I aldolases. The adjacent carboxylic acid group of the enamine intermediate... 

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 review starts with a discussion of the mechanism of keto-enol tautomerisation and with kinetic data. Included in this section are results on stereochemical aspects of enolisation (or enolate formation) and on regioselec-tivity when two enolisation sites are in competition. The next section is devoted to thermodynamic data (keto-enol equilibrium constants and acidity constants of the two tautomeric forms) which have greatly improved in quality over the last decade. The last two sections concern two processes closely related to enolisation, namely the formation of enol ethers in alcohols and that of enamines in the presence of primary and secondary amines. Indeed, over the last fifteen years, data have shown that enol-ether formation and enamine formation are two competitive and often more favourable routes for reactions which usually occur via enol or enolate. 

An addition-elimination mechanism of enamine formation has been proposed in some elimination reactions355,356 (e.g. equation 24). 

An unusual transformation occurred when triethylamine reacted with disulfur dichloride and 1,4-diazabicy-clo[2.2.2]octane (DABCO) to form heptathiocane 103 (mp 72-73 °C) and thienopentathiepine 104 (Scheme 7) <20030L1939>. The proposed mechanism involved the adduct 102 and oxidation of the intermediate complex 105, followed by the formation of enamines 106 and 107. The intermediate 106 outlined a pathway to the extended polysulfur chain, such as in 107, which cyclized into heptathiocane 103. Incorporation of only one carbon into the heterocyclic ring from the ethyl group rather than both was presumably controlled by the reactivity of the enamine 107. For the mechanism of formation of thienopentathiepine 104, Chapter 13.17, CHEC-3 should be consulted. The rare heptathiocane ring stmcture was proved by X-ray crystallography (Section 14.09.3.3). 

It should be noted that in contrast to the reactions of ,/ -enones with sulfilimines (see Section 7.3.1.1.2.1.), in the case of the a,/S-unsaturated oxosteroids no enamine formation occurs. The amides 37 (R1 = R2 = OAc R3 = Ac) and 39, formed in the reactions of 35 with 21-ace-toxysteroids 34 (R1 = R2 = OAc) and 38, followed by acetylation, are not in accordance with the proposed mechanism for such reactions113. The formation of these amides is explained by the participation of the 21-acetoxy group in the transition state formation. 

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