Enamines as reaction intermediates

As noted earlier, the development of new alkylation and acylation methods for compounds bearing carbonyl groups has fostered the use of enamines as reaction intermediates. 

Similar reactions with primary and secondary amines result in the formation of 3-aUcylamino- or 3-dialkylamino-l-butyne in 30-80% yield (TON = 3-9) [243-247]. In one example, the TOP could be estimated as 0.2 h" [246]. Enamines were proposed as reaction intermediates. It was later shown that enamines effectively react with terminal aUcynes, including acetylene, to afford the expected aminoalkynes without catalyst or, more rapidly, sometimes exothermically, in the presence of CujCf [248]. Aromatic amines do not react under the same conditions. However, in the presence of organic acids, e.g. acetic acid, 3-arylamino-l-butynes can be isolated in moderate yields (Eq. 4.59) [246, 247, 249]. 

Since most of the fundamental chemical transformations of the tropane alkaloids were discovered during the pioneering elucidation of the structures, the most important reactions have been described in earlier chapters in this treatise (7-5). Two developments will be discussed here the recent progress in the demethylation of tropane derivatives and the use of tropinone enamines as synthetic intermediates. 

Lee and coworkers117 used lithium enamines as synthetic intermediates in oxidation reactions with perbenzoic acid for the synthesis of 65 as a main intermediate in the synthesis of tansindiol 66 (equation 44). 

The use of enamines as synthetic intermediates for the alkylation and acylation at the a-carbon of aldehydes and ketones was pioneered by Gilbert Stork of Columbia University. This use of enamines is called the Stork enamine reaction. 

Enamine acylations have been extended to include the Vilsmeier reaction (409) and thus provide a method for the generation of formyl ketones without the use of strong base. By this method an unsaturated potential trialdehyde could be formed as an intermediate in a pyridine-3-carboxaldehyde synthesis (410). 

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

XIX. Rearrangements of Enamines and Reactions where Enamines Occur as Intermediates... 

The same reaction sequence may be used to convert cyclo-dodecanone to cyclotetradecanone. Preparation of the pyrrolidine enamine of cyclododecanone requires 2-3 days at reflux, and reaction of the enamine with methyl propiolate is best carried out in refluxing hexane. The enamine-propiolate reaction may also be used to convert cycloheptanone to cyclononanone. In this case the procedure must be modified to provide for partial hydrogenation of the intermediate amino ester without prior hydrolysis.8 The reduced intermediate is saponified as described in the present procedure. 

The word enamine was coined in 1927 by Wittig [27], However, at that time, enamines were usually not considered as reactive intermediates. An early example of enamine catalysis that was not explicitly recognized as enamine-based reaction was the reaction of isatin with ketone nucleophiles (acetone and acetophenone), first pnblished by Lindwall and coworkers in 1932 [28, 31]. Later, the interconversion of imininm ions and enamines in enzymatic reactions was recognized by Westheimer [32, 354]. The first person to propose a modem enamine-based... 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

In addition to previously described syntheses4-5 by diazo group transfer with deformylation,6 2-diazocyclohexanone has been prepared by two variants of this method. In one, the reaction of 2-(hydroxymethylene)cyclohexanone with -toluene-sulfonyl azide is carried out in ether/diethylamine, and an enamine is assumed to be formed as an intermediate 7 in the other, the sodium salt of the hydroxymethylene compound was treated with the lithium salt of p-carboxybenzenesulfonyl azide... 

Enzymologists have freely proposed enolate anions, enols, and enamines as intermediates for many years. Such intermediates have been demonstrated for some nonenzymatic acid- or base-catalyzed reactions, but how can enzymes form enolates at pH 7 without the use of strong acids or bases The microscopic pRa value of an a-hydrogen in a ketone or aldehyde is about 17-20.72 98"... 

The reaction of a,/3-unsaturated carbonyl compounds with enamines also leads to dihydropyrans, although it is not always possible to isolate these since they react further to give either ring-opened by-products or bicyclic derivatives arising from a Stork annelation. There has been considerable discussion on the mechanism of this reaction, although the initial nucleophilic attack of the enamine on the /3-carbon of the diene is not in doubt (63JA207). It is possible that a zwitterionic species is involved, either as an intermediate or merely in equilibrium with the dihydropyran (67JCS(C)226). 

First steps to elucidate the reaction mechanism of PDC were achieved by the investigation of model reactions using ThDP or thiamine [36,37], Besides the identification of C2-ThDP as the catalytic center of the cofactor [36], the mechanism of the ThDP-catalyzed decarboxylation of a-keto acids as well as the formation of acyloins was explained by the formation of a common reaction intermediate, active acetaldehyde . This active species was first identified as HEThDP 7 (Scheme 3) [38,39]. Later studies revealed the a-carbanion/enamine 6 as the most likely candidate for the active acetaldehyde [40 47] (for a comprehensive review see [48]). The relevance of different functional groups in the ThDP-molecule for the enzymatic catalysis was elucidated by site-directed substitutions of the cofactor ThDP by chemical means (for a review see... 

One explanation is that attack at C2 results in disruption of the aromaticity of the benzenoid ring, as in intermediate 7.25. This is therefore a high-energy intermediate, and this reaction pathway is slower because the first step is ratedetermining. Also the C3 selectivity is in accord with the electrophile attacking the site of highest electron density on the ring. In essence, indole tends to react like an enamine towards electrophiles, with substitution... 

The enamine C as the intermediate of the primary reaction is generated in situ from the small amount of L-proline that is added as a catalyst. The more stable but unreactive enamine D is formed too, but it equilibrates with C. 

ENAMINES AS INTERMEDIATES IN ISOTOPE EXCHANGE AND HALOGENATION REACTIONS... 

Nitro-3-phenylisoxazole-5-carboxylates (290) act as heterocyclic 1-azadiene components in [4 + 2] cycloaddition reaction with some enamines affording bicyclo derivatives 295 probably via a stepwise ionic cycloaddition involving the Michael adducts 292 as primary intermediates. Further intramolecular attack by the isoxazole nitrogen on the immonium carbon followed by elimination of the amine and aromatization of dihydropyridine 293 afforded 294, which was transformed into pyridine 295 by simple reduction164 (equation 63). 

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