Electrophilic reagents, reactions with enamines

For synthetic purposes, the electrophilic reagents that give the best yields of a-substituted aldehydes and ketones on reactions with enamines are the following ... 

The reaction of enamines with ketene (146) and sulfene (147) are presumed to proceed by a two-step process involving an iminium intermediate such as 99. In fact, reaction with all electrophilic olefins such as acrylonitrile and related reagents could be thought of as going through an iminium intermediate similar to 99. Another example is given by addition to an enamine... 

A. Reactions of Electrophilic Reagents with the Double Bond of Enamines. 277... 

Reactions of Heterocyclic Enamines with Other Electrophilic Reagents... 

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. 

A. Reactions of electrophilic reagents with the double bond of enamines. 

Reactions of Enamines with Other Electrophilic Reagents Addition of aldehydes to enamines, followed by hydrolysis, leads to monoalkylidene and monoarylidene ketones (81).272 An example in which this reaction occurs intramolecularly is provided by the alkaloid ajmaline.273... 

Deprotonation of the imine 86 (R1 = H, R2 = Bn, entry 1) with LDA (1 equiv.) at -35 °C afforded an azaenolate which was diastereoselectively attacked at -78 °C by the electrophilic reagent DBAD (1.5 equiv.). After 3 min the reaction was quenched with a 10 % aqueous NH4C1 solution. After classical work-up and flash chromatography, the aminated product 87 was obtained in 66% yield as a 7 3 mixture of diastereomers 87a 87b (method A). The major diastereomer was characterized by NMR spectroscopy (DMSO-d6,100 °C). Due to an imine-enamine tautomer-ism, 86 could be aminated without previous deprotonation 86 reacted with DBAD (1.4 equiv.) in THF at 0 °C for 1 h. After evaporation of the solvent and flash chromatography, 87a and 87b were isolated in 72 % yield with a diastereomeric ratio of 75 25 (method B). 

It is of great interest to compare this last value with the keto-enol equilibrium constant obtained similarly for acetone = 0.35 x 10-8). Indeed, in many enzyme-catalysed reactions, aldolisation for example, enamine formation is not rate-limiting, and the rate is usually controlled by subsequent electrophilic additions. Consequently, the rate depends on enamine reactivity and on the enamine concentration at equilibrium. Therefore, if one wants to compare the two processes, via enol and via enamine, in order to explain why the enamine route is usually preferred, the difference in equilibrium constants for enol and enamine formation must be taken into account. Data on ketone to enol and ketone to enamine equilibrium constants show that the enamine and enol concentrations are of similar magnitude even for relatively small concentrations of primary amine. Thereafter, since the enamine is much more reactive than the enol for reactions with electrophilic reagents (in a ratio of 4-6 powers of ten for proton addition), it can be easily understood why the amine-catalysed pathway is energetically more favourable. 

Many common reactions of aliphatic amines, ethers, and sulfides 1 involve initial addition of an electrophilic reagent utilizing the lone pair of electrons on the heteroatom salts, quaternary salts, coordination compounds, amine oxides, sulfoxides, and sulfones are formed in this way. Corresponding reactions are very rare (cf. Section 3.3.1.3) with pyrroles, furans, and thiophenes. These heterocycles react with electrophilic reagents at the carbon atoms 2, 3 rather than at the heteroatom. Vinyl ethers and enamines 4 show intermediate behavior, reacting frequently at the -carbon but sometimes at the heteroatom. 

The regioselectivity of reaction of 2-tetralone enamines depends on the amine moiety as well as the electrophilic reagent. For example, / -nitrostyrene reacts with the morpholine enamine mainly at Cl9 whereas the pyrrolidine enamine reacts exclusively at C3, in contrast to phenyl isocyanate which reacts with both enamines at (V11. / -Nitrostyrene reacts with the morpholine enamine of fraw.s-decalin-2-one at C3 from an axial direction,... 

C-Alkylations of hindered aldehyde enamines can be effected with a variety of alkylating agents, but only allylic and benzylic reagents are useful for alkylations of unhindered systems.Acyclic, homoan-nular and heteroannular dienamines undergo alkylation primarily at the a-positions. ° As discussed above, reactions of enamines with electrophiles containing sp -hybridized carbon atoms have numerous limitations. On the other hand, enamine reactions with electrophilic alkenes are highly useful and have received wide coverage in the literature. 

Nevertheless, chemical reactions between imines and electrophilic reagents have revealed that imine-enamine tautomerization exists and that the enamine tautomers are the reactive species which undergo the reactions . For example, imines 12 prepared from aliphatic amines and a variety of ketones react with aryl azides to afford triazolines 14 in good yields, On heating or in the presence of catalytic amounts of an acid, triazolines 14 are converted to triazoles 15 in a process which may proceed via rearrangement and a deamination pathway (equation 4). Formation of 14 demonstrates clearly the existence of imine-enamine tautomerism during the reaction ... 

Enamines derived from ketones undergo some of the same reactions described for enol ethers, for example with arenesulfonyloxy carbamates as in Eq. 96120 121 3" and with ethyl azidoformate as in Eq. 98.302 303 The reaction with activated azo compounds occurs readily at room temperature or below and diamination often cannot be avoided with the more electrophilic reagents (Eq. lOl).400,401 The proline-catalyzed reaction of ketones with azodicarboxylic esters, which proceeds by way of the enamines, has been mentioned above (Eq. 91). 

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