Enamines with electrophilic reagents

These anhydro-bases are heterocyclic equivalents of enamines and enol ethers and react readily with electrophilic reagents to give products which can often lose a proton to give a new resonance-stabilized anhydro-base. Thus, anhydro-l,2-dimethylpyridinium hydroxide (645) reacts with phenyl isocyanate to give an adduct (646) which is converted to the stabilized product (647 - 648). A similar sequence with carbon disulfide yields the dithio acid (644). 

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. 

Fluorination of Enamines with Electrophilic Fluorinating Reagents... 

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. 

Application of 7r-allylpalladium chemistry to organic synthesis has made remarkable progress[l]. As deseribed in Chapter 3, Seetion 3, Tt-allylpalladium complexes react with soft carbon nucleophiles such as maionates, /3-keto esters, and enamines in DMSO to form earbon-carbon bonds[2, 3], The characteristie feature of this reaction is that whereas organometallic reagents are eonsidered to be nucleophilic and react with electrophiles, typieally earbonyl eompounds, Tt-allylpalladium complexes are electrophilie and reaet with nucleophiles such as active methylene compounds, and Pd(0) is formed after the reaction. 

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... 

An impressive number of alkaloids has been generated from the synthon (202), which is accessible by an acid catalyzed rearrangement of the appropriately substituted cyclopropyl-imine. The endocyclic enamine (202) should react with electrophiles on the /8-carbon in a process which simultaneously renders the a-carbon electrophilic and therefore susceptible to capture by nucleophilic reagents. The application of this methodology to the synthesis of ipalbidine (191a) and septicine (204) is shown in Scheme 30. Here, the unusual 3-phenylthio-2-pyrroline intermediate (203) serves as a relatively stable equivalent synthon of the unsubstituted 2-pyrroline analogue which is notoriously unstable (77ACR193). 

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). 

Enamines are classical bidentate reagents that interact with electrophilic species via both their nitrogen and their / carbon atoms. The simplest instance of such reaction (equation 2) is a proton attack which results in the formation of an iminium cation (5) and an... 

Similarly, the enamine of a 2-substituted cyclohexanone is alkylated by electrophilic alkenes such as acrylonitrile or methyl acrylate at the exposition in methanol or acetonitrile. However, prolonged reaction time (66 h) of the pyrrolidine enamine of 2-methylcyclohexanone with these reagents in dioxane or benzene under reflux gives a 1 1 mixture of 2,2- and 2,6-disubstituted cyclohexanones (38 and 39)82>83 (Scheme 23). 

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,... 

A, A -Bis(trimethylsilyl) enamines are weak nucleophilic reagents and fail to react with electrophiles at the / -carbon. However, under the influence of fluoride ion catalysis,... 

Except for protic and Lewis acids, other electrophilic reagents can also promote the aliphatic 3-aza Cope rearrangement. In fact, the first example of a [3,3]-sigmatropic rearrangement of 7V-allylenammonium salt may date back to the early 1960s102. When enamine 152 reacted with crotyl bromide at 80 °C, it gave after hydrolysis 2,2,3-trimethyl-4-pentenal (153) rather than 2,2-dimethyl-4-hexenal (equation 32). 

Enamines, which are readily obtained from the corresponding ketones, can be converted into a-fluoro ketones by treatment with a reagent capable of delivering electrophilic fluorine ( F ). 

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