Enamine , reactivity

Donor- and acceptor-substituted allenes with general structures 1 or 2 (Scheme 8.1) have the most obvious synthetic potential among functionalized allene derivatives and therefore they serve as versatile building blocks in many synthetic endeavors [1], As expected, the reactivity of the double bonds of 1 or 2, which are directly connected to the activating substituents, are strongly influenced by these groups. Hence there is enol ether or enamine reactivity of 1 and Michael acceptor type chemistry of 2. In addition, the terminal double bonds are also influenced by these functional groups. 

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. 

As mentioned in Section I, one of the remarkable features of 1,1-enediamines is the enhanced enaminic reactivity of the / -carbon atom. 1,1-Enediamines can serve as nucleophiles in substitution of and addition reactions to a wide variety of electron-deficient reagents. In this section we discuss mainly the alkylation, arylation and acylation reactions of 1,1-enediamines, emphasizing their synthetic utilities, especially those of secondary enediamines. 

Rajappa and coworkers20 used isothiocyanates as a probe to examine the enaminic reactivity of nitro-substituted enamines and enediamines. The results were usually consistent with predictions based on the chemical shift of the vinyl proton and on extended Huckel calculations. However, cyclic enediamine 7 was found to be unreactive toward aryl and alkyl isothiocyanates (see Section II.A). Very recently, the same reaction has been re-examined21 and it has been found that cyclic enediamine 7 indeed reacts easily with aryl isothiocyanate to give the addition products 176 in 54-65% yield (equation 68). 

This catalytic cascade was first realized using propanal, nitrostyrene and cinnamaldehyde in the presence of catalytic amounts of (9TMS-protected diphenylprolinol ((.S )-71,20 mol%), which is capable of catalyzing each step of this triple cascade. In the first step, the catalyst (S)-71 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction (Hayashi et al. 2005). The following hydrolysis liberates the catalyst, which is now able to form the iminium ion of the a, 3-unsaturated aldehyde C to accomplish in the second step the conjugate addition of the nitroalkane (Prieto et al. 2005). In the subsequent third step, a further enamine reactivity of the proposed intermediate leads to an intramolecular aldol condensation. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 72 (Fig. 8) (Enders and Hiittl 2006). 

The reduction of l-methyl-4-cyanopyridinium iodide (72) in aqueous methanol gave solely the tetrahydropyridine 73. However, in methanol/ sodium hydroxide two different temperature-dependent products could be isolated. The [4 + 2] product 74 predominated above — 20°C, whereas the [2 -I- 2] adduct75 was the sole product at or below —45° C. Similar behavior is observed with the 2-cyano derivative 76 (R = H) again, the initially formed [2 + 2] adduct 79 (R = H) thermally rearranges to the [4 -I- 2] product 80 (R = H). In this case pH and temperature control are not as important because enamine reactivity is diminished by the presence of the cyano group. Other pyridinium salts behave similarly in strong base. Reduction... 

The equilibrium between imine (7) and enamine (8) forms of harmaline has been demonstrated by exchange at the C-1 methyl group in methanolic solution and the enamine reactivity of tautomer (8) by alkylation, as in the reaction with methyl acrylate under mild conditions. Intramolecular enamine acylation occurs after initial alkylation at in reactions at higher temperature (Scheme 2). 

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