Enamines Michael reaction intermediates

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). 

The origin of the observed 1,4-asymmetric induction in Michael reactions of chiral imines (Scheme 28) has been rationalized by conformational transmission of chirality. Thus, the phenethylamine auxiliary forces the cyclohexene part of the intermediate enamine into a half-chair conformation (140) that is 0.8 kcal mol-1 lower in energy than (141). Axial attack as shown then leads to the major product the energy difference between (140) and (141) roughly correlates with the observed diastereoselectivity ( 9 l).105... 

Reaction of the N-oxide (44) with acetic anhydride-pyridine provides a direct means for the in situ generation of the highly reactive dehydrosecodine intermediate (45). This species undergoes spontaneous cyclization to give vincadifformine (46 12%) via an intramolecular Michael reaction followed by B/c ring closure (Scheme 8). i((-Vincadifformine (48) is also produced in this reaction via the enamine... 

Very recently, Lu and coworkers successfully applied aminocatalysis via the enamine intermediate to the Michael addition of cyclic ketones to vinyl sulfones 181 [56]. In the presence of the cinchonidine-derived primary amine salt 179, the Michael reactions between vinyl sulfones 181 and cyclic ketones 180 proceeded smoothly, affording the desired adduct 182 in very high yield and with excellent enantioselectivity (up to 97% ee) (Scheme 9.63). They also successfully applied this methodology to the synthesis of sodium cyclamate. However, this protocol gave poor yields and ee values for acyclic ketones. 

General comments about the Michael reaction procedures are analogous to those developed in the aldol and Mannich reactions.For example, the O-TMS-protected diphenylprolinol compound 20 in cooperation with benzoic acid catalyses the asymmetric Michael addition of aldehydes to nitroalkenes, in a simple, practical and efficient procedure. Benzoic acid promotes the rapid formation of the enamine intermediate and the reaction takes place in the highly concentrated organic phase of the aqueous biphasic system. 

The nucleophilic properties of enamines uncovered by Stork have found a wide application in Michael additions. Secondary enamines are usually in equilibrium with the corresponding imines. These imines are generally more stable, unless the tautomeric enamine is stabilized by conjugation (Figure 7.71). The primary product of the reaction of an enamine with an a,P-unsaturated carbonyl compound is a dipolar intermediate 7.108. This intermediate is converted to a 1,5-dicarbonyl compound on exposure to aqueous add. Proton transfers can take place before hydroysis to the ketone occurs, and the stereoselectivity of the process may be determined by such steps. Moreover, the enamine addition reaction can be reversible. These problems notwithstanding, the use of chiral amines to generate imines or enamines for use as Michael donors has been widely developed. The chiral imine/enamine can be preformed or, espedally in the case of intramolecular reactions, the amine can be added to the reaction medium in stoichiometric amounts. 

We know how stabilized carbanions such as enols and enolated enamines are key intermediates in biological isomerization reactions and in carbon-carbon bond-forming and bond-breaking events. In this chapter, we will look at two more important reaction types, called Michael additions and -eliminations, which involve stabilized carbanion species as intermediates. In a Michael addition, a nucleophile and a proton are added to the two carbons of an alkene that is conjugated to a carbonyl group. The reverse of a Michael addition is called a -elimination. 

A particularly difficult situation arises when combining in the same reaction the use of these rather unreactive acceptors such as enones with the incorporation of ketones as Michael donors in which the formation of the intermediate enamine by condensation with the amine catalyst is much more difficult. For this reason, the organocatalytic Michael addition of ketones to enones still remains rather unexplored. An example has been outlined in Scheme 2.22, in which it has been shown that pyrrolidine-sulfonamide 3a could catalyze the Michael reaction between cyclic ketones and enones with remarkably good results, although the reaction scope was exclusively studied for the case of cyclic six-membered ring ketones as nucleophiles and 1,4-diaryl substituted enones as electrophiles. In this system the authors also pointed toward a mechanism involving exclusively enamine-type activation of the nucleophile, with no contribution of any intermediate iminium species which could eventually activate the electrophile. Surprisingly, the use of primary amines as catalysts in this transformation has not been already considered. 

After the Michael reaction step had taken place, an intermediate containing both an iminiiim and an enamine moiety was generated and their direct reaction between each other followed by elimination was proposed to account for... 

E-ajp-unsaturated ester was employed, while a single diastereoisomer was obtained using the corresponding Z substrate. This reaction design has also been extended to the use of an a,p-unsaturated aldehyde as the initial Michael acceptor, in this case it being necessary to consider the possible dual activation of the Michael donor and acceptor by the catalyst through the formation of the corresponding enamine and iminium intermediates. ... 

Finally, the enamine intermediate generated after this second Michael reaction underwent intramolecular aldol reaction followed by dehydration, delivering the final highly functionalized cyclohexenecarbaldehyde product. 

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