Enamine-Michael

There are two advantages to the enamine-Michael reaction versus the enolate-ion-Michael that make enamines so useful in biological pathways. First, an enamine is neutral, easily prepared, and easily handled, while an enolate ion is charged, sometimes difficult to prepare, and must be handled with care. 

VI. Sequential Enamine Michael Additions A. Addition to Nitroolefins... 

The focus of this chapter is on the stereoselectivity of the conjugate addition of the Lewis acid and enamine Michael additions. Only donors that are formally enol equivalents are considered. Selectivity that results from preferential addition to one of the faces of an endocyclic enamine or enol ether as a result of the influence of a stereocenter in the ring is not emphasized. In general, the factors that control the stereochemistry in these instances are analogous to those active in the reactions of other electrophiles with such compounds. 

The possibility that the stereoselectivity arises from either a thermodynamic preference or a subsequent process (cyclization) is less likely with imines as conjugate addition leads to an N-protonated immonium ion, which should rapidly undergo proton transfer. The resulting neutral product should be substantially less likely to undergo reversal to starting material than the dipolar intermediate involved in enamine Michael additions. 

On first inspection, the enamine Michael addition appears to be a mechanistically simple reaction where neutral starting materials go to neutral products. Stereochemical studies have revealed, however, that the process is exceedingly complex. Initially, at least four different types of product (not counting stereoisomers ) can be obtained prior to hydrolysis (see Scheme 3). The point at which stereochemical differentiation occurs has yet to be convincingly... 

Seebach and Golinski advanced a topological rule to account for the stereochemistry of enamine Michael additions along with many other... 

For a brief discussion of enamine Michael additions in asymmetric synthesis see Valentine, D., Jr. Scott, J. W. Synthesis 1978, 329-356. 

Scheme 5.34. (a) Suprafacial Michael addition-proton transfer of a tertiary enamine [180], (b) aza-ene-like transition structure for secondary enamine Michael additions [179]. 

Other examples shed some light on the importance of the proton transfer in these enamine Michael additions. For example, the A 1 2 enamine of P-tetralone (Scheme 5.36c) afforded high yields of 3-substituted Al<2 enamine products, even though the A2.3 enamine isomer was not present in the reaction mixture [187] (see also ref [188]). Under the reaction conditions (toluene or ether, stirring for 3-4 days), the Al>2 isomer must isomerize to the A A isomer which reacts much faster, probably due to the greater acidity of the benzylic proton of the A2.3 isomer compared to the C3-proton of the A1-2 isomer. 

The products could be easily isolated by filtration, and recrystallizafion from elhanol led to the pure desired compounds. The authors suggested an iminium ion-catalyzed Knoevenagel condensation mechanism, followed by enamine-Michael addition and intramolecular cyclization. One year later, the same group reported the diammonium hydrogenphosphate-catalyzed synthesis of various pyrano-pyrimidinones by exchanging dimedone by barbituric and thiobarbituric add in aqueous ethanol at ambient temperature [13]. The desired compounds could be afforded in good yields. 

SCHEME 13.16 Piperidine-catalyzed Knoevenagel/enamine-Michael addition/cyclization sequence. 

An acid-catalyzed version of this reaction was published by Wang et al. in 2013 [50]. A substoichiometric amount of acetic acid in refluxing ethanol mediates the Knoevenagel/ enamine-Michael addition/cyclization sequence to provide the spirodihydropyridines in high yields. 

The reaction of dimedone-derived enamines 110, methyl (2-cyano)acetate 109, and formaldehyde 72 mediated by lithium perchlorate led to the formation of a Knoevenagel/ enamine-Michael addition product (Scheme 13.33) [52], This could be cyclized in a one-pot procedure with substoi-chiometric amounts of triphenyl phosphine to provide... 

SCHEME 13.34 Direct cyclization of Knoevenagel/enamine-Michael addition products to the corresponding pyridone derivatives 115, 118, and 122 [53-55],... 

Jiang et al. described the proline-catalyzed reaction of several amines 143 with alkynes 141, various aldehydes 142, and 1,3-dicarbonyl compounds 144 to afford 1,4-dihydro-pyridines 145 in moderate to good yields (65-85%) (Scheme 13.37) [62]. Mainly three reactions are involved in the production of those products the first one is a proline-catalyzed Knoevenagel reaction between the aldehydes 142 and the 1,3-dicarbonyl compounds 144 to give Michael acceptors. The second one is a hydroamination reaction of the alkyne 141 to yield enamines, which in the third reaction undergo an enamine-Michael addition/cyclization sequence to provide the desired products. 

In an interesting example, two unsaturated aldehydes form each the corresponding enamine in the presence of a proUne-derived catalyst. A first iminium-enamine Michael addition is followed by a second addition onto the unsaturated ester function present in one of the initial reagents. Photoinduced electron transfer and debromination give a radical that adds onto methacrylic aldehyde and cyclize to a highly functionalized decaline 60 (see Scheme 8.27) [46]. 

Polyhydro-azine preparation with carbanionic species is well known, and many variants using enamines, Michael acceptors, etc. have been described in the past. This year s selection includes work on Reissert reactions of phthalazines (Scheme 43) various enamine annelations leading to alkaloid skeletons [for example... 

As for iminium catalysis, the enamine Michael addition was shown to have a great potential for the fast construction of simple drugs. The group led Benjamin List reported on the highly challenging addition of acetaldehyde to nitroolefins for the synthesis of three different small bioactive natural products (Scheme 11.21). " The Michael adducts 83 obtained using commercial catalyst in 88% to 94% ee and containing both aldehyde and nitro functionality could be transformed by a classic one- to three-step transformation... 

Carbon nucleophiles enamines Michael addition of cyclohexanone and other cyclic ketones to chalcones Ar CH=CHCOAr, catalysed by the pyrrolidine-based phthalimide and/or 1,8-naphthalimide (316) (30mol%) in the presence of PhC02H (10mol%), neat at 20 C, has been found to exhibit good stereoselectivity (<99 1 dr, <96% ee) Similar results were obtained with the C2-sytnmetric tetraamine (317) as 0 catalyst (20 mol%) with <99 1 dr and 93% ee in the presence of 4-Me0-C6H4C02H (20 mol%) (neat, r.t.). Here, a mechanism has been proposed, based on the ESI-MS study of the intermediates. ... 

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