Consecutive reactions, with Michael

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

When the cnolate of an enone is brought into reaction with an enone, usually a carbocyclic system is prepared by two consecutive Michael additions (M1MIRC reactions). Due to the lower temperatures employed and the absence of diene polymerization these reactions are useful alternatives for Diels-Alder reactions and proceed in general with high diastereoselectivities. When neither enolate nor enone is cyclic a monocyclic system is formed 338 which can be converted into a bicyclic system when the Michael addition is followed by an aldol reaction339. When, however, the enolate is cyclic a bicyclic or a tricyclic system is formed340 341. 

Michael reactions of silyl enol ethers.1 2 3 The silyl enol ether of 1-acetylcy-clohexene (1) undergoes two consecutive Michael reactions with an a,p-enone or -enal in the presence of this Lewis acid to form 1-decalones. 

Enolate D of Figure 13.71 can undergo an aldol reaction with the C=0 double bond of the ketone. The bicyclic compound A is formed as the condensation product. It is often possible to combine the formation and the consecutive reaction of a Michael adduct in a one-pot reaction. The overall reaction then is an annulation of a cyclohexenone to an enolizable ketone. The reaction sequence of Figure 13.71 is the Robinson annulation, an extraordinarily important synthesis of six-membered rings. 

The first step in the reaction of aminocycloalkenones with quinones is a normal Michael addition to yield hydroquinone adducts, as is known from the Nenitzescu reaction with / -ketoenamines. However, the consecutive cyclization is quite different, and the structure of the heterocycles formed depends on the substitution at the nitrogen and the size of the cycloalkane ring. 

While zeolites are mostly used in acid catalysts, there are various procedures to introduce basic sites with variable strength into these materials. Depending on the nature of the active site, one is able to selectively catalyze reactions with different basicity requirements, and this is probably the main virtue of base catalysis with zeolites. For instance, in a classical Knoevenagel condensation, the reaction selectivity can be decreased by a consecutive Michael reaction, since the Knoevenagel product can serve itself as a Michael receptor -. 

A spectacular example is the synthesis of the bicyclic keto-ester 93. Two consecutive Michael disconnections reveal the a extended enolate of cyclohexanone 95 and methyl acrylate. The synthesis is even easier kinetic enolisation of cyclohexenone with LDA and reaction with methyl... 

One of the first examples of this type of reactions was reported in 2009 by Melchiorre and coworkers with a three-component cascade Michael-Michael-aldol reaction with unsaturated aldehydes as electrophiles or a complementary consecutive Michael-Michael sequence with enones [9]. In the first case (Scheme 10.1),... 

Domino Sequences Involving Oxindoles as Pronucleophiles Another commonly used approach for the synthesis of spirooxindoles relies on the use of simple oxindoles as pronucleophiles with several Michael acceptors. For example, we developed a highly enantioselective methodology for the synthesis of spirooxindoles by a Michael-Michael-aldol cascade (Scheme 10.19) [30]. Simple 2-oxindole (58) undergoes two consecutive Michael reactions with enals 16 catalyzed by the Jprgensen-Hayashi catalyst I. Next, an intramolecular aldol reaction catalyzed by the same catalyst takes place to afford, after dehydration, the corresponding spirooxindoles 59. 

This cmcial result suggested the plausible mechanism described in Scheme 4.11. Two pathways are proposed for the transformation of the product resulting from the CDC reaction of 11-A (l) either a direct Sn2 reaction or (2) a consecutive sequence with a Cope-(ype elimination then a Michael addition. 

The fluorine containing 7t-exTTF 550 was obtained in the 1,3-dipolar cycloaddition of DMAD to dithiocarboxylic moiety of the dithiocrotonate 549 and subsequent reaction of the resulting intermediate ylide with the starting 549 as a Michael acceptor in an addition-elimination process followed by ethyl bromide elimination. Formation of the second 1,3-dithiole moiety in 550 was connected with the consecutive cycloaddition followed by ethyl bromide elimination (Equation 71) <2003CEJ4324>. 

An interesting domino reaction of 2-chloro-2-cyclopropylideneacetates was achieved with a variety of cycloalkadienolates. Thus, in a one-pot procedure tricyclic compounds such as 27 were obtained in high yields from 25 (X = Cl), whereas bicyclic products 26 result from 25 (X = H, Me). These are obviously formed via a [4-1-2] cycloaddition. For X = Cl in 25 a subsequent y-elimination of lithium chloride results in the formation of an additional three-membered ring. An alternative mechanism via two consecutive Michael reactions or a carbene intermediate can also be envisaged, but appears to be less likely. For examples see Table 5. 

CsLa-MCM-41 catalyzes the Michael addition of ethyl cyanoacetate (2) to ethyl acrylate (14) (Scheme 9). Besides formation of the mono adduct (15), bis adduct 16, formed by a double Michael addition, is produced consecutively. Although the basicity of CsLa-MCM-41 is quite mild, its performance in this reaction is very good. Table 4 compares the activity and selectivity obtained with different catalysts. Although product selectivity is probably also controlled by the mesoporous MCM-41 support, the basicity of CsLa-MCM-41 is too weak to catalyze the Michael addition of diethyl malonate under the same conditions. 

Alkylideneglutaronitriles are readily formed by consecutive Michael and Wittig reactions. The process involves addition of the cyanomethylphosphonate anion to acrylonitrile and quenching the homologated anion with aldehydes. 

In 2013, the Hui group developed an efficient NHC-catalyzed stereoselective aza-Michael-Michael-lactonization cascade reaction of 2-amino phenyl-enones and 2-bromoenals. Functionalized tetrahydroquinolines with three consecutive stereogenic centers were obtained in high yields with excellent diastereo- and enantioselectivity. This approach is attractive due to the mild reaction conditions and the potential application of the products in medicinal chemistry. In addition, this strategy extends the scope of NHC catalysis and provides a simple protocol for the NHC-catalyzed cascade reaction (Scheme 7.100). 

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