Consecutive reactions, with Michael additions

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. 

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. 

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. 

In 2011, Moreau, Greek and coworkers reported a multicatalytic process [6] merging two consecutive enamine catalytic cycles based on a Michael addition/a-amination cascade reaction [7]. The Michael addition of aldehydes to p-nitrostyrene followed by the electrophilic amination were catalyzed, respectively, by the diphenylprolinol silylether 5 and the 9-amino-(9-deoxy)-cpf-cinchonine 6 (Scheme 12.4), both previously described by Hayashi and coworkers [8] and Melchiorre and coworkers [9]. One interesting feature of this reaction is that diphenylprolinol silylether 5 can specifically catalyze the Michael addition, while 9-amino-(9-deoxy)-ep/-cinchonine 6 is required to promote the electrophilic amination. The Michael addition of propionaldehyde to p-nitrostyrene was achieved by using only 5 mol% of catalyst 5 in chloroform at 0 C. After completion of the reaction, dibenzyl azodicarboxylate (DEAD, 1.5 equiv), trifluoroacetic acid (15 mol%) and the second catalyst 6 (5 mol%) were added. The expected product 7 was obtained as a single diastereomer in good yield (80%) and with excellent enantioselectivity (ee 96%). Various nitroalkenes bearing electron-rich and electron-deficient aryl... 

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. 

An organocatalytic triple cascade reaction, followed by an intramolecular sulfa-Michael addition to produce bicyclic rings with six consecutive stereocenters, was also realized [46]. 

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. 

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). 

In addition to conventional Diels-Alder reactions, consecutive [4-1-2] reactions have been subjected to extensive investigation through the iminium-enamine catalytic sequence. Wang, Rios, and others simultaneously described enantioselective cascade sulfa-, oxa-, and aza-Michael/aldol/dehydration reactions promoted by chiral secondary amines. An initial strategy for a one-pot synthesis of chiral thiochromenes with good to high enantioselectivities was reported (Schemes 1.46 and 1.47) [71]. 

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