Enones as Michael acceptors

Despite this, bifunctional thiourea-tertiary amine catalysts have also emerged as useful and very convenient compounds for the activation of enones in Michael reactions. The mentioned problems associated to the single position available for H-bonding interactions and to the lower Bronsted basicity of the carbonyl moiety are circumvented by the formation of a double H-bonding network in which both lone pairs at the oxygen atom participate with two 

Quinine 84a has also been found to be an excellent catalyst for the conjugate addition of p-ketoesters to quinones. In this case, the reaction proceeded in the usual way, but the obtained conjugate addition products, in which the quinone 

Finally, it should be pointed out that this methodology has been extended to the use of other nucleophiles that are not based exclusively on stabilized car-banions like enolates or related species. In particular, alkenylboronic acids have 

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The higher activity of primary amines in the reaction involving enones as Michael acceptors has also been extended to the use of different bifunctional catalysts (Scheme 3.19), which usually contain a primary amine functionality connected to a basic site by means of a chiral scaffold, as is the case in the use of 280 and 55. These diamine catalysts have been found to be excellent promoters of the Michael reaction of enones with cyclic 1,3-dicarbonyl compounds and malonates respectively, the tertiary amine basic site present at the catalyst structure being responsible for assisting in the deprotonation of the Michael donor in order to increase the concentration of the nucleophile species. In a different approach, bifunctional thiourea-primary amine catalyst 56a has also... 

Scheme 3.24 Enantioselective conjugate Friedel-Crafts alkylations using enones as Michael acceptors.

To end this section, it has to be mentioned that there is a single example of a conjugate Friedel Crafts alkylation involving enones as Michael acceptors. In particular, a camphor-based sulfonic acid (94) has been used as catalyst in the reaction of indoles with chalcones (Scheme 4.57). It has also to be noted that the best conditions involved the use of catalyst 94 together with an ionic liquid (l-butyl-3-methyl-l//-imidazolium bromide BmimBr). However, although excellent yields were obtained for a set of different substrates tested, the enantioselectivities remained in rather low values. 

There is also an interesting example of an enantioselective thiourea-catalyzed oxa-Michael reaction using enones as Michael acceptors in which phe-nylboronic acid was employed as hydroxyl anion equivalent (Scheme 4.64) The authors demonstrated that amine bases were able to activate these kinds of reagents by complexation, thus becoming effective reagents for the transfer of the OH group to the Michael acceptor. The reaction had to proceed in an intramolecular way and, for this reason, y-hydroxy-a,(3-unsaturated ketones had to be employed as substrates. In the enantioselective version, 71b was identified as a very efficient catalyst, providing a series of (3,y-dihydroxy ketones in excellent yields and enantioselectivities, after oxidative work-up. The process consists of the initial reaction of the boronic add first with the y-hydroxy... 

The catalytic performance of the lithium salt of (5)- or (f )-3,3 -bis[bis-(phenyl) hydroxymethyl]-2,2 -dihydroxy-dinaphthalene-l,l (4, BIMBOL) in asymmetric Michael additions of malonic acid derivatives and toluedine has been studied. Using nitrostyrene and cyclohex-2-enone as Michael acceptors efficient asymmetric C-C and C-N bond formations with up to 95% ee at room temperature were observed. A transition-state model of the malonic ester addition to cyclohex-2-enone has been proposed based on the molecular stmcture of the acetone solvate of BIMBOL. 

When cyclic enones were used as Michael acceptors, both malonates and acetoacetates gave impressive yields and enantioselectivities of the desired Michael addition products (Scheme 5.2Q) NMR spectra and single-crystal X-ray data supported the following ruthenium intermediate (Scheme 5.21) and transition state (Figure 5.8). 

The reaction of both pyrrole and N-methylpyrrole (321) with dimethyl p-nitrobenzylidene malonate (326) in the presence of the catalyst (S)-93 gave the Michael adducts 327-328 in excellent yields (99%) [98], but the enantioselectivity of the products was quite low (28-36% ee), respectively (Scheme 71). Regarding catalyst 93, the Michael adduct 329 was obtained from N-methylpyrrole (321) and the alkylidene malonate in moderate yield (62%) and low enantioselectivity 18% ee (Scheme 71) [100]. But, the bis(oxazoline) 93-catalyzed reaction of both pyrrole (1) and N-methylpyrrole (321) with various (/-hydroxy enones 95 as Michael acceptor worked perfectly (Scheme 71) [99]. The elaboration of these adducts through sequen-... 

The mild reaction conditions (relatively weak amine bases, short reaction times) of the CIR of (hetero)aryl halides and l-(hetero)aryl propargyl alcohols opens a modular entry to chalcones, which are as Michael acceptors suitable starting points for consecutive multicomponent syntheses of heterocycles in a one-pot fashion [28, 86]. Both catalytic generations of ynones and enones have set stages for diversity-oriented multicomponent syntheses of heterocycles in a consecutive one-pot fashion. 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

In a previous study Kotsuki s group reported reactions of / -ketoesters with enones or acrylates under 800 MPa (Scheme 10.12) [41]. Table 10.11 compares the yields obtained under biactivation conditions (pressure -h lanthanide catalysis) on one side and in the presence of a catalytic system consisting of Yb(OTf)3 -I- silicagel at ambient pressure on the other. Both methods reveal similar efficiency, although operation under pressure reduces reaction time. However, association of pressure and lanthanide catalysis proves its usefulness when acrylates are involved as Michael acceptors. In this case, no reaction occurs with the ambient pressure method even after prolonged reaction times. 

Some improvement might be possible by means of enantioselective conjugate addition of a chiral organocuprate [128] to 2-ethylcyclopeait-2-enone (133b) as Michael acceptor Scheme 66). 

Internal ynones and alkynes have been frequently used as starting materials for the synthesis of quinoline compounds. Ynones can act as Michael acceptors with various nucleophiles, affording intermediate enones, which are readily cyclized to quinolines. ... 

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