Reverse Michael addition

Shi, B. Greaney, M. F. Reversible Michael addition of thiols as a new tool for dynamic combinatorial chemistry. Chem. Commun. 2005, 886-888. 

Tomalia et al. (5) develop a synthetic method for preparing functionalized dendritic compositions having high thermal stability that did not undergo a reversible Michael addition reaction. 

Aldol condensation with aldehydes and ketones gives hydroxy compounds (265 — 267) which usually spontaneously lose water (by a reverse Michael addition) to give unsaturated compounds (268). 

Substituted allyl alcohols can be prepared on insoluble supports under mild conditions using the Baylis-Hillman reaction (Figure 7.2). In this reaction, an acrylate is treated with a nucleophilic tertiary amine (typically DABCO) or a phosphine in the presence of an aldehyde. Reversible Michael addition of the amine to the acrylate leads to an ester enolate, which then reacts with the aldehyde. The resulting allyl alcohols are valuable intermediates for the preparation of substituted carboxylic acids [43,44],... 

Whilst the elementary steps of the reaction were postulated in the earliest publications [3], and remain (globally) even today as the core of the mechanistic discussion, the fine details of the reaction - and in particular those controlling the asymmetric induction - have been highlighted only recently. The first critical mechanism [15a, 45, 46], which is based on pressure-dependence data, established a reversible Michael addition of the nucleophilic base to the activated al-kene (Scheme 5.3). In the following step, the formed zwitterionic enolate 11 adds to the electrophile and forms a second zwitterionic adduct 13. This step was considered to be the rate-determining step (RDS) of the reaction. Subsequent proton transfer and release of the catalyst provides finally the desired product 14. 

Similar mechanisms account for the double bond geometry obtained in aldol reactions followed by dehydration to give a,(3-unsaturated carbonyl compounds. Any Z-alkene that is formed is equilibrated to Eby reversible Michael addition during the reaction. 

The double aldol product from acetone and benzaldehyde, known as dibenzylidene acetone (dba), is a constituent of some sun-protection materials and is used in organometallic chemistry as a metal ligand. It is easily made geometrically pure by a simple aldol reaction—again, reversible Michael addition equilibrates any Zproduct to E... 

Recently, thiols have also been shown to participate in a series of new reversible reactions suitable for DCC. Such reactions include (1) the thioester exchange reaction (Fig. 6b), (2) the thiazolidine exchange reaction (Fig. 6c), and (3) the reversible Michael addition of thiols (Fig. 6d). 

Fig. 6 (a) Thiol-disulfide exchange, (b) Thiol-thioester exchange, (c) Thiazolidine exchange, (d) Reversible Michael addition of thiols... 

Slowly in solution crystals are formed and these are the more stable fumarate ester. The process is enormously accelerated by adding a trace of an amine and must occur by reversible Michael addition of the amine or even of traces of methanol or any other stray nucleophile.7... 

The relative rates in this manifold should be dependent on the substitution pattern of the substrates. For example, a substituent R capable of electron donation (i.e., an alkoxy group) should stabilize the oxonium intermediate 59.1, thereby slowing the reverse Michael addition and potentially the rate of... 

Oxidation of dihydrobenzenes. Ethyl 2,4-pentadienoate (2) reacts with A1-pyrrolidinocyclohexene (1) to give the 1 1 adduct of 1,4-cycloaddition (3), which undergoes reverse Michael addition and tautomerism to give (4). This is conveniently oxidized to the aromatic system (5) by Attenburrow manganese dioxide.47... 

In their 1977 paper Davies and Whitham [26] studied muconaldehyde and reported that the Z,Z to Z, isomerization was slower than the Z, to , isomerization. This contradicted the initial study by Nakajimaet al. [77] and all subsequent studies. Soon afterwards, Adam and Balci [32] noted that (Z,Z)-6-keto-2,4-heptadi-enal isomerized in 3 h at 135 °C to the (Z, )-isomer. This supports the view that Z, to , isomerization is much slower. These authors also noted that Z,Z to , isomerization is catalyzed by thiourea, presumably via reversible Michael addition... 

A more recent study of this issue by Golding et al. [53] found that, in the absence of added nucleophiles, (Z,Z)-inuconaldehyde isomerized to the(Z, )-iso-mer in under 16 h at SS °C, while further isomerization to the ( , )-isomer did not occur under these conditions. They postulated a thermally allowed electrocycliza-tion to form a minute concentration of 2 -pyran-2-carboxaldehyde (19) to explain this interesting stereospecificity (see Scheme 2) [55]. Rotations of C=C bonds are expected to have barriers too high for this isomerization mode to occur [34]. If such rotation were to occur, then it would be expected to allow Z, to , isomerization. The reversible formation of 19 would explain why Z, to , thermal isomerization is too slow to observe. Golding et al. [55] also found that triethylamine catalyzes isomerization of (Z, )-muconaldehyde to the ( , )-isomer, presumably by reversible Michael addition and they corroborated the earlier-cited results for 6-keto-2,4-hexadienal. 

If we compare the estimated enthalpies of formation (Table 1) for (Z,Z)-mucon-aldehyde (14a) and rroRj-cyclobutene-l,2-dicarboxaldehyde (see Eq. 4), we find that the isomerization to 22b is endothermic by 16.9 kcal/mol, about 11 kcal/mol more endothermic than isomerization to the 2f/-pyran 19. This plausibly explains the rapid Z,Z to Z,E isomerization coupled with very slow Z, to , isomerization in the absence of nucleophiles. Thus, the first step could be unimolecular thermal rearrangement, while the second step under metabolic conditions could be the reversible Michael addition-isomerization. Of course, both steps could result from attack by nucleophiles either in the medium or on biological macromolecules. 

Similar observations of base catalysis have been used to invoke the ElcB mechanism for elimination from 4,4-dicyano-3-p-nitrophenyl-1 -phenylbutan-1 -one in neutral and acidic methanol (34) , and l,l,l,3-tetranitro-2-phenylpro-pane in methanol in the presence of hydrochloric acid and pyridine-pyridine hydrochloride buffers (36) . In the former reaction, an example of a reverse Michael addition, the carbanion intermediate with the electron pair alpha to the carbonyl rather than in the gamma position is favoured, as the methyl isomer (35) eliminates more rapidly than the parent compound. 

Ireland and co-workers used a Wichterle sequence in their stereoselective syntheses of diterpenoid resin acids when annulations with methyl vinyl ketone resulted in polymeric tars. Stereoselective alkylation of cyclohexanone 34 with Wichterle s reagent afforded 35 as a single stereoisomer. Studies performed on this system determined that alkylation was favored cis to the C2 methyl group. After hydrolysis of the vinylic chloride 35 to the diketone 36, cyclization proved difficult due to the large amount of steric hindrance present in the molecule. Base-catalyzed cyclization resulted in only partial conversion to the desired octalone 37. It was found that a significant portion of the material was cleaved to the starting material for this sequence, monoketone 34, via facile reverse Michael addition when the side chain adopted an equatorial confirmation. 

There are also a series of more complex eliminations that you should be aware of (Eqs. 10.63-10.67), although we are not going to look at these in any detail. One is the elimination of 1,2-dihaloalkanes and 1,4-dihaloalkanes (the Grob fragmentation) using Zn to create al-kenes or dienes (Eqs. 10.63 and 10.64, respectively). The first step in both reactions involves the oxidative addition of Zn to a C-X bond, a reaction we will cover in detail in Chapter 12. Other eliminations involve y-amino alkyl halides, which can spontaneously undergo elimination (Eq. 10.65), and the base-induced eliminations of both (3-hydroxyketones (Eq. 10.66, the reverse aldol reaction) and 8-ketoketones (Eq. 10.67, the reverse Michael addition). 

In some cases, where possible, an internal Michael reaction may lead to ring closure. A case in point is the formation of 80 from jS-aminocrotonic acid ester and MA. Szilagyi and Wamhoff reported the cyclization due to internal polarization. However, amide nitrogen shares its electrons with difficulty. It is possible that a reversible Michael addition triggered by the amine brings about the closure. Carbon-carbon bond formations due to reversible Michael reactions have been reported. 

In a separate communication Roush and Spada (119) utilized their chiral ribbons in a synthesis of trichoverrol B (69) as shown in Scheme 26. Verrucarol (82) was selectively esterified at C-15 to yield the monoester (232). Formation of the sodium alkoxide and acylation with the mixed anhydride (230) successfully introduced the diene fragment with no observable diene isomerization. The authors hypothesized that the lack of a nucleophilic species capable of undergoing reversible Michael additions with the diene unit accounts for the absence of olefin isomerization. Simple treatment with fluoride then yielded the monoester trichoverrol B (69). 

Considering the rapid growth of asymmetric construction of oxindoles, Sun et al. recently reported their assembly of chiral spirooxindoles by combining secondary amine and palladium catalysis in a cascade reaction [55]. The reaction was initiated by the reversible Michael addition of 3-substituted oxindole to enal, which was followed by a metal/organic-cocatalyzed carbocyclization of the aUcyne tether (Scheme 9.60). Similar to the aforementioned dynamic kinetic asymmetric transformations, this chemistry highlighted the cooperative effects of the two catalysts in the same reaction vessel, while either catalyst could not solely promote the overall reaction, and unsatisfactory results were observed when this reaction was conducted in a two-step mode. 

In the classical Morita-Baylis-Hillman (MBH) reaction an a,P-unsaturated ester (electrophilically activated alkene), is activated by the reversible Michael-addition of a tertiary amine catalyst (e.g. DABCO), producing a zwitterion intermediate, the enolate moiety of which can react with an aldehyde to form an aldolate zwitterion. Retro-Michael-addition then regenerates the catalyst and the MBH-product (Scheme 7.22). The catalyst is sometimes used in high amounts (over stoichiometric) and often the reaction is very sensitive to the Michael acceptor used. 

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