Reversible conjugate addition

Even after conversion to the dienal, reversible conjugate addition of water would allow cis/trans interconversion. 

In accordance with the generally accepted mechanism ofthe MBH reaction, the aza MBH reaction involves, formally, a sequence of Michael addition, Mannich type reaction, and (3 elimination. A commonly accepted mechanism is depicted in Scheme 13.2. A reversible conjugate addition of the nucleophilic catalyst to the Michael acceptor generates an enolate, which can intercept the acylimine to afford the second zvdtterionic intermediate. A proton shift from the a carbon atom to the P amide followed by P elimination then affords the aza M BH adduct with concurrent regeneration of the catalyst [5]. 

Fortunately this is not so and the Baylis-Hillman reaction40 allows an escape from these problems. The enone is mixed with the aldehyde and a catalyst, usually a tertiary amine or phosphine, is added. The catalyst need not be basic as its role is reversible conjugate addition 150. This gives the enolate, as we saw in chapter 10, that does the aldol addition 151. The product 152 forms a new enolate that eliminates 153 (ElcB) the catalyst to give the product 148. 

The unusual catalyst 113 must add to the unusual ester 111 in a reversible conjugate addition 114 to give the enolate that adds to the aldehyde in the asymmetric step 116. The bicyclic amine must be placed close to the carbonyl group of the aldehyde Hatakeyama suggests an H-bonding interaction with the OH group on the quinoline ring of the catalyst. Finally, elimination of the catalyst launches a second cycle. The next few years are likely to see considerable development here. 

There are many methods that can be used to tackle this question. The only snags are protecting the OH group if necessary and care in isolating the Z-compound as it may isomerize easily to the E-compound by reversible conjugate addition. One way to the Z-alkene uses reduction of an alkyne to control the stereochemistry. The OH group is protected as a benzyl ether removed by hydrogenation, perhaps under the same conditions as the reduction of the alkyne. 

It is proposed that this reaction involves a reversible conjugate addition of phosphine to electron-deficient alkenes, followed by a Michael Addition of the resulting carbanion to the second alkene, and subsequent proton migration and elimination of phosphine,as illustrated here by the tricyclohexylphosphine catalyzed reaction of ethyl acrylate. 

Formally, the MBH reaction involves a sequence of Michael addition, aldol reaction and P-elimination. The commonly proposed mechanism consists in a reversible conjugate addition of the nncleophile to the starting enone 237, generating an intermediate enolate 238. This enolate reacts with the electrophilic aldehyde in an aldol-type process, in which two stereogenic centers are formed, to give 239, which suffers an intramolecnlar acid-base eqnilibrinm to give another enolate 240. From this intermediate, the p-elimination of the nncleophile provides the MBH product... 

Tertiary amines undergo reversible conjugate addition to a, 3-unsaturated ketones (see Chapter 18). This process is the basis for the Bayhs-HUhnan reaction, which is catalyzed by tertiary amines, that resembles a crossed aldol reaction. An example is shown below. 

Elfamycins having 4-hydroxy-2-pyridone moieties (1—6,12) readily undergo reversible internal cyclizations by conjugate addition of either oxygen functionahty on the pyridone ring at C-9. These products can be isolated as exemplified by isoefrotomycin (58). 

Enantioselectivities were found to change sharply depending upon the reaction conditions including catalyst structure, reaction temperature, solvent, and additives. Some representative examples of such selectivity dependence are listed in Scheme 7.42. The thiol adduct was formed with 79% ee (81% yield) when the reaction was catalyzed by the J ,J -DBFOX/Ph aqua nickel(II) complex at room temperature in dichloromethane. Reactions using either the anhydrous complex or the aqua complex with MS 4 A gave a racemic adduct, however, indicating that the aqua complex should be more favored than the anhydrous complex in thiol conjugate additions. Slow addition of thiophenol to the dichloromethane solution of 3-crotonoyl-2-oxazolidinone was ineffective for enantioselectivity. Enantioselectivity was dramatically lowered and reversed to -17% ee in the reaction at -78 °C. A similar tendency was observed in the reactions in diethyl ether and THF. For example, a satisfactory enantioselectivity (80% ee) was observed in the reaction in THF at room temperature, while the selectivity almost disappeared (7% ee) at 0°C. 

Both primary and secondary amines add to a /S-unsaturated aldehydes and ketones to yield /3-amino aldehydes and ketones rather than the alternative imines. Under typical reaction conditions, both modes of addition occur rapidly. But because the reactions are reversible, they generally proceed with thermodynamic control rather than kinetic control (Section 14.3), so the more stable conjugate addition product is often obtained to the complete exclusion of the less stable direct addition product. 

Water can add reversibly to o ,/3-unsalurated aldehydes and ketones to yield /3-hydroxy aldehydes and ketones, although the position of the equilibrium generally favors unsaturated reactant rather than saturated adduct. A related addition to an c /S-unsaturated carboxylic acid occurs in numerous biological pathways, such as the citric acid cycle of food metabolism where ds-aconitate is converted into isocitrate by conjugate addition of water to a double bond. 

Dimethylsulfonium methylide is both more reactive and less stable than dimethylsulfoxonium methylide, so it is generated and used at a lower temperature. A sharp distinction between the two ylides emerges in their reactions with a, ( -unsaturated carbonyl compounds. Dimethylsulfonium methylide yields epoxides, whereas dimethylsulfoxonium methylide reacts by conjugate addition and gives cyclopropanes (compare Entries 5 and 6 in Scheme 2.21). It appears that the reason for the difference lies in the relative rates of the two reactions available to the betaine intermediate (a) reversal to starting materials, or (b) intramolecular nucleophilic displacement.284 Presumably both reagents react most rapidly at the carbonyl group. In the case of dimethylsulfonium methylide the intramolecular displacement step is faster than the reverse of the addition, and epoxide formation takes place. 

With the more stable dimethylsulfoxonium methylide, the reversal is relatively more rapid and product formation takes place only after conjugate addition. 

Conjugate addition of enolates under some circumstances can be carried out with a catalytic amount of base. All the steps are reversible. 

Crosslinking using diazonium compounds usually creates deeply colored products characteristic of the diazo bonds. Occasionally, the conjugated molecules may turn dark brown or even black. The diazo linkages are reversible by addition of 0.1 M sodium dithionite in 0.2 M sodium borate, pH 9.0. Upon cleavage, the color of the complex is lost. 

The advantage of this approach to liposome conjugation is that the linkage between the lectin complex and the membrane bilayer is noncovalent and reversible. The addition of a saccharide containing the proper sequence or sugar type recognized by the lectin breaks the binding... 

Addition of Lewis acids may not only accelerate the reaction rate of a conjugate addition but may also alter the stereochemical outcome of a cuprate addition. Interestingly when the 6-t-butyl-substituted cyclohexenone derivative 17 was exposed to dibutylcuprate, followed by silylation of the resulting enolate, the cis enol ether 18 was obtained (Scheme 6.3) [8]. If, however, the cuprate addition was performed in the presence of chlorotrimethylsilane, the stereochemical outcome of the conjugate addition reaction was reversed to give trans enol ether 19. 

If tlie 1,2-addition is reversible (the nucleophile is a good leaving group), then we get thermodynamic control and the conjugate addition product predominates. When the 1,2-addition is not reversible (the nucleophile is a poor leaving group), we get kinetic control and simple addition. Stereochemical considerations are also partly responsible, since it will be easier for larger nucleophiles, especially enolate... 

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