Reversible reactions, Michael

These reversible reactions are cataly2ed by bases or acids, such as 2iac chloride and aluminum isopropoxide, or by anion-exchange resias. Ultrasonic vibrations improve the reaction rate and yield. Reaction of aromatic aldehydes or ketones with nitroparaffins yields either the nitro alcohol or the nitro olefin, depending on the catalyst. Conjugated unsaturated aldehydes or ketones and nitroparaffins (Michael addition) yield nitro-substituted carbonyl compounds rather than nitro alcohols. Condensation with keto esters gives the substituted nitro alcohols (37) keto aldehydes react preferentially at the aldehyde function. 

Mannich bases (see 16-15) and p-halo carbonyl compounds can also be used as substrates these are converted to the C=C—Z compounds in situ by the base (16-15, 17-12). Substrates of this kind are especially useful in cases where the C=C—Z compound is unstable. The reaction of C=C—Z compounds with enamines (12-18) can also be considered a Michael reaction. Michael reactions are reversible. 

Jenner investigated the kinetic pressure effect on some specific Michael and Henry reactions and found that the observed activation volumes of the Michael reaction between nitromethane and methyl vinyl ketone are largely dependent on the magnitude of the electrostriction effect, which is highest in the lanthanide-catalyzed reaction and lowest in the base-catalyzed version. In the latter case, the reverse reaction is insensitive to pressure.52 Recently, Kobayashi and co-workers reported a highly efficient Lewis-acid-catalyzed asymmetric Michael addition in water.53 A variety of unsaturated carbonyl derivatives gave selective Michael additions with a-nitrocycloalkanones in water, at room temperature without any added catalyst or in a very dilute aqueous solution of potassium carbonate (Eq. 10.24).54... 

In selective etherification, it is important to distinguish between reversible and irreversible reactions. The former class comprises etherifications with dimethyl sulfate, halogen compounds, oxirane (ethylene oxide), and diazoalkanes, whereas the latter class involves addition reactions of the Michael type of hydroxyl groups to activated alkenes. In this Section, irreversible and reversible reactions are described separately, and a further distinction is made in the former group by placing the rather specialized, diazoalkane-based alkylations in a separate subsection. 

It should be noted here that a regioselective control may also be exerted by just controlling the experimental conditions. Thus, working under strictly kinetic conditions (low temperature, absence of oxygen and slow addition of the ketone to an excess of a solution of an aprotic base) the less substituted enolate of carvomenthone can also be selectively generated and may be then submitted to different kind of reactions. However, reversible reactions like the Michael addition would equilibrate the reaction mixture to the thermodynamically more stable enolate. 

Strained bonds will be cleaved particularly readily if there is a reversible reaction by which these bonds might have been formally formed. Such reactions could be the Diels-Alder reaction, aldol additions, Michael additions, or related processes... 

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). 

In 2005, the Michael addition of thiols to enones was added to the list of reversible reactions compatible with the concept of DCC (Fig. 6d). Shi and Greaney investigated the reactivity of glutathione (GSH) toward a series of ethacrynic acid (EA) derivatives in a mixture of DMSO and water at pH 8 [51]. A DCL of six GSH-EA derivatives, products of the Michael addition, was generated which proved responsive to changes in pH. Thermodynamic equilibrium was typically attained after 3 h. Acidification to pH 4 has the immediate effect of switching off the Michael addition and therefore represents a practical way to freeze the equilibrium before analyzing the composition of the DCL. 

The Michael addition, a reversible reaction, produces alkylation at C3 [83AP988 86JCR(S)374] as exemplified by the formation of 166, which can further be elaborated to 167 and 168 [86JCR(S)374]. A preparation of the natural product 94 involves hydrogenation of 158 [82ZN B) 105]. 

Noteworthy was the increase of the selectivity in water toward the 1 1 adduct when using nitromethane. Under slightly alkaline conditions, cetyltrimethylam-monium chloride was shown to catalyze the addition of various nitroalkanes onto conjugated enones [176]. Amines also reacted in aqueous Michael additions, especially with a, -unsaturated nitriles [177]. The lack of apparent reactivity of a, -unsaturated esters comes from the reverse reaction which is particularly accelerated in water. In these amine additions, water activation was compared with high pressure giving support to the implication of the hydrophobic effect. A related reaction is the Baylis-Hillman reaction which proceeds readily in water with a good rate enhancement (Scheme 34) [178]. 

A quinone methide is a relatively unstable species the unsubstituted case has been reported to have a lifetime of 15 seconds in methanol at room temperature [47], However, more substituted, more hindered quinone methides can be prepared in the presence of water and can have long lifetimes (years) in chloroform solutions [48], The instability of quinone methides can be attributed to facile reactions that regenerate an aromatic system. An anion (nucleophile) can add to the a-carbon to rearomatize the system via a familiar Michael reaction [49], The added anion can also be a leaving group (Figure 10.6, step 1) in other words, quinone methide formation is a reversible reaction... 

The stereochemical course of the subsequent Michael addition of malonic ester to the unsaturated ketone (23) proved to be unexpected. The kinetically controlled product 27 of addition was obtained in the presence of sodium methoxide and an excess of dimethyl malonate however, the thermodynamically preferred ester 28, also obtainable by base-catalyzed equilibration of 27, was the major product of the reaction. According to the IR (absence of Bohlmann bands) and NMR spectra, both 27 and 28 contained cis-quinolizidine ring systems formed possibly by reversible retro-Michael cleavage of the C-3 to Aj, bond in 23. This possibility explains the observed rapid destruction of 23 in the presence of very strong base with simultaneous appearance of a UV maximum at 410 nm presufiaably due to the conjugated enone system present in 29. 

Table 10.30 clearly shows that water and ethylene glycol promote the Michael-type reactions. Excellent yields of /i-aminonitriles are obtained in these media when a,yS-unsaturated nitriles are reacted. In all cases the yields are higher than those reached at 300 MPa in acetonitrile solution [100]. Notable exceptions are observed with methyl methacrylate reactions. In these reactions no Michael adduct is formed in aqueous solution, at variance with the pressure-assisted reaction which leads to modest yields (11-23 %). Such a dichotomy in reactivity is relevant to the prevalence of the reverse reaction. yff-Aminoesters undergo rapid reversion to reactants in aqueous solutions which are highly polar, while they are quite stable in acetonitrile [74]. The absence of reactivity in water persists even at 300 MPa meaning that the use of higher pressure is unable to shift the equilibrium toward the aminoester. 

The yields of, 8-aminonitriles obtained in the diol at 300 MPa are comparable to those obtained in aqueous solution. However, as shown above (Sect. 10.3.2.1), ethylene glycol is a dissociating medium promoting ionogenesis in the same way as water does. The Michael reaction between amines and acrylic esters is as sluggish in the diol as it is in water. The yield is not enhanced by pressure, suggesting again a predominant reverse reaction. As an example, 65 % of the / -aminoester synthe-... 

Recently, Lin et al. demonstrated that the propargyl alcohol could participate in such a transformation for the synthesis of chiral dihydrofurans [53]. The reaction began with a challenging oxa-Michael addition to cinnamaldehyde derivatives, which was followed by a secondary amine/Pd complex-catalyzed nucleophilic addition/ isomerization of the alkyne moiety in excellent yields and enantioseleclivities (Scheme 9.58). Since the oxa-Michael addition of propargyl alcohol to 0[,P-unsaturated aldehydes was a slow process, this cascade reaction proceeded through a dynamic kinetic asymmetric transformation (DYKAT) process, whereby it made the overall reaction proceed efficiently and with high stereocontrol using the second reaction with precise stereocontrol to shift the first reversible oxa-Michael addition selectively. 

In the above reaction one molecular proportion of sodium ethoxide is employed this is Michael s original method for conducting the reaction, which is reversible and particularly so under these conditions, and in certain circumstances may lead to apparently abnormal results. With smaller amounts of sodium alkoxide (1/5 mol or so the so-called catal3rtic method) or in the presence of secondary amines, the equilibrium is usually more on the side of the adduct, and good yields of adducts are frequently obtained. An example of the Michael addition of the latter type is to be found in the formation of ethyl propane-1 1 3 3 tetracarboxylate (II) from formaldehyde and ethyl malonate in the presence of diethylamine. Ethyl methylene-malonate (I) is formed intermediately by the simple Knoevenagel reaction and this Is followed by the Michael addition. Acid hydrolysis of (II) gives glutaric acid (III). 

Both C-S bonds are now P to carbonyl groups and so can be discomiected in turn by reverse Michael reactions. 

Michael condensations are catalyzed by alkaU alkoxides, tertiary amines, and quaternary bases and salts. Active methylene compounds and aUphatic nitro compounds add to form P-substituted propionates. These addition reactions are frequendy reversible at high temperatures. Exceptions are the tertiary nitro adducts which are converted to olefins at elevated temperatures (24). 

The reactions of pyrroles with dimethyl acetylenedicarboxylate (DMAD) have been extensively investigated. In the presence of a proton donor the Michael adducts (125) and (126) are formed. However, under aprotic conditions the reversible formation of the 1 1 Diels-Alder adduct (127) is an important reaction. In the case of the adduct from 1-methylpyrrole, reaction with a further molecule of DMAD can occur to give a dihydroindole (Scheme 48) (82H(19)1915). 

Hydroxyethyl Undergo reverse Michael reaction readily (lose H2O) /3-Hydroxy ketones... 

Various competitive reactions can reduce the yield of the desired Michael-addition product. An important side-reaction is the 1,2-addition of the enolate to the C=0 double bond (see aldol reaction, Knoevenagel reaction), especially with a ,/3-unsaturated aldehydes, the 1,2-addition product may be formed preferentially, rather than the 1,4-addition product. Generally the 1,2-addition is a kinetically favored and reversible process. At higher temperatures, the thermodynamically favored 1,4-addition products are obtained. 

This type of reaction usually gives good yields here the possible iV-alkylation is reversible—through a retro-Michael-type reaction ... 

The intramolecular Michael addition11 of a nucleophilic oxygen to an a,/ -unsaturated ester constitutes an attractive alternative strategy for the synthesis of the pyran nucleus, a strategy that could conceivably be applied to the brevetoxin problem (see Scheme 2). For example, treatment of hydroxy a,/ -unsaturated ester 9 with sodium hydride furnishes an alkoxide ion that induces ring formation by attacking the electrophilic //-carbon of the unsaturated ester moiety. This base-induced intramolecular Michael addition reaction is a reversible process, and it ultimately affords the thermodynamically most stable product 10 (92% yield). 

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