Michael adducts, reactions

If a Michael reaction uses an unsymmetrical ketone with two CH-groups of similar acidity, the enol or enolate is first prepared in pure form (p. llff.). To avoid equilibration one has to work at low temperatures. The reaction may then become slow, and it is advisable to further activate the carbon-carbon double bond. This may be achieved by the introduction of an extra electron-withdrawing silyl substituent at C-2 of an a -synthon. Treatment of the Michael adduct with base removes the silicon, and may lead as well to an aldol addition (G. Stork, 1973, 1974 B R.K. Boeckman, Jr., 1974). 

Glycosidic thiol groups can be introduced into glycosyl bromides by successive reactions with thiourea and aqueous sodium disulfite (D. Horton, 1963 M. Cemy, 1961, 1963). Such thiols are excellent nucleophiles in weakly basic media and add to electrophilic double bonds, e.g., of maleic esters, to give Michael adducts in high yields. Several chiral amphiphiles have thus been prepared without any need for chromatography (J.-H. Fuhrhop, 1986 A). 

The Michael addition reaction has attracted many researchers as a route to convert high melting BMI building blocks into resins with improved processibihty as compared with the BMI precursors. Heat-resistant resin compositions are prepared from BMI and para- or y /i7-aminophenol (38). The idealized stmcture of such a BMI—y -aminophenol adduct follows. 

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). 

Further investigations revealed that the disubstituted indolo[3,2-fl]carbazoles 117a-b may be conveniently obtained in moderate yields simply by heating 115 with dimethyl or diethyl acetylenedicarboxylate in xylene, while the use of lower-boiling solvents (benzene, toluene) led to the formation of the presumed intermediate Michael adducts 118a-b as the major products. The reaction of 115 with 2-chloroacrylonitrile furnished the indolo[3,2-fl]carbazole derivative 119 where aromatizaticRi did not take place (99T2371). 

Cacchi and Palmier (83T3373) investigated a new entry into the quinoline skeleton by palladium-catalyzed Michael-type reactions. They found that phenyl mercurial 134 was a useful intermediate for the synthesis of quinoline derivatives, and that by selecting the reaction conditions the oxidation level of the heterocyclic ring in the quinoline skeleton can be varied. On such example is shown in Scheme 16. PdCla-catalyzed coupling between organomercurial reagent 134 and enone 135 delivered adduct 136 which was subsequently cyclized to quinoline 137 under acidic conditions. 

Reaction of the mesoionic oxazolone 620 with acetylenedicarboxylic ester 621 gave the cycloadduct 622 in aprotic solvents and the Michael adducts... 

The formation of Zj -adducts—e.g. 8 by a consecutive Michael addition reaction, is observed in some cases. This reaction is formulated as a 1,4-addition of a second molecule of the CH-acidic starting material 2 to the initially formed a ,/3-unsaturated carbonyl compound 3 ... 

The Michael type reaction of f3/f -5-r-butyldimethysiloxy-3-phenyl-l//-pyrrolo[l,2-c oxa2ole with nitroethylene proceeds in the presence of Lev/is acid to give the alkylated product in good chemical yield and diastereoselecdvity In the case of nitroethylene, the Diels-Alder type transition state is favored to give the ryu-adduct selectively fEq 4 72 ... 

The reaction of conjugated nitroalkenes v/ith a,fi-unsaturated esters, ketones, nitnles, and sulfones is catalyzed by TMG to give the Michael adduct of allyiic nitro compounds fEq. 4.108. -... 

The net effect of the Stork reaction is the Michael addition of a ketone to an cn/3-unsaturated carbonyl compound. For example, cyclohexanone reacts with the. cyclic amine pyrrolidine to yield an enamine further reaction with an enone such as 3-buten-2-one yields a Michael adduct and aqueous hydrolysis completes the sequence to provide a 1,5-diketone (Figure 23.8). 

The reductive cleavage of the alkylcobalamine is facilitated by light irradiation and can then proceed at a much more positive potential. A demonstration photoelec-trochemical reactor for the Bij-catalyzed photoelectrochemical synthesis of Michael adduct 17, the alarm pheromone of the ant atta texana (Scheme 9) has been constructed where the complete device is driven solely by solar energy . Hopefully, mediated photoelectrochemical reactions of this type will also be realized at chemically modified electrodes. 

Surprisingly, the 7t-system geometry in a substrate has a notable influence in the enzymatic aminolysis of esters. The reaction of diethyl fumarate with different amines or ammonia in the presence of CALB led to the corresponding trans-amidoesters with good isolated yields, but in the absence of enzyme, a high percentage of the corresponding Michael adduct is obtained (Scheme 7.9). Enzymatic aminolysis of diethyl maleate led to the recovery of the same a, P-unsaturated amidoester, diethyl fumarate, and diethyl maleate. The explanation of these results can be rationalized via a previous Michael/retro-Michael type isomerization of diethyl maleate to fumarate, before the enzymatic reaction takes place. In conclusion, diethylmaleate is not an adequate substrate for this enzymatic aminolysis reaction [23]. 

However, when 2,6-dimethylbenzoquinone with sodium ( >3,5-hexadienoate (generated in situ) was reacted in water in the presence of a catalytic amount of sodium hydroxide, pentacyclic adducts were formed via deprotonation of the Diels-Alder adduct followed by tandem Michael-addition reactions with another molecule of 2,6-dimethylbenzoquinone (Eq. 12.25).83 Similar results were obtained with sodium ( >4,6-heptadienoate. 

Moreover, by using only TEMPO without addition of 2-714 the Michael adduct 2-713 is transformed into the isopropenylcyclopentane 2-715b as the major product. The process can also be extended by another radical reaction step [364]. 

Nitroalkenes react with lithium dianions of carboxylic acids or with hthium enolates at -100 °C, and subsequent treatment of the Michael adducts with aqueous acid gives y-keto acids or esters in a one-pot operation, respectively (Eq. 4.52).66 The sequence of Michael addition to nitroalkenes and Nef reaction (Section 6.1) provides a useful tool for organic synthesis. For example, the addition of carbanions derived from sulfones to nitroalkenes followed by the Nef reaction and elimination of the sulfonyl group gives a,P-unsaturated ketones (Eq. 4.53).67... 

The synthesis of 2,3,5-trialkylpyrroles can be easily achieved by conjugate addition of nitroalkanes to 2-alken-l,4-dione (prepared by oxidative cleavage of 2,5-dialkylfuran) with DBU in acetonitrile, followed by chemoselective hydrogenation (10% Pd/C as catalyst) of the C-C- double bond of the enones obtained by elimination of HN02 from the Michael adduct. The Paal-Knorr reaction (Chapter 10) gives 2,3,5-trialkylpyrroles (Eq. 4.124).171... 

The bispyrazolodihydropyran 435 was obtained directly as a rapidly formed insoluble by-product in the reaction of 3-methyl-l-phenylpyrazol-5-one 433 with activated nitriles 434 in the presence of catalytic piperidine (Equation 117) <2000MOL746, 2000JCCS937>. It is proposed that the reaction proceeds by loss of the active methylene moiety from the initial Michael adduct, allowing attack by a second molecule of pyrazol-5-one. 

The reaction of 5-[2-(iV,./V-dimethylamino)ethyl]-l,2,4-oxadiazole with methyl iodide forms the quaternary ammonium salt 170 (Scheme 22), which undergoes elimination in the presence of base (diisopropylethylamine (DIEA), TEA, l,8-diazabicyclo[4.3.0]undec-7-ene, etc.) to form an intermediate 5-vinyl-l,2,4-oxadiazole 171, which undergoes in situ Michael addition with nucleophiles to furnish the Michael adducts 172. As an example, also shown in Scheme 22, 3-hydroxy-pyrrolidine allows the synthesis of compound 172a in 97% yield. Mesylation followed by deprotonation of the 1,2,4-oxadiazole methylene at C-5 enables Sn2 displacement of the mesylate to give the 5-azabicycloheptyl derivative 173, which is a potent muscarinic agonist <1996JOC3228>. 

A new three-component approach to the highly substituted 2,5-dihydro-l,2,4-oxadiazoles 359 has been reported from the reaction of nitriles 354 under mild conditions with iV-alkylhydroxylamines 355 in the presence of electron-deficient alkynes 356 (Scheme 60) <20050L1391>. This synthesis is proposed to proceed via the initial formation of the alkyl or arylamidoximes 357, which then undergo a sequential double Michael addition to the electron deficient alkyne. The intermediate alkyl or arylamidoximes 357 can be isolated and then reacted with the alkyne to produce the product. The initial Michael adduct 358 is stable in cases where R2 is H. 

Bifunctional thiourea-catalysed enantioselective Michael reaction has been achieved. The thiourea moiety and an amino group of the catalyst activated a nitroolefin and a 1,3-dicarbonyl compound, respectively afford the Michael adduct with high enantioselectivity.177,178 Thioureas work as one of the most effective and general enantioselective nitro-Mannich reaction and carbonyl cyanation catalyst.179,180... 

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