Ethyl Michael addition

The Michael Addition Reaction consists in the addition of the sodio-derivative of ethyl acetoacetate, ethyl malonate or ethyl cyanoacetate to an olefine group... 

The addition of active methylene compounds (ethyl malonate, ethyl aoeto-acetate, ethyl plienylacetate, nltromethane, acrylonitrile, etc.) to the aP-double bond of a conjugated unsaturated ketone, ester or nitrile In the presence of a basic catalyst (sodium ethoxide, piperidine, diethylamiiie, etc.) is known as the Michael reaction or Michael addition. The reaction may be illustrated by the addition of ethyl malonate to ethyl fumarate in the presence of sodium ethoxide hydrolysis and decarboxylation of the addendum (ethyl propane-1 1 2 3-tetracarboxylate) yields trlcarballylic acid ... 

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). 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

Section 21 9 Michael addition of the enolate ions derived from ethyl acetoacetate and diethyl malonate provides an alternative method for preparing their a alkyl derivatives... 

Remarkably few examples of this type of ring construction are available. The cobalt carbonyl hydride catalyzed hydroformylation of A/,A/ -diallylcarbamates has provided 3-pyrrolidinones (Scheme 61a) (81JOC4433). The pyrrole synthesis shown in Scheme 61b depends on Michael addition of ethyl a-lithioisocyanoacetate to ethyl a-isocyanocrotonate (77LA1174). 

Imidazole, 2-ethyl-1 -(o-nitrophenyl)-cyclization, S, 431 Imidazole, 4-ethyl-2-phenyl-oxidation, S, 405 Imidazole, ethynyl-Michael addition, S, 437 Imidazole, 4-ethynyl-2-phenyl-synthesis, S, 494 Imidazole, 1-formyl-reactions, S, 452 Imidazole, 2-formyl-mass spectra, S, 360 Imidazole, 4-formyl-synthesis, S, 475-476 Imidazole, 2-formyl-1,5-dimethyl-mass spectra, S, 360 3-oxide... 

A thiol, usually under basic catalysis, can undergo Michael addition to an activated double bond, resulting in protection of the sulfhydryl group as a substituted 5-ethyl derivative. 

At least two pathways have been proposed for the Nenitzescu reaction. The mechanism outlined below is generally accepted." Illustrated here is the indolization of the 1,4-benzoquinone (4) with ethyl 3-aminocrotonate (5). The mechanism consists of four stages (I) Michael addition of the carbon terminal of the enamine 5 to quinone 4 (II) Oxidation of the resulting hydroquinone 10 to the quinone 11 either by the starting quinone 4 or the quinonimmonium intermediate 13, which is generated at a later stage (HI) Cyclization of the quinone adduct 11, if in the cw-configuration, to the carbinolamine 12 or quinonimmonium intermediate 13 (IV) Reduction of the intermediates 12 or 13 to the 5-hydroxyindole 6 by the initial hydroquinone adduct 7 (or 8, 9,10). 

The best yields of 5-hydroxyindoles are obtained when equimolar amounts of the quinone and enamine are used. An excess of enamine gives rise to non-indolic products derived from reaction of two enamine units and one quinone unit or the product which results from the initial Michael addition of the enamine to the quinone. Use of excess quinone has been reported less frequently, but limited studies indicate no advantage. When 2,5-dichloro-l,4-benzoquinone (32) was treated with a 50% excess of ethyl 3-... 

Boron trifluoride etherate, is also a good catalyst for this hydride transfer to chalcone. Unlike triphenylmethyl perchlorate, however, chalcone is able to enter Michael additions with the 1,5-diketone followed by eliminations leading to unexpected products, e.g., 3-benzyl-2,4,6-triphenylpyrylium from 2-carbethoxy-l,3,5-tri-phenylpentane-l,5-dione and chalcone the benzyl group originates from chalcone, the elimination product being ethyl benzoylacetate. ... 

II result of some side effects, their use is restricted to veteri-ii.iry practice. Michael addition of dimethylamine to ethyl cro-... 

The Michael addition of the copper-zinc reagent derived from ethyl 4-bromobntyrate to the plperonal-derived nitroalkene proceeds cleaniy to give the nitre ester, which is an intermediate for the synthesis of lycoricidine alkaloids fEq. 4.85. ... 

Another approach is the Michael addition to ethyl (3-nitroacrylate, as shown in Eq. 7.123, which has been used in the synthesis of a-methylenebutyrolactone, a moiety characteristic of many sesquiterpenes. ... 

Michael additions of III to reactive acceptors appear feasible. Derivatives were formed from acrylonitrile and ethyl acrylate. Although these were not fully characterized, they were observed by HPLC analysis. 

There are many possibilities and I shall simply analyse the published synthesis. Removal of the methyl group from (50) gives ketone (51) which can be made from enone (52) by Michael addition of an ethyl group. Unambiguous cross-condensation between enolisable (54) and reactive (53) gives (52). 

The combination of CsF with Si(OMe)4 58 is an efficient catalyst for Michael additions, e.g. of tetralone 130 to methacrylamide, followed hy cyclization of the addition product to the cyclic enamide 131 in 94% yield [67]. Likewise, addition of the lactone 132 to methyl cinnamate affords, after subsequent cyclization with tri-fluoroacetic acid, the lactam 133 in 58% yield [68] whereas < -valerolactam 134, with ethyl acrylate in the presence of Si(OEt)4 59/CsF, gives 135 in 98% yield [69]. Whereas 10mol% of CsF are often sufficient, equivalent amounts of Si(OEt)4 59 seem to be necessary for preparation of 135 [69] (Scheme 3.11). 

PAMAM dendrimers are synthesized in a multistep process. Starting from a multifunctional amine (for example ammonia, ethylenediamine, or tris(2-amino-ethyl)amine) repeated Michael addition of methylacrylate and reaction of the product with ethylenediamine leads to dendrimers of different generation numbers [1,9]. Two methylacrylate monomers are added to each bifunctional ethylenediamine generating a branch at each cycle. Unreacted ethylenediamine has to be completely removed at each step to prevent the initiation of additional dendrimers of lower generation number. Excess methylacrylate has also to be removed. Bridging between two branches of the same or of two different dendrimers by ethylenediamine can also be a problem, and has to be avoided by choosing appropriate reaction conditions. 

For the Michael addition of 2,4-pentanedione enolate to ethyl propiolate, improvements in conversion were determined. This example serves also to demonstrate that proper process conditions are mandatory to have success with micro-reactor processing. A conversion of only 56% was achieved when using electroosmotically driven flow with a two-fold injection, the first for forming the enolate and the second for its addition to the triple bond (batch synthesis 89%) [151]. Using instead a stopped-flow technique to enhance mixing, a conversion of 95% was determined. 

Figure 4.70 Flow configuration for the Michael addition using 2,4-pentanedione and ethyl propiolate in a two-mixing tee microreactor [8].

Ethyl ethylthiomethyl sulphoxide anion 325 has been found to give better yield of 1,4-adducts compared with its methyl analogue . This anion has been used by Schlessinger and coworkers as a key reagent in the synthesis of 1,4-dicarbonyl precursors of naturally occurring cyclopentenones, e.g. dihydrojasmone 379 (equation 219). Michael addition of the anion of optically active (-l-)-(S)-p-tolyl p-tolylthiomethyl sulphoxide 380 to the properly substituted cyclopentenone constitutes an important step in the asymmetric synthesis of optically active cyclopentenone 381, which is a precursor of 11-deoxy-ent-prostanoids (equation 220). The reaction proceeds with a high and y-asymmetric induction (92%), but with a poor a-stereoselection (52 48). 

The above is an example of the Guareschi reaction. It is applicable to most dialkyl ketones and to alicyclic ketones (e.., cj/clohexanone, cyclopentanone, etc.). The condensation product (I) is probably formed by a simple Knoe-venagel reaction of the ketone and ethyl cyanoacetate to yield ethyl a-cyano-pp dimethylacrylate (CH3)2C=C(CN)COOC2Hj, followed by a Michael addition of a second molecule of ethyl cyanoacetate finally, the carbethoxyl groups are converted to the cyclic imide structure by the action of ammonia. 

Et2Zn also participates in the reductive coupling as a formal hydride source. Results for the Ni-catalyzed, Et2Zn-promoted homoallylation of carbonyl compounds with isoprene are summarized in Table 7 [30]. Et2Zn is so reactive that for the reaction with reactive aromatic aldehydes it causes direct ethylation of aldehydes, and the yields of homoallylation are diminished (runs 1 and 2). Unsaturated aldehydes seem to be subject to the Michael addition of Et2Zn. Accordingly, for the reaction with cinnamaldehyde, none of the expected homoallylation product is produced instead, the 1,4-addition product of Et2Zn, 3-phenylpentanal is produced exclusively (run 3). 

The titanated bislactim ethers of cyclo(L-Val-Gly-) are added to nitroalkenes with high diastereo-selectivity (Eq. 4.60).SOa Michael addition of lactam bearing (S)-2-( 1-ethyl-1-methoxypropyl) pyrrolidine as auxiliary on the lactam nitrogen to nitroalkenes proceeds with high selectivity (de >96%, ee >96%).80b... 

A series of 2-(thiazol-5-yl)acetamides and acetates 35a/b has been prepared in one pot from the reactions of benzotriazolylthione derivatives 32 with A,A-dimethyl-4-A ,A -bis(trimethylsilyl)aminobut-2-yne amide 31a and ethyl 4-A,A-bis(trimethylsilyl)aminobut-2-ynoate 31b, respectively <06TL8661>. Presumably, the initial adducts 33a/b undergo intramolecular thia-Michael addition to give 34a/b, which isomerize to thiazoles 35a/b. 

Imidazole has been condensed via a 1,4 Michael addition with ethyl acrylate by use of basic clays (Li+ and Cs+ montmorillonites) under solvent-free conditions with microwave irradiation [77] (Eq. 24). 

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