Michael addition, acidic conditions

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). 

Torgov introduced an important variation of the Michael addition allylic alcohols are used as vinylogous a -synthons and 1,3-dioxo compounds as d -reagents (S.N. Ananchenko, 1962, 1963 H. Smith, 1964 C. Rufer) 1967). Mild reaction conditions have been successful in the addition of ],3-dioxo compounds to vinyl ketones. Potassium fluoride can act as weakly basic, non-nudeophilic catalyst in such Michael additions under essentially non-acidic and non-basic conditions (Y. Kitabara, 1964). 

Krohnke observed that phenacylpyridinium betaines could be compared to 3-diketones based on their structure and reactivity, in particular, their ability to undergo Michael additions. Since 3-dicarbonyls are important components in the Hantzsch pyridine synthesis, application of these 3-dicarbonyl surrogates in a synthetic route to pyridine was investigated. Krohnke found that glacial acetic acid and ammonium acetate were the ideal conditions to promote the desired Michael addition. For example, N-phenacylpyridinium bromide 50 cleanly participates in a Michael addition with benzalacetophenone 51 to afford 2,4,6-triphenylpyridine 52 in 90% yield. 

In certain cases, Michael reactions can take place under acidic conditions. Michael-type addition of radicals to conjugated carbonyl compounds is also known.Radical addition can be catalyzed by Yb(OTf)3, but radicals add under standard conditions as well, even intramolecularly. Electrochemical-initiated Michael additions are known, and aryl halides add in the presence of NiBr2. Michael reactions are sometimes applied to substrates of the type C=C—Z, where the co-products are conjugated systems of the type C=C—Indeed, because of the greater susceptibility of triple bonds to nucleophilic attack, it is even possible for nonactivated alkynes (e.g., acetylene), to be substrates in this... 

There is a possibiUty that (hydroxymethyl)phosphines might be catalyzing hydration of activated olefinic moieties in lignin. The Michael addition reaction shown in eq. (6a) is catalyzed by 5% THP in water at ambient conditions, with 70% conversion of the acrylonitrile no such reaction is seen with aciyhc acid or the methyl ester, but analogous hydromethoxylation of these compounds is seen in MeOH (42) (eq. (6b), R = H or Me). There is a report on similar catalytic use of tiialkylphosphines, which, like THP, are strong nucleophiles (43). 

The Michael addition products 28-a and 28-b can be reketalized under Lewis acidic conditions to form 29-a and 29-b which presumably further eliminate methanol to aromatize to form the target 30. 

Since mild activation conditions appear to be important, a number of solution activation conditions were tested. PAMAM dendrimers are comprised of amide bonds, so the favorable conditions for refro-Michael addition reactions, (low pH, high temperature and the presence of water) may be able to cleave these bonds. Table 1 shows a series of reaction tests using various acid/solvent combinations to activate the dendrimer amide bonds. Characterization of the solution-activated catalysts with Atomic Absorption spectroscopy, FTIR spectroscopy and FTIR spectroscopy of adsorbed CO indicated that the solution activation generally resulted in Pt loss. Appropriate choice of solvent and acid, particularly EtOH/HOAc, minimized the leaching. FTIR spectra of these samples indicate that a substantial portion of the dendrimer amide bonds was removed by solution activation (note the small y-axis value in Figure 4 relative... 

The high acidity of a-nitroketones makes it possible to perform the Henry reactions or Michael additions under extremely mild conditions. The reaction proceeds in the presence of catalytic amounts of Ph3P to give the C-C bond formation products under nearly neutral conditions. Thus, 1,5-dicarbonyl compounds78 and a-methylenecarbonyl compounds79 are prepared by the denitration of a-nitroketones, as shown in Eqs. 7.67 and 7.68, respectively. 

An acid-catalyzed double-Michael addition of water to the bridged bis-dioxine moiety in a larger macrocyclic framework has been described by the Kollenz group (Scheme 6.134) [269]. While conventional reaction conditions failed to provide any of the desired functionalized 2,4,6,8-tetraoxaadamantane product, microwave heating of the hydrophobic macrocyclic bisdioxine in a 1 1 mixture of 1,2-dichloroethane and acetic acid containing excess concentrated hydrochloric acid at 170 °C for 40 min provided a 35% isolated yield of the desired oxaadamantane compound. 

Allyl sulphones can be converted to dienes by alkylation and elimination of sulphinic acid under basic conditions (equation 64)105. Several vitamin A related polyenes have been synthesized following this two-step protocol (Table 10)106. The poor leaving-group ability of the arylsulphonyl group requires treatment with strong base for elimination. However, elimination of the allylsulphonyl group takes place readily under palladium catalysis (equation 65)107. Vinyl sulphones can be converted to dienes via Michael addition, alkylation with allyl halides and elimination of sulphinic acid sequence (equation 66)108. 

In contrast to these transformations, Michael additions of simple enolates to acceptor-substituted dienes often yield mixtures of 1,4- and 1,6-addition products27-30. For example, a 70 30 mixture of 1,4- and 1,6-adducts was isolated from the reaction of the lithium enolate of methyl propionate with methyl sorbate30. This problem can be solved by using the corresponding silyl ketene acetal in the presence of clay montmorillonite as acidic promoter under these conditions, almost exclusive formation of the 1,4-addition product (syn/anti mixture) was observed (equation ll)30. Highly regioselective 1,4-additions... 

The regioselectivity of Michael additions of thiolates to 2,4-dienones can be altered drastically by variation of the reaction conditions and addition of Lewis acids to the reaction mixture. Lawton and coworkers examined the reaction of 2-mercaptoethanol with l-(3-nitrophenyl)-2,4-pentadien-l-one and observed a high regioselectivity in favor of the 1,6-addition product at 45 °C (equation 42)123,124. Lowering of the reaction temperature caused an increase in the amount of 1,4-adduct, and at —40°C, a product ratio of 40 60 was found. These events suggest that kinetic control favors the 1,4-addition product whereas the 1,6-adduct is thermodynamically more stable. If, however, the reaction was carried out with a complex of the dienone and titanium tetrachloride, only the 1,4-adduct was isolated after hydrolytic workup123. Obviously, this product is trapped as a metal chelate which prevents formation of the 1,6-adduct by retro-Michael/Michael addition. In the absence of the chelating Lewis acid, the 1,4-addition product can indeed be converted... 

Michael addition of methylene imines with alkenes under solid Iiquid two-phase conditions provides a route to substituted a-amino acids [26, 27] (Scheme 6.22). When ethyl glycine is (V-protected with (S)-menthone, C-alkylation under soliddiquid... 

Allenic amino acid derivatives 50, which are of special interest as selective vitamin Bg decarboxylase inhibitors [35], are accessible through 1,6-cuprate addition to 2-amino-substituted enynes 49 (Eq. 4.22) [36]. Because of the low reactivity of these Michael acceptors, however, the reaction succeeds only with the most reactive cuprate the t-butyl cyano-Gilman reagent tBu2CuLi-LiCN. Nevertheless, the addition products are obtained with good chemical yields, and selective deprotection of either the ester or the amino functionality under acidic conditions provides the desired target molecules. 

Simple addition to carbonyl compounds occnrs nnder mild acidic conditions. Examples given illns-trate reaction with acetone, an aldol-like reaction, and conjngate addition to methyl vinyl ketone, a Michael-like reaction. The first-formed alcohol products in aldol-like reactions usually dehydrate to give a 3-alkylidene-3//-indolium cation. 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

The same group utilized thiourea 12 (10mol% loading) for the catalysis of the enantioselective Michael addition of thioacetic acid to various chalcones [214]. At room temperature and otherwise unchanged conditions, in comparison to the... 

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