Enols from Michael reactions

Several points arise from consideration of this mechanism (i) unlike alkylation of stabilized enolates, the Michael reaction regenerates a basic species and thus usually catalytic quantities of base can be utilized 7 7 12 (ii) the high acidity of the doubly activated methylene permits the use of weaker bases, e.g. simple amines (piperidine, triethylamine etc.) or hydroxides (Triton B, i.e. benzyltrimethylammoni-um hydroxide) (iii) it was recognized early that, when a full equivalent of base was used, the final more... 

There are two advantages to the enamine-Michael reaction versns the enolate-ion-Michael reaction that make enamines so useful in biological pathways. First, an enamine is neutral, easily prepared, and easily handled, while an enolate ion is charged, is sometimes difficult to prepare, and must be handled with care. Second, an enamine from a monoketone can be used in the Michael addition, whereas enolate ions from only jS-dicarbonyl compounds can be used. 

In a sequence that is the equivalent of an oxocarbenium-induced C-C bondforming reactirai, McQuade and coworkers have used organic catalysts to carry out the coupling of 2-hydroxy tetrahydrofuran 48 with methyl ketones 49 to give 2-alkyl furans (Scheme 15) [13]. Mechanistically the reaction is proposed to proceed through the addition of a thiourea-stabiUzed enolate from the reaction of 49 with 51 to an iminium intermediate that comes from the condensation of 48 with proline catalyst 50. Hydrolysis and Michael cyclization or displacement of the ammonium ion subsequent to the Mannich reaction gives the observed product 52. 

A synthetically useful reaction known as the Michael reaction, or Michael addition, involves nucleophilic addition of carbanions to a p unsaturated ketones The most common types of carbanions used are enolate 10ns derived from p diketones These enolates are weak bases (Section 18 6) and react with a p unsaturated ketones by conjugate addition... 

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... 

The best Michael reactions are those that take place when a particularly stable enolate ion such as that derived from a /i-keto ester or other 1,3-dicarbonyl compound adds to an unhindered a,/3-unsaturated ketone. Tor example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide to yield the conjugate addition product. 

A Michael reaction involves the conjugate addition of a stable enolate ion donor to an o,/3-unsaturated carbonyl acceptor, yielding a 1,5-dicarbonyl product. Usually, the stable enolate ion is derived from a /3-diketone, jS-keto ester, malonic ester, or similar compound. The C—C bond made in the conjugate addition step is the one between the a carbon of the acidic donor and the (3 carbon of the unsaturated acceptor. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

Thus the product in such cases can exist as two pairs of enantiomers. In a di-astereoselective process, one of the two pairs is formed exclusively or predominantly as a racemic mixture. Many such examples have been reported. In many of these cases, both the enolate and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters, (E) enolates gave the syn pair of enantiomers (p. 146), while (Z) enolates gave the anti pair. Addition of chiral additives to the reaction, such as proline derivatives, or (—)-sparteine lead to product formation with good-to-excellent asynunetric induction. Ultrasound has also been used to promote asymmetric Michael reactions. Intramolecular versions of Michael addition are well known. ... 

Route (b) offers a short cut since the reaction between (5) and PhCHO under dehydrating conditions needs no control as (3) is the only possible enone from a ketone enolate attacking the more reactive aldehyde (p T 167). The Michael reaction is also better by this route as explained on p T 171, This is the published synthesis. 

Scheldt and co-workers have also accessed enolate equivalents from enals to furnish cyclopentanes 236 asymmetrically. Formation of the enolate equivalent from enals 235 with the NHC, followed by an intramolecular Michael reaction and 0-acylation, gives the lactone products 236, which are readily opened by either alcohols or amines to generate functionalised cyclopentane derivatives 237 in excellent ee. 

The mechanistic considerations of a catalytic asymmetric Michael reaction suggest that the reaction of a alkali metal enolate derived from a malon-ate derivative with an enone should lead to an intermediary aluminum enolate. Is it possible that such an A1 enolate could then be trapped by an... 

Mukaiyama Michael reactions of alkylidene malonates and enolsilanes have also been examined (244). The stoichiometric reaction between enolsilane (342a) and alkylidene malonate (383) proceeds in high selectivity however, catalyst turnover is not observed under these conditions. The addition of HFIP effectively promotes catalyst turnover, presumably by protonation and silyl transfer from the putative copper malonyl enolate generated in this reaction. The reaction proved general for bulky P-substituents (aryl, branched alkyl), Eq. 209. 

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... 

These are reacted together in basic solution. It can be deduced that the 1,3-diketone is more acidic than the monoketone substrate, so will be ionized by removal of a proton from the carbon between the two carbonyls to give the enolate anion as a nucleophile. This attacks the a,P-unsaturated ketone in a Michael reaction. It is understandable that this large nucleophile prefers to attack the unhindered -position rather than the more congested ketone carbonyl. 

The asymmetric allylic C-H activation of cyclic and acyclic silyl enol ethers furnishes 1,5-dicarbonyl compounds and represents a surrogate of the Michael reaction [136]. When sufficient size discrimination is possible the C-H insertion is highly diastereoselective, as in the case of acyclic silyl enol ether 193 (Eq. 22). Reaction of aryldia-zoacetate 192 with 193 catalyzed by Rh2(S-DOSP)4 gives the C-H insertion product 194 (>90% de) in 84% enantiomeric excess. A second example is the reaction of the silyl enol ether 195 with 192 to form 196, a product that could not be formed from the usual Michael addition because the necessary enone would be in its tautomeric naphthol form (Eq. 23). 

The radicals generated from esters of halogenodifluoroacetic acid or halogenodi-fluorophosphonic acid add onto olefins and enolates. When these reactions are intramolecular, they afford tetrahydrofurans. In the presence of copper dust, ethyl bromodifluoroacetate can couple with aromatic and vinyl halides or can add onto Michael acceptors (Figure 2.13). ... 

Michael adducts can also be obtained with this catalyst from the reaction of a,fi-unsuturaied ketones with silyl enol ethers. 

Michael reaction. In the presence of (C6H5)3CC104, silyl enol ethers undergo Michael addition to a,p-enones. The adducts can be isolated or rearranged to 1,5-diketones by base. The intermediates cannot be isolated from reactions catalyzed by TiCl4 or CsF. 

The Michael reaction is the conjugate addition of a soft enolate, commonly derived from a P-dicarbonyl compound 24, to an acceptor-activated alkene such as enone 41a, resulting in a 1,5-dioxo constituted product 42 (Scheme 8.14) [52]. Traditionally, these reactions are catalyzed by Bronsted bases such as tertiary amines and alkali metal alkoxides and hydroxides. However, the strongly basic conditions are often a limiting factor since they can cause undesirable side- and subsequent reactions, such as aldol cyclizations and retro-Claisen-type decompositions. To address this issue, acid- [53] and metal-catalyzed [54] Michael reactions have been developed in order to carry out the reactions under milder conditions. 

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

The ruthenium complex Cp Ru(bipyridyl)Cl has been developed as a catalyst for the first regioselective tandem Michael addition-allylic alkylation of activated Michael acceptors. The net outcome is the decarboxylative insertion of Michael acceptors into allyl /3-keto esters to produce (215). The reaction combines the generation of Ru-tt-allyl and enolate from (213) the enolate is first added to the Michael acceptor (214) and the resulting species is captured by the Ru-tt-allyl.254... 

Michael reactions of this sort work best when they follow a catalytic cycle. Malonate anion 28 adds to an enone to give the enolate anion 30 that collects a proton from malonate 27 and forms another molecule of the anion 28 for the next cycle. 

The general reaction mechanism of the Michael reaction is given below (Scheme 4). First, deprotonation of the Michael donor occurs to form a reactive nucleophile (A, C). This adds enantioselectively to the electron-deficient olefin under the action of the chiral catalyst. In the final step, proton transfer to the developed enolate (B, D) occurs from either a Michael donor or the conjugate acid of a catalyst or a base, affording the desired Michael adduct. It is noteworthy that the large difference of stability between the two enolate anions (A/B, C/D) is the driving force for the completion of the catalytic cycle. 

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