Enolate ions Michael

There are two advantages to the enaroine-Michael reaction versus the enolate-ion-Michael that make enamines so useful in biological pathways. First, an enamine is neutral, easily prepared, and easily handled, while an enolate ion is charged, sometimes difficult to prepare, and must be handled with care. 

A Michael reaction takes place when a stable enolate ion (Michael donor) adds to the... 

Reagent 1 also undergoes asymmetric Michael additions with enolate ions. Michael additions with disubstituted lithium eno-lates proceed with almost complete tt-facial diastereoselectivity. Starting with these Michael additions, (—)-methyl jasmonate (eq 4) and (—)-estrone methyl ether (eq 5) can be obtained in high enantiomeric purities. 

CONJUGATE ADDITIONS OF ENOLATE IONS MICHAEL ADDITION AND ROBINSON ANNULATION... 

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... 

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 car banions used are enolate ions derived from p-diketones. These enolates are weak bases (Section 18.6) and react with a,p-unsaturated ketones by conjugate addition. 

Exactly the same kind of conjugate addition can occur when a nucleophilic enolate ion reacts with an ,j6-unsaturated carbonyl compound—a process known as the Michael reaction. 

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. 

Michael reactions take place by addition of a nucleophilic enolate ion donor to the /3 carbon of an a,(3-unsaturated carbonyl acceptor, according to the mechanism shown in Figure 23.7. 

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. 

In addition to enolate ions, other kinds of carbon nucleophiles also add to a jjS-iinsaturated acceptors in Michael-like reactions. Among the most important such nucleophiles, particularly in biological chemistry, are enamines, which are... 

Enamines behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork reaction, for example, an enamine adds to an aqQ-unsaturated carbonyl acceptor in a Michael-like process. The initial product is then hydrolyzed by aqueous acid (Section 19.8) to yield a 1,5-dicarbonyi compound. The overall reaction is thus a three-step sequence of (11 enamine formation from a ketone, (2) Michael addition to an a,j3-unsaturated carbonyl compound, and (3) enamine hydrolysis back to a ketone. 

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). 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

Michael reaction (Section 23.10) The conjugate addition reaction of an enolate ion to an unsalurated carbonyl compound. 

The Michael addition is an enolate ion addition to an a,(3 unsaturated Ccirbonyl. This reaction takes advantage of the increased acidity of a hydrogen atom that s a to two carbonyl groups. This enolate ion is very stable, so it s less reactive than normal enolates. The more-stable enolate leads to a greater control of the reaction so that only one or two products form instead of multiple products from a less stable (and therefore more reactive) enolate. An example of this type of reaction is in Figure 11-24 with the mechanism in Figure 11-25. 

The very stable enolate ion is a Michael donor, all of which react like the enolate in Figure 11-25. Some important Michael donors are shown in Figure 11-26. The a,p unsaturated carbonyl is a Michael acceptor. Figure 11-27 shows some important Michael acceptors, which behave like the a,p unsaturated carbonyl in Figure 11-25. 

Aldol reactions are often used to close five- and six-membered rings. Because of the favorable entropy (p. 211), such ring closures generally take place with ease, even where a ketone condenses with a ketone. An important example is the Robinson annulation reaction which has often been used in the synthesis of steroids and terpenes. In this reaction a cyclic ketone is converted to another cyclic ketone, with one additional six-membered ring containing a double bond. The substrate is treated with methyl vinyl ketone (or a simple derivative of methyl vinyl ketone) and a base.551 The enolate ion of the substrate adds to the methyl vinyl ketone in a Michael reaction (5-17) to give a diketone that undergoes or... 

The stability of an a-silyl carbanion is responsible for the unproved synthetic utility of the Stork annulation over other annulations195,196. These reactions involve the Michael addition of an enolate ion to an enone, and in the absence of a a-silyl substituent suffer drawbacks due to the reversibility of the Michael reaction. However, the addition of enolate ions to a-trimethylsilylvinyl ketones is not reversible, owing to a-silicon stabilization of the canonical form 152 shown in equation 122. 

The enolate ion of the jS-keto ester [see part (d)] undergoes Michael addition to the carbon-carbon double bond of acrolein. 

The expected intramolecular 1,3-dipolar cydoaddition product 171 was only a minor product (3%). The formation of major product 169 was explained through an intramolecular Michael reaction of the enolate ion. 

The conjugate addition of nucleophiles to a,/3-unsaturated carbonyl compounds at the /3-position was described in Section 18.10. Enolate and related carbanion nucleophiles also add in a conjugate manner to a./Tunsaturated carbonyl compounds in a process known as the Michael reaction or Michael addition. In many of the examples the enolate ion is one that is stabilized by two carbonyl (or similar) groups. The ,/3-unsatura(cd compound is called the Michael acceptor. 

The product, formed in 92% yield in this case, has a bond from the a-carbon of the original enolate ion to the /3-carbon of the Michael acceptor. 

A large number of reactions have been presented in this chapter. However, all of these reactions involve an enolate ion (or a related species) acting as a nucleophile (see Table 20.2). This nucleophile reacts with one of the electrophiles discussed in Chapters 8, 18, and 19 (see Table 20.3). The nucleophile can bond to the electrophilic carbon of an alkyl halide (or sulfonate ester) in an SN2 reaction, to the electrophilic carbonyl carbon of an aldehyde or ketone in an addition reaction (an aldol condensation), to the electrophilic carbonyl carbon of an ester in an addition reaction (an ester condensation) or to the electrophilic /3-carbon of an a,/3-unsaturated compound in a conjugate addition (Michael reaction). These possibilities are summarized in the following equations ... 

The following example shows lithium divinylcuprate serving as a Michael donor, adding to the double bond of an a,/3-unsaturatcd ketone. In this conjugate addition, the vinyl group adds to the (3 carbon atom to give an enolate ion. Protonation at the a carbon gives the product. 

Michael additions are useful in acetoacetic ester syntheses and malonic ester syntheses because the enolate ions of both of these esters are good Michael donors. As an example, let s consider the addition of the malonic ester enolate to methyl vinyl ketone (MVK). The crucial step is the nucleophilic attack by the enolate at the carbon. The resulting enolate is strongly basic, and it is quickly protonated. 

Moving to a,/3-unsaturated esters, hydroxide ion and alkoxide ion (hard nucleophiles) react with ethyl acrylate 4.77 by direct attack at the carbonyl group to give ester hydrolysis and exchange, respectively, whereas the /3-dicar-bonyl enolate ion 4.78 (a soft nucleophile) undergoes a Michael reaction. There is no certainty in this latter reaction that the attack of the enolate anion on the carbonyl group is not a more rapid (and reversible) process. 

Exactly the aame kind of oottjtmate addition can occur when a rtucleO philic enolate ion reacts with an or.. -uiisaturated cavbonyl compound—a process knovm as tho Michael reaction. 

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