Michael reaction ketones

Keywords 1,3-dicarbonyl compound, a,/ -unsaturated ketone, Michael reaction, FeCl3H20, 1,5-dicarbonyl compound... 

Isomerization of C5-ketones Michael reaction with C5 ketones... 

Isomerization of Ci7 ketones Ci7a -ketones Michael reaction with Cii -ketones Ci4 ketones Ci7a-ketones Alkylation of... 

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 ... 

There is one special case worth discussing in some detail. When yinyl ketones (e.g. TM 122) are needed for Michael reactions they may obyiously be made by the usual disconnection ... 

Alkylation of the product (a Matinich Base A) gives a compound (B) which gives the required vinyl ketone on elimination in base. This last step is usually carried out in the basic medium of the Michael reaction itself so that the reactive vinyl ketone (TM 122) need never be isolated. 

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). 

Addition of Carbanions to a B Unsaturated Ketones The Michael Reaction... 

ADDITION OF CARBANIONS TO a, p-UN SATURATED KETONES THE MICHAEL REACTION... 

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... 

Ba.se Catalyzed. Depending on the nature of the hydrocarbon groups attached to the carbonyl, ketones can either undergo self-condensation, or condense with other activated reagents, in the presence of base. Name reactions which describe these conditions include the aldol reaction, the Darzens-Claisen condensation, the Claisen-Schmidt condensation, and the Michael reaction. 

Michael reactions Vinyl ) EthynylJ Undergo Michael additions readily q ,/3- Unsaturated ketones... 

Hydroxyethyl Undergo reverse Michael reaction readily (lose H2O) /3-Hydroxy ketones... 

The ratio of the two diastereomeric products 190 and 191 was found to depend on the reaction temperature and reaction time. The addition of acrolein or methyl vinyl ketone proceeded smoothly, but in the case of methylacrylate or acrylonitrile the reaction did not proceed under the same conditions (EtsN THF 30°C). An accompanying AMI calculation of these Q ,/3-unsaturated compounds [LUMOs for acrolein, -0.13877 for methyl vinyl ketone, -0.06805 (s-trans) for methyl acrylate, -0.01413 (s-tmns) for acrylonitrile, 0.04971] suggested the low reactivity of methyl acrylate and acrylonitrile toward the Michael reaction (99H1321). 

Besides a polymerization of the Michael acceptor, a double alkylation of the starting ketone, by reaction with a second Michael acceptor molecule, may take place as a side reaction, and thus further reduce the yield. The polymerization of the enone 2 as well as the double alkylation of the starting ketone can be avoided by application of a modern procedure for the Robinson annulation that uses an organotin triflate as catalyst." ... 

The second synthesis follows an entirely different synthetic plan—one dependent upon a double-Michael reaction to establish the spiran junction. Chlorophenol, 7, is reacted with chloro-acetylchloride to give coumaranone, 16. This is treated with methoxyethynyl propenyl ketone (17) (itself prepared by 1,2-... 

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. 

The Michael reaction occurs with a variety of a,/3-unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thio-esters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor component in Michael reactions (Table 23.1). Similarly, a variety of different donors can be used, including /3-diketones, /3-keto esters, malonic esters, /3-keto nitriles, and nitro compounds. 

Active Figure 23.7 MECHANISM Meehan ism of the Michael reaction between a jS-keto ester and an a,/3-unsaturated ketone. Sign in at www. thomsonedu.com to see a simulation based on this figure and to take a short quiz. 

The nucleophile adds to the e,/3-unsaturated ketone electrophile in a Michael reaction to generate a new enolate as product. 

Figure 23.8 The Stork reaction between cyclohexanone and 3-buten-2-one. Cyclohexanone is first converted into an enamine, the enamine adds to the a -unsaturated ketone in a Michael reaction, and the conjugate addition product is hydrolyzed to yield a 1,5-diketone.

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

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. 

The conjugate addition of a carbon nucleophile to an a./3-unsiituratcd acceptor is known as the Michael reaction. The best Michael reactions take place between unusually acidic donors (/3-keto esters or /3-diketones) and unhindered n,/3-unsaturated acceptors. Knamines, prepared by reaction of a ketone with a disu Instituted amine, are also good Michael donors. 

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. ... 

---