The Michael reaction

Like the aldol and Claisen reactions, the Michael reaction involves tvro carbonyl components-the enolate of one carbonyl compound and an o,P-unsaturated carbonyl compound. 

Recall from Section 20.15 that a,P-unsaturated carbonyl compounds are resonance stabilized and have two electrophilic sites— the carbonyl carbon and the P carbon. 

All conjugate additions add the elements of H and Nu across the a and P carbons. In the Michael reaction, the nucleophile is an enolate. Enolates of active methylene compounds are particularly common. The a,p-unsaturated carbonyl component is often called a Michael acceptor. 

The Michael reaction always forms a new carbon-carbon bond on the P carbon of the Michael acceptor. Reaction [2] is used to illustrate the mechanism of the Michael reaction in Mechanism 24.6. The key step is nucleophilic addition of the enolate to the p carbon of the Michael acceptor in Step [2]. 

Base removes the acidic proton between the two carbonyl groups, forming the enolate In Step [1]. Only one of the three resonance structures is drawn. 

Problem 24.22 Which of the following compounds can serve as Michael acceptors  

Arthur Michael (1853-942) was born to a wealthy family in Buffalo, New York. Although he received no forma) university degrees, he studied in Heidelberg, Berlin, and the cole de Medecine, Paris, Returning to the United States, he became Professor of Chemistry at Tufts University (1882-1889, 1894-190 7), and then at Harvard University (1912-1936). Perhaps his most important contribution to science was his instrumental role in bringing the European model of graduate education to the United States. 

We saw in Section 19.14 that nucleophiles can react with a,/3-unsaturated aldehydes and ketones to give the conjugate addition product, rather than 

Exactly the same kind of conjugate addition can occur when a nucleophilic enolate ion reacts with an ,/3-unsaturated carbonyl compound—a process known as the Michael reaction. 

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

Mechanism of the Michael reaction between a 0-keto ester and an t,0-unsaturated ketone, 

Enones derived from carbonyl condensations can undergo further carbon-carbon bond-forming reactions on addition of carbon nucleophiles. When the nucleophile adds at the 4-position (rather than the 2-position) of the enone, this is known as the Michael reaction. 

Notice that in both 1,2- and 1,4-addition, a pair of electrons moves on to the oxygen atom of the enone 

The enone in a Michael reaction is sometimes called the Michael acceptor 

A large delocalised nucleophile, with the charge spread out, such as MeCOCH COMe, reacts by 1,4-addition, rather than 1,2-addition 

The addition of active methylene compounds (ethyl malonate, ethyl aceto-acetate, ethyl plienylacetate, nitromethane, acrylonitrile, etc.) to the ap-double bond of a conjugated unsaturated ketone, ester or nitrile in the presence of a basic cataljst (s ium ethoxide, piperidine, diethylamiue, 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 tricarballylic 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 catalytic 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 diethylamlne. Ethyl methylene-malonate (I) is formed intermefll-ately by the simple Knoevenagel reaction and this is followed by the Michael addition. Acid hydrolysis of (II) gives glutaric acid (III). 

It Is of Interest to note that the preparation of dimethyldihydroresorcinol (also named dimed one and methone Section VII, 15) involves an initial IVIichael addition to mesityl oxide, followed by an internal Claisen condensation. 

The mechanism of the Michael reaction probably follows the following course. Writing RCH=CHCOOC H5 for C2HjOOCCH=CHCOOC H5 and B for OCjHj or (CjHsljNH for the sake of simplicity, we have  

Tricarballylic acid. Place 228 g. (204 ml.) of ethyl propane-1 -.1 2 3-tetracarboxylate and 240 ml. of 1 1-hydrochloric acid in a 1-litre threenecked flask, fitted with a mechanical stirrer and a fractionating colunm with condenser set for downward distillation attach a receiver with side tube to the condenser and coimect the side tube to a wash bottle containing water. Boil the mixture, with continual stirring, at such a rate that the 

Problem 23.13 What product would you expect on treatment of diethyl 4-methylheptanedioate with sodium ethoxide, followed by acidification  

Problem 23.14 Dieckmann cyclization of diethyl 3-methylheptanedioate gives a mixture of two /3-keto ester products. What are their structures, and why is a mixture formed  

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The mechanism of cyanoethylatlon is similar to that given in Section VI,21 for the Michael reaction. Acrylonitrile is the simplest ap-uiisaturated organic nitrile. 

So far in this section we have combined enolate anions with other carbonyl compounds by direct attack at the carbonyl group. We can expand the scope of this reaction by using a,p-unsaturated carbonyl compounds as the electrophiles. This is the Michael reaction. Remind yourself of tliis by writing out the mechanism of a Michael reaction such as ... 

The Michael reaction plays a part in some more extended synthetic sequences of great importance. Analyse TM 116 as an a,p-unsaturated carbonyl compound and continue your analysis by the Michael reaction. 

Choosing the Michael disconnection at a rather than b since we can then use the CChEt control group both for the alkylation and for the Michael reaction. 

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. 

Synthesis An activating group is necessaiy to control the Michael reaction ... 

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

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. 

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). 

Especially with the ordinary aldol reaction a number of side reactions can be observed, as a result of the high reactivity of starting materials and products. For instance, the a ,/3-unsaturated carbonyl compounds 4 can undergo further aldol reactions by reacting as vinylogous components. In addition compounds 4 are potential substrates for the Michael reaction. 

The 1,4-addition of an enolate anion 1 to an o ,/3-unsaturated carbonyl compound 2, to yield a 1,5-dicarbonyl compound 3, is a powerful method for the formation of carbon-carbon bonds, and is called the Michael reaction or Michael addition The 1,4-addition to an o ,/3-unsaturated carbonyl substrate is also called a conjugate addition. Various other 1,4-additions are known, and sometimes referred to as Michael-like additions. 

The overall process is the addition of a CH-acidic compound to the carbon-carbon double bond of an o ,/3-unsaturated carbonyl compound. The Michael reaction is of particular importance in organic synthesis for the construction of the carbon skeleton. The above CH-acidic compounds usually do not add to ordinary carbon-carbon double bonds. Another and even more versatile method for carbon-carbon bond formation that employs enolates as reactive species is the aldol reaction. 

The Michael reaction is of great importance in organic synthesis. 

The Michael reaction with enamines is exemplified in this procedure. In a second (spontaneous) step of the reaction, an aldol-type condensation occurs resulting in cyclization. Finally, the morpholine enamine of the product forms and is hydrolized by the addition of water to yield a mixture of octalones, which is separated by fractional crystallization. J -Octalone-2 can be reduced by lithium in anhydrous ammonia to the saturated tra/i5-2-decalone (Chapter 3, Section III). 

An elegant example of sequence of reactions involving the Henry reaction, the Michael reaction, and elimination of HNO is demonstrated in a short synthesis of anthracyclmones. Nitromethane is used to introduce the ClO-gronp simultaneously v/irh the C9-hydroxy group fEq. 7,136. ... 

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 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. 

Ethyl 3-nitroacrylate is an extremely reactive receptor in the Michael reaction. It has found use in the synthesis of the a-methylene-butyrolactone moiety3 characteristic of many sesquiterpenes, as shown... 

The preparation of 5-ACETYL-l,2,3,4,5-PENTAMETHYLCYCLO-PENTADIENE is of value in the synthesis of pentamethyleyclo-pentadiene and many pentamethylcyclopentadienyl metal carbonyl derivatives that are more soluble in organic solvents than those derived from cyclopentadiene. Simple preparations of 5,6-DIHYDRO-2-PYRAN-2-0NE and 2-//-PYRAN-2-ONE make these hitherto rather inaccessible intermediates available for cycloaddition and other reactions. The already broad scope of the Michael reaction has been widened further by including an efficient preparation of ETHYL (E)-3-NITROACRYLATE. Workers in the field of heterocyclic chemistry will find a simplified method for the preparation of 2,3,4,5-TETRA-HYDROPYRIDINE of help. 

Posner and coworkers have published a series of papers in which they described a successful application of the Michael reaction between a variety of carbanionic reagents and chiral cycloalkenone sulphoxides 557 to the synthesis of chiral organic compounds (for reviews see References 257, 649, 650). In several cases products of very high optical purity can be obtained. Subsequent removal of the sulphinyl group, serving as a chiral adjuvant, leads to optically active 3-substituted cycloalkenones 558 (equation 356 Table 27). 

An illustrative example of the Michael reaction is that of the thiirene dioxide 19b with either hydroxylamine or hydrazine to give desoxybenzoin oxime (87) and desoxybenzoin azine (88), respectively, in good yields6 (see equation 29). The results were interpreted in terms of an initial nucleophilic addition to the a, j8-unsaturated sulfone system, followed by loss of sulfur dioxide and tautomerization. Interestingly, the treatment of the corresponding thiirene oxide (18a) with hydroxylamine also afforded 86 (as well as the dioxime of benzoin), albeit in a lower yield, but apparently via the same mechanistic pathway6. 

With any substrate, when Y is an ion of the type Z—CR2 (Z is as defined above R may be alkyl, aryl, hydrogen, or another Z), the reaction is called the Michael reaction (see 15-21). In this book, we will call all other reactions that follow this mechanism Michael-type additions. Systems of the type C=C—C=C—Z can give 1,2, 1,4, or 1,6 addition. Michael-type reactions are reversible, and compounds of the type YCH2CH2Z can often be decomposed to YH and CH2=CHZ by heating, either with or without alkali. 

In particular, a,P-unsaturated aldehydes seldom give 1,4 addition. The Michael reaction has traditionally been performed in protic solvents, with catalytic amounts of base, but more recently better yields with fewer side reactions have... 

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