Reactions Michael

The Michael reaction involves the attack of a stabilized enolate (or enol) nucleophile onto the beta carbon of an a,P-unsaturated carbonyl electrophile. The resulting enolate intermediate is protonated to give a 1,5-dicarbonyl product. If this pattern is present in a target molecule, it is an indication that the TM might be the product of a Michael reaction, and a Michael disconnection will be one option for retrosynthesis. 

Like the aldol and the Claisen, the Michael reaction also involves an enolate, so the mechanism begins with the deprotonation of an alpha carbon. In the Michael reaction, however, the electrophile is not an ordinary carbonyl, but an a,P-unsaturated carbonyl. Attack of the stable enolate nucleophile occurs at the beta carbon of the a,P-unsaturated carbonyl (called a 1,4-addition or conjugate addition or even Michael addition) to give an enolate intermediate. Protonation at the alpha carbon of the enolate gives the final product, a 1,5-dicarbonyl compound. 

Ordinary enolates are very reactive (strong nucleophiles and strong bases) and can give mixtures of 1,2- and 1,4-addition reactions with a,P-unsaturated carbonyl compounds. The Michael reaction requires a softer enolate, such as a stabilized enolate with two EWGs. Otherwise, an enamine can be used as the synthetic equivalent of an enolate (followed by hydrolysis to regenerate the carbonyl). 

The product of this reaction is a 1,5-dicarbonyl that contains a newly formed carbon-carbon bond between the alpha carbon of one of the carbonyls and the beta carbon of the other. This is the key bond to be identified in a 1,5-dicarbonyl TM a disconnection at this bond will lead to a Michael retrosynthesis. 

The Michael reaction is currently catalyzed by bases. Since strong bases sometimes cause side-reactions, the use of other catalysts such as transition-metal complexes [30], alumina [31, 32], lanthanides [33], phase-transfer cata- 

The Michael reaction is accelerated under high pressure and therefore should be facilitated by water as solvent in agreement with the observation that the aqueous medium promotes reactions between hydrophobic molecules having a negative activation volume. 

The Michael reaction of a,p-unsaturated ketones, such as methyl vinyl ketone and 3-penten-2-one, with P-dicarbonyl compounds has been investigated in aqueous solution in the presence of CTABr and other cationic surfactants [39]. The reaction yield depends on the temperature, concentration, nucleophile precursor, surfactant and structure of the substrate. 

An example of asymmetric Michael addition carried out in water is the reaction of aromatic thiols with 2-cyclohexanone and maleic acid esters via formation of their crystalline CD complexes [40]. The best chiral inductions (ee ca. 30%, yield 50-93%) were obtained by the combination of the crystalline p-CD complex of benzenethiol with 2-cyclohexenone and octyl maleate, respectively. The opposite combination gives very low ee. 

Lewis-acid-catalyzed carbon-carbon bond-forming reactions have been of great interest in organic synthesis because of their unique reactivities and selectivities, and for the mild conditions used [1]. While various kinds of Lewis-acid-promoted reactions have been developed and many have been applied in industry, these reactions must be carried out under strict anhydrous conditions. The presence of even a small amount of water stops the reaction, because most Lewis acids immediately react with water, rather than with the substrates, and decompose or deactivate. This fact has restricted the use of Lewis acids in organic synthesis. 

It is an addition reaction between an a,P-unsaturated carbonyl compound and a compound with an active methylene group (e.g., malonic ester, acetoacetic ester, cyanoacetic ester, nitroparaffms etc.) in presence of a base, e.g., sodium ethoxide or a secondary amine (usually piperidine). 

Use of methyl alcohol as a solvent (in place of H O) gave 1 1 mixture of A and B. The above reaction does not occur in neat conditions or in solvents like THF, PhMe etc. in the absence of a catalyst. 

Introduction Conjugate, 1,4- or Michael addition vs direct or 1,2-addition Sulfur and phosphorus ylids Where direct (1,2-) addition is necessary Using Copper (I) to Achieve Michael Addition 

Stereoselectivity in Michael additions of organo-copper(I) compounds Trapping the enolate intermediate by silylation Michael Addition followed by Reaction with Electrophiles Tandem Michael/aldol reactions A Double Nucleophile An Interlude without Copper 

A Michael Reaction Coupled to a Photochemical Cyclisation Copper Again Michael Additions of Heteroatom Nucleophiles 

Michael Additions with and without Copper Functionalised Michael Donors 

Introduction Conjugate, 1,4- or Michael addition vs direct or 1,2-addition 

Reproduced from Chen L, Betsegaw E, Lemma BE, Rich JS, Mack J. Freedom a copper-free, oxidant-free and solventfree palladium catalysed homocoupling reaction. Green Chem 2014 16 1101-3. 

With permission from the Royal Society of Chemistry. 

80 CHAPTER 2 Carbon-Carbon Bond-Forming Reactions 

Reproduced from Zhang Z, Dong Y-W, Wang G-W. Komatsu K. Highly efficient mechanochemi-cal reactions of 1,3-dicarbonyl compounds with chalcones and azachalcones catalyzed by potassium carbonate. Synlett 2004 61-4. With permission from Thieme Publishers. 

Entry Catalyst (equiv.) Vibration Frequency (rpm) Yield 

The significant synthetic advantage of this approach is the isolation of regio-and stereo-defined enol silyl ethers of optically active y-nitro aldehydes (Table 4.2). For example, after the reaction of 16a with trans-cinnamaldehyde, the resulting mixture can be directly purified by silica gel column chromatography to produce the optically active enol silyl ether 20a in 90% yield (Table 4.2, entry 1). High 

This unique Michael addition protocol has been successfully extended to cyclic a,/ -unsaturated ketones such as cyclohexenone, where (R,R)- 15a was suitable to 

The Lewis acid-catalyzed conjugate addition of silyl enol ethers to a,y3-unsaturated carbonyl derivatives, the Mukaiyaraa Michael reaction, is known to be a mild, versatile method for carbon-cabon bond formation. Although the development of catalytic asymmetric variants of this process provides access to optically active 1,5-dicarbonyl synthons, few such applications have yet been reported [108], Mukiyama demonstrated asymmetric catalysis with BINOL-Ti oxide prepared from (/-Pr0)2Ti=0 and BINOL and obtained a 1,4-adduct in high % ee (Sch. 43) [109]. The enantioselectiv-ity was highly dependent on the ester substituent of the silyl enol ether employed. Thus the reaction of cyclopentenone with the sterically hindered silyl enol ether derived from 5-diphenylmethyl ethanethioate proceeds highly enantioselectively. Sco-lastico also reported that reactions promoted by TADDOL-derived titanium complexes gave the syn product exclusively, although with only moderate enantioselectiv-ity (Sch. 44) [110]. 

The (hetero) Diels-Alder reaction also is one of the most efficient carbon-carbon bond-forming processes in the construction of six-membered rings, by virtue of the high regioselectivity and stereoselectivity obtained at up to four newly created chiral centers [111]. 

Narasaka has demonstrated that TADDOL-Ti dichloride prepared from TADDOL and Cl2Ti(OPr )2 in the presence of MS 4A acts as an efficient catalyst in asymmetric catalytic Diels-Alder reactions with oxazolidinone derivatives of acrylates, a results in extremely high enantioselectivity (Sch. 45) [112]. Narasaka reported an intramolecular version of the Diels-Alder reaction, the product of which can be transformed into key intermediates for the syntheses of dihydrocompactin and dihydromevinolin (Sch. 46) [113]. Seebach and Chapuis/Jurczak [114] independently reported asymmetric Diels-Alder reactions promoted by chiral TADDOL- and 3,3 -diphenyl BINOL-derived titanium alkoxides. Other types of chiral diol ligands were also explored by Hermann [115] and Oh [116]. 

Several researchers have reported synthetic approaches based on asymmetric Diels-Alder reactions catalyzed by TADDOL-Ti complexes [117-120]. Dendritic [121] and polymer-supported TADDOL-Ti complexes [122] have also been employed as recoverable and reusable catalysts to give comparatively high enantioselectivity. Transition-state models have been proposed independently by several groups for TADDOL-type titanium catalysis [121,123]. 

The TADDOL-derived titanium catalyst has also been used for inverse electron-demand Diels-Alder reactions [124-127], although Posner favored the use of a BINOL-derived titanium catalyst in his inverse electron-demand Diels-Alder reactions for the synthesis of la,25(OH)2D3 (Sch. 47) [125,126]. 

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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 ... 

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

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. 

Mccrwein-Pormdorf-Verley reduction Michael reaction Oppenauer oxidation... 

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 ... 

Both routes are acceptable and both get back to the same three starting materials. Route a uses a Michael reaction with a stable airion so this is preferable. 

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. 

This sequence of Michael reaction and cyclisation is known as tile Robinson annelation since it makes a ring. 

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. 

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. 

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

Synthesis We shall need the usual activating group for both Michael reactions it can t be a CO2R group as there isn t room, so it will have to be an enamine. The synthesis is therefore ... 

Analysis The electrophile is an enone since a reyerse Michael reaction cleaves the C-N bond ... 

Both C-S bonds are now P to carbonyl groups and so can be discomiected in turn by reverse Michael reactions. 

These are 1,5-dicarbonyls so we shah make them by Michael reactions e.g. 

We now have a 1,5-di O relationship which could be made by a Michael reaction if we have two carbonyl groups. 

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). 

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... 

Acrolein reacts slowly in water to form 3-hydroxypropionaldehyde and then other condensation products from aldol and Michael reactions. Water dissolved in acrolein does not present a hazard. The reaction of acrolein with water is exothermic and the reaction proceeds slowly in dilute aqueous solution. This will be hazardous in a two-phase adiabatic system in which acrolein is suppHed from the upper layer to replenish that consumed in the lower, aqueous, layer. The rate at which these reactions occur will depend on the nature of the impurities in the water, the volume of the water layer, and the rate... 

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. 

N-Unsubstituted pyrazoles and imidazoles add to unsaturated compounds in Michael reactions, for example acetylenecarboxylic esters and acrylonitrile readily form the expected addition products. Styrene oxide gives rise, for example, to 1-styrylimidazoles (76JCS(P1)545). Benzimidazole reacts with formaldehyde and secondary amines in the Mannich reaction to give 1-aminomethyl products. 

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

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

Selenophene, 2,5-dimethyl-3-mercapto-synthesis, 4, 956 tautomerism, 4, 946 Selenophene, 2,4-diphenyl-synthesis, 4, 135 Selenophene, 2,5-diphenyl-lithiation, 4, 949 UV spectra, 4, 941 Selenophene, 2-ethoxycarbonyl-mercuration, 4, 946 Selenophene, halo-reactions, 4, 955 Selenophene, 2-hydroxy-Michael reaction, 4, 953 tautomerism, 4, 36, 945, 953 Selenophene, 3-hydroxy-tautomerism, 4, 36, 945 Selenophene, 3-hydroxy-2,5-dimethyl-tautomerism, 4, 945, 953 Selenophene, 2-hydroxy-5-methyl-methylation, 4, 953 tautomerism, 4, 945 Selenophene, 2-hydroxy-5-methylthio-tautomerism, 4, 945 Selenophene, 3-iodo-synthesis, 4, 955 Selenophene, 3-lithio-reactions, 4, 79 synthesis, 4, 955 Selenophene, 2-mercapto-tautomerism, 4, 38 Selenophene, 3-mercapto-tautomerism, 4, 38 Selenophene, 2-mercapto-5-methyl-synthesis, 4, 956 tautomerism, 4, 946 Selenophene, 3-methoxy-lithiation, 4, 949, 955 synthesis, 4, 955 Selenophene, methyl-oxidation, 4, 951 synthesis, 4, 963 Selenophene, 2-methyl-lithiation, 4, 949 Selenophene, 3-methyl-synthesis, 4, 963... 

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