Carbonyl compounds Michael additions

Keywords 1,3-dicarbonyl compound, a,/ -unsaturated carbonyl compound, Michael addition, EUCI3, microwave irradiation... 

The RuH2(PPh3)4-catalyzed addition of active methylene compounds can also be applied to conjugate additions to a,/3-unsaturated carbonyl compounds (Michael additions). In 1989, Murahashi reported the first example of the transition metal-catalyzed Michael addition of active methylene compounds [74]. One of the notable advances of this catalytic reaction is that the addition of C-H bonds to a,/3-unsaturat-ed carbonyl compounds give Michael adducts without contamination by the corresponding aldol products (Eq. 9.56) [74]. Recently, Murahashi applied their aldol and Michael addition reactions to a solid-phase synthesis using polymer-supported nitriles (Scheme 9.12) [76]. In this case, four component reactions took place with high diastereoselectivity. 

Addition to a,]8-unsaturated carbonyl compounds. Michael addition. Discussed in Sec. 27.7. 

We have discussed palladium chemistry in chapter 8 where there was a brief description of palladium o-complexes. In this chapter we shall see the results of adding palladium o-complexes to unsaturated carbonyl compounds. Michael addition occurs but the palladium leaves the intermediate in such a way that the original alkene is restored.19 We shall take a simple example first -the addition of iodobenzene to methyl acrylate. 

The batch procedure for the addition of secondary amines to a, 3-unsaturated carbonyl compounds (Michael addition Scheme 6.8), such as acrylic acids, acrylic acid esters or acrylonitrile, gives good yields, in some cases even exceeding 85%... 

Section 23-3 reinforces the fact that anions of (i-dicarbonyl compounds are still enolates. Thus, you will find that they do 1,4-additions to a, (3-unsaturated carbonyl compounds (Michael additions). Furthermore, these additions can be followed by Robinson annulations. thereby resulting in six-membered rings. 

FIGURE 19.84 The two possible reactions of a nucleophile (Nu ) with an a,P-unsaturated carbonyl compound. Michael addition preserves the carbonyl group and is usually favored thermodynamically. 

NUCLEOPHILIC ADDITION TO CONJUGATED CARBONYL COMPOUNDS MICHAEL 3,4-ADDITION... 

Y. Yamamoto, S. G. Pyne, D. Schinzer, B. L. Feringa, J. F. G. A. Jansen, Formation of C-C Bonds by Reactions Involving Olefinic Double Bonds - Addition to a,/3-Unsaturated Carbonyl Compounds (Michael-Type Additions), in Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952, Stereoselective Synthesis (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds.), Vol. E21b, 2041, Georg Thieme Verlag, Stuttgart, 1995. 

Claisen condensations usually give 1,3-dicarbonyl products, with one I saturated carbon between two carbonyl groups. Michael additions commonly give 1,5-dicarbonyl products, with three saturated I carbons between two carbonyl I groups. When you need a compound with three carbons between two carbonyl groups,... 

CCS can be introduced into injectable materials by separately modifying soluble polymer chains with a pair of molecules that have specific affinity to each other. When these modified polymeric chains are injected simultaneously to the cross-linking site, they undergo rapid cross-linking to give rise to a covalent cross-linked network. The most commonly used pairs of molecules with specific affinities towards each other are iV-hydr-oxysuccinimide (-NHS) to amine (-NH2), 1,4-addition of a doubly stabilized carbon nucleophile to an a,p-unsaturated carbonyl compound (Michael-type addition reaction), and alkyne to azide (click chemistry). In these types of reactions, the rate, stability, and kinetics of network formation are solely dependent upon the strength of the affinity of one molecule to its counterpart. 

Hydrolysis of the ester functional groups of this Michael product followed by decarboxylation yields a 5-keto acid. In general, the Michael addition of 1,3-dicarbonyl donors to typical a,P-unsaturated carbonyl compounds (Michael acceptors) yields 1,5-dicarbonyl compounds. 

The anions, generated in situ by desilylation of silylacetylenes, allylsilanes, propargylsilanes, a-silyloxetanones, bis(trimethylsilylmethyl) sulfides, and other silane derivatives,can undergo nucleophilic addition to ketones and aldehydes (eq 11). Al-(C,C-bis(trimethylsilyl)methyl) amido derivatives can add to aldehydes followed by Peterson alkenation to form acyl enamines. Treatment of 2-trimethylsilyl-l,3-dithianes can generate dithianyl anions, which are capable of carbocyclization via direct addition to carbonyl or Michael addition (eq 12). The fluoride-catalyzed Michael additions are more general than Lewis acid-catalyzed reactions and proceed well even for those compounds with enolizable protons and/or severe steric hindrance (eq 13). ... 

The target compound is searched for a rctron. A retron is the structural subunit required to be present in the target in order to apply a transform. In Figure 10,3-30 the rctron of a Michael addition is a sequence of five carbon atoms with two carbonyl functions in the 1,5-position. For a Michael addition transform to be applied, it has to be present,... 

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). 

The synthesis of spiro compounds from ketones and methoxyethynyl propenyl ketone exemplifies some regioselectivities of the Michael addition. The electrophilic triple bond is attacked first, next comes the 1-propenyl group. The conjugated keto group is usually least reactive. The ethynyl starting material has been obtained from the addition of the methoxyethynyl anion to the carbonyl group of crotonaldehyde (G. Stork, 1962 B, 1964A). 

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... 

Methyl group (Section 2 7) The group —CH3 Mevalonic acid (Section 26 10) An intermediate in the biosyn thesis of steroids from acetyl coenzyme A Micelle (Section 19 5) A sphencal aggregate of species such as carboxylate salts of fatty acids that contain a lipophilic end and a hydrophilic end Micelles containing 50-100 car boxylate salts of fatty acids are soaps Michael addition (Sections 18 13 and 21 9) The conjugate ad dition of a carbanion (usually an enolate) to an a 3 unsatu rated carbonyl compound... 

Methacryhc acid and its ester derivatives are Ctfjy -unsaturated carbonyl compounds and exhibit the reactivity typical of this class of compounds, ie, Michael and Michael-type conjugate addition reactions and a variety of cycloaddition and related reactions. Although less reactive than the corresponding acrylates as the result of the electron-donating effect and the steric hindrance of the a-methyl group, methacrylates readily undergo a wide variety of reactions and are valuable intermediates in many synthetic procedures. 

These reversible reactions are cataly2ed by bases or acids, such as 2iac chloride and aluminum isopropoxide, or by anion-exchange resias. Ultrasonic vibrations improve the reaction rate and yield. Reaction of aromatic aldehydes or ketones with nitroparaffins yields either the nitro alcohol or the nitro olefin, depending on the catalyst. Conjugated unsaturated aldehydes or ketones and nitroparaffins (Michael addition) yield nitro-substituted carbonyl compounds rather than nitro alcohols. Condensation with keto esters gives the substituted nitro alcohols (37) keto aldehydes react preferentially at the aldehyde function. 

The mechanism of both syntheses has been studied in detail, and well summarized (44,45). Interesting questions remain for example, in neither of these sequences is it certain whether the carbonyl compound or its Schiff base is undergoing Michael addition. 

The Michael-type addition of maleic hydrazide and other pyridazinones to activated alkenes, such as methyl acrylate, acrylonitrile, methyl vinyl ketone and other a,/3-unsatu-rated carbonyl compounds, results in the formation of mono-lV-substituted products. 

Michael addition (Sections 18.13 and 21.9) The conjugate addition of a carbanion (usually an enolate) to an a,(3-unsatu-rated carbonyl compound. 

When the enamine is in conjugation with a carbonyl function, as in a-aminomethylene aldehydes (528,529), ketones (530), or esters (531), a Michael addition is found in vinylogous analogy to the reactions of amides. An application to syntheses in the vitamin A series employed a vinyl lithium compound (532). 

Michael addition reaction of 1-hydroxytryptamines to Q ,/3-unsaturated carbonyl compounds is worthy of note (99H2815). Addition of Ab-acetyl- 1-hydroxy-tryptamine (39) to methyl acrylate and methyl crotonate in the presence of... 

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