A Michael addition

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,... 

Figure 10.3-30. The retrosynthetic point of view the transform of a Michael addition. The structure fragment with a gray background is the retron of the Michael addition transforin.

A similar approach is followed in a recent study of the Lewis-acid catalysis of a Michael addition in acetonitrile. See Fukuzumi, S. Okamoto, T. Yasui, K Suenobu, T. Itoh, S. Otera, J. Chem. Lett. 1997, 667. 

Robinson annotation (Section 18 13) The combination of a Michael addition and an intramolecular aldol condensation used as a synthetic method for nng formation... 

In the absence of a base, the ayiridine ring can be quaterni2ed and opened by the nucleophile. A pyrroli2idine synthesis, in which such a reaction proceeds intramoleculady followed by a Michael addition (159), is shown as follows ... 

With acrylonitrile, mono- and dialkanolamines undergo a Michael addition to give the P-aminonitrile. 

Vinylpyridine (23) came into prominence around 1950 as a component of latex. Butadiene and styrene monomers were used with (23) to make a terpolymer that bonded fabric cords to the mbber matrix of automobile tires (25). More recendy, the abiUty of (23) to act as a Michael acceptor has been exploited in a synthesis of 4-dimethylaminopyridine (DMAP) (24) (26). The sequence consists of a Michael addition of (23) to 4-cyanopyridine (15), replacement of the 4-cyano substituent by dimethylamine (taking advantage of the activation of the cyano group by quatemization of the pyridine ring), and base-cataly2ed dequatemization (retro Michael addition). 4-r)imethyl aminopyri dine is one of the most effective acylation catalysts known (27). 

Another approach to processible bismaleimide resins via a Michael addition chain extension, is the reaction of bismaleimide, or alow melting mixture of bismaleimides, with aminobenzoic hydrazide to provide a resin that is soluble in various solvents, such as acetone [67-64-1methylene chloride [75-09-2] and dimethylform amide [68-12-2] (33). The idealized chemical stmcture for a 2 1 BMI—aminobenzoic hydrazide resin is as follows ... 

Cyanoethylation. One of the eadiest examples of etherification of ceUulose by an unsaturated compound through vinyl addition is the cyanoethylation of cotton (58). This base-cataly2ed reaction with acrylonitrile [107-13-1/, a Michael addition, proceeds as foUows ... 

Hydrogen cyanide adds to an olefinic double bond most readily when an adjacent activating group is present in the molecule, eg, carbonyl or cyano groups. In these cases, a Michael addition proceeds readily under basic catalysis, as with acrylonitrile (qv) to yield succinonitnle [110-61-2], C4H4N2, iu high yield (13). Formation of acrylonitrile by addition across the acetylenic bond can be accompHshed under catalytic conditions (see Acetylene-DERIVED chemicals). 

The trifluorinated a, J-ethylenic ketone shown in equation 36 was prepared by two different methods and behaves like a Michael addition acceptor in reactions... 

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). 

The Bsmoc derivative is formed from the chloroformate or the A -hydroxy-succinimide ester. It is cleaved rapidly by a Michael addition with tris(2-aminoethyl)amine at a rate that leaves Fmoc derivatives intact. More hindered bases, such as A -methylcyclohexylamine or diisopropylamine, do not react with the Bsmoc group, but do cleave the Fmoc group, illustrating the importance of steric effects in additions to Michael acceptors. 

Krohnke observed that phenacylpyridinium betaines could be compared to 3-diketones based on their structure and reactivity, in particular, their ability to undergo Michael additions. Since 3-dicarbonyls are important components in the Hantzsch pyridine synthesis, application of these 3-dicarbonyl surrogates in a synthetic route to pyridine was investigated. Krohnke found that glacial acetic acid and ammonium acetate were the ideal conditions to promote the desired Michael addition. For example, N-phenacylpyridinium bromide 50 cleanly participates in a Michael addition with benzalacetophenone 51 to afford 2,4,6-triphenylpyridine 52 in 90% yield. 

While this reaction to pyridine 56 occurs in a single pot, it is proposed to proceed via the 1,5-diketo derivative 55 obtained by a Michael addition of the pyridinium species 53 to enone 54. Although one does not typically isolate this intermediate, it has been obtained in reactions of the isoquinolinium series. ... 

Similarly, methyl propiolate and methyl phenylpropiolate give the cyclazine (67) and its 2-phenyl derivative, respectively, as would be expected of reactions initiated through a Michael addition to the acetylenic ester. 

More serious limitations and precautions apply to compounds in which not all three R, R, and R" groups are aromatic. Autocondensation of benzylideneacetone (111) yields an unstable chloroferrate which may be 113 or 115, according to whether a Michael addition to 112 or a crotonic condensation to 114 is first involved. Since compound 113 could readily be prepared from 2,6-dimethyl-4-phenylpyrylium and benzaldehyde, the structure of the reaction product should be easily soluble. Another equivocal product is formed from two moles of benzylideneacetone, but a definite structure (116) results from chalcone and benzylideneacetone. ... 

Recently, the cyclopenta[c]pyran (122) was obtained as a secondary product along with 1,2,3-tribenzoylcyclopropane from phenacyl-trimethylammonium hydroxide a complicated sequence was proposed involving a Michael addition to 1,2-dibenzoylethylene intermediately formed. 

In a similar manner, overnight refluxing of 1-methyl-1,2,5,6-tetrahydropyridine-3-carbonitrile (112) with p-chlorothiophenol (108) at 100°C gave a Michael addition product as a 1 1 mixture of two isomers 113a and 113b in 70% total yield (Fig. 3). However, if the reaction was carried out at low temperature for 4 hours, kinetic isomer 113a was detected in 50% yield (84JHC981). 

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

Enamines react with acceptor-substituted alkenes (Michael acceptors) in a conjugate addition reaction for example with o ,/3-unsaturated carbonyl compounds or nitriles such as acrylonitrile 8. With respect to the acceptor-substituted alkene the reaction is similar to a Michael addition ... 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

Halogenovinyl sulphoxides 551 react with nucleophiles to give -substituted vinyl sulphoxides 552. The first step in the reaction is a Michael addition, followed by an elimination of a halide anion605,627 (equation 351). 

As indicated, many of the more highly fimctionalized building blocks did not result in 2-pyridones. However, a thorough structure elucidation of by-products and intermediates was used to propose a mechanism for the formation of the 2-pyridone core based on a Michael addition followed by a Dimroth-type rearrangement (Fig. 3). 

In the case of alkenes simply substituted by an electron-withdrawing group (without a y-hydroxy group), the stabilized ylides give first a Michael addition and most often a subsequent prototropic shift resulting in new functionalized ylides (Scheme 8). Then a possible evolution of the resulting ylides can occur to give the final products [40-44]. 

A more logical approach was to adjust the oxidation level of (23) and to reconnect in the manner of (17a) to give symmetrical (26), easily made by a Michael addition. 

PTC has been extensively used for making cyclopropyl derivatives. The most common reaction involves generation of dichlorocarbene from chloroform, using NaOH and a quaternary ammonium hydroxide. The carbene subsequently reacts with an alkene in high yield. Hydrolysis of dichlorocarbene, normally rapid in the presence of water, is minimal. An interesting and very efficient example of a Michael addition to produce a cyclopropyl derivative is shown in Scheme 4.26. 

For a Michael addition, however, the same isomeric ratio (99% trans 1% cis) was observed for micro-reactor and batch operations [151]. 

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