Michael addition condensation

Michael Addition (Condensation, Reaction) The addition of a carbon nucleophile to an activated unsaturated system. 

Michael addition-condensation sequence of menthyl chloroacetate and menthyl acrylate, and cobalt(O) or nickel(0) complex-catalyzed cyclopropanation of dimenthyl fumarate with dibromomethane. The present method is characterized by good chemical and high optical yields, simple operation, preparation of both enantiomers with equal ease, and the ready availability of the starting materials. 

From the pjtrroloisoquinohne carboxylic acid ester 149 (Scheme 22) generated from homoveratrylamine (52) and dioxopentenoic acid ester (148) by a combined Michael addition/condensation, the A ring has been constructed by an intramolecular aldol condensation of the diketone 150 affording 3-demethoxyeiythtatidinone (62) (79). 

Huge success of benzodiazepenes as pharmaceutical scaffolds has prompted preparation and evaluation of het-erocyde-annulated benzodiazepine derivatives. A tandem Michael addition-condensation sequence xmder MW irradiation was also proved to be useful for the synthesis of amino-substituted pyrimidine-fused diazepine derivatives of the type 96 from 4,5,6-triaminopyrimidine and chalcones [57]. Similarly, the pyridine-fused derivatives (97) were prepared xmder MW-assisted solvent and catalyst-free condition [58], Condensation of thiadiazole-annulated phen-ylene diamines with appropriate carbonyl compounds using sulfamic acid as organocatalyst led to the formation of corresponding diazepine derivatives 98 in excellent yields [59] (Figure 4). 

Robinson Annulation Sequential Michael addition/aldol condensation between a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-l-one... 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

Acetoxy-l,7-octadiene (40) is converted into l,7-octadien-3-one (124) by hydrolysis and oxidation. The most useful application of this enone 124 is bisannulation to form two fused six-membered ketonesfl 13], The Michael addition of 2-methyl-1,3-cyclopentanedione (125) to 124 and asymmetric aldol condensation using (5)-phenylalanine afford the optically active diketone 126. The terminal alkene is oxidi2ed with PdCl2-CuCl2-02 to give the methyl ketone 127 in 77% yield. Finally, reduction of the double bond and aldol condensation produce the important intermediate 128 of steroid synthesis in optically pure form[114]. 

The method was applied to the synthesis of (-t-)-l9-nortestosterone by the following sequence of reactions. Michael addition of the bisannulation reagent 124 to the optically active keto ester 129 and decarboxylation afforded 130, and subsequent aldol condensation gave 131. Selective Pd-catalyzed oxidation of the terminal double bond afforded the diketone 132 in 78% yield. Reduction of the double bond and aldol condensation gave ( + )-19-nortestosterone (133)[114]. 

The product of this Michael addition has the necessary functionality to undergo an intramolecular aldol condensation... 

The synthesis of cyclohexenone derivatives by Michael addition followed by intramolec ular aldol condensation is called the Robinson annulation, after Sir Robert Robinson who popularized its use By annulatwn we mean the building of a ring onto some start mg molecule (The alternative spelling annelation is also often used)... 

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

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. 

Woodward s total synthesis of cephalosporin C begins with L-cysteine (48) which establishes the chiral center at C-7. The cis geometry at C-6,7 is achieved in intermediate (49) which is cyclized to (50) by treatment with triethylaluminum. The dihydrothiazine ring is constructed by Michael addition to the condensation product of trichloroethyl glyoxylate... 

Fusion of SIX membered nngs by reactnn of cyclanones with vinyl ketones (base or acd catalyzed), a tandem Michael addition aldol condensation... 

As will be discussed in the next section, 1,5-pentanediones are obtained by Michael addition of acetophenones to chalcones. The addition and cyclization may be merged in one step (see Section II,C,2,g). When acetophenone was condensed with chalcone (74) in the presence of or of HC104, jS-phenylpropio-... 

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. ... 

The best method to achieve a high regioselectivity is the use of preformed enolates. A double annulation reaction is possible if, for example, a diketone such as 11 is used as starting material. The product of the Michael addition 12 can undergo two subsequent aldol condensation reactions to yield the tricyclic dienone 13 ... 

Incorporation of a carbonyl group into the alkyl side chain also proved compatible with biologic activity. The key intermediate (76) is obtainable by Michael addition of the anion from diethyl malonate to methylvinyl ketone followed by ketalization with ethylene glycol. Condensation of 76 with hydrazobenzene leads to the pyrazolodione hydrolysis of the ketal group affords ketasone (78). ... 

Aldol condensation of the methoxymethyl ether of m-methoxybenzaldehyde (83) with cyclohexanone affords the conjugated ketone 84. Michael addition of dimethyl amine leads to the ami noketone Reduction of the ketone... 

A fully unsaturated tricyclic indole derivative serves as the aromatic moiety for a nonsteroid antiinflammatory agent. Preparation of this compound starts with the Michael addition of the anion from methyl diethylmalonate to cyclohexanone. The product (32) is then hydrolyzed and decarboxylated to give ketoester 33. Fischer condensation with p-chlorophenylhydrazine leads to the indole This is then esterified (35) and dehydrogenated to the carbazole 36. Saponification leads... 

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. 

In contrast, the diastereoselectivity of the conjugate addition of a chiral alkenylcoppcr-phosphinc complex to 2-mcthyl-2-cyclopentenone was dictated by the chirality of the reagent63. The double Michael addition using the cyclopentenone and 3-(trimethylsilyl)-3-buten-2-one and subsequent aldol condensation gave 4 in 58 % overall yield. The first Michael addition took place from the less hindered face of the m-vinylcopper, in which chelation between copper and the oxygen atom fixed the conformation of the reagent. 

The intramolecular Michael addition of acyclic systems is often hampered by competing reactions, i.e., aldol condensations. With the proper choice of Michael donor and acceptor, the intramolecular addition provides a route to tram-substituted cyclopentanones, and cyclopentane and cyclohexane derivatives. Representative examples are the cyclizations of /3-oxo ester substituted enones and a,/J-unsaturated esters. 

This intramolecular Michael addition, when followed by an aldol condensation provides a useful route to tram-octahydroindenes methylated in the ring fusion positions. 

A very efficient method for annulations158 is based on the addition of lithium or silyl enolates to a-silylated enones as a key step. The diastereoselective 1,4-addition is followed by an aldol condensation. This procedure allows Michael additions under aprotic conditions, whereby the silyl substituent stabilizes the enolate of the Michael adduct preventing polymerization of the enone, 59 l63. 

These reactions imply an aldol condensation following the initial Michael addition. Two examples in which absolute stereocontrol over three or four new stereogenic centers is achieved in a single operation illustrate the potential of these methods. 

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