Michael addition Conjugate substitution reaction

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. 

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 ... 

As in the case of addition reactions of carbon nucleophiles to activated dienes (Section HA), organocopper compounds are the reagents of choice for regio- and stereoselective Michael additions to acceptor-substituted enynes. Substrates bearing an acceptor-substituted triple bond besides one or more conjugated double bonds react with organocuprates under 1,4-addition exclusively (equation 51)138-140 1,6-addition reactions which would provide allenes after electrophilic capture were not observed (cf. Section IV). 

The chemical behavior of heteroatom-substituted vinylcarbene complexes is similar to that of a,(3-unsaturated carbonyl compounds (Figure 2.17) [206]. It is possible to perform Michael additions [217,230], 1,4-addition of cuprates [151], additions of nucleophilic radicals [231], 1,3-dipolar cycloadditions [232,233], inter-[234-241] or intramolecular [220,242] Diels-Alder reactions, as well as Simmons-Smith- [243], sulfur ylide- [244] or diazomethane-mediated [151] cyclopropanati-ons of the vinylcarbene C-C double bond. The treatment of arylcarbene complexes with organolithium reagents ean lead via conjugate addition to substituted 1,4-cyclohexadien-6-ylidene complexes [245]. 

An attractive method to generate C5-monoalkyl-substituted Meldrum s acids consists of a two-step synthesis (Scheme 10). In the first step, a Knoevenagel reaction between Meldrum s acid (22) and an aldehyde (or sometimes a ketone) yields the C5-alkylidene derivative 23. In the following step, the alkylidene derivative 23 is reduced, to generate the C5-monoalkyl-substituted Meldrum s acid 24.[43 71 104 1051 Alternatively, in the second step, Michael addition of a nucleophile to the conjugated C=C bond in the C5-alkylidene derivative generates a Meldrum s acid 25 monosubstituted on C5 by a more elaborated alkyl.t106 ... 

Aziridines can add to carbon—carbon multiple bonds. Elevated temperature and alkali metal catalysis are required in the case of nonpolarized double bonds (193—195). On the other hand, the addition of aziridines onto the conjugated polarized double or triple bonds of a,p-unsaturated nitriles (196—199), ketones (197,200), esters (201—205), amides (197), sulfones (206—209), or quinones (210—212) in a Michael addition-type reaction frequendy proceeds even at room temperature without a catalyst. The adducts obtained from the reaction of aziridines with a,p-unsaturated ketones, eg, 4-aziridinyl-2-butanone [503-12-8] from 3-buten-2-one, can be converted to 1,3-substituted pyrrolidines by subsequent ring opening with acyl chlorides and alkaline cyclization (213). 

Complexes of unsymmetrically substituted conjugated dienes are chiral. Racemic planar chiral complexes are separated into their enantiomers 84 and 85 by chiral HPLC on commercially available /f-cyclodextrin columns and used for enantioseletive synthesis [25]. Kinetic resolution was observed during the reaction of the meso-type complex 86 with the optically pure allylboronate 87 [26], The (2R) isomer reacted much faster with 87 to give the diastereomer 88 with 98% ee. The complex 88 was converted to 89 by the reaction of meldrum acid. Stereoselective Michael addition of vinylmagnesium bromide to 89 from the opposite side of the coordinated Fe afforded 90, which was converted to 91 by acetylation of the 8-OH group and displacement with EtjAl. Finally, asymmetric synthesis of the partial structure 92 of ikarugamycin was achieved [27],... 

One potential problem in the reactions of stabilized allylic or propargylic carb-anions is the dimerization of the starting material if the carbanions are not formed stoichiometrically. Alkenes substituted with electron-withdrawing groups are good Michael acceptors, to which nucleophiles will undergo conjugate addition. For instance, the Baylis-Hillman reaction of allyl cyanide with benzaldehyde requires careful optimization of the reaction conditions to avoid dimerization of the nitrile (Scheme 5.12). This problem is related to a common side reaction of Michael additions reaction of the product with the Michael acceptor (Scheme 10.21). 

Lewis acidity of hiBr3 toward coordination and acid nucleophiles was not affected. Cozzi et al. described a sequential, one-pot InBr3-catalyzed 1,4-then 1,2-addition to enones, indicating that this is a versatile catalyst for the Michael additions [56]. When InBr3 (10 mol%) catalyst is used together with trimethylsilylcyanide (TMSCN), the reactions start by the 1,4-conjugate addition of indoles to a,fl-ketones and then finish by the 1,2-addition of TMSCN to the -substituted ketones in one pot (Scheme 12). 

A Michael addition consists of the addition of the enolate of an active-methylene compound, the anion of a nitroalkane, or a ketone enolate to an acceptor-substituted alkene. Such Michael additions can occur in the presence of catalytic amounts of hydroxide or alkoxide. The mechanism of the Michael addition is shown in Figure 13.67. The addition step of the reaction initially leads to the conjugate base of the reaction product. Protonation subsequently gives the product in its neutral and more stable form. The Michael addition is named after the American chemist Arthur Michael. 

The prototype of copper-mediated conjugate addition reactions is the transformation of acceptor-substituted alkenes and alkynes into the corresponding adducts (Scheme 1). Whereas full control of the regio- and chemoselectivity in these Michael additions has been possible for a long time,3 the emphasis of the last decade has been put on the use of new copper reagents, the broadening of the substrate scope, and the control of the stereoselectivity of the conjugate addition. 

On the basis of this palladium-mediated Michael addition cyclization process, a novel two-step synthetic entry into functionalized furan derivatives 67 has also been devised (Scheme 28). Substitution of benzylidene (or alkyli-dene) malonates for their ethoxymethylene analog (65) as activating olefins gave rise to the formation of the corresponding 2-ethoxy-4-arylidene tetrahy-drofurans 66. An in situ addition of potassium ferf-buloxidc induced a decar-boxylative elimination reaction which was followed by an isomerization of the exocyclic double bond. The entire process successively involved a conjugate addition, a palladium-catalyzed cyclization-coupling reaction, a base-induced eliminative decarboxylation, and finally, a double bond isomerization [73]. 

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