Michael addition to unsaturated

Michael addition to unsaturated amides. This system (1 equiv. of each) effects Michael addition of ketones, nitro compounds, ethyl cyanoacetate, and diethyl malonate to a,(3-unsaturated amides. Addition to methacrylamides is interesting because the final products are glutarimides or dihydropyridinones. 

Nafion resins have been used not only for the opening of epoxides but also for their isomerization to aldehydes or ketones [137]. Various other rearrangements and isomerizations are catalyzed by this solid acid, in some cases with selectivities higher than those obtained with other solid catalysts [138-140]. Other reactions that have been studied include the Peterson methylenation of carbonyl compounds [141], hetero-Michael additions to unsaturated ketones [142], the Koch-type carbon-ylation of alcohols to form carboxylic acids [143], dimerization of a-methylstyrene [144], addition of carboxylic acids to olefins [145] and Diels-Alder reactions [146]. Notably, in most cases, reutilization of the catalyst is considered but only after an appropriate washing protocol to regenerate its acidity/activity. 

Michael additions to unsaturated sugars have been utilized for synthesizing the branched-chaln sugars (48), and hence, using excess roethoxide, to the dimeric derivative (49). Levoglucos-... 

Using a similar strategy, Hayashi described synthesis of dipeptidyl peptidase IV inhibitor ABT-421. The key reaction was Michael addition of acetaldehyde to a nitroalkene, followed by another Michael addition to unsaturated phosphonate and then HWE annulation. Lu and coworkers applied a different approach to the same molecule. They used ot,p-unsaturated aldehyde and a premade nitrophosphonate. ... 

There are a number of chemical methods for the preparation of racemic p -amino acids. Selected methods are shown in Scheme 14.1, and include Michael addition to unsaturated carboxylic acids (a), homologation of a-amino acids (b), Thorpe reaction followed by reduction (c), nitrile reduction (d), and nitrile hydrolysis (e), among many others. Strategies for the stereoselective synthesis of p-amino acids are emerging, but there is not as yet a method that is generally appHcable [24, 25]. 

As an analog of alkyl zincate, 5i -zincate was synthesized as early as in 1985 by Oshima and co-workers, using ZnR2 and silyllithium instead of alkyllithium (Eq. 9) [35]. In 1999, Krief and co-workers reported the synthesis of 5n-zincates from stannyllithium in a similar way [36]. Such Si- and Sn-zincates undergo silylzincation or silyl/stannyl Michael addition to unsaturated compounds. The Michael addition employing zincates has been well reviewed elsewhere, so it will not be considered in detail here [8]. Another application of S/-zincate, silylzincation, will be discussed later. 

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... 

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 behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork reaction, for example, an enamine adds to an aqQ-unsaturated carbonyl acceptor in a Michael-like process. The initial product is then hydrolyzed by aqueous acid (Section 19.8) to yield a 1,5-dicarbonyi compound. The overall reaction is thus a three-step sequence of (11 enamine formation from a ketone, (2) Michael addition to an a,j3-unsaturated carbonyl compound, and (3) enamine hydrolysis back to a ketone. 

Fermenting baker s yeast also catalyzes the 1,4-addition of a formal trifluoroethanol-d1-synthon to a,/i-unsaturated aldehydes, to give optically active l,l,l-trifluoro-2-hydroxy-5-alka-nones52. Presumably, the mechanism involves oxidation of the alcohol to the corresponding aldehyde followed by an umpolung step with thiamine pyrophosphate and Michael addition to the a,/i-unsaturated aldehyde. For example, l,l,l-trifluoro-2-hydroxy-5-hexanone (yield 26%, ee 93%) is thus obtained from trifluoroethanol and l-bnten-3-one. 

Sulphonylbenzofurans 638 a-Sulphonyl carbanions 760, 766, 767, 797, 813, 951, 961 acylation of 627-636 addition to unsaturated bonds 636-642 alkylation of 627-636, 781 halogenation of 1058-1060 Michael addition of 642-649 miscellaneous reactions of 653-655 Ramberg-Backlund reaction of 649-653, 1057, 1058... 

Scheme 5.21 Lipase-catalyzed Michael additions to a./J-unsaturated carbonyl compounds.

Nitroalkenes react with lithium dianions of carboxylic acids or with hthium enolates at -100 °C, and subsequent treatment of the Michael adducts with aqueous acid gives y-keto acids or esters in a one-pot operation, respectively (Eq. 4.52).66 The sequence of Michael addition to nitroalkenes and Nef reaction (Section 6.1) provides a useful tool for organic synthesis. For example, the addition of carbanions derived from sulfones to nitroalkenes followed by the Nef reaction and elimination of the sulfonyl group gives a,P-unsaturated ketones (Eq. 4.53).67... 

Aminopyrimidines are also known to undergo Michael additions to a,P-unsaturated carbonyl compounds. This methodology was utilized by Insuasty and co-workers using triaminopyrimidines 70 with conjugated ketones 71 to produce a variety of pyrimidine-fused diazepines 72 <00JHC193,00JHC401>. 

Dibasic forms of phosphorus (III) species also have been reported to undergo Michael-type additions to unsaturated substrates. Hypo-phosphorous acid adds to acrylamides to generate free phosphonous acids in good yield,430 as well as to vinyl acetate.431 Further, methyl hypophosphite adds to a variety of unsaturated substrates,432 as does the ammonium salt of mono(2-ethylhexyl) phosphite (Equation 3.27).433... 

The potassium cyanide complex of 18-crown-6 in benzene or acetonitrile undergoes Michael addition to unsaturated carbonyl compounds (Liotta et al., 1977). In the presence of acetone cyanohydrin, the catalytic (i.e. catalytic in potassium cyanide and crown ether) cycle for hydrocyanation shown in (21)... 

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