Esters Michael acceptors

The reactivity of the dimetallic compounds 186a and 186b was then investigated and these species were less reactive than their formulas would lead to predict, as no reaction occurred with ketones, esters, Michael acceptors or trimethylsilyl chloride. In the presence of BF3 OEt2, addition occurred to aldehydes and led after /3-elimination to the corresponding olefination products 189 with good to excellent (E) stereoselectivity (equation 92)127. 

E+ = RX RCHO R2CO RCOC1 enone a, -unsaturated esters Michael acceptors R3SiCl R... 

Dicarbonyl compounds Perhalo ketones Epoxides Sulfonate esters Michael acceptors... 

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. 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

Van Leusen and co-workers also demonstrated the utility of dilithio-tosylmethyl isocyanide (dilithio-TosMIC) to extend the scope of the application. Dilithio-TosMIC is readily formed from TosMIC and two equivalents of n-butyllithium (BuLi) in THF at -70"C. Dilithio-TosMIC converts ethyl benzoate to oxazole 14 in 70% yield whereas TosMIC monoanion does not react. In addition, unsaturated, conjugated esters (15) react with dilithio-TosMIC exclusively through the ester carbonyl to provide oxazoles (16). On the other hand, use of the softer TosMIC-monoanion provides pyrroles through reaction of the carbon-carbon double bond in the Michael acceptor. 

In the Michael addition of achiral enolates and achiral Michael acceptors the basic general problem of simple diastereoselection (see Section D.1.5.1.3.2.), as described in Section 1.5.2.3.2. is applicable. Thus, the intermolecular 1,4-addition of achiral metal enolates to enones, a.jS-unsat-urated esters, and thioamides, results in the formation of racemic syn-1,2 and/or anti-3,4 adducts. 

The geometry of the ester enolate dictates the configuration of the cxtracyclic asymmetric center an (ii)-enolate gives mainly an anti-adduct and a (Z)-cnolate gives a wn-adduct. This is in accordance with the stereochemical results with tram-acyclic esters bearing in mind the fact that in this case a cw-unsaturated ester is present in the cyclic Michael acceptor. 

A proline derived chiral nickel complex 1 may be used instead of oe,/J-unsaturated esters of lactones modified with a chiral alcohol as the Michael acceptor. The a,(9-unsaturated acid moiety in 1 reacts with various enolates to afford complexes 2 with diastereomcric ratios of 85 15 to 95 5. Hydrolysis of the imine moiety yields the optically active /(-substituted r-alanines. A typical example is shown296. 

The y-keto nitriles shown in Table I were prepared by the cyanide-catalyzed procedure described here. This procedure is generally applicable to the synthesis of y-diketones, y-keto esters, and other y-keto nitriles. However, the addition of 2-furancarboxaldehyde is more difficult, and a somewhat modified procedure should be employed. Although the cyanide-catalyzed reaction is generally limited to aromatic and heterocyclic aldehydes, the addition of aliphatic aldehydes to various Michael acceptors may be accomplished in the presence of thioazolium ions, which are also effective catalysts for the additions. 

Rovis and co-workers have also shown that pre-catalyst 129 is competent with a wide range of Michael acceptors including oc,P-unsaturated aldehydes, amides, nitriles, esters, thioesters, vinylphosphonates and vinylphosphine oxides (Scheme 12.25) [58,60],... 

Among Michael acceptors that have been shown to react with ketone and ester enolates under kinetic conditions are methyl a-trimethylsilylvinyl ketone,295 methyl a-methylthioacrylate,296 methyl methylthiovinyl sulfoxide,297 and ethyl a-cyanoacrylate.298 Each of these acceptors benefits from a second anion-stabilizing substituent. The latter class of acceptors has been found to be capable of generating contiguous quaternary carbon centers. 

Additional evidence for the contention that metathesis carbenes are nucleophilic was offered by Gassman in an interesting series of trapping experiments utilizing Michael acceptors as carbene traps (15, 17). Thus, an ethylidene carbene generated from 2-butene was trapped by ethyl acrylate to yield the expected ethylcyclopropyl ester, although yields were quite low. 

Suicide or irreversible inhibitors of GST Pl-1 include agents that bind covalently to glutathione, thereby forming thioether adducts that are stabilized at the active site of the enzyme. These agents include activated aromatic systems (2, 3), epoxides (4, 5), esters (6), and Michael acceptors such as ethacrynic acid (7), cycloalkenones (8, 9), and haloenol lactones (10-13), among others [3,48,54-57],... 

Michael reaction of enamines of u-alkyl- -keto esters. The chiral lithioen-amine (1), prepared from (S)-valine /-butyl ester, does not react with methyl vinyl ketone or ethyl acrylate unless these Michael acceptors are activated by ClSi(CH3)3... 

Most aryl alkyl sulphones react with electron-deficient alkenes in the expected manner [e.g. 4-8] and a-(arenesulphonyl)acetic esters undergo a catalysed one-pot double Michael addition with Michael acceptors (Scheme 6.24) [8], The two Michael acceptors can be either identical or different. 

Vitamin B12 reacts with alkyl halides to form a cobalt (III) alkyl intermediate. Irradiation with visible light leads to the expulsion of a carbon-centered radical and a cobalt (II) species. The latter is easily reduced at —0.8 V to reconvert it to a cobalt (I) intermediate that reenters the catalytic cycle by reacting with a second molecule of the halide. The radical is capable of undergoing a number of interesting transformations, including conjugate addition to a Michael acceptor. The example illustrated in Scheme 9 provided a straightforward route to ester... 

Allenic amino acid derivatives 50, which are of special interest as selective vitamin Bg decarboxylase inhibitors [35], are accessible through 1,6-cuprate addition to 2-amino-substituted enynes 49 (Eq. 4.22) [36]. Because of the low reactivity of these Michael acceptors, however, the reaction succeeds only with the most reactive cuprate the t-butyl cyano-Gilman reagent tBu2CuLi-LiCN. Nevertheless, the addition products are obtained with good chemical yields, and selective deprotection of either the ester or the amino functionality under acidic conditions provides the desired target molecules. 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Also known as Morita-Baylis-Hillman reaction, and occasionally known as Rauhut-Currier reaction. It is a carbon—carbon bond-forming transformation of an electron-poor alkene with a carbon electrophile. Electron-poor alkenes include acrylic esters, acrylonitriles, vinyl ketones, vinyl sulfones, and acroleins. On the other hand, carbon electrophiles may be aldehydes, a-alkoxycarbonyl ketones, aldimines, and Michael acceptors. 

Fn and co-workers describe Umpolung reactivity of Michael acceptors catalyzed by triazolinylidene carbenes (Eq. 33) [168], Nncleophilic addition followed by tantomerization renders the [3 position of the Michael acceptor nncleophilic, which snbseqnently nndergoes alkylation. Compatible leaving gronps inclnde Br, Cl, and OTs. a,P-unsatnrated esters, nitriles, and amides all provide good to excellent yields of cyclized products. 

The high Michael acceptor reactivity of chloro esters 1,2 opens wide possibilities for the preparation of various carbo- and heterocycles with different ring sizes and substituents. This maybe achieved either by chemical transformations of primary Michael adducts or by addition of a bidentate nucleophile onto 1 or... 

The radicals generated from esters of halogenodifluoroacetic acid or halogenodi-fluorophosphonic acid add onto olefins and enolates. When these reactions are intramolecular, they afford tetrahydrofurans. In the presence of copper dust, ethyl bromodifluoroacetate can couple with aromatic and vinyl halides or can add onto Michael acceptors (Figure 2.13). ... 

Phosphorus ylides can be generated from triphenylphosphine, 3-chloro-(3//, 5//)-furan-2,4-dione, and alkynyl esters. Additional alkynyl ester, acting as a Michael acceptor, reacts with the ylides in a [4+2] cycloaddition reaction that results in the formation of furo[2,3-3]pyran derivatives (Equation 30) <2000T5221>. 

The Michael acceptor can be an a, -unsaturated carboxylic ester. This possibility is illustrated with the conjugate addition of phenylmagnesium bromide to ethyl arecaidinate, which leads to 4-phenylnipecotic acid (equation 33). 

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