Michael addition Of Grignard reagents

Few a-ketosulphoxides 123 were prepared by trapping the enolate anions 124, which are generated by the Michael addition of Grignard reagents to easily available a, jS-unsaturated carbonyl compounds 125, with methanesulphinyl chloride174 (equation 65). 

An arenethiolatocopper (I) complex has been used by van Koten et al. to catalyse the 1,4-Michael addition of Grignard reagents to acyclic enones, providing the corresponding products with excellent chemoselectivities, high... 

Mukaiyama et al. 200) synthesized optically active 3-substituted succinialdehyde acid esters (204) via a Michael-addition. The methyl ester of fumaraldehydic acid was converted into the corresponding aminal (203) by treatment with the (S)-proline-derived chiral diamine (99). The Michael-addition of Grignard reagent to the aminal, followed by hydrolysis produced stereoselectivily 3-substituted succinaldehydic acid ester (204) in good yield. 

Variations in the 5-substituent of chiral oxazolines cause considerable fluctuations in the degree of asymmetrical alkylation of these substrates, showing that steric as well as chelation factors are important in this method of obtaining chiral carboxylic acids. An impressive example of asymmetric induction is the synthesis of 3-substituted-3-phenylpropionic acids (5) of ca. 99% optical purity, from the 1,4-oxazepine (4) (derived from a-ethoxycarbonylcinnamic acid and /-ephedrine hydrochloride), by Michael addition of Grignard reagents in the presence of nickel chloride, followed by hydrolysis and decarboxylation."... 

Substituted glycines (171) have been prepared by Michael addition of Grignard reagents to 2-isocyanoacrylate esters (170), and the a-metallated isocyanide species (172) is found to react with simple Schiff s bases to give 2-imidazolines which on... 

High ees were achieved recently with Cu-JOSIPHOS complexes for the Michael addition of Grignard reagents to various substrates (302). Another ferrocene-based ligand, TANIAPHOS, was also efficient in the copper-catalyzed reductive addition of aldehydes and ketones to methyl acrylate (303). 

Copper salts promote the Michael addition of Grignard reagents to a6-unsaturated esters derived from L-arabinose, leading to the... 

Mukaiyama has reported that the Michael addition of Grignard reagents to chiral a,/3-unsaturated carboxylic acid amides derived from 1-ephedrine (6) affords optically active -substituted alkanoic acids (7) after acid hydrolysis. Yields of 48—99% for the addition, and 73— 97% for the hydrolysis were... 

Some studies on Meyer s route to chiral carboxylic acids (1, 1 2, 10) have revealed that stereoselectivity in the deprotonation of chiral oxazolines is very dependent on the particular base-solvent combination used. A further route to chiral acids is by alkylation (with primary halides) and subsequent hydrolysis of the bis-anionic species (1) derived from acid anhydrides and /-ephedrine. Chemical yields are in the range 50—70%, while optical yields are around 75%. A full report has appeared on the general approach to chiral acids by the Michael addition of Grignard reagents to oxazepinedione derivatives (2), also derived from /-ephedrine. Optical yields of 80—99% have been claimed (2,11 3, 27). 

Mukaiyama T, Iwasawa N. A facile asymmetric synthesis of P-substituted alkanoic acid the highly stereoselective Michael addition of Grignard reagents to a,p-unsaturated carboxylic amides derived from L-ephedrine. Chem. Lett. 1981 10 913-916. 

Michael addition of Grignard reagents ArMgX to enones can be catalysed by the Cu complex of the TADDOL-derived ligands (474) (4 mol%) in Me-THF at -78 C with <95% ee Other A-heterocyclic Cu complexes that catalyse the Michael addition of Grignard reagents to (cyclic) enones were derived from (475) and (476). ... 

Additions of nucleophiles to electron-deficient double bonds, e.g. the classical Michael addition or the Cu -mediated 1,4-addition of Grignard reagents to a,3-unsaturated carbonyl compounds (see previous... 

The most conspicuous property of aliphatic amines, apart from their fishy smell, is their high basicity, which usually precludes N-alkylations under acidic reaction conditions (last reaction, Scheme 6.3). Hence, alkylation of amines with tertiary alkyl groups is not usually possible without the use of highly stabilized carbocations which can be formed under basic reaction conditions. Rare exceptions are N-alkyla-tions of amines via radicals (Scheme 4.2), copper-catalyzed propargylations (Scheme 6.3), and the addition of amines to some Michael acceptors and allyl palladium or iridium complexes. Better strategies for the preparation of tert-alkylamines include the addition of Grignard reagents to ketone-derived imines [13] or the reduction of tert-alkyl nitro compounds. 

Spescha et al. [4] used the copper complex 6, which was obtained from a thioglucofuranose derivative, as catalyst for 1,4-additions of Grignard reagents to 3, and observed enantioselectivities of up to 60 % ee. The dihydrooxazolylthiophenolato copper complex 7 was employed by Pfaltz et al. 5] for the enantioselective catalysis of Michael additions to cyclic enones the best results were obtained with tetrahydrofuran as solvent and HMPA as additive. There was a pronounced dependence of the stereoselectivity on the ring size of the substrate 16-37 % ee for 2-cyclopente-none, 60-72 % ee for 3, and 83-87 % ee for 2-cycloheptenone. Alexakis et al. [6] used the heterocycle 8, which is readily accessible from... 

Chiral -substituted 4-butanolides. (S)-( + )-2-(p-Tolylsulfinyl)-2-buten-4-olide (2), which can be prepared in several steps from propargyl alcohol (equation 1), is an effective Michael acceptor for stereocontrol led conjugate addition of Grignard reagents. 

The Knoevenagel condensation is the method of choice for the preparation of a,p-unsaturated dicarbonyl compounds and related compounds and only a few alternative methods have been developed. However, with the traditional Knoevenagel condensation there are problems with the reactivity of ketones, with the competitive Michael addition occuring in the reaction of some active methylene compounds. There is also a problem with steieocontrol in the synthesis of Knoevenagel products from unsymmetrical 1,3-dicarbonyl compounds. An alternative method is the addition of Grignard reagents to vinylogous carbamates (see Section 11.2.6). Another possibility is the reaction of a metal ketimate with malonodini-trile to yield ylidenemalonodinitriles (see Section 11.3.1.7). ... 

Asymmetric Michael additions of zinc reagents, as with Grignards, are effected with a variety of ligands, some of which are also useful in other types of... 

Michael-Peterson Condensation. 3-Trimethylsilyl-3-buten-2-one also undergoes smooth Michael addition with Grignard reagents (R = Me, n-Pr, i-Pr, f-Bu, Ph), generating magnesium enolates which are then trapped with benzaldehyde to give ( )-and (Z)-enone isomers after Peterson condensation (eq 6). For example, treatment of the a-silyl vinyl ketone with methylmagne-sium iodide followed by reaction with benzaldehyde yields a 7 1... 

The useful Michael acceptors (132) can be obtained by the addition of Grignard reagents to the vinylogous carbamate (131), itself readily available from the parent Meldrum s acid/ 5-Aryl derivatives (133 = alkyl or Ph) of the... 

Silylethenyl ketones undergo smooth Michael addition with Grignard reagents or alkyllithiums to give the enolates 178, which are then trapped with benzalde-hyde to afford the E- and Z-isomers of enones 179 after the Peterson reaction (Scheme 2.114) [307]. ( )-Alkenes become the major products when the condensation with benzaldehyde is carried out under thermodynamic control at room temperature in diethyl ether, while Z-isomers are more favored as kinetically controlled products at 78 °C in THF. 1-Silyl acrylates show reactivities similar to those of 1-silylethenyl ketones [308]. 

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