Methine compounds

Active methylene or methine compounds, to which two EWGs such as carbonyl, alko.xycarbonyl, formyl, cyano, nitro, and sulfonyl groups are attached, react with butadiene smoothly and their acidic hydrogens are displaced with the 2,7-octadienyl group to give mono- and disubstituted compounds[59]. 3-Substituted 1,7-octadienes are obtained as minor products. The reaction is earned out with a /3-keto ester, /9-diketone, malonate, Q-formyl ketones, a-cyano and Q-nitro esters, cya noacetamide, and phenylsulfonylacetate. Di(octadienyl)malonate (61) obtained by this reaction is converted into an... 

Kuwano and his co-workers also found a more effective reaction system by using [Cp( -C3H5)Pd] 123 in place of [Pd( 7 -C3H5)(cod)]BF4 117 as a palladium catalyst precursor. In this reaction system, benzylic alkylation of benzyl carbonates with a variety of active methine compounds gives alkylated products in excellent yields even in the absence of a base (Equation (47)). Addition of a catalytic amount of 1,5-cyclooctadiene (cod) to this reaction system promotes benzylic alkylation of benzylic carbonates with a variety of active methine compounds to give the... 

There was no reaction between the sodium salts of active methine compounds and 16049 (cf. Section II,A,4). 

Active methylene and methine compounds bearing a leaving group (X) on the y-carbon atom can afford cyclopropyl derivatives via 1,3-elimination of HX. 1,2-Elimination to give alkenes and direct nucleophilic substitution by base may compete with the 1,3-elimination, particularly in the preparation of excessively strained cyclopropyl derivatives. The preferred reaction course is, however, highly dependent on reaction conditions, especially on the nature of the base and solvent employed, as exemplified by the reactions of 4 (equation 7) 4. 

Oxiranyl carbanions undergo regioselective intramolecular substitution to give cyclo-propylmethoxide ions. Thus, epoxidation of y,<5-unsaturated active methylene and methine compounds followed by treatment with appropriate base provides substituted cyclopropylmethanols (equation 13)24. The use of chiral epoxides, e.g. prepared by... 

Alkylation Alkylation of the phenylindanone 31 with catalyst 3a by the Merck group demonstrates the reward that can accompany a careful and systematic study of a particular phase-transfer reaction (Scheme 10.3) [5d,5f,9,36], The numerous reaction variables were optimized and the kinetics and mechanism of the reaction were studied in detail. It has been proposed that the chiral induction step involves an ion-pair in which the enolate anion fits on top of the catalyst and is positioned by electrostatic and hydrogen-bonding effects as well as 71—71 stacking interactions between the aromatic rings in the catalyst and the enolate. The electrophile then preferentially approaches the ion-pair from the top (front) face, because the catalyst effectively shields the bottom-face approach. A crystal structure of the catalyst as well as calculations of the catalyst-enolate complex support this interpretation [9a,91]. Alkylations of related active methine compounds, such as 33 to 34 (Scheme 10.3), have also appeared [10,11]. 

The representative reaction system applied in asymmetric phase-transfer catalysis is the biphasic system composed of an organic phase containing an acidic methylene or methine compound and an electrophile, and an aqueous or solid phase of inorganic base such as alkaline metal (Na, K, Cs) hydroxide or carbonate. The key reactive intermediate in this type of reaction is the onium carbanion species, mostly onium enolate or nitronate, which reacts with the electrophile in the organic phase to afford the product. 

The fate of the onium carbanion Q+R incorporated into the organic phase depends on the electrophilic reaction partner. The most studied area in the asymmetric phase-transfer catalysis is that of asymmetric alkylation of active methylene or methine compounds with alkyl halides, in an irreversible manner. The reaction mechanism illustrated above is exemplified by the asymmetric alkylation of glycine Schiff base (Scheme 1.5) [8]. 

The asymmetric Michael addition of active methylene or methine compounds to electron-deficient olefins, particularly o,[l-unsaturated carbonyl compounds, represents a fundamental - yet useful - approach to construct functionalized carbon frameworks [36]. 

The precursor semicarbazones 256 and 260 were also prepared from the reaction of 1,2-diaza-l,3-butadienes 254 and 258 and activated methinic compounds such as diethylphenylmalonate, trimethylmetanetricarboxylate, 2,2-dimethyl-5-phenyll,3-dioxane-4,6-dione, 255, and dimethyl nitromalonate 259 in the presence of catalytic amount of MeONa or NaH in THF (Scheme 34) <2003JOC1947>. 

It is noted that the coupling of aryl halides, especially iodides, with a number of active methylene and methine compounds are promoted effectively by a stoichiometric amount of copper(I) halides [8, 37, 38]. The reaction using cy-anoacetate esters and 1,3-diketones can catalytically proceed [39-41]. 

The ferrocenylphosphine (R)-(S)-8a is also effective for the asymmetric allylation of several other active methine compounds, including 2-acetyl-1-tetralone, 6,6-dimethyl-2-acetylcyclohexanone, 2-acetylcyclooctanone, 1 -phenyl-2-methylbutane-1,3-dione, 2-phenylpropanal, and methyl a-isocyano(phenyl)acetate [43, 44], The allylation products and the values of enantiomeric excess are shown in Scheme 2-26. 

Tanaka, M., Oota, O., Hiramatsu, H., Fujiwara, K. The Knoevenagei reactions of aldehydes with carboxy compounds. I. Reactions of p-nitrobenzaldehyde with active methine compounds. Bull. Chem. Soc. Jpn. 1988, 61, 2473-2479. 

The addition of C-H bond of active methine compounds to carbon-carbon double bond in the allene moiety proceeds in intramolecular fashion in the presence of palladium catalyst, leading to the five- or six-membered carbocycles (Eq. 69) [142]. Similar intramolecular carbocyclization can be applied to the methine compounds having the acetylene moiety, leading to the five-membered exo-methylene cyclopentanes in good to excellent yields [143]. 

The reaction of active methine compounds, e.g., ethyl methylcyanoacetate and methylmalononitrile, with vinyltins using palladium catalyst gives 3 -hexene derivatives (Eq. 71) [145]. Participation of two molecules of the methyne compound and two vinyl moieties of the vinyltin in this reaction is obvious, though the actual reaction pathway was not clarified. 

When the reaction of active methine compounds with methylenecyclopro-pane was carried out in the presence of Pd(PPh3)4 as the catalyst, two types of ring-opening product were obtained (Eq. 72) [146]. This observation suggests that the reaction does not proceed through the trimethylenemethane-palladium intermediate, from which one ring-opening product would be formed predominantly [147]. 

When active methine compounds were used instead of active methylene compounds, 1,2-dia-cylcyclopropanes 10 were obtained. The mechanism involves migration of an acyl group. 

Kitagawa, O., Suzuki, T., Inoue, T., and Taguchi, T., Intramolecular carbotitanation reaction of active methine compounds having an unactivated alkyne mediated by TiCl4-EliN- Tetrahedron Lett., 39, 7357, 1998. 

Miscellaneous Reactions. - p-Toluenesulfonaraide undergoes Mitsunobu-type reactions in the presence of alcohols and cyanomethylenetriphenyl-phos-phorane (56) to give predominantly mono-N-alkylation products. This reaction has also been applied to the synthesis of cyclic ethers from diols and cyclic amines from amino alcohols and to carbon-carbon bond formation. Examples of cyclic amine synthesis include that of (+)-a-skytanthine (57). A comparative study of the reactions of active methine compounds (58) as nucleophiles using... 

The Michael addition of active methylene (and methine) compounds to activated 7t-systems is one of the more useful C—C bond-forming reactions (Scheme 5.10). Classical basic activation of the nucleophile can generate by-products from competing side reactions. Therefore, much effort has been dedicated to the development of catalysts for Michael reactions, mainly transition metals and lanthanides [92], The current challenge is the development of heterogeneous catalytic systems. 

Radical addition reactions were also recently added to the repertoire of 2-nitroin-dole (21), previously dominated by nucleophilic reactions [17]. Treatment of the indole with activated methylene compounds such as dimethyl malonate, malonitrile and pentane-2,4-dione in a refluxing solution of Mn(0Ac)3-2H20 in acetic acid gave mainly 2-oxo-indolin-ylidenes 22 after an in situ Nef reaction. The expected 3-subsitiuted 2-nitroinole 23, however, was only observed with the methine compounds 3-methylpentane-2,4-dione and 5-oxo-4-propionyUieptane-nitrile. 

Enantioselective fluorination reactions of active methine compounds, particularly, oxindole derivatives catalyzed by chiral palladium complexes 06SL1467. 

New synthesis of pyridones using conjugate addition reactions of active methine compounds to alkynyl imines and ketones 06Y251. 

Dimethyl malonate derivatives containing an allenyl sulfone substituent at the y- or 3-position undergo endo-mode ring closure to give cyclopentene or cyclohexene derivatives upon treatment with 1.5 equiv of t-BuOK in t-BuOH at rt. The intermediate unsaturated cycloadducts undergo demethoxycarbonylation and double bond isomerization under the reaction conditions (eq 53). Other active methine compounds behave similarly. A threefold excess of i-BuOK is more effective than certain amine bases for the conversion of phenylsulfonyl methyl derivatives of aromatic or heteroaromatic compounds into the corresponding dithio esters upon reaction with an excess of elemental sulfur. ... 

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