Active methylene/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... 

With Compounds Containing Active Methylene or Methine Groups. Compounds containing active -CH2- or -CH- groups, such... 

The methine type comprises isoindoline derivatives which, like tetrachloro-isoindolinone pigments, have only recently been described. One or usually two equivalents of a compound containing an activated methylene moiety are attached to one equivalent of isoindoline. The list of compounds featuring activated methylene groups includes cyanacetamide or heterocycles such as barbituric acid or tetrahydroquinolinedione. 

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... 

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]. 

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 a-alkylation of carbonyl compounds by their conversion into nucleophilic enoiates or enolate equivalents and subsequent reaction with electrophilic alkylating agents provides one of the main avenues for regio- and stereo-selective formation of carbon-carbon a-bonds. " Classical approaches to a-alkylation typically involve the deprotonation of compounds containing doubly activated methylene or methine groups and having p/iTa values of 13 or below by sodium or potassium alkoxides in protic solvents. Since these conditions lead to monoenolates derived from deprotonation only at the a-site of the substrate, the question of the regioselectivity of C-alkylation does not arise (however, there is competition between C- and 0-alkylation in certain cases). In more recent years, dienolates of p-dicarbonyl compounds have been utilized in -alkylations with excellent success. 

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]. 

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. 

The designation ester condensations includes all reactions of carboxylic or carbonic esters with compounds that contain an activated methylene or methine group. These reactions occur in an alkaline medium, with loss of an alcohol and formation of a new carbon-carbon bond, and can be formulated generally as ... 

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. 

C.xi. Doubly Activated Methylene and Methines (C—H Acidic Compounds) as the H—Y Trapping Reagent Inter- and Intramolecular Diene Coupling... 

Azacrown ethers containing formazan moieties are obtained by reaction of bis(2-azoaryl)-oligooxoalkanes with compounds containing activated methylene or methine groups, namely malonic, acetoacetic, cyanoacetic, phenylmalonic, or 4-nitrophenylacetic acids in alkaline medium with the addition of pyridine on copper(II), zinc(II) or nickel(II) matrices [152, 163-165], For instance, crown formazans LI475 to LI484 are built up in this way (Scheme 6-6). 

Dimethylformamide dimethyl acetal has been used as a methine group source for various heteroring closures, particularly for an efficient 2-step indole synthesis from nitro compounds . The investigation of 3H-1,4-benzodiazepines with their two imino functions, particularly one with an a-iminonitrile function, has been added to the highly versatile chemistry of these heterocyclics Barbituric acid and 2,3,5-trioxopyrrolidine derivatives have been obtained through easy base-catalyzed reactions of active methylene compounds with isocyanates From the neighboring biochemical area come these contributions in preparative enzyme chemistry a-Chymotrypsin as well as citrus... 

Sever2il different ligand types (Figure 8.8) were used by several authors for the Cul-catalyzed inter-molecular and intramolecular arylation reactions of activated methylene and methine compounds with aryl iodides and bromides. Impressively, until that date and as far as we are aware, aryl chlorides have never been used as arylating agents. 

Figure 8.8 Types of ligands used for the Cul-catalyzed intermolecular and intramolecular a-arylation of activated methylene or methine compounds with aryl halides [114-116].

Methine isoindolinones of generic structure 23 can be prepared by the reaction of active methylene compounds with either phthalimides [e.g., 22], or iminoisoindoli-nones [e.g., 23], or a-cyanobenzoates by analogy with the methods described above for azomethine type isoindolinones. 

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