Active methylene compounds mechanism

Wylation under neutral conditions. Reactions which proceed under neutral conditions are highly desirable, Allylation with allylic acetates and phosphates is carried out under basic conditions. Almost no reaction of these allylic Compounds takes place in the absence of bases. The useful allylation under neutral conditions is possible with some allylic compounds. Among them, allylic carbonates 218 are the most reactive and their reactions proceed under neutral conditions[13,14,134], In the mechanism shown, the oxidative addition of the allyl carbonates 218 is followed by decarboxylation as an irreversible process to afford the 7r-allylpalladium alkoxide 219. and the generated alkoxide is sufficiently basic to pick up a proton from active methylene compounds, yielding 220. This in situ formation of the alkoxide. which is a... 

A more detailed study of the reaction with malonitrile revealed that the yields are dependent of the molar ratio malonitrile/quinazoline. The yield increases from 29 (ratio 1.0) to 81% (ratio 2.0), suggesting that the mechanism of the ring transformation involves the contribution of 2 mol of malonitrile. Reaction of quinazoline 3-oxide with the above-mentioned active methylene compounds gives about the same results, although the yields are poor (Scheme 12) (73CPB1943, 75CPB746). 

Conversely, but following a similar mechanism, compound 200 reacts with active methylenic compounds such as cyanoacetohydrazide and ethyl acetoacetate, in refluxing dioxane in the presence of piperidine, leading to the spiro-2-pyridone 201 and 6-aminopyran 202 (Scheme 9) <2000FES641>. 

Various transition metals have been used in redox processes. For example, tandem sequences of cyclization have been initiated from malonate enolates by electron-transfer-induced oxidation with ferricenium ion Cp2pe+ (51) followed by cyclization and either radical or cationic termination (Scheme 41). ° Titanium, in the form of Cp2TiPh, has been used to initiate reductive radical cyclizations to give y- and 5-cyano esters in a 5- or 6-exo manner, respectively (Scheme 42). The Ti(III) reagent coordinates both to the C=0 and CN groups and cyclization proceeds irreversibly without formation of iminyl radical intermediates.The oxidation of benzylic and allylic alcohols in a two-phase system in the presence of r-butyl hydroperoxide, a copper catalyst, and a phase-transfer catalyst has been examined. The reactions were shown to proceed via a heterolytic mechanism however, the oxidations of related active methylene compounds (without the alcohol functionality) were determined to be free-radical processes. 

Decarboxylation of 1,3-dimethylorotic acid in the presence of benzyl bromide yields 6-benzyl-1,3-dimethyluracil and presumably involves a C(6) centered nucleophilic intermediate which could nonetheless have either a carbene or ylide structure. Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry has been used to explore the gas-phase reactions of methyl nitrate with anions from active methylene compounds anions of aliphatic ketones and nitriles react by the 5n2 mechanism and Fco reactions yielding N02 ions are also observed nitronate ions are formed on reaction with the carbanions derived from toluenes and methylpyridines. 

The base-catalyzed condensation of azides with activated methylene compounds is a well-established route to IJT-triazoles. In particular, it is the best route to triazoles bearing a 5-amino or hydroxy substituent and an aryl or carbonyl-containing function in the 4-position. The addition is regiospecific. The reaction is a stepwise one, since anomerism of glycosyl azides has been observed in their reaction with activated methylene compounds, indicating the presence of an intermediate. The mechanism can be envisaged as a nucleophilic attack by the car-banion on the terminal nitrogen of the azide, followed by cyclization to a... 

Sulfonyl azides are exceptional in that they do not normally give triazoles with activated methylene compounds nucleophilic attack by the carbanion is usually followed by loss of the sulfonamide anion, giving a diazo compound as the product. Possible mechanisms for the reaction are illustrated (Scheme 8) for diethyl malonate. Attack of the carbanion on the terminus of the azide gives the anion of the linear triazene (1). 

Higashino et al. have exploited the reaction between active methylene compounds and pyrazolo[3,4-d]pyrimidines (89) (as free base,101 N-oxide,102,103 or salts92,101) to prepare a large number of 6,7-substituted derivatives (54 R2 = R3 = H). A mechanism was suggested.92... 

The condensation of 2,3,3-trichloropropenal with cyclic active methylene compounds affords fused pyran-2-ones (58CB320, 58CB330, 60CB2294). Instead of elimination of water, loss of hydrogen chloride is observed in accord with the previously postulated mechanism. 

Two mechanisms have been proposed for the Knoevenagel reaction. In one, the role of the amine is to form an imine or iminium salt (378) which subsequently reacts with the enolate of the active methylene compound. Under normal circumstances elimination of the amine would give the cinnamic acid derivative (379). However, when an o-hydroxy group is present in the aromatic aldehyde intramolecular ring closure to the coumarin can occur. The timing of the various steps may be different from that shown (Scheme 118). 

In the second postulated mechanism, the carbanion derived from the active methylene compound by deprotonation by the amine is considered to attack the carbonyl group without further intervention by the base (Scheme 119). 

Cyclopropanation of active methylene compounds has been achieved with ethylene carbonate as the cyclopropanating agent in the presence of potassium carbonate at 150 °C and a mechanism suggested (Scheme 54).88... 

Fig. 13.52. Mechanism of the Knoevenagel reaction of active-methylene compounds -H indicates the migration of a proton.

A Michael addition consists of the addition of the enolate of an active-methylene compound, the anion of a nitroalkane, or a ketone enolate to an acceptor-substituted alkene. Such Michael additions can occur in the presence of catalytic amounts of hydroxide or alkoxide. The mechanism of the Michael addition is shown in Figure 13.67. The addition step of the reaction initially leads to the conjugate base of the reaction product. Protonation subsequently gives the product in its neutral and more stable form. The Michael addition is named after the American chemist Arthur Michael. 

Fig. 13.67. Mechanism of the base-catalyzed Michael addition of active-methylene compounds (top) and of ketones (bottom), respectively. Subst refers to a substituent, and EWG stands for electron-with-drawing group.

As in benzenoid chemistry, some nucleophilic displacement reactions can be copper catalyzed. Illustrative of these reactions is the displacement of bromide from 3-bromothiophene-2-carboxylic acid and 3-bromothiophene-4-carboxylic acid by active methylene compounds (e.g., AcCH2C02Et) in the presence of copper and sodium ethoxide (Scheme 136). Analogously, 2-methoxythiophene can be prepared in 83% yield by refluxing 2-bromothiophene in methanol containing excess sodium methoxide, along with copper(I) bromide as catalyst. For the analogous preparation of 3-methoxythiophene, addition of a polar cosolvent (e.g., l-methyl-2-pyrrolidone) is beneficial. In the case of halothiophenes, an SrnI mechanism is involved. 

A following article has demonstrated the generality of this reaction using various active methylene compounds as nucleophilic partners [97] (Scheme 43). Concerning the mechanism of this sequential reaction, the... 

Quinazoline is transformed into quinoline derivatives 5 or 6 on treatment with active methylene compounds in the absence of a base catalyst or with carboxylic acid anhydrides. The possible mechanism involves an addition, ring opening between the 2- and 3-positions and a ring-closure sequenceor an addition, ring opening between the 3- and 4-positions and a ring-closure sequence. All possible mechanisms involve 4-substituted 3,4-dihydroquinazoli-nes formed by addition to the 3,4-double bond of quinazoline (cf p 165) as intermediates. ... 

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