Alkylation of active-methylene compounds

Alkylation or acylation of ethyl malonate, ethyl acetoacetate, or other compounds containing methylene groups activated by strongly electron-attracting groups are very fruitful preparative methods. Reactions according to the schemes  

The alkylation is generally effected by bringing together a solution or suspension of the sodio derivative of the compound to be alkylated and the alkylating agent, usually an alkyl halide, at any suitable temperature, and it is rarely necessary to isolate the sodio derivative in substance. The sodio derivatives are obtained by reaction of the active methylene compound with sodium, sodamine or sodium hydride in an inert solvent, e.g., ether alcoholic solutions of the sodio compounds are obtained by treating the methylene components with the calculated amount of sodium alkoxide solution. 

Sodamide in liquid ammonia is often used. Compounds containing reactive methylene groups can be treated with very reactive halides (e.g., allyl or benzyl 

Recently anion-exchange resins have been used successfully as bases for such reactions.371,372 

The preparation of diethyl butylmalonate380 is an example of alkylation by an alkyl halide A cooled and stirred solution of sodium alkoxide (from 115 g of sodium and 2.5 1 of anhydrous ethanol) is treated gradually with refractionated ethyl malonate (b.p. within 5° 825 g) with further cooling as necessary, this ester is followed by butyl bromide (685 g) during 1 h. Then the solution is heated on a water-bath until neutral to litmus (2-3 h), after which alcohol (21) is distilled off from a water-bath, the residue is treated with its own volume of water, and the organic phase is separated and distilled in a vacuum. A forerun of unchanged malonic ester is followed by the diethyl butylmalonate (89-92%, 960-990 g), b.p. 144-145°/40 mm. 

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Alkylation of Active Methylene Compounds with Alcohols... 

The carbon-bond-forming reactions based on hydrogen transfer catalyzed by Cp Ir complex have been extended to the alkylation of active methylene compounds. Grigg et al. reported the alkylation of arylacetonitriles catalyzed by the... 

The iridium catalytic system can also be applied to the a-alkylation of active methylene compounds. The alkylation of cyanoacetates 93 with primary alcohols 94 was achieved by using [lrCl(coe)2]2 and PPhs to afford saturated a-alkylated products 95 (Equation 10.20) [42]. Here, the alkylation reaction was efficiently accomplished, without the need for any base. 

Good results have been achieved in phosphonio-catalysed alkylation of active methylene compounds and imides which may be steroselective873 (equation 269). Aqueous sodium hydroxide deprotonation of the phosphonium salt itself in view of a Wittig reaction is... 

Quaternary ammonium salts of heterocyclic compounds have been used in liquid-liquid phase-transfer syntheses. When these compounds are achiral, they show a behavior very similar to that of other quaternary ammonium salts. For example, 2-dialkylamino-l-alkylpyridinium tetrafluoroborates have been used by Tanaka and Mukayama282 in the alkylation of active methylene compounds PhCH2CN, PhCH(Et)CN, and PhCH(Me)COPh. However, comparative studies of the efficiency of the catalysts show that alkylpyridinium bromides283 or N-alkyl-Af-benzyl-piperidinium chloride284 have a smaller catalytic activity compared to tetraalkylammonium halides. McIntosh285 has described the preparation of azapropellane salts 186 as potential chiral phase transfer catalysts. 

Many of the standard methods of C-C bond formation in aliphatic systems can be extended to heterocyclic systems, e.g. the Dieckmann reaction (,cf 51 — 52) and alkylation of active methylene compounds (e.g. 53 —+ 54). 

Other chiral PTC alkylations of active methylene compounds leading to amino acid derivatives have been reported [24] as have other alkylations [25]. Several reported asymmetric PTC alkylations have been disputed [26-29]. 

Generally, the alkylation of active methylene compounds proceeds in good yield. However, in this case, as illustrated below, the alkylation requires displacement of... 

Many of the standard methods of C-C bond formation in aliphatic systems can be extended to heterocyclic systems, e.g., the Dieckmann reaction (cf. 66 67) and alkylation of active methylene compounds (e.g., 68 69). An example of the application of the Dieckmann reaction to the preparation of 3-thiepanone 70 is shown in Scheme 42 <1952JA917>. Several more recent examples of applications of the Dieckmann condensation in the synthesis of substituted 4- and 3-piperidones are discussed in CHEC-III . 

The use of [,3CJformaldehyde resulted in the formation of 80% of the dilabeled ethylene glycol, indicating that the ethylene glycol formation proceeds preferentially via reductive carbon-carbon coupling over hydro-formylation of formaldehyde the catalytic turnover is not given (166). Ru3(CO),2 was also found to catalyze the reductive alkylation of active methylene compounds with formaldehyde under synthesis gas. For example, pentan-2,4-dione is converted into 3-methylpentan-2,4-dione... 

Remu BC, Baneijee S, Jana R (2007) Ionic Uquid as catalyst and solvent the remarkable effect of a betsic ionic liquid, [bmim][OH] on Michael addition and alkylation of active methylene compounds. Tetiahedron 63 776-782... 

The hydridoiron complex has also been used in the alkylation of active methylene compounds by formaldehyde or benzaldehyde (equations II and III). 

Alkylations. BUjP=CHCN is a useful catalyst for promoting Mitsunobu-type alkylation of p-toluenesulfonamide with alcohols at room temperature. Alkylation of active methylene compounds is similarly achieved. ... 

Usually, the aqueous salt could be too hydrophilic to allow the quaternary salt to dissolve in the organic phase, and resided exclusively in the aqueous phase anion exchange occured at or near the interface. The mechanism is applied to carbanion reactions, carbene reactions, condensation of polymerization, and C-alkylation of active methylene compounds such as activated benzylic nitriles, activated hydrocarbons, and activated ketones under PTC/OH. In most cases, the reaction involves the Q OH complex because QOH is highly hydrophilic and has extremely low solubility in the organic phase. 

A difficulty sometimes encountered in the alkylation of active methylene compounds is the formation of unwanted dialkylated products. During the alkylation of the sodium salt of diethylmalonate, the monoalkyl derivative formed initially is in equilibrium with its anion. In ethanol solution, dialkylation does not take place to any appreciable extent because ethanol is sufficiently acidic to reduce the concentration of the anion of the alkyl derivative, but not that of the more acidic diethylmalonate itself, to a very low value. However, replacement of ethanol by an inert solvent favours dialkylation. Dialkylation also becomes a more serious problem with the more acidic cyanoacetic esters and in alkylations with very reactive electrophiles such as allyl or benzyl halides or sulfonates. 

Calix[n]arenes 1-3 were used as inverse PT catalysts in the alkylation of active methylene compounds with alkyl halides in aqueous NaOH solutions,and in aldol-type eondensation and Michael addition reactions. In the aikylation of phenylacetone with octyl bromide, the IPTC procedure enhanced the alkylation versus hydrolysis and C versus O alkylation selectivities with respect to those observed xmder classical PTC reactions in the presence of tetrabutylammonium bromide (TBAB) or hexadecyltributylammonium bromide (HTPB). Moreover, the aqueous catalyst solution was easily separated from the organic phase eontaining the products, and no organic solvent was required. In the case of the aldol-type condensation of benzaldehyde with indene or acetophenone in aqueous NaOH (Fig. 9), IPTC reaetions eatalyzed by I were compared with those conducted in aqueous micelles in the presence of cetyltrimethylammonium bromide (CTAB) as the sufactant. Although selectivities and yields were similar, the IPTC proeedure avoided the formation of emulsions, thus faciUtating product separation and catalyst recovery. In the light of the results obtained, water-soluble calix[ ]arenes 1-3 were proposed... 

Shimizu, S. Suzuki, T. Sasaki. Y. Hirai, C. Water-soluble calixarenes as new inverse phase-transfer catalysts. Their application to C-alkylations of active methylene compounds in water. Synlett 2000, 1664— 1666. 

The dianions of /S-keto-esters undergo Claisen ester condensation in the expected manner via the y-carbanion. In an extension of a method reported for the preparation of amines from alcohols loc. cit.), the same Japanese authors have described the direct alkylation of active methylene compounds with alcohols (Scheme 42) the method is limited to relatively acidic compounds, with pJ Tg < 11 diethyl malonate (pX 13.3) does not react. 

A slightly different group of catalysts that have been developed for the PTC alkylation of active methylene compounds are the 2-dialkylaminopyridinium salts... 

Catalysis of reactions between components of immiscible aqueous and organic solutions by quaternary ammonium salts was first reported in 1951 and was brought to the attention of synthetic chemists by Makosza and by Starks.Makosza investigated the alkylation of active methylene compounds such as phenylacetonitrile with benzyltriethylammonium chloride in the presence of concentrated aqueous sodium hydroxide (eq 1). Starks used more lipophilic onium... 

The economic promise of polystyrene-supported phase transfer catalysts depends on their reuse in industrial processes. Under some of the reaction conditions described for nucleophilic displacement reactions and for alkylation of active methylene compounds, the... 

Anhydrous sodium or potassium carbonates have been shown to act as efficient strong bases in solid-organic liquid two-phase systems in the presence of crown ethers this by-passes the requirement for concentrated aqueous hydroxide solutions in the equivalent liquid-liquid techniques. Among the reactions possible with this new method are the alkylation of active methylene compounds, the Williamson ether synthesis, and the Darzens reaction. 

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