Catalysis, base active methylene

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]. 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

An interesting comparison of the activity of primary and tertiary amino groups linked to MTS silicas in the reaction of benzaldehyde with ethyl cyanoacetate (Scheme 3.21, R = CN, R ElOCO, Ph, II) was reported. The results showed that catalysis induced by tertiary amine was relevant to classical base activation of the methylene group followed by nucleophilic attack to the carbonyl function, whereas primary amines could activate the carbonyl group by imine formation followed by Mannich-like nucleophilic attack by the activated ethyl cyanoacetate, as shown in Scheme 3.9. 

Disappointing results have been obtained from the Michael addition of compounds containing active methylene groups to vinylphosphonates. For example, cyanoacetate reacts with the diethyl vinyphosphonate under the conditions of base catalysis to give a mixture of 1 1 and 1 2 adduct resulting of one or two additions to the vinylphosphonate. When 2-pyridylacetonitrile and cyanomethylphosphonate are subjected to this reaction, diethyl 3-(2-pyridyl)- or 3-diethoxy-phosphinyl-3-cyanopropylphosphonates are obtained in 61% and 98% yields, respectively (Scheme 6.35). 

Carbon Acids. One of the more common uses of sodium hydride is the deprotonation of activated methylene compounds to generate highly reactive carbanions. A shuttle-deprotonation system has been described in which sodium hydride is the stoichiometric base and is used in conjunction with a crown ether cocatalyst to generate ketenes used in asymmetric catalysis. Enaminones can be converted to naphthyridinones using sodium hydride in THE (eq 47). ... 

The representative reaction system applied in asymmetric phase-transfer catalysis is the biphasic system composed of an organic phase containing an active methylene or methine compound and an electrophile, and an aqueous or solid phase of inorganic base such as alkali 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 react with the electrophile in the organic phase to afford the product. 

Salicylaldehydes can be condensed, by base or acid catalysis, with ketones that have an a-methylene. When base catalysis is used, the intermediate hydroxy-chalcones can be isolated, but overall yields are often better when the whole sequence is carried out in one step, using acid. It is important to note that because this route does not rely upon an electrophilic cychsation onto the benzene ring, 1-benzopyryliums free from benzene ring (activating) substituents can be produced. 

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