Reactive methylene

The Mannich Reaction involves the condensation of formaldehyde with ammonia or a primary or secondary amine and with a third compound containing a reactive methylene group these compounds are most frequently those in which the methylene group is activated by a neighbouring keto group. Thus when acetophenone is boiled in ethanolic solution with paraformaldehyde and dimethylamine hydrochloride, condensation occurs readily with the formation of... 

The term Knoevenagel Condensation was originally applied to the base-catalysed condensation of the carbonyl ( CO) group of aldehydes and ketones with the reactive methylene group of malonic acid, with loss of w ater ... 

The role of the base is apparently primarily that of a proton remover from the reactive methylene group thus if B represents the base, reaction (i) gives the carbanion, which then combines with the positive carbon of the carbonyl group (reaction ii) the product regains a proton from the piperidinium ion, and then by loss of water followed by mono-decarboxylation of the malonic acid residue gives the final acid. 

The preparation of 2 4-dimethyl-3 5-dicarbethoxypyrrole (II) is an example of the Knorr synthesis of pyrrole derivatives, involving the reaction of an -aminoketone (or a derivative thereof) with a reactive methylene ketone (or a derivative thereof). The stages In the present synthesis from ethyl acetoacetate (I) may be represented as follows ... 

Aromatic nitro compounds are often strongly colored. They frequently produce characteristic, colored, quinoid derivatives on reaction with alkali or compounds with reactive methylene groups. Reduction to primary aryl amines followed by diazotization and coupling with phenols yields azo dyestuffs. Aryl amines can also react with aldehydes with formation of Schiff s bases to yield azomethines. 

The most interesting product arising from more drastic degradation experiments is a base, C Hi ONa, m.p. 115-120°, obtained by distilling mitragynine with zinc dust. It contains a methoxyl and a methylimino group, and has a reactive methylene group, since it forms a p-nitrobenzyl-idene derivative, m.p. 255°. This base closely resembles both ind- and jM/r-iV-methylharmine, but is not identical with either. 

Formally analogous to the foregoing Grignard additions are the intramolecular condensations of amides with aromatic systems, found in the Bischler-Napieralski reaction 101), which is of particular interest in isoquinoline and indole alkaloid syntheses (102). Condensations of amidines with reactive methylene compounds also led to enamines (103-106). 

FCIO3 also acts as a mild fluorinating agent for compounds possessing a reactive methylene group, e.g. ... 

The 1,3-dicarbonyl components can be replaced by an enol ether, which can be prepared by Claisen condensation from an ortho ester and a reactive methylene compound. ... 

The hydroxythiophenes which exist predominantly as the thiolen-2-ones also show reactions characteristic of the enol form. They can be methylated at the oxygen with dimethyl sulfate of diazomethane and they can also be acylated. - - They also react as thio-lene-2-ones showing a reactive methylene group which can be condensed with benzaldehyde. The danger of using chemical reactivity data for drawing conclusion as to the physical state of these tautomerizable systems has been pointed out. ... 

Mefenidil (78) is a cerebral vasodilator which may be of value in treating geriatric cerebral circulatory problems. It can be synthesized by reacting benzamidine (76) with biacetyl to produce the highly reactive methylene benzimidazole adduct 77. Reaction of the latter with sodium cyanide completes the synthesis 1,26]. 

Selenium dioxide may be used for the oxidation of reactive methylene groups to carbonyl groups. An example is the oxidation of cyclohexanone to cyclohexane-1,2-dione (27). In the procedure, the reaction is carried out on camphor to give camphor... 

The formed metal carbide (M-C) is then hydrogenated to a reactive methylene metal species. 

A variety of products has been obtained from benzopentathiepin and reactive methylene compounds in the presence of triethylamine or sodium ethoxide. Malononitrile and ethyl cy-anoacetate yield the benzodithiins 9, R = CN and C02Et, respectively, ethyl acetoacetate and acetylacetone give benzodithioles 10, R = C02Et and Ac, respectively, and ethyl 2-chloro-propanoate gives the benzotrithiin 11, accompanied by a small amount of the benzodithiole 12.410... 

If R2 contains an a-hydrogen the method cannot be applied as enaminc formation occurs. Bisamides (or -carbamates) are often used in amidoalkylations of aryl and reactive methylene compounds, but the rather harsh reaction conditions severely limit application in the synthesis of more complicated molecules with other functional groups. 

Other compounds with reactive methylene and methyl groups are completely analogous to the nitroalkanes. Compounds with ketonic carbonyl groups are the most important. Their simplest representatives, formaldehyde and acetone, were considered for many decades to be unreactive with diazonium ions until Allan and Podstata (1960) demonstrated that acetone does react. Its reactivity is much lower, however, than that of 2-nitropropane, as seen from the extremely low enolization equilibrium constant of acetone ( E = 0.9 x 10-7, Guthrie and Cullimore, 1979 Guthrie, 1979) and its low CH acidity (pK = 19.1 0.5, Guthrie et al., 1982). ... 

Primary amines and substances with reactive methylene groups react with 1,2-naphthoquinone-4-sulfonate to yield intensely colored p-quinoid derivatives, which, in the case of aryl amines, are indophenol dyes [12, 13]. 

Both overt carbanions and organometallic compounds, such as Grignard reagents, are powerful nucleophiles as we have seen in their addition reactions with C=0 (p. 221 et seq.) they tend therefore to promote an SN2 pathway in their displacement reactions. Particularly useful carbanions, in preparative terms, are those derived from CH2(C02Et)2, (3-ketoesters, l,3-( 3-)diketones, e.g. (55), a-cyanoesters, nitroalkanes, etc.—the so-called reactive methylenes ... 

Nitration of furfuryl alcohol (2-furylmethanol) in acetic anhydride yields the nitro-nitrate 57 which possesses both a reactive methylene group able to undergo aldol reactions, etc., and also a nitrate ion leaving group for nucleophilic substitutions.137 Detailed studies of the nitration disclose various products resulting from the addition of one or even two acetic acid residues to the furan nucleus in competition with the nitrations.138,139... 

A method of general utility is the classical condensation of appropriate reactive methylene compounds (like malononitrile or cyanoacetate) with cyclopropenones73 74 — improved by bifunctional acid-base catalysis67 - in acetic anhydride solution ... 

Resin cures utilise phenol-formaldehyde resins with reactive methylene groups and a small added amount of either a chlorinated rubber, e.g., polychloroprene, or stannous chloride. If halogenated phenolic resins are used the additional source of a halogen may not be required. Resin cures give butyl compounds excellent heat stability and are used to good effect where this is required, e.g., in tyre curing bags which have to resist service at 150 °C in a steam atmosphere. 

V) with a reactive methylene group at C6. According to modern concepts, the phenolic hydroxyl group is believed to activate the positions ortho and para to it. In the case of kojic acid, of the three positions in question, only the one ortho position, namely at C6, is available for substitution. This activating effect of the phenolic function would be particularly marked in alkaline media, where kojic acid probably exists in the form of a phenoxide ion (LXIII) the negative charge would be shared by C6 (LXIV), where it... 

Diazo transfer. This azide is recommended as a relatively safe substitute for tosyl azide for diazo-transfer reactions to reactive methylene groups. Either DBU or N(C2H5)i is a suitable base. It is also suitable for synthesis of vinyl diazo compounds. 1... 

Similarly with other reactive methylene groups like P diketones we get mono and dialkylated... 

Selenium dioxide has been used to oxidise reactive methylene group to carbonyl compound. This methylene group is in a-position to a carbonyl group. Thus cyclohexanone has been oxidised to cyclohexane -1, 2 dione. 

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