Reaction with reactive methylene compounds

Many synthetic approaches are based on reactions with reactive methylene compounds and hydrazones, a reaction that was first introduced by Schmidt and Druey in 1954. Benzil or monohydrazones of benzil or related... 

Reaction with reactive-methylene compounds. Claisen" developed a method for the preparation of diethyl ethoxymethylenemalonate by heating a mixture of triethyl orthoformate, malonic ester, and acetic anhydride with a catalytic amount of zinc chloride. The yield cited is that obtained in a standardized procedure."... 

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). 

Another useful method to convert thioureas into carbodiimides involves their reaction with reactive chlorine compounds, such as SOCI2, SO2CI2, SCI2 or S2CI2, The use of the sulfur chlorides involves chloroformamidines as intermediates (see Section 2.2.6). The reaction of thioureas 11 with methanesulfonyl chloride in methylene chloride in the presence of triethylamine/DMAP (4-dimethylaminopyridine) at room temperature produces carbodiimides 12 in 85-100% yield... 

Many furanquinones, derivatives of 84, were formed in the reaction of 2,3-dichloro-1,4-naphthoquinone with reactive methylene compounds in the presence of various basic reagents. The reaction can proceed in one step or by a two-step route via 3-substituted 2-chloro-l,4-naphthoquinones (1900CB2402 53P1A(A)534 57JA5489 65JOC3819 71ZOR1031). 

The reaction of (f /Z)-4-arylidenepyrazol-3-ones 491a-c with reactive methylene compounds such as diethyl or dimethyl malonate, ethyl cyanoacetate or cyano-acetamide in alcoholic solution containing sodium hydroxide afforded the corresponding addition products 492c-j. These adducts were found to be almost exclusively enol tautomers (79AP478) (Scheme 151). 

Synthesis of thiazolo[3, 272,3]ll,2,4]triazino[5,6-i)]indoles has been reported <04IJC(B)1585>. Different functionalizations of l,2,4-triazino[5,6-f>]indoles have been carried out <04JCR(S)183>. Reaction of 3-diazopyrazolo[3,4-clpyridazine with reactive methylene compounds yielded condensed 1,2,4-triazine derivatives <04H1143>. 

A wasteful side reaction which sometimes occurs in the alkylation of 1,3-dicarbonyl compounds is the formation of the 0-alkylated product. For example, reaction of the sodium salt of cyclohexan-l,3-dione with butyl bromide gives the 0-alkylated product (37%) and only 15 % of the C-alkylated 2-butylcyclohexan-1,3-dione. In general, however, 0-alkylation competes significantly with C-alkylation only with reactive methylene compounds in which the equilibrium concentration of enol is relatively high (as in 1,3-dicarbonyl compounds). The extent of C- versus 0-alkylation for a particular 1,3-dicarbonyl compound depends on the choice of cation, solvent and electrophile. Cations (such as Li+) that are more covalently bound to the enolate oxygen atom or soft electrophiles (such as alkyl halides) favour C-alkylation, whereas cations such as K+ or hard electrophiles (such as alkyl sulfonates) favour 0-alkylation. 

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. 

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. 

Classical Aldol. Aldol reaction is an important reaction for creating carbon-carbon bonds. The condensation reactions of active methylene compounds such as acetophenone or cyclohexanone with aryl aldehydes under basic or acidic conditions gave good yields of aldols along with the dehydration compounds in water.237 The presence of surfactants led mainly to the dehydration reactions. The most common solvents for aldol reactions are ethanol, aqueous ethanol, and water.238 The two-phase system, aqueous sodium hydroxide-ether, has been found to be excellent for the condensation reactions of reactive aliphatic aldehydes.239... 

Considering the electrophilic nature of the reaction mechanism, suitable coupling components for the synthesis of azo pigments should carry a nucleophilic center on the aromatic ring system (naphthols) or should be enolizable compounds with reactive methylene functions. Naphthols enter the reaction as naphtholates compounds with reactive methylene groups participate as enolates. 

The Knoevenagel reaction consists in the condensation of aldehydes or ketones with active methylene compounds usually performed in the presence of a weakly basic amine (Scheme 29) [116], It is well-known that aldehydes are much more reactive than ketones, and active methylene substrates employed are essentially those bearing two electron-withdrawing groups. Among them, 1,3-dicarbonyl derivatives are particularly common substrates, and substances such as malonates, acetoacetates, acyclic and cyclic 1,3-diketones, Meldrum s acid, barbituric acids, quinines, or 4-hydroxycoumarins are frequently involved. If Z and Z groups are different, the Knoevenagel adduct can be obtained as a mixture of isomers, but the reaction is thermodynamically controlled and the major product is usually the more stable one. 

Hydrazino groups attached to cationic rings (as 763) undergo oxidative coupling reactions with amines, phenols (to give e.g. 764) and reactive methylene compounds, e.g. (763) + CH2(CN)2 — (765). 

The reactive 3-carbonyl group in compounds of type (279) undergoes aldol condensation with active methylene compounds such reactions of isatin with indoxyl, oxindole (Section 3.3.2.5.4) and with thiophenes (Section 3.3.1.5.7.ii) have already been mentioned. These compounds also react with Grignard reagents and phosphorus halides as expected, e.g. isatin (279 Z = NH) with MeMgBr and PC13 yields (285) and (286), respectively. 

Azo coupling reactions are frequently observed in diazo transfer processes in which 4-toluenesulfonyl and other azides react with highly reactive methylene compounds, e. g., with dicarbonyl compounds (see Sect. 2.6, Schemes 2-56, 2-59, and 2-63). Such reactions were not, however, investigated mechanistically. Thus, although it is likely that alkanediazonium ions are intermediates, there is no direct evidence for their intermediacy. 

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