Active methylene compounds coupling with malonates

In 2004—2005, we reported direct alkylation of tautomerizable heterocycles with activated methylene compounds such as malonate via phosphonium coupling to produce alkylated heterocyclic compounds. Activated methylene compounds are weak nucleophiles, therefore the NaOi-Bu-promoted... 

Although arylation or alkenylation of active methylene compounds can be carried out using a Cu catalyst, the reaction is sluggish. However, the arylation of malononitrile (390) or cyanoacetate proceeds smoothly in the presence of a base and Pd catalysts [189], Tetracyanoquinodimethane (392) is prepared by the coupling of / -diiodoben-zene with malononitrile (390) to give 391, followed by oxidation [190], Presence of the cyano group seems to be essential for intermolecular reactions. However, the intramolecular arylation of malonates, / -keto esters and /i-diketones proceeds smoothly [191]. The bromoxazole 393 reacts with phenylsulphonylacetonitrile (394)... 

In the case of 1,3-dicarbonyl compounds, the solvent frequently interferes with the coupling reaction. So with diethyl sodio malonate in ethanol [212b], methanol [212b], dimethylacetamide [212b], or HMPTA [216], besides the dimer and the trimer, the compounds LIXa-c are obtained. They are presumably formed by oxidation of the solvent to the aldehyde and its condensation with the active methylene compound. No dimer was detected in the oxidation of sodio acetoacetate in ethanol, with the major product being LX [217]. Anodic oxidation of cyclic 1,3-diketones in aqueous methanolic sodium hydroxide does not yield the dimer but product LXI, formed by condensation of the starting compound with formaldehyde [218]. 

CuI/L-proUne (LI) was proved to be a quite efficient catalytic system for this coupling. The reaction proceeded smoothly in DMSO at 40-50°C in the presence of CS2CO3 (Table 9.14, entry 1) [67]. Both aryl iodides and bromides were suitable substrates. A wide range of activated methylene compounds, including ethyl ace-toacetate, ethyl benzoyl acetate, and diethyl malonate were compatible with these reaction conditions. This catalytic system could also be used for the arylation of aryl iodides with acetylacetone and ethyl cyanoacetate (entry 2) [68]. Recently, it was found that 2-picoUnic acid (L4) could lead to the arylation of aryl iodides and diethyl malonate worked at room temperature (entry 3) [69]. For hindered substrates or aryl bromides, higher reaction temperatures were still required. Additionally, Chxn-Py-Al (L16) was revealed to accelerate the Cul-catalyzed coupling of iodobenzene with diethyl malonate, ethyl cyanoacetate and malononitrile (entry 4) [26],... 

Barbituric acid can be considered as a cyclized malonic acid diamide (malonyl-urea). It is therefore a cyclic diketone that may be classified, in the sense of the compounds discussed in Section 12.6, as a coupling component with a methylene group activated by two carbonyl groups in the a- and a -positions. The reaction with arenediazonium salts was studied by Nesynov and Besprozvannaya (1971). These authors obtained coupling products (in good yield) that they considered to be arylhydrazones. Coupling with 4-(phenylazo)benzenediazonium chloride was studied by Chandra and Thosh (1991). The lH NMR spectra of these compounds are consistent with the arylhydrazone structure 12.68. 

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