Malonitrile Michael reaction

Some more significant applications. Aldol reaction in ionic liquids is catalyzed by 0-silylserines. Michael reaction between malonitrile and chalcones proceeds without the usual catalysts using ionic liquids as reaction media, presumably the acidity of the carbon acid is enhanced/... 

Takemoto et al developed a novel bifunctional thiourea catalyst bearing amine moiety (9), which promoted the Michael reaction of malonate with nitroalkenes to give corresponding adducts with high enantioselectivity (Scheme 2.34) [85]. The bifunctional thiourea catalyst is effective for the 1,4-addition of the anion of malonitrile to a,P-unsaturated imide (Scheme 2.35) [86]. 

Catalytic asymmetric Michael addition is an important reaction for creating carbon-carbon bonds with enantioselectivity. This reaction can be combined with other catalytic transformations to build up complex organic structures. A successful example is the enantioselective cascade Michael addition/H -hydrogenation catalyzed by ruthenium hydride borohydride complexes containing P-aminophosphine ligands 26 (Scheme 5.13) [19]. This approach has been extended to pentenones, heptenones, and nitrostyrene Michael acceptors and malonitrile Michael donors. 

An one-pot convenient method for the synthesis of a variety of 2,2 -dicyanoalkylphosphonates (557) by a tandem Knoevenagel-phospha-Michael reaction of triethyl phosphite (556) with aryl/heteroaryl/alkyl aldehydes (554) and malonitrile (555) in an aqueous micellar solution of sodium stearate,using surfactants, such as cetyltrimethylammonium bromide as a eationic mieelle and TritonX-100 as a neutral micelle at their critical micellar eoncentrations (CMC), has been described by Sobhani and Parizi (Scheme 138). ... 

J0rgensen has also reported a sequential Michael/Michael/aldol condensation for the three component coupling of malonitrile 111 and a,P-unsaturated aldehydes that involves two iminium ion catalysed Michael additions followed by an intramolecular aldol condensation (Scheme 43) [170]. Using diarylprolinol ether 55 (10 mol%) in a concentrated toluene solution of malonitrile 111 and 3 equivalents of a,P-unsaturated aldehyde the reaction products can be isolated in just 1 8 h (57-89% yield 97-99% ee). The atom efficiency of this three component reaction is remarkable and the ability to prepare these complex products under... 

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

An alternative pathway for the above reactions has also been proposed by the authors, involving first a Michael addition of the nucleophile, followed by a subsequent interception of the palladium intermediate species. Nevertheless, the authors opinion is in favor of the first mechanism as proved, in a control experiment, by no isolation of Michael adduct when benzylamine was used as the sole reagent and in the absence of carbon monoxide. In the case of allene, when malonitrile was used as the nucleophile (YH2) and the reaction stopped before completion, a mixture of intermediate 104 and final product was isolated giving an evidence for the proposed mechanism. 

Sharpless bis-cinchona alkaloids such as [DHQD]2PYR (163a) have proved to serve as highly efficient catalysts for the asymmetric vinylogous Michael addition of the electron-deficient vinyl malonitriles 164 as the nucleophilic species to nitroole-fins 124 [50], This process exhibited exclusive y-regioselectivity and high diastereo-and enantioselectivity. Only the anti-products 165 were observed in all reactions (Scheme 9.57). Of note, 1-tetralone did not react with nitroolefins under these... 

The nucleophilic carbanion can also be generated from a,a-dihalomalonates or malonitriles and a suitable metal. Examples have been reported of zinc metal, magnesium metal, indium metal,dialkyltelluride, trialkylstibene, trialkylarsane, and trialkylbithmuthane mediated cyclopropanations of Michael acceptors. These reactions are closely related to the examples mentioned above. 

A library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[l)]thiophene-4,6-dicarbonitriles was synthesized by a one-pot domino reaction of 5-aryldihydro-3(2H)-thiophenes, malonitrile, and aromatic aldehydes in the presence of morpholine (13BMCL2101). A mechanism was proposed that involves a sequence of Knovenagel condensation, Michael addition, intramolecular Thorpe-Ziegler cyclization, tautomerization, and elimination. The compounds were evaluated for their AChE (acetylcholinase) activity. The 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[l)] thiophene-4,6-dicarbonitrile was found to be the most potent with IC50 4.16 xmol/L. 

A three-component reaction related to the Hantzsch-synthesis of dihydropyrid-ines was recently reported by Yuan and colleagues who developed a domino cascade Knoevenagel/Michael/cyclization sequence converting isatin derivatives 182, malonitrile (183), and symmetrical acyclic 1,3-diketones or (3-ketoesters 184... 

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