Cyanoacetates Michael reactions

P-keto esters with a,p-unsaturated aldehydes liquidrliquid two-phase conditions [20] but, in contrast, under analogous conditions a-cyanoacetic esters produce aldol adducts with a,p-unsaturated aldehydes [20], Ethyl acetoacetate undergoes a catalysed Michael reaction addition with trans but-2-en-l,4-diones the products are generally insufficiently stable for isolation, but can be converted into furans [21 ]. 

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

The first investigations on iron-catalyzed Michael reactions utilized Fe(acac)3 as catalyst. However, this metal complex is itself catalytically almost inactive. Yields of only up to 63% could be achieved, if BF3OEt2 is used as a co-catalyst [55], Polystyrene-bound Fe(acac)3 catalysts were also reported to give yields up to 63% [56], FeCl3 was used as a co-catalyst for clay-supported Ni(II). Yields achieved with this heterogeneous system ranged from 40 to 98% [57]. The double Michael addition of acrylonitrile to ethyl cyanoacetate is smoothly catalyzed by a complex generated from [Fe(N2) (depe)2] [depe = l,2-bis(diethylphosphano)ethane]. At 23 °C and after 36h, an 88% yield is obtained with 1 mol% of this Fe(0) catalyst [58]. 

Solid-phase synthesis is of importance in combinatorial chemistry. As already mentioned RuH2(PPh3)4 catalyst can be used as an alternative to the conventional Lewis acid or base catalyst. When one uses polymer-supported cyanoacetate 37, which can be readily obtained from the commercially available polystyrene Wang resin and cyanoacetic acid, the ruthenium-catalyzed Knoevenagel and Michael reactions can be performed successively [27]. The effectiveness of this reaction is demonstrated by the sequential four-component reaction on solid phase as shown in Scheme 11 [27]. The ruthenium-catalyzed condensation of 37 with propanal and subsequent addition of diethyl malonate and methyl vinyl ketone in TH F at 50 °C gave the adduct 40 diastereoselectively in 40 % yield (de= 90 10). 

Another impressive example of the transition metal-catalyzed Michael reaction was reported by Sawamura and Ito in 1992 (Scheme 6) [7]. a-Methylcyanoacetate was treated with enones using 1 mol% Rh-TRAP (12) complex, and the corresponding adduct 13 was formed in up to 93 % ee. For this reaction, the trans-coordination mode of the chiral diphosphine 12 was essential for high asymmetric induction. It was proposed that coordination of the nitrile group to Rh, then oxidative addition of the active methine C-H bond gave not the a-C-bound enolate, but the nitrile-coordinating enolate 14, which was considered to be a reactive intermediate. The unique structure of this enolate was supported by X-ray analysis of a similar achiral Ru-cyanoacetate complex [8]. 

The most important kinds of conjugate addition reactions are Michael reactions, which involve the addition of C nucleophiles to C=C 7r bonds. The nucleophiles are often 1,3-dicarbonyl compounds such as malonates, cyanoacetates, j8-ketoesters, and 1,3-diketones, but simple carbonyl compounds may also be used. Only catalytic amounts of base are usually required. 

The Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

MCM-41-TBD catalyst has been used in the Michael reaction between 2 cyclopenten-l-one and ethyl cyanoacetate (Scheme 3.17). ... 

Arylidenebarbituric and thiobarbituric acids react with compounds containing an active methylene group under Michael reaction conditions.246,247 Compounds 69 (R = H, p-N02, p-Cl X = O, S) have been obtained in the reaction of 5-arylidenebarbituric or thiobarbituric acids with cyclohexanone, benzyl phenyl ketone, camphor, ethyl ester of phenylacetic acid, or nitromethane. The reaction with ethyl cyanoacetate or ethyl... 

Michael reaction of a-substituted t-butyl cyanoacetates to t-butyl prop3moate establishes a quaternary carbon center in the adducts. Excellent asymmetric induction is achieved by much more bulky ammonium salt. ... 

Aza-Henry reaction is rendered asymmetric by quaternary salts of Cinchona alkaloids. Addition reactions. Changing the 9-hydroxy group of Cinchona alkaloids to a 9-epiamino group not only is synthetically expedient, such products often show excellent catalytic activities in many asymmetric reactions. Those derived from dihydrocinchona alkaloids mediate Michael reactions to good results, including addition of indole to enones, and carbonyl compounds to nitroalkenes. Salt 4 has also been successfully employed in the alkenylation of t-butyl a-aryl-a-cyanoacetate. ... 

Malonate and related activated methylene compounds have also been used as the nucleophile in conjugate addition/Michael reactions. Taylor and co-workers have developed a new methodology that utilizes (salen)aluminum complexes such as 43 as a catalyst to effect the enantioselective conjugate addition to a,p-unsaturated ketones by a variety of nucleophiles.25 For example, nitriles, nitroalkanes, hydrazoic acids, and azides have found utility in this reaction. Additionally, cyanoacetate (42) has been demonstrated to undergo a highly enantioselective conjugate addition to 41. The Krapcho decarboxylation is then necessary to produce cyanoketone 44, an intermediate in the synthesis of enantioenriched 2,4-cw-di substituted piperidine 45. 

Aldol reaction. The Rh-complexes that also contain the ethyl cyanoacetate anion are active in promoting both aldol and Michael reactions, for example, involving cyanoacetic esters. 

Aldol and Michael reactions. Active methylene compounds such as ethyl cyanoacetate and malonic esters react with aldehydes and electron-deficient alkenes in the aldol and Michael mode, respectively. 

Scheme 5.17 Enantioselective Michael reaction of cyanoacetates with acetylenic ketones.

The Michael reaction of a-substituted cyanoacetates with acetylenic esters can also be carried out in a very efficient way using a different... 

The COj species in the HT interlayer could be exchanged with OH ions by calcination at 723 K and hydration at room temperature. A spinel phase of Mg-Al mixed oxide obtained after the calcination transforms into the original layered structure during the hydration. This reconstruction is known as the memory effect of HT materials. The reconstructed HT catalyzed the Knoevenagel condensation of various aldehydes with nitriles in the presence of water [119]. The reconstracted HT also showed an aqueous Michael reaction of nitriles with a,p-unsaturated compounds. The layered double-hydroxide-supported diisopropylamine catalyzed the Knoevenagel condensation of aromatic carbonyl compounds with malononitrile or ethyl cyanoacetate [120]. This solid base could be recycled at least four times, and exhibited activity for aldol, Henry, Michael, transesterification, and epoxidation of alkenes. 

In 2004, Fossey and Richards [21] reported the synthesis of 2,6-bis(2-oxazolinyl) phenylplatinum(I I) NCN-Pincer complexes (63a-d) (Scheme 16.20). These cationic complexes were employed as Lewis acid catalysts for the Michael reaction between methyl vinyl ketone (49c) and ethyl cyanoacetate (64) and Diels-Alder reaction between acrylonitrile (67) and cyclopentadiene (14). The highest rates of the Michael reactions were observed when Pt-oxazolines (63a) and (63b) were used as catalysts, and the lowest rates of the Diels-Alder reaction was observed when Pt-oxazoline (63c) was used as a catalyst. Introduction of a nitro substituent on para position as shown for (63c) resulted in higher Lewis acidity but reduced catalytic activity. 

The use of supported organocatalysts in flow chemistry is not new. A pioneering work using an organic base catalyst was reported by Venturello. Knoevenagel condensations of aromatic aldehydes, cyclohexanone, and acetophenone with acetoa-cetate, cyanoacetate, or malonate were catalyzed by aminopropyl-functionalized silica gel (56), which was packed in a gravity-fed column, under continuous-flow conditions (Scheme 7.40) [149]. A flowcell microreactor, whose wall surfaces were coated with aminopropylsilica, was utilized in Knoevenagel and Michael reactions [150]. 

A variant in the production of an intermediate in the Robinson synthesis, the tricyclic ABC diketone (18), was developed by Banerjee and co-workers [635, 636] (Scheme 58). The triester (22) was obtained from a-ethoxycarbonylcyclohexanone (21) by the Michael reaction with methyl acrylate, alkaline cleavage, and esterification, and it was then cyclized by Dieckmann s method with subsequent bromination and dehydrogenation to give the unsaturated keto diester (23). The addition of cyanoacetic ester gave compound (26) from which the keto triester (25) was obtained by methylation, acid hydrolysis, and esterification. The latter, by Dieck-mann cyclization and hydrolysis, gave the BC fragment (24). Selective ketalization, reduction, and hydrolysis of the ketal led to the hydroxy-ketone (27). The trans-B/C linkage present in it required the protection... 

Aminopropylated functionalized hexagonal mesoporous silicas (HMS) and SBA-15 materials with different amino-loadings (5-30 wt. % NH ) were synthesized by Pineda et al. (2013). These play important role as catalyst in the microwave-assisted Knoevenagel condensation of cyclohexanone and ethyl cyanoacetate as well as in the Michael reaction between 2-cyclohexen-l-one and nitromethane. The low loaded HMS-5%NH2 and higher loaded SBA-15-20% NH were found to give the best activities in the reactions. High activities and selectivities to the condensation product could be achieved in short times of microwave irradiation for both these base-catalyzed processes. 

The Michael Addition Reaction consists in the addition of the sodio-derivative of ethyl acetoacetate, ethyl malonate or ethyl cyanoacetate to an olefine group... 

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