Cyanoacetates, Michael addition

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

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

Fig. 30 Asymmetric aza-Claisen rearrangement of (Z)-configured trifluoroacetimidates 44 3.1.2 Bispalladium-Catalyzed Michael-Addition of a-Cyanoacetates...

The above is an example of the Guareschi reaction. It is applicable to most dialkyl ketones and to alicyclic ketones (e.., cj/clohexanone, cyclopentanone, etc.). The condensation product (I) is probably formed by a simple Knoe-venagel reaction of the ketone and ethyl cyanoacetate to yield ethyl a-cyano-pp dimethylacrylate (CH3)2C=C(CN)COOC2Hj, followed by a Michael addition of a second molecule of ethyl cyanoacetate finally, the carbethoxyl groups are converted to the cyclic imide structure by the action of ammonia. 

A dodecakis(NCN-Pdn) catalyst, synthesized in the group of Van Koten (Figure 4.24), was applied in the a continuous double Michael addition reaction between methyl vinyl ketone (MVK) and ethyl a-cyanoacetate.[34] The reaction was performed in the deadend reactor discussed in paragraph 4.2.1. Two catalytic runs were performed differing in the amount of catalyst and in the applied flow (both increased by a factor 2.5). Both runs showed high productivity for more than 24 h (Figure 4.25). 

Intermediates such as 224 resulting from the nudeophilic addition of C,H-acidic compounds to allenyl ketones such as 222 do not only yield simple addition products such as 225 by proton transfer (Scheme 7.34) [259]. If the C,H-acidic compound contains at least one carbonyl group, a ring dosure is also possible to give pyran derivatives such as 226. The reaction of a similar allenyl ketone with dimethyl mal-onate, methyl acetoacetate or methyl cyanoacetate leads to a-pyrones by an analogous route however, the yields are low (20-32%) [260], The formation of oxaphos-pholenes 229 from ketones 227 and trivalent phosphorus compounds 228 can similarly be explained by nucleophilic attack at the central carbon atom of the allene followed by a second attack of the oxygen atom of the ketone at the phosphorus atom [261, 262], Treatment of the allenic ester 230 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidone (NMP) affords the cephalosporin derivative 232 [263], The authors postulated a Michael addition of copper(I) hydride to the electron-... 

The same hyperbranched polyglycerol modified with hydrophobic palmitoyl groups was used for a noncovalent encapsulation of hydrophilic platinum Pincer [77]. In a double Michael addition of ethyl cyanoacetate with methyl vinyl ketone, these polymer supports indicated high conversion (81 to 59%) at room temperature in dichloromethane as a solvent. The activity was stiU lower compared with the noncomplexed Pt catalyst. Product catalyst separation was performed by dialysis allowing the recovery of 97% of catalytic material. This is therefore an illustrative example for the possible apphcation of such a polymer/catalyst system in continuous membrane reactors. 

Following work on Michael addition of triazoles to nitro-olefins (discussed in Sect. 2.5), bifunctional chiral thiourea catalysts were used in the addition of triazoles to chalcones [83]. The catalytic system was applicable to enones bearing aromatic groups of varying electronic natures to provide good yields and moderate selectivity. a-Cyanoacetates [84] were also applied in Michael addition to chalcones under similar catalytic conditions (Scheme 33). 

The phosphine-containing ruthenium dihydride dendrimer 33 was found to be an active catalyst for the diastereoselective Michael addition of ethyl cyanoacetate to diethyl ethylidenemalonate in THF (Scheme 12). The dendritic catalyst showed an activity and selectivity similar to those of the reference compound RuH2(PPh3)4 (100% conversion after 24 h and a diastereoselectivity of 7/3) (40). The dendritic catalyst was recycled twice by precipitation with diethyl ether without loss of activity or selectivity. Complex 34 showed similar activity and recoverability over three runs like that of complex 33. 

The same group reported that bifunctional thiourea 12 catalyzed the enantiose-lective Michael addition [149-152] of a-alkyl and also a-aryl cyanoacetates to alkyl vinyl ketones and aryl vinyl ketones, respectively, to give the desired... 

Scheme 6.66 Products of the 12-catalyzed asymmetric Michael addition of a-alkyl cyanoacetates to vinyl sulfone and exemplary conversion of one adduct to the respective 3 amino acid. The values in parentheses were obtained after single recrystallization the absolute configurations of the products were not determined.

Scheme 6.69 Products obtained from the 12-catalyzed asymmetric Michael addition of malononitrile, nitromethane, and methyl a-cyanoacetate to N-cinnamoylbenzamide derivatives (acylic imides) and 12-catalyzed derivatization of the Michael adduct.

Scheme 6.92 Product range of the 79-catalyzed Michael addition of a-aryl cyanoacetates to phenyl vinyl sulfone and conversion of one exemplary adduct (R = Ph) to the corresponding protected 3-amino acid. The absolute configurations of the adducts were not determined.

In 2007, Chen and co-workers reported the 122-catalyzed (10mol% loading) enantioselective Michael addition [149-152] of ethyl a-cyanoacetate to various electron-rich and electron-deficient trans-chalcones [283]. The reaction was performed for a broad spectrum of chalcones and gave the corresponding adducts in yields of 80-95% and in ee values of 83-95%, but at low sy /a ti-diastereoselectiv-ities as shown for representative products 1-8 in Scheme 6.125. 

Mettler and colleagues reported an alternative synthesis of malonate 16 in the same paper (Griffiths et al., 1991) in which they condensed cyclohexanone with ethyl cyano-acetate instead of diethyl malonate in the Knoevenagel reaction to give ethyl cyano(cyclohexylidene)-acetate (18). In the presence of a catalytic amount of sodium cyanide, the Michael addition of HCN to cyanoacetate 18 proceeded in good yield at room temperature to generate the dicyanoester 19. Intermediate 19 was selectively converted to malonate 16 with pressurized HCI treatment in ethanol (Scheme 16.4). 

The cyclization of 5-oxonitriles offers an attractive route to 2-amino-4//-pyrans (Scheme 18) (78JHC57). The starting materials, a-benzoylcinnamonitriles, are available from benzoyl-acetonitrile and an aromatic aldehyde. Michael addition of ethyl cyanoacetate or malononitrile to the benzoylcinnamonitrile affords the oxonitrile and is followed by cyclization to the imine. The reaction proceeds at room temperature in the presence of either piperidine or sodium ethoxide. 

Michael addition to unsaturated amides. This system (1 equiv. of each) effects Michael addition of ketones, nitro compounds, ethyl cyanoacetate, and diethyl malonate to a,(3-unsaturated amides. Addition to methacrylamides is interesting because the final products are glutarimides or dihydropyridinones. 

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]. 

Three equivalents of FeCl3 are required for the reaction of chalcone 41 j with ethyl cyanoacetate to give a-pyridone derivative 72 (Scheme 8.32) [100]. The reaction is carried out at 140 °C under strongly acidic conditions (FeCl3 dissolved in propionic acid). It proceeds presumably by an initial Michael addition yielding intermediate 73. Excess of iron(III) is required, because this is the oxidizing reagent for the introduction of the second C—C double bond in intermediate 74. 

The Michael addition of oxygen nucleophiles to vinyl sulfones185 and the addition of dimethyl malonate and ethyl cyanoacetate to a,fl-unsaturated sulfones in the presence of Triton-B and K2CO3 have been studied.186... 

Scheme 2 shows Rapoport s synthesis [15]. The cinnamic acid derivative 3 prepared from m-methoxy benzaldehyde [20] was ethylated by diethyl sulfate to give ethyl cinnamate derivative 4, followed by Michael addition with ethyl cyanoacetate to afford compound 5. Compound 5 was converted to lactam 6 by the reduction of the cyano group and subsequent cyclization. Selective reduction of the lactam moiety of 6 was achieved by treatment with trimethy-loxonium fluorob orate followed by sodium borohydride reduction. Amine 8 was obtained by the reductive methylation of amine 7. Amine 8 was converted to compound 9 by methylene lactam rearrangement [21], followed by selenium dioxide oxidation to provide compound 10. Allylic rearrangement of compound 10 and subsequent hydrolysis gave compound 12. The construction of the decahydroisoquinoline structure began with compound 12,... 

The racemic complex 4 containing 50% of NCN-pincer platinum(II) and 50% of tosylate groups has been tested in catalytic double Michael addition of methyl vinyl ketone and ethyl cyanoacetate using (1 mol %) of catalyst. 

In Michael additions of ethyl cyanoacetate, diethylmalonate and 1,3-diones to acrolein, methylvinylketone and other enones, the catalytic activity on the system was... 

CsX is useful for the simple Knoevenagel reaction of benzaldehyde with ethyl cyanoacetate even a simple NaY is sufficiently basic to form carbamates starting from primary aromatic amines and dialkyl carbonates (35, 36). At contrast CsjO-MCM-41 can also be used for the addition of C02 to epoxides, or for Michael addition of one or two molecules of diethyl malonate on neopentylglycol diacrylate (37, 38) ... 

In contrast with the widespread application of zeolites as solid acid catalysts (see earlier), their use as solid base catalysts received scant attention until fairly recently [121]. This is probably because acid-catalyzed processes are much more common in the oil refining and petrochemical industries. Nonetheless, basic zeolites and related mesoporous molecular sieves can catalyze a variety of reactions, such as Knoevenagel condensations and Michael additions, which are key steps in the manufacture of flavors and fragrances, pharmaceuticals and other specialty chemicals [121]. Indeed, the Knoevenagel reaction of benzaldehyde with ethyl cyanoacetate (Fig. 2.36) has become a standard test reaction for solid base catalysts [121]. 

Cesium-exchanged zeolite X was used as a solid base catalyst in the Knoevenagel condensation of benzaldehyde or benzyl acetone with ethyl cyanoacetate [121]. The latter reaction is a key step in the synthesis of the fragrance molecule, citronitrile (see Fig. 2.37). However, reactivities were substantially lower than those observed with the more strongly basic hydrotalcite (see earlier). Similarly, Na-Y and Na-Beta catalyzed a variety of Michael additions [122] and K-Y and Cs-X were effective catalysts for the methylation of aniline and phenylaceto-nitrile with dimethyl carbonate or methanol, respectively (Fig. 2.37) [123]. These procedures constitute interesting green alternatives to classical alkylations using methyl halides or dimethyl sulfate in the presence of stoichiometric quantities of conventional bases such as caustic soda. 

Carbon-carbon bond formation via the Michael addition of a,P-unsaturated ketone and 1,3-diketone is achieved in high yields and short times to give (61) by employing catalytic amounts of EUCI3 in dry media under microwave irradiation (Soriente et al, 1997). Ranu et al. (1997) reported the Michael addition of ethyl acetoacetate, acetyl acetone, and ethyl cyanoacetate to cycloalkenones, P-substituted enones and enal. The reaction accomplished efficiently on the surface of alumina under microwave irradiation in dry media. Baruah et al. (1997a,b) also demonstrated the BiClj and Cdl2 catalyzed solvent-free Michael addition of 1,3-dicarbonyl compounds under microwave irradiations with good yields. 

Scheme 7.16 Deng s Michael addition/enantioselective protonation with acyclic cyanoacetates [19].

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. 

In 2006, Chen and coworkers reported that cinchona-based thioureas (79a or 81b) serve as catalysts for the Michael addition of a-phenyl cyanoacetate (94) to phenyl vinyl sulfone (177) at room temperature, affording the addition product 178. Nearly quantitative yields were obtained. However, the obtained ee values were only moderate (43-54% ee) (Scheme 9.62) [55]. 

Disappointing results have been obtained from the Michael addition of compounds containing active methylene groups to vinylphosphonates. For example, cyanoacetate reacts with the diethyl vinyphosphonate under the conditions of base catalysis to give a mixture of 1 1 and 1 2 adduct resulting of one or two additions to the vinylphosphonate. When 2-pyridylacetonitrile and cyanomethylphosphonate are subjected to this reaction, diethyl 3-(2-pyridyl)- or 3-diethoxy-phosphinyl-3-cyanopropylphosphonates are obtained in 61% and 98% yields, respectively (Scheme 6.35). 

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