Methyl cyanoacetate, Michael

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-... 

Scheme 19.22 Asymmetric Michael additions of malononitrile and methyl cyanoacetate to a,p-unsaturated imides catalysed by [(salen)Al]20.

Condensation Reactions. In the presence of dipolar apro-tic additives, e.g. hexamethylphosphoric triamide (eq 4) or 12-crown-4, which reduce the degree of aggregation, f-BuOLi catalyzes the Michael addition of methyl cyanoacetate to benzylideneacetophenone. A similar yield of the Michael adduct is obtained if f-BuOK is used as the base, and no additive is required. 

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). 

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. 

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.

The addition of nitromethane (56% yield/168h 87% ee) or methyl a-cyanoacetate (94% yield/52h 82% ee) as alternative CH-acidic methylene compounds required increased reaction temperatures (60 to 80 °C) to furnish the adducts 7 and 8. As exemplarily depicted in Scheme 6.69 for benzylic alcohol thiourea 12 catalyzes the transformation of the obtained malononitrile Michael products to the respective carboxyhc acid derivatives (89% yield/88h). This method of derivatization also described for methanol (87% yield/24h rt), benzyl amine (77% yield/3h rt), and N,0-dimethylhydroxyamine (75% yield/20h 60°C) as nucleophiles was reported to be feasible as a one-pot strategy without isolation of the initially formed Michael adduct [222]. 

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,... 

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). 

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. 

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. 

Rann et al. reported the dramatic influence of a new tailor-made, task-specific, and stable ionic liquid, butyl methyl imidazolium hydroxide ([bmim][OH]), in Michael addition. They have discovered that a task-specific ionic liqnid [bmim][OH] efficiently promoted the Michael addition of 1,3-dicarbonyl compounds, cyano esters, and nitro alkanes to a variety of conjugated ketones, carboxylic esters, and nitriles withont reqniring any other catalyst and solvent (Fig. 12.21) [16]. Very interestingly, all open-chain 1,3-dicarbonyl componnds such as acetylacetone, ethyl ace-toacetate, diethyl malonate, and ethyl cyanoacetate reacted with methyl vinyl ketone and chalcone to give the usual monoaddition products, whereas the same reactions with methyl acrylate or acrylonitrile provided exclusively bis-addition products. 

In addition, it has been shown that the catalytic use of PS-N3PAPT (10 mol%) was very effective for Michael addition reactions of a variety of Michael donors such as p-ketoesters, ot-nitroketones and nitroalkanes with activated olefins such as methyl acrylate and methyl vinyl ketone [41] (Scheme 6.9). The recyclability of the catalyst was established after it had been used 12 times. When diethyl malonate or ethyl cyanoacetate was used as the Michael donor substrate, the expected disubstituted adducts were obtained in moderate to good yields. 

Double Michael addition reactions between methyl vinyl ketone (MVK) and ethyl a-cyanoacetate under continuous conditions (dead-end reactor) were performed with a dodecakis (NCN-Pd") catalyst by the van Koten group (12). A high productivity and retention (99.5%) of the catalyst for more than 24 h was observed, but slow deactivation of the system occurred after a stable conversion level had been reached [23]. 

The dialdehydes from periodate oxidation of methyl 4,6-0-benzylidene-a-and -p-D-glucopyranoside reacted with appropriate Wittig reagents to give such dienes as (400) that afforded cyclized products [e.g. (401)] with nitromethane by a double Michael condensation, whereas only one of the olefinic linkages was attacked, without cyclization, with ethyl cyanoacetate and malononitrile. Details of the reactions of these dialdehydes with nitroalkanes (see Vol. 8, p. 108), ethyl cyanoacetate (see VoL 8, p. IlOX and other carbanions to give various branched-chain heptoseptanosides have also been reported. ... 

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. 

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... 

The corresponding monohydroxy[ C]methyl derivatives, accessible through reaction of equimolar amounts of H CHO and alkyl cyanoacetates or dialkyl malonates readily eliminate water to give alkyl 2-cyano[3- C]acrylates till. =CN) and dialkyl [ " C]-methylenemalonates till. R = COOR ), respectively, which are highly valuable intermediates in Michael additions, Diels—Alder reactions and epoxidations. Unfortunately, carbon-14-labeled acrylates are unstable towards radiation induced polymerization. In order to circumvent this undesirable side effect, it has been recommended to run the formation in the presence of anthracene in order to trap the [ Clacrylates in situ as stable Diels-Alder adducts 112. These can be purified and stored briefly. Their subsequent thermolysis in the presence of maleic acid anhydride re-generates the acrylates 111 for immediate use in further reactions. ... 

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