Knoevenagel/Michael

Ramachary, D.B. Barbas, C.R III (2004) Towards Organo-Click Chemistry Development of Organocatalytic Multicomponent Reactions Through Combinations of Aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen Cycloaddition Reactions. Chemistry A European Journal, 10, 5323-5331. 

Scheme 2.70. Asymetric domino Knoevenagel/Michael addition reaction.

Multicomponent reactions of this type, in the concepts of Tietze, who introduced the term domino reactions (96CRV115), can also be regarded as domino reactions of the type Knoevenagel-Michael-ljef-ero-Thorpe-Ziegler in accordance with the probable mechanistic scheme (Scheme 32). 

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. 

Base-catalysed reactions such as the Knoevenagel, Michael and aldol reactions continue to be of importance in industrial routes to synthetic chemicals and are often inherently clean, with water (or nothing) as the by-product. Traditional homogeneous methods of catalysis often require upwards of 40 mol% catalyst (such as piperidine) with the attendant difficulties in recovery and reuse of the catalyst. They often offer extremely poor selectivity to the desired products, either due to competing processes (side reactions) or further reaction of the first-formed product. 

Modified clays (e.g. montmorilonite K-10) as mild Lewis acid catalysts in Knoevenagel, Michael, Diels-Alder reactions, aromatic chlorination and nitration. 

A three-component expeditious synthesis of 3,6-diaryl-5-mercaptoperhydro-2-thioxo-l,3-thiazin-5-ones from 2-methyl-2-phenyl-l,3-oxathiolan-5-one, an aromatic aldehyde, and an N-aryldithiocarbamic acid has recently appeared [194]. The synthesis is diastereoselective and involves tandem Knoevenagel, Michael, and ring transformation reactions occurring under solvent-free MW irradiation conditions in a single pot (Scheme 8.81). 

Scheme 10.32 Three-component domino Knoevenagel/Michael/cyclization reaction.

W. -C. Ynan, Org. Lett. 2010, 12, 3132-3135. Highly enantioselective construction of spiro[47f-pyran-3,3 -oxindoles] through a domino Knoevenagel/Michael/cyclization sequence catalyzed by cupreine. 

Yuan and coworkers have reported an enantioselective three-component domino Knoevenagel/Michael/cyclization sequence using 226, a 1,3-dicarbonyl compound 228, and malononitrile 227 catalyzed by cinchona alkaloid cupreine 229 (Scheme 6.32). The spirocychc oxindole pyrans 231 were obtained in high yields (85-99%) and enantioselectivi-ties (up to 96% ee) [63]. Inconveniently, the reaction requires high dilutions (0.1-0.005 M) resulting in a large amount of used solvents. Macaev and coworkers have used chiral catalyst (-)-(S)-brevicolline 230 for the obtainment of the same... 

J. Kamalraja, D. Muralidharan, P. T. Perumal, Synlett 2012, 23, 2894—2898. An efficient, one-pot regioselective synthesis of highly functionalized chromene-5-ones and pyrano[3,2-c] chromene-5-ones via a tandem Knoevenagel-Michael-cycli-zation sequence. 

The use of special enamines in the three-component Knoevenagel-Michael addition/cyclization sequence directly led to Af-alkyl- or Af-aryl-substituted 2-amino-4//-pyrans. Perumal et al. therefore applied catalytic amounts of piperidine in ethanol at ambient temperature to add ( )-Al-methyl-l-(methylthio)-2-nitroethenamine 49 to the previously formed Michael acceptor in a one-pot fashion (Scheme 13.16) [7]. This protocol provides the desired lV-methyl-2-amino-4//-pyrans 50/51 in good yields. The methylthio substituent serves as a good leaving group facilitating the cyclization subsequent to the Michael addition reaction by nucleophilic substitution. 

In 2012, Rueping et al. reported the proline-mediated reaction of 1,3-diketones with aldehydes to provide 2-hydroxy-3,4-dihydro-2//-pyran derivatives in good to excellent yields [46]. The reaction mechanism involves a Knoevenagel-Michael addition sequence with subsequent hemiacetalization. The haniacetal was oxidized with TPAP/ NMO or PCC to give the corresponding lactones 96. An enantioselective variant utilizing stoichiometric amounts of an... 

A similar reaction was published by Song et al. in 2013 (Scheme 13.29) [47]. 2-Hydroxynaphthoquinone 75 was reacted with aromatic aldehydes 97 and ethyl 4,4,4-lrifluoro-3-oxobutanoate 98 catalyzed by a mixture of ammonium acetate and acetic acid (25mol% each). A Knoevenagel-Michael addition sequence was followed by hemiketal formation to give the desired product 99 in moderate to good yields. Dehydration of the product yielded the 4 f-pyran derivatives. 

M. N. Elinson, R. F. NasybuUin, G. I. Nikishin, C. R. Chim. 2013, 16, 789-794. Sodium acetate catalyzed tandem Knoevenagel-Michael multicomponent reaction of aldehydes, 2-pyrazolin-5-ones, and cyano-functionalized C-H acids facile and efficient way to 3-(5-hydroxypyrazol-4-yl)-3-aryl-propionitriles. 

In a related transformation, the same group described a three-component domino reaction of 2-hydroxy-l,4-naphthoquinone, acting as a P-dicarbonyl surrogate, aromatic aldehydes and 1-(2-oxo-2-phenylethyl)pyridinium bromides in the presence of ammonium acetate, in water under microwave irradiation, that affords naphtho[2,3-Z)]furan-4,9-diones 31 [22]. Mechanistically, this domino reaction probably follows the same Knoevenagel-Michael intramolecular S 2 pathway described for the preparation of compounds 28, with ammonium acetate acting in this case as the base, to give intermediates 33. These compounds, which can be considered as tautomers of a hydroquinone species, would be finally transformed into the observed quinones by air-promoted oxidation, yielding the final products 31 (Scheme 1.16). 

Scheme 12.5 Palladium(0)-catalyzed Alder-ene cydoisomerization-Knoevenagel-Michael addition sequence.

In 2012, a chiral cinchona alkaloid-derived primary amine was associated by Wang et al. to a (R)-BINOL-derived phosphoric acid to induce a three-component domino Knoevenagel-Michael reaction between isatins, malononitrile, and acetone, providing the corresponding domino products in generally excellent yields and enantioselectivities, as shown in Scheme 2.13. A hypothetic cooperative catalysis can be envisaged to explain these excellent results. 

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