Michael Knoevenagel domino reactions

Scheme 2.70. Asymetric domino Knoevenagel/Michael addition reaction.

Scheme 10.32 Three-component domino Knoevenagel/Michael/cyclization 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 ability of L-Pro to promote the Knoevenagel reaction has been harnessed in domino reaction sequences for the preparation of important target products. Several bicyclic and polycyclic systems have been obtained by these means. As an example, coumarines were prepared by the one-pot condensation reaction of o-hydroxybenzaldehydes with active methylene compounds (Scheme 2.8). In a related procedure, flavanones were synthesised from aromatic (3-ketoesters and aldehydes (Scheme 2.8). The domino sequence comprises in this case, a proline-catalysed Knoevenagel condensation and an intramolecular Michael addition. 

Scheme 8.22 Domino reaction involving Michael/Knoevenagel reaction sequence.

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... 

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). 

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. 

Scheme 2.13 Three-component domino Knoevenagel-Michael reaction catalysed by a combination of a chiral cinchona alkaloid-derived primary amine and a chiral phosphoric acid.

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... 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

An early example of an asymmetric domino Michael/Knoevenagel reaction was reported by Jorgensen et al. [167] in 2006, providing the synthesis of chiral cyclohexenones from the reaction of tert-butyl 3-oxobutyrate and a, 3-unsaturated aldehydes catalyzed by chiral diphenylprolinol silyl ether derivative. Soon after, the... 

In 2009, Hayashi et al. reported a novel asymmetric domino Michael-Knoevenagel reaction catalysed by silylated biphenylprolinol occurring between an a,(3-unsaturated aldehyde and dimethyl 3-oxopentanedioate, affording the corresponding chiral substituted cyclohexenone derivatives, which were further converted into the corresponding alcohols as single dia-stereomers by treatment with NaBH4 with excellent enantioselectivities of up to 99% ee (Scheme 1.39). °... 

A closely related methodology was applied by Zhao et al. to the enantio-selective synthesis of tetrasubstituted thiochromanes on the basis of a domino thia-Michael-Knoevenagel reaction between 2-mercaptobenzaldehydes and benzylidenemalonates with the same quinine thiourea catalyst. Steric and electron effects were found to affect profoundly the stereoselectivities of the reaction. Thus, it was shown that the diastereoselectivity of the reaction... 

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