Knoevenagel/Michael/cyclization

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. Perumal, Synlett 2012, 23, 2894-2898. An efficient, one-pot regioselective synthesis of highly functionalized chromen-5-ones and pyrano[3,2-c]chro-men-5-ones via a tandem Knoevenagel-Michael-cyclization sequence. 

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... 

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. 

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). 

Generally, MCRs based on aminoazoles and synthetic precursors of a,p-unsaturated carbonyl compounds proceed via a sequence of Knoevenagel-type condensation, which was already mentioned (see Scheme 3), Michael-like addition, cyclization, and water elimination. For example, the authors of [47] considered the following mechanism (Scheme 9). 

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

The three-component reaction of indole (2) with sugar hydroxyaldehyde 281 and Meldrum s acid 282, with a catalytic amount of D,L-proline, afforded the 3-substitution product 283 as a single isomer [203]. The substituent possesses the czs-fused furo [ 3,2- b ] pyranonc skeleton. The proline catalyzes the Knoevenagel condensation of the sugar aldehyde 281 and Meldrum s acid 282 to provide the alkylidene derivative 284 of Meldrum s acid. Then a diastereo-selective Michael addition of indole and an intramolecular cyclization of this adduct 285 with evolution of carbon dioxide and elimination of acetone furnish the furopyranone in one-pot (Scheme 62). 

Quaternary ammonium hydroxides anchored on MCM-41 provide stronger base catalysts than amine analogues11731 and were able to catalyse the same reaction as previously reported namely for the intermolecular Michael reaction leading to flavanone.[181] Moreover, this catalyst induced the successive intramolecular olefinic attack of the phenolic group from the Knoevenagel condensation product of salicylaldehyde and diethyl glutaconate (Scheme 9.6). This fast cyclization leads to chromene derivatives (1) from which subsequent conversions induced by proton abstraction from the alpha position of the ester function gives coumarin... 

Knoevenagel condensation of aldehydes with malononitrile under mechanochemi-cal mixing in the presence of MgO resulted in adducts of general structure 138 (Scheme 27), which were further treated with either ethylacetoacetate or 5,5-dimethylcyclohexane-l,3-dione to provide products 139 and 140 [63]. The transformation of 138 and 139 or 140 proceeded via a Michael-type nucleophilic addition of the enolizable ketoester or dione, followed by intramolecular cyclization. 

The first step of this process involves the Knoevenagel condensation of an aldehyde with malononitrile to form the corresponding Knoevenagel product (5). The second molecule of malononitrile then undergoes Michael addition to 5 followed by simultaneous thiolate addition to C N of the adduct and cyclization to dihydropyridine (6) which on aromatization and oxidation (air) under the reaction conditions leads to pyridine. 

A one-pot three-component reaction of 2-aminobenzimidazoles, aldehydes 71 and P-ketoesters 72 has been developed for the synthesis of 4//-pyrimido[2,l-6]benzothiazoles 75 <05BMCL5553>. The reaction presumably proceeds in two steps Knoevenagel condensation of 71 with 72 produces 3-benzylidene-2,4-pentanedione 73 Michael addition of 73 with 2-aminobenzothiazole then generates 74, which cyclizes to 75. 

---