Annulations Knoevenagel reaction

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

This method affords an easy access to this privileged scaffold by a [3 + 2+1] annulation catalyzed by EtjN. The mechanism of the reaction is shown in Scheme 11.22. First, the Knoevenagel reaction of aromatic aldehydes 53 with 2-hydroxy-1,4-naphthoquinone 113 affords 116 that undergoes the aza-ene reaction with the ketene aminal 114 rendering 117. Next, the intramolecular hemiaminal 118 formation and dehydration afford the corresponding benzolylimidazo [l,2-a]quinolinediones 115 in good yields (60-88%). 

Davis and co-workers have carried out the first examples of the Knoevenagel condensation and Robinson annulation reactions [61] in the ionic liquid [HMIM][PFg] (HMIM = l-hexyl-3-methylimidazolium) (Scheme 5.1-33). The Knoevenagel condensation involved the treatment of propane-1,3-dinitrile with a base (glycine) to generate an anion. This anion added to benzaldehyde and, after loss of a water molecule, gave l,l-dicyano-2-phenylethene. The product was separated from the ionic liquid by extraction with toluene. 

In order to study any chemoselectivity influences of microwave irradiation on the domino Knoevenagel/hetero-Diels-Alder process (the so-called Tietze reaction), Raghunathan and coworkers [31a] investigated the transformation of 4-hydroxy coumarins (10-85) with benzaldehydes 10-86 in EtOH to afford pyrano[2,3-c]cou-marin 10-87 and pyrano[2,3-b]chromone derivatives 10-88. Normal heating of 10-85a and 10-86a at reflux for 4h gave a 68 32 mixture of 10-87a and 10-88 in 57% yield, whereas under microwave irradiation a 97 7 mixture in 82% yield was obtained. Similar results were found using the benzo-annulated substrates 10-85b and 10-86b. 

What is described as a domino Knoevenagel-hetero-Diels-Alder reaction , involving the reaction of the glucose-derived aldehyde 93 with a 1,3-dicarbonyl compound in presence of either proline or ethylenediammonium acetate, leads to the doubly annulated 5 6 6-fused compound 94 (Scheme 30) <2004S1150>. If the dicarbonyl compound is Meldmm s acid, however, the sequence is completed by spontaneous elimination of acetone and carbon dioxide from the Diels-Alder adduct, to give compound 95 <2005ASC1353>. 

Major modifications to the Friedlander reaction frequently involve different starting materials that deviate from the conventional examples. A one-pot combination of a modified Friedlander annulation and a Knoevenagel condensation have provided 2-styrilquinolines 152 in the presence of 1-methylimidazolium trifluoroacetate ([HmimJTFA) (Scheme 28) (08TL5366). 

A similar aqueous domino Knoevenagel/lietero-DA reaction of o-propargylated salicylaldeliyde with l-methylindoline-2-thione in the absence of any Lewis acid has been developed by Majumdar and coworkers [78]. Seven examples of new indole-annulated pentacyclic heterocycles 138 were obtained in 72-80% yields (Scheme 12.54). 

Kiamehr, M. and Moghaddam, F. M. 2009. An efficient ZnO-catalyzed synthesis of novel indole-annulated thiopyrano-chromene derivatives via Domino Knoevenagel-hetero-Diels-Alder reaction. Tetrahedron Lett. 50(48) 6723-6727. 

Historical perspective C. H. Heathcock, Comp. Org. Syn. 2, 133-179 (1991). General review T. Mukaiyama, Org. React. 28,203-331 (1982). Application of lithium and magnesium enolates C. H. Heathcock, Comp. Org. Syn. 2, 181-238 (1991) of boron enolates B. M. Kim etal, ibid. 239-275 of transition metal enolates I. Paterson, ibid. 301-319. Stereoselective reactions of ester and thioester enolates M. Braun, H. Sacha, J. Prakt. Chem. 335,653-668 (1993). Review of asymmetric methodology A. S. Franklin, I. Paterson, Contemp. Org. Syn. 1,317-338 (1994). Cf. Claisen-Schmidt Condensation Henry Reaction Ivanov Reaction Knoevenagel Condensation Reformatskv Reaction Robinson Annulation. 

A range of pentacyclic thiopyran indole-annulated benzo-6-sultone deriratives are obtained through a domino Knoevenagel-hDA reaction of 2-formylphenyl (B)-2-phenylethenyl sulfonates with indohne-2-thiones in water (Scheme 99) (13TL2685). 

In 2007, Ramachary et al. reported an asymmetric Knoevenagel/hydrogenation/Robinson annulation sequence to obtain Wieland-Miescher ketone 189 [88] (Scheme 2.62). The reaction of 5 equiv of aldehyde 9 with the 1,3-dicarbonyl compounds 186 (with CH acid) and Hantzsch ester 187 under proline catalysis furnished the expected cyclo-hexane-1,3-dione B in good yields. Once the solvent was removed by vacuum pump, the crude reaction mixture was diluted with DMF and treated with methyl vinyl ketone 188 in the presence of (S)-proline (1) furnishing the expected... 

Keywords Aldehydes, malononitrile, C-H activated acids, urea, organocatalyst, ethanol-water (1 1), room temperature, tandem Knoevenagel-cyclocondensation, one-pot three-component reaction, chemoselectivity, functionalized 2-amino-3-cyano-4//-pyrans and pyran annulated heterocycles... 

A two-step synthesis of annulated dihydropyrano[3,4-c]chroheme derivatives has been developed via Knoevenagel condensation followed by a microwave-assisted intramolecular hetero-Diels-Alder reaction in presence of 20 mol% Cul in MeCN (Jha et al., 2011). The yield was 60-71% nnder microwave irradiation. 

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