Amino acids catalyst, Knoevenagel reaction

Both natural and non-natural compounds with a 2ff,5ff-pyrano[4,3-fc]pyran-5-one skeleton are of interest in medicinal chemistry. Several natural products, such as the pyripyropenes, incorporate this bicyclic ring system. The group of Beifuss has described an efficient microwave-promoted domino synthesis of the 2ff,5H-pyr-ano[4,3-fo]pyran-5-one skeleton by condensation of a,/3-unsaturated aldehydes with 4-hydroxy-6-methyl-2]-f-pyran-2-one (Scheme 6.244) [428]. It is assumed that in the presence of an amino acid catalyst a Knoevenagel condensation occurs first, which is then followed by a 6jr-electron electrocyclization to the pyran ring. While the conventional thermal protocol required a reaction time of up to 25 h (refluxing ethyl... 

Amino acids may also be applied as catalysts in the Knoevenagel reaction 914,915 thus ethyl 2-cyano-4-methyl-2-pentenoate has been prepared in 87% yield from 2-butanone and ethyl cyanoacetate in the presence of /9-alanine.916 Other catalysts that have been recommended are benzylamine (additional to the salt of a secondary amine), 917 ion-exchangers,918 and alkali fluorides.919... 

In the formation of the first synthetic intermediate in Sequence D, the very effective Verley-Doebner modification of the fundamental Knoevenagel condensation is used. This modification uses malonic acid in place of the conventional ester to promote enoUzation. In addition, the heterocyclic amine, pyridine, functions as both the base catalyst and the solvent. A cocatalyst, P-alanine (an amino acid), is also introduced. Mechanistically, the reaction closely resembles the aldol condensation in that in both cases a carbanion is generated by abstraction, by base, of a proton alpha to a carbonyl group. The resulting carbanion is stabilized as an enolate anion (see below). 

Despite these mechanistic and theoretical studies, intermolecular amine-catalyzed aldolizations have only rarely been used on a preparative scale. A few note vorthy exceptions in vhich aldehydes are used as donors are sho vn in Scheme 4.6 [51-55]. These reactions are often performed neat or in the presence of small amounts of an organic solvent. The catalyst usually used is either a primary or secondary amine, a combination of an amine vith a carboxylic acid, or simply an amino acid. These catalyst systems have previously been used in the Knoevenagel condensation and it is apparent that synthetic amine-catalyzed aldolizations originate from Knoevenagel s chemistry [56]. 

I2/K2C03, tetrabutylammonium hydroxide, tungsten phosphoric acid, ionic liquids, reactions in water, solvent-free conditions, microwave promoted reactions, reactions promoted by phase-transfer catalysts, and finally, for some very reactive substrates, uncatalyzed reactions. " Unfortunately for the practicing chemist, few of these conditions are well worked out enough or understood well enough to have become common, and almost all examples of the Knoevenagel condensation in the literature employ an amine base, or a salt thereof (Cope conditions, or amino acid catalysis) or TiCl4/Base(Lehnert conditions). ... 

Further projects dealt with the fabrication of heterogeneous, basic or acidic solid-state catalysts or adsorbents carrying, for instance, amino or sulfonic acid groups. Amino-functionalized silicas were prepared and analyzed for the catalytic activity in Knoevenagel condensation reactions of aldehydes or ketones with ethyl cyanoace-tate ions by Macquarrie et al.154 155 Recently, Zhang et al.156,157 reported on the successful preparation of amino-functionalized silica thin films by means of the EISA approach. 

On the basis of the proposed catalytic cycle, aldehyde 9 reacts with 1,3-indandione 178 by amine-catalyzed Knoevenagel condensation to provide the benzylidene-indandione B via iminium ion A, which is an excellent organic Lewis acid. This intermediate thns undergoes a Diels-Alder or a double Michael reaction with the soft nucleophile 2-amino-1,3-butadiene C generated in situ from enone 84 and the amine catalyst to produce the... 

Because of the huge importance of pyridine derivatives, a considerable amoimt of effort has been directed to the development of multicomponent routes for their synthesis, including reactions performed in water. For instance, a one-pot four-component condensation of aldehydes, malononitrile and thiophenols in the presence of boric acid as catalyst in aqueous medium afforded high yields of 2-amino-3,5-dicaibonitrile-6-thiopyridines 46 [29], either by conventional heating or under ultrasound-aided conditions (Scheme 1.21). This reaction can also be performed in an aqneons snspension of basic almnina [30] or in water with microporous mo-lecnlar sieves as catalysts [31]. Mechanistically, this transformation involves an initial Knoevenagel condensation of the aldehyde with a molecule of malononitrile, followed by the Michael addition of the second molecule of malononitrile, reaction of one of the nitrile groups with the thiol, cyclization and a final air oxidation step. 

---