Ultrasound Knoevenagel reaction

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. 

Palmisano et al. [103] worked with ultrasound at 60 W power and 19.6 kHz, for 1.5 h, to get a wide range of (het)-3-arylmethyl-4-hydroxycoumarins (134) through a tandem Michael Knoevenagel-reductive reaction (Scheme 34). The efficient ultrasoxmd method promoted the reaction in the absence of organic solvents, with temperature control at 30-40 °C in an open vessel, without the need of an excess of Hantzsch 1,4-dihydropyridine. These compoxmds have biological properties such as anticoagulant, photosensitizing, and antineoplastic. 

Additionally, they have examined the Knoevenagel-Doebner reaction in the aqueous media under simultaneous irradiation and observed to be greatly benefited [46]. Cravotto and Cintas have reviewed recently the combined use of ultrasound and microwave heating in the process chemistry [47]. 

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