Esters synthesis, Knoevenagel reaction

Because of the mild reaction conditions, and its broad applicability, the Knoevenagel reaction is an important method for the synthesis of a ,/3-unsaturated carboxylic acids. Comparable methods are the Reformatsky reaction, the Perkin reaction, as well as the Claisen ester condensation. The Knoevenagel reaction is of greater versatility however the Reformatsky reaction permits the preparation of a ,/3-unsaturated carboxylic acids that are branched in a-position. 

Various methods have been used to lengthen a carbon side chain, in the syntheses of quinuclidyl-3-acetic acid (113) (Scheme 1). The lowest yield is in the sodiomalonic ester synthesis (13.4% ).125 Much better results are afforded by the Reformatsky reaction (40%)125 and Knoevenagel condensation (65-70%).129 The best yield (nearly quantitative) may be obtained by application of the Wittig-Horner reaction.155... 

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

Gold(I)-Catalyzed Aldol Reaction. In 1986 an elegant enantioselective and diastereoselective synthesis of dihydrooxazolines was reported, using the aldol reaction of an aldehyde with an a-isocyanoacetate ester (formally a Knoevenagel reaction) using a cationic gold(I) complex of (1) (eq 1). ... 

Introduction of these photocrosslinkable structures in macro-molecular chains can be performed by esterification of hydroxyla-ted polymers with cinnamoyl chloride. Cellulose Q).condensation products (4, ) and mainly poly(vinyl alcohol) have Been treated( by this method. Other chemical modifications have been studied as ester interchange of poly(vinyl acetate) 7) and Knoevenagel reaction on polyesters (8). Very few results on the synthesis of such photocrosslinkable polymers by polymerization have been reported. Therefore free radical polymerization of cinnamic acid vinyl derivatives did not lead to the expected polymers, but to insolubilization reactions. Howewer cationic procedure can be a good way in some cases since Kato et al. could polymerize by this way with high yields p-vinyl phenylcinnamate (9) and B-vinyloxyethyl cinnamate (10). 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

An interesting approach to the substituted 6,8-bisdehydro[13]annulenone (238) includes a double Knoevenagel reaction of the mixed acetonedicarboxylic ester (235) with aldehyde (236) in the presence of piperidine to give (237). Oxidative coupling of the acetylene moieties in (237) with Cu(OAc)2 in pyridine affords (238) in 10% yield (Scheme 47).2 a,p-Unsaturated malonodinitriles are suitable intermediates for the synthesis of a variety of carbocyclic systems. Cyclization of the benzylidene malonodinitrile (239) to form a five-membered carbocyclic ring (240) can be achieved upon treatment with acid and subsequent hydrolysis (Scheme 48). A similar cyclization of (241) affords six-mem-bered carbocyclic ring systems. ... 

Steroidal ketones have been used extensively in the Knoevenagel reaction. Thus, die transformation of 17-oxoandrostane derivatives (309), which are readily available by microbiological degradation of sitosterin, are employed for the synthesis of enantiomerically pure cardiotonic steroids such as bufa-dienolide and cardenolide (311). In toth syntheses the substitutent at C-17 is introduced by a Knoevenagel reaction of the 17-oxoandrostane derivative (309) with ethyl cyanoacetate in the presence of ammonium acetate to give the cyano ester (310), presumably as a mixture of the ( )- and (Z)-isomers, in 89% yield.5 5... 

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