Malonodinitrile Knoevenagel reaction

The Knoevenagel reaction is a synthetic method with a broad scope. The educts are simple and cheap, reaction conditions are mild, and a wide variety of solvents can be used. In addition, the Knoevenagel products are reactive compounds and may be employed in sequential transformations (see also Section 1.1.1.4). This is why the Knoevenagel reaction is widely employed, especially in the formation of heterocycles. The most used active methylene in these reactions is malonodinitrile. In many syntheses of natural products, drugs, dyes and other compounds, the condensation of a carbonyl group with an activated methylene compound is found. It is beyond the scope of this review to discuss all examples described in the literature, so only a few recent examples are given in this section. 

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. ... 

Like malonodinitrile, cyanoacetic esters are sufficiently reactive to undergo Knoevenagel condensation with a wide variety of aldehydes and ketones. In contrast to the reaction with malonodinitrile, only the Knoevenagel products and usually no Michael adducts are obtained under standard conditions. Nearly all known Knoevenagel catalysts can be successfully employed. 

In some cases it is appropriate to use an imine48,227-229 instead of a carbonyl compound. Thus, benz-alaniline reacts with activated methylenes in the presence of carbocyclic acid anhydrides to give the corresponding Knoevenagel products (Scheme 27).229 Similarly, the enamine (170) reacts with cyanoacetic acid in ethyl acetate230 or dimethylformamide231 to afford the cyclohexylidene compound (171 Scheme 28). Acetals may be employed instead of the free ketones. An example is the reaction of fluorenone cyclic acetal (172) with malonodinitrile, which occurs in butanol without added catalyst to af-... 

Af-ylides (prepared from their corresponding pyridinium salts 241) with aromatic aldehydes 242 and malonodinitrile 21 to give tetracychc 1,10-phenanthrohne derivatives 243 (Scheme 13.57) [93]. The reaction is complete within 15min and provides the desired products in high yields over 80%. The 4CR of phenanthridine 245, aromatic aldehydes 244, malonodinitrile 21, and several isonitriles 246 gives tetracychc phenanthridine derivatives 247 in excellent yields over 90% and reaction times between 16 and 48h at rt, as published by Marandi et al. [94], Both reactions follow a Knoevenagel con-densation/Michael addition/cychzation mechanism. 

The morpholine-promoted reaction of Af-alkyl piperi-dine-4-one with malonodinitrile and p-nitrostyrene derivatives in refluxing EtOH directly led to substituted tetrahydroisoquinoline derivatives in moderate to good yields [121], The reaction is initiated by a Knoevenagel condensation, in which a Michael addition/Thorpe-Ziegler sequence follows. Oxidation by air is the last step to occur providing the desired products. 

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