Knoevenagel reaction standard conditions

Most aldehydes easily undergo Knoevenagel condensation using secondary amines or their salts as a catalyst. Under standard conditions, reaction of simple unbranched aliphatic aldehydes and of most ketones is difficult. However, the use of TiCWamine allows reaction even of refractory aldehydes and a multitude of ketones in good to very good yields." -" For example, the synthesis of Knoevenagel adducts (72) from 5-formyl-octaethylporphyrin (71) and different malonic esters in the presence of TiCU/pyridine at 0 "C has been achieved in 75-94% yield." ... 

Meldrum s acid undergoes standard Knoevenagel condensaticms with aromatic and heteroaromatic aldehydes,with hindered aliphatic aldehydes R R CCHO and with reactive, simple aliphatic ketones. - Condensation with less reactive ketones can be performed in the presence of TiCU/amine 2 > 5 or by prior conversion of the ketone into the corresponding ketimine. The reaction with simple aliphatic aldehydes under standard conditions usually gives the corresponding Michael products as described in Section 1.11.2.6. Knoevenagel condensations of some other cyclic esters of ma-lonic acid have also been reported. 

Malonomonoamides can be condensed with aldehydes to give acrylamides or cinnanamides, but condensation with malonodiamides is of only minor impjortance. In contrast to Meldrum s acid (58), Knoevenagel reactions of barbituric acid (56) and A A -dimethylbarbituric acid have been less explored. However, several aliphatic, aromatic and heteroaromatic aldehydes are known to react easily and with high yields in most cases. Reactions of 1,2-dimethyl-3,5-pyrazolidinedione (93) with several aliphatic and aromatic aldehydes using standard conditions yield Knoevenagel products in good yield. A similar reactivity is observed with 2-phenyl-3,5-dioxoisoxazolidine (94) and oxazepanediones (45 see Section 1.11.2.5). Recently, the oxidations of alcohols to carbonyl compxiunds and thiols to disulfides with 5-arylidene-l,3-dimethylbarbituric acids (95) have been described Mechanistically (95) mimics enzymic oxidation by flavin adenine dinucletide (FAD). ... 

Hydrogenation of Knoevenagel products of 2,4-alkanediones over Raney nickel provides a simple route to 3-substituted 2.4-diones. Alternatively, reductive deacetylation can be accomplished using tetracarbonylhydridoferrate(0) in ethanol to prepare alkyl ketones. If the reaction is carried out in THF or acetone, exclusive reduction of the a,p-unsaturated double bond is observed. - Reactions of aldehydes with cyclic 1,3-diketones generally lead to the formation of Michael adducts under standard conditions. Indane-l,3-dione (103) yields Knoevenagel products with different aldehydes, ketones and ketimines, whereas perinaphthindane-l,3-dione (KM) gives the Michael adducts. ... 

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. 

Initial reports from Knoevenagel used secondary amines such as piperidine or diethylamine as the catalyst, usually in an alcohol as solvent, and at temperatures between 0 °C and room temperature. The range of possible promoters of the Knoevenagel condensation was soon expanded by Harm and Lapworth to include tertiary amines, and soon thereafter, many, many modified reaction conditions were discovered, some of which had clear advantages over the standard conditions, while the benefits of others are less clear. This section will focus on those modifications that have shown some advantage over the standard conditions. 

Cyanoacetamides yield a-cyanoacrylamides (124) stereoselectively upon reaction with aldehydes and nonselectively with ketones under standard Knoevenagel conditions. a-Cyanoacrylamides (124) are also obtained by partial hydrolysis of methylenemalonodinitriles. With 1,3-diketones, e.g. acetyl-acetone, pyridones like (125) are formed upon reaction with cyanoacetamides. Base-catalyzed dimerization of a-cyanoacrylamides (124) yields piperidones. ... 

Condensations of aryiacetic acids, arylacetates and arylacetonitriles with aromatic aldehydes and ketones proceed under standard Knoevenagel conditions, providing access to stilbenes or substituted stil-benes. - Thus 3-nitrobenzaldehyde and 4-nitrophenylacetic acid react in the presence of different amines to give (130), (131) and (132). The ratio of the products varies greatly with the amine used. (131) and (132) could easily be transformed into (130) in high yield. Reaction of arylacetates with o-hydroxybenzaldehydes yields the corresponding coumarins. The condensation of 2-hydroxy-4-meth-oxybenzaldehyde (133) with pyridylacetates like (134) yields 7-methoxy-3-pyridylcoumarins like (135) (Scheme 20). 

---