Arylacetonitrile Condensation with ketones

Reductive cyanation. Aromatic ketones condense with aminoacetonitrile in the presence of TiCl4-Et3N. ot-Substituted arylacetonitriles are obtained upon treatment of the resulting imines with K2CO3 in refluxing DMF. 

A recent literature report described a green procedure for the condensation of arylacetonitriles with cyclic ketones using phase-transfer catalysis. This process was applied to the synthesis of venlafaxine, which was realized in overall 30% yield in two steps from commercially available 14. The condensation step was run in aqueous sodium hydroxide in the presence of tetrabutylammonium sulfate, to provide quantitative yield of intermediate 15. Hydrogenation in a formalin-methanol mixture provided the final product venlafaxine (1) in 30% overall yield. This protocol did not necessitate intermediate purification steps, making it attractive from the commercial standpoint. 

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). 

Aminopyrimidine-5-carbaldehydes,24 prepared by Vilsmeier formylation, condense in a Friedlander-type reaction with a variety of active methylene partners such as ketones, j3-oxo esters, malonic add derivatives or arylacetonitriles, the latter preferably with electron-withdrawing substituents. 

Such important processes as alkylation of arylacetonitriles, cyclopentadiene hydrocarbons, aldehydes and ketones, esters, sulfo-nes etc., condensation of carbanions with aldehydes and ketones, the Knoevenagel, Darzens, Michael and related reactions as well as many reactions involving sulfonium and phosphonium ylides have been successfully carried out under these conditions. 

The aldol-type condensation of aromatic aldehydes with arylacetonitriles is catalysed in a two-phase system by polyethylene glycol dimethyl ethers, " and the Wadsworth-Emmons olefination of an aromatic aldehyde or ketone with an arylmethanephosphoriate and sodium hydride to produce stilbene derivatives has been found to be accelerated in the presence of 15-crown-5. ... 

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