Patent GB-582191-A (GB)
Title: Improved process for carrying out condensation reactions of substances containing reactive methylene or methine groups
Filed: 1944-03-02
Abstract: Condensation reactions between a substance containing a reactive methylene or methine group, i.e. wherein the hydrogen is activated by the immediate vicinity of groups containing double bonds such as carbonyl or esterified carboxyl groups or aromatic nuclei, and an alkyl or aralkyl halide or other monohalogen compound containing an alkyl group substituted by a reactive halogen, such as alkyl halogenoacetates and halogeno-acetonitriles, or an aldehyde or ketone are effected in the presence of a complex obtained by interaction of potassium hydroxide and an acetal, ketal or dialkyl ether of ethylene glycol.  Such a complex is preferably prepared by heating potassium hydroxide with acetaldehyde - dibutylacetal while stirring.  At about 150 DEG  C., the complex liquifies and forms a bottom layer which solidifies on cooling to a microcrystalline powder suspended in the excess acetal.  Lower boiling acetals may be used.  The acetal is chosen so as to allow separation from the end product and any unchanged starting material by fractionation. Other acetals and ketals specified are those from methyl ethyl ketone and glycol, propion- or butyr-aldehyde and ethyl alcohol, acetaldehyde and propyl alcohol, butyraldehyde and isopropyl alcohol, 2-ethyl-hexanal and methyl alcohol, acetaldehyde and isobutyl or n-butyl alcohol, and butyraldehyde and butyl alcohol. They may be prepared by mixing the reactants in the presence of a solution of gaseous hydrochloric acid in the alcohol used.  The materials to be condensed are added to the complex, preferably at 0 DEG  C., reaction being completed by heating if necessary.  Water may be added to remove inorganic material, the organic layer being fractionated.  In condensations with alkyl halide, potassium halide is formed; in other cases, the aqueous phase contains the potassium hydroxide which can be recovered as by heating with organic liquids.  Substances containing reactive methylene or methine groups include b -keto-esters such as ethyl acetoacetate, cyclopentanone-2-carboxylate, heterocyclic ketones with an esterified carboxyl group in the a -position, and ethyl ethoxalyl acetate, ethyl cyano-acetate and substitution products such as ethyl cyclohexenylcyano-acetate esters and hydrocarbons having a CH2 or CH group next to an aromatic radical or other unsaturated group, for example ethyl phenylacetate, fluorene, indene, and 9-alkyl or aryl fluorenes, and benzyl cyanide.  Of the halides used in the condensations, benzyl and methallyl chlorides, and alkyl brom-acetates are very reactive, then come isobutyl bromide, and finally normal alkyl halides.  In examples: (1) ethyl aceto-acetate is alkylated to give mono- or di-alkyl derivatives depending upon the ratio of the reagents.  Reaction is rapid at 80 DEG  C. and, for methallyl chloride, lower temperatures are advisable.  Using the complex of KOH and acetaldehyde diethyl acetal, ethyl aceto-acetate is condensed with 1 or 2 molar proportions of benzyl chloride giving mixtures of ethyl benzyl- and dibenzyl-aceto-acetate, and ethyl benzyl-aceto-acetate is condensed with benzyl chloride to give the dibenzyl compound; using the complex with acetaldehyde dipropyl or dibutyl acetal or ethylene glycol ethyl butyl ether, ethyl-aceto-acetate is condensed with n-butyl bromide; with the complex with acetal or acetaldehyde dipropyl acetal, ethyl n-butyl-aceto-acetate is condensed with benzyl chloride; with the acetaldehyde dipropyl acetal complex, ethyl-aceto-acetate is condensed with isobutyl bromide or methallyl chloride, while this last condensation using 2 molar proportions of methallyl chloride is also effected with acetaldehyde dibutyl acetal to yield ethyl dimethallyl aceto-acetate; (2) diethyl benzyl malonate is made by condensing diethyl malonate and benzyl chloride in the presence of the complex of KOH with acetal or butyraldehyde dibutyl acetal; (3) ethyl ethoxalyl acetate with 1 or 2 molar proportions of benzyl chloride and KOH-acetal or acetaldehyde diethyl acetal yields the mono- or di-benzyl derivative which decomposes into diethyl benzyl or dibenzyl malonate; (4) ethyl cyclopentanone-2-carboxylate with benzyl chloride, isobutyl bromide and ethyl bromacetate respectively yields ethyl 2-benzyl or isobutyl-cyclopentanone - 2 - carboxylate or diethyl cyclopentanone - 2 - carboxylate - 2 - acetate; (5) ethyl phenyl-acetate with benzyl chloride gives ethyl phenyl-benzyl-acetate; (6) butyl isobutyrate and benzyl chloride yield butyl a -benzyl-isobutyrate; (7) ethyl cyanoacetate with 1 or 2 molar proportions of benzyl chloride gives mainly mono- or di-benzyl derivative respectively; ethyl cyclohexenyl-cyanoacetate is similarly benzylated; (8) indene with anisaldehyde gives 3-anisylidene-indene, with benzophenone, diphenyl-benzofulvene, with acetone, dimethyl-benzofulvene, with 2-ethyl-hexanal, 2-ethyl-hexylidene-indene, and with benzyl chloride, 1-benzyl-indene and some 1,3-dibenzylindene; (9) ethyl phenyl-cyanoacetate with chloracetonitrile yields a -phenyl-a -carbethoxysuccinic acid dinitrile.  The Provisional Specification comprises an example of the condensation of benzyl cyanide and benzophenone using a complex of KOH and acetaldehyde-dibutylacetal giving triphenyl acrylonitrile. Specification 580,922 is referred to.