By the Willgerodt reaction

Hendecanedioic acid has been prepared by hydrolysis of the corresponding dinitrile, obtained from 1,9-dibromononane or 1,9-diiodononane 4-6 by oxidation of 11-hydroxyhendecanoic acid 7,8 by the Arndt-Eistert synthesis from 9-carbethoxynonanoyl9 and nonanedioyl chloride 10 and by the Willgerodt reaction on un-decylenic acid.11 The present method, previously described briefly,12 13 appears to represent the most convenient preparation of dibasic acids having an odd number of carbon atoms greater than ten. It has been applied to several other dibasic acids.14... 

The conversion of a carbonyl compound by ammonium polysulphide solution into an amide with the same number of carbon atoms is known as the Willgerodt reaction. The procedure has been improved by the addition of about 40 per cent, of dioxan or of pyridine to increase the mutual solubility of the ketone and aqueous ammonium polysulphide the requisite temperature is lowered to about and the yield is generally better. 

An aryl alkyl ketone 1 can be converted into an tn-arylalkane carboxylic amide 2 by employing the Willgerodt reaction The number of carbon centers is retained. The reaction is carried out by treating the ketone with an aqueous solution of ammonium polysulfide. A variant that has been developed by Kindler, and which is called the Willgerodt-Kindler reaction, uses a mixture of sulfur and a secondary amine instead of the ammonium polysulfide. 

The Willgerodt reaction starts with the formation of an enamine 4 from the ketone, e.g. from acetophenone 3. The further course of the reaction cannot be described by a single mechanism that would apply to all examples known. For aryl methyl ketones 3 the mechanism for the Kindler variant is formulated as follows ... 

The Willgerodt reaction yields amides 2 as products, while the Willgerodt-Kindler reaction yields N,N-disubstituted thioamides 5. Both types of products can be converted to the corresponding carboxylic acid 6 by alkaline hydrolysis. 

The mechanism of the Willgerodt reaction is not completely known, but some conceivable mechanisms can be excluded. Thus, one might suppose that the alkyl group becomes completely detached from the ring and then attacks it with its other end. However, this possibility is ruled out by experiments such as the following When isobutyl phenyl ketone (42) is subjected to the Willgerodt reaction, the product is 43, not 44, which would arise if the end carbon of the ketone became bonded to the ring in the product ... 

These are usually prepared by the following methods (a) the Willgerodt reaction on the corresponding methyl ketone,82,98,337,485, 557 (6) hydrolysis of the corresponding cyanomethyl compound,77,337, 485,499,517,521,568 cyclization reactions (Section IV, C) (for 3-acetic acids only),143,209,310,311,313,351 or (d) the Arndt-Eistert reaction on the corresponding carbonyl chloride, which may lead directly to the acetic acid 689 or its amide.337, 568... 

A further improvement is embodied in the Kindler variation of the Willgerodt reaction which is illustrated by several examples in Expt 6.148. This consists of heating the ketone with approximately equal amounts of sulphur and a dry amine (e.g. morpholine) instead of aqueous ammonium polysulphide. The principal product is a thioamide, and subsequent hydrolysis with acid or alkali affords the carboxylic acid, usually in good yield. 

Carlson, R. and Lundstedt, T. Scope of Organic Synthetic Reactions. Multivariate Methods for Exploring the Reaction Space. An example by the Willgerodt-Kindler Reaction. Acta Chem. Scand., 1987, B41, 164-173. 

Complete multi-level factorial designs would usually yield too large a number of test systems for a first approach to new reaction systems. It is possible to reduce the number of test systems and yet achieve a selection which covers a large part of the entire reaction space. This can be achieved by a selection made from a two-level fractional factorial design. The principles are illustrated by an example provided by the Willgerodt-Kindler reaction. 

The most useful application of sulfur is the Willgerodt reaction—the conversion of ketones into acids having the same number of carbon atoms [498]. The conversion is accomplished by heating ketones with sulfur and ammonium sulfide [499, 500, 501, 502] at 160-210 °C under pressure. The Kindler modification avoids operation under pressure by using sulfur and high-boiling secondary amines such as morpholine, instead of ammonium sulfide [503, 504]. Such a reaction carried out at reflux gives the thio-morpholides, which are subsequently hydrolyzed to acids. 

The amides and thioamides obtained by the Willgerodt-Kindler reaction are, sometimes without isolation, converted into acids by refluxing with 15-20% sodium or potassium hydroxide or converted into esters by refluxing for 3 h with alcohols in the presence of gaseous hydrogen chloride [501]. 

The Willgerodt reaction is frequently used to convert alkyl aryl ketones, which are synthesized easily by the Friedel-Crafts reaction, into aryl alkanoic acids with or without isolation of the intermediate thiomor-pholides [499, 504, 1170] (equation 416). 

Two secondary amines which are commonly used are piperidine (bp 106°) and morpholine (bp 129°). The former is often used in conjunction with pyridine in condensations with malonic acid and similar reactions, and the latter is often used as the solvent and also one reactant in the Willgerodt reaction. Both amines are satisfactorily purified by distillation. 

Methyldauricine (15) has been synthesised from the diphenyl ether (14 R = H) by Friedel-Crafts acetylation to the diketone (14 R = COCHg), conversion of this by a Willgerodt reaction... 

Although the Willgerodt reaction was known through standard references, it was used by only a few workers > and remained a chem-... 

That a carbonamide rather than a thioamide is isolated in the Willgerodt reaction with aqueous ammonia does not constitute an argument against the above scheme, for hot aqueous ammonia is known to convert thioamides to carbonamides. The isomerization of straight-chain acetylenic compounds (with and without aromatic substituents) to products having the acetylene function in the terminal position is known to take place in the presence of sodium amide. The assumption that such unsaturated substances are intermediates in the Willgerodt reaction offers an explanation of the appearance of certain by-products. Tetra-hydronaphthoic acid, isolated in small amounts from the reaction of ethyl 6-tetralyl ketone with morpholine and sulfur, may arise from an oxidative attack by sulfur on an unsaturated intermediate. The presence of traces of thiophenes in the reaction mixtures is explicable when it... 

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