Willgerodt reactions

In order to obtain good yields from a Weiss reaction sequence, the H+-concentration has to be adjusted properly in the reaction mixture. The reaction is usually carried out in a buffered, weakly acidic or weakly basic solution. By the Weiss reaction simple starting materials are converted into a complex product of defined stereochemistry. There is no simpler procedure for the synthesis of the l,5-c -disubstituted bicyclo[3.3.0]octane skeleton it has for example found application in the synthesis of polyquinanes.  

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 Willgerodt reaction is usually carried out under high pressure, thus requiring special laboratory equipment, while with the Kindler variant this is not necessary. The Kindler variant is of wider scope, and yields are generally better. In addition aromatic compounds with vinyl substituents may be employed as substrates instead of the ketone, e.g. styrene 7  

Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig, Organic Synthesis Highlights, VCH, Weinheim, 1991, p. 121-125. 

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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. 

A further improvement is embodied in the Klndler variation of the Willgerodt reaction this consists in heating the ketone with approximately equal amounts of sulphur and a dry amine instead of aqueous ammonium polysulphide. The principal product is a thioamide, and hydrolysis with acid or alkali affords the carboxylic acid, usually in good yield. 

It has been tentatively suggested that one mechanism underlies the Willgerodt reaction and the Kindler modification of it. A labile intermediate is first formed which has a carbon—carbon bond in the side chain. The scheme is indicated below it postulates a series of steps involving the addition of ammonia or amine (R = H or alkyl), elimination of water, re addition and eUmination of ammonia or amine until the unsaturation appears at the end of the chain then an irreversible oxidation between sulphur and the nitrogen compound may occur to produce a thioamide. 

Stephen reaction Stobbe condensation UUmann reaction Willgerodt reaction. ... 

The Willgerodt reaction can proceed normally. Thus the 3-acetylpyrazole (403) is converted into the morpholide (404) (57JCS2356). 

Through careful studies of the experimental conditions, it has become possible to apply the Willgerodt reaction to the synthesis of thienylacetic acids from acetylthiophenes. " ... 

The Willgerodt reaction also works with hetaryl alkyl ketones, but often gives unsatisfactory yields. Yields generally decrease with increasing chain length of the alkyl group. 

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 ... 

Reactions Known to Require High Temperatures 2.6.4.1 Willgerodt Reactions... 

Phenylacetamides were prepared in the MBR from the corresponding styrene or acetophenone derivatives by Willgerodt reactions (Scheme 2.8) [44]. Yields were comparable with those obtained by others with conventional heating. At similar temperatures, the microwave-heated reactions were completed within minutes rather than hours. Optimization was readily accomplished through the capabilities of the MBR for rapid heating and cooling. The substantially shorter reaction times probably re-... 

Scheme 2.8 Willgerodt reaction under microwave conditions.

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