Willgerodt—Kindler reaction

Conversion of ketones to the corresponding thioamide and/or ammonium salt. 

A slightly different mechanism has also been proposed  

In Carmack s mechanism [5], the most unusual movement of a carbonyl group from methylene carbon to methylene carbon was proposed to go through an intricate pathway via a highly reactive intermediate with a sulfur-containing heterocyclic ring. The sulfenamide serves as the isomerization catalyst  

Example 1, the Willgerodt-Kindler reaction was a key operation in the initial synthesis of racemic Naproxen  

Reza Darabi, H. Aghapoor, K. Tajbakhsh, M. Tetrahedron Lett. 2004, 45, 4167. 

Purrello, G. Some aspects of the Willgerodt-Kindler reaction and connected reactions. Heterocycles 2005, 65, 411-449. (Review). 

Conversion of a ketone to thioamide, wifli innctional group migration. 

In Carmack s mechanism, the most unusual movement of a carbonyl group from 

Example 3, A domino annulation reaction under Willgerodt-Kindler conditions  

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 287, Springer International Publishing Switzerland 2014 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 268, Springer-Verlag Berlin Heidelberg 2009 

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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 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. 

Methyl arylacetates.2 Aryl methyl ketones are converted into methyl arylacetates by reaction with BF3 etherate and lead tetraacetate in benzene at room temperature (equation I). Thallium(lll) nitrate (4, 496) has also been used for this modified Willgerodt-Kindler reaction. 

The Willgerodt-Kindler reaction has been used to synthesize O-methyldauri-cine (17). The product was evidently a mixture of diastereomers (272-274). A similar approach provided stebisimine (409), obaberine (80), and isotetrandrine (236) (275). In a variation, enamine thioether 410 reacted with 411 to generate bis amide intermediates for the synthesis of 80, 236, and 409 (276). 

Details of the syntheses of stebisimine (409) and racemic forms of obaberine (80) and isotetrandrine (236), using enaminothioethers and the Willgerodt-Kindler reaction, have been described (592,593). 

Aromatic ketones are important intermediates in the production of fine chemicals and pharmaceuticals1,2. Thus, the anti-rheumatic Naproxen is produced by the Friedel-Crafts acetylation of 2-methoxynaphthalene into 2-acetyl-6-methoxynaphthalene and subsequent Willgerodt-Kindler reaction. Commercial acylation processes involve over-stoechiometric amounts of metal chlorides (e g. AICI3) as catalysts and acid chlorides as acylating agents, which results in a substantial formation of by-products and in corrosion problems. This is why the substitution of these corrosive catalysts by solid acid catalysts and of acid chlorides by anhydrides or acids is particularly desirable. 

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. 

All chemicals were obtained from the Aldrich Chemical Company, Inc. It is advisable to distill acetophenone and morpholine. The sulfur should be small particles and must not form lumps. Excess morpholine is generally recommended in Willgerodt-Kindler reactions. 

Fig. 5. Normal probability plot of estimated model parameters obtained in the screening experiment for the Willgerodt-Kindler reaction...

A set of 126 primary, secondary, and tertiary amines characterized by seven property descriptors afforded two significant principal components which described 85% of the total variance. For details, see [63]. A preliminary study of 29 amines was used for the selection of co-substrates in studies on the Willgerodt-Kindler reaction [21]. 

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 Willgerodt-Kindler reaction was studied for a series of para substituted acetophenones with different amines in different solvents. 

Prediction of Optimum Conditions for New Substrates in the Willgerodt-Kindler Reaction [19]... 

The example shows a sequential approach to the study of discrete variations. The Willgerodt-Kindler reaction was studied with a set of para substituted acetophenones, see Schema 9. As the reaction failed with strong electron-withdrawing substituents, the study was limited to include donor, alkyl, and halogen substituents. 

Table 15. Optimum conditions in the Willgerodt-Kindler reaction of substituted acetophenones...

Various condensations of 3-acetyl-l,2,5-thiadiazole (83) have been carried out which indicate a high degree of reactivity of both the carbonyl and the methyl group. The reactions investigated include the aldol condensation of 88, the Mannich reaction to 89, triscyano-ethylation to 90, and the Willgerodt-Kindler reaction to 91. The reactions proceeded under mild conditions and the normal products were obtained in good yield in each case. ... 

Fig. 4 Example of a three-step synthesis of a series of rather elaborated peptidomimetic compounds synthesized using straightforward reactions that can be easily automated in a fast parallel synthesis process. Methods (a) acetic acid, poly-phosphoric acid, 85°C (b) RI, DMF, anhydrous potassium carbonate, room temperature (c) Willgerodt-Kindler reaction (sulfur, secondary amine HNAB, DMF, 110°C).

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]. 

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