Kindler reaction

A novel type of ring closure is the reaction of 6-amino-5-dichloroacetylaminopyrimidines (285) with sulfur and morpholine under the conditions of a Kindler reaction (B-64MI21605). 7-Morpholinopteridin-6-ones (287) are formed, either via thiooxamide derivatives (286) or via corresponding 7,8-dihydropteridines (284 equation 102). Chloral hydrate also reacts with 2-substituted 5,6-diaminopyrimidin-4-ones to form pteridin-6-ones (56JCS3311, 64JCS565) by a so far unknown mechanism. 

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. 

Carmack20 has suggested that thiirenes are intermediates in the classic Willgerodt and Kindler reactions of aldehydes or ketones with amines and sulfur (Scheme 3). 

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

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

Looking at Schemes 4 and 5, it is obvious that Woodward-Doering s synthetic route suffered from the lack of stereocontrol, which led to the production of their precursors of homomeroquinene target compound as a mixture of stereoisomers. The fact that the yield of such a transformation was not clearly determined, in addition to the anticipated difficult separation of the four isomers obtained at the end of the reaction (cf. Rabe-Kindler reaction), rendered this reaction commercially unpractical. Moreover, it is well accepted that Woodward and Doering never physically produced any quinine in their lab, and the success of their method is based on the assumption that Rabe and Kindler partial synthesis was a fact. This would be the center of the controversy when Stork later characterized what he called the quasi-universal impression that Woodward and Doering achieved the total synthesis of quinine as a widely believed myth . The whole story is very juicy and interested readers should refer to the amazing review published in Angewandte Chemie by Seeman in 2007. Nevertheless, in 2008, Smith and Williams successfully revisited the Rabe-Kindler conversion... 

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. 

Zbruyev, O.I., Stiansi, N. and Kappe, C.O., Preparation ofthioamide building blocks via microwave-promoted three-component kindler reaction,/. Comb. Chem, 2003, 5(2), 145-148. 

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. 

Significant Variables in a Wilgerodt-Kindler Reaction, Fractional Factorial... 

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]... 

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