Pyrroles Clauson-Kaas synthesis

The Clauson-Kaas pyrrole synthesis was adapted to a soluble polyglycerol (PG) support <060L403>. Electrochemical oxidation of furan 33 in the presence of methanol followed by hydrogenation gave 2,5-dimethoxytetrahydrofuran 34. Cyclocondensation with primary arylamines gave A-arylpyrroles 35. Removal from the PG support was then accomplished by treatment of 35 with LiOH which gave 2-pyrrolepropanoic acids 36. 

A milder Clauson-Kaas pyrrole synthesis was reported that alleviated the need for acid or heat <06TL799>. The innovation involved the hydrolysis of 2,5-dimethoxytetrahydrofuran giving 2,5-dihydroxytetrahydrofuran. The latter was converted into pyrroles by treatment with primary amines in an acetate buffer. The Clauson-Kaas pyrrole synthesis was studied utilizing a K-10 montmorillonite acid catalyst and microwave irradiation <06OPP495>. Mild reaction conditions (cat. p-TsOH) allowed for the preparation of pyrrole-3-carboxaldehydes from 2,5-dimethoxytetrahydrofuran-3-carboxaldehydes <06S1494>. 

Clauson-Kaas) are perhaps the most utilized methods for the de novo synthesis of pyrroles. Recent advances include the following novel approaches to 1,4-diketones Stetter addition of aldehydes to chalcones <07SC1109> ruthenium-catalyzed isomerization of 1,4-alkynediols <07TL5115> and Zn/iodine-mediated dimerization of a-bromoketones <07TL7215>. 

Provide the mechanims of the Clauson-Kaas pyrrole synthesis. 

The Clauson-Kaas pyrrole synthesis involves the acid-catalyzed cyclization of a primary amine and a dialkoxytetrahydrofuran to form an A -substituted pyrrole. ... 

The Clauson-Kaas reaction has also seen some utility in the synthesis of complex heterocycles where the pyrrole is generally installed early and then further functionalized. Plasencia and co-workers have a fine example of this strategy in their reported synthesis of quinoxalinhydrazides (27), which showed some anticancer activity. 

The key stage in the synthesis of pyrrolo[l,2-a]quinoxalines 183 (Scheme 3.54) by type PA3 (Campiani et al. 1991, 1997) involves intramolecular substitution of a fluorine atom in the aromatic ring by the carboxamide group formed in sim in the l-aryl-2-cyanopyrroles 182 by the action of KOH. The formation of compounds 182 is a multistage process synthesis of the 1-arylpyrroles by the Clauson-Kaas reaction (Clauson-Kaas and Tyle 1952) and introduction of the CN group at position 2 of the pyrrole ring according to the Scheme 3.54. 

The Clauson-Kaas pyrrole synthesis involving the reaction of primary amines with 2, 5-dialkoxytetrahydrofurans was traditionally carried out in refluxing acetic acid (AcOH). Extension to less activated nitrogen nucleophiles often necessitates the use of acidic promoters. Miles et al. (2009) reported that the synthesis of N-substituted pyrroles can be carried out under microwave conditions (10-30 min) using acetic acid or water without additional catalysts. The reaction is successful for all common nitrogen inputs in the case of acetic acid, where as benzamide and benzylamine are resistant to cyclocondensation under aqueous conditions. 

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