Pyrroles from 2,5-dimethoxytetrahydrofuran

In an application of the Paal-Knorr pyrrole synthesis, the synthetic equivalents 3 of 1,4-ketoaldehydes were prepared by the radical addition of ketones 4 to vinyl pivalate. Treatment of the intermediates 3 with amines gave pyrroles 5 <03SL75>. Other new extensions of this popular pyrrole synthesis include the preparation of a number of pyrroles from hexane-2,5-dione and amines under solvent-free conditions in the presence of layered zirconium phosphate or phosphonate catalysts <03TL3923>, and the development of a solid-phase variant of this reaction <03SL711>. Likewise, the preparation of iV-acylpyrroles from primary amides and 2,5-dimethoxytetrahydrofuran in the presence of one equivalent of thionyl chloride has also been reported <03S1959>. 

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>. 

Torok and co-workers312 have reported the one-pot synthesis of /V-arylsulfonyl heterocycles through the reaction of primary aromatic sulfonamides with 2,5-dimethoxytetrahydrofuran. When triflic acid is used in catalytic amount, IV-arylsulfonylpyrroles are formed (Scheme 5.34). Equimolar amount of triflic acid results in the formation of N- ary I s u I fo n y I i n do I e s, whereas /V-arylsu Ifonylcar-bazoles are isolated in excess acid (Scheme 5.34). In the reaction sequence 1,4-butanedial formed in situ from 2,5-dimethoxytetrahydrofurane reacts with the sulfonamide to give the pyrrole derivative (Paal-Knorr synthesis). Subsequently, one of the formyl groups of 1,4-butanal alkylates the pyrrole ring followed by a second, intramolecular alkylation (cyclialkylation) step. 

Quite interestingly, the hydrazido(2-) Hgands derived from the ligating N2 in complexes 1 and 2 are transformed into N-hetero cyclic compounds by application of the condensation and related methods (Scheme 6). Thus, their reactions with 2,5-dimethoxytetrahydrofuran, pyrylium salts, and phthalaldehyde, followed by workup of the complexes containing N-heterocyclic ligands with LiAlH4 or KOH/alcohol, result in the formation of pyrroles [29], pyridines [30], and phthalimidines [31], respectively. 

The best synthon for unstable succindialdehyde, for the ring synthesis of C-unsubstituted pyrroles, is 2,5-dimethoxytetrahydrofuran (section 15.1.4), or 1,4-dichloro-1,4-dimethoxybutane obtainable from it. 2,5-Dimethoxytetrahydrofuran will react with aliphatic and aromatic amines, amino esters, arylsulfonamides, trimethylsilylethoxycarbonylhydrazine, or primary amides to give the corresponding A-substituted pyrroles. 

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