Heterocycle synthesis Paal-Knorr pyrrole

Cribble, G. W. Knorr and Paal-Knorr Pyrrole Synthesis. In Name Reactions in Heterocyclic Chemistry, Li, J. J., Ed. John Wiley Sons Hoboken, NJ, 2005 pp 79-88. 

Paal-Knorr synthesis It is a useful and straightforward method for the synthesis of five-membered heterocyclic compounds, e.g. pyrrole, furan and thiophene. However, necessary precursors, e.g. dicarbonyl compounds, are not readily available. Ammonia, primary amines, hydroxylamines or hydrazines are used as the nitrogen component for the synthesis of pyrrole. 

Similar reaction conditions as those by Bose were used for a range of other applications, for example, the synthesis of heterocycles. A combination of a microwave-assisted Paal-Knorr reaction15 with a transfer hydrogenation takes place in the preparation of 2,5-di- and 1,2,5-trisubstituted pyrroles from -l,4-diaryl-2-butene-l,4-diones in a one-pot operation. Hydrogenation was achieved with ammonium formates and 10% Pd/C as catalyst in PEG-200. Yields of up to 92% were obtained within 0.5-2 min (Scheme 4.2)16. 

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. 

The Paal-Knorr synthesis of furans as well as thiophenes and pyrroles has been carried out on solid support and a library of heterocyclic compounds has been prepared <2003SL711>. It has been shown that the acid-catalyzed synthesis of 2,3>4-substituted furans from 1,4-diketones can be assisted by microwave irradiation <20040L389>. 

Pyrrole is one of the most prominent heterocycles in several natural products and synthetic pharmaceuticals. The most common approach to pyrroles is the Paal-Knorr reaction. Taddei and coworkers have investigated a rapid and versatile synthesis of tetrasubstituted pyrroles in few highly efficient steps ... 

Approaches to the synthesis and medicinal importance of pyrroles have been reviewed. The synthesis of pyrroles using multicomponent reactions was reviewed and advances in this area from mid-2009 to the end of 2013 are covered (14CSR4633). Another review covered the synthesis of pyrroles using the Paal-Knorr reaction (14AHC95).The synthetic approaches and biosynthetic hypotheses of pyrrole—imidazole alkaloids were discussed in another report (14CC8628). Synthesis of pyrrole-based heterocyclic molecules through metal triflate-catalyzed addition reactions of pyrrole to C—C and C-N bonds was reviewed (14PAC925). 

Veisi, H., Azadbakht, R., Ezadifar, M., and Hemmati, S. (2013). An efficient and green procedure for synthesis of pyrrole derivatives by Paal-Knorr condensation using sodium dodecyl sulfate in aqueous micellar. 7. Heterocyclic Chem., 50, E241-E246. 

Syntheses of the heterocyclopentadienes use a variety of cyclization strategies. A general approach is the Paal-Knorr synthesis (for pyrroles) and its variations (for the other heterocycles). The target molecule is made from an enolizable y-dicarbonyl compound that is treated with an amine derivative (for pyrroles) or P2O5 (for furans) or P2S5 (for thiophenes). 

Simple and efficient, the Stetter hydroacylation reaction quickly became a popular route for the production of 1,4-dicarbonyl compounds as precursors for the synthesis of pyrrole, furan, and pyridazine heterocycles. The Parke-Davis route to atorvastatin (Lipitor ) illustrates the use of a Stetter/Paal-Knorr sequence to access a high value pharmaceutical intermediate (16) from 4-fluorobenzaldehyde 12 and benzylidine amide 13. ... 

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