Paal-Knorr sequences

The 1,4-dicarbonyl compounds provide access to Paal-Knorr sequences. A one-pot, three-step reaction sequence has been reported ... 

The CIR is exceptionally well suited as an entry to multi-component syntheses of aromatic heterocycles and on this basis Muller and coworkers [91f, 92] designed a coupling-isomerization-Stetter-Paal-Knorr sequence as a diversity-oriented approach to highly substituted furans and pyrroles (Scheme 5.22). 

Braun RU, Zeitler K, Muller TJJ (2001) A novel one-pot pyrrole synthesis via a coupling-isomerization-stetter-paal-knorr sequence. Org Lett 3 3297-3300... 

Braun RU, Muller TJJ (2004) Coupling-isomerization-stetter and coupling-isomerization-stetter-paal-knorr sequences - a multicomponent approach to furans and pyrroles. Synthesis 2391-2406... 

Braun, R. U., Zeitler, K., Mueller, T. J. J. A Novel One-Pot Pyrrole Synthesis via a Coupling-lsomerization-Stetter-Paal-Knorr Sequence. Org. Lett. 2001, 3, 3297-3300. 

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. ... 

An interesting family of polycyclic pyrroles was described in 2005 using again the synthetic sequence of a Stetter reaction for the preparation of the starting 1,4 diketones followed by a microwave-assisted Paal-Knorr condensation [35]. For example, cyclopentenone 23 (obtained in a Pauson-Khand cyclization) reacted imder Stetter reaction conditions to give the amino ketone 25 (Scheme 8). The microwave-assisted Paal-Knorr cyclization of 25 with different amines gave a small collection of tricychc pyrrole 2-carbox-amides. 

The retro-Paal-Knorr ring opening reaction leading to 1,4-dicarbonyl compounds was accomplished by heating iV-substituted pyrroles in a citrate buffer <06SL1428>. The sequence was coupled with a forward Paal-Knorr reaction enabling the exchange of the N-substituent on pyrroles. 

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 Br0nsted-acid-catalysed rearrangement of t-butyl peroxides provides for the construction of 2,3-disubstituted furans via 1,2-aryl migration. t-Butyl peroxides are reported to be transformed into 2,3,5-trisubstituted or 2,5-disubstituted furans through a sequence of base-catalysed Kornblum-DeLaMare rearrangements and acid-promoted Paal-Knorr reactions (Scheme 70). °°... 

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