Paal- Knorr cyclization

Hydroxypyrroles. Pyrroles with nitrogen-substituted side chains containing hydroxyl groups are best prepared by the Paal-Knorr cyclization. Pyrroles with hydroxyl groups on carbon side chains can be made by reduction of the appropriate carbonyl compound with hydrides, by Grignard synthesis, or by iasertion of ethylene oxide or formaldehyde. For example, pyrrole plus formaldehyde gives 2-hydroxymethylpyrrole [27472-36-2] (24). The hydroxymethylpyrroles do not act as normal primary alcohols because of resonance stabilization of carbonium ions formed by loss of water. 

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. 

In a recent patent, Hu et al. reported a similar procedure where the acceptor aldehyde contains aminoalkyl substituents in place of chloride. Subsequent to lactol oxidation and amine deprotection, these intermediates can directly undergo Paal-Knorr cyclization with the appropriate diketone to produce atorvastatin, thus avoiding the use of cyanide chemistry. 

Aromatic 5-membered heterocycles can be obtained by a Paal-Knorr cyclization, which involves the carboxylic derived C=0 and an additional carbonyl suitably placed in one of the Passerini or Ugi component (Fig. 11). In this way... 

Fig. 11 Synthesis of various heterocycles by IMCR followed by Paal-Knorr cyclizations...

Scheme 3 Paal-Knorr cyclization under microwave irradiation...

Other reactions must be mentioned beside the major reactions described above. These reactions may be responsible for the transformation of a toxic metabolite into the ultimate toxicant. Rearrangements and cyclizations are examples of reactions involved in these processes. In the case of the solvent hexane (Figure 33.19), the toxic metabolite, 2, 5-hexanedione, is formed by four successive oxidations of the molecule. The condensation of the -dicetone with the lysyl amino group of a neurofilament protein is followed by a Paal-Knorr cyclization reaction. This is the initial process that explains the hexane-induced neurotoxicity." A further auto-oxidation of the A-pyrrolyl derivatives leads to the cross-linking of the axonal intermediate filament proteins and the subsequent occurrence of peripheral neurotoxicity." ... 

A similar conclusion can be drawn in the Paal-Knorr cyclization [168] between an amido-1,4-diketone and a large variety of primary amines, performed under microwave activation (Eq. 85), the rate-determining step being the nucleophilic attack of the amine on the carbonyl moiety via a dipolar TS. 

Celecoxib (Celebrex) is a selective cyclooxygenase-2 (COX-2) inhibitor prescribed as a nonsteroidal anti-inflammatory drug (NSAID). The Paal-Knorr cyclization was the crucial step in preparing tri-substituted keto-pyrroles as COX-2 inhibitors. Here, the tri-ketone substrates were prepared in situ from phenacyl bromide and 1,3-diketone. ... 

The Paal-Knorr cyclization was employed to produce highly aryl-substituted pyrrole carboxylates as useful medicinal chemistry leads. Therefore, l,4-diketone-2,3-diester was assembled from an Sn2 displacement of ethyl 2-bromoacetoacetate with the anion of the ketoester. Condensation with an aniline then provided a library of fully substituted pyrroles. 

The regioselective synthesis of pyrroles via [3,3]- and [l,3]-sigmatropic rearrangements of 0-vinyl oximes formed by iridium-catalysed isomerization of 0-allyl oximes is such that when enolization is favoured, a [3,3]-rearrangement followed by a Paal-Knorr cyclization gives a 2,3,4-trisubstituted pyrrole and when enolization is disfavoured, a [l,3]-rearrangement occurs prior to enolization to give a 2,3,5-trisubstituted pyrrole after cyclization (Scheme 10). ... 

The pyrrole ring 35 was synthesized (Scheme 14) by first making a diketone 34 followed by a Paal-Knorr cyclization. The pyrrole ring 35 then was reacted with phenylisocyanate (Scheme 15) to produce the triaryl pyrrole ring system 36. Tien, through a series of reactions designed to extend die alkyl... 

The TBIN 38 is reduced to the corresponding amine 41 and under Paal Knorr conditions reacted with the diketone 37 (Scheme 19) 12), Through experimental design, the )deld of the Paal-Knorr cyclization was optimized and presently achieves greater than 70% yield of 42. Key conditions were defined to... 

The classical Paal-Knorr cyclization of 1.4-diketones to give pyrroles was dramatically speeded up under microwave irradiation with high yields (70-90%). 

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