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. 

A facile way of promoting the cyclization is to increase the nucleophilicity of the aryl system when possible. In the total synthesis of diazadiquinomycins A and B, for example, the authors were able to effect a double Knorr cyclization with concomitant in situ oxidation to the internal diquinone 23 by deprotecting the hydroquinone thereby lowering the activation barrier for the desired transformation. If the hydroquinone is left protected as the di-MOM ether, the reaction does not take place. ... 

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...

A modified Knorr cyclization has also been reported using ethyl 4,4,4-trifluoroacetoacetate in the synthesis of potent nonsteroidal androgen receptor agonists (Equation 30) <1998JME623, 1999BML1335, 1999BML1009>. 

When a -amino ketones with an additional acyl or alkoxycarbonyl substituent are used, the cyclization can follow one of two alternative courses (Scheme 6) (71JOC853). The first represents the normal Knorr cyclization. The product of the competing deacylation pathway is also a pyrrole and the utilization of the reaction gives a pyrrole synthesis, as is described in Section 3.06.3.5. The reaction does, however, constitute a limitation on the Knorr synthesis itself. 

The intermediates which are assumed to be involved in the Knorr cyclization can also be prepared by addition of a-amino ketones to electrophilic alkynes (equation 77). This methodology has found use primarily with dimethyl acetylenedicarboxylate to form pyrrole-2,3-dicarboxylate esters (equation 77), but methyl propiolate is also reactive (68T1567,69T527, 64JA107, 62JOC3346). 

Knorr cyclization of a range of iV-susbtituted butyramides in triflic acid yields 4-methyl-17/-quinolin-2-one derivatives704 [Eq. (5.257)]. Suggested intermediates of the transformation directly observed by low-temperature multinuclear NMR spectroscopy (HSO3F SbF5 S02C1E, 40°C) are distonic superelectrophiles formed by diprotonation of the two carbonyl oxygen atoms. 

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

The reader should always bear in mind that spontaneous oxidation in air can occur if a hydroquinone is sufficiently activated towards oxidation. An example of this is exemplified by Kelly et al in a short synthesis of diazaquinomycin A (68). The synthesis incorporates the first reported use of a double Knorr cyclization. The key intermediate 66) was prepared in just two steps from the MOM-protected hydroquinone (65). Cyclization of the compound (66) then gave diazaquinomycin B (67), which either under the reaction conditions or by careful isolation prior to simply stirring the solution in an open flask afforded the antibiotic diazaquinomycin A (68), thereby confirming the structure of the only recorded example of the tricyclic 1,8-diazaanthraquinone ring system (Scheme 14). 

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." ... 

Diethyl 3-furylphosphonates are prepared in fair to good yields (55-90%) by a two-step procedure based on ceric ammonium nitrate (CAN)-promoted oxidative addition of diethyl 2-oxoalkyl- or 2-oxo-2-phenylphosphonates to vinylic acetates followed by an acid-induced Pall-Knorr cyclization reaction (Scheme 3.120). ... 

Comf>ounds containing an —NHCOCH COR side-chain are cyclized to this ring by mineral acid (the Knorr reaction) but the course of this reaction varies according to the substituent R loss of a methyl group may also occur. A double Knorr cyclization is a step in the synthesis of the antibiotic diazaquinomycin A (35.12). 

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. 

The total synthesis of diazaquinomycin B was achieved in three steps starting from 67, and further oxidation of B gave diazaquinomycin A. The product from the reaction between 67 and 68 was deprotected, because phenols are more reactive toward electrophilic aromatic substitution, and hence the phenolic product 69 allowed double Knorr cyclization to proceed successfully. 

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. 

This reaction was first reported by Knorr in 1886. It is the synthesis of 2-hydroxyquinolines via the cyclization and dehydration of an anilide intermediate condensed from )0-ketoesters and anilines at a relatively high temperature. Right after this report, Conrad and Limpach also reported a similar reaction between anilines and )0-ketoesters but at low temperatures, which resulted in the formation of 4-hydroxy quinolines from the intermediate of alkyl crotonate. Thus this reaction is known as the Knorr synthesis, Knorr-Limpach method, Knorr cyclization, Conrad-Limpach-Knorr reaction, or Knorr quinoline synthesis. It has been reported that the formation of an alkyl crotonate intermediate is favored at moderate or low temperature in the presence of iodine or an acid catalyst, whereas intermediate anilide is formed at high temperatures. ... 

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). ... 

---