Knorr reaction, involving

Different reaction mechanisms are postulated for die synthesis of 2-or 4-quinolone derivatives. The Knorr reaction involves a nucleophilic attack of aniline nitrogen on the ester of P-ketoester component, providing anilide, which undergoes Friedel-Crafls cyclization followed by dehydration with sulfuric acid to yield 2-quinolones. On die other hand, a completely different pathway is involved in the case of Conrad-Limpach reaction. Condensation of aniline derivative with P-ketoester provides the corresponding enamino-ester. Enolization was followed by a 67c-electrocyclization reaction to form a 4-quinolone. A postulated alternative reaction padiway invokes the formation of an iminoketene prior to the cyclization step. 

The preparation of a glycoside by the Koenigs-Knorr reaction involves treatment of an 0-acetylglycosyl halide with the corresponding alcohol or phenol, in certain inert solvents when necessary, and in the presence of excess silver carbonate or silver oxide. 

Separately, Paal and Knorr described the initial examples of condensation reactions between 1,4-diketones and primary amines, which became known as the Paal-Knorr pyrrole synthesis. Paal also developed a furan synthesis in related studies. The central theme of these reactions involves cyclizations of 1,4-diketones, either in the presence of a primary amine (Paal-Knorr pyrrole synthesis), in the presence of a sulfur(II) source (Paal thiophene synthesis), or by dehydration of the diketone itself (Paal furan synthesis). 

Although the Koenigs-Knorr reaction appears to involve a simple backside S 2 displacement of bromide ion by alkoxide ion, the situation is actually more complex. Both a and /3 anomers of tetraacetyl-o-glucopyranosyl bromide give the same /3-glycoside product, implying that they react by a common pathway. 

The synthesis93 of N-(2,4-dinitrophenyl)-3-0-(tetra-0-acetyl-/ -D-glu-copyranosyl)-L-threonine methyl ester (131) involved a two-step procedure. First, formation of the intermediate, L-threonine orthoester 130 was achieved by treatment of tetra-O-acetyl-a-D-glucopyranosyl bromide (128) with the methyl ester of N-(2,4-dinitrophenyl)-L-threonine94 (129) under the conditions of the Koenigs-Knorr reaction (see next paragraph), and this was then converted into the L-threonine glycoside 131. 

The Paal-Knorr reaction was also employed by Steglich in likely biomimetic approaches to the marine alkaloids lamellarin L <00CEJ1147> as well as purpurone and ningalin C <00TL9477>. The overall approach employed herein involved initial oxidative coupling of two arylpyruvic acids followed by condensation of the resulting 1,4-diketones with suitable... 

Alternatively, Ballini devised a new strategy to synthesize tri-alkylated pyrroles from 2,5-dialkylfurans and nitroalkanes <00SL391>. This method involves initial oxidation of 2,5-dimethylfuran with magnesium monoperoxyphthalate to cA-3-hexen-2,5-dione (6). Conjugate addition of the nitronate anion derived from the nitro compound 7 to 6 followed by chemoselective hydrogenation of the C-C double bond of the resulting enones 8 (obtained by elimination of nitrous acid from the Michael adduct) completes the conversion to the alkylated y-diketones 9. Final cyclization to pyrroles 10 featured improved Paal-Knorr reaction conditions involving reaction of the diketones with primary amines in a bed of basic alumina in the absence of solvent. 

A number of glycosides were available to Fischer by way of the Koenigs-Knorr reaction and his own glycoside synthesis, which involves treatment of... 

Further examples of the Knorr reaction for the synthesis of 3-hydroxy-4,7-phenanthrolines are reported. A modification of the original synthesis239 of 3-hydroxy-1-methyl-4,7-phenanthroline involves isolation of the intermediate acetoacetanilide followed by ring closure with sulfuric acid.232 10-Amino-3-hydroxy-l-methyl-4,7-phenanthroline was obtained similarly from 4-amino-6-acetoacetamidoquinoline. Several 2-substituted l,3-dihydroxy-4,7-phenanthrolines were obtained likewise from diethyl alkylmalonates.101... 

While normal Knorr conditions involve initial N-C bond formation, the overall reaction can also be accomplished under conditions which begin with C-C bond formation. Condensation of the dimethyl ketal of acetamidoacetone with silyl enol ethers give adducts which cyclize to pyrroles (Scheme 49) <88S38l). 

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." ... 

Methods derived from the Koenigs-Knorr approach are useful for glycosylation reactions involving reactive alcohols, such as primary alcohols. Unfortunately,... 

In the early amidation approach, 2 may be assembled by condensation of aldehyde-amide 4 with 5-fluorooxindole 3. The aldehyde-amide would arise from a Knorr pyrrole reaction involving oxime 5 (derived from t-butyl acetoacetate) and (3-ketoamide 6, which can, in turn, be synthesized from diketene 7 and A,iV-diethylethylenediamine 8. 

In the late amidation approach, free base 2 may be synthesized from acid-aldehyde 9, 5-fluorooxindole 3, and A,A-diethylethylenediamine 8. Acid aldehyde 9 can be synthesized from diester 10 which would arise out of a Knorr pyrrole reaction involving oxime 5 and ethyl acetoacetate 11. 

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