Hydrazones, aryl

Anomalous Fischer cyclizations are observed with certain c-substituted aryl-hydrazones, especially 2-alkoxy derivatives[l]. The products which are formed can generally be accounted for by an intermediate which w ould be formed by (ip50-substitution during the sigmatropic rearrangement step. Nucleophiles from the reaction medium, e.g. Cl or the solvent, are introduced at the 5-and/or 6-position of the indole ring. Even carbon nucleophiles, e.g. ethyl acetoacelate, can be incorporated if added to the reaction solution[2]. The use of 2-tosyloxy or 2-trifluoromethanesulfonyloxy derivatives has been found to avoid this complication and has proved useful in the preparation of 7-oxygen-ated indoles[3]. 

Substituted aryl hydrazones can be converted to geminal difluondes in satis factory yields by molecular fluorine [H4, iodine fluoride [ 5], and N bromo-suc-cinimide-pyridinium polyhydrogen fluoride or A -bromosuccinimide-polyvi-nylpyridinium polyhvdrogen fluoride [5(5] (equation 21) (Table 6)... 

Table 6. Conversion of Aryl Hydrazones to Geminal Difluorides...

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

Heating of an aryl hydrazone 1 in the presence of a catalyst leads to elimination of ammonia and formation of an indole 2. This reaction is known as the Fischer indole synthesisy and is somewhat related to the Benzidine rearrangement. 

The bis-aryl hydrazone bond formed by this reaction is stable in aqueous solution over a broad pH range (pH 2-11) and under elevated temperature conditions (up to 94°C) (Solulink web site). 

Figure 18.15 NHS-chromogenic-PEG3-biotin contains an amine-reactive NHS ester that can be used to label biomolecules through an amide linkage. The chromogenic bis-aryl hydrazone group within the spacer arm of the reagent allows the degree of biotinylation to be quantified by measuring its absorbance at 354 nm. The compound also contains a hydrophilic PEG spacer, which provides greater water solubility.

The key intermediate in these transformations was the hydrazide 83 obtained from the ester 82 by simple treatment with hydrazine hydrate. This intermediate was then transformed by aldehydes, sulfonic chlorides, and isothiocyanates to obtain various aryl hydrazones 84, sulfonylhydrazines 85, and thiocarbazides 86. 

Alkyl- and aryl-hydrazones of aldehydes and ketones readily peroxidise in solution and rearrange to azo hydroperoxides [1], some of which are explosively unstable [2], Dry samples of the p-bromo- and p-fluoro-hydroperoxybenzylazobenzenes, prepared by oxygenation of benzene solutions of the phenylhydrazones, exploded while on filter paper in the dark, initiated by vibration of the table or tapping the paper. Samples were later stored moist with benzene at —60°C to prevent explosion [3], A series of a-phenylazo hydroperoxides derived from the phenyl-or p-bromophcnyl-hydrazones of acetone, acetophenone or cyclohexanone, and useful for epoxidation of alkenes, are all explosive [4], The stability of several substituted phenylazo hydroperoxides was found to be strongly controlled by novel substituent effects [5],... 

Formazans are conveniently produced under phase-transfer catalytic conditions from Af-aryl hydrazones and aryl diazonium salts [24], Yields vary from ca. 50% to 70%, but the procedure is superior to the standard synthesis. 

A novel way of preparing s-triazolo[3,4-a]pyridinium salts (105) by anodic oxidation of aryl hydrazones (104) of 2-acetylpyridine, 2-benzoylpyri-dine, and 2-formylpyridine in CH3CN-Et4NX (X=C104) p-TsO, or BF4) has been reported165 [Eq. (80)]. 

Glycoside/aminoglycoside antibiotics, 1, 207 Glycosmicine occurrence, 3, 148 Glycosminine occurrence, 3, 148 Glyoxal, aryl-hydrazone... 

Coupling of Diazonium Compounds with Hydrazones. The most common method for the production of formazans is the coupling of diazonium salts with aryl hydrazones in an alkaline medium, possibly in presence of an organic solvent. 

The conversion of aryl hydrazones to indoles requires elevated temperatures and the addition of Br msted or Lewis acids. For example a milder conversion when iV-trifluoroacetyl enehydrazines are used as substrates. 

Most recently, Wagaw, Yang, and Buchwald published a full account of the synthesis of indoles using the palladium-catalyzed amination process [185]. From the standpoint of catalysis, new results included improved turnover numbers and rates when Xantphos was used as ligand. Moreover, this ligand allowed diarylation of the hydrazone, including a one-pot sequential diarylation to provide mixed diaryl hydrazones. A procedure for the alkylation of N-aryl hydrazones was also reported. These procedures allow the formation of N-aryl and N-alkyl indoles after subjecting the products to Fischer conditions for indole synthesis. 

There are only two examples in which a heterobicyclic ring system is synthesized in a one-pot procedure from acyclic precursors. The first involves formation of the rare [l,2,4]triazino[6,5-e]-1,2,3-oxathiazine ring system (486) by condensation of the aryl hydrazone (485) with chlorosulfonyl isocyanate (Equation (98)) <91SC1695>. The second involves formation of the [l,3,4]thiadiazino[6,5-e][l,3,4]-thiadiazine (488) as a minor by-product when (487) is heated with triethyl orthoformate (Equation (99)) <71TL4985>. 

The key step is the elimination of the aryl sulfinate and this has been improved by using aryl hydrazones with bulky isopropyl groups on the 2-. 4-, and 6-positions ofthe aromatic ring to accelerate the elimination. The weakness of this approach to vinyl silanes is that the position ofthe... 

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