Arylhydrazines, formation

They are formed by treatinga-diketones, a-hyd-roxyaldehydes, hydroxyketones, aminoalde-hydes or aminoketones with arylhydrazines. Sugars can be identified by their osazones which have characteristic melting-points, formation times or crystal appearance. 

Construction of the indole ring via Fischer synthesis. Starting from a variety of 3,4-dihydro-lH-benzo[l ]azepine-2,5-diones 40 and arylhydrazines Fischer syntheses of indolo benzazepinones 41 have been reported (Scheme 8 (1999JMC2909)). Usually, the reaction comprises a two-step one-pot procedure with the formation of intermediate arylhydrazones in warm acetic acid followed... 

The electrophilic substitution of the 3-aryl compounds (265, R = Ar, R = H) exemplified by the formation of 5-bromo- (265, R = Ar, R = Br) and 5-nitro derivatives (265, R = Ar, R = NOj) has been put forward as evidence against the meso-ionic formulation 265. lliis approach is unacceptable since ground state charge distribution cannot be deduced from reaction products. The aluminum-amalgam reduction of meso-ionic l,2,3-thiadiazol-4-ones (265) yields either N-mercaptoacetyl-A-arylhydrazines or Ar-acyl-A-arylbydrazines. Triethyl-oxonium tetrafluoroborate and meso-ionic l,2,3-thiadiazol-4-ones (265) yield 1,2,3-thiadiazolium tetrafluoroborates (267). The effect of solvent on the ultraviolet spectra of meso-ionic l,2,3-thiadiazol-4-ones (265) has been reported. ... 

Ring hydrolysis of 2-amino-5-arylamino-l,3,4-oxadiazoles by ammonium hydrogen sulfide leads to the formation of l-aryl-4-carbamoylthiosemicarbazide (63).98 Arylhydrazine dicarboxamides... 

Section 4.09.7.7.8), and 8-chlorocaffeine is similarly obtained from 8-hydrazinocaffeine (55CB1932). 6-Hydrazinopurine is also converted into 6-thioxo-l,6-dihydropurine in 60% yield when heated with thiolacetic acid. The hydrazinopurines give azidopurines with nitrous acid and undergo other reactions typical of arylhydrazines, including formation of exocyclic pyrazole and triazole rings. 

The arylhydrazine derivatives can also participate in other than benzidine isomeriza-tions. Thus, a novel rearrangement of fused /V-arylamino-substituted 1,4-dihydropyridines 137 resulted in the formation of quinindoline derivatives 1392 30,231 (equation 53). A proposed mechanism of this reaction assumes a [3,3]-sigmatropic shift like a Cope rearrangement through unstable intermediate 138. 

Schiff base formation in the Busch reaction may be avoided by employing N-( 1 -chlorobenzyl)benzimidoyl chloride, in which the aldehyde one-carbon fragment is already incorporated into the N-(l-chlorobenzyl) moiety both chlorine atoms participate in the reaction with arylhydrazine, to give modest yields of a A3-l,2,4-triazoline (Scheme 5) (79ZOR1181). 

Fischer phenylhydrazine synthesis. Formation of arylhydrazines by reduction of diazo compounds with excess sodium sulfite and hydrolysis of the substituted hydrazine sulfonic acid salt with hydrochloric acid. The process is a standard industrial method for production of arylhydrazines. 

Addition to the Carbonyl Group — The internal, cyclic hemiacetal formation is one of the illustrations of such addition. The H2N-X nucleophiles, with X being NH2 (hydrazine), NHAr (arylhydrazines), OH (hydroxylamine), NHCONH2 (semi-carbazide), NHCSNH2 (thiosemicarbazide), or alkyl (primary amine), produce hydrazones, arylhydrazones, oximes, semicarbazones, thiosemicarbazones, and alkyl imines (Schiff bases), respectively, following the following path 5.4 + 5.15 — 5.16 ->. .. -> 5.21. 

Using a-acetyl-y-butyrolactone as the carbonyl component in the Fischer synthesis, decarboxylation occurs and it is thus possible to prepare a 1,2-disub-stituted indol-3-ylethanol [2637]. In a related reaction, a y-haloaldehyde or a y-haloketone reacts with an arylhydrazine to give a tryptamine in which the side-chain nitrogen is derived from the terminal nitrogen of the reacting phenylhydrazine this and related reactions were reviewed in 1974 and 1988 [2641,3461). The course of Fischer indolization of the preformed monophenyl-hydrazone of cyclohexane-1,3-dione changes when the reaction is allowed to proceed under conditions which encourage ketal formation [2565]. 

Although in favorable circumstances the reaction may be effected thermally, it is usually conducted as an acid-catalyzed reaction. Both Brpnsted and Lewis acids are effective. The principal function of the catalyst is to accelerate the formation of the enehydrazine from the arylhydrazone [5,6]. It is not usually necessary to isolate the latter the reaction can be conducted as a one-pot procedure starting from ketone or aldehyde and arylhydrazine. Catalysts employed include mineral acids (hydrochloric, sulfuric, polyphosphoric), organic acids such as acetic acid, and metal-halide Lewis acids. Among the most generally reported are ZnCl2 and alcoholic hydrogen chloride. 

X-alkyl-X-arylhydrazin.es39,40 43,95-99 or heterocyclic hydrazines 93,100-108 or with semicarbazide83 and thiosemicarbazide.109 Arylhydrazincs have been extensively used for the characterization and identification of saccharides, in contrast, alkylhydrazincs have been seldom used because the alkylhy-drazon.es formed are difficult to crystallize and possess unfavorable equilibrium constants for their formation. 

Kunze, K.L. and PR. Ortiz de Monteiiano (1983). Formation of a sigma-bonded aryl-iron complex in the reaction of arylhydrazines with hemoglobin and myoglobin. J. Am. Chem. Soc. 105, 1380-1381. 

Electrophilic cyclisation onto the aromatic ring achieves the synthesis of 3-aminoindazoles when arylhydrazines are reacted with Ar-(dichloromethylene)-AT,A -dimethylammonium chloride, as shown. The formation of l-benzyl-3-hydroxyin-dazole by heating A -benzylphenylhydrazine with urea at 285 °C involves the electrophilic cyclisation of a first formed semicarbazide. ... 

Fischer indole synthesis. This reaction can be carried out by reaction of a ketone (1 equiv.) and an arylhydrazine hydrochloride (1 equiv.) in refluxing pyridine (1-18 hours). Pyridinium chloride (1 equiv.) is formed and acts as catalyst for the cyclization to indoles. No prior formation of a hydrazone is required. In several instances, higher yields are obtained by this method than by use of other catalysts. ... 

In addition to direct formation from an arylhydrazine and a carbonyl compound, iV-aryl-hydrazones can be prepared from aryldiazonium ions by coupling with enolates or enamines (Japp-Klingemann reaction). This reaction has most frequently been applied to j -ketoesters. The coupling product undergoes deacylation so that the ultimate product of Fischer cycUzation is an indole-2-carboxylate ester (Scheme 58) <92JMC4823>. 

The hydrolysis of hydrazidoyl halides in hydrochloric acid gives rise to the formation of the corresponding arylhydrazines Reduction... 

A number of excellent variations on the classic Fischer indolization are known that fall outside of the previous three categories. Like solid-phase synthesis, multicomponent and domino reactions are of major interest to organic chemists. Ganem reported a three-component Fischer indole variation that embraces the union of nitriles or carboxylic acids with organometaUics followed by the addition of arylhydrazine. This exquisite method is summarized in Scheme 16 [117]. In both variations, in situ formation of the requisite arylhydrazones culminates in indolization. The presence of sufficient arylhydrazine hydrochloride... 

Willoughby and coworkers reported a solid-phase strategy for the preparation of 2-arylindole combinatorial libraries in a split-and-pool format (Figure 11.61). Twenty different arylalkyl ketoacids were immobilized onto a sulfonamide resin, mixed, and separated into twenty equal portions. The Fischer indole cyclization was carried out with 20 arylhydrazines in the presence of ZnCl2 and acetic acid. The resin was mixed, separated into 80 equal portions, and finally alkylated under Mitsunobu conditions. A library of 12,800 compounds was generated, and led to the discovery of potent ligands for a variety of G-protein coupled receptors. 

Arylhydrazines (ArNHNH2), which include phenylhydrazine, 4-nitrophenylhy-drazine, and 2,4-dinitrophenylhydrazine, are commonly used to make crystalline derivatives of carbonyl compounds. The formation of a 2,4-dinitrophenylhydra-zone 3 is represented by Equation 25.9, and the mechanism of this transformation typifies that followed by a number of compounds, RNH2, that may be considered derivatives of ammonia. Thus, the overall reaction involves initial acid-catalyzed addition of the elements of N-H across the carbonyl Tr-bond to afford a tetrahedral intermediate, which subsequently dehydrates to the product (Eq. 25.9). 

The synthesis of 2-aryl-l,2-dihydrophthalazines 12 via a Lewis-acid-catalyzed domino condensation/intramolecular substitution reaction of 2-(bromomethyl)benzaldehydes 13 with arylhydrazines 14 in the presence of ferric chloride and potassium carbonate in acetonitrile at 100 °C was reported by the Beifuss group (Scheme 7) (13JOC1045). It was determined that substituents on either of the starting materials did not impede the formation of the desired 2-aryl-l,2-dihydrophthalazines 12. 

Electrophilic iV-aminations have been performed with hydroxylamine-O-sulfonic acid (HOSA)," O-(2,4-dinitrophenyl)hydroxylamine and 0-mesitylenesulfonylhydroxylamine. The use of HOSA is mainly restricted to aqueous reaction media. Imide sodium salts of some heterocycles such as theobromine (88) can be converted to hydrazine derivatives by treatment with 0-(diphenylphosphinyl)hydroxylamine (equation 35).This reaction has been extended to synthesis of -arylhydrazines, where R and R are hydrogen, alkyl or aryl (equation 36)." Similarly, trisubstituted hydrazines can be prepared by the use of yV-aryl-O-acetylhydroxylamines and secondary amines." A recent publication" concerning the synthesis of l-acyl-2-dkylhydrazines from hydroxamic acids and amines in the presence of activating agents has been found to be erroneous no N—N bond formation occurs under these conditions. "... 

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