SYNTHESIS arylhydrazines

Heterocycle synthesis. Arylhydrazines and 1-alkynes react to form A-heterocycles. l-Aiyl-2-pyrazolene are produced from 3-butynol, whereas 2-methyl-3-aIkylindoles are obtained from other 1-alkynes." ... 

Owing to their particular interest two individual reactions will now be discussed separately. The reaction of methoxycarbonylhydrazine and 3-bromo-2,4-pentanedione affords, in addition to the expected pyrazole (608), a pyrazolium salt (609), the structure of which was established by X-ray crystallography (74TL1987). Aryldiazonium salts have been used instead of arylhydrazines in the synthesis of pyrazolines (610) and pyrazoles (611) (82JOC81). These compounds are formed by free radical decomposition of diazonium salts by titanium(n) chloride in the presence of a,/3-ethylenic ketones. 

In order to allow further transformation to an indole, the carbonyl compound 8 must contain an a-methylene group. The hydrazone 1 needs not to be isolated. An equimolar mixture of arylhydrazine 7 and aldehyde or ketone 8 may be treated directly under the reaction conditions for the Fischer indole synthesis. ... 

The l-arylpyrazol-5-ones (4.9), prepared by the two-step condensation of an arylhydrazine with ethyl acetoacetate, are the most commonly used coupling components for the synthesis of greenish yellow azo dyes. Coupling occurs at the 4-position of the pyrazolone ring which, as in the case of the acetoacetarylamides discussed above, is activated towards electrophilic attack by the two flanking unsaturated carbon atoms (Scheme 4.14). 

Hydroxyprolines react as aldehyde equivalents with arylhydrazines in the Fischer indole synthesis to give Al-protected L-tryptophans in moderate to good yields (Scheme 16). The reaction is more suitable for the l series because of the price of the o-Pro starting material (84CPB2126). 

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... 

A new, efficient and general synthesis of 4-amino-3-arylcinnolines has been described recently, starting from arylhydrazines and aryl trifluoromethyl ketones, and the following is a typical example. Addition of a THF solution of the hydrazone formed from phenylhydrazine and 2-trifluoroacetylthiophene to 5 equivalents of KHMDS in THF at -78°C, then slow warming of the mixture to room temperature and stirring at room temperature for several hours, gave 4-amino-3-(2-thienyl)cinnoline in 68% yield after work-up (quench with ether, then a wash with brine). 

The synthesis of dialkyl 3-aryl-2-indolylphosphonates 171 by the Fischer indole synthesis by the cycloaddition of arylhydrazines with a-ketophosphonates in polyphosphoric acid or under the influence of zinc chloride was described [183] ... 

Based on the assumptions about the reaction mechanism, one can predict that this technique will be applicable to other binucleophiles for the synthesis of perfluoroalkylated heterocyclic compounds. For example, the reaction of arylhydrazine with perfluoro-2-methylpent-2-ene in the presence of triethylamine led to N-arylperfluoro-3-ethyl-4-methylpyrazole 58 and N-arylperfluoro-4-methyl-5-ethylpyrazole 59 in different ratios depending on the reaction conditions (89RP1456419, 87RP1456418, 90IZY2583 89JAP(K)01 22855 99JFC(98)29). Syn- and /-aminoimines are intermediates in syntheses of pyrazoles they were isolated individually. On heating in the presence of triethylamine they are transformed into mixtures of 58 and 59. 

The reduction of diazonium salts by sodium sulfite forms monosub-stituted arylhydrazines. An improved procedure for the synthesis of phenylhydrazine in 84% yield is typical. Arylhydrazine salts substituted in the nucleus with halo," ether, carboxyl, or nitro groups have been prepared. The free bases are liberated from the salts by the action of aqueous sodium hydroxide or sodium acetate. 

A few examples of the reduction of aliphatic diazo compounds to hydrazines exist," but this is not a generally applicable method for the synthesis of alkylhydrazines. On the other hand, arylhydrazines can be prepared by reduction of aromatic diazonium salts.The most commonly used reagents for this conversion are sulfur dioxide (or sodium sulfite) and tin(II) chloride, these being used to reduce arenediazo-nium chlorides in aqueous solution. Several other reagents, including sodium amalgam and triphenylphosphine, have been used for specific reductions of this type. Arenediazonium tetrafluoro-borates have been reduced to the correspwnding hydrazinium salts (3) by benzeneselenol in dichloro-... 

The addition of hydrazines to chalcones gives dihydropyrazoles, which can be functionalized further. Eor example, a,/3-unsaturated ketones 643 were condensed with arylhydrazines to yield dihydropyrazoles 644 these can be further alkylated and oxidized to l,3,5-triaryl-4-alkylpyrazoles 645, which are novel ligands for the estrogen receptor (Scheme 80) <20000L2833>. A parallel solution-phase synthesis of an N-substituted 2-pyrazoline library 648... 

A versatile synthesis of pyrazoles from benzophenone hydrazones was demonstrated with a variety of 1,3-bifunctional substrates under acidic conditions <2002TL2171>. Hydrazones 668 and 671, prepared from palladium-catalyzed heteroaryl halides with benzophenone hydrazone, reacted with 1,3-bifunctional substrates 669 and 672 under acidic conditions to yield pyrazoles 670 and 673, respectively (Equations 139 and 140) <2004TL5935>. Enolates of a-chloro-/3-oxoaldehydes react with arylhydrazines in the presence of acetic acid or / -oxo-a-chlorenamines react with arylhydrazines to produce osazones of carbonyl-substituted glyoxals, which under conditions of acid catalysis undergo intramolecular heterocyclization to the corresponding functionalized pyrazoles <1998CHE167>. 

The most common method for the preparation of pyrazoles from other heterocycles is from pyranone-type compounds. Condensation of 2,3-dihydro /7-pyran -ones 787 with various aryl hydrazines in the presence of montmorillonite KSF clay under mild conditions proceeded rapidly to afford enantiomerically pure 5-substituted pyrazoles 788 (Equation 172) <2004TL6033>. Comparable results were obtained when arylhydrazines were reacted with 2-formyl glycals under microwave irradiation <2004TL8587>. Phenylhydrazine and hydrazine were reacted with 3-acetyl-4-hydroxy-6-methyl-2/7-pyran-2-one to afford 4-acetoacetyl-3-methylpyrazolin-5-ones, which were employed in the synthesis of bipyrazoles and pyrazoloisoxazoles <1999JHC1291>. Reaction of 3,3-dialkyl-6-(trifluoromethyl)-2,3-dihy-dro -pyrones with hydrazine hydrate afforded 3-(trifluoromethyl)-5-substituted-pyrazoles <1998RCB1365>. 

Direct alkylation of hydrazine itself with halides and sulfates usually gives mixtures of mono- and poly-alkylated hydrazines. It is possible to get useful yields of the monoalkylhydrazine by using an excess of hydrazine. Several specific procedures leading to monoalkylhydrazines are based on selective alkylation of hydrazine derivatives with protecting groups attached. So, easily prepared acetone N-(diethoxyphosphoryl)hydrazone (75) can be used. Phase-transfer catalyzed N-alkylation of (75), followed by deprotection with p-toluenesulfonic acid provides monoalkylhydrazine sulfonates (76 Scheme 17). Similarly, N-alkyl-N-arylhydrazines have been prepared by phase-transfer catalyzed N-alkylation of arylhydrazones (Scheme 18). An efficient, one-pot method for the synthesis of a variety of polysilyl-ated hydrazines employs hexamethyldisilane (equation 30). Polysilylated hydrazines were found to react with aldehydes or ketones to give hydrazones under anhydrous conditions. By treatment with triphenylphosphine and diethyl azodicarboxylate primary and secondary alcohols can be converted to hy-dr ine derivatives (equation 31). ... 

IV-Aryl hydrazones are used in agricultural applications. Additionally, they can be cleaved to form IV-arylhydrazines for pyrazole synthesis, and the hydrazine portion can be transferred to ketones to generate substrates for the Fischer indole synthesis136. 

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. 

Table 6.5. Variation of the arylhydrazine in the pyrazolone synthesis by using 4-trifluoromethylbenzalde-hyde and ethyl acetoacetate as constant building blocks...

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]. 

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