Hydrazines, aryl, formation

The nitrosation of secondary amines is reversible in acid solution, so A-nitrosamines may be hydrolized at low pH. Such hydrolysis is especially important for diaryl nitrosamines but also significant for aryl akyl nitrosamines. The NO liberated in the hydrolysis may react with the reduction product from the A-nitrosamine, the unsymmetrical hydrazine, with formation of amine and N2O [213,214] ... 

In principle, the heterocyclization between these p-substituted ketones and monosub-stitnted hydrazines proceeds by a Michael addition-elimination on the p-carbon atom by the more nncleophilic nitrogen of the hydrazine, followed by cyclodehydration to give mixtnres of 3-triflnoromelhyl and 5-trifluoromethylpyrazoles. In general, condensation reactions with melhylhydrazine lead to the 3-trifluoromethylpyrazole derivatives as only or major regioisomers, whereas with aryl or heterocyclic aromatic hydrazines, the formation of 5-trifluoromethylpyrazole prevails. 

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. 

An ingenious synthesis of 1-arylisoindolcs has been developed by Vebor and Lwowski, based upon the reaction of an o-phthalimido-methylbenzophenone (41, R = aryl) with hydrazine (Table IV). The benzophenone is prepared by a Friedel-Crafts reaction with o-phthalimidomethylbenzoyl chloride (40). The mechanism of isoindole formation can be represented sehematically by a sequence involving attack by hydrazine at the imide to give the ring-opened hj drazide (42), followed by cyclization to phthalazine-l,4-dione (44) with displacement of the o-aminomethylbenzophenone (43). Intramolecular condensation of the latter can lead, via the isoindolenine... 

Parallel array synthesis was used to access the 3-aryl-tetrahydro-l,2-diazepines 90 (and other related compounds) by cyclisation of the chloro ketones 88 on reaction with hydrazine to give 89 followed by sulfonamide formation the Si-TrisAmine was added at the end as a scavenger to remove any unreacted arylsulfonyl chloride remaining <06MCL3777>. 

Hydrazinolysis of the imidate and carboxylic ester functions of 1-aryl-oxycarbonyl-l,6-dihydro-2-methoxypyrimidines (61) with 1 molar equivalent of hydrazine hydrate culminated in the formation of the 1,2,4-tria-zolo[4,3-a]pyrimidine-3-ones 63 [89GEP(0)3839711] (Scheme 25). 

For 1-aryl-substituted benzo[c]pyrylium salts 10, hydrazine acts as a 1,2-dinucleophile with the formation of benzodiazepines 175 (69MIP1 74CB3883). 

Practically all linear 1,3-diketones13 7-142 give the corresponding pyrazoles with hydrazine104 143 and its derivatives.144-149 The reaction of aliphatic diketones should be moderated by dilution, cooling, or the addition of acid.137 Since pyrazole rings are stable, severe conditions may be used in their preparation where necessary. For details of the hydrazine/acetylacetone reaction see Wiley and Hexner.150 Evidently the reaction proceeds via the formation of the monohydrazone (11)151 which, when aryl-substituted, is less reactive and may be isolated.83,152-159 (However, see reference 159a.) It is not known if the monohydrazones are cyclic (12) or not, but they are... 

The scope aromatic C-N bond formation extends beyond simple amine substrates. For example, selected imines, sulfoximines, hydrazines, lactams, azoles, and carbamates give useful products from intermolecular aromatic C-N bond formation. Intramolecular formation of aryl amides has been reported. In addition, allylamine undergoes arylation, providing a readily cleaved amine alternative to the ammonia surrogates benzylamine, t-butylcarbamate, or benzophenone imine. Although it is an amine substrate, the reaction of this reagent is included here because of its special purpose. 

Mahy JP, Gaspard S, Delaforge M et al (1994) Reactions of prostaglandin-H synthase with monosubstituted hydrazines and diazenes - formation of iron(II)-diazene and iron(III)-sigma-alkyl or iron(III)-sigma-aryl complexes. Eur J Biochem 226 445 157... 

Via Organometallic Intermediates. Metabolic reactions of xe-nobiotics such as halocarbons, hydrazines, or sydnones result in the formation of N-substituted porphyrins. An organometallic complex, in the form of an iron(II)-carbene (for the sydnones and halocarbons) or an iron(III)-<7-alkyl (c-aryl) (hydrazines), is an isolable intermediate in this process. The novelty of the biological organometallic chemistry has induced a flurry of research activity in this area. 

More recently, Stedman and coworkers have examined the kinetics of the nitrosation of hydrazine (Perrott et al., 1976), some methyl hydrazines (Perrott et al., 1977) and aryl hydrazines (Stedman and Uysal, 1977). Again (8) is obeyed with S = RNHNH3, and rate constants are believed to represent an encounter-controlled process. Since it is not possible to calculate the true rate constants for processes such as (9) because the equilibrium constant for HjNO formation is not known, arguments are based on the relative constancy of k-values (eqn 8) over a wide range of very reactive species. The products from the reaction of hydrazine itself are ammonia and hydrazoic acid in ratios which vary with the acidity. Both are thought to arise from a common intermediate as laid out in Scheme 4. With excess HNOj, hydrazoic... 

In general the synthesis of suitably protected amino acid and peptide hydrazides from the corresponding alkyl or aryl esters by reaction with hydrazine hydrate is carried out in alcohols or DMF at ambient temperature.P However, with C-terminal branched amino acids such as valine or isoleucine, or larger peptides, more vigorous conditions are required, i.e. higher temperature (25-80°C) and longer reaction times. To avoid formation of symmetrical bis(A-acyl-aminoacyl)hydrazides an excess of hydrazine hydrate or hydrazine is recommended, which also enhances the reaction rates. In this context, the solvent is known to play an important role, with alcohols being more appropriate than DMFP 0 or solvent mixtures such as dioxane/methanol.f l The use of hydrazine hydrate without any solvent has also been reported. ... 

Intramolecular palladium-catalyzed cyclization reactions have also been used to synthesize pyrazole derivatives. iV-Aryl-iV-(o-bromobenzyl)hydrazines 494 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2//-indazoles 495 (Equation 101) <20000L519>. Palladium-catalyzed intramolecular C-N bond formation of iV-acetamino-2-(2-bromo)arylindolines 496, followed by hydrolysis and air oxidation in the presence of aluminium oxide, allowed the preparation of indolo[l,2-3]indazoles 498 via intermediate 497 (Scheme 58) <2002TL3577>. 3-Substituted pyrazoles have been prepared from the intramolecular cyclization of A -tosyl-iV-(l-aryl/ vinyl-1-propyn-3-yl)hydrazine and then exposme of the reaction mixture of the cyclization to potassium /i //-butoxide <1997SL959>. iV-Aryl-iV -(o-bromobenzyl)hydrazines 499 or [A -aryl-A -(t>-bromobenzyl)hydrazinato-A ]-triphenyl-phosphonium bromides 501 participated in a palladium-catalyzed intramolecular amination reaction to give 1-phenyl-l//-indazoles 500 (Scheme 59) <2001TL2937>. 

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