Hydrazine, tosyl, formation

The enhanced acidity of the NH group in phthalimide permits formation of the anion, which is readily alkylated by alkyl halides or tosylates. The amine can then be liberated by reaction of the substituted phthalimide with hydrazine. 

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>. 

The reaction has been shown to be of very broad scope with a multitude of nucleophiles Nu such as imides.23,24,29,32,33,36,37,42 amines,10,32 cyanide,25,32 hydroxide,10,32 alkox-ide,10,26,32 electron-rich isocyclic or heterocyclic aromatic compounds,28 carboxamides,31 lactams,31 ureas,31 sulfonamides,31 cyanate,31 formate (to give products with Nu = H),34 C-H acidic compounds,35 hydrazines and hydrazides,38 and sulfinates.38 The amino group NR R2 of cyclopropane-1,1-diamines and the nucleophile Nu in bicycles 8, 9 or 12, respectively, can be easily replaced with other nucleophiles Nu, such as water,10,32,33 alkoxide,10,32-34,42 Grignard compounds,27,42 amines,29,30,36,37,42,43 cyanide,29,33,42,44 hydride,34,42,44 and C-H acidic compounds39-41,43,44 (see Section 5.2.1.). Therefore, it is currently the most important method for the preparation of substituted bicyclic cyclopropylamines. The toxic and costly reagent methyl fluorosulfate can be avoided in a modified synthetic route, which instead of the fluorosulfate 5 proceeds via the corresponding tetraphenylborate, hexafluorophosphate, or (most conveniently) via the tosylate.23 The different steps of the method can often be combined in a one-pot procedure. Results are summarized in Table 3. 

Formation of heterocycles. Five membered heterocycles Phenacylmalononitrile underwent cyclization in acidic media to yield substituted furans 136164 and 137166. Cyclization with anilines afforded pyrroles 138166. Benzylmalononitriles have been cyclized with hydrazine or hydroxylamine to yield 3,5-diaminopyrazoles or isoxazoles, respectively 6. Aminomalononitrile tosylate can be reacted with aliphatic or aromatic isothiocyanates to yield 2,5-diaminothiazole-4-carbonitrilesi6. ... 

Pyrazoles.—Formation. 3-Amino-4-ethylthio-5-methylpyrazole (311) is formed by the action of hydrazine on the nitrile MeBrC=C(SEt)CN. Acetylenic hydrazones R C=C-C(R )=NNHTos (R = H, Pr, or Ph R = H or Me) cyclize in the presence of potassium carbonate to the pyrazoles (312) via the iV-tosyl derivatives. Treatment of the (p-chlorophenyl)hydrazone (313) of ethyl 2-furylpyruvate with sulphuric acid affords only 10% of the expected ethyl 3-(2-furyl)indole-2-carboxyIate the main product is the pyrazole (314), formed presumably by way of the spiro-intermediate shown. ... 

A multitude of similar routes have been reported employing such intramolecular C—N bond formation. A-Tosyl hydrazones have also been established as effective indazole precursors [78] and were utilized in the synthesis of the natural product nigel-licine [79]. 3-Amino- l/f-indazoles were also prepared by similar palladium-catalyzed cyclizations [80]. Generating the appropriate halo-substituted arylhydrazone or aryl-hydrazine in situ has proved a popular tactic and has led to the development of effective one-pot processes [81-85]. 

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