2- Aryl-2//-indazoles, formation

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>. 

Indazoles.—iV-Aryl-o-azidobenzamides (391) yield the chloro-indazoles (392) on treatment with thionyl chloride.The formation of 1,3-diphenylindazole (393) by the action of trifluoromethanesulphonic anhydride on benzaldehyde... 

Another system where C—N bond formation was observed is in the synthesis of indazoles 112. The synthesis of heterocycles 112 from (Z)-2-bromoacetophenone tosylhydrazones 111 involves a catalytic system composed of a diamine as ligand, such as A, AP-dimethylethane-1,2-diamine and KjCOj at rt (Eq. 10.38) [83]. The mechanism proposed is the intramolecular ET from the nucleophilic center to the pendant aryl bromide, fragmentation, and radical-radical coupling (seeEq. 10.31) ... 

A wide variety of reagents have been used in 1,3-dipolar cycloadditions with arynes. For example, a general method for the preparation of Al-unsubstituted indazoles 27 and 1 -arylindazoles 28 by the [3+2] cycloaddition of aiynes generated from o-(silyl)aryl triflates and diazomethane daivatives has been developed. The selective formation of 27 or 28 depends on the relative amounts of the... 

The Jacobsen synthesis can be performed as an efficient one-pot procedure (AC2O, alkylnitrite, KOAc in benzene) [445] modified by addition of 18-crown-6 [446]. Due to formation of N-acetyl-6 under these reaction conditions, an additional hydrolysis step is required. Analogously, indazoles 6 were obtained from cyclization of aryl azosulfides (8, S-tBu instead of OAc) by means of KOtBu [447]. 

H.K. Lee, G.S. Gho, Gopper powder-catalyzed C-N bond formation of arylhydrazones of 2-bromobenzaldehydes leading to 1-aryl-lH-indazoles, Synth. Gommun. 43 (2013) 915-921. 

Routes involving intramolecular C—N bond formation have proved to dominate this area. A number of researchers have reported the cycUzation of appropriately substituted arylhydrazones, as illustrated by Scheme 24.16. Intramolecular coupling of bromo-substituted arylhydrazone 35 using a palladium catalyst derived from biden-tate ligand 36 delivers l//-indazole 37 in good yield [76]. The scope of such a transformation was expanded when it was shown that arylhydrazines such as 38 could also be used. In this case, in situ aromatization occurs following intramolecular N-arylation to yield the desired heterocycle [77]. 

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]. 

A strategy involving intermolecular C—N bond formation has also been described by Lefebvre et al. They demonstrated that arylation of benzophenone hydrazone with a 2-bromobenzonitrile derivative and subsequent acid-catalyzed cyclization is also an effective route toward the synthesis of 1/f-indazoles [91]. A route to 2H-indazoles incorporating an intermolecular C—N bond formation has also been demonstrated by Kumar et al. They reported a novel one-pot three-component approach utilizing 2-bromobenzaldehydes, primary amines, and sodium azide under the action of a copper... 

The nucleophilicity of an organocobalt(III) species was utilized by Hummel and Ellman to achieve condensation of an azobenzene and an aldehyde to afford an A/ -aryl-2//-indazole derivative (Scheme 10.13) [35]. A combination of a cationic Cp Co complex bearing a noncoordinating B(CgF5)4 anion and acetic acid promotes direct addition of the azobenzene to the aldehyde through azo-directed ortho-metalation and subsequent insertion of the C=0 bond into the aryl-Co bond. While these catalytic steps are likely reversible, intramolecular dehydrative condensation of the azo and the alcohol moieties in the aldehyde adduct serves as a driving force for the formation of the indazole product. The reaction shows a substrate scope comparable to that of the same reaction catalyzed by a Cp Rh catalyst [36] and is applicable to both symmetrical and unsymmetrical azobenzene derivatives and to aromatic, heteroaromatic, and aliphatic aldehydes. 

Scheme 37 Synthesis of 2-aryl-2//-indazoles and l-atyl-l//-indazoles via Pd-catalyzed intramolecular C-N bond formation...

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