1- Aryl-1//-indazoles

Song and et al. discovered that W-aryl-Af-(o-bromobenzyl)hydrazines 102 or Af-aryl-Af -(o-bromobenzyl)hydrazines 104 could be effected by the Pd(OAc)2/dppf catalytic system to afford 2-aryl-2//-indazoles 103 [71] and 1-aryl-1//-indazoles 105 [72] with reasonable yields (Scheme 37). Further investigations indicated that [77-aryl-A -(o-bromobenzyl)hydrazinato-77 ]-triphenylphosphonium bromides 106 were also suitable substrates for this reaction, affording 1-aryl-1/7-indazoles 105 in moderate yields. 

From UV studies of 4-phenyl-, 4-nitro- and 4-nitroso-pyrazoles, Habraken et al. (67RTC1249,72JHC939) conclude that the 4-pyrazolyl group acts as an electron-donating group. UV spectra of pairs of 1-aryl- and 2-aryl-indazoles and their utility in the determination of isomeric structures are discussed in (67BSF2619) many other UV data on indazole derivatives can be found in (71PMH(3)67). 

Diazo compounds have also been used as precursors in the preparation of pyrazoles and indazoles. The copper-promoted cycloaddition reaction of lithium acetylides 18 with diazocarbonyl compounds 19 provided a direct and efficient approach to the synthesis of pyrazoles 20 <07AG(I)3242>. A facile, efficient, and general method for the synthesis of 1-arylated indazoles 22 and A-unsubstituted indazoles 23 by the 1,3-dipolar cycloaddition of benzynes, generated from 21, with diazomethane derivatives has been reported <07AG(I)3323>. Reaction of diazo(trimethylsilyl)methylmagnesium bromide with aldehydes or ketones gave 2-diazo-2-(trimethylsilyl)ethanols, which were applied to the synthesis of di- and trisubstituted pyrazoles via [3+2] cycloaddition reaction with ethyl propiolate or dimethyl acetylenedicarboxylate <07S3371>. 

The reaction has been extended to indazole (67BSF2619) from which both isomers have been obtained, and to pyrazolones (68BSF5019). In the latter system N-, O- and C-aryl and even diaryl derivatives have been isolated from the reaction with l-fluoro-2,4-dinitrobenzene. 

Indazole-3-carboxylic acid, 1-aryl-ring cleavage, 5, 246... 

Acid- and base-promoted methods have also been used in the syntheses of pyrazoles. Hydrogenation of methyl 2-Cbz(hydrazine)-3-hydroxy-4,4-dimethoxybutanoate 11 followed by cyclization in the presence of trifluoroacetic acid afforded the first asymmetric synthesis of the (4S,5.R)-5-carbomethoxy-4-hydroxy-A2-pyrazoline 12 <00TL8795>. Reaction of 2-nitrobenzyl triphenylphosphonium ylide (13) with aiyl isocyanates afforded 2-aryl-2H-indazoles 14 <00TL9893>. Base-promoted reaction of nitrobenzenes 15 with aryl imines 16 afforded aryl pyrazoles 17 . 

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. V-Aryl-lV-(c>-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2W-indazoles 27 . Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. 

In addition, 2-aryl pyridyl indazoles have been reported in the patent literature [25]. For example, compound 13 is reported to inhibit AKT-1 (IC50 < 0.18 pM). No kinase selectivity data were presented. 

A highly efficient one-pot, two-step microwave procedure has been developed for the synthesis of l-aryl-l/7-indazoles. Microwave heating of 2-halobenzaldehydes or 2-haloacetophenones with phenylhydrazines at 160°C for 10 min quantitatively yielded the arylhydrazones, which were further cyclized to give l-aryl-17/-indazoles via Cul/diamine-catalyzed... 

So erhalt man aus 4-Formyl-benzofurazan-l-oxid mit primaren Aminen die entsprechenden 2-Alkyl-7-nitro- und 2-Aryl-7-nitro-2H-indazole (s.Bd.E8b)270 ... 

An alternate approach for the 1-arylation of pyrroles is offered by their copper catalyzed coupling with aryl bromides and iodides, as depicted in 6.68. The process, run in the presence of trans-N,N -dnnethyl-cyclohcxane-diamine, was also efficient in the A-arylation of pyrazole, imidazole, triazoles and indazole, giving a mixture of isomers in the latter case.100... 

The reaction of l-aryl-4,6,6-trimethyl-3-phenyl-l,6-dihydropyrano[2,3-cjpyrazoles 88a-d with DMAD in dimethylformamide (DMF) at reflux is the first example of a Diels-Alder reaction involving the pyrazole ring. The reaction afforded an indazole 89 by elimination of a molecule of acetone from the intermediate cycloadduct (83S852). The s-cis conformation of the reactive diene fixed by the dihydropyran and the aromatization process to afford the indazole by elimination of acetone could be the driving force for this reaction. 

A similar theme was used by Pabba in the synthesis of indazoles via a one-pot and two-step condensation-arylation sequence [97]. Here Cu(I) catalysis was used to assemble aryl hydrazines with 2-halobenzaldehydes or 2-halo-acetophenones to deliver the target molecules in high yields after two short... 

Thermal cyclization was also the route employed to prepare 9-hydroxy-7-methyl-l/f-pyrazolo[3,4-/]quinoline (74) from the 6-aminoindazole/ethyl acetoacetate condensation adduct shown in Equation (41) <92JMC4595>. The hydroxyl substituent of compound (74) was then converted (POCl3, DMF) to a chloro, which in turn was displaced by treatment with aryl amines to give tricyclics with potent in vivo immunostimulatory activity like that noted for regioisomeric l//-imidazo[4,5-/]quinolines but unlike the inactive pyrazolo[4,3-/]quinolines. Although it was noted with some interest that none of the linear tricyclic isomer had been isolated, this finding actually parallels that reported earlier for the similar condensation of 1- and (V(6)-alkyl and unsubstituted 6-amino-indazoles with diethyl ethoxymethylenemalonate <83JHC1351>. 

In the case of the indazole 85 and benzotriazole 86, the reaction with />-tolyllead triacetate 58 led to mixtures of the arylation products on both nitrogen atoms110 (Equations (87) and (88)). 

A versatile and efficient synthesis of 3-substituted-l//-indazoles 199 is based on the generation and subsequent cyclization of the intermediate hydrazones from aryl mesylates 198 and hydrazines (Scheme 119) <1999S588, CHEC-111(4.01.9.1.2)94>. 

Intramolecular palladium-catalyzed cyclization reactions are commonly used to synthesize indazole derivatives . For example, A-Aryl-A-(<9-bromobenzyl)hydrazines 203 participate in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2//-indazoles 204 (Scheme 121) <20000L519>. 

Reaction of 2-nitrobenzyl triphenylphosphonium ylide 205 with aryl isocyanates affords 2-aryl-2//-indazoles 206 (Scheme 122) <2000TL9893>. 

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