2-Aryl-27/-indazoles. synthesis

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>. 

Scheme 16.43 C-H arylation of indazoles synthesis of YD-3, YC-1, and nigellidine hydrobromide.

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>. 

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... 

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... 

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>. 

Diazonium intermediates have also been employed in the synthesis of pyrazoles. A convenient one-pot procedure for the preparation of 3-phenyl- or 3-pyridylpyrazoles 27 from the 1,3-dipolar cycloadditions of phenylacetylene or 3-(pyridyl)acetylene with diazo compounds 26 generated in situ from aldehydes 25 has been reported <03JOC5381>. Cyclization of ortho-(arylethynyl)benzene diazonium salts 28 having substituents at the para-position of the aryl ring furnished indazoles 29 <03TL5453>. 

A copper(ii) oxide-catalyzed regioselective synthesis of 1-alkyl- and l-aryl-l//-indazoles from ortho-hzXogcnztcA alkanoylphenones, benzophenones, and arylcarboxylic acids with hydrazines in the presence of potassium carbonate has been developed <20070L525>. A palladium-catalyzed C-H activation/intramolecular amination reaction sequence provided a new route to 3-aryl/alkylindazoles <20070L2931>. 

Electrophilic cyclisation onto the aromatic ring achieves the synthesis of 3-amino-indazoles when aryl-hydrazines are reacted with A-(dichloromethylene)-iV,iV-dimethylammoninm chloride, as shown. ... 

Several reports have been published on the synthesis of indazoles. [3-i-2]-Cycloaddition of lithium trimethylsilyldiazomethane with benzynes, generated from halobenzenes 19, gave the corresponding 3-trimethylsilylindazoles 20 and 21 in various ratios <04TL1769>. These trimethylsilylindazoles could also react with aryl aldehydes in the presence of cesium fluoride to give 3-(arylhydroxymethyl)indazoles in good to moderate yields <04S1183>. 2-... 

By employing ortho-(trimethylsilyl)aryl triflates as benzyne precursors, Jin and Yamamoto have reported the synthesis of indazoles under mild reaction conditions by the [3-1-2] cycloaddition of benzyne with diazomethane derivatives, followed by a 1,3-hydrogen shift (Scheme 12.54) [103]. Depending on the stoichiometry of the reagents and the reaction conditions, either 1-arylindazoles 194 or IH-inda-zoles 195 are readily produced in fair to good yields. 

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) ... 

The cross-coupling reactions of hydrazines with aryl halides to give substituted hydrazines is very important from the point of view of nitrogen heterocyde synthesis (for example, indoles, indazoles, pyrazoles, and aryltriazoles, and before this report by Straddiotto s group [28a], there was no literature method for the Pd-catalyzed cross-coupling of hydrazine to aryl electrophiles. Hydrazines are difficult substrates because of their reducing power and the reactivity of the mono-arylated hydrazine product to further arylation. 

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]. 

The palladium-catalyzed Suzuki-Miyaura reaction is an extremely effective and versatile approach for selective carbon-carbon bond formatiOTi. Thus, the coupling between aiylboronic acids and aryl halides or triflates is frequently utilized for the preparation of biaryls [52,81,87,88,144—152] or fused heterocycUc systems [139-141, 153-157]. Other applications involve the synthesis of indazole-based thienyl... 

Silver was postulated to function as a halide sequestration agent other alkali metal carbonates were ineffective. The reaction was equally efficient for aryl iodides and aryl bromides (76% for Arl vs. 71 % for ArBr). Electronically different and sensitive functional groups were permissible for both indazole and aryl halide, furnishing the arylated product in good to exceUent yields (71—96%). Steric hindrance was observed for ort/io-substituted aryl iodides, generating diminished yields. This methodology could be apphed to the synthesis of hver X receptor agonists, which had been synthesized previously in five steps (eq 31). 

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