Synthesis of Indazoles

Lavis and Ellman reported an efficient method for the preparation of Af-aryl-2//-indazoles 18 by Rh(III)-catalyzed C-H bond addition of azobenzenes to aldehydes without external oxidant (Eq. (5.18)) [13]. In this reaction, the regioselective activation of azobenzenes can be controlled either by electronic or by steric effects, and the azo moiety serves as a nucleophile to trap the initial aldehyde addition product. A wide range of aldehydes and azobenzenes participate in the reaction to afford differently substituted indazoles. An interesting feature of this reaction 

Glorius described a tandem Rh-catalyzed C-N bond and Cu-catalyzed N-N bond formation between aryhmidates and organic azides to provide l//-indazoles [14a]. The reaction is scalable and O2 is used as the terminal oxidant (Eq. (5.19)). The l//-indazoles were obtained in moderate to high yields with good functional group tolerance. The formation of the N-N bond in this process does not appear to be Rh catalyzed. Similarly, Kim and coworkers demonstrated a Rh(IIl)-catalyzed oxidative olefination of 1,2-disubstituted arylhydrazines with electron-deficient terminal alkenes and an intramolecular aza-Michael reaction to synthesize 2,3-dihydro-l//-indazoles in good yields (Eq. (5.20)) [14b]. 

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The synthesis of indazoles from their 4,5,6,7-tetrahydroderivatives (439) by means of sulfur or, better, by catalytic dehydrogenation over palladium on charcoal (67HC(22)l) can also be included here. 

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... 

Synthesis of indazole-1 -15iV, indazole-2-15JV and their derivatives. . . 1149... 

An interesting case of intramolecular azo coupling to an activated methyl group is the well-known synthesis of indazoles 72 starting from o-toluenediazonium salts 69 or from N-nitroso-N-acetyl-o-toluidine 67 . Recently the reaction mechanism (32) was elucidated When the reaction is run in the presence of D O or... 

CH3COOD, no deuterium is incorporated in the diazonium salt 69. On the other hand, the synthesis of indazol 74 starting from the optically active diazonium salt 73 results in complete racemization (33). Therefore it can be concluded that the reaction... 

Lyubchanskaya, V. M., Alekseeva, L. M., Granik, V. G. The aza-Nenitzescu reaction. Synthesis of indazole derivatives by condensation of quinones with hydrazones. Chem. Met. Comp. (New York) (Translation ofKhim. Geterot. Soed.) 999, 35, 570-574. 

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-... 

This reaction has been modified by using quinone mono-ketals to control the regioselectivity. In addition, an aza-Nenitzescu reaction involving the condensation between quinones and hydrazones has been developed for the synthesis of indazole derivatives. ... 

This type of rearrangement can also occur as a consequence of in situ formation of a suitable intermediate, such as in the case of tandem or cascade reactions. Examples of the isoxazole-to-oxazole rearrangement have been studied both computationally and experimentally, providing evidence of the involvement of a 1,2,4-oxadiazole intermediate (2009JOC351). Synthetically useful cascade rearrangements have also been reported for the one-pot synthesis of indazoles (2011SL3018) and a series of isoxazolo-pyrimidines (2011OL4749). 

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. 

In continuation of our efforts in the development of new synthetic methods for the synthesis of various heterocyclic compounds, we have developed a green and eco-friendly protocol for the synthesis of indazole derivatives from 0-hydroxy aromatic... 

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 indazole derivatives are pharmacologically important compounds as their ring system forms a large number of dmg molecules, such as granisetron, SHTj receptor antagonist, which are used as an antiemetic in cancer chemotherapy [94], Gaikwad et al. [95] developed an efficient approach for the synthesis of indazoles 67 from ortho-alkoxyacetophenone and hydrazine hydrate using DMSO as a solvent and molecular iodine as a catalyst. In the absence of iodine, the reaction did not proceed even after 24 h (Scheme 10.49). 

Gaikwad DD, Abed S, Pawar RP (2009) Molecular Iodine as an efficient eatalyst for the synthesis of indazole. Int J Chem Tech Res 1 442-445... 

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... 

SCHEME 3.87 Synthesis of indazole derivatives using copper catalysts [45]. 

Palladium- and copper-catalyzed C—N bond formations can also be utilized effectively in the synthesis of quinolones. As in the synthesis of indazoles, intramolecular cyclizations have proved an efficient route. Battistuzzi et al. described such a route via cyclization of o-bromocinnamamide 43 [93]. The same palladium diacetate catalytic conditions were also found to be effective for an initial intermolecular Heck process, and thus 4-substituted 2-quinolones could be produced (Scheme 24.20). A brief mechanistic investigation confirmed that the Heck reaction occurred before the intramolecular C—N bond formation. 

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