Indazole - Synthesis and Reactions as a Chemical Reagent

Physical Properties 

Indazole is a colorless crystalline and weakly basic solid with an mp of 145°C. It is soluble in acid but insoluble in water,  ether, and alcohol.

Indazole is a bicyclic heteroaromatic nitrogen heterocycle, constituted by fusion of benzene with the “d” site of  the 1,2-azole (pyrazole) ring. It is also known as benzo[d]pyrazole and exists in three tautomeric structures: 1H-indazole, 2H-indazole, and 3H-indazole. Out of three tautomeric structures, 1H-indazole is more stable compared to  2H-indazole. The free energy of the 1H- tautomer is 2.3 kcal/mol more than the 2H-tautomer and thus is energetically  more stable than the 2H- form. However, 3H-indazoles are not very common. The free energy of 1-methylindazole  is 3.2 kcal/mol and is more stable than its 2-methylindazole. The MP2/6-31G* level of theory predicts an energy difference of 3.6 kcal/mol when thermal energy correction and entropy effects are taken into account. Thermochemical  and photochemical studies on the equilibrium of 1H- and 2H- forms also indicated the greater stability of the 1H-form regardless of the effect of solvents. However, only a few examples of the 3H- form with alkyl and aryl substituents on the five-membered ring are documented in the literature. 2H-Indazole derivatives are stronger bases than  1H-indazoles because the ring nitrogen–proton affinity in 2H-indazoles is higher than in 1H-indazoles.

Compounds of the indazole ring system are meagerly known in the chemical literature. The three indazole-based  alkaloids isolated from natural resources are shown in the following scheme.

The indazole ring is very important in the heterocyclic system of biological importance. There are numerous  synthetic drugs of the indazole ring system and some of the important drugs in clinical use are mentioned in the  following scheme.

Synthesis of 1H-Indole 

From Isatin 1H-Indazole-3-carboxylic acid has been prepared by the ring opening of isatin in aqueous alkali to amino phenylglyoxylic acid followed by diazotization and subsequent reductive cyclization.

From o-Toluidine

Toluidines are used as precursors for the construction of 1H-indazole. The methodology involves the diazotization  of o-toluidine by NaNO2  in acetic acid at room temperature followed by ring closure involving the methyl group to  yield 1H-indazole.

From 2-Alkynylanilines

The diazotization-cyclization protocol has also been successfully applied using o-alkynylanilines to obtain  3-substituted 1H-indazole. The diazotization of o-alkynylanilines with subsequent cyclization provided 3-substituted  1H-indazoles.

From o-Methylacetanilide 

A general route for the synthesis of 1H-indazole has been developed through nitrosation of o-methylacetanilide  followed by rearrangement and cyclization.

From Anthranilic Acid

Diazonium salt prepared from o-aminobenzoic acid on reaction with NaNO2  and HCl at 0°C on reductive cyclization with aqueous Na2 SO3  afforded 1H-indazole.

From 2-Fluorobenzaldehydes and Ketones 

(a) o-Halobenzaldehyde or ketone on condensation with hydrazine under heating yielded 1H-indazoles. Alternatively, it has also been prepared by heating o-fluorobenzaldehyde with O-methyl hydroxylamine hydrochloride and K2 CO3  in DME for 4–5 h, and the oxime intermediate so formed was cyclized on heating with excess  hydrazine in 98% yields.

(b) Reaction of 2-fluorobenzonitrile with hydrazine hydrate in n-butanol under reflux for 4–5 h gave 3-amino  indazole.

2-Formylcyclohexanone on condensation-cyclization with hydrazine followed by dehydrogenation over Pd/C  afforded 1H-indazole.

Aldehydes with the nitro group at position 2 of the phenyl ring are used as precursors for the synthesis of 1Hindazoles. 2-Nitrobenzaldehyde on condensation with malonic acid in the presence of ammonium formate in EtOH  gave an intermediate, which on reductive cyclization in the presence of base yielded 2-(1H-indol-3-yl)acetic acid in  54% yield.

One-pot synthesis of 1H-indazole has been developed from 2-haloacetophenones through CuOcatalyzed amination with methyl hydrazine in the presence of potassium carbonate followed by intramolecular  dehydration-cyclization.

2-Hydroxybenzaldehyde or ketone on condensation with hydrazine hydrochloride in ethanol under reflux afforded functionalized 1H-indazoles.

4-Formyl-1-methylpyrazole has been used as a precursor for the construction of substituted indazoles. Thus  a reaction of 1-methyl-1H-pyrazol-4-carboxaldehyde with ethyl succinate followed by acylation yielded ethyl  7-hydroxy-1-methyl-1H-indazole-5-carboxylate.

Highly functionalized 1H-indazoles are prepared by [3+2] annulation reactions in two steps. 1,3-Diphenyl-5- cyanomethylpyrazole on condensation with α-oxoketene dithioacetals followed by intramolecular cyclization in the  presence of p-toluenesulfonic acid (PTSA) afforded 1H-indazole regioselectively.

1-Aryl-2-(2-nitrophenylbenzylidene) hydrazines undergo intramolecular amination in the presence of t-BuOK  in DMF at 100°C to deliver 1-aryl-1H-indazoles in good yields.

[3+2] Cycloaddition of a variety of diazo compounds with 2-(trimethylsilyl)aryl triflates in the presence of CsF  or TBAF at room temperature afforded substituted 1H-indazoles.

Chemical Reactivity 

Indazoles being heteroaromatics undergo electrophilic substitution reactions such as halogenation, nitration, sulfonation, alkylation, acylation, and many more. Due to the presence of imino hydrogen in the indazole ring, alkylation, acetylation, and metalation reactions are very facile. Halogenations The chlorination of 1H-indazole in acid medium yielded 3-chloro- and 3,5-dichloro,3,5,7-trichloro-1H indazoles  nonregioselectively but 3-chloro-1H-indazole has been prepared by chlorination of indazole selectively with sodium  hypochlorite in 75%–80% yields.

Applications

Indazole and its derivatives have a wide range of biological and pharmaceutical applications such as antibacterial, antifungal, antihypertensive, antiinflammatory, antidepressant, anticancer, antioxidant, antiobesity, and many  more. Besides these, they are useful as agrochemicals, dyes, and synthetic intermediates for the construction of new  heterocycles of biological importance.

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