Synthesis of new (pyrazol-1-yl)(7-nitro-1h-indol-2-yl)ketone derivatives

2.1 Preparation of substituted 2-nitrophenylhydrazones 2(a–c)

Phenylhydrazones 2(a–c) were generally prepared starting from substituted ortho-nitroanilines 1(a–c) via diazotization, followed by Japp Klingemann reaction using ethyl a-methylacetoacetate in the presence of KOH/EtOH. Phenylhydrazones 2(a–c) thus prepared consisted of Z- and E-geometrical isomers (Scheme 1). We showed that these geometrical isomers are rapidly interconvertible by the polyphosphoric acid as catalyst used for Fischer indolization and thus give the same result on Fischer indolization.

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Scheme 1

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2.2 Fischer indolization

The Fischer indolization of the phenylhydrazones 2(a–c) was carried out mainly with polyphosphoric acid (PPA) which caused the reaction to proceed the most rapidly instead of other catalysts (Scheme 1).

The identification of the indolic products 3(a–c) was based on spectroscopic data. In the ¹HNMR spectra of these products, we noted the upfield-shifted proton NH to 10 ppm and the disappearance of the singlet of methyl group during Fischer indolization.

2.3 Synthesis of carbohydrazides 4(a–c)

For the synthesis of the carbohydrazide 4(a–c), we have used the method reported by literature (Harrison et al., 2006; Narayana et al., 2005; Farghaly, 2004). The reaction between the ethyl 7-nitroindole-2-carboxylates and hydrazine hydrate lead to the titled products (Scheme 1). The identification of the structure was based on spectroscopic data.

The ¹HNMR spectra of the carbohydrazide 4a displayed two singlets at 4.61 and 11.25 due to protons of NHNH₂ group instead of ethyl group protons in the ethyl 7-nitroindole-2-carboxylate.

2.4 Synthesis of pyrazolylindole derivatives 5(a–c)

Acid-catalyzed substitution reactions on indole derivatives containing only 7-nitro substituent in the benzene ring, in general, are prohibited by the acid lability of the indole nucleus, and in those cases where these reactions are possible, the substituent orientation and the remaining functionality are not always the most desired. Ready access has provided the impetus to investigate synthetic schemes that might be expected to provide various indole-substituted by pyrazole moiety (Farghaly, 2004; Hiremath et al., 1988; Farhanullah et al., 2004; Jukic et al., 1999; Przheval’skii et al., 2004). This work describes general procedure by which (3,5-dimethyl-1H-pyrazol-1-yl)(7-nitro-1H-indol-2-yl)ketone derivatives 5(a–c) may be conveniently prepared in neutral medium by the reaction of the carbohydrazides with acetylacetone.

The establishment of the structure of these compounds 5(a–c) has been confirmed by spectroscopic data. The ¹HNMR spectra of the compound 5a showed the presence of the sharp singlets at 2.36 and 2.62 due to protons of two methyl groups of pyrazole moiety and the methine proton appeared at 6.04 ppm. The ¹³CNMR spectra of 5a exhibited two signals at 13.2 and 13.6 assignable to carbons of two methyl groups. The molecular ion peak at m/z 284 was observed in the mass spectrum of 5a. These spectra data and elemental analysis supported the structure of 5a.

4.1 Preparation of o-nitrophenylhydrazones 2(a–c)

Solid NaNO₂ (32 mmol) was added portion wise to a solution of substituted ortho-nitroaniline (29 mmol) and concentrated HCl (6.4 g) in H₂O (22 ml) at 0–4 °C. The resulting diazonium salt solution was added dropwise to a solution of ethyl α-methylacetoacetate (29 mmol) and 50% aqueous KOH in EtOH (28 ml) at 0–7 °C, and the whole was stirred for 1 h under ice-cooling. The reaction mixture was poured into H₂O and extracted with Et₂O. The organic solution was dried over MgSO₄ and evaporated. The residue was recrystallized from ethanol.

4.2 Synthesis of ethyl 7-nitroindole-2-carboxylate derivatives 3(a–c)

A mixture of the hydrazone 2(a–c) (7.5 mmol) and polyphosphoric acid (10 g) was heated at 120 °C for 30 min. The reaction mixture was poured into water and extracted with dichloromethane. The solvent was evaporated. The crude product was filtered and recrystallized from ethanol.

4.3 Synthesis of 7-nitroindole-2-carbohydrazide derivatives 4(a–c)

A mixture of (2 mmol) ethyl 7-nitroindole-2-carboxylate derivatives 3(a–c), 10 mmol hydrazine hydrate and 30 ml of ethanol was shaken at room temperature for 30 min. It was left for about 1 h, and then the hydrazide was separated out by filtration and crystallized from ethanol.

4.4 Condensation of 7-nitroindole-2-carbohydrazide derivatives 4(a–c) with acetylacetone

The 7-nitroindole-2-carbohydrazide derivatives 4(a–c) (2.4 mmol) and acetylacetone (3.6 mmol) were heated under reflux for 5 h. After cooling, the obtained solid product was filtered off, and then recrystallized from ethanol.