6′-Amino-5,7-dibromo-2-oxo-3′-(trifluoromethyl)-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile

Abstract

The multicomponent reactions are environmentally benign synthetic methods of building-up of complex molecules and several levels of structural diversity for diverse applications. Spirooxindoles are an important synthetic target possessing extended biological activity and drug discovery applications. In this communication, the multicomponent transformation of 5,7-dibromoisatin, malononitrile, and 5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one in EtOH at reflux in the presence of sodium acetate was carefully investigated to give 6′-amino-5,7-dibromo-2-oxo-3′-(trifluoromethyl)-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile in excellent yield. The structure of the new compound was established by means of elemental analysis, mass and nuclear magnetic resonance, and infrared spectroscopy.

1. Introduction

Multicomponent reactions (MCRs) are environmentally benign synthetic methods of the building-up of complex molecules and several levels of structural diversity for diverse applications [1]. Performing MCRs is well regarded as one of the potential techniques in achieving the greenness of a chemical process. The advantages of MCRs over multistep synthesis include atom-economy and step-efficiency, which reduce waste generation in particular [2]. MCRs show a very high bond-forming index (BFI) as several non-hydrogen atom bonds are formed in one synthetic transformation [3]. Hence, MCRs are a very promising synthetic instrument today.

The indole ring system is probably the most ubiquitous heterocycle in nature. Owing to the great structural diversity of biologically active indoles, it is not surprising that the indole ring system has become an important structural component in many pharmaceutical agents [4]. The numerous chemical compounds consisting of indole as a core nucleus exhibit such activities as anti-inflammatory [5], anticonvulsant [6], antidiabetic [7], antimicrobial [8], anticancer [9], and others.

Pyrazole is one of the most popular rings in bioactive compounds, including drugs and agrochemicals [10]. Fluorinated pyrazoles play an important role in medicinal chemistry, drug discovery, agrochemistry, coordination chemistry, and organometallic chemistry [11].

Spirooxindoles are an important synthetic target possessing extended biological activity and drug discovery applications. In the modern broad range of pharmaceuticals, spiro compounds are not widely used, and spirooxindoles are absent. At the same time, this type of core is prevalent in a number of spiro leader-compounds and drug candidates with different directions of action [12], such as anti-cancer [13], antitumor [14], and cardiotonic [14]. Therefore, multicomponent synthesis of new spirooxindoles is a promising area of organic chemistry.

2. Results and Discussion

We previously carried out a multicomponent transformation of isatins, malononitrile, and different C-H acids into functionalized spirooxindoles [15,16,17,18]. These reactions were carried out both in solution and in ‘on-solvent’ and ‘solvent-free’ formats.

Now, we wish to report our results on the efficient multicomponent transformation of 5,7-dibromoisatin 1, malononitrile 2, and 5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one 3 into the previously unknown 6′-amino-5,7-dibromo-2-oxo-3′-(trifluoromethyl)-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile 4 in boiling ethanol in the presence of sodium acetate for 1 h, as shown in Scheme 1.

When the reaction was finished, the final compound 4 was directly crystallized in pure form. Compound 4 was synthesized in a 91% yield.

The BFI of this process was three, since three new bonds were formed in one stage, namely 2 C-C bonds, and 1 C-O bonds.

Previously, similar spiro[indole-3,4′-pyrano[2,3-c]pyrazoles] were obtained by a four-component reaction of trifluoacetoacetic ether, hydrazine, isatins, malononitrile, and 5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-ones; however, the isolated residue had to be purified by column chromatography [19]. Spiro[indole-3,4′-pyrano[2,3-c]pyrazoles] with a trifluoromethyl group can inhibit the enzyme Plasmodial serine hydroxymethyltransferase, which makes them promising antimalarial drugs [20].

The structure of compound 4 was confirmed by ¹H, ¹³C and ¹⁹F NMR, and IR spectroscopy as well as mass spectrometry data and elemental analysis (Supplementary Materials). Only one set of signals was observed in ¹H, ¹³C, and ¹⁹F NMR spectra.

Signals from four carbon atoms in the ¹³C spectrum (carbons of the pyrazole fragment) are not observed due to too large line broadening caused by the tautomerism of the pyrazole N–H proton (Scheme 2).

Taking into consideration our previous results [16,17] and literature data [19], the following mechanism for the multicomponent transformation of 5,7-dibromoisatin 1, malononitrile 2, and 5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one 3 was proposed, as shown in Scheme 3.

The first stage of the process is a rapid Knoevenagel condensation with the formation of intermediate 6 with the expulsion of a hydroxide anion [21]. This hydroxide anion instantly catalyzes a rapid Michael addition of electron-deficient intermediate 6 to anion A. Then, the resulting anion B is protonated and undergoes Pinner cyclization. Next, 1,3-proton shift occurs, leading to 6′-amino-5,7-dibromo-2-oxo-3′-(trifluoromethyl)-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile 4.

3. Materials and Methods

3.1. General Methods

The solvents and reagents were purchased from commercial sources and used as received. 5,7-Dibromoisatin 1 was obtained from isatin according to the literature [22]. 5-(Trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one 3 was synthesized according to the standard procedure [23].

The melting point was measured with Gallenkamp melting-point apparatus (Gallenkamp & Co., Ltd., London, UK). ¹H and ¹³C NMR spectra were recorded in DMSO-d₆ and acetone-d₆ with Bruker AM300 spectrometer (Bruker Corporation, Billerica, MA, USA) at ambient temperature. IR spectrum was registered with a Bruker ALPHA-T FT-IR spectrometer (Bruker Corporation, Billerica, MA, USA) in KBr pellets. The MS spectrum (EI = 70 eV) was obtained directly with a Kratos MS-30 spectrometer (Kratos Analytical Ltd., Manchester, UK). For elemental analysis, a 2400 Elemental Analyzer (Perkin Elmer Inc., Waltham, MA, USA) was used.

3.2. Multicomponent Synthesis of 6′-Amino-5,7-dibromo-2-oxo-3′-(trifluoromethyl)-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile 4

5,7-Dibromoisatin 1 (0.305 g, 1 mmol), malononitrile 2 (0.066 g, 1 mmol), 5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one 3 (0.152 g, 1 mmol), and sodium acetate (0.008 g, 0.1 mmol) were refluxed in 3 mL of EtOH for 1 h. After the reaction was completed, the formed solid was filtered, washed with well-chilled ethanol (3 mL × 2 mL), and dried to isolate pure 6′-amino-5,7-dibromo-2-oxo-3′-(trifluoromethyl)-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile 4.

6′-Amino-5,7-dibromo-2-oxo-3′-(trifluoromethyl)-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile (4). White solid; yield 91% (0.460 g); mp = 305–306 °C (decomp.) (from EtOH); FTIR (KBr) cm⁻¹: 3405 (N-H), 3316 (NH₂), 3176 (N-H), 2205 (CN), 1715 (C = O), 1654 (C-C Ar), 1163 (C-F), 1147 (C-F). ¹H NMR (300 MHz, DMSO-d₆):δ 7.51 (d, ⁴J = 1.4 Hz, 1H, CH Ar), 7.61 (s, 2H, NH₂), 7.74 (d, ⁴J = 1.4 Hz, 1H, CH Ar), 11.19 (s, 1H, NH isatin), 14.43 (br s, 1H, NH pyrazole) ppm; ¹³C NMR (75 MHz, DMSO-d₆): δ 48.4 (C(3)-CN), 55.2 (br s, C(4) spiro), 102.8 (C(7′)-Br Ar), 114.5 (C(5′)-Br Ar), 117.5 (CN), 127.0 (C(4′)H Ar), 134.0 (C(6′)H Ar), 136.0 (C(3a′) Ar), 140.7 (C(7a′) Ar), 161.1 (C(2)-NH₂), 177.0 (C = O) ppm (pyrazolone moiety C-signals were not detected due to tautomerism); ¹⁹F NMR (282 MHz, acetone-d₆): δ –62.62 (s, CF₃) ppm; MS (m/z, relative intensity %): 507 [⁸¹Br, ⁸¹Br, M]⁺ (26), 505 [⁸¹Br, ⁷⁹Br, M]⁺ (52), 503 [⁷⁹Br, ⁷⁹Br, M]⁺ (27), 479 [⁸¹Br, ⁸¹Br, M - CN]⁺ (63), 477 [⁸¹Br, ⁷⁹Br, M - CN]⁺ (100), 475 [⁷⁹Br, ⁷⁹Br, M - CN]⁺ (45), 422 [⁸¹Br, ⁸¹Br, M - C₃H₃N₂O]⁺ (12), 420 [⁸¹Br, ⁷⁹Br, M - C₃H₃N₂O]⁺ (25), 418 [⁷⁹Br, ⁷⁹Br, M - C₃H₃N₂O]⁺ (12), 410 [⁸¹Br, ⁸¹Br, M - C₂F₃N]⁺ (15), 408 [⁸¹Br, ⁷⁹Br, M - C₂F₃N]⁺ (30), 406 [⁷⁹Br, ⁷⁹Br, M - C₂F₃N]⁺ (16), 355 [⁸¹Br, ⁸¹Br, C₁₁H₅Br₂N₃O]⁺ (3), 353 [⁸¹Br, ⁷⁹Br, C₁₁H₅Br₂N₃O]⁺ (6), 351 [⁷⁹Br, ⁷⁹Br, C₁₁H₅Br₂N₃O]⁺ (4), 229 [C₈H₄F₃N₄O]⁺ (5), 152 [C₄H₃F₃N₂O]⁺ (3); Anal. calcd. for C₁₅H₆Br₂F₃N₅O₂: C, 35.67; H, 1.20; N, 13.87%; found: C, 35.72; H, 1.23; N, 13.83%.

4. Conclusions

The title compound, 6′-amino-5,7-dibromo-2-oxo-3′-(trifluoromethyl)-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile, was synthesized in excellent yield using the simple and efficient multicomponent approach with available equipment and starting compounds. The previously unknown compound was characterized by spectroscopic methods (NMR, IR and MS-EI) and elemental analysis.

Author Contributions

Y.E.R.—conceptualization, spectroscopic analysis and writing the manuscript; V.M.K.—synthesis, spectroscopic analysis; M.N.E.—conceptualization, supervision and writing the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data for the compounds presented in this study are available in the Supplementary Materials of this article.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Schemes

Scheme 1. Reaction of 5,7-dibromoisatin 1, malononitrile 2, and 5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one 3.

Scheme 2. Tautomerization of spiro[indole-3,4′-pyrano[2,3-c]pyrazole] 4.

Scheme 3. Mechanism of 5,7-dibromoisatin 1, malononitrile 2, and 5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one 3 transformation into spiro[indole-3,4′-pyrano[2,3-c]pyrazole] 4.

Supplementary Materials

Compound 4 spectra: ¹H NMR (Figure S1), ¹³C NMR (Figure S2), ¹⁹F NMR (Figure S3), IR (Figure S4), MS (Figure S5).

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