Triethylammonium 2-(3-Hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate

Abstract

In recent years, the application of privileged structures has become a powerful approach in the discovery of new biologically active molecules. Ion pairing is a strategy used to enhance the permeation of ionized topical drugs. A convenient and efficient method for the synthesis of triethylammonium 2-(3-hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate has been developed. The presented protocol includes an aldol reaction and the formation of an ammonium salt. Triethylamine is both a reactant and a catalyst in the process. The structure of the synthesized title compound has been established by ¹H, ¹³C-NMR and IR spectroscopy, mass spectrometry, and elemental analysis.

1. Introduction

Scaffolds are a core concept in medicinal chemistry [1]. The notion of “privileged scaffolds” refers to molecular frameworks that are capable of serving as ligands for multiple targets and/or that occur more often in biologically active molecules [2]. The term “privileged structure” was first introduced in 1988 by Evans et al., who used it to describe repeating, useful structural motifs for discovering new active substances [3,4]. They had noticed that particular chemical structures are able to bind with equal affinity to more than one type of receptor. Following that, an approach for drug design was developed. According to this approach, sensible modifications in these “privileged structures” could lead to the proposal of new potent agonists or antagonists of receptors.

The dimedone moiety is a “privileged scaffold” (acting as a primary pharmacophore) recognizable in many compounds that are useful to treat several diseases, for example tropical infectious diseases [5]. Dimedone and its derivatives exhibited numerous biological properties, including antibacterial [6,7], antifungal [7], and antioxidant [8].

The isatin fragment could be considered as a “privileged scaffold” for the creation of new biologically active compounds [9]. Several types of biological activities could be achieved by substitution in the isatin scaffold, such as anticancer [10], human immunodeficiency virus reverse transcriptase inhibition [11], neuroprotective [12], antifungal [13], and antidiabetic [14] activities.

Ion pairing is a strategy used to increase the permeation of ionized topical drugs [15]. Formation occurs when the electrostatic energy of attraction between oppositely charged ions exceeds their average thermal energy, allowing them to be drawn together and attain a critical distance [16]. The formation of the neutral particle makes it easier to penetrate into a lipid environment.

Taking into account the data mentioned above, the discovery and optimization of dimedone- and isatin-based therapeutic agents have consistently attracted the interest of medicinal chemists, and this goal remains relevant at the moment. Ion pairing is a demanding and useful strategy in medicinal chemistry. As a result, we were inspired to develop the synthesis of the compound with the benefits of isatin and dimedone scaffolds in the form of an ion pair (salt).

2. Results and Discussion

2.1. Synthesis of Triethylammonium 2-(3-Hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate 4

Previously, our scientific group carried out the synthesis of 3-hydroxy-3-(2-hydroxy-6-oxocyclohex-1-en-1-yl)indolin-2-ones in two ways (Scheme 1). In the first case, the aldol reaction was carried out using electrolysis in alcohol at 20 °C, and the yields were 70–85% [17]. In the second method, the process was implemented in water without any catalyst at room temperature, and the yields varied in the range of 87–98% [18].

In the course of our studies, we have found that if an aldol reaction between isatin 1 and dimedone 2 is carried out in boiling ethanol with an equivalent amount of triethylamine 3, a triethylammonium 2-(3-hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate 4 is formed (Scheme 2).

The efficient transformation of isatin (1), dimedone (2), and triethylamine (3) into the previously unknown triethylammonium 2-(3-hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate (4) was completed in 4 h in EtOH at 78 °C (Scheme 2). The yield of the final compound (4) was 79%. The amine acts as both a reagent and a base catalyst.

The structure of the synthesized compound (4) was confirmed by spectral methods (¹H and ¹³C NMR, IR spectroscopy), mass spectrometry data, and elemental analysis (see Supplementary Materials).

The chemical reaction of isatin and a carbonyl compound in the presence of a base to yield substituted quinoline-4-carboxylic acids is known as the Pfitzinger reaction [19,20]. In our case, not even traces of quinoline were detected in the ¹H-NMR spectrum. Apparently, triethylamine is too weak a base for this reaction.

Taking into consideration our previous results [17,18,21,22,23] and aldol reaction data [24], the following mechanism for the transformation of isatin (1), dimedone (2), and triethylamine (3) was proposed, as shown in Scheme 3.

At the first stage, dimedone (2) was deprotonated with triethylamine (3). Then, an aldol condensation occurred between isatin (1) and the cyclic 1,3-diketone anion, A. The resulting anion (B) was first protonated and then deprotonated again to form the final triethylammonium 2-(3-hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate (4).

2.2. NMR Study of Triethylammonium 2-(3-Hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate 4 Structure

3-Hydroxy-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)indolin-2-one 5 has two hydroxyl groups. Accordingly, any of them can participate in the formation of an ion pair with triethylamine. In order to understand which hydroxyl group became an anion, we compared the ¹H-NMR spectra of compounds 4 and 5 (Figure 1).

In the case of compound 5, the methyl groups appear on the spectrum as a single signal (singlet) and the methylene fragments as a wide multiplet (Figure 1b). This is due to the free rotation of the dimedone moiety and keto-enol tautomerism.

If the formation of an ion pair occurs with the participation of the hydroxyl group of the dimedone fragment, the signals of the protons of the methyl groups look like separate singlets, and the signals of the protons of the methyl groups look like doublets (Figure 1a). This is due to the fact that tautomerism becomes impossible. There is one set of signals on ¹H- and ¹³C-NMR spectra (see Supplementary Materials); therefore, there is one form of triethylammonium salt in solution.

The conclusions drawn from the comparison of the ¹H-NMR spectra are also confirmed by the pKa values. The pKa value of dimedone (Figure 2) is known; it is 5.23 [25]. Unfortunately, the pKa values for dioxindole (Figure 2) or similar compounds were not known in the literature. However, SciFinder [26] gives a value of 11, calculated on the basis of the software from the ACD/Labs software package [27]. Accordingly, the hydroxyl group of dimedone has a higher acidity.

Thus, it can be concluded that the hydroxyl group of the dimedone fragment was involved in the formation of the ion pair in compound 4.

3. Materials and Methods

3.1. General Methods

All of the solvents and chemicals were easily obtained from commercial sources, and they were all used without further purification.

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

3.2. Synthesis of Triethylammonium 2-(3-Hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate 4

Isatin (1) (0.441 g, 3 mmol), dimedone (2) (0.420 g, 3 mmol), and triethylamine (3) (0.303 g, 3 mmol) were refluxed in 10 mL of EtOH for 4 h. After the reaction was finished, the precipitate was filtered, washed with well-chilled ethanol (4 mL × 2), and dried to isolate the pure triethylammonium 2-(3-hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate 4.

Triethylammonium 2-(3-hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate (4). Yellowish powder; yield 79% (0.918 g); mp = 297–298 °C (decomp.) (from EtOH); FTIR (KBr) cm⁻¹: 3272 (O-H), 3182 (N-H), 2963 (CH₂-N), 2639 (NH⁺), 2498 (NH⁺), 1721 (C=O), 1578 (C=C Ar), 1521 (C=C Ar), 1485 (CH₂), 1441 (CH₃), 1390 (CH₃), 1357 (C(CH₃)₂), 1153 (C-N), 1063 (C-O), 760 (C=C dim.). ¹H NMR (300 MHz, DMSO-d₆): δ 1.07 (s, 3H, CH₃ dim.), 1.10 (s, 3H, CH₃ dim.), 1.20 (t, ³J = 7.2 Hz, 9H, 3 CH₃ amine), 2.05 (d, ²J = 16.1 Hz, 1H, CH₂ amine), 2.16 (d, ²J = 16.1 Hz, 1H, CH₂ dim.), 2.34 (d, ²J = 16.5 Hz, 1H, CH₂ dim.), 2.49 (d, ²J = 16.5 Hz, 1H, CH₂ dim.), 3.12 (q, ³J = 7.2 Hz, 6H, 3 CH₂ amine), 6.78–7.22 (m, 3H, 3 CH Ar), 7.13 (t, ³J = 7.4 Hz, 1H, CH Ar), 8.38–9.22 (br s, 1H, HN⁺), 9.41 (s, 1H, NH), 9.51 (s, 1H, OH isatin) ppm; ¹³C NMR (75 MHz, DMSO-d₆): δ 8.6 (3C, 3 CH₃ amine), 26.5 (CH₃ dim.), 29.0 (CH₃ dim.), 31.9 (C(CH₃)₂), 40.7 (CH₂ dim.), 45.8 (3C, 3 CH₂ amine), 50.5 (CH₂ dim.), 78.5 (C(3)-OH), 103.4 (C(2′)=C(1′)-O⁻), 115.3 (C(7)H Ar), 120.7 (C(4)H Ar), 123.1 (C(5)H Ar), 126.7 (C(6)H Ar), 127.5 (C(3a)), 135.2 (C(7a)), 152.0 (C(2)=O), 180.3 (C(1′)-O⁻), 191.9 (C(3′)=O) ppm; MS (m/z, relative intensity %): 286 [C₁₆H₁₆NO₄]⁺ (1), 271 [C₁₆H₁₆NO₄ − CH₃]⁺ (24), 140 [C₈H₁₂O₂ dimedone]⁺ (5), 101 [Et₃N]⁺ (18), 86 [Et₃N − CH₃]⁺ (100), 27 [C₂H₃]⁺ (65); Anal. calcd. for C₂₂H₃₂N₂O₄: C, 68.01; H, 8.30; N, 7.21%; found: C, 68.45; H, 8.36; N, 7.12%.

4. Conclusions

In summary, a convenient and efficient reaction for the preparation of triethylammonium 2-(3-hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate was carried out. The proposed method is based on the reaction of isatin, dimedone, and triethylamine. The process includes an aldol reaction and the formation of an ammonium salt. In addition, the amine is both a reactant and a catalyst. Easily available starting chemicals and a simple work-up process are advantages of this approach. The structure of the obtained compound was confirmed by ¹H, ¹³C-NMR, IR spectroscopy, mass spectrometry with electron impact ionization (EI-MS), and elemental analysis.