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4a′-Hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione

by
Yuliya E. Ryzhkova
1,*,
Varvara M. Kalashnikova
1,2,
Fedor V. Ryzhkov
1,
Artem N. Fakhrutdinov
1 and
Michail N. Elinson
1
1
N. D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences, 47 Leninsky Prospekt, 119991 Moscow, Russia
2
Higher Chemical College at the Russian Academy of Sciences, D. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya Sq., 125047 Moscow, Russia
*
Author to whom correspondence should be addressed.
Molbank 2023, 2023(3), M1721; https://doi.org/10.3390/M1721
Submission received: 7 August 2023 / Revised: 4 September 2023 / Accepted: 6 September 2023 / Published: 8 September 2023
(This article belongs to the Section Organic Synthesis and Biosynthesis)
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Abstract

:
Pseudo-multicomponent reactions (Pseudo-MCRs) have led to a variety of compounds with interesting biological properties, especially desirable in the pharmaceutical industry. The isatin nucleus could be considered a privileged scaffold for the design of biologically active substances. Dimedone is an interesting and versatile molecule for most organic transformations, especially one-pot and multicomponent reactions. Xanthene derivatives are still an attractive research field for both academia investigations and industry. In this investigation, a simple and efficient tandem Knoevenagel–Michael protocol with subsequent cyclization for the synthesis of the previously unknown 4a′-hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione was elaborated. The suggested method is based on the pseudo-MCR of 5,7-dimethylisatin and dimedone. The structure of the earlier unknown compound was proven using 1H, 13C-NMR, and IR spectroscopy, mass spectrometry, and elemental analysis. To compare the developed protocol with the existing ones, unsubstituted spiro[indole-3,9′-xanthene] was synthesized. Its structure has been proven using two-dimensional (2D) NMR spectroscopy techniques.

1. Introduction

Pseudo-multicomponent reactions (pseudo-MCRs) are a type of multicomponent reaction in which at least one of the reagents takes part in two or more reaction steps. The final compounds of pseudo-MCRs contain two or more components of the reagents [1]. Also, pseudo-MCRs are domino-type one-pot processes, equal to classical MCRs, but the stoichiometry for one or more reactants is duplicated, triplicated, or more [2]. However, pseudo-MCRs have some limitations in comparison to classical MCRs, such as less structural diversity and less functional flexibility, which are offset by the high molecular symmetry that can be achieved with them [3]. Pseudo-MCRs have led to a variety of compounds with interesting biological properties, especially desirable in the pharmaceutical industry [2].
The isatin nucleus could be considered a privileged scaffold for the design of biologically active substances [4]. The discovery and optimization of isatin-based therapeutic agents have consistently attracted the interest of medicinal chemists and the chemistry community [5]. Several kinds of biological activities could be achieved by introducing new fragments to the isatin scaffold, such as anticancer [6,7], HIV reverse transcriptase inhibition [8], neuroprotective [9], antifungal [10], antibacterial [11], and antidiabetic properties [12].
Dimedone is an interesting and versatile molecule for most organic transformations, especially one-pot and multicomponent reactions [13]. Dimedone and its derivatives exhibited a wide range of biological characteristics, including anticarcinogenic [14], antioxidant [15], antihistaminic [16], and anticoagulant properties [17].
Xanthene derivatives are still an attractive research field for both academia investigations and industry [18]. Xanthenes are very important compounds with tremendous biological applications, such as antispasmodic [19], antiparkinsonian [20], and antipsychotic ones [20]. They are also used in the treatment of urinary incontinence [21] and bronchitis [22].
Therefore, the development of a novel synthetic approach based on isatins and dimedone pseudo-multicomponent reactions is quite interesting.

2. Results and Discussion

2.1. Synthesis of 4a′-Hydroxy-3′,3′,5,6′,6′,7-Hexamethyl-3′,4′,4a′,6′,7′,9a′-Hexahydrospiro[Indole-3,9′-Xanthene]-1′,2,8′(1H,2′H,5′H)-Trione 3

Herein, we develop an efficient tandem Knoevenagel–Michael approach with subsequent cyclization to synthesize 4a′-hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione (3) on the basis of the pseudo-multicomponent reaction of 5,7-dimethylisatin (1) and dimedone (2) (Scheme 1).
We have previously demonstrated that the syntheses of isatin and dimedone derivatives can be achieved using various multicomponent and one-pot approaches [23,24,25,26].
In this research, the transformation of 5,7-dimethylisatin (1) and dimedone (2) in n-propanol for 6 h under reflux resulted in 4a′-hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione (3).
When the reaction was finished, the precipitate formed during the process was filtered off and dried. The precipitate was then recrystallized with a small amount of methanol. The resulting spiro[indole-3,9′-xanthene] 3 in pure form was filtered off and dried in the vacuum of a water jet pump. Final compound 3 was obtained with an 86% yield.
The bond-forming index (BFI) [27] of this pseudo-three-component process was three as three new bonds were formed in one stage, namely, two C-C bonds and one C-O bond.
The structure of earlier unknown 4a′-hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione (3) was determined by means of 1H, 13C NMR, and IR spectroscopy, mass spectrometry, and elemental analysis (see Supplementary Materials).
To compare the developed method with those previously published, we synthesized 4a′-hydroxy-3′,3′,6′,6′-tetramethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione (5) (Scheme 2). However, compound 5 has been prepared previously in several ways. By stirring the starting compounds in methanol in the presence of neutral aluminum for 30 min, spiro[indole-3,9′-xanthene 5 was obtained with a yield of 88% [28]. When carrying out the reaction in ethanol at boiling in the presence of acid, the yield of spiro[indole-3,9′-xanthene 5 was 93% [29]. Therefore, the method developed by us is easier to implement and also more efficient.
The structure of spiro[indole-3,9′-xanthene] 5 was confirmed by data from 1H and 13C NMR spectroscopy, as well as using 2D NMR spectroscopy techniques (see Supplementary Materials and Section 2.2).
A plausible mechanism for the formation of spiro[indole-3,9′-xanthene] 3 is shown in Scheme 3. Protonation of a carbonyl group of 5,7-dimethylisatin (1) promotes a nucleophilic attack of the first molecule of dimedone (2) to yield intermediate 6, which reacts further with the second molecule of dimedone (2). Subsequent cyclization leads to the earlier unknown 4a′-hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione (3).

2.2. 2D NMR Study of Compound 5

The structure of the spiro[indole-3,9′-xanthenes] was confirmed using NMR spectroscopy. Although the compound has been previously described, there is no proof of its structure in the references mentioned [28,29]. The full assignment of the signals was carried out on the basis of two-dimensional (2D) NMR experiments, including 1H-1H COSY, 1H-13C HSQC, and 1H-13C HMBC methods (see Supplementary Materials and Section 3.2).
All signals from CH2-groups appeared as multiplets (doublet (d) or doublet of doublets (dd)) with a geminal constant with their neighbor. Low-field chemical shifts of C(5′a) and C(8′a) (169.1 and 112.1 ppm, respectively) indicate the presence of a double bond between these carbons. The atom C(4′a) has a chemical shift of 101.0 ppm, which is typical for carbons bonded to two oxygen atoms. All of the above proves the cyclic structure of compound 5. Key 2D NMR correlations between atoms are shown by arrows in Figure 1.

3. Materials and Methods

3.1. General Methods

All reagents and solvents were used without further purification and purchased from commercial sources.
Melting points were determined on the Gallenkamp melting-point apparatus (Gallenkamp & Co., Ltd., London, UK) and were uncorrected. 1H and 13C NMR spectra were taken with a Bruker AM300 spectrometer (Bruker Corporation, Billerica, MA, USA) at ambient temperature in CDCl3 solutions. 1H and 13C, as well as 2D NMR spectra, were registered with a Bruker AV600 spectrometer (Bruker Corporation, Billerica, MA, USA). The IR spectrum was measured with a Bruker ALPHA-T FT-IR spectrometer (Bruker Corporation, Billerica, MA, USA) in KBr pellet. A high-resolution mass spectrum (HRMS) was obtained on a Bruker micrOTOF II instrument (Bruker Corporation, Billerica, MA, USA) using electrospray ionization (ESI). Elemental analysis was performed on an Elemental Analyzer 2400 (Perkin Elmer Inc., Waltham, MA, USA).

3.2. Synthesis of 4a′-Hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione (3)

5,7-Dimethylisatin 1 (0.175 g, 1 mmol) and dimedone 2 (0.280 g, 2 mmol) were refluxed in 3 mL of n-PrOH for 6 h. After the reaction was finished, the precipitate was filtered, washed with well-chilled methanol (4 mL × 2), and dried. After recrystallization of the precipitate in methanol, pure spiro[indole-3,9′-xanthene] 3 was isolated.
4a′-Hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione (3). White powder; yield 86% (0.376 g); mp = 242–243 °C (from MeOH); FTIR (KBr) cm−1: 3458 (O-H), 3366 (N-H), 3290 (O-H), 2959 (C-H), 2873 (C-H), 1724 (C=O dim.), 1693 (C=O is.), 1652 (C-H Ar), 1601 (C=C Ar), 1485 (CH2), 1469 (CH3), 1374 (C=C Ar), 1345 (CH2), 1234 (C-N), 1180 (C-O), 965 (C=C dim.). 1H NMR (300 MHz, CDCl3): δ 1.03 (s, 3H, 6′-CH3 dim.), 1.06 (s, 3H, 6′-CH3 dim.), 1.12 (s, 3H, 3′-CH3 dim.), 1.13 (s, 3H, 3′-CH3 dim.), 2.00–2.53 (m, 14H, 2 CH3 is. + 4 CH2 dim.), 3.49 (s, 1H, C(1′a)H), 6.46 (s, 1H, C(6)H Ar), 6.80 (s, 1H, C(4)H Ar), 8.01 (s, 1H, NH), 8.87 (d, 4J = 1.6 Hz, 1H, OH) ppm; 13C NMR (75 MHz, CDCl3): δ 16.3 (C(7)-CH3), 21.2 (C(5)-CH3), 27.0 (2C, 6′-CH3 + 3′-CH3), 29.2 (6′-CH3), 31.6 (C(6′)), 33.2 (3′-CH3), 33.7 (C(3′)), 43.4 (C(5′)), 47.1 (C(9′)), 48.2 (C(4′)), 50.8 (C(7′)), 55.0 (C(2′)), 60.7 (C(1′a)), 100.9 (C(4′a)), 112.1 (C(8′a)), 118.8 (C(5)-CH3), 119.1 (C(4)H), 130.6 (C(6)H), 131.9 (C(7)-CH3), 132.2 (C(4a)), 139.5 (C(1a)), 168.7 (C(5′a)), 181.8 (C(2)=O), 195.3 (C(8′)=O), 202.4 (C(1′)=O) ppm; HRMS-ESI: m/z [M + H]+, calcd for C26H32NO5 438.2275, found 438.2268; Anal. calcd. for C26H31NO5: C, 71.37; H, 7.14; N, 3.20%; found: C, 71.46; H, 7.19; N, 3.11%.

3.3. Synthesis of 4a′-Hydroxy-3′,3′,6′,6′-Tetramethyl-3′,4′,4a′,6′,7′,9a′-Hexahydrospiro[Indole-3,9′-Xanthene]-1′,2,8′(1H,2′H,5′H)-Trione (5)

Isatin 4 (0.147 g, 1 mmol) and dimedone 2 (0.280 g, 2 mmol) were refluxed in 3 mL of n-PrOH for 6 h. After the reaction was finished, the precipitate was filtered, washed with well-chilled methanol (4 mL × 2), and dried to isolate pure spiro[indole-3,9′-xanthene] 5.
4a′-Hydroxy-3′,3′,6′,6′-tetramethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione (5). White powder; yield 93% (0.380 g); mp = 240–241 °C (from n-PrOH) (lit. [29] mp = 241–243 °C C); 1H NMR (600 MHz, CDCl3): δ 1.03 (s, 3H, 6′-CH3 dim.), 1.07 (s, 3H, 6′-CH3 dim.), 1.12 (s, 3H, 3′-CH3 dim.), 1.13 (s, 3H, 3′-CH3 dim.), 2.08 (dd, 2J = 16.5 Hz, 4J = 1.7 Hz, 1H, C(7′)H), 2.14 (dd, 2J = 13.9, 4J = 2.2 Hz, 1H, C(4′)H), 2.15 (dd, 2J = 13.2, 4J = 2.2 Hz, 1H, C(2′)H), 2.20 (d, 2J = 16.5 Hz, 1H, C(7′)H), 2.28 (d, 2J = 13.2 Hz, 1H, C(2′)H), 2.31 (dd, 2J = 13.9, 4J = 2.2 Hz, 1H, C(4′)H), 2.35 (dd, 2J = 17.7, 4J = 1.7 Hz, 1H, C(5′)H), 2.45 (d, 2J = 17.7 Hz, 1H, C(5′)H), 3.52 (s, 1H, C(1′a)H), 6.81 (d, 3J = 7.4 Hz, 1H, C(4)H Ar), 6.86 (d, 3J = 7.7 Hz, 1H, C(7)H Ar), 6.92 (td, 3J = 7.5 Hz, 4J = 1.0 Hz, 1H, C(5)H Ar), 7.17 (td, 3J = 7.7 Hz, 4J = 1.2 Hz, 1H, C(6)H Ar), 8.26 (s, 1H, NH), 8.86 (d, 4J = 2.2 Hz, 1H, OH) ppm; 13C NMR (151 MHz, CDCl3): δ 27.0 (6′-CH3), 27.1 (3′-CH3), 29.5 (6′-CH3), 31.7 (C(6′)), 33.3 (3′-CH3), 33.8 (C(3′)), 43.5 (C(5′)), 46.8 (C(9′)), 48.3 (C(4′)), 50.9 (C(7′)), 55.0 (C(2′)), 60.7 (C(1′a)), 101.0 (C(4′a)), 110.5 (C(7)H), 112.1 (C(8′a)), 120.7 (C(4)H), 122.6 (C(5)H), 128.6 (C(6)H), 132.6 (C(4a)), 143.3 (C(1a)), 169.1 (C(5′a)), 181.6 (C(2)=O), 195.3 (C(8′)=O), 202.4 (C(1′)=O) ppm.

4. Conclusions

The title compound, 4a′-hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione, was synthesized with a good yield using the facile and efficient pseudo-multicomponent approach with simple equipment and available starting compounds. The novel compound was characterized using spectroscopic methods (NMR, IR, and MS-EI) and elemental analysis. The structure of 4a′-hydroxy-3′,3′,6′,6′-tetramethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione was proved using two-dimensional NMR techniques.

Supplementary Materials

Compound 3 spectra: 1H NMR (Figure S1), 13C NMR (Figure S2), IR (Figure S3), HRMS (ESI) (Figure S4); compound 5 spectra: 1H NMR (Figure S5), 13C NMR (Figure S6), 1H-1H COSY (Figure S7), 1H-13C HSQC (Figure S8), 1H-13C HMBC (Figure S9).

Author Contributions

Conceptualization, Y.E.R. and M.N.E.; methodology, M.N.E.; validation, Y.E.R. and F.V.R.; formal analysis, V.M.K. and A.N.F.; investigation, V.M.K. and A.N.F.; data curation, Y.E.R.; writing—original draft preparation, Y.E.R. and F.V.R.; writing—review and editing, M.N.E.; supervision, M.N.E. 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 compound presented in this study are available in the Supplementary Materials of this article.

Conflicts of Interest

The authors declare no conflict of interest.

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Molbank 2023 m1721 sch001
Scheme 1. Pseudo-three-component reaction of 5,7-dimethylisatin (1) and dimedone (2).
Scheme 1. Pseudo-three-component reaction of 5,7-dimethylisatin (1) and dimedone (2).
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Scheme 2. Pseudo-three-component reaction of isatin (4) and dimedone (2).
Scheme 2. Pseudo-three-component reaction of isatin (4) and dimedone (2).
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Scheme 3. A plausible mechanism for the formation of spiro[indole-3,9′-xanthene] 3.
Scheme 3. A plausible mechanism for the formation of spiro[indole-3,9′-xanthene] 3.
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Figure 1. The structure of 4a′-hydroxy-3′,3′,6′,6′-tetramethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione 5. Key 2D NMR correlations are shown by arrows.
Figure 1. The structure of 4a′-hydroxy-3′,3′,6′,6′-tetramethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione 5. Key 2D NMR correlations are shown by arrows.
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MDPI and ACS Style

Ryzhkova, Y.E.; Kalashnikova, V.M.; Ryzhkov, F.V.; Fakhrutdinov, A.N.; Elinson, M.N. 4a′-Hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione. Molbank 2023, 2023, M1721. https://doi.org/10.3390/M1721

AMA Style

Ryzhkova YE, Kalashnikova VM, Ryzhkov FV, Fakhrutdinov AN, Elinson MN. 4a′-Hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione. Molbank. 2023; 2023(3):M1721. https://doi.org/10.3390/M1721

Chicago/Turabian Style

Ryzhkova, Yuliya E., Varvara M. Kalashnikova, Fedor V. Ryzhkov, Artem N. Fakhrutdinov, and Michail N. Elinson. 2023. "4a′-Hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione" Molbank 2023, no. 3: M1721. https://doi.org/10.3390/M1721

APA Style

Ryzhkova, Y. E., Kalashnikova, V. M., Ryzhkov, F. V., Fakhrutdinov, A. N., & Elinson, M. N. (2023). 4a′-Hydroxy-3′,3′,5,6′,6′,7-hexamethyl-3′,4′,4a′,6′,7′,9a′-hexahydrospiro[indole-3,9′-xanthene]-1′,2,8′(1H,2′H,5′H)-trione. Molbank, 2023(3), M1721. https://doi.org/10.3390/M1721

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