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Article

Thermal Rearrangement of 5-(2-Hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines

by
Yuliya E. Ryzhkova
,
Fedor V. Ryzhkov
,
Michail N. Elinson
*,
Anatoly N. Vereshchagin
,
Roman A. Novikov
and
Artem N. Fakhrutdinov
N. D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences, 47 Leninsky Prospekt, 119991 Moscow, Russia
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(7), 3139; https://doi.org/10.3390/molecules28073139
Submission received: 13 March 2023 / Revised: 27 March 2023 / Accepted: 29 March 2023 / Published: 31 March 2023
(This article belongs to the Special Issue Feature Papers in Organic Chemistry (Volume II))
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Versions Notes

Abstract

:
Some of the most important transformations in organic chemistry are rearrangement reactions, which play a crucial role in increasing synthetic efficiency and molecular complexity. The development of synthetic strategies involving rearrangement reactions, which can accomplish synthetic goals in a very efficient manner, has been an evergreen topic in the synthetic chemistry community. Xanthenes, pyridin-2(1H)-ones, and 1,6-naphthyridines have a wide range of biological activities. In this work, we propose the thermal rearrangement of 7,9-dihalogen-substituted 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines in DMSO. Previously unknown 5,7-dihalogenated 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridines and 10-(3,5-dihalogen-2-hydroxyphenyl)-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridines were synthesized with excellent yields (90–99%). The investigation of the transformation using 1H-NMR monitoring made it possible to confirm the ANRORC mechanism. The structures of synthesized compounds were confirmed by 2D-NMR spectroscopy.

Graphical Abstract

1. Introduction

Some of the most important transformations in organic chemistry are rearrangement reactions, which play a crucial role in increasing synthetic efficiency and molecular diversity [1]. The concomitant cleavage and reconstruction of chemical bonds to form new useful molecules is a process of remarkable complexity in synthetic organic chemistry. Two significant scientific topics in synthetic chemistry are the highly effective formation of carbon–carbon bonds and the building of corresponding molecular skeletons [2]. As a result, the development of synthetic strategies involving rearrangement reactions that can effectively accomplish these two synthetic goals in a very efficient manner is still an evergreen topic in the synthetic chemistry community.
There is a plethora of rearrangement reactions that have been developed and applied in organic chemistry. They have different mechanisms and drastically different reaction conditions. They include the Wagner–Meerwein, Tiffeneau–Demjanov, Beckman, Baeyer–Villiger, Claisen, Wolf, and Pinacol reactions, amongst others [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19].
ANRORC rearrangement occurs in the nucleophilic substitution of heterocyclic compounds and represents a process of the subsequent Addition of the Nucleophile, Ring Opening, and Ring Closure in the same molecule [20,21]. These rearrangements have been studied extensively [22]. Many heterocyclic rearrangements are known: aminoimidazoles [23], oxadiazoles [24,25,26], triazole-carboxamides [27], and imidazo[1,4]thiazine [28].
Transformations of chromeno[2,3-b]pyridines are quite common in the literature. However, these are typically just modifications of functional groups [29,30]. The most interesting reactions are those that are caused by the formation of entirely new compounds. However, publications about these are scarce. Among them are ones about rearrangement [31] and cyclization [32].
Xanthenes (Figure 1) exhibit these types of pharmacological activities such as antiproliferative [33], antibacterial [34], and antioxidant [35] activities; additionally, they are able to inhibit neuropeptide receptors, which have considerable therapeutic benefits for treating obesity [36].
Pyridin-2(1H)-ones (Figure 1) exhibit antiproliferative properties [37], and they also increase the body’s resistance to oxidative stress [38].
Derivatives of 1,6-Naphthyridine (Figure 1) act as anticancer [39], antiviral [40], antiasthmatic [41], anticonvulsant [42], and analgesic [43] agents.
The dimedone fragment (Figure 1) can be found in numerous compounds that are effective in treating a variety of disorders, such as tropical infectious diseases [44]. Dimedone and its derivatives have shown numerous biological properties, including antibacterial [45,46], antifungal [46], and antioxidant [47] properties.
Finally, the straightforward and simple synthesis of novel complex compounds that are valuable from the perspective of biological activity is a relevant goal in organic chemistry.

2. Results and Discussion

Previously, our scientific group synthesized a wide variety of chromeno[2,3-b]pyridines with various structures [48,49,50,51,52,53]. In particular, 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1 were synthesized by two methods (Scheme 1): using three- [54] and pseudo-four-component reactions [55].

2.1. Thermal Rearrangement of 5-(2-Hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines

This rearrangement was discovered during the development of the approach to 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1 (Scheme 1) [54,55]. It has been found that 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine 2a appears in the 1H-NMR spectrum after standing dichloro-substituted compound 1 in an NMR tube with DMSO-d6 for one week.
Individual experiments revealed that depending on the temperature conditions, 7,9-dihalogen-substituted chromeno[2,3-b]pyridines 1a–c are converted into the corresponding 5,7-dihalogenated 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridines 2a–c and 10-(3,5-dihalogen-2-hydroxyphenyl)-5,6,7,8,9,10-hexahydrobenzo-[b][1,6]naphthyridines 3a–c (Scheme 2).
Regarding the example of compound 1a, optimal rearrangement conditions were found (Table 1). First of all, the reaction was studied in DMSO and DMF. After chromeno[2,3-b]pyridine 1a was heated in DMSO at 100 °C for 1 h, 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine 2a was obtained, with 99% yield (Table 1, Entry 1).
Heating at 120 °C resulted in a mixture of compounds 2a and 3a in a ratio of 9:1 (Table 1, Entry 2). After heating chromeno[2,3-b]pyridine 1a at 150 °C in DMSO, 5,6,7,8,9,10-Hexahydrobenzo[b][1,6]naphthyridine 3a was isolated, with a yield of 98% (Table 1, Entry 3).   Slightly lower yields of target compounds 2a and 3a were achieved in DMF (Table 1, Entries 4 and 5).
Heating 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridine 1a in water, acetonitrile, n-propanol, and dioxane did not show good results (Table 1, Entries 6–9).  In these reactions, mixtures of starting compound 1a, the target 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine 2a, and 5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridine 3a were mainly isolated. Reducing the reaction time in the best solvent, DMSO, resulted in a decrease in the yields of the compounds 2a and 3a (Table 1, Entries 10 and 11).
Under these found optimal conditions, the thermal rearrangement of 7,9-dihalogen-substituted 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1a–c leads to 5,7-dihalogenated 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridines 2a–c and 3a–c with 90–99% yields after 1 h (Table 2).
By using 1H and 13C NMR data (see Supplementary Materials), IR spectroscopy, mass spectrometry, and elemental analysis, the structures of the obtained compounds, 2a–c and 3a–c, were confirmed. Additionally, two-dimensional (2D) NMR spectroscopy methods were used to carry out structure investigations for compounds 2a and 3a (see Section 2.3 and Supplementary Materials).
After the reaction in DMSO had completed, water was added to the reaction mixture, and target compounds 2 or 3 crystallized in a pure form without the need for chromatographic purification or additional recrystallization. Thermal rearrangement is easy to perform and only requires the use of basic equipment.
Additionally, it was found that isolated 5,7-dihalogenated 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridines, 2a–c, are able to be converted into 10-(3,5-dihalogen-2-hydroxyphenyl)-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridines, 3a–c, with 93–97% yields when they are heated up to 150 °C in DMSO for 1 h (Scheme 3).
Further, the generality of this thermal rearrangement was investigated (Figure 2, Table 3). Upon heating unsubstituted chromeno[2,3-b]pyridine 1d, as well as 9-methoxy- and 7-bromo-9-methoxy-substituted compounds 1e and 1h at 100 °C, the starting compound was isolated (Table 3, Entries 1, 2, and 5). The heating of chromeno[2,3-b]pyridines 1d, 1e, and 1h at 150 °C for 1 h resulted in the decomposition of initial structure 1 (Table 3, Entries 1, 2, and 5).
Involving monohalogenated compounds 1f and 1g in the rearrangement showed different results (Table 3, Entries 3 and 4). The rearrangement proceeded partly at 100 °C, but at 150 °C, it resulted in the formation of compounds 2 and 3, as well as a partial decomposition of starting chromeno[2,3-b]pyridines 1f and 1g.
The rearrangement of chromeno[2,3-b]pyridine 1i is also possible. It is supposed that a strong acceptor in molecule 1, in this case, a nitro group in the seventh position, makes the rearrangement more favorable. The rearrangement takes place even during the synthesis of starting chromeno[2,3-b]pyridine 1i. According to the 1H NMR spectra, all three compounds (1i, 2i, and 3i) were detected at once in a ratio of approximately 1:1:1 in the reaction mixture after the synthesis of chromeno[2,3-b]pyridine 1i.
In the case of 1,3-cyclohexanedione derivatives 1j and 1k, the rearrangement also take place with 78–82% yields (Table 3, Entries 6 and 7). At both temperatures, however, it is accompanied by the partial decomposition of the starting dihalogen-substituted chromeno[2,3-b]pyridines, 1j and 1k. Compounds 2j,k and 3j,k could not be isolated in pure forms, even after several recrystallizations.
Previously, the synthesis of benzo[b][1,6]naphthyridine derivatives in a basic medium via the rearrangement of 6,7,8,9,10-tetrahydro-5H-chromeno[2,3-b]pyridines has been described (Scheme 4) [22]. However, for our compounds, 1, these conditions were not suitable. Chromeno[2,3-b]pyridines 1d, 1e, and 1g remained unchanged, and upon trying to introduce chromeno [2,3-b]pyridines 1a–c,f,g,i–k into the reaction, only mixtures of compounds 2 and 3 formed in various ratios.

2.2. The 1H-NMR Monitoring of Thermal Rearrangement

The following ANRORC (Addition of the Nucleophile, Ring Opening, and Ring Closure) mechanism of the thermal rearrangement of chromeno[2,3-b]pyridines 1 into 5,7-dihalogenated 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridines 2 and 10-(3,5-dihalogen-2-hydroxyphenyl)-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthy-ridines 3 (Scheme 5) was proposed based on the literature data [21,31].
At the first stage, a nucleophilic attack of the DMSO molecule at the pyridine fragment of chromeno[2,3-b]pyridine 1 takes place. This results in the opening of the pyran ring. The intramolecular interaction of the oxygen anion of the dihalogen-substituted benzene fragment with the electron-deficient carbon atom of cyclohexanedione leads to the formation of another pyran ring (ring closure). Additionally, 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine 2 (Scheme 5) is formed with the expulsion of the DMSO molecule. The first stage occurs regardless of whether the process is carried out at 100 °C or 150 °C.
Further, if the process is carried out at 150 °C, compound 2 is also attacked by the DMSO molecule and undergoes pyran ring opening. Then, the amino group of pyridinone participates in cyclization (ring closure) to form a dihydropyridine fragment of the final structure. Further transformations form 5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridine 3 (Scheme 5).
This rearrangement process was investigated using 1H-NMR monitoring (Figure 3 and Figure 4). The experiments were carried out in NMR tubes with dilute solutions (15 mg of substance per 600 μL of DMSO-d6).
The first stage involves investigating the transformation of chromeno[2,3-b]pyridine 1b at 100 °C. Figure 3 shows the change in intensity of signals from the protons of methyl groups and aromatic protons in the 1H-NMR spectra. The process proceeds rapidly; 2 min after the start of the heating phase, 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine 2b begins to prevail over starting compound 1b. chromeno[2,3-b]pyridine 1b almost completely converts to 2,3,4,9-tetrahydro-1H-xanthene 2b after 10 min.
At the next stage, we studied the transformation of chromeno[2,3-b]pyridine 1b at 150 °C. Figure 4 shows the change in the intensity of signals from the protons of methyl groups in the 1H-NMR spectra. This rearrangement also proceeds rapidly. After 10 min, 2,3,4,9-tetrahydro-1H-xanthene 2b is mostly converted to 5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridines 3b.
Therefore, the thermal rearrangement mechanism proposed above (Scheme 4) does not contradict the monitoring data.

2.3. Confirmation of the Structure of the Synthesized 2,3,4,9-Tetrahydro-1H-xanthenes 2 and 5,6,7,8,9,10-Hexahydrobenzo[b][1,6]naphthyridines 3

The structures of compounds 2a and 3a were additionally confirmed by 1H, 13C, and 15N NMR spectroscopy, including two-dimensional (2D) methods (see Supplementary Information). Key correlation interactions are shown by the arrows in Figure 5 and Figure 6.
First, 5-(2,3,4,9-Tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine 2a (Figure 5) was considered. From the {1H-15N}-HSQC spectrum, it was revealed that the molecule contains two NH2 groups and one NH group. From the {1H-1H}-NOESY spectrum, the following NOE interactions were revealed: one between the methyl groups and an NH2 group at C4; one between a proton at C9′ and an NH2 group at C4; one between the protons at C9′ and C8′. It should be especially noted that there are no correlations between the cyclohexanedione and the condensed benzene fragment; therefore, they are in the same plane and form a tricyclic system.
In addition, no interactions between the pyridinone ring and the xanthene system were recorded in the {1H-13C} HMBC spectrum.
Based on the results obtained, as well as the data from IR spectroscopy and mass spectrometry, it can be concluded that the proposed structure for compound 2a is correct.
Next, 10-(3,5-dichloro-2-hydroxyphenyl)-5,6,7,8,9,10-hexahydrobenzo[b][1,6]-naphthyridine 3a was considered (Figure 6). From the 15N- and {1H-15N}-HSQC spectra, it was revealed that the molecule contains one NH2 group and one NH group. From the {1H-1H}-NOESY spectrum, the following NOE interactions were revealed: one between the methyl groups and an aromatic proton at C4; one between an aromatic proton at C6 and an NH2 group; one between a proton at C10′ and hydroxy groups, as well as N(5′)H. It should be especially noted that there are no correlations between the cyclohexanedione and pyridine fragments; therefore, they are in the same plane and form a tricyclic system.
A tricyclic system was also confirmed by the {1H-13C} HMBC spectrum. Cross peaks were found for aliphatic NH and CH2. In addition, no interactions between the dihalogen-substituted benzene fragment and the naphthyridine system were detected.
Based on the results obtained, as well as the data from IR spectroscopy and mass spectrometry, it can be concluded that the proposed structure for compound 3a is correct.
The 2D NMR spectra of the compounds 2a and 3a are presented in the Supplementary Materials.

3. Materials and Methods

3.1. General Methods

Solvents were purchased from commercial suppliers and used as received, without purification. The synthesis of 5-(2-Hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridine-3-carbonitriles 1 was performed in accordance with the following methods [54,55].
Using Gallenkamp melting-point apparatus (Gallenkamp & Co., Ltd., London, UK), melting points were measured. At room temperature, 1H and 13C-NMR spectra were obtained in DMSO-d6 with a Bruker AM300 spectrometer (Bruker Corporation, Billerica, MA, USA). The values for chemical shift are given in relation to Me4Si. A Bruker AV500 spectrometer (Bruker Corporation, Billerica, MA, USA) was used to record two-dimensional (2D) NMR spectra. A Bruker AV400 spectrometer (Bruker Corporation, Billerica, MA, USA) was used to register the 1H-NMR monitoring spectra. IR spectra were determined with a Bruker ALPHA-T FT-IR spectrometer (Bruker Corporation, Billerica, MA, USA) in KBr pellets. With a Kratos MS-30 spectrometer (Kratos Analytical Ltd., Manchester, UK), mass spectra (EI = 70 eV) were acquired. For elemental analysis, a 2400 Elemental Analyzer (Perkin Elmer Inc., Waltham, MA, USA) was applied.

3.2. Thermal Rearrangement of 7,9-Dihalogenated 5-(2-Hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridine-3-carbonitriles 1 at 100 °C

A solution of 7,9-dihalogenated 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]-pyridine-3-carbonitrile 1 (0.5 mmol) was stirred in DMSO (0.5 mL) for 1 h at 100 °C. Upon completion of the reaction, the reaction mixture was allowed to cool to room temperature, water (5 mL) was added to the reaction mixture, and the resulting precipitate of pure 5,7-dihalogenated 5-(1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihyd-ropyridine-3-carbonitrile 2 was separated by filtration, washed with cold ethanol (2 × 3 mL), and dried.
2,4-Diamino-5-(5,7-dichloro-3,3-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (2a): Yellowish solid; yield—99% (0.220 g); m.p. = 296–297 °C (decomp.) (from DMSO-H2O); FTIR (KBr) cm−1: 3214, 2952, 2203, 1655, 1620, 1573, 1458, 1376, 1242, and 1034. 1H-NMR (300 MHz, DMSO-d6): δ 0.98 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.09 (d, 2J = 16.2 Hz, 1H, CH2), 2.27 (d, 2J = 16.2 Hz, 1H, CH2), 2.44 (d, 2J = 16.2 Hz, 1H, CH2), 2.59 (d, 2J = 16.2 Hz, 1H, CH2), 4.89 (s, 1H, CH), 6.34 (br s, 2H, NH2), 6.54 (br s, 2H, NH2), 6.92 (s, 1H, CH Ar), 7.43 (s, 1H, CH Ar), and 9.67 (br s, 1H, NH) ppm; 13C-NMR (75 MHz, DMSO-d6): δ 26.4, 27.5, 28.9, 31.8, 40.3, 50.3, 62.1, 98.2, 110.2, 116.8, 120.4, 126.8 (2C), 126.9, 129.4, 145.2, 153.0, 154.6, 159.8, 164.4, and 196.4 ppm; MS (m/z, relative intensity %): 448 (37Cl, 37Cl, [M]+, 1), 446 (37Cl, 35Cl, [M]+, 6), 444 (35Cl, 35Cl, [M]+, 9), 364 (37Cl, 37Cl, 3), 362 (37Cl, 35Cl, 18), 360 (35Cl, 35Cl, 24), 283 (11), 279 (7), 243 (37Cl, 37Cl, 1), 241 (37Cl, 35Cl, 5), 239 (35Cl, 35Cl, 8), 166 (11), 150 (17), 122 (27), 77 (39), and 43 (100); Anal. calcd. for C21H18Cl2N4O3: C, 56.64; H, 4.07; N, 12.58%; found: C, 56.57; H, 4.12; N, 12.54%.
2,4-Diamino-5-(5,7-dibromo-3,3-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (2b): Yellowish solid; yield—98% (0.262 g); m.p. = 294–295 °C (decomp.) (from DMSO-H2O); FTIR (KBr) cm−1: 3330, 3228, 2202, 1654, 1620, 1563, 1453, 1376, 1240, and 1031. 1H-NMR (300 MHz, DMSO-d6): δ 0.98 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.08 (d, 2J = 15.9 Hz, 1H, CH2), 2.26 (d, 2J = 15.9 Hz, 1H, CH2), 2.42 (d, 2J = 15.9 Hz, 1H, CH2), 2.58 (d, 2J = 15.9 Hz, 1H, CH2), 4.89 (s, 1H, CH), 6.35 (br s, 2H, NH2), 6.54 (br s, 2H, NH2), 7.07 (s, 1H, CH Ar), 7.63 (s, 1H, CH Ar), and 9.65 (br s, 1H, NH) ppm; 13C-NMR (75 MHz, DMSO-d6): δ 26.3, 27.5, 28.9, 31.7, 40.3, 50.3, 62.0, 98.2, 109.9, 110.3, 114.9, 116.8, 129.7, 130.3, 132.1, 146.6, 153.0, 154.6, 159.7, 164.4, and 196.2 ppm; MS (m/z, relative intensity %): 536 (81Br, 81Br, [M]+, 6), 534 (81Br, 79Br, [M]+, 14), 532 (79Br, 79Br, [M]+, 8), 452 (81Br, 81Br, 12), 450 (81Br, 79Br, 27), 448 (79Br, 79Br, 13), 385 (2), 371 (81Br, 81Br, 4), 369 (81Br, 79Br, 8), 367 (79Br, 79Br, 4), 283 (7), 227 (2), 220 (5), 150 (18), 83 (21), and 41 (100); Anal. calcd. for C21H18Br2N4O3: C, 47.22; H, 3.40; N, 10.49%; found: C, 47.16; H, 3.45; N, 10.44%.
2,4-Diamino-5-(5,7-diiodo-3,3-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine-3-carbonitrile (2c): Yellowish solid; yield—98% (0.308 g); m.p. = 268–269 °C (decomp.) (from DMSO-H2O); FTIR (KBr) cm−1: 3317, 3206, 2199, 1617, 1578, 1475, 1440, 1374, 1243, and 1019. 1H-NMR (300 MHz, DMSO-d6): δ 0.98 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.07 (d, 2J = 16.2 Hz, 1H, CH2), 2.25 (d, 2J = 16.2 Hz, 1H, CH2), 2.42 (d, 2J = 16.2 Hz, 1H, CH2), 2.57 (d, 2J = 16.2 Hz, 1H, CH2), 4.83 (s, 1H, CH), 6.32 (br s, 2H, NH2), 6.53 (br s, 2H, NH2), 7.21 (s, 1H, CH Ar), 7.87 (s, 1H, CH Ar), and 9.61 (br s, 1H, NH) ppm; 13C-NMR (75 MHz, DMSO-d6): δ 26.3, 27.4, 28.9, 31.7, 40.3, 50.3, 86.1, 88.0, 98.3, 110.6, 116.8, 129.1, 136.5, 136.9, 143.1, 149.6, 152.9, 154.6, 159.6, 164.7, and 196.1 ppm; MS (m/z, relative intensity %): 628 ([M]+, 13), 544 (9), 463 (23), 336 (4), 283 (10), 209 (51), 150 (63), 127 (70), 41 (100), and 15 (25); Anal. calcd. for C21H18I2N4O3: C, 40.15; H, 2.89; N, 8.92%; found: C, 40.10; H, 2.96; N, 8.87%.

3.3. Thermal Rearrangement of 7,9-Dihalogenated 5-(2-Hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridine-3-carbonitriles 1 at 150 °C

A solution of 7,9-dihalogenated 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]-pyridine-3-carbonitrile 1 (0.5 mmol) was stirred in DMSO (0.5 mL) for 1 h at 150 °C. Upon completion of the reaction, the reaction mixture was allowed to cool to room temperature, water (5 mL) was added to the reaction mixture, and the resulting precipitate of pure 3,5-dihalogenated 10-(2-hydroxyphenyl)-1-hydroxy-7,7-dimethyl-9-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridine-4-carbonitrile 3 was separated by filtration, washed with cold ethanol (2 × 3 mL), and dried.
3-Amino-10-(3,5-dichloro-2-hydroxyphenyl)-1-hydroxy-7,7-dimethyl-9-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridine-4-carbonitrile (3a): Yellowish solid; yield—98% (0.218 g); m.p. = 274–275 °C (decomp.) (from DMSO-H2O); FTIR (KBr) cm−1: 3294, 3179, 2204, 1655, 1626, 1518, 1468, 1377, 1227, and 1010. 1H-NMR (300 MHz, DMSO-d6): δ 1.02 (s, 3H, CH3), 1.07 (s, 3H, CH3), 2.10 (d, 2J = 16.1 Hz, 1H, CH2), 2.28 (d, 2J = 16.1 Hz, 1H, CH2), 2.60 (d, 2J = 16.1 Hz, 1H, CH2), 2.79 (d, 2J = 16.1 Hz, 1H, CH2), 4.97 (s, 1H, CH), 6.72 (s, 1H, CH Ar), 7.03 (br s, 2H, NH2), 7.27 (s, 1H, CH Ar), 9.22 (br s, 1H, NH), and 11.25 (br s, 2H, 2 OH) ppm; 13C-NMR (75 MHz, DMSO-d6): δ 27.0, 28.2, 29.7, 32.5, 40.2, 50.2, 63.4, 96.5, 110.2, 115.2, 123.5, 123.8, 126.6, 127.3, 138.3, 146.4, 149.7, 153.0, 155.1, 162.6, and 195.4 ppm; MS (m/z, relative intensity %): 446 (37Cl, 35Cl, [M]+, 1), 444 (35Cl, 35Cl, [M]+, 1), 341 (1), 283 (37Cl, 37Cl, 1), 281 (37Cl, 35Cl, 3), 279 (35Cl, 35Cl, 4), 239 (1), 199 (1), 166 (37Cl, 37Cl, 2), 164(37Cl, 35Cl, 8), 162 (35Cl, 35Cl, 14), 113 (4), 78 (84), 63 (100), and 15 (54); Anal. calcd. for C21H18Cl2N4O3: C, 56.64; H, 4.07; N, 12.58%; found: C, 56.55; H, 4.12; N, 12.55%.
3-Amino-10-(3,5-dibromo-2-hydroxyphenyl)-1-hydroxy-7,7-dimethyl-9-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridine-4-carbonitrile (3b): Yellowish solid; yield—98% (0.262 g); m.p. = 267–268 °C (decomp.) (from DMSO-H2O); FTIR (KBr) cm−1: 3289, 3180, 2204, 1655, 1626, 1518, 1466, 1376, 1226, and 1010. 1H-NMR (300 MHz, DMSO-d6): δ 1.03 (s, 3H, CH3), 1.08 (s, 3H, CH3), 2.09 (d, 2J = 16.1 Hz, 1H, CH2), 2.29 (d, 2J = 16.1 Hz, 1H, CH2), 2.60 (d, 2J = 16.1 Hz, 1H, CH2), 2.79 (d, 2J = 16.1 Hz, 1H, CH2), 4.96 (s, 1H, CH), 6.88 (s, 1H, CH Ar), 7.04 (br s, 2H, NH2), 7.50 (s, 1H, CH Ar), 9.23 (s, 1H, NH), 11.25 (br s, 1H, OH), and 11.39 (s, 1H, OH) ppm; 13C-NMR (75 MHz, DMSO-d6): δ 26.4, 27.8, 29.3, 32.0, 39.7, 49.7, 63.0, 96.0, 109.8, 111.0, 113.2, 114.6, 129.6, 132.2, 137.9, 146.0, 150.5, 152.5, 154.5, 162.2, and 194.8 ppm; MS (m/z, relative intensity %): 536 (81Br, 81Br, [M]+, 6), 534 (81Br, 79Br, [M]+, 11), 532 (79Br, 79Br, [M]+, 7), 437 (81Br, 81Br, 1), 435 (81Br, 79Br, 2), 433 (79Br, 79Br, 1), 384 (3), 371 (81Br, 81Br, 4), 369 (81Br, 79Br, 8), 367 (79Br, 79Br, 6), 283 (61), 254 (81Br, 81Br, 33), 252 (81Br, 79Br, 74), 250 (79Br, 79Br, 36), 172 (6), 143 (9), 78 (61), and 15 (100); Anal. calcd. for C21H18Br2N4O3: C, 47.22; H, 3.40; N, 10.49%; found: C, 47.16; H, 3.49; N, 10.44%.
3-Amino-1-hydroxy-10-(2-hydroxy-3,5-diiodophenyl)-7,7-dimethyl-9-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridine-4-carbonitrile (3c): Yellowish solid; yield—90% (0.283 g); m.p. = 258–259 °C (decomp.) (from DMSO-H2O); FTIR (KBr) cm−1: 3412, 3192, 2204, 1627, 1515, 1460, 1373, 1295, 1225, and 1013. 1H-NMR (300 MHz, DMSO-d6): δ 1.02 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.05 (d, 2J = 16.0 Hz, 1H, CH2), 2.28 (d, 2J = 16.0 Hz, 1H, CH2), 2.59 (d, 2J = 16.0 Hz, 1H, CH2), 2.76 (d, 2J = 16.0 Hz, 1H, CH2), 4.89 (s, 1H, CH), 6.97–7.09 (m, 3H, NH2 + CH Ar), 7.73 (s, 1H, CH Ar), 9.20 (s, 1H, NH), 11.22 (br s, 1H, OH), and 11.48 (s, 1H, OH) ppm; 13C-NMR (75 MHz, DMSO-d6): δ 26.7, 28.3, 30.0, 32.4, 50.1, 63.5, 83.5, 90.5, 96.7, 110.4, 115.0, 136.9, 137.4, 141.5, 143.8, 146.4, 153.0, 153.9, 154.9, 162.8, and 195.6 ppm; MS (m/z, relative intensity %): 628 ([M]+, 1), 592 (6), 467 (1), 346 (100), 283 (7), 220 (10), 191 (4), 127 (14), 92 (7), and 18 (12); Anal. calcd. for C21H18I2N4O3: C, 40.15; H, 2.89; N, 8.92%; found: C, 40.10; H, 2.96; N, 8.88%.

3.4. Thermal Rearrangement of 5,7-Dihalogenated 5-(1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine-3-carbonitriles 2 at 150 °C

A solution of 5,7-dihalogenated 5-(1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine-3-carbonitriles 2 (0.5 mmol) was stirred in DMSO (0.5 mL) for 1 h at 150 °C. Upon completion of the reaction, the reaction mixture was allowed to cool to room temperature, water (5 mL) was added to the reaction mixture, and the resulting precipitate of pure 3,5-dihalogenated 10-(2-hydroxyphenyl)-1-hydroxy-7,7-dimethyl-9-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridine-4-carbonitrile 3 was separated by filtration, washed with cold ethanol (2 × 3 mL), and dried.
3-Amino-10-(3,5-dichloro-2-hydroxyphenyl)-1-hydroxy-7,7-dimethyl-9-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridine-4-carbonitrile (3a): Yellowish solid; yield—97% (0.216 g); m.p. = 274–275 °C (decomp.) (from DMSO-H2O); 1H-NMR (300 MHz, DMSO-d6): δ 1.02 (s, 3H, CH3), 1.07 (s, 3H, CH3), 2.10 (d, 2J = 16.1 Hz, 1H, CH2), 2.28 (d, 2J = 16.1 Hz, 1H, CH2), 2.61 (d, 2J = 16.1 Hz, 1H, CH2), 2.79 (d, 2J = 16.1 Hz, 1H, CH2), 4.97 (s, 1H, CH), 6.72 (s, 1H, CH Ar), 7.04 (br s, 2H, NH2), 7.27 (s, 1H, CH Ar), 9.23 (br s, 1H, NH), and 11.24 (br s, 2H, 2 OH) ppm.
3-Amino-10-(3,5-dibromo-2-hydroxyphenyl)-1-hydroxy-7,7-dimethyl-9-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridine-4-carbonitrile (3b): Yellowish solid; yield—97% (0.259 g); m.p. = 267–268 °C (decomp.) (from DMSO-H2O); 1H-NMR (300 MHz, DMSO-d6): δ 1.03 (s, 3H, CH3), 1.08 (s, 3H, CH3), 2.09 (d, 2J = 16.1 Hz, 1H, CH2), 2.29 (d, 2J = 16.1 Hz, 1H, CH2), 2.61 (d, 2J = 16.1 Hz, 1H, CH2), 2.79 (d, 2J = 16.1 Hz, 1H, CH2), 4.96 (s, 1H, CH), 6.88 (s, 1H, CH Ar), 7.05 (br s, 2H, NH2), 7.50 (s, 1H, CH Ar), 9.23 (s, 1H, NH), 11.26 (br s, 1H, OH), and 11.39 (s, 1H, OH) ppm.
3-Amino-1-hydroxy-10-(2-hydroxy-3,5-diiodophenyl)-7,7-dimethyl-9-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridine-4-carbonitrile (3c): Yellowish solid; yield—93% (0.292 g); m.p. = 258–259 °C (decomp.) (from DMSO-H2O); 1H-NMR (300 MHz, DMSO-d6): δ 1.02 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.05 (d, 2J = 16.0 Hz, 1H, CH2), 2.27 (d, 2J = 16.0 Hz, 1H, CH2), 2.59 (d, 2J = 16.0 Hz, 1H, CH2), 2.76 (d, 2J = 16.0 Hz, 1H, CH2), 4.89 (s, 1H, CH), 6.97–7.10 (m, 3H, NH2 + CH Ar), 7.73 (s, 1H, CH Ar), 9.21 (s, 1H, NH), 11.22 (br s, 1H, OH), and 11.48 (s, 1H, OH) ppm.

4. Conclusions

In summary, the thermal rearrangement of 7,9-dihalogen-substituted 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridine-3-carbonitriles into previously unknown 5,7-dihalogenated 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-di-hydropyridines and 10-(3,5-dihalogen-2-hydroxyphenyl)-5,6,7,8,9,10-hexahydrobenzo-[b][1,6]naphthyridines was observed. The developed approach is facile and easy for isolating pure final compounds directly from the reaction mixture using the addition of water, and the yields of the final compounds are 90–99%.
The proposed structures of synthesized 2,3,4,9-tetrahydro-1H-xanthenes and 5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridines were clearly confirmed by 2D NMR spectroscopy.
During the investigation of the reaction mechanism using 1H-NMR monitoring at temperatures of 100 °C and 150 °C, it was found that the reaction proceeded in polar solvents. The reaction occurred via the ANRORC mechanism. It was found that the reaction occurred rapidly. Heating at 100 °C resulted in 2,3,4,9-tetrahydro-1H-xanthene formation; heating at 150 °C also lead to 2,3,4,9-tetrahydro-1H-xanthene, which then transformed into 5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridine.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28073139/s1, Figures S1–S6: The 1H and 13C spectra of synthesized compounds 2a–c; Figures S7–S12: The 1H and 13C spectra of synthesized compounds 3a–c; Figures S13–S16: The 15N- and 2D-NMR spectra of 2a; Figures S17–S20: The 15N- and 2D-NMR spectra of 3a.

Author Contributions

Conceptualization, M.N.E. and Y.E.R.; methodology, A.N.V.; validation, Y.E.R., F.V.R., A.N.V. and M.N.E.; formal analysis, A.N.V.; investigation, Y.E.R., R.A.N. and A.N.F.; data curation, Y.E.R. and A.N.V.; writing—original draft preparation, Y.E.R. and F.V.R.; writing—review and editing, M.N.E.; visualization, F.V.R.; 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

Data are contained within the article or Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 1, 2, and 3 are available from the authors.

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Molecules 28 03139 g001 550
Figure 1. Pharmacophore fragments of biologically active compounds.
Figure 1. Pharmacophore fragments of biologically active compounds.
Molecules 28 03139 g001
Molecules 28 03139 sch001 550
Scheme 1. Multicomponent synthesis of 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1.
Scheme 1. Multicomponent synthesis of 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1.
Molecules 28 03139 sch001
Molecules 28 03139 sch002 550
Scheme 2. Thermal rearrangement of 7,9-dihalogen-substituted 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1.
Scheme 2. Thermal rearrangement of 7,9-dihalogen-substituted 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1.
Molecules 28 03139 sch002
Molecules 28 03139 sch003 550
Scheme 3. Thermal rearrangement of 5,7-dihalogenated 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridines 2.
Scheme 3. Thermal rearrangement of 5,7-dihalogenated 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridines 2.
Molecules 28 03139 sch003
Molecules 28 03139 g002 550
Figure 2. Other 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1 studied as objects of thermal rearrangement.
Figure 2. Other 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1 studied as objects of thermal rearrangement.
Molecules 28 03139 g002
Molecules 28 03139 sch004 550
Scheme 4. ANRORC rearrangement of 6,7,8,9-tetrahydro-5H-chromeno[2,3-b]pyridines.
Scheme 4. ANRORC rearrangement of 6,7,8,9-tetrahydro-5H-chromeno[2,3-b]pyridines.
Molecules 28 03139 sch004
Molecules 28 03139 sch005 550
Scheme 5. Proposed mechanism of thermal rearrangement of 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1.
Scheme 5. Proposed mechanism of thermal rearrangement of 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1.
Molecules 28 03139 sch005
Molecules 28 03139 g003 550
Figure 3. Monitoring of the rearrangement process at 100 °C by 1H-NMR (for compound 1b). Black captions used for 1b; blue captions used for 2b.
Figure 3. Monitoring of the rearrangement process at 100 °C by 1H-NMR (for compound 1b). Black captions used for 1b; blue captions used for 2b.
Molecules 28 03139 g003
Molecules 28 03139 g004 550
Figure 4. Monitoring of the rearrangement process at 150 °C by 1H-NMR (for compound 1b).
Figure 4. Monitoring of the rearrangement process at 150 °C by 1H-NMR (for compound 1b).
Molecules 28 03139 g004
Molecules 28 03139 g005 550
Figure 5. The structure of 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine 2a. Key 2D NMR correlations are shown by arrows.
Figure 5. The structure of 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine 2a. Key 2D NMR correlations are shown by arrows.
Molecules 28 03139 g005
Molecules 28 03139 g006 550
Figure 6. The structure 10-(3,5-dichloro-2-hydroxyphenyl)-5,6,7,8,9,10-hexahydrobenzo[b][1,6]-naphthyridines 3a. Key 2D NMR correlations are shown by arrows.
Figure 6. The structure 10-(3,5-dichloro-2-hydroxyphenyl)-5,6,7,8,9,10-hexahydrobenzo[b][1,6]-naphthyridines 3a. Key 2D NMR correlations are shown by arrows.
Molecules 28 03139 g006
Table
Table 1. Optimization of thermal rearrangement conditions 1.
Table 1. Optimization of thermal rearrangement conditions 1.
EntrySolvent, mLTemperature, °CTime, hYield of 2a, %Yield of 3a, %
1DMSO, 0.5100199 2–
2DMSO, 0.512018810
3DMSO, 0.51501–98 2
4DMF, 0.5100195 2–
5DMF, 0.51501–94 2
6H2O, 2100165
7MeCN, 0.58218–
8n-PrOH, 0.597125–
9Dioxane, 0.51011––
10DMSO, 0.51000.582 2–
11DMSO, 0.51500.5–80 2
1 We heated 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridine 1a (0.5 mmol) in the corresponding solvent. 2 Yields of isolated compounds 2a and 3a (in other cases according to NMR data).
Table
Table 2. Thermal rearrangement of 7,9-dihalogen-substituted 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1 1.
Table 2. Thermal rearrangement of 7,9-dihalogen-substituted 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines 1 1.
Molecules 28 03139 i001
Molecules 28 03139 i002
1 Isolated yields. Procedure for compounds 2: a solution of 0.5 mmol 7,9-dihalogenated chromeno[2,3-b]pyridine-3-carbonitrile 1 was stirred in 0.5 mL DMSO for 1 h at 100 °C. Procedure for compounds 3: a solution of 0.5 mmol of 7,9-dihalogenated chromeno[2,3-b]pyridine-3-carbonitrile 1 was stirred in 0.5 mL of DMSO for 1 h at 150 °C.
Table
Table 3. Verification of the generality of the thermal rearrangement of chromeno[2,3-b]pyridines 1 with other substituents 1,2.
Table 3. Verification of the generality of the thermal rearrangement of chromeno[2,3-b]pyridines 1 with other substituents 1,2.
EntryChromeno[2,3-b]pyridine 1Heating in DMSO at 100 °CHeating in DMSO at 150 °C
Yield of 2, %Yield of 3, %Yield of 2, %Yield of 3, %
11d––Decomposition
21e––Decomposition
31f7–37
41g11–47
51h––Decomposition
61j80––78
71k82––80
1 We heated 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridine 1 (0.5 mmol) in DMSO (0.5 mL) at 100 °C or 150 °C within 1 h. 2 Yields according to NMR data.
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Ryzhkova, Y.E.; Ryzhkov, F.V.; Elinson, M.N.; Vereshchagin, A.N.; Novikov, R.A.; Fakhrutdinov, A.N. Thermal Rearrangement of 5-(2-Hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines. Molecules 2023, 28, 3139. https://doi.org/10.3390/molecules28073139

AMA Style

Ryzhkova YE, Ryzhkov FV, Elinson MN, Vereshchagin AN, Novikov RA, Fakhrutdinov AN. Thermal Rearrangement of 5-(2-Hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines. Molecules. 2023; 28(7):3139. https://doi.org/10.3390/molecules28073139

Chicago/Turabian Style

Ryzhkova, Yuliya E., Fedor V. Ryzhkov, Michail N. Elinson, Anatoly N. Vereshchagin, Roman A. Novikov, and Artem N. Fakhrutdinov. 2023. "Thermal Rearrangement of 5-(2-Hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines" Molecules 28, no. 7: 3139. https://doi.org/10.3390/molecules28073139

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