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

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.


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.
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.
By using 1 H and 13 C 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.
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 1 H 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.
Therefore, the thermal rearrangement mechanism proposed above (Scheme 4) does not contradict the monitoring data.   First, 5-(2,3,4,9-Tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridine 2a ( Figure 5) was considered. From the { 1 H-15 N}-HSQC spectrum, it was revealed that the molecule contains two NH 2 groups and one NH group. From the { 1 H-1 H}-NOESY spectrum, the following NOE interactions were revealed: one between the methyl groups and an NH 2 group at C 4 ; one between a proton at C 9 and an NH 2 group at C 4 ; one between the protons at C 9 and C 8 . 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 { 1 H-13 C} 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 15 N-and { 1 H-15 N}-HSQC spectra, it was revealed that the molecule contains one NH 2 group and one NH group. From the { 1 H-1 H}-NOESY spectrum, the following NOE interactions were revealed: one between the methyl groups and an aromatic proton at C 4 ; one between an aromatic proton at C 6 and an NH 2 group; one between a proton at C 10 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 { 1 H-13 C} HMBC spectrum. Cross peaks were found for aliphatic NH and CH 2 . In addition, no interactions between the dihalogensubstituted 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.
Using Gallenkamp melting-point apparatus (Gallenkamp & Co., Ltd., London, UK), melting points were measured. At room temperature, 1 H and 13 C-NMR spectra were obtained in DMSO-d 6 with a Bruker AM300 spectrometer (Bruker Corporation, Billerica, MA, USA). The values for chemical shift are given in relation to Me 4 Si. 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 1 H-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.