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11Т 61 (12)
ИЗВЕСТИЯ ВЫСШИХ УЧЕБНЫХ ЗАВЕДЕНИИ. Серия «ХИМИЯ И ХИМИЧЕСКАЯ ТЕХНОЛОГИЯ»
2018
V 61 (12)
IZVESTIYA VYSSHIKH UCHEBNYKH ZAVEDENII KHIMIYA KHIMICHESKAYA TEKHNOLOGIYA
RUSSIAN JOURNAL OF CHEMISTRY AND CHEMICAL TECHNOLOGY
2018
DOI: 10.6060/ivkkt.20186112.5784
УДК: 547.815 + 547.786
СИНТЕЗ 4-(2-ГИДРОКСИФЕНИЛ)-5,6,7,8-ТЕТРАГИДРОИЗОКСАЗОЛО
[5,4-В]ХРОМЕН-5(4Н)-ОНОВ
А.Н. Пырко
Анатолий Николаевич Пырко
Кафедра экологической химии и биохимии, Международный государственный экологический институт им. А.Д. Сахарова, Белорусский государственный университет, ул. Долгобродская, 23/1, Минск, Республика Беларусь, 220070 E-mail: pyrko@yandex.ru
Целью данной работы является синтез новых тетрагетероциклических соединений, представляющих интерес в качестве потенциальных биологически активных веществ, которые включают изоксазольный и хромоновый фрагменты в своей структуре. Синтез таких соединений осуществляли в две стадии. Конденсацией Кнёвенагеля 3-метил-1,2-изоксазол-5(2Н)-она с салициловым альдегидом был получен (4Z)-4-(2-гидроксибензилиден)-3-метил-1,2-изоксазол-5(4Н)-он. Для увеличения выхода продукта в этой реакции использовали избыток альдегида, равный половине эквивалентного количества. В качестве катализатора использовали пиперидин. Реакцию проводили путем кипячения компонентов в этилацетате. Реакцию полученного производного бензилидени-зоксазола с циклогексан-1,3-дионом или димедоном проводили путем кипячения компонентов в этаноле без использования катализатора. Механизм взаимодействия включает гетеродиеновую конденсацию Дильса-Альдера с последующей дегидратацией одной молекулы воды. В результате получали 3-метил-4-(2-гидроксифенил)-5,6,7,8-тетрагидроизоксазоло [5,4-Ь]хромен-5(4Н)-он и 3,7,7-триметил-4-(2-гидроксифенил)-5,6,7,8,9-тетрагидро-изоксазоло[5,4-b]хромен-5(4H)-он. Очистка синтезированных соединений проводилась кристаллизацией из этанола. Все полученные соединения были охарактеризованы данными ИК, 1H ЯМР и УФ спектроскопии. В спектре 1Н ЯМР имеются сигналы метиль-ных групп изоксазольного кольца при 2,26, 2,29, 2,34 м.д. соответственно. В УФ-спектре плоской молекулы (4Z)-4-(2-гидроксибензилиден)-3-метил-1,2-изоксазол-5(4H)-она имеется максимум длинноволнового поглощения (400,9 нм), соответствующий совместной системе сопряженных связей изоксазольного и ароматического кольца. Структура полученных соединений была подтверждена данными масс-спектрометрического анализа высокого разрешения. В спектрах 3-метил-4-(2-гидроксифенил-5,6,7,8-тетрагидро-изоксазоло[5,4-Ь]хромен-5(4Н)-она и 3,7,7-триметил-4-(2-гидроксифенил)-5,6,7,8,9-тетрагидроизоксазоло [5,4-b] хромен-5(4Н)-она имеется пик иона [M + Na]+. Наличие пиков фрагмента [M + Na - CO]+ и [M + Na - CO - H2O]* подтверждает наличие гидрок-сильных и карбонильных групп в молекулах.
Ключевые слова: изоксазолохромены, конденсация Кнёвенагеля, диеновая конденсация
SYNTHESIS OF 4-(2-HYDROXYPHENYL)-5,6,7,8-TETRAHYDROISOXAZOLO
[5,4-B] CHROMENE-5(4H)-ONES
A.N. Pyrko
Anatoliy N. Pyrko
Department of Environmental Chemistry and Biochemistry, International Sakharov Environmental Institute,
Belarussian State University: Dolgobrodskaya st., 23/1, Minsk, 220070, Belarus
E-mail: pyrko@yandex.ru
The aim of this work is the synthesis of new tetraheterocyclic compounds of interest as potential biologically active substances that include the isoxazole and chromone moieties in their structure. The synthesis of such compounds was carried out with two stages. By Knoevenagel condensation of 3-methyl-1,2-isoxazol-5(2H)-on with salicylic aldehyde (4Z)-4-(2-hydro-xybenzyliden)-3-methyl-1,2-oxazol-5(4H)-on was obtained. In this reaction an excess of half of the aldehyde equivalent was used to increase the yield of the product. Pyperidine was used as a catalyst. The reaction was carried out by boiling the components in ethyl acetate. The reaction of the resulting benzylidenisoxazole derivative with cyclohexane-1,3-dione or dimedone was performed by boiling the components in ethanol without the use of a catalyst. The interaction mechanism includes heterodiene Dielsa-Aldera condensation followed by dehydration of one water molecule. As a result, 3-methyl-4-(2-hydroxyphenyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]chromene-5(4H)-one and 3,7,7-trimethyl-4-(2-hydroxyphenyl)-5,6,7,8,9-tetrahydroisoxazolo[5,4-b]chromen-5(4H)-one were obtained. Purification of the synthesized compounds was carried out by crystallization from ethanol. All the obtained compounds were characterised by IR 1H NMR and UV spectroscopies. In 1H NMR spectra there are signals of the methyl groups of the isoxazole ring of compounds at 2.26, 2.29, 2.34 ppm respectively. In the UV spectrum of a plane molecule of (4Z)-4-(2-hydroxybenzyliden)-3-methyl-1,2-oxazol-5(4H)-on there is a long-wave absorption maximum (400.9 nm) corresponding to the joint system of conjugated bonds of the isoxazole and aromatic rings. The structures of the obtained compounds were confirmed by high resolution mass-spectrometry analysis. In the spectra of 3-methyl-4-(2-hydroxyphenyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]chromene-5(4H)-one and 3,7,7-trimethyl-4-(2-hydroxyphenyl)-5,6,7,8,9-tetrahydroisoxazolo[5,4-b]chromen-5(4H)-one the[M + Na]+ ion peaks were observed. The presence of fragment peaks [M + Na - CO]+ and [M + Na - CO - H2O]* confirms the presence of hydroxy and carbonyl groups in the molecules.
Key words: isoxazole chromes, Knoevenagel condensation, diene condensation
Для цитирования:
Пырко А.Н. Синтез 4-(2-гидроксифенил)-5,6,7,8-тетрагидроизоксазоло [5,4-Ь]хромен-5(4Н)-онов. Изв. вузов. Химия
и хим. технология. 2018. Т. 61. Вып. 12. С. 43-48 For citation:
Pyrko A.N. Synthesis of 4-(2-hydroxyphenyl)-5,6,7,8-tetrahydroisoxazolo[5,4-b]chromene-5(4H)-ones. Izv. Vyssh. Uchebn.
Zaved. Khim. Khim. Tekhnol. 2018. V. 61. N 12. P. 43-48
INTRODUCTION
Synthesis of new xanthene derivatives has received special attention due to their diverse array of biological activities such as antiinflammatory, antibacterial and antiviral activities [1-5]. They are one of the most widely distributed classes of natural compounds.
On the other hand, isoxazol scaffold represents an important class of heterocycles which have a wide range of pharmacological properties. A variety of biological activities has been reported for isoxazol deriva-
tives such as protein-tyrosine phosphatase 1B (PTP1B) inhibitory, anticonvulsant, antifungal, HDAC inhibitory, analgesic, antitumor, antioxidant, antimicrobial, COX-2 inhibitory, anti-inflammatory, anticancer, antiviral, antituberculosis and antimycobacterial [6-13].
The condensation of two molecules of 1,3-cyclo-hexanediones with aromatic aldehydes usually produces 9-substituted octahydroxanthene [14-16] and tetrahydroxanthene derivatives with 2-hydroxyaromatic aldehydes [17]. The reaction mechanism involves the condensation of Knoevenagel of the molecule of cy-
clohexanedione with aldehyde and subsequent Michael addition of the second molecule to formed a, P-unsaturated diketone. The use of a heterocyclic 1,3-dicarbonyl compounds instead of a second cyclohex-anedione molecule allows the preparation of a tetra-hydroxanthene derivatives comprising a heterocycle as a substituent at the position 9 of the hydroxanthene fragment. Methods for conducting three-component condensation in one flask have been developed [2, 18]. This article describes the synthesis of tetracyclic compounds that include the isoxazole and chromone moieties in their structure.
MATERIALS AND METHOD
In order to exclude the possibility of formation of bis-adducts of condensation of salicylic aldehyde with two molecules of 1,3-cyclohexanedione or with two molecules of a heterocyclic 1,3-dicarbonyl com-
pound, the synthesis of putative isoxazolotetrahy-droxanthenes, including both the tetrahydroxanthene and isoxazole moieties, was carried out in two stages.
a, P-Unsaturated carbonyl compound 3 was obtained by the reaction of isoxazolone 1 with salicylic aldehyde 2 (Fig.). This substance was used in the reaction with cyclohexanediones 4a,b for the synthesis of isoxazolotetrahydroxanthenes 8a,b. To increase the yield of the Knoevenagel condensation product 3, a 50% excess of aldehyde was used, since the formation of the bis-isoxazole derivative is possible in this reaction. Condensation of a, P-unsaturated carbonyl 3 and 1,3-cyclohexanediones 4a,b was accomplished by heating the components in ethanol. The reaction was performed under catalist-free conditions. It was found that as a result of the experiment, not isoxazoloxanthene derivatives 8a,b were obtained, but the isomeric structures 7a,b.
Fig. Scheme of synthesis of 4-(2-hydroxyphenyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]chromene-5(4H)-ones Рис. Схема синтеза 4-(2-гидроксифенил)-5,6,7,8-тетрагидроизоксазоло [5,4-b] хромен-5(4Н)-он
EXPERIMENTAL
All compounds and solvents used were purchased from Sigma-Aldrich and used without further purification. The UV spectra were recorded on a
Specord M-400 spectrophotometer. The IR spectra were obtained in KBr on a UR-20 spectrometer. The :H NMR spectra were recorded on a Bruker AC-200 spectrometer at 200 and 50 MHz, respectively; tetra-methylsilane was used as internal reference. The pro-
gress of reactions and the purity of products were monitored by TLC on Silufol UV-254 plates using EtOAc - hexane (1:1) as eluent; spots were visualized under UV radiation or by treatment with iodine vapor, followed by calcination at 250-350 °C. The melting points were determined on a Boetius hot stage. Chro-matographic-mass spectrometric analysis was carried out on liquid hybrid chromatography mass spectrometer LTQ Orbitrap Discovery (Thermo Electron Corporation, USA), which includes a linear Quadruple trap LTQ XL and the orbital trap of high permission. Ioni-zation of the sample was carried out electrospray with using the source H-ESI II Ion Max. Calibration of linear and orbital traps LTQ Orbitrap Discovery was carried out using a standard solution, containing caffeine (m/z 195), L-methionyl-arginyol-phenylalanine acetate (MRFA, m/z 524) and Ultramark 1621 (mic-sture of fluorinated phosphazines). As an internal calibrant during the removal of mass spectra indapamide was used (m/z 66,0674).
4Z-4-(2-Hydroxybenzylidene)-3-methyliso-xazole-5(4H)-one (3). A mixture of 0.99 g (10 mmol) of isoxazolone 1, 1.83 g (15 mmol) of salicylaldehyde 2 and three drops of piperidine in 20 ml of ethyl acetate was boiled for 15 min. After a day, the precipitated crystals were filtered and crystallized from ethanol. Yield 1.50 g (74%), m.p. 199-201 °C (from ethanol) (m.p. 198-200 °C [13]). IR spectrum, cm-1: 1560, 1580, 1600 (C = C, C = O, C = N), 2750-3440 (OH). UV spectrum (EtOH), W, nm (log s): 400.9 (4.10), 262.7 (3.78), 244.5 (3.70) .1H NMR spectrum (CDCl3, 5, ppm, J, Hz): 2.26 (3H, s, CH3), 6.93 (1H, d, J = 8.0 Hz), 7.04 (1H, t, J = 8.0 Hz), 7.53 (1H, t, J = 8.0 Hz), 8.01 (1H, s), 8.88 (1H, d, J = 8.0 Hz), 10.18 (1H, s).
3-methyl-4-(2-hydroxyphenyl)-5,6,7,8-tetra-hydroisoxazolo [5,4-b] chromene-5(4H)-one (7a). A mixture of 1.02 g (5 mmol) of hydroxyben-zylidesoxazolone 3 and 0.56 g (5 mmol) of cyclohex-anedione 4a in 20 ml of ethanol was boiled for 40 min, then cooled to room temperature. After 24 h, the precipitated crystals were filtered off, washed with alcohol and dried in air. Yield 1.41 g (89%), m.p. 218-220 °C (ethanol). IR spectrum, cm-1: 1585, 1615, 1720 (C = C, C = O, C = N), 3060, 3450 (OH). UV spectrum (EtOH), Imax, nm (log s): 217.30 (4.16), 278.85 (4.07). NMR spectrum (DMSO-d6, 5, ppm, J, Hz): 1.76 (1H, m), 1.92 (1H, m), 2.29 (3H, s, CH3), 2.47 (2H, m), 2.65 (1H, m), 2.86 (1H, m), 4.89 (1H, s, H-9), 7.03 - 7.29 (4H, m, H Ar), 11.83 (1H, brs, OH). Found, %: C, 68.58; H 5.05; N, 4.79. C17H15NO4. Calculated, %: C, 68.66; H, 5.09; N, 4.71.
3,7,7-trimethyl-4-(2-hydroxyphenyl)-5,6,7, 8,9-tetrahydroisoxazolo[5,4-b] chromene-5(4H)-one (7b) was prepared in a similar manner from 1.02 g (5 mmol) of hydroxybenzylidenisoxazole 3 and 0.70 g (5 mmol) of dimedone 4b. Yield 1.39 g (81%), m.p. 194-196 °C (ethanol). IR spectrum, v, cm-1: 1590, 1620, 1650, 1730 (C = C, C = O, C = N), 3175, 3445 (OH). UV spectrum (EtOH), U«, nm (log s): 219.25 (4.12), 267.70 (4.12). 1H NMR spectrum (CD3OD, 5, ppm, J, Hz): 1.04 (3H, s, CH3), 1.09 (3H, s, CH3), 2.19 and 2.31, (2H, AB system, Jab = 16 Hz, CH2), 2.34 (3H, s, CH3), 2.54 (2H, s, CH2), 4.72 (1H, s, H-9), 6.95-7.23 (4H, m, Ar). Found, %: C, 70.22; H, 5.95; N, 4.40. C19H19NO4. Calculated, %: C, 70.13; H, 5.89; N, 4.31.
RESULTS AND DISCUSSION
The structures of the obtained compounds are confirmed by the data of the :H NMR, UV, IR spectra, elemental and chromatographic-mass spectromet-ric analysis. Thus, in the UV spectrum of a plane molecule [19] of benzylidenisoxazolone 3, there is a long-wave absorption maximum (400.9 nm) corresponding to the joint system of conjugated bonds of the isoxazole and aromatic rings. Both n-bond systems of the compounds 7a,b are separated by C-9 saturated carbon atom, so in their spectra long-wavelength peaks shift to the short-wavelength region (278.85 and 267.70 nm respectively). In 1H NMR spectra there are signals of the methyl groups of the isoxazole ring of compounds 3, 7a,b at 2.26, 2.29, 2.34 ppm respectively. The presence of a chiral carbon atom (C-9) in molecules 7a,b defines nonequiva-lence of geminal protons of methyl and methylene groups therefore their signals do not coincide.
The presence of a one-proton singlet signal (4.89 and 4.72 ppm) in the spectra of each of them, corresponding to the methine proton in position 4 of the tricyclic fragment, is a confirmation of the conformity of the assigned structure. In the case of alternative structures 8a,b in the spectra of these compounds in the region of 3 -5 ppm there would be two one-proton doublets of interacting protons.
The structures of compounds 7a,b were confirmed by high resolution mass-spectrometry data (Table). In the spectra of both compounds observed [M + Na]+ ion peaks. The presence of fragment peaks [M + Na - CO]+ and [M + Na - CO - №O]+ confirms the presence of hydroxy and carbonyl groups in the molecules.
Table
Data of mass-spectrometric measurement for compounds 7a,b
compound Calculated m/z Observed m/z Simulated formulaion Mass measurement error (Appm) Mass resolving power (R)
7a 320.08933 320.08902 CnH^NNa [M + Na]+ -0.966 39801
292.09441 292.09464 CieHisOsNNa [M +Na - CO]+ 0.770 42104
274.08385 274.08423 Ci6Hi3O2NNa [M + Na - CO -H2O]+ i.390 41204
7b 348.12063 348.12036 Ci9Hi9O4NNa [M + Na]+ -0.773 38401
320.12571 320.12570 Ci8Hi9O3NNa [M +Na - CO]+ -0.05 41004
302.11515 302.11528 Ci8Hi7O2NNa [M + Na - CO -H2O]+ 0.36 40404
Obviously, if the reaction of the unsaturated carbonyl compound 3 with cyclohexadiones 4a,b occurred by the Michael addition to form the intermediate tricycles 6a,b, followed by cyclization with the participation of the more active ketone carbonyl, dehydration would result in the formation of compounds 8a,b, but not 7a,b. Compounds 7a,b formation mechanism includes a hetero Diels-Alder reaction to form adducts 5a,b. Their dehydration gives the products 7a,b.
It should be noted that the a, P-unsaturated carbonyl compound 3 is a latent form of the cross-conjugated endion system of the easily react with enolic dienophiles via heterocyclization of Diels-Alder. At the same time, a pyran cycle is formed [20-22].
CONCLUSION
In conclusion, a convenient method for the synthesis of (2-hydroxyphenyl)-5,6,7,8-tetrahydro-isoxazolo[5,4-b]chromene-5(4H)-ones have been developed.
It was shown that (4Z)-4-(2-hydro-xybenzyli-den)-3-methyl-1,2-oxazol-5(4H)-on reacts with cy-clohexane-1,3-dions following the pattern of a hetero Diels-Alder reaction with the formation of 4-(2-hydroxyphenyl) -5,6,7,8-tetrahydro-isoxazolo [5,4-b] chromene-5(4H)-one derivatives.
Two new substances were obtained and characterized.
ACKNOWLEDGEMENT
The author is sincerely thankful to Syahovich Vitaliy Eduardovich for his help in carrying out mass-spectrometric analysis of compounds.
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Поступила в редакцию 16.03.2018 Принята к опубликованию 30.10.2018
Received 16.03.2018 Accepted 30.10.2018
