Direct CH/CH functionalization of 1,3-dihydroxy-9H-xanthen-9-one and 1,3-dimethoxy-9H-xanthen-9-one with 1,2,4-triazines and quinazoline 233 D O I: 1 0. 15 82 6/ ch im te ch .2 02 0. 7. 4. 17 Sharapov A. D., Fatykhov R. F., Khalymbadzha I. A., Chupakhin O. N. Chimica Techno Acta. 2020. Vol. 7, no. 4. P. 233–236. ISSN 2409–5613 Direct CH/CH functionalization of 1,3-dihydroxy-9H- xanthen-9-one and 1,3-dimethoxy-9H-xanthen-9-one with 1,2,4-triazines and quinazoline A. D. Sharapov*, R. F. Fatykhov, I. A. Khalymbadzha, O. N. Chupakhin Ural Federal University, 19 Mira st., Ekaterinburg, 620000, Russian Federation *email: sharapovaienur27@mail.ru Abstract. An electron-deficient series of 1,2,4-triazines and quinazoline have been used for cross-dehydrogenative coupling with 1,3-dihydroxy and 1,3-dimethoxyxanthones to give stable nucleophilic addition products. The adducts and their subsequent oxida- tion products were obtained in good yields and the structures of the compounds were confirmed by 1H NMR spectroscopy. These results expand the scope of the methodology of nucleophilic substitution of hydrogen with the participation of xanthones with azines. Moreover, this methodology makes it possible to obtain new organic materials based on xanthones, which have a wide spectrum of biological activity. Keywords: сross-dehydrogenative coupling reactions; 1,2,4-triazines; quinazolines; xanthones Received: 20.10.2020. Accepted: 19.12.2020. Published:30.12.2020. © Sharapov A. D., Fatykhov R. F., Khalymbadzha I. A., Chupakhin O. N., 2020 Introduction Mangiferin is  a  representative of  xanthones. It is  present in  significant quantities in higher plants and in particular in  fruits, stems, leaves, bark and kernels of mangoes. It is a promising antioxidant with many health-related properties such as  antiviral, antineoplastic, antidiabetic, antioxidant, immunomodulatory, hepato- protective, and analgesic (Fig. 1) [1]. O O OH OH HO HO OH HO HO OH O Fig. 1. Mangiferin as a biologically active representative of xanthones The  transformation of  xanthones with azaheterocyclic compounds may be promising not only for obtaining new bio- logical properties, but also for developing the methodology of nucleophilic substitu- tion of hydrogen in chemistry of natural compounds. Reactions of nucleophilic substitution of hydrogen (SN H) in a series of π-deficient heterocycles are one of the types of cross- dehydrogenation coupling (CDC) and proceed as the addition of a nucleophile to  an  electrophile with the  formation of  the  so-called σH-adduct, which can subsequently be oxidized to  a  product with a  completely aromatic structure (Scheme 1). 234 This direction makes it possible to  abandon the  preliminary functionali- zation of the initial reagents and to reduce the amount of side reagents-waste [2]. Thus, the  present work is  devoted to  the  study of  the  reactivity of  natural- ly occurring nucleophilic systems such as  xanthones containing two active sites with 1,2,4-triazines and quinazoline. Results and discussion 1,3-Dihydroxyxanthones contain two different nucleophilic centers in the m-di- hydroxybenzene ring (carbon atoms C2 and C4) and in reactions with electrophiles are capable of  producing two isomeric products. We found that when 1,3-dihy- droxyxanthone 1 interacts with 1,2,4-tria- zines a or b and quinazoline c in trifluoro- acetic acid a mixture of two σH-adducts 2 and 3 is formed. These are products of nu- cleophilic attack at the C4 and C2 positions with a ratio of 85:15, respectively, with total yields of 68–72% (Scheme 2). The reaction of fully methylated 1,3-di- hydroxyxanthone 4 with azines a, b and quinazoline c in the presence of MeSO3H in  acetic acid at  room temperature pro- ceeds regioselective with the  formation of  С4 σH-adduct 5a-c. The  adducts are subsequently oxidized under the  action of  2,3-dichloro-5,6-dicyano-1,4-benzo- quinone (DDQ) to nucleophilic substitu- tion of hydrogen products 6a-c in 60–71% yields (Scheme 3). Thus, using calculations in the “Gaussi- an Interface program”, in the case of 1,3-di- hydroxanthone, carbon C2 has a more neg- ative charge than carbon atom C4. It can be assumed in connection with the  data obtained that in  the  case of  xanthone 1 there is a competition between orbital and charge control, which leads to the forma- tion of a mixture of products. Experimental Unless otherwise noted, all commer- cially available compounds were used with- out further purification. 1H NMR spectra was recorded at am- bient temperature on a  Bruker Avance II 400  MHz spectrometer at  400 and 100  MHz, respectively, in  DMSO-d6 as a solvent. 1,3-Di hydroxyxanthone 1 and 1,3-dimethoxyxantone 4 were prepared according to known procedures [3,4]. Typical procedure for synthesis 2a-c and 3a-c. Xanthone 1 (1 mmol) and azines a, b or c (1 mmol) were dissolved in TFA (10 mL). The mixture was allowed to stand for 72  h. The  mixture was diluted with NaHCO3 (5  mL), the precipitate formed was collected by filtration, and recrystal- lized from benzene. 4-(3-(Methylthio)-4,5-dihydro-1,2,4-tri- azin-5-yl)-1,3-dihydroxy-9H-xanthen-9-one 2a. 1H NMR (DMSO-d6): δ = 10.98 (s, 1H, 3-OH), 9.74 (s, 1H, 1-OH), 9.70 (s, 1H, NH), 7.84 (s, 1H, H’5), 7.67–7.77 (m, 4H, benzene), 6,51 (s, 1H, C2H), 5,30 (s, 1H, sp3-CH), 2.49 (s, 1H, CH3). H Catalyst Oxidizing reagent Nu Nu-nucleophilic particle H H Nu σH-adduct H2ONu Scheme 1. General scheme of reaction of nucleophilic substitution of hydrogen 235 4-(3,6-Diphenyl-4,5-dihydro-1,2,4-tria- zin-5-yl)-1,3-dihydroxy-9H-xanthen-9-one 2b. 1H NMR (DMSO-d6): δ = 11.15 (s, 1H, 3-OH), 9.68 (s, 1H, 1-OH), 7.45–7.65 (m, 4H, Ph), 7.43 (2m, 10H, Ph) 6,12 (s, 1H, C2H), 3,52 (s, 1H, sp3-CH). 4-(3,4-Dihydroquinazolin-4-yl)-1,3-di- hydroxy-9H-xanthen-9-one 2c. 1H NMR (DMSO-d6): δ = 11.15 (s, 1H, 3-OH), 9.68 (s, 1H, 1-OH), 7.84–7.95 (m, 4H, Quin), 7.67–7.77 (m, 4H, Ph), 6,12 (s, 1H, C2H), 5,52 (s, 1H, sp3-CH). Typical procedure for synthesis of 5a-c. Xanthone 4 (1 mmol) and azines a,b or c (1 mmol) were dissolved in AcOH (10 mL) and was added MeSO3H (3 equiv). The mixture was allowed to stand for 72 h. The  mixture was diluted with NaHCO3 (5  mL), the  precipitate formed was col- lected by filtration, and recrystallized from benzene. 4-(3-(Methylthio)–4,5-dihydro-1,2,4-tri- azin-5-yl)-1,3-dimetoxy-9H-xanthen-9-one 5a. 1H NMR (DMSO-d6): δ = 9.75 (s, 1H, NH), 7.84 (s, 1H, H’5), 7.67–7.77 (m, 4H, Ph), 6,51 (s, 1H, C2H), 4,35 (s, 1H, sp3-CH), 2.62 (s, 3H, CH3), 2.49 (s, 3H, CH3). 4-(3,6-Diphenyl-4,5-dihydro-1,2,4-tria- zin-5-yl)-1,3-dimetoxy-9H-xanthen-9-one 5b. 1H NMR (DMSO-d6): δ = 7.45–7.65 (2m, 10H, Ph), 6,12 (s, 1H, C2H), 3,52 (s, 1H, sp3-CH), 2.74 (s, 3H, CH3), 2.67 (s, 3H, CH3). 4 - ( 3 , 4 - D i h y d r o q u i n a z o l i n - 4-yl)-1,3-dimetoxy-9H-xanthen-9-one 5c. 1H NMR (DMSO-d6): δ = 7.84–7.95 (m, 4H, Quin), 7.67–7.77 (m, 4H, benzene), MeSO3H, AcOH 4 N H O O OMe OMe NH O O OMe OMe a,b or c 5a-c 6a-c N N N N N N N N SMe Ph Ph 6a (60%) 6b (63%) 6c (71%) O O OMe OMe N DDQ DCE, reflux Scheme 3. Interaction of 1,3-dimetoxyxanthone with 1,2,4-triazines and quinazoline O CF3COOH 1 O OH OH N H O O OH OH NH O O OH OH N H a or b or c 2a-c 3a-c N H N N N H N N N NH SMe Ph Ph 2a, 3b (72%) 2b, 3b (68%) 2c, 3c (70%) NH = Scheme 2. Interaction of 1,3-dihydroxyxanthone with 1,2,4-triazines and quinazoline 236 6,12 (s, 1H, C2H), 4,53 (s, 1H, sp3-CH), 2.76 (s, H, CH3), 2.45 (s, H, CH3). Typical procedure for oxidation of 5a- c. To a solution of 5a-c (1 mmol) in DCE (4 mL) was added DDQ (3 equiv). The re- action mixture was heated at 65 °C for 6 h and diluted with DCM (5 mL). The solu- tion was passed through an alumina pad and evaporated yielding pure 6a-c. 4 - ( 3 - M e t h y l t h i o - 1 , 2 , 4 - t r i a z i n - 5-yl)-1,3-dimetoxy-9H-xanthen-9-one 6a. 1H NMR (DMSO-d6): δ = 9.75 (s, 1H, NH), 7.84 (s, 1H, H’5), 7.67–7.77 (m, J = 2.44, 4H, benzene), 6,51 (s, 1H, C2), 2.62 (s, 6H, 2CH3), 2.49 (s, 3H, CH3). 4 - ( 3 , 6 - D i p h e n y l - 1 , 2 , 4 - t r i a z i n - 5-yl)-1,3-dimetoxy-9H-xanthen-9-one 6b. 1H NMR (DMSO-d6): δ = 9.75 (s, 1H, NH), 7.84 (s, 1H, H’5), 7.67–7.77 (m, 4H, Ph), 6,51 (s, 1H, C2H), 2.62 (s, 3H, 2CH3), 2.44 (s, 3H, CH3). 4-(3,4-Quinazolin-4-yl)-1,3-dime- toxy-9H-xanthen-9-one 6c. 1H NMR (DMSO-d6): δ = 9.75 (s, 1H, NH), 7.84 (s, 1H, H’5), 7.67–7.77 (m, 4H, Ph), 6,51 (s, 1H, C2H), 2.62 (s, 3H, CH3), 2.44 (s, 3H, CH3). Conclusions In summary, we have developed a con- venient method introduction of 1,3-dihy- droxy and 1,3-dimetoxyxanthones into 1,2,4-triazines and quinazoline based on nucleophilic substitution of hydrogen SN H in these nitrogen-containing heterocycles. The direct reaction CH/CH-functionaliza- tion was performed using MsOH or TFA as  catalyst for the  addition step, DDQ as  oxidant. High yields of  the  coupling products, short reaction times, and mild conditions appear to be the main advan- tages of this promising synthetic approach. Acknowledgements This work was finantionally supported by the Presidential Council on Grants NSh- 2700.2020.3 and Ministry of Science and Higher Education of the Russian Federation (project FEUZ-2020-005). References 1. Dar A, Shaheen F. Analgesic and antioxidant activity of mangiferin and its deriva- tives: the structure activity relationship. Biol Pharm Bull. 2005;28:596–600. doi:10.1248/bpb.28.596 2. Khalymbadzha IA, Fatykhov RF, Chupakhin ON. 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