Novel synthesis of 3-(Phenyl) (ethylamino) methyl)-4-hydroxy-2H-chromen-2-one derivatives using biogenic ZnO nanoparticles and their applications Chimica Techno Acta LETTER published by Ural Federal University 2022, vol. 9(1), No. 20229105 eISSN 2411-1414; chimicatechnoacta.ru DOI: 10.15826/chimtech.2022.9.1.05 1 of 4 Unusual nicotinoylation of 4-phenyl-5,7-dihydroxycoumarin A.D. Sharapov * , R.F. Fatykhov, I.A. Khalymbadzha, A.P. Potapova, P.A. Slepukhin, O.N. Chupakhin Ural Federal University, 620002 Mira st., 19, Yekaterinburg, Russia * Corresponding author: a.d.sharapov@urfu.ru This short communication (letter) belongs to the MOSM2021 Special Issue. © 2021, The Authors. This article is published in open access form under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Abstract In the present work, we report a convenient synthesis of 5- and 7- substituted-4-phenyl coumarins. In contrast to previous results ob- tained with 4-alkylcoumarins, nicotinoylation of 5,7-dihydroxy-4- phenylcoumarin with nicotinoyl benzotriazole or nicotinoyl azide se- lectively provides 5-O protected ester. The combination of the nico- tinoylation reaction followed by tosylation-denicotinoylation yields 5-hydroxy-7-tosyloxy-coumarin derivative, which may be useful in the synthesis of inophyllum, a tetracyclic HIV reverse transcriptase inhibitor, as well as its analogues. Keywords 5,7-dihydroxy-4- phenylcoumarin nicotinoylation esterification protecting group inophyllum Received: 18.11.2021 Revised: 21.12.2021 Accepted: 21.01.2022 Available online: 26.01.2022 1. Introduction Asymmetrically O-substituted 5,7-dihydroxycoumarins attract attention as important building blocks for the syn- thesis of biologically active compounds. Compounds of this class are widespread both in nature, especially in plants in the form of mono- and diterpenes, and in synthetic com- pounds with important biological activity [1–4]. They have anti-cancer, antibacterial [5, 6], anti-HIV, anti- inflammatory and others activities, For example, inophyl- lums (Fig. 1), a series of natural HIV reverse transcriptase inhibitors isolated from Calophyllum inophyllum tree [7], comprise asymmetrically O-substituted 5,7- dihydroxycoumarin scaffold. Asymmetrically O-substituted 5,7-dihydroxycoumarins also can be used to prevent and treat Parkinson’s disease, brain lesions, and dementia [8]. Fig. 1 Structure of naturally occurring inophyllums We have previously demonstrated that nicotinoylation of 5,7-dihydroxy-4-alkylcoumarins is a convenient method for the synthesis of both 5- and 7-hydroxy-substituted coumarins [9,10]. In this case, the nicotinoylation reaction proceeds at the sterically less hindered hydroxy group at position C7 of coumarin system (Scheme 1). Subsequent modification of free 5-OH hydroxy group with a protective group orthogonal to nicotinoyl (tosyl or di(tert- butyl)phenylsilyl) and removal of the nicotinoyl moiety under acidic conditions allows the synthesis of comple- mentary 5-OH protected coumarins [9]. In the presented work, we expand this methodology of selective nicotinoylation to 4-aryl-5,7-dihydroxycoumarins. 2. Experimental Unless otherwise noted, all commercially available com- pounds were used without further purification. 1-Nicotinoyl benzotriazole [10], nicotinoyl azide [11], and 5,7-dihydroxy-4-phenylcoumarin [12] were prepared in accordance with published procedures. 1H and 13C NMR spectra were recorded at ambient tem- perature on a Bruker Avance II 400 MHz spectrometer at 400 and 100 MHz, respectively, in DMSO-d6 or DMSO- d6:CCl4 mixture as a solvent. Chemical shifts (δ) are given in ppm relative to the DMSO residual peak (2.50 ppm) as an internal standard. http://chimicatechnoacta.ru/ https://doi.org/10.15826/chimtech.2022.9.1.05 https://orcid.org/0000-0003-1582-5462 http://creativecommons.org/licenses/by/4.0/ Chimica Techno Acta 2022, vol. 9(1), No. 20229105 LETTER 2 of 4 Scheme 1 Nicotinoylation of 5,7-dihydroxy-4-alkylcoumarin The X-ray diffraction data for compound 2 were ob- tained from a 0.30×0.25×0.20 mm single crystal (color- less prism) at 295(2) K on an Xcalibur E diffractometer with a CCD detector (Cu Kα radiation, λ = 154.184 pm, graphite monochromator). 2.1. Procedure for synthesis of 2, 3, and 4 compounds 2.1.1. 7-Hydroxy-2-oxo-4-phenyl-2H-chromen-5-yl nico- tinate 2 5,7-Dihydroxy-4-phenylcoumarin (2.540 g, 10.0 mmol), triethylamine (1.111 g, 11.0 mmol), and nicotinoyl azide or nicotinoylbenzotriazole (10.0 mmol) were dissolved in acetone (30 ml). The mixture was allowed to stand for 12 hours and the precipitate formed was filtered. Yield 1.860 g (52%). 1H NMR (400 MHz, DMSO-d6 + CCl4) δ 10.83, 8.67 (d, J = 4.9 Hz, 1H), 8.57 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 8.0 Hz, J = 4.9 Hz, 1H), 7.22–7.22 (m, 2H), 7.04–7.08 (m, 2H), 6.77–6.80 (m, 2H), 6.54 (s, 1H), 5.88 (s, 1H). 13C NMR (101 MHz, DMSO) δ 162.62, 161.26, 158.68, 156.03, 153.50, 153.13, 149.99, 147.91, 137.59, 136.73, 127.79, 127.45, 126.72, 123.53, 122.81, 113.28, 108.29, 104.88, 101.44. Anal. Calcd. for C21H13NO5: C, 70.19; H, 3.65; N, 3.90. Found: C, 70.01; H, 3,75; N, 3.79. An empirical correction for absorption (μ = 0.875 mm–1) was applied. Triclinic crystal system, space group P-1; unit cell parameters: a = 9.240(7), b = 9.946(8), c = 10.604(10) Å; α = 83.33(7)°; β = 69.90(8)°; γ = 63.77(8)°; V = 820.2(12) Å3; Z = 2. Total of 8848 reflection intensities were measured in the range 4.44<θ<65.28, including 2705 independent reflections (Rint = 0.0517), and 1795 reflections with I>2σ(I); completeness 96.2% for θ = 65.28°. The structure was solved by the direct method and was refined by the least-squares method using SHELXTL package [13]. All hydrogen atoms were placed in directly calculated posi- tions which were refined according to the riding model in isotropic approximation. Goodness of fit S = 1.005; final divergence factors: R1 = 0.0569, wR2 = 0.0942 for reflec- tions with I>2σ(I); R1 = 0.0419, wR2 = 0.0971 for all inde- pendent reflections. The X-ray diffraction data for com- pound 2 were deposited to the Cambridge Crystallographic Data Centre (CCDC entry no. 2129495) [14]. 2.1.2. 2-Oxo-4-phenyl-7-(tosyloxy)-2H-chromen-5-yl nico- tinate 3 To a suspension of 7-hydroxy-2-oxo-4-phenyl-2H- chromen-5-yl nicotinate 2 (1795 mg, 5.0 mmol) in DCM (35 ml) was added dimethylaminopyridine (2440 mg, 10.0 mmol) and tosyl chloride (1194 mg, 6.25 mmol). The mixture was stirred for 30 min., washed with water (3×50 ml), dried and evaporated to yield 3 (1.638 g, 65%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (dd, J = 4.9 Hz, J = 1.7 Hz, 1H), 8.57 (d, J = 2.5 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.80 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.41 (dd, J = 8.0 Hz, J = 4.8 Hz, 1H), 7.21–7.28 (m, 4H), 7.07–7.11 (m, 2H), 6.82 (dd, J = 7.51 Hz, 1H), 6.27 (s, 1H), 2.43 (s, 3H). 13C NMR (101 MHz, DMSO) δ 162.64, 158.09, 154.58, 153.99, 152.01, 150.35, 150.03, 147.70, 146.40, 137.04, 136.77, 130.90, 130.46, 128.31, 128.01, 127.90, 126.98, 123.33, 123.20, 117.90, 114.45, 112.04, 108.98, 21.18. Anal. Calcd. for C28H19NO7S: Elemental analysis: C, 65.49; H, 3.73; N, 2.73. Found: C, 65.35; H, 3,58; N, 2.93. 2.1.3. 5-Hydroxy-2-oxo-4-phenyl-2H-chromen-7-yl 4- methylbenzenesulfonate 4 A suspension of 2-oxo-4-phenyl-7-(tosyloxy)-2H-chromen- 5-yl nicotinate 3 (1008 mg, 2.0 mmol) was stirred in a mixture of ethanol (20 ml) and 30% hydrochloric acid (12 ml) at 80 °C for 4 hours. The mixture was cooled and precipitate was filtered off. Yield 710 mg, 87%. 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.32–7.38 (m, 5H), 6.57 (d, J = 2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.04 (s, 1H), 2.43 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 158.89, 156.90, 155.37, 154.71, 151.29, 146.15, 138.63, 131.20, 130.38, 128.22, 128.06, 127.40, 127.32, 114.70, 106.42, 104.82, 101.03, 21.19. Anal. Calcd. for C22H16O6S: Elemental analysis: C, 64.70; H, 3.95. Found: C, 64.57; H, 4.02; N, 3.00. 3. Results and discussion We found that nicotinoylation of 5,7-dihydroxy-4- phenylcoumarin 1 with nicotinoylbenzotriazole (X = ben- zotriazolyl) or nicotinic acid azide (X = N3) leads to unex- pected 5-nicotinoyloxy-4-phenylcoumarin 2 (Scheme 2). Chimica Techno Acta 2022, vol. 9(1), No. 20229105 LETTER 3 of 4 Scheme 2 Nicotinoylation of 5,7-dihydroxy-4-phenylcoumarin The reaction takes place at most sterically hindered 5-OH position as confirmed by X-ray structural analysis of com- pound (Fig. 2). One may assume that the selectivity of this re- action is associated with non-covalent interactions in the tran- sition state, such as π-π stacking between the pyridyl ring of nicotinoyl derivatives and the phenyl ring of coumarin. Fig. 2 The X-ray structure (CCDC 2129495) of compound 2 To obtain 5-hydroxy-7-O-subsituted derivatives of cou- marin 1, we carried out the exchange of hydroxy protec- tive groups. Thus, tosylation of 2 with p-toluenesulfonyl chloride followed by denicotinoylation of 3 in an acidic media provides 7-protected tosyloxy derivative 4 (Scheme 3). Compound 4 may be further converted to in- ophyllum or inophillum analogues using adapted proce- dures [9]. 4. Conclusions Thus, we presented a convenient synthesis of 5- and 7- substituted 4-phenyl coumarins. It was demonstrated that 4- phenyl-5,7-dihydroxycoumarins, unlike 4-alkyl compounds, react with nicotinoylazide with the involvement of the 5- hydroxy group in the reaction. The structure of the nicotinoyl derivative was proved by X-ray diffraction analysis. Combi- nation of the nicotinoylation with tosylation– denicotinoylation allows one to obtain 7-hydroxy protected 5,7-dihydroxycoumarins. Acknowledgments This work is financially supported by Russian Science Foun- dation (Ref No. 21-13-00382). Declaration of competing interests The authors declare that they have no known competing fi- nancial interests or personal relationships that could have appeared to influence the work reported in this paper. Scheme 3 Protective groups exchange in compound 2 Chimica Techno Acta 2022, vol. 9(1), No. 20229105 LETTER 4 of 4 References 1. Fatykhov RF, Chupakhin ON, Inyutina AK, Khalymbadzha IA. Synthetic Approaches to Unsymmetrically Substituted 5,7- Dihydroxycoumarins. Synthesis. 2020;52:660–672. doi:10.1055/s-0039-1690780 2. Murray RDH. The naturally occurring coumarins. Fortschr Chem Org Naturst. 2002;83:1–619. doi:10.1007/978-3-7091-6172-2_1 3. Srikrishna D, Godugu C, Dubey PK. A Review on Pharmacolog- ical Properties of Coumarins. Mini Rev Med Chem. 2018;18:113–141. doi:10.2174/1389557516666160801094919 4. Stefanachi A, Leonetti F, Pisani L, Catto M, Carotti A. Couma- rin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds. 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