8-Hydroxy-5-nitroquinoline as a C-nucleophilic reagent in the reaction of C, C-coupling with quinazoline 237 D O I: 1 0. 15 82 6/ ch im te ch .2 02 0. 7. 4. 18 Yuri A. Azev, Olga S. Koptyaeva, Oleg S. Eltsov, Anton N. Tsmokalyuk, Tatyana A. Pospelova Chimica Techno Acta. 2020. Vol. 7, no. 4. P. 237–241. ISSN 2409–5613 8-Hydroxy-5-nitroquinoline as a C-nucleophilic reagent in the reaction of C, C-coupling with quinazoline Yuri A. Azev,* Olga S. Koptyaeva, Oleg S. Eltsov, Anton N. Tsmokalyuk, Tatyana A. Pospelova Ural Federal University, 19 Mira st., Ekaterinburg, 620002, Russian Federation *email: azural@yandex.ru Abstract. The first example of the reaction of 5-nitro-8-hydroxyquinoline as a C-nu- cleophile with quinazoline is described. As a result of the reaction of C, C-coupling, a stable σ-adduct containing the drug nitroxalin on a heterocyclic carrier was obtained. The structure of the resulting adduct was confirmed by 2D 1H-13C HSQC, 1H-13C HMBC, and 1H-15N HMBC spectra. Keywords: 5-nitro-8-hydroxyquinoline; quinazoline; C, C-coupling Received: 20.11.2020. Accepted: 23.12.2020. Published:30.12.2020. © Yuri A. Azev, Olga S. Koptyaeva, Oleg S. Eltsov, Anton N. Tsmokalyuk, Tatyana A. Pospelova, 2020 Introduction 5-nitro-8-hydroxyquinoline (ni- troxaline) is an antimicrobial agent from the  group of  hydroxyquinolines. It has a wide spectrum of action, including selec- tively suppressing the synthesis of bacterial DNA, forms complexes with metal-con- taining enzymes of the microbial cell [1, 2]. Preparations containing 8-hydrox- yquinoline are highly toxic. In this regard, the  search for new derivatives of  these compounds that are less toxic is urgent. It seems promising to carry out the syn- thesis of new derivatives of 8-hydroxyqui- nolines by  means of  environmentally friendly C–C coupling reactions, during which the  addition of  a  C-nucleophile to the 8-hydroxyquinoxaline molecule oc- curs, followed by the replacement of a hy- drogen atom [3]. Theoretically, this type of transformation is waste-free and pos- sible under conditions of acid activation of heterocyclic azines. Reactions of nucleophilic substitution of hydrogen in 5-nitroquinolines have been described, which proceed in  the  ortho- position to the nitro group in interaction with nucleophiles containing a vicarious group (vicarious substitution) [4]. The re- action of  amination of  nitroquinolines with trimethylhydrazinium iodide oc- cured in a solution of anhydrous DMSO in the presence of potassium tert-butylate [5]. Vicarious amination of nitroquinolo- nes with 4-amino-1,2,4-triazole was carried out under similar conditions and occured at the C6 atom of nitroquinolone [6]. It was known that 5-nitro-8-hydroxyquinoline 1 reacted with formaldehyde in the presence of amines, to form 7-substituted aminome- thyl derivatives of 5-nitroquinoline-8-ol 2 [7] (Scheme 1). 238 Experimental All reagents used were commercially available and were used without further purification (Sigma Aldrich, Merck). The  reaction progress and purity of  the  obtained compounds were con- trolled by TLC method on Sorbfil UV-254 plates, using visualization under UV light. Melting points were determined on a Stu- art SMP10 melting point apparatus. 1H, 13C and 19F NMR spectra were ac- quired on Bruker Bruker Avance NEO — 600 spectrometer in DMSO-d6 solutions, using TMS as internal reference for 1H and 13C NMR or CFCl3 for 19F NMR. Mass- spectra (EI, 70eV) were recorded on Mi- crOTOF-Q instrument (Bruker Daltonics) at 250 °C. Elemental analysis was performed us- ing a Perkin-Elmer 2400 Series II CHNS / O analyzer. To  calculate molecular orbitals, we used the  B3LYP exchange correlation functional in the 6-31G++ (d, p) basis set, in the framework of the Density Functional Theory. The energy of solvation in acetoni- trile was taken into account when calcu- lating. The  calculations were performed using the GAUSSIAN09 package similarly to work [8]. 4 - ( 8 - h y d r ox y - 5 - n i t r o q u i n o l i n - 7-yl)-1,4-dihydroquinazolin-3-ium 2,2,2-trifluoroacetate 4 0.095  g (0.5 mmol) of  quinazoline 3 is heated with 0.5 mmol of 5-nitro-8-hy- droxyquinoline 1 in  2.0 ml of  trifluoro- acetic acid for 70 hours at 110 °C. The reac- tion mixture is evaporated under vacuum. The residue was treated with 3 ml of alco- hol, the precipitate of product 4 was filtered off, washed with 2–3 ml of ethanol, 0.105 g (32%) was obtained, m.p. > 300 °C. 1H NMR (600  MHz, DMSO-d6, δ, ppm): 6.93 (s, 1H), 6.94 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 8.23 (s, 1H), 8.30 (dd, J = 9.0, 5.4 Hz, 1H), 8.58 (s, 1H), 9.22 (d, J = 5.2 Hz, 1H), 10.00 (d, J = 8.9 Hz, 1H), 11.60 (s, 9H), 13C NMR (151  MHz, DMSO-d6, δ, ppm): 50.23, 111.39, 114.21 (q, J = 283.5 Hz, CF3), 117.88, 123.80, 125.54, 127.59, 128.43, 129.14, 129.31, 130.60, 130.72, 136.63, 144.46, 144.68, 148.27, 151.08, 160.72 (q, J = 43.2 Hz, COCF3), 180.20. 15N NMR (61 MHz, DMSO-d6, δ, ppm): 118.48, 125.63, 184.09, 364.34. Mass spectrum (EI), 321 (20), 320 (100) [M]+, 301(20), 288 (24), 272 (56), 271 (59). Found, %: C 52.54; H 3.02; N 12.90. C19H13N4O5F3 Calculated, %: C 52.68; H 3.08; N 13.01. N NO2 OH N NO2 OH N R1 R2HN R1 R2 (CH2O)n 1 2 R1 = H; R2 = CH2CH2OH, (CH2)2-C6H5 Scheme 1 239 Results and discussion The data presented in the literature con- firm the presence of an electrophilic center on the C6 atom and a nucleophilic center on the C7 atom in the 5-nitro-8-hydrox- yquinoline molecule. It is obvious that the oxygen-containing substituents (8-hydroxy and 5-nitro group) cause a polarization of the electron density in the aromatic nucleus that is higher than that in the heterocyclic part of the nitroxa- line molecule. This has been confirmed using quantum chemical calculations. The electron density in the high occu- pied molecular orbital (HOMO, Fig. 1a) is most localized on the C5, C7, and C8 at- oms of the aromatic nucleus. In this case, due to  the  absence of  steric hindrances, the  C7 atom of  the  nitroxaline can be the most effective nucleophilic center. The lowest unoccupied molecular or- bital (LUMO, Fig.  1b) are localized on the nitrogen atoms of the nitro group, C6 and C8 atoms of nitroxaline. These posi- tions of molecule 1 are characterized by in- creased electrophilic properties. Taking into account the  absence of  steric hin- drances to the formation of a stable C–C bond at the C6 position of nitroxaline, it can be assumed that this electrophilic cent- er is the most active when interacting with nucleophiles, which is confirmed by data from the literature [4–6]. In  this work, it was found that 5-ni- tro-8-hydroxyquinoline 1 interacts with quinazoline 3 in the presence of trifluoro- acetic acid to  form a  stable σ-adduct 4 (Scheme 2). An ion peak corresponding to the mo- lecular weight of  compound 4 was ob- served in the mass spectrum of electron impact. In the 1H NMR spectrum of adduct 4, the signal of the H4’ atom of the quina- zoline nucleus was found at 6.93 ppm, and the signal of the corresponding sp3-hybrid- ized C4’ atom in the 13C NMR spectrum was observed at 50.23 ppm. The assignment of signals from 1H, 13C, and 15N atoms of adduct 4 was carried out in the analysis of 2D 1H-13C HSQC, 1H-13C HMBC, and 1H-15N HMBC spectra. 2D Fig. 1. Distribution of electron density in the nitroxoline 1: (a) HOMO, (b) LUMO. N NO2 OH N N + 1 3 4 3 2 N 1 4 8 7 6 5 4' HO N 3' 2' NH 1' 8' 7' 6' 5' H NO2 TFA, 110 oC, 70 h H CF3COO - Scheme 2 240 1H-15N HMBC spectrum with assignment of  signals of  1H and 15N atoms is  shown in Fig. 2. Apparently, 5-nitro-8-hydroxyquino- line 1 reacted as a C-nucleophile at the C7 position of the molecule to form a stable adduct under conditions of acid activation of the quinazoline nucleus. Conclusions In conclusion, it should be noted that a stable σ-adduct consisting of a biologi- cally active drug (nitroxaline) on a hetero- cyclic quinazoline carrier was obtained for the first time by means of the C,C-coupling reaction under the conditions of acid ca- talysis. References 1. Mashkovsky MD. Lekarstvennyye sredstva [Medicines]. Moscow: Nauka; 1993. 347 p. Russian. 2. Ragno R, Gioia U, Laneve P, Bozzoni I, Mai A, Caffarelli E. Identification of Small- Molecule Inhibitors of the XendoU Endoribonucleases Family. Chem Med Chem. 2011;6:1797–1805. doi:10.1002/cmdc.201100281 3. Charushin VN, Chupakhin ON. Topics in Heterocyclic Chemistry: Metal-free C-H functionalization of aromatic compounds through the action of nucleophilic rea- gents. Eds.: Charushin VN, Chupakhin ON. Switzerland: Springer; 2014;37:1–50. 4. Makosza M, Wojciechowski K. Topics in Heterocyclic Chemistry: Nucleophilic Sub- stitution of Hydrogen in Arenes and Heteroarenes. Eds.: Charushin VN, Chupakhin ON. Switzerland: Springer; 2014;37:51–105. 5. Grzegozek M. Vicarious nucleophilic amination of nitroquinolines by 1,1,1- trimeth- ylhydrazinium iodide. J Heterocyclic Chem. 2008;45:1879–82. doi:10.1002/jhet.5570450652 Fig. 2. 1H-15N HMBC spectrum of adduct 4 241 6. Szpakiewicz B, Grzegozek M. Vicarious nucleophilic amination of Nitroquinolines with 4-amino-1,2,4-triazole. Can J Chem. 2008;86:682–685. doi:10.1139/V08–051 7. Movrin M, Maysinger D, Marok E. Biologically active Mannich bases derived from nitroxoline. Pharmazie. 1980;35:458–60. 8. Azev YuA, Koptyaeva OS, Eltsov OS, Yakovleva YuA, Tsmokalyuk AN, Ivoilova AV, Seliverstova EA, Pospelova TA, Bakulev VA. Indole-3-carbaldehydes Arylhydra- zones as Multisite C-Nucleophiles in the Reactions with Quinazoline. J Gen Chem. 2020;9:1601–10. doi:10.1134/S1070363220090030