New pathways for the synthesis of indolyl-containing quinazoline trifluoroacetohydrazides 109 D O I: 1 0. 15 82 6/ ch im te ch .2 02 0. 7. 3. 03 Yu. A. Azev, O. S. Koptyaeva, O. S. Eltsov, Yu. A. Yakovleva, T. A. Pospelova Chimica Techno Acta. 2020. Vol. 7, no. 3. P. 109–115. ISSN 2409–5613 Yu. A. Azev,* O. S. Koptyaeva, O. S. Eltsov, Yu. A. Yakovleva, T. A. Pospelova Ural Federal University 620002, 19 Mira St., Ekaterinburg, Russian Federation *email: azural@yandex.ru New pathways for the synthesis of indolyl‑containing quinazoline trifluoroacetohydrazides The reactions of indole-3-carbaldehyde arylhydrazones with quinazoline in TFA proceed at the 7’ position of the aryl part of the hydrazone molecule to form σ-adducts of quinazoline trifluoroacetohydrazides. Keywords: arylhydrazones; indole-3-carboxaldehydes; С,С-coupling; trifluoroacetyl quinazoline hydrazides. Received: 19.08.2020. Accepted: 28.09.2020. Published: 07.10.2020. © Yu. A. Azev, O. S. Koptyaeva, O. S. Eltsov, Yu. A. Yakovleva, T. A. Pospelova, 2020 Introduction It is  known that the  quinazo- line core is part of natural alkaloids [1, 2]. Among the quinazoline derivatives, com- pounds have been identified that have vari- ous types of biological activity, including antimicrobial, antiallergic, hypotonic, and antiviral [3]. Quinazoline derivatives have been synthesized, which have shown anti- tumor [4] and radioprotective activity [5]. The  addition of  C-nucleophiles to  3-methylquinazolinium iodide with the formation of 4-substituted 3,4-dihydro- quinazolines has been reported [6]. It is al- so known that unsubstituted quinazoline reacts with indole, 3-methyl-1-phenylpyra- zolone-5, 1,3-dimethylbarbituric acid, and pyrogallol in the presence of acid to form 4-σ-adducts [7]. Examples of  arylation of quinazoline with 1,3,5-trimethoxyben- zene, 1-(4-methoxybenzylidene) — 2-phe- nylhydrazine, and o-phenylenediamine derivatives have been described [8]. To  create effective drugs based on quinazoline, it is  important to  be able to change substituents (pharmacophoric fragments) in  the  structure of  the  com- pound. Theoretically, this will allow to af- fect their physicochemical properties (hy- drophilicity, lipophilicity, etc.), changing their bioavailability and activity. Indole is  part of  tryptophan and its metabolites and this one is  also present in a number of natural alkaloids and anti- biotics [9]. Indole derivatives exhibit anti- tumor, antiviral, anti-inflammatory, anti- depressant, and other types of activity [10]. This work is a continuation of research related to the development of methods for the synthesis of biologically active deriva- tives of quinazoline [7]. It should be noted that within the framework of this direction, atomic-economical reactions correspond- ing to the principles of green chemistry are a particular value [11]. This type of interac- tions includes nucleophilic reactions of C,C- coupling under conditions of acid catalysis, which proceed without using of metal cata- lysts and are theoretically waste-free [12,13]. 110 Experimental section Unless otherwise indicated, all com- mon reagents and solvents were used from commercial suppliers without further pu- rification. 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 acquired on Bruker Avance-400 and Bruker Avance NEO  — 600 spectrom- eters 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 MicrOTOF-Q instrument (Bruker Daltonics) at 250˚C. The  general method for the  reaction of  indole carbaldehyde 1 with hydrazines 2a-2d 2-Methyl-1Н-indole-3-carbaldehyde 1 (0.5 mmol) was dissolved in ethanol (3 ml). Then this solution was added to mixture of the corresponding hydrazine 2 and hy- drochloric acid (0.02 ml) in water (3.0 ml). The resulting mixture was refluxed for 5–10 minutes and then was cooled. The result- ing solid was filter off and dried. The crude hydrazones were used directly in the next step without additional purification. Spectral data for hydrazones 3a‑c were described earlier [14]. 2‑Methyl‑3‑{[2‑(4‑methylphenyl) hydrazono]methyl}‑1H‑indole (3d) Yield 55%, mp 185–186°C. 1H NMR spectrum (600 MHz, DMSO-d6), δ, ppm: 2.21 s (3H, CH3), 2.48 s (3H, C 2CH3), 6.93 d (2H, J 8.4 Hz, Ho), 7.02 d (2H, J 8.4 Hz, Hm), 7.07–7.11 m (2H, H 5 and H6), 7.30 m (1H, H7), 8.12–8.15 m (2H, H1’ and H4), 9.61 br.s (1H, N3’H), 11.19 s (1H, N1H). MS, m/z (Irel,%): 263 (M +, 100). 2‑Methyl‑3‑[(2‑phenylhydrazinyl) methyl]‑1H‑indole (3e). Yield 59%, m. p. 192–193 °C. 1H NMR spectrum (600 MHz, DMSO-d6), δ, ppm: 2.49 s (3H, CH3), 6.67 t.t (1H, J 7.3, 1.2 Hz, Hp), 7.03 d.d (2H, J 8.5, 1.2 Hz, Ho), 7.08–7.12 m (2H, H5, H6), 7.21 d.d (2H, J 8.5, 7.3 Hz, Hm), 7.31 m (1H, H 7), 8.15 m (1H, H4), 8.17 с  (1H, H1’), 9.78 br.s (1H, N3’H), 11.23 s (1H, N1H). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 136.06 (C2), 118.04 (C3), 129.91 (C3a), 130.99 (C4), 127.76 (C5), 127.49 (C6), 127.78 (C7), 132.84 (C7a), 139.22 (C1’), 139.44 (Ci), 124.4 (Co), 129.27 (Cm), 127.67 (Cp), 115.98 (CF3), 155.28 (C=O). 15N NMR spectrum (61 MHz, DMSO-d6), δ, ppm: 126.8 (N1), 305 (N3’), 218.5 (N3’). MS, m/z (Irel,%): 249 (M +, 100). The  general method for the  reaction of hydrazones 3d-3e with quinazoline 4 A mixture of quinazoline 4 (0.5 mmol) and the  corresponding hydrazone 3d,e in  TFA (3.0 ml) was refluxed for 65–70 h. The  solvent was removed under re- duced pressure. Water (2.0 ml) was added to  the  residue; the  solid was filtered off. The resulting product 6a,b was analytically pure and no additional purification was required. 4‑(4‑(2‑((1H‑indol‑3‑yl)methyl‑ ene)  — 1‑(2,2,2‑trifluoroacetyl)hy‑ drazinyl)phenyl) — 1,4‑dihydroquina‑ zolinium‑3 2,2,2‑ trifluoroacetate (6a). Yield 51%, m.p. 112–113 °C. 1H NMR spectrum (600 MHz, DMSO-d6), δ, ppm: 6.24 s (1H, H4’’), 7.07 d (1Н, J 7.4 Hz, H5’’), 7.20–7.24 m (2H, H6’’, H7’’), 7.37 t (1Н, J 7.7 Hz, 1H, H5), 7.41 d (1Н, J 6.7 Hz, H4), 7.43–7.45 m (2H, H6,7), 7.61 d 111 (2Н, J 8.4 Hz, H5’), 7.69 d (2Н, J 7.6 Hz, H8’’), 7.92 d (2Н, J 8.4 Гц, H6’), 7.98 s (1H, H1’), 8.57 s (1H, H2’’), 8.80 s (1H, H2), 11.18 s (2H, N1H, N3’’H), 12.37 s (1H, COOH). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 54.61 (C 4’’), 116.39 q (1С, J 288.7 Hz, CF3), 117.59 (C 8’’), 119.17 (C3), 121,42 (C6’), 122.42 (C4a), 126.86 (C7), 127.83 (C6’’), 128.22 (C7’), 128.60 (C5’), 128.73 (C5’’), 129.34 (C7’’), 129.48 (C4), 129.82 (C8a), 130.07 (C3a), 131.90 (C7a), 132.0 (C4’), 139.89 (C7), 140.54 (C5), 141.1 (C6), 149.14(C2’’), 156.00 q (1С, 2J 36.3 Hz, COCF3), 158.44 q (1С, 2J 30.7 Hz, COOH). 19F NMR spectrum (376 MHz, DMSO-d6), δ, ppm: — 73.50, — 74.12. 15N NMR spectrum (61 MHz, DMSO-d6), δ, ppm: 126.9 (N 1”, N3’’), 218.6 (N1, N3’), 301.6 (N2’). MS, m/z (Irel,%): 461 (M+, 20), 369 (11), 131 (100). 4‑(4‑(2‑((2‑methyl‑1H‑indol‑3‑yl) methylene)  — 1‑(2,2,2‑trifluoroacetyl) hydrazinyl)phenyl)  — 1,4‑dihydroqui‑ nazolinium‑3 2, 2,2‑trifluoroacetate (6b). Yield 55%, m.p. 121–122 °C. 1H NMR spectrum (600 MHz, DMSO-d6), δ, ppm: 2.21 s (3H, CH3), 6.28 s (1H, H 4’’), 7.11 d (1H, CHar), 7.24 m (2H, CHar), 7.38 t (1Н, J 7.7 Hz, CHаr), 7.44 s (5H, 4CHind, CHar), 7.63 s (3H, CHar), 7.64 s (1H, H 1’), 8.57 s (1H, H2’’), 11.03 m (2H, NH), 12.37 br.s (1H, COOH). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 11.34 (СH3), 55.96 (C 4’’), 115.33 q (1С, J 147.38 Hz, CF3), 118.06 (C 8’’), 119.17 (C3), 123.08 (C6’), 124.11 (C4a), 124.53 (C7), 127.50 (C6’’), 127.67 (C7’), 127.74 (C5’), 127.78 (C5’’), 127.95 (C7’’), 129.85 (C8a), 130.97 (C4), 132.86 (C7a), 136.05 (C3a), 138.50 (C4’), 138.87 (C7), 138.87 (C5), 144.98 (C6), 146.48 (C2’’), 155.30 q (1С, J 36.5 Hz, COCF3), 158.17 q (1С, 2J 30.9 Hz, COOH). 19F NMR spectrum (376 MHz, DMSO- -d6), δ, ppm: — 73.72, — 74.07. MS, m/z (Irel,%): 475 (M +, 27), 345(25), 131 (100). General procedure for the  synthesis of compounds 7a,b 0.3 Mmol of  corresponding hydra- zone 3d,e was heated in TFA for 45–50 h. The solvent was removed under reduced pressure. The  solid residue was treated with water (2.0 ml) and ammonia solution (15%) to adjust pH to 7–8. The precipitate was filtered off and washed with water (2.0 ml). The resulting product 7a,b was ana- lytically pure and no additional purifica- tion was required. 2,2,2‑Trifluoro‑N’ — [(1H‑indolyl‑3) methylene] — N‑phenylacetylhydrazide (7а). Yield 55%, m.p. 154–155 °C. 1H NMR spectrum (600 MHz, DMSO-d6), δ, ppm: 7.34 t.t (1H, J 7.5, 1.0 Hz, Hp), 7.39 m (1H, H6), 7.43–7.46 m (2H, H5, H6), 7.54 d.d (2H, J 8.6, 7.5 Hz, Hm), 7.70 m (1H, H 4), 7.85 d.d (2H, J 8.6, 1.0 Hz, Hz, Ho), 7.97 s (1H, H1’), 8.78 s (1H, H2), 11.15 s (1H, N1H). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 116.08 q (CF3, J 288.6 Hz), 118.22 (Co), 120.64 (C 3), 126.19 (C2), 126.49 (Cp), 127.57 (C 6), 128.18 (C5), 128.18 (C7), 129.08 (C4), 129.64 (Cm), 131.36 (C 7a), 139.39 (Ci), 139.7 (C 1’), 155.52 q (C=O, J 36.2 Hz). 19F NMR spectrum (376 MHz, DMSO-d6), δ, ppm: 74,52 (s, CF3). MS, m/z (Irel,%): 331 (M +, 100), 262 (44). 2,2,2‑Trifluoro‑N’ — [(2‑methyl‑1H‑ ‑indolyl‑3)methylene] — N‑phenylace‑ tylhydrazide (7b). Yield 64%, m.p. 164– 165 °C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm: 2.21 s (3H, CH3), 7.43–7.47 m (5H, H4, H5, H6, H7 and Hp), 7.52 d.d (2H, J  8.5, 1.4 Hz, Ho), 7.57 d.d (2H, J 8.5, 7.2 Hz, Hm), 7.63 s (1H, H 1’), 10.99 s (1H, N1H). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 115.98 q (CF3, J 288.8 Hz), 118.04 (C 3), 124.4 112 (Co), 127.49 (C 6), 127.67 (Cp), 127.76 (C 5), 127.78 (C7), 129.27 (Cm), 130.99 (C 4), 136.06 (C2), 132.84 (C7a), 139.22 (C1’), 139.44 (Ci), 155.28 q (C=O, J 36.2 Hz). 19F NMR spectrum (376 MHz, DMSO-d6), δ, ppm: — 74,45 (s, CF3). MS, m/z (Irel,%): 345 (M+, 80), 276 (100). Results and discussion Arylhydrazones of indole-3-carbalde- hydes 3а‑е, which were obtained by heating indole-3-carbaldehydes 1a,b with phenyl- hydrazines 2а‑d in ethanol with the addi- tion of HCl, were used as C-nucleophiles for the  studies (Scheme 1). It is  known that the E-configuration of the C=N bond is more thermodynamically favorable for ar- ylhydrazones. This was confirmed by the da- ta of X-ray structural analysis [15, 16]. We previously described that heating of  quinazoline 4 with hydrazones 3a‑c in TFA resulted in the formation of prod- ucts 5a‑c (Scheme 2) [14]. In  current work, we have found that hydrazones 3d,e, which do not con- tain substituents in the phenyl fragment of the molecule, are added to quinazoline 4 at the C7’ atom. The reaction of quinazoline 4 with hy- drazones 3d,e in TFA yielded adducts 6a,b (Scheme 3). The  mass spectra of  compounds 6 contain molecular ions corresponding to  the  addition products of  hydrazones 3d,e to  quinazoline 4. The  mass spectra of  compounds 6 contain molecular ions corresponding to  the  addition products of hydrazone to quinazoline. The 1H NMR N H N HN 1 2 33a 4 5 6 7 7a 1' 2' 3' R1NH H2N HN R2R1 O 3a-e + R2 1a,b 3: a: R1 = Me; R2 = NO2 b: R1 = Me; R2 = Me c: R1 = Me; R2 = F d: R1 = H; R2 = H e: R1 = Me; R2 = H ∆, EtOH, HCl 2a-d 4' 5' 6' 7' 1: a: R1 = H b: R1 = Me 2: a: R2 = NO2 b: R2 = Me c: R2 = F d: R2 = H Scheme 1 N N H N N NHH3CR NHN H N H CH3 N HN R N H N N O CF3 RCH3 NHN H 4 3a-c A 5a-c 3,5: a R=NO2, b R=CH3, c R=F 1'' 4'' 3''2'' 5'' 6'' 7'' 8'' 4a'' 8a'' 1 2 3 45 6 7 3a 7a 1' 2' 3' 4' 5' 6' 7' 8' 8 CF3COO - TFA H 65–71% Scheme 2 113 spectrum contain characteristic signals: the  H4’’ proton singlet at  6.24 ppm (6a) and a pair of two-proton doublets of aro- matic protons H6’, H5’ (7.61 and 7.92 ppm, respectively (6a)). These data confirm the addition of hydrazones 3d,e to com- pound 4 by the p-position of the phenyl group. Since the signal of the NH-proton of the indole fragment is retained in ad- ducts 6, it is  obvious that the  hydrazine part of the molecule undergoes acylation. It should be noted that the 2D 1H-13C gHMBC spectra of adducts 6a,b contain intense cross peaks between the  charac- teristic quartet of  C8’ atom in  the  trif- luoroacetyl group, in particular, at 155.9 ppm for compound 6а (2JС-F = 36.3 Hz), and the  broadened signal of  the  N1H proton (see Fig. 1), indicating the  pres- ence of an intramolecular hydrogen bond N-H…O=C. Due to the presence of an in- tramolecular hydrogen bond in the mol- ecule, it can be assumed that the C=N bond of compounds 6а,b in DMSO-d6 has the Z- configuration, as in adducts 5. We suggest that the formation of tri- fluoroacetyl derivatives of  quinazoline 6, as well as adducts 5, occurs in several stages. Initially, the  addition of  hydra- zone to quinazoline takes place, followed by  acylation of  the  adduct with TFA at  the  N3’H-group with the  formation of compounds 6. Since acylation of  the  NH group oc- curred during the C,C-coupling described above, we assumed that the same reaction would take place upon heating hydrazones 3 in  TFA in  the  absence of  quinazoline. This was confirmed in  the  course of  ex- periments and hydrazides 7 were obtained (Sheme 4). The  structure of  acylation products 7a,b was confirmed by  1H, 13C, 15N, and N N H N N NHR NHN H 4 3d,e A 6a,b 3: d R=H, e R=CH3 1 2 3 4 5 6 7 3a 7a 1'2' 3' 4' 5'6' 7' 8' 8 TFA 51-55% NH N N H R NHN H 1'' 3''2'' 5'' 6'' 7'' 8'' 4a'' 8a'' CF3COO - H N N N F3C O H R 6: a R=H, b R=CH3 Scheme 3 N N NN H N NH O O F3C H H H TFA N N N OH O CF3 H H N N N O F3C H 3d,e 7a,b -H2O R R R R d R=H; e R=CH3 A B a R=H; b R=CH3 Scheme 4 Fig. 1. Fragment of the NMR 2D 1H-13C HMBC spectrum for compound 6a 114 19F NMR spectroscopy including 2D 1H-13C HSQC / HMBC correlation experiments. Due to the fact, that the spectra of com- pounds 7a,b contain signals of  the  NH- protons of the indole fragment, it is obvi- ous that the hydrazine part of the molecule undergoes acylation. 2D 1H-13C HMBC spectra of compounds 7a,b contain char- acteristic intense cross-peaks between the  carbon quartet of  the  trifluoroacetyl group (155.4 ppm, 2JC-F = 36.7 Hz) and the  N1H proton of  the  indole fragment (11.01 ppm). We believe that these cross peaks are due to the spin-spin interaction through the hydrogen bond (see Fig. 2). It should be mentioned that the  ob- tained hydrazides 7 do not react with quinazoline 4. Heating of  quinazo- line 4 with hydrazides 7a, b in TFA gave the starting compounds 7. The inertness of  hydrazides 7 in  the  studied reactions of  C,C-coupling confirms that the  first stage of  the  multistep reaction is  pre- cisely the  addition of  the  hydrazone 3 to  the  quinazoline 4, and then the  stage of acylation with acid occurs. Conclusions As a result of this work, it was found that the reactions of indole-3-carbaldehyde arylhydrazones with quinazoline can pro- ceed either at 5- or 7’ — position of the ar- ylhydrazone molecule. It was shown that in the absence of substituents at both po- sitions, the C7 atom is the most active nu- cleophilic center. Acknowledgements The  authors are grateful to  the  Russian Foundation for Basic Research (grant 18-33-00727 mol_a) for financial support of the research. References 1. D’yakonov AL, Telezhenetskaya MV. Quinazoline alkaloids in  nature. Chem. Nat. Compd. 1997;33:221–267. DOI: 10.1007/BF02234869 2. Aniszewski T. Alkaloids (Second Edition). Helsinki: Elsevier Science, 2015. 496 p. 3. Asif M. Chemical Characteristics, Synthetic Methods, and Biological Potential of Quina- zoline and Quinazolinone Derivatives. Int. J. Med. Chem. 2014;ID 395637:1–27. DOI: 10.1155/2014/395637 4. Solyanik GI. Quinazoline compounds for antitumor treatment. Exp. Oncology. 2019;41:3–6. 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