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Abstract

The synthesis and characterization of substituted (trifluoromethoxy, thiomethyl, and methoxy) phenyl quinolines is described. Dichlorobis(triphenylphosphine)palladium(II)-catalyzed Suzuki–Miyaura cross-coupling of 6-bromo- and 6,8-dibromo-1,2,3,4-tetrahydroquinolines, 5-bromo-8-methoxyquinoline, and 5,7-dibromo-8-methoxyquinoline with substituted phenylboronic acids affords the corresponding 6-aryl- (13a–d), 6,8-diaryl- (14a–c), 5-aryl- (15), and 5,7-diaryl- (16b, c) tetrahydroquinolines and quinolines in high yields (68%–82%). The structures of all the products are characterized by ¹H NMR, ¹³C NMR,¹⁹F NMR, and Fourier transform infrared spectroscopy and by elemental analysis.

Keywords

aryl quinolines nuclear magnetic resonance spectroscopy quinolines substituted phenyls Suzuki–Miyaura cross-coupling tetrahydroquinolines

Introduction

Quinoline derivatives are found in many natural products¹ and synthetic drugs.² The quinoline scaffold has been used to develop compounds exhibiting a wide range of medicinal benefits,^3,4 such as anti-asthmatic, anti-inflammatory, antimalarial,⁴ anticancer,⁵ and antibiotic activity.⁶

Tetrahydroquinolines have an important position in synthetic organic chemistry due to the fact they possess high reactivity, a wide spectrum of chemical properties⁷ and form the basis of many bioactive natural substances^8–12 and potential drugs.^13,14

Halogenated tetrahydroquinoline derivatives are important initiators of progress in new methods for the development of medicinal chemistry. In the literature, the halogenation of 1,2,3,4-tetrahydroquinoline (1) is accomplished with halogens (bromine, chlorine, etc.), N-halosuccinimides, aqueous solutions of sodium chlorate and bromate, affording various halogen-substituted tetrahydroquinolines (Scheme 1) as key compounds and as precursors for numerous bioactive quinoline derivatives.¹⁵

Scheme 1.

Preparation of brominated tetrahydroquinolines (2 and 3) and quinolines (5 and 6).

Arylated quinolines were previously prepared by classic reactions, such as the Skraup, Doebner–Miller, Conrad–Limpach, Friedländer, and Pfitzinger syntheses.¹⁶ Arylated quinolines are also prepared by cross-coupling reactions and other transition-metal-catalyzed transformations.^17–19 For example, arylated quinolines were prepared by Suzuki–Miyaura coupling of arylboronic acids with haloaromatic compounds.²⁰ Although numerous studies on the transformation of haloquinolines into aryl quinolines are reported in the literature, there are fewer reports on the preparation of aryl tetrahydroquinolines. For example, Mphahlele et al. were interested in the palladium-catalyzed cross-coupling reactions of dihalogenoquinolines for the preparation of substituted tetrahydroquinolines and decided to investigate the synthesis of 2-aryl-6,8-dibromo-1,2,3,4-tetrahydroquinolines (8) (Scheme 2).^21–23 In other work, 5,7-diarylquinolines were prepared by Suzuki–Miyaura coupling of 5,7-dihalogenated quinolines.²⁴ Moreover, the synthesis of arylated quinolines was reported by Suzuki–Miyaura reactions of 5,7-dibromo-8-(trifluoromethylsulfonyloxy)quinoline (11) (Scheme 2).²⁵

Scheme 2.

Reported synthetic strategies toward arylated quinolines and tetrahydroquinolines.^21–23,25

In the literature, many studies on the pharmacological features of aryl-substituted quinolines have been reported. The 6- or 8-aryl substituted 2,4-dimethoxyquinolines were found to exhibit high activity against the agriculturally important nematode, Haemonchus contortus.²⁶ Furthermore, 2-phenyl-quinoline-4-carboxylic acid derivatives were found to have significant effects on antibacterial activity.²⁷ In other work on phenyl quinolines, 2-(4-phenylquinolin-2-yl)phenol derivatives produced significant anti-inflammatory, analgesic and antipyretic activities and demonstrated efficient inhibition of the COX-2 enzyme.²⁸ A number of substituted 2-phenylquinolines displayed superior ERβ affinity in a cell-based transcriptional assay,²⁹ potent antiplatelet activities,³⁰ antimitotic activity,^31–33 and antiproliferative activity against the growth of certain cancer cells such as HCT-116 (colon cancer), MCF7 (breast cancer), and MDA-MB-435 (breast cancer) with low GI₅₀ values.³⁴

Previously, we carried out the bromination of 1,2,3,4-tetrahydroquinoline (1)^15,35,36 with molecular bromine leading to the formation of polyfunctional quinoline derivatives, which was followed by transformation into their respective derivatives.^35,37–39 As an extension of the investigation of 1,2,3,4-tetrahydroquinoline (1) derivatives, we studied the regioselective bromination of methoxy-, cyano-, hydroxy-, and amino-substituted quinolines^38,40,41 with bromine under different conditions. The polyfunctional substituted quinolines were tested for their anticancer potentials and enzyme inhibition activities. It was found that substituted quinolines with different functional groups, especially 6,8-dibromo-1,2,3,4-tetrayhdroquinoline (3),⁴² 5,7-dibromo-8-methoxyquinoline (6),⁴³ 5,7-dibromo-8-hydroxyquinoline,⁴³ and 6,8-diphenylquinoline⁴⁴ had anticancer activities against HeLa (human cervix carcinoma), HT29 (human colon carcinoma), C6 (rat glioblastoma), and MCF7 (human breast adenocarcinoma) cell lines, and monophenyl-substituted quinolines showed inhibitory effects on AChE (acetylcholinesterase), BChE (butyrylcholinesterase), and carbonic anhydrase isoenzymes I and II (hCA I and II).²⁰

The promising anticancer activities of the analogous 6,8-dibromotetrahydroquinoline (3), 6,8-diphenylquinoline, and 5,7-dibromo-8-(hydroxy/methoxy)quinolines encouraged us to synthesize novel and potentially bioactive quinoline compounds. Based on our continued interest in the palladium-catalyzed cross-coupling reactions of bromoquinolines,⁴⁴ we herein describe the Suzuki–Miyaura cross-coupling reactions of 6-bromo- and 6,8-dibromo-1,2,3,4-tetrahydroquinolines (2 and 3), and 5-bromo- and 5,7-dibromo-8-methoxyquinolines (5 and 6) with substituted arylboronic acids to afford aryl-substituted tetrahydroquinoline and quinoline derivatives (Scheme 3).

Scheme 3.

Synthetic strategies toward arylated quinolines and tetrahydroquinolines in this study.

Results and discussions

Attempted Suzuki–Miyaura cross-coupling of 6-bromo-1,2,3,4-tetrahydroquinoline (2) with a mixture of unsubstituted phenyl or 4-substituted (4-methoxy-, 4-trifluoromethoxy-, and 4-thiomethylphenyl) phenylboronic acids (1.0 equiv.) and 2 M K₂CO₃ in dimethylformamide in the presence of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄) afforded 6-phenyl-, 6-(4-methylthio)phenyl-, 6-(4-trifluoromethoxy)phenyl-, and 6-(4-methoxy)phenyl-1,2,3,4-tetrahydroquinoline derivatives in high yields (68%–81%). 6-Phenyl-1,2,3,4-tetrahydroquinoline (13a)⁴⁵ and 6-(4-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroquinoline (13b)⁴⁶ were recent-ly reported and the published spectral data confirmed the data obtained in this study. Moreover, 6,8-dibromo-1,2,3,4-tetrahydroquinoline (3) was treated with the same phenylboronic acids under identical reaction conditions to give 6,8-diphenyl-, 6,8-bis[4-(methylthio)phenyl)-, and 6,8-bis(4-(trifluo-romethoxy)phenyl]-1,2,3,4-tetrahydroquinolines in yields of 80%, 82%, and 78%, respectively (Table 1).

Table 1.

The yields and melting points of 13a–d and 14a–c.

Product	X	Yield (%)	M.p. (°C)
13a	H	81
13b	H	73	55–57
13c	H	68	71–73
13d	H	76	82–84
14a		80	100–101
14b		78
14c		82	73–75

The structures of all substituted phenyl-containing compounds 13a–d were confirmed by ¹H and ¹³C NMR, Fourier transform infrared (FTIR), and elemental analysis. The ¹H NMR signals of coupled compounds 13a–d are similar to starting material 2 except for the aromatic phenyl signals. The aliphatic triplets in the ¹H NMR spectra of compounds 13a–d (3.39–3.35, ³J = 5.6 Hz and 2.88–2.83, ³J = 6.4 Hz; 3.37–3.33, ³J = 5.4 Hz and 2.86–2.81, ³J = 6.3 Hz; 3.36–3.32, ³J = 5.4 Hz and 2.85–2.81, ³J = 6.3 Hz; 3.35–3.31, ³J = 5.4 Hz and 2.85–2.81, ³J = 6.3 Hz, respectively) and aliphatic multiplet (2.02–1.94 ppm for all compounds 13a–d) belong to the characteristic H-2, H-4, and H-3 protons in the nitrogen-containing rings of the tetrahydroquinolines (Figure 1). Multiplets for the aryl H signals of the quinoline and phenyl scaffolds of 13a–d were observed in the range of 6.91–7.56 ppm. The H-7 protons of 13a–d gave doublet signals at about 6.55 ppm (Figure 1). Moreover, the singlets in the ¹H NMR spectra of 13c and 13d at 2.52 and 3.84 ppm, respectively, verified the attachment of the 4-(methylthio)phenyl and 4-(methoxy)phenyl groups at C-6 of the quinoline ring (Figure 1). In the ¹³C NMR spectra of compounds 13a–d, three aliphatic carbon resonances (approx. 22.2, 27.1, 42.0 ppm) in the sp³ region and ten aromatic carbon resonances are also in agreement with the suggested structures. Moreover, the signals at 122.5 (q, ²J_{C, F} = 260 Hz, OCF₃), 16.5 (SCH₃), and 55.6 (OCH₃) ppm are consistent with proposed structures 13b, 13c, and 13d, respectively. In the ¹⁹F NMR spectrum of 13b, a singlet at −58.2 ppm provided evidence for the 4-(trifluoromethoxy)phenyl at the C-6 position of the quinoline.

Figure 1.

¹H NMR spectra of 6-bromo-1,2,3,4-tetrahydroquinoline (2) (top; starting material) and the coupling derivatives 13a–d.

The ¹H NMR spectra of 14a–c showed the formation of diaryl (diphenyl, bis(4-trifluoromethoxy)phenyl, and bis(4-methylthio)phenyl) tetrahydroquinolines. The aliphatic triplets in the ¹H NMR spectra of compound 14a–c (approx. 3.32 (³J = 5.4 Hz) and 2.92 (³J = 6.3 Hz) ppm) and aliphatic multiplets (approx. 2.00 ppm) belong to the characteristic H-2, H-4, and H-3 protons in the nitrogen-containing ring of the tetrahydroquinolines. The ¹H NMR spectrum of compound 14a displayed multiplets for the aryl H signals of the quinoline and phenyl scaffolds in the range of 7.26–7.62 ppm while the aryl protons of 14c gave multiplet signals at higher field (7.15–7.48 ppm) due to the electron-rich feature of the methylthio group. Moreover, the two singlets in the spectrum of 11c at 2.50 and 2.53 ppm and the appearance of two singlets in the ¹⁹F NMR spectrum of 14b at −58.2 and −58.3 ppm indicated the attachment of the 4-(methylthio)phenyl and 4-(trifluoromethoxy)phenyl groups, respectively, at the C-6 and C-8 positions of the quinoline ring.

The high reactivities of 13a–d and 14a–c toward halogenation should enable them to act as valuable precursors for novel compounds used in a wide range of applications. Our recent publications showed that cyano-³⁸ and methoxy-substituted⁴¹ tetrahydroquinolines underwent further bromination to give 3-brominated aromatic derivatives. 6-Aryl-8-bromotetrahydroquinoline and 6-aryl-3,8-dibromoquinoline derivatives can be obtained by bromination of 6-aryltetrahydroquinolines 13a–d in two steps by our developed methods.^15,35,47 Also, these arylbromoquinolines can be transformed into substituted quinolines bearing different substituents by exchanging the bromine atom with different functional groups via metal-catalyzed substitution^35,48 or coupling reactions.²⁰ Therefore, substituted quinolines bearing three different groups at C-3, C-5, and C-8 can be synthesized.

In our previous publication,⁴⁰ the direct bromination of 8-methoxyquinoline was reinvestigated and treatment of 8-methoxyquinoline with different equivalents of molecular bromine afforded 5-bromo-8-methoxyquinoline (5) and 5,7-dibromo-8-methoxyquinoline (6). In this study, compounds 5 and 6 were reacted with substituted phenylboronic acids via Suzuki–Miyaura cross-coupling reactions. These reactions furnished 8-methoxy-5-(4-(trifluoromethoxy)phenyl]quinoline (15), 8-methoxy-5,7-bis[4-(trifluoromethoxy)phenyl)quinoline (16a) and 8-methoxy-5,7-bis(4-(methylthio)phenyl) (16b) in good yields (70%–85%) (Table 2).

Table 2.

The yields and melting points of 15 and 16a,b.

Product	Ar¹	Yield (%)	M.p. (°C)
15	H	73	80–82
16a		70	–
16b		85	172–174

The ¹H and ¹³C NMR, IR, and elemental analysis supported the assignment of compounds 15 and 16a,b containing substituted phenyl groups. The ¹H NMR spectrum of 15 indicated the presence of an OCH₃ signal at 4.08 ppm, a characteristic doublet of doublets at 8.92 ppm (³J = 3.9 Hz, ⁴J = 1.8 Hz) corresponding to H-2, two doublets at 8.13 (³J = 8.4 Hz, H-4) and 7.06 (³J = 8.4 Hz, H-7) ppm, and six aromatic protons as a multiplet at 7.28–7.42 ppm. Moreover, in the ¹⁹F NMR spectrum of 15, the singlet appearing at −58.2 ppm was consistent with the proposed structure. These data led to the assignment of 15 as 8-methoxy-5-(4-(trifluoromethoxy)phenyl)quinoline. In the ¹H NMR spectrum of 16a, a characteristic doublet of doublets at 9.00 ppm (³J = 4.2 Hz, ⁴J = 1.5 Hz) corresponding to H-2, a doublet at 8.23 ppm (³J = 8.4 Hz) belonging to H-4, another doublet of doublets at 7.45 ppm (³J = 8.4 Hz, ³J = 4.2 Hz, H-3), a singlet due to OCH₃ at 3.87 ppm and the aromatic signals at 7.32–7.39 (m, 4H), 7.52 (d, ³J = 9.6 Hz, 3H), and 7.77 (d, ³J = 8.7 Hz, 2H) ppm were consistent with the proposed structure. Similarly, the assignment of 16b as 8-methoxy-5,7-bis(4-(methylthio)phenyl]quinoline was based on its ¹H NMR spectral data, which included two thiomethyl singlets at 2.54 and 2.56 ppm, a methoxy signal at 3.89 ppm and twelve aromatic proton signals.

Conclusion

In conclusion, we have demonstrated that the Suzuki–Miyaura cross-coupling of 6-bromo-1,2,3,4-tetrahydroquinoline, 6,8-dibromo-1,2,3,4-tetrahydroquinoline, 5-bromo-8-methoxyquinoline, and 5,7-dibromo-8-methoxyquinoline with substituted phenylboronic acids occurs without selectivity to afford the corresponding 6-aryl- (13a–d), 6,8-diaryl- (14a–c), 5-aryl (15), and 5,7-diaryl- (16a,b) tetrahydroquinolines and quinolines in a single-pot reaction. The aryl-substituted tetrahydroquinolines 13a–d and 14a–c could be important starting materials for the synthesis of polyfunctionalized quinoline derivatives due to their high reactivity toward further bromination.^38,41 Studies are currently underway in our laboratory to investigate the reactivity and biological properties of the synthesized aryl-substituted quinolines.

Experimental

General

All the reagents and solvents were commercially available. Thin-layer chromatography was carried out on Merck silica F₂₅₄ 0.255 mm plates, and spots were visualized by UV fluorescence at 254 nm. Classic column chromatography was performed using Merck 60 (70–230 mesh) silica gel. Melting points were determined on a Thomas–Hoover capillary melting point apparatus. Solvents were concentrated under reduced pressure. NMR spectra were recorded on an Oxford Instruments Varian at 300 MHz for ¹H NMR, at 75 MHz for ¹³C NMR, and at 282 MHz for ¹⁹F NMR. IR spectra were recorded on a Bruker Vertex 70v FTIR instrument. Elemental analyses were recorded on an ElementarVario MICRO Cube instrument. The NMR spectrums of all compounds are presented as Supplemental material.

One-pot Suzuki cross-coupling; general procedure

To a solution of bromotetrahydroquinoline or bromoquinoline 2, 3, 5 or 6 (1.0 equiv.) in 1,4-dioxane (30 mL) in a two-necked flask was added aq K₂CO₃ (3.0 M, 15 mL) and the mixture was stirred for 10 min at room temperature under an N₂ atmosphere. Pd(PPh₃)₄ (0.05 equiv.) and the unsubstituted or 4-substituted phenylboronic acid (1.3 equiv. for monobromides, 2.6 equiv. for dibromides) were added. The mixture was refluxed for 4 h at 90 ºC. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with H₂O and extracted with CHCl₃ (3 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane/EtOAc) to afford the product.

6-Phenyl-1,2,3,4-tetrahydroquinoline ( 13a ): Yellow oil, yield 81% (0.40 g), R_f = 0.41 (6:1, hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃): δ 1.58 (br s, 1H, NH), 1.99–2.03 (m, 2H, H3), 2.86 (t, ³J = 6.4 Hz, 2H, H4), 3.37 (t, ³J = 5.6 Hz, 2H, H2), 6.57 (d, ³J = 7.6 Hz, 1H, H7), 7.25–7.56 (m, 7H). ¹³C NMR (100 MHz, CDCl₃): δ 22.2, 27.1, 42.0, 114.4, 121.6, 125.5, 125.9, 126.3 (2C), 128.2, 128.6 (2C), 129.9, 141.5, 144.3. FTIR (cm⁻¹): 3432, 3023, 2945, 2921, 2832, 1597, 1483, 1434, 1359, 1331, 1287, 1201, 1185, 1128, 1100, 1073, 1025, 894, 861, 765, 699, 594, 575, 524, 498, 454. Anal. calcd for C₁₅H₁₅N (209.12): C, 86.08; H, 7.22; N, 6.69; found: C, 86.24; H, 7.13; N, 6.62.

6-(4-(Trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroquinoline ( 13b ): Brown solid, yield 73% (0.26 g), m.p. 55–57 °C. R_f = 0.43 (6:1, hexane/EtOAc). ¹H NMR (300 MHz, CDCl₃): δ 1.95–2.02 (m, 2H, H3), 2.84 (t, 2H, ³J = 6.3 Hz, H2), 3.35 (t, ³J = 5.4 Hz, 2H, H4), 3.63 (s, 1H, NH), 6.55 (d, ³J = 9.0 Hz, 1H, H7), 7.19–7.26 (m, 4H), 7.49–7.55 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 22.3, 27.4, 42.2, 114.6, 119.1, 121.4 (2C), 121.8, 122.5 (q, ²J_{C, F} = 260 Hz, OCF₃), 125.7, 127.6 (2C), 128.4, 128.6, 140.5, 144.9. ¹⁹F NMR (282 MHz, CDCl₃): δ −58.2. FTIR (cm⁻¹): 3450, 2953, 2836, 1610, 1526, 1493, 1443, 1402, 1358, 1214, 1133, 1009, 922, 897, 845, 804, 664, 610, 579, 523, 430. Anal. calcd for C₁₆H₁₄F₃NO (293.10): C, 65.52; H, 4.81; N, 4.78; found: C, 65.54; H, 4.83; N, 4.82.

6-(4-(Methylthio)phenyl]-1,2,3,4-tetrahydroquinoline ( 13c ): Brown needles, yield 68% (0.20 g), m.p. 71–73 °C. R_f = 0.25 (8:1, hexane/EtOAc). ¹H NMR (300 MHz, CDCl₃): δ 1.94–2.02 (m, 2H, H3), 2.52 (s, 3H, SCH₃), 2.83 (t, 2H, ³J = 6.3 Hz, 2H, H2), 3.34 (t, ³J = 5.4 Hz, 2H, H4), 3.70 (s, 1H, NH), 6.54 (d, ³J =9.3 Hz, 1H, H7), 7.20–7.32 (m, 4H), 7.45–7.48 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 16.5 (SCH₃), 22.4, 27.4, 42.2, 114.8, 121.9, 125.5, 126.9 (2C), 127.5 (2C), 128.1, 129.5, 135.8, 138.8, 144.3. FTIR (cm⁻¹): 3308, 3030, 2944, 2924, 2837, 1612, 1585, 1522, 1487, 1438, 1419, 1360, 1327, 1310, 1292, 1268, 1260, 1245, 1180, 1143, 1093, 1075, 1007, 952, 908, 827, 801, 724, 691, 603, 572, 505. Anal. calcd for C₁₆H₁₇NS (255.11): C, 75.25; H, 6.71; N, 5.48; found: C, 75.34; H, 6.73; N, 5.52.

6-(4-Methoxyphenyl)-1,2,3,4-tetrahydroquinoline ( 13d ): Yellow solid, yield 76% (0.40 g), m.p. 82–84 °C. R_f = 0.38 (8:1, hexane/EtOAc). ¹H NMR (300 MHz, CDCl₃): δ 1.94–2.02 (m, 2H, H3), 2.83 (t, 2H, ³J = 6.3 Hz, 2H, H2), 3.33 (t, ³J = 5.4 Hz, 2H, H4), 3.84 (s, 3H, OCH₃), 6.54 (d, ³J = 8.7 Hz, 1H, H7), 6.91–6.96 (m, 2H), 7.17–7.20 (m, 2H), 7.43–7.48 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 22.5, 27.4, 42.3, 55.6 (OCH₃), 114.3, 114.8, 121.9, 125.4, 127.5 (2C), 128.1, 130.0, 134.5, 144.0, 158.4. FTIR (cm⁻¹): 3337, 3300, 2943, 2928, 2834, 1608, 1494, 1463, 1297, 1272, 1238, 1179, 1040, 1021, 900, 822, 785, 725, 559, 525, 453. Anal. calcd for C₁₆H₁₇NO (239.13): C, 80.30; H, 7.16; N, 5.85; found: C, 80.34; H, 7.13; N, 5.82.

6,8-Diphenyl-1,2,3,4-tetrahydroquinoline ( 14a ): White solid, yield 80% (1.25 g), m.p. 100–101 °C. R_f = 0.51 (6:1, hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃): δ 2.02–2.06 (m, 2H, H3), 2.96 (t, ³J = 6.0 Hz 2H, H2), 3.33 (t, ³J = 6.0 Hz, 2H, H4), 4.14 (s, 1H, NH), 7.26–7.62 (m, 12H). ¹³C NMR (100 MHz, CDCl₃): δ 22.0, 27.7, 42.1, 121.6, 126.0, 126.3 (2C), 126.8, 126.9, 127.2, 127.5, 128.6 (2C), 128.8, 128.9 (2C), 129.2, 129.4 (2C), 139.5, 141.3. FTIR (cm⁻¹): 3322, 3044, 2939, 2843, 2722, 1594, 1498, 1472, 1363, 1301, 1225, 1167, 1152, 1071, 1024, 1000, 886, 827, 810, 752, 691, 618, 594, 531, 508, 456. Anal. calcd for C₂₁H₁₉N (285.15): C, 88.38; H, 6.71; N, 4.91; found: C, 88.34; H, 6.73; N, 4.87.

6,8-Bis(4-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroquinoline ( 14b ): Light brown oil, yield 78% (0.53 g), R_f = 0.40 (9:1, hexane/EtOAc). ¹H NMR (300 MHz, CDCl₃): δ 1.97–2.01 (m, 2H, H3), 2.92 (t, ³J = 6.3 Hz, 2H, H2), 3.32 (t, ³J = 5.4 Hz, 2H, H4), 4.10 (br s, 1H, NH), 7.14–7.34 (m, 6H), 7.48–7.57 (m, 4H). ¹³C NMR (75 MHz, CDCl₃): δ 22.1, 27.9, 42.8, 119.3 (q, ²J_{C, F} = 264.8 Hz, OCF₃), 121.5 (2C), 121.8 (2C), 122.2, 122.7, 125.8, 127.0, 127.6 (2C), 128.1, 128.2, 129.1, 130.2 (2C), 138.4, 140.3, 141.8, 148.0, 148.8. ¹⁹F NMR (282 MHz, CDCl₃): δ −58.2, −58.3. FTIR (cm⁻¹): 3433, 2935, 2843, 1605, 1493, 1470, 1449 1339, 1247, 1203, 1158, 1104, 1018, 921, 844, 806, 679, 652, 543. Anal. calcd for C₂₃H₁₇F₆NO₂ (453.12): C, 60.93; H, 3.78; N, 3.09; found: C, 60.84; H, 3.73; N, 3.05.

6,8-Bis(4-(methylthio)phenyl]-1,2,3,4-tetrahydroquinoline ( 14c ): Yellow cubic, yield 82% (1.06 g), m.p. 73–75 °C. R_f = 0.45 (6:1, hexane/EtOAc). ¹H NMR (300 MHz, CDCl₃): δ 1.57 (br s, 1H, NH), 1.95–2.03 (m, 2H, H3), 2.50 (s, 3H, SCH₃), 2.53 (s, 3H, SCH₃), 2.90 (t, ³J = 6.3 Hz, 2H, H2), 3.27 (t, ³J = 5.4 Hz, 2H, H4), 7.15–7.48 (m, 10H). ¹³C NMR (75 MHz, CDCl₃): δ 16.0, 16.4, 22.1, 27.8, 42.3, 122.2, 126.7, 126.9 (2C), 127.1 (2C), 127.4 (2C), 127.5, 129.1, 130.1 (2C), 136.0, 136.1, 137.8, 138.4, 141.1. FTIR (cm⁻¹): 3415, 2950, 2921, 2810, 1599, 1512, 1486, 1433, 1331, 1291, 1252, 1186, 1086, 1012, 961, 886, 813, 750, 721, 532, 507, 474, 439. Anal. calcd for C₂₃H₂₃NS₂ (377.13): C, 73.17; H, 6.14; N, 3.71; found: C, 73.24; H, 6.10; N, 3.75.

8-Methoxy-5-(4-(trifluoromethoxy)phenyl)quinoline ( 15 ): Brown solid, yield 73% (0.24 g), m.p. 80–82 °C. R_f = 0.41 (3:1, hexane/EtOAc). ¹H NMR (300 MHz, CDCl₃): δ 4.08 (s, 3H, OCH₃), 7.06 (d, ³J = 8.4 Hz, 1H, H7), 7.28–7.42 (m, 6H), 8.13 (d, ³J = 8.4 Hz, 1H, H4), 8.92 (dd, ⁴J = 1.8 Hz, ³J = 3.9 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃): δ 56.3, 107.2, 119.0, 121.2 122.0 122.4, 127.7, 130.8, 131.2 (2C), 134.2, 138.3, 140.3, 148.7, 149.4, 155.3. ¹⁹F NMR (282 MHz, CDCl₃): δ −58.2. FTIR (cm⁻¹): 3064, 2966, 2943, 2841, 1575, 1509, 1469, 1440, 1370, 1256, 1204, 1159, 1109, 1021, 996, 917, 859, 813, 782, 720, 669, 639, 595, 539, 491. Anal. calcd for C₁₇H₁₂F₃NO₂ (319.08): C, 63.95; H, 3.79; N, 4.39; found: C, 63.74; H, 3.90; N, 4.25.

8-methoxy-5,7-bis(4-(trifluoromethoxy)phenyl]quinoline ( 16a ): Yellow oil, yield 70% (0.21 g). R_f = 0.38 (3:1, hexane/EtOAc). ¹H NMR (300 MHz, CDCl₃): δ 3.87 (s, 3H, OCH₃), 7.32–7.39 (m, 4H), 7.45 (dd, ³J = 8.4 Hz, ³J = 4.2 Hz, 1H, H3), 7.52 (d, ³J = 9.6 Hz, 3H), 7.77 (d, ³J = 8.7 Hz, 2H), 8.23 (d, ³J = 8.4 Hz, 1H, H4), 9.00 (dd, ⁴J = 1.5 Hz, ³J = 4.2 Hz, 1H, H2). ¹³C NMR (75 MHz, CDCl₃): δ 62.3, 116.6, 119.0 (q, ²J_{C, F} = 256.5 Hz, OCF₃), 121.1 (2C), 121.4 (2C), 121.9, 122.4, 122.7, 127.7, 130.0, 131.2 (2C), 131.6 (2C), 132.2, 136.5, 137.7, 143.2, 149.0, 149.2, 150.2, 153.2. ¹⁹F NMR (282 MHz, CDCl₃): δ −58.1, −58.2. FTIR (cm⁻¹): 2917, 2848, 1742, 1601, 1510, 1462, 1392, 1354, 1249, 1207, 1162, 1105, 1077, 1019, 990, 922, 881, 847, 797, 714, 678, 612, 591, 565, 530. Anal. calcd for C₂₄H₁₅F₆NO₃ (479.10): C, 60.13; H, 3.15; N, 2.92; found: C, 60.24; H, 3.10; N, 2.95.

8-Methoxy-5,7-bis(4-(methylthio)phenyl)quinoline ( 16b ): Yellow solid, yield 85% (0.14 g), m.p. 172–174 °C. R_f = 0.51 (6:1, hexane/EtOAc). ¹H NMR (300 MHz, CDCl₃): δ 2.54 (s, 3H, SCH₃), 2.56 (s, 3H, SCH₃), 3.89 (s, 3H, OCH₃), 7.34–7.42 (m, 7H), 7.52 (s, 1H, H6) 7.68 (d, ³J = 8.4 Hz, 2H), 8.24 (dd, ³J = 8.7 Hz, ⁴J = 1.5 Hz, 1H, H4), 9.00 (dd, ⁴J = 1.5 Hz, ³J = 3.9 Hz, 1H, H2). ¹³C NMR (75 MHz, CDCl₃): δ 15.9, 16.0, 62.2, 121.4, 126.4 (2C), 126.7 (2C), 127.5, 129.7, 130.1 (2C), 130.7 (2C), 132.7, 134.7, 134.8, 135.6, 136.0, 138.2, 138.4, 143.6, 150.1, 152.7. FTIR (cm⁻¹): 3023, 2920, 2835, 1904, 1596, 1492, 1454, 1427, 1380, 1340, 1267, 1222, 1189, 1077, 989, 960, 924, 823, 805, 727, 695, 509, 484, 437. Anal. calcd for C₂₄H₂₁NOS₂ (403.11): C, 71.43; H, 5.25; N, 3.47; found: C, 71.28; H, 5.20; N, 3.55.

Supplemental Material

Supplementary_Material_ – Supplemental material for Synthesis of aryl-substituted quinolines and tetrahydroquinolines through Suzuki–Miyaura coupling reactions

Supplemental material, Supplementary_Material_ for Synthesis of aryl-substituted quinolines and tetrahydroquinolines through Suzuki–Miyaura coupling reactions by Salih Ökten in Journal of Chemical Research

Footnotes

Acknowledgements

The author is thankful to research assistant Yavuz Derin for his assistance in isolation of compounds.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by grants from the Scientific and Technological Research Council of Turkey (TUBITAK; project number: 112T394).

ORCID iD

Salih Ökten

Supplemental material

Supplemental material for this article is available online.

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