Synthesis and Anticancer Activity of 3,4-Diaryl-1,2-dihydro- and 1,2,3,4-Tetrahydroquinolines

Abstract

Tetrahydroquinolines are key structures in a variety of natural products with diverse pharmacological utilities and other applications. A series of 3,4-diaryl-5,7-dimethoxy-1,2,3,4-tetrahydroquinolines were synthesized in good yield by reacting 3-aryl-5,7-dimethoxy-2,3-dihydroquinolin-4-ones with different Grignard reagents followed by the dehydration of the intermediate phenolic compounds. Subsequent reduction and deprotection were carried out to achieve the desired tetrahydroquinolone moiety. The lead compound 3c showed low micromolar inhibition of various cancer cell lines. Demethylation under different reaction conditions was also investigated to afford the corresponding monohydroxy analogues.

1. Introduction

Quinolones and their derivatives occur in numerous natural products, and many of them display interesting biological activities. In particular, hydrogenated quinoline moieties are important structures in various natural products that exhibit a broad range of biological properties and potential pharmaceutical applications [1].

Rapid development in the chemistry of tetrahydroquinolines has been observed in recent years, because they are core structures in many important pharmacological agents [2] and drug molecules, such as antiarrhythmic and cardiovascular agents, anticancer drugs, and immunosuppressants, and ligands for 5-HTTA and NMDA receptors [3]. Besides their pharmaceutical applications, tetrahydroquinoline derivatives are useful as pesticides [4,5], antioxidants [6,7,8], and corrosion inhibitors [9] and are active components of various dyes [10,11]. In addition, they also have found application in modern recording technologies [12,13].

Many relatively simple 1,2,3,4-tetrahydroquinolines have been tested as potential drugs. Amongst them are oxamniquine, a schistosomicide [14,15,16], virantmycin, a novel antibiotic [17,18,19], and nicainoprol, an antiarrhythmic drug [20,21,22]. Tetrahydroquinolin L-689560 is also one of the most potent NMDA antagonists yet found [23,24,25].

Several compounds of this class are found to occur in nature. For example, discorhabdin C, a polycyclic system based on tetrahydroquinoline, is a marine alkaloid [2,26,27] and dynemicin A, a natural antitumor antibiotic, has a complex structure built on the tetrahydroquinoline nucleus [28,29]. A 2,4,6-trisubstituted tetrahydroquinoline, isolated from Martinella iquitosensis, exhibits activity as a bradykinin antagonist against α-adrenergic and histaminergic receptors [30].

2-Substituted tetrahydroquinolines have also recently been discovered as a class of natural products, that includes angustureine, cuspareine, oxamniquine, and galipeine. Some members of this family exhibit interesting pharmacological properties [31].

The dihydroquinolone structure can be found in a variety of natural products [32,33] and in a large number of compounds, which display biological activity. For example, 2,2,4-trisubstituted-1,2-dihydroquinolines have been used to produce potent compounds that possess antibacterial, antidiabetic, and anti-inflammatory activities [34]. Compounds possessing this motif have also been shown to act as lipid peroxidation inhibitors, 4 HMG-CoA reductase inhibitors, ileal bile acid transporter inhibitors, and progesterone agonists and antagonists [34].

Due to the diverse biological activities exhibited by this class of compounds, we were interested in synthesizing dihydrogenated and tetrahydrogenated derivatives of quinolines. It was envisaged that these hydrogenated compounds would show promising biological activities, due to the pharmacological applications shown by the isoflavone class of compounds. The isoflavone analogue triphendiol 1 (Figure 1) has recently been granted orphan drug status by the FDA for pancreatic and bile duct cancers and late-stage melanoma. Inspired by the success of triphendiol 1 it was decided to introduce an aryl group at the C4 position of the 3-substituted quinolone ring system and keep the oxygenation pattern similar to that of natural isoflavones to generate azaisoflavene 2 and azaisoflavan 3 structures. Furthermore, many biologically active isoflavones suffer from poor oral bioavailability and rapid CYP450 metabolism [35,36]. Our objective in this study was to synthesize biologically active tetrahydroquinolines with improved solubility and metabolic stability compared to current isoflavone analogues. The biological activity of the tetrahydroquinolines was investigated through a single concentration screen in different cancer cell lines.

2. Results and Discussion

The project mainly involved the synthesis of a series of 3,4-diaryl-5,7-dimethoxy 1,2-dihydro and 1,2,3,4-tetrahydroquinolines. Various demethylating conditions were investigated in order to obtain the corresponding hydroxyl analogues, which could possibly show greater biological activity.

2.1. Attempted Synthesis of 3,4-Diaryl-1,2-dihydroquinolines by Nucleophilic Addition

It was envisaged that 3,4-diarylazaisoflavenes 2 could be obtained by the nucleophilic addition of aryl groups to the carbonyl group of 2,3-dihydroquinolin-4-ones to give the corresponding 3,4-diarylazaisoflavan-4-ols, which subsequently could undergo dehydration to give the desired target compounds.

For this, 3-substituted-5,7-dimethoxy-2,3-dihydroquinolin-4(1H)-one 4 was treated with arylmagnesium bromide in THF at reflux for 4 h to give 3,3-diaryl-5,7-dimethoxy-1,2,3,4-tetrahydroquinolin-4-ols 5 in 72–77% yield. The intermediate 5a was characterized by its ¹H NMR spectrum, which showed two doublets of doublets at δ 3.12 and 3.24 ppm (J = 3.0, 9.0 Hz) corresponding to the two H2 protons. The H3 proton appeared as a multiplet at δ 3.46 ppm. The OH group was seen as a singlet at δ 3.79 ppm and the phenyl ring protons appeared as a multiplet at δ 7.11–7.20 ppm.

The acid-catalyzed dehydration of 5 did not result in the formation of the desired 3,4-diaryl-1,2-dihydroquinoline 2 but was found to preferentially generate the more highly stabilized 3,4-diaryl-5,7-dimethoxyquinoline 6 in 54–66% yield instead (Scheme 1). The formation of the quinoline moiety can be attributed to further dehydrogenation presumably due to aerial oxidation, occurring together with the dehydration reaction. The quinoline structure was confirmed by ¹H NMR spectroscopy, which showed the disappearance of the aliphatic protons H2 and H3 present in 5. The presence of a significantly downfield shifted singlet at δ 8.75 ppm in 6 correlating to H2 was the key resonance signal for the identification of compound 6.

This result was found to be consistent with literature reports [37,38], which state that 1,2-dihydroquinolines that are unsubstituted at the nitrogen atom and have at least one hydrogen at C2 are unstable. These dihydroquinolines are rapidly oxidized in air to the quinoline or undergo disproportionation by trace acids to give a mixture of the quinoline and tetrahydroquinoline.

To overcome this problem, it was decided to protect the NH group and then perform the Grignard reaction on the N-protected dihydroquinolin-4-ones to give the corresponding N-protected azaisoflavan-4-ol, followed by dehydration and deprotection to give the desired 3,4-diaryl-azaisoflavenes 2.

Hence, compound 7 was heated at reflux for 4 h with aryl magnesium bromide. This reaction gave a mixture of 3,4-diaryl-5,7-dimethoxy-1,2,3,4-tetrahydroquinolin-4-ol 5 and ethyl-3,4-diaryl-4-hydroxy-5,7-dimethoxy-3,4-dihydroquinoline-1(2H)-carboxylate 8. The ratio of 5 to 8 was found to be dependent upon the reaction conditions. The use of three equivalents of arylmagnesium bromide afforded 5 and 8 in 30% and 50% yield, respectively, whereas the use of two equivalents of arylmagnesium bromide gave only 8 in 78–88% yield. The structure of compound 8 was confirmed by ¹H NMR spectroscopy data. Compound 8a showed the presence of the COOEt group as a triplet and a quartet at δ 1.19 ppm (J = 6.0 Hz) and 4.15 ppm (J = 6.0 Hz) for the CH₃ and CH₂ groups, respectively. The OH proton was present as a singlet at δ 5.04 ppm and the phenyl ring protons as a multiplet at δ 7.07–7.14 ppm. The ¹H NMR data indicate that 8 was formed as a single diastereomer. Due to the presence of an aryl substituent at the C3 position, we assume that the Grignard reagent attacks the planar carbonyl group from the opposite side to the aromatic ring.

The acid-catalyzed dehydration of 8 with BF₃.OEt₂ in DCM resulted in the formation of ethyl 3,4-diaryl-5,7-dimethoxy-quinoline-1(2H)-carboxylate 9 in 52–58% yield. The structure of compound 9 was also confirmed by ¹H NMR spectroscopy data. Compound 9a indicated the disappearance of the H3 proton and the appearance of a singlet at δ 4.54 ppm integrating for two protons, correlating to H2 and a triplet at δ 1.29 ppm (J = 9.0 Hz) and quartet at δ 4.24 ppm (J = 9.0 Hz) indicating the presence of the protecting group, -COOEt.

Subsequent deprotection of 9 was investigated using both acidic and basic conditions under an inert atmosphere. When HBr in AcOH [39] was utilized, 9 underwent dehydrogenation in addition to deprotection, giving the more stable quinoline moiety 6. Alternatively, heating 9 at reflux with 10% NaOH in EtOH for 5 h generated a mixture of two compounds by TLC (Scheme 2). Separation of these two compounds was attempted using various methods, such as column chromatography, crystallization, and preparative TLC, but was ultimately unsuccessful. When the crude mixture was analyzed using ¹H NMR spectroscopy, it was found to contain compounds 2 and 6 in an approximate ratio of 30:70. The presence of compound 2 was confirmed by the DEPT-135 NMR experiment, which showed the presence of a CH₂ at δ 47.5 ppm.

Therefore, the proposed synthesis of 3,4-diaryl-5,7-dimethoxy-1,2-dihydroquinoline 2 could not be accomplished via the methodologies used in this project. Instead, the more stable quinoline derivatives 6 were prepared in similar yields using the two strategies outlined in Scheme 1 and Scheme 2.

2.2. Synthesis of 3,4-Diaryl-1,2,3,4-tetrahydroquinolines

The literature indicates that direct reduction of quinolines is the most efficient method of preparing tetrahydroquinolines [40]. Direct reduction of the 2,3-dihydroquinolin-4-ones is also possible [41,42,43], but this would lead to a C4-unsubstituted product. Hence, attempts were made to reduce the quinoline 6 to 3,4-diaryl-tetrahydroquinoline 3 directly by applying two different reduction conditions. The first one involved heating the quinoline 6 with LAH at reflux and the second involved catalytic hydrogenation with hydrogen over palladium on charcoal. However, both reaction conditions gave multiple spots by TLC, which could not be separated to allow successful identification of the compounds formed.

In another approach, it was decided to reduce the N-substituted 3,4-diarylazaisoflavenes 9 to N-substituted 3,4-diaryl-tetrahydroquinolines 10 and then investigate the deprotection of 10 to synthesize the 3,4-diaryl tetrahydroquinoline 3.

For instance, ethyl-3,4-diaryl-5,7-dimethoxy-quinoline-1(2H)-carboxylate 9 was hydrogenated in THF using Pd/C and hydrogen gas overnight to give ethyl-3,4-diaryl-5,7-dimethoxy-3,4-dihydroquinoline-1(2H)-carboxylate 10 in 91–95% yield (Scheme 3). The structure of compound 10 was confirmed by ¹H NMR spectroscopy data. Compound 10 showed a doublet of a triplet for the H3 proton at δ 3.36 ppm (J = 3.0, 12.0 Hz) and a doublet for the H4 proton at δ 4.45 ppm (J = 3.0 Hz) and triplet at δ 3.67 ppm (J = 12.0 Hz) and a doublet of doublet of doublet at δ 4.09 ppm (J = 3.0, 6.0, 12.0 Hz) for two H2 protons.

The expected cis stereochemistry of the compound 10 was established on the basis of the coupling constant of J = 3.0 between H3 and H4. Moreover, NOE correlations between the H3 and H4 protons were evident in the 2D NMR experiment, further confirming the cis configuration (Figure 2 and Figure S11).

The deprotection of compound 10 was carried out by heating at reflux in 10% NaOH in EtOH for 6 h to give the desired 5,7-dimethoxy-3,4-diaryl-1,2,3,4-tetrahydroquinolines 3 in 82–90% yield. The structure of 3 was confirmed by the lack of protons correlating to the –COOEt group in the ¹H NMR spectrum and the presence of a NH proton as a singlet at δ 4.14 ppm. The coupling constant between H3 and H4 protons (J = 3.0 Hz) indicated the cis configuration had been retained, and this was further confirmed by X-ray crystallographic analysis. The ORTEP diagram of compound 3c is shown in Figure 3. Packing of molecules was dominated by CH₃–π and slipped π–π interactions (Figure S1).

Using this approach, some 3,4-diaryl-5,7-dimethoxytetrahydroquinoline analogues (

Table 1. Analogues of 3,4-diaryl-5,7-dimethoxy-1,2,3,4-tetrahydroquinolines.

Entry	R	Ar	Yield (%)
3b	4-OMe	4-OMeC6H4	82
3c	4-OMe	Ph	87
3d	4-OMe	4-tBuC6H4	90
3e	4-OMe	4-MeC6H4	87
3f	H	Ph	86
3g	H	4-MeC6H4	91

) were synthesized and their spectroscopic data were found to be consistent with those of compounds 3c.

2.3. Demethylation of 3,4-Diaryl-5,7-dimethoxy-1,2,3,4-tetrahydroquinolines

After synthesizing the dimethoxy-substituted tetrahydroquinolines, the subsequent aim was to investigate suitable demethylation conditions to generate the hydroxyl analogues.

Initially, tetrahydroquinoline 3c was heated at reflux with aluminum chloride in chlorobenzene for 1 h. Two compounds were obtained after aqueous work up and column chromatography. However, only one compound was pure enough to be characterized as 12 in 13% yield (Scheme 4). The reaction with AlCl₃ therefore resulted in subsequent aromatization and dearylation in addition to demethylation.

The second compound that was obtained from this reaction is hypothesized to be 11c, however, its purity was very poor and decomposed during purification. Meanwhile, the ¹H NMR spectrum of compound 12 lacked the phenyl group protons at C4 in addition to the methoxy protons. Three signals as a singlet corresponding to the hydroxyl protons were present at δ 9.40, 9.69, and 10.26 ppm, which confirmed that the demethylation had occurred. Doublets at δ 8.19 ppm and 8.75 ppm (J = 2.4 Hz) for H3 and H4 indicated that aromatization had occurred. The structure of compound 12 was further confirmed by HRMS, giving a molecular ion peak [M + H]⁺ at 254.0805 corresponding to the molecular formula.

To improve the yield and the purity of the dihydroxy analogues, BBr₃ in DCM was examined as an alternate demethylating agent. According to the previous results, two equivalents of BBr₃ were required for the cleavage of one methoxy group. Hence, the same strategy was applied and tetrahydroquinoline 3e was stirred with seven equivalents of BBr₃ in DCM at room temperature for 1 h (Scheme 5). However, the product of this reaction could not be purified even after several attempts. This could possibly be due to the presence of three hydroxyl groups in compound 11 rendering the compound significantly unstable. Therefore, it was decided to demethylate tetrahydroquinoline 3f, which has only two methoxy groups, with five equivalents of BBr₃ in DCM at room temperature for 1 h (Scheme 5). However, purification of compound 11f proved to be similarly problematic and pure spectra of the product could not be obtained.

In an attempt to improve the purity of the hydroxyl compounds, the number of equivalents of BBr₃ was reduced. Tetrahydroquinoline 3f was stirred with three equivalents of BBr₃ in DCM for 1 h. Work up and purification with column chromatography resulted in a 38% yield of compound 13f (Scheme 6,

Table 2. Hydroxy analogues of tetrahydroquinolines.

Entry	R	Ar	Yield (%)
13d	OH	4-tBuC6H4	30
13f	H	Ph	38
13g	H	4-MeC6H4	32

). The ¹H NMR spectrum of compound 13f still showed the presence of a methoxy group at δ 3.69 ppm and only one hydroxyl group was evident at δ 7.78 ppm. To confirm the structure of this compound a NOE experiment was performed, which showed a correlation between the methoxy and the H6 and H8 protons while the hydroxy signal only correlated to the H6 proton. This indicated that demethylation had occurred at the C5 position, thus giving 5-hydroxy-7-methoxytetrahydroquinoline 13f.

By the application of this strategy three monohydroxyl analogues were synthesized (Table 2).

2.4. Biological Activity of 3,4-Diaryl-1,2,3,4-tetrahydroquinolines

A selection of the synthesized methoxy tetrahydroquinoline compounds were screened for their anticancer activity (Figure 4).

The compounds selected for this screen gave a valuable insight into the structure–activity relationship of functionality of both aryl groups of the tetrahydroquinolines (Figure 4, Table S1). In vitro growth inhibition assays were performed at a fixed concentration of 25 μM in a range of cancer cell lines, including H460 lung carcinoma, DU145 prostate carcinoma, A-431 skin (epidermoid) carcinoma, HT-29 colon adenocarcinoma, and MCF7 breast adenocarcinoma.

The potent activity of the 1,2,3,4-tetrahydroquinolines in Figure 5 shows that incorporating an aryl group into position 4 of the quinoline structure dramatically increased the antiproliferative effect by up to 90% compared to the parent compound 4. Compound 3c showed the greatest antiproliferative effect with an unsubstituted phenyl ring at the 4 position. Adding a substituent to this ring led to a total loss of activity in the DU145 prostate carcinoma cell lines. However, compounds 3b and 3e maintained a fairly good level of activity in the H460 lung carcinoma cell line, (30.7% and 32.5%, respectively) and in the MCF7 breast adenocarcinoma cell lines (25.4% and 23.9%, respectively). It is important to note that all the tetrahydroquinoline analogues tested (3b, 3c, and 3e) were still more effective than their original quinoline structures 4.

Due to its notable biological activity, the lead compound 3c was further tested across various concentrations in these cell lines. The compound demonstrated effective activity in the H460 lung carcinoma, A-431 skin carcinoma, and HT-29 colon adenocarcinoma cells, with IC₅₀ values of 4.9 ± 0.7, 2.0 ± 0.9, and 4.4 ± 1.3 μM, respectively. Therefore, compound 3c showed its most potent inhibition effects against skin carcinoma cells. Although the IC₅₀ values were marginally higher in the DU145 prostate carcinoma and MCF7 breast adenocarcinoma cells, they still indicated substantial levels of activity, with values at 12.0 ± 1.6 and 14.6 ± 3.9 μM, respectively.

3. Materials and Methods

• Analytical data

Melting points (uncorrected) were measured using a Mel-Temp melting point apparatus. The Microanalysis Unit of the University of Otago, New Zealand, performed microanalyses. Infrared spectra were recorded as Nujol mulls on a Perkin-Elmer 298 (Beaconsfield, UK) or a Perkin-Elmer 580B spectrometer. Ultraviolet–visible spectra were recorded in methanol (unless otherwise stated) on a Hitachi UV-3200 spectrometer (Hitachinaka, Japan). ¹H and ¹³C NMR spectra were obtained for the designated solvents on a Bruker AC300F (300 MHz) spectrometer (Bruker Pty Ltd., Preston, NSW, Australia). ¹H NMR data were recorded as follows: chemical shift measured in parts per million (ppm) downfield from TMS (δ), multiplicity, observed coupling constant (J) in Hertz (Hz), proton count. Multiplicities are reported as singlet (s), broad singlet (bs), doublet (d), triplet (t), quartet (q), quintet (quin), and multiplet (m). ¹³C NMR chemical shifts are reported in ppm downfield from TMS and identifiable carbons are given. The EI and ES mass spectra were recorded on an AEI MS 12 mass spectrometer (Washington, D.C., USA) at 70 eV ionizing potential and 8000 V accelerating voltage with an ion source temperature of 210 °C. Kieselgel 60H (Merck, Rahway, NJ, USA, Art 7736) was employed for flash chromatography and thin layer chromatography (TLC) was performed on DC Aluminium Foil Kieselgel F₂₅₄ (Merck, Art 5554). Solvents and reagents were purified by literature methods. Petroleum ether refers to the hydrocarbon fraction of boiling range 60–80 °C. Compounds were detected by short and long ultraviolet light and with iodine vapor.

• Cell culture

MCF-7, H-460, A-431, and DU-145 cells were maintained in Dulbecco’s modified Eagle’s medium (Gibco, Life Technologies, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum, while HT-29 was maintained in RPMI media (Gibco, Life Technologies) supplemented with 10% fetal bovine serum. All cell lines were cultured at 37 °C, under 5% CO₂ in a humidified atmosphere.

• In vitro growth inhibition assays

In vitro growth inhibition assays were performed in triplicate using the Alamar Blue assay. Briefly, cells in logarithmic phase growth were seeded onto 96-well plates at densities as follows:

MCF-7 = 6000 cells/well, 6 h Alamar Blue incubation;

HT-29 = 650 cells/well, 3 h Alamar Blue incubation;

H-460 = 600 cells/well, 6 h Alamar Blue incubation;

A-431 = 2100 cells/well, 6 h Alamar Blue incubation;

DU-145 = 2000 cells/well, 6 h Alamar Blue incubation.

A Multidrop 384 (Thermo Scientific, Waltham, MA, USA) was used and cells were allowed to adhere. After 24 h of incubation, test compounds, positive control (25 µM thonzonium bromide), and vehicle only (DMSO) controls were added to duplicate wells using a Hamilton Nimbus robotic platform. After 72 h of drug exposure, metabolic activity was detected by addition of Alamar Blue reagent and determined by measurement of fluorescence intensity (excitation 555 nm, emission 585 nm) using a SpectraMax M5 (Molecular Devices, San Jose, CA, USA) plate reader. Percentage of cell viability was determined at a fixed drug concentration of 25 μM. A value of 0% is indicative of total cell growth inhibition. Compounds showing appreciable percentage growth inhibition underwent further dose response analysis allowing for the calculation of an IC₅₀ value. This value is the drug concentration at which cell growth is inhibited to its half maximal value.

3.1. General Procedures

• Synthesis of 3,4-diaryl-5,7-dimethoxy-1,2,3,4-tetrahydroquinolin-4-ols (5a–b)

To a solution of azaisoflavone 4 (2.7 mmol) in anhydrous THF (10 mL) was slowly added phenylmagnesium bromide (5.5 mmol) in an atmosphere of nitrogen. The reaction mixture was heated at reflux for 5 h, then quenched with NH₄Cl solution (25 mL, 20%) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude product was then purified using column chromatography (8% ethyl acetate in n-hexane) to give 3,4-diaryl-azaisoflavan-4-ol 5 as a white solid.

• Synthesis of 3,4-diaryl-5,7-dimethoxy-quinolines (6a–b)

To a solution of 3,4-diaryl-5,7-dimethoxy-1,2,3,4-tetrahydroquinolin-4-ol 5 (2 mmol) in DCM (25 mL) was added 5 drops of BF₃·OEt₂ at room temperature. The reaction mixture was further stirred at room temperature for 4 h. After the completion of the reaction, it was quenched by the addition of a saturated solution of NaHCO₃ (25 mL). The organic layer was collected, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude solid was purified using column chromatography (10% ethyl acetate in n-hexane) to give 3,4-diaryl-5,7-dimethoxy quinoline 6 as a white solid.

• Synthesis of 3,4-diaryl-5,7-dimethoxy-quinolines (6c–e)

The suspension of ethyl 3,4-diaryl-5,7-dimethoxy quinoline-1(2H)-carboxylate 9 (0.45 mmol) in HBr in AcOH (2 mL) was stirred at room temperature overnight. The reaction was quenched with ice water and the precipitate was filtered and washed with cold water. The crude solid was purified by column chromatography (10% ethyl acetate in n-hexane) to give the title compound 6 as a white solid (0.08 g, 46%).

• Synthesis of Ethyl 3,4-diaryl-4-hydroxy-5,7-dimethoxy-3,4-dihydroquinoline-1(2H)-carboxylates (8a–g)

To a solution of azaisoflavone 7 (3.45 mmol) in anhydrous THF (15 mL) was slowly added phenylmagnesium bromide (6.9 mmol) in an atmosphere of nitrogen. The reaction mixture was heated at reflux for 4 h, then quenched with NH₄Cl solution (25 mL, 20%) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude product was purified using column chromatography (4% ethyl acetate in n-hexane) to give the title compound 8 as a white solid.

• Synthesis of Ethyl 3,4-diaryl-5,7-dimethoxy-quinoline-1(2H)-carboxylates (9a–g)

To a solution of 3,4-diaryl-4-hydroxy-5,7-dimethoxy-quinoline-1(2H)-carboxylate 8 (2.9 mmol) in DCM (25 mL) were added 5 drops of BF₃·OEt₂. The reaction mixture was stirred at room temperature for 4 h. After the completion of reaction, it was quenched by the addition of saturated solution of NaHCO₃ (25 mL). The organic layer was collected, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude solid was purified by column chromatography (3% ethyl acetate in n-hexane) to give the title compound 9 as a white solid.

• Synthesis of -Ethyl cis-3,4-diaryl-5,7-dimethoxy-3,4-dihydroquinolin-1(2H)-carboxylates (10b–g)

To a solution of ethyl 3,4-diaryl-5,7-dimethoxy-quinoline-1(2H)-carboxylate 9 (1.35 mmol) in THF (10 mL) was added 10% palladium charcoal (0.2 g). The mixture was hydrogenated at atmospheric pressure for 24 h. The catalyst was removed by filtration through Celite^® and the filtrate was concentrated under vacuum. The crude solid was purified using column chromatography (2% ethyl acetate in n-hexane) to give the title compound 10 as a white solid.

• Synthesis of cis-3,4-diaryl-5,7-dimethoxy-1,2,3,4-tetrahydroquinolines (3b–g)

The suspension of ethyl cis-3,4-diaryl-5,7-dimethoxy-3,4-dihydroquinoline-1(2H)-carboxylate 10 (1 mmol) was heated at reflux in 10% NaOH in ethanol (10 mL) for 8 h. After the completion of reaction, ethanol was concentrated under vacuum. The residue was taken in ethyl acetate (50 mL), washed with water (20 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude solid was purified using column chromatography (2% ethyl acetate in n-hexane) to give the title compound 3 as a white solid.

• Synthesis of 5,7-dihydroxy-3-(4-hydroxyphenyl)quinoline (12)

The solution of 5,7-dimethoxy-3-(4-methoxyphenyl)-4-phenyl-1,2,3,4-tetrahydroquinoline 3c (0.2 g, 0.5 mmol) in chlorobenzene (5 mL) was heated at reflux with aluminum chloride (0.2 g, 1.6 mmol) for 1 h. The reaction mixture was then quenched with ice-water to give a yellow precipitate. The crude solid was purified using column chromatography (15% ethyl acetate in n-hexane) to give the title compound 12 as a brown solid.

• Synthesis of 3,4-diaryl-5-hydroxy-7-methoxy-1,2,3,4-tetrahydroquinolines (13d,f,g)

To a solution of 3,4-diaryl-5,7-dimethoxy-1,2,3,4-tetrahydroquinoline 3 (0.55 mmol) in DCM (5 mL) was added boron tribromide (1.65 mmol). The reaction mixture was further stirred at room temperature for 1 h, quenched with MeOH (2 mL), and concentrated under vacuum. The crude residue was taken in DCM (50 mL), washed with sat. NaHCO₃ (10 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude solid was purified using column chromatography (8% ethyl acetate in n-hexane) to give title compound 13 as a yellow solid.

3.2. Experimental Data

• 3-(4-Bromophenyl)-5,7-dimethoxy-4-phenyl-1,2,3,4-tetrahydroquinolin-4-ol (5a)

White solid (0.9 g, 77%). M.p. 164–166 °C; UV (MeOH): λ_max 201 (ε 49,266 cm⁻¹M⁻¹), 221 (68532) nm; IR (KBr): ν_max 3367, 3007, 2944, 1605, 1589, 1501, 1487, 1201, 1149, 1132, 1075, 1061, 994, 819, 751, 721, 699 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 3.12 (dd, J = 3.0, 9.0 Hz, 1H, H2a), 3.24 (dd, J = 3.0, 9.0 Hz, 1H, H2b), 3.35 (s, 3H, OMe), 3.43–3.49 (m, 1H, H3), 3.79 (s, 4H, OMe, OH), 4.14 (bs, 1H, NH), 5.87 (s, 2H, ArH6, ArH8), 6.90 (d, J = 9.0 Hz, 2H, ArH2′, ArH6′), 7.11–7.20 (m, 5H, Ph), 7.30 (d, J = 9.0 Hz, 2H, ArH3′, ArH5′); ¹³C NMR (75.6 MHz, CDCl₃): δ 43.7 (CH₂NH), 53.4 (CHAr′), 55.1 (OMe), 55.2 (OMe), 74.0 (C-OH), 90.2 (ArC6), 91.6 (ArC8), 108.5 (ArC), 120.3 (ArC4′), 125.5 (ArC2″, ArC6″), 126.0 (ArC4″), 127.2 (ArC3″, ArC5″), 130.3 (ArC2′, ArC6′), 131.4 (ArC3′, ArC5′), 146.9 (ArC1″), 150.0 (ArC1′, ArC), 159.8 (ArC7), 160.7 (ArC5); HRMS (ESI) m/z Calcd. for C₂₃H₂₃BrNO₃ (M + H)⁺ 440.0861. Found 440.0848; Anal. Calcd. for C₂₃H₂₂BrNO₃: C, 62.74; H, 5.04; N, 3.18. Found: C, 62.97; H, 5.14; N, 3.14.

• 5,7-Dimethoxy-3,4-bis(4-methoxyphenyl)-1,2,3,4-tetrahydroquinolin-4-ol (5b)

White solid (1.4 g, 72.3%). M.p. 172–174 °C; UV (MeOH): λ_max 203 (ε 58,256 cm⁻¹M⁻¹), 222 (58631) nm; IR (KBr): ν_max 3388, 3000, 2938, 2838, 1603, 1585, 1508, 1201, 1180, 1165, 1149, 1132, 1067, 1025, 824, 751, 728, 701 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.85 (dd, J = 3.0, 12.0 Hz, 1H, H2a), 2.91 (dt, J = 3.0, 12.0 Hz, 1H, H2b), 3.16 (s, 3H, OMe), 3.40–3.46 (m, 1H, H3), 3.64 (s, 3H, OMe), 3.65 (s, 3H, OMe), 3.66 (s, 3H, OMe), 4.60 (s, 1H, OH), 5.69 (d, J = 3.0 Hz, 1H, ArH6), 5.85 (d, J = 3.0 Hz, 1H, ArH8), 6.08 (bs, 1H, NH), 6.62 (m, 4H, ArH2′, ArH3′, ArH5′, ArH6′), 6.78 (d, J = 9.0 Hz, 2H, ArH2″, ArH6″), 6.87 (d, J = 9.0 Hz, 2H, ArH2″, ArH6″); ¹³C NMR (75.6 MHz, CDCl₃): δ 43.1 (CH₂NH), 53.6 (CHAr′), 55.0 (OMe), 55.1 (2 × OMe), 55.3 (OMe), 73.1 (C-OH), 89.0 (ArC6), 91.5 (ArC8), 108.9 (ArC), 112.3 (ArC3′, ArC5′), 112.6 (ArC3″, ArC5″), 126.6 (ArC2′, ArC6′), 130.8 (ArC2″, ArC6″), 132.4 (ArC1″), 143.0 (ArC1′), 147.9 (ArC), 157.0 (ArC4′), 157.7 (ArC4″), 160.2 (ArC7), 160.2 (ArC5); HRMS (ESI) m/z Calcd. for C₂₅H₂₈NO₅ (M + H)⁺: 422.1967. Found: 422.1953.

• 3-(4-Bromophenyl)-5,7-dimethoxy-4-phenylquinoline (6a)

White solid (0.55 g, 66%). M.p. 192–194 °C; UV (MeOH): λ_max 207 (ε 61,432 cm⁻¹M⁻¹), 255 (53,581), 343 (3880) nm; IR (KBr): ν_max 2961, 1609, 1578, 1366, 1204, 1150, 1082, 1040, 829, 771, 753, 723, 708, 692 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 3.38 (s, 3H, OMe), 3.96 (s, 3H, OMe), 6.46 (d, J = 3.0 Hz, 1H, ArH6), 6.92 (d, J = 9.0 Hz, 2H, ArH2′, ArH6′), 7.00–7.04 (m, 2H, Ph), 7.13 (d, J = 3.0 Hz, 1H, ArH8), 7.17–7.19 (m, 3H, Ph), 7.25 (d, J = 9.0 Hz, 2H, ArH3′, ArH5′), 8.75 (s, 1H, H2); ¹³C NMR (75.6 MHz, CDCl₃): δ 55.3 (OMe), 55.5 (OMe), 99.8 (ArC6), 100.4 (ArC8), 114.5 (ArC), 120.8 (ArC3), 126.3 (ArC3′, ArC5′), 126.6 (ArC4′, ArC1′), 129.0 (ArC4″), 130.7 (ArC2′, ArC6′), 131.8 (ArC2″, ArC6″), 137.4 (ArC3″, ArC5″), 139.9 (ArC4), 144.9 (ArC1″), 150.7 (ArC), 151.2 (ArC2), 157.6 (ArC7), 160.9 (ArC5); HRMS (ESI) m/z Calcd. for C₂₃H₁₉BrNO₂ (M + H)⁺ 420.0599. Found: 420.0584; Anal. Calcd. for C₂₃H₁₈BrNO₂: C, 65.73; H, 4.32; N, 3.33. Found: C, 65.79; H, 4.34; N, 3.27.

• 5,7-Dimethoxy-3,4-bis(4-methoxyphenyl)quinoline (6b)

White solid (0.7 g, 54%). M.p. 180–182 °C; UV (MeOH): λ_max 202 (ε 380,769 cm⁻¹M⁻¹), 206 (380,769), 212 (384,615), 256 (280,769), 341 (65,384) nm; IR (KBr): ν_max 2935, 2837, 1610, 1578, 1555, 1510, 1450, 1408, 1365, 1330, 1286, 1203, 1147, 1117, 1042, 1027, 826, 801, 787, 722, 656 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 3.43 (s, 3H, OMe), 3.76 (s, 3H, OMe), 3.79 (s, 3H, OMe), 3.96 (s, 3H, OMe), 6.46 (d, J = 3.0 Hz, 1H, ArH6), 6.71–6.75 (m, 4H, ArH3′, ArH5′, ArH3″, ArH5″), 6.93–6.98 (m, 4H, ArH2′, ArH6′, ArH2″, ArH6″), 7.12 (d, J = 3.0 Hz, 1H, ArH8), 8.75 (s, 1H, H2); ¹³C NMR (75.6 MHz, CDCl₃): δ 55.1 (OMe), 55.2 (OMe), 55.5 (OMe), 55.6 (OMe), 99.8 (ArC6, ArC8), 100.5 (ArC), 112.1 (ArC3′, ArC5′), 112.2 (ArC3″, ArC5″), 113.2 (ArC1′), 115.0 (ArC), 130.3 (ArC1″), 130.4 (ArC2′), 131.0 (ArC6′), 131.4 (ArC2″), 132.5 (ArC6″), 132.8 (ArC4), 150.5 (ArC), 152.0 (ArC2), 157.8 (ArC7), 157.9 (ArC5), 158.1 (ArC4′), 160.5 (ArC4″); HRMS (ESI) m/z Calcd. for C₂₅H₂₄NO₄ (M + H)⁺: 402.1705. Found: 402.1692.

• 5,7-Dimethoxy-3-(4-methoxyphenyl)-4-phenylquinoline (6c)

White solid (0.08 g, 46%). M.p. 216–218 °C; UV (MeOH): λ_max 209 (ε 70,446 cm⁻¹M⁻¹), 257 (73,791), 347 (4089) nm; IR (KBr): ν_max 2961, 2837, 1614, 1510, 1366, 1240, 1203, 1149, 1116, 1041, 1026, 837, 829, 767, 700 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 3.38 (s, 3H, OMe), 3.74 (s, 3H, OMe), 3.96 (s, 3H, OMe), 6.45 (d, J = 3.0 Hz, 1H, ArH6), 6.70 (d, J = 9.0 Hz, 2H, ArH2′, ArH6′), 6.97 (d, J = 9.0 Hz, 2H, ArH3′, ArH5′), 7.02–7.06 (m, 2H, Ph), 7.13 (d, J = 3.0 Hz, 1H, ArH8), 7.17–7.19 (m, 3H, Ph), 8.76 (s, 1H, ArH2); ¹³C NMR (75.6 MHz, CDCl₃): δ 55.0 (OMe), 55.3 (OMe), 55.4 (OMe), 99.7 (ArC6, ArC8), 100.4 (ArC), 113.0 (ArC5′, ArC3′), 114.6 (ArC1′), 126.0 (ArC3), 126.5 (ArC2″, ArC6″), 129.0 (ArC3″, ArC5″), 130.7 (ArC4″), 131.3 (ArC2′, ArC6′), 132.0 (ArC4), 140.4 (ArC1″), 144.6 (ArC), 150.3 (ArC2), 157.6 (ArC4′), 158.1 (ArC7), 160.5 (ArC5); HRMS (ESI) m/z Calcd. for C₂₄H₂₂NO₃Na (M + Na)⁺: 393.1979. Found: 393.1968; Anal. Calcd. for C₂₄H₂₁NO₃: C, 77.61; H, 5.70; N, 3.77. Found: C, 77.38; H, 5.81; N, 3.73.

• 4-(4-(tert-Butyl)phenyl)-5,7-dimethoxy-3-(4-methoxyphenyl)quinoline (6d)

White solid (0.06 g, 38%). M.p. 172–174 °C; UV (MeOH): λ_max 205 (ε 48,702 cm⁻¹M⁻¹), 257 (34,961) nm; IR (KBr): ν_max 2923, 2853, 1615, 1511, 1449, 1204, 1148, 1125, 1105, 1030, 824, 591 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.30 (s, 9H, 3 × Me), 3.36 (s, 3H, OMe), 3.74 (s, 3H, OMe), 3.96 (s, 3H, OMe), 6.45 (d, J = 3.0 Hz, 1H, ArH6), 6.70 (d, J = 9.0 Hz, 2H, ArH3′, ArH5′), 6.93–6.99 (m, 4H, ArH2″, ArH3″, ArH5″, ArH6″), 7.14 (d, J = 3.0 Hz, 1H, ArH8), 7.20 (d, J = 8.4 Hz, 2H, ArH2′, ArH6′), 8.77 (s, 1H, ArH2); ¹³C NMR (75.6 MHz, CDCl₃): δ 30.1 (MeC), 31.5 (MeC), 32.0 (MeC), 34.5 (CMe), 55.2 (2 × OMe), 55.6 (OMe), 100.0 (ArC6, ArC8), 100.4 (ArC), 113.2 (ArC3′, ArC5′), 117.8 (ArC1′), 122.9 (CHAr′), 123.5 (ArC2″, ArC6″), 128.9 (ArC3″, ArC5″), 131.0 (ArC2′, ArC6′), 131.5 (ArC1′), 132.3 (ArC4), 137.5 (ArC), 149.1 (ArC2), 151.9 (ArC4″), 157.9 (ArC5), 158.2 (ArC7), 160.7 (ArC4′); HRMS (ESI) m/z Calcd. for C₂₈H₃₀NO₃ (M + H)⁺: 428.2226. Found: 428.2213.

• 5,7-Dimethoxy-3-(4-methoxyphenyl)-4-(p-tolyl)quinoline (6e)

White solid (0.08 g, 46.5%). M.p. 186–188 °C; UV (MeOH): λ_max 211 (ε 70,077 cm⁻¹M⁻¹), 256 (48,353), 340 (11,212) nm; IR (KBr): ν_max 2954, 1614, 1511, 1449, 1239, 1203, 1150, 1040, 1030, 840, 832, 811, 719, 582 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.24 (s, 3H, MeAr″), 3.32 (s, 3H, OMe), 3.67 (s, 3H, OMe), 3.88 (s, 3H, OMe), 6.37 (d, J = 2.4 Hz, 1H, ArH6), 6.63 (d, J = 8.7 Hz, 2H, ArH3′, ArH5′), 6.84 (d, J = 8.1 Hz, 2H, ArH3″, ArH5″), 6.88–6.92 (m, 4H, ArH2′, ArH6′, ArH2″, ArH6″), 7.05 (d, J = 2.1 Hz, 1H, ArH8), 8.67 (s, 1H, ArH2); ¹³C NMR (75.6 MHz, CDCl₃): δ 21.2 (MeAr″), 55.1 (OMe), 55.2 (OMe), 55.5 (OMe), 99.8 (ArC6, ArC8), 100.5 (ArC), 113.1 (ArC3′, ArC5′), 113.2 (ArC1′, ArC3), 127.2 (ArC2″, ArC6″), 127.3 (ArC3″, ArC5″), 129.0 (ArC2′, ArC6′), 131.4 (ArC1″, ArC4″), 135.4 (ArC4), 144.9 (ArC), 150.5 (ArC2), 157.8 (ArC5), 158.1 (ArC7), 160.5 (ArC4′); HRMS (ESI) m/z Calcd. for C₂₅H₂₄NO₃ (M + H)⁺: 386.1756. Found: 386.1744.

• Ethyl 3-(4-bromophenyl)-4-hydroxy-5,7-dimethoxy-4-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate (8a)

White solid (1.6 g, 88.5%). M.p. 144–146 °C; UV (MeOH): λ_max 219 (ε 64,000 cm⁻¹M⁻¹), 247 (16,666), 336 (7333) nm; IR (KBr): ν_max 3532, 2982, 1706, 1576, 1488, 1455, 1384, 1304, 1237, 1213, 1066, 1042, 1010, 823, 759, 723, 704 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.19 (t, J = 6.0 Hz, 3H, CH₃CH₂), 3.02 (dd, J = 3.0, 12.0 Hz, 1H, H2a), 3.19 (s, 3H, OMe), 3.82 (t, J = 12.0 Hz, 1H, H3), 3.74 (s, 3H, OMe), 4.11–4.18 (m, 3H, CH₂CH₃, H2b), 6.28 (d, J = 3.0 Hz, 1H, ArH6), 6.63 (d, J = 9.0 Hz, 2H, ArH2′, ArH6′), 6.89–6.92 (m, 2H, Ph), 7.00 (d, 3.0 Hz, 1H, ArH8), 7.07–7.14 (m, 3H, Ph), 7.27 (d, J = 9.0 Hz, 2H, ArH3′, ArH5′); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.4 (Me), 46.0 (CH₂N), 54.5 (CHAr′), 55.3 (OMe), 55.5 (OMe), 62.1 (OCH₂), 74.5 (C-OH), 97.0 (ArC6, ArC8), 100.1 (ArC), 116.7 (ArC4′), 120.7 (ArC4″), 125.1 (ArC2″, ArC6″), 126.2 (ArC5″), 127.2 (ArC3″), 130.3 (ArC2′, ArC6′), 131.5 (ArC3′, ArC5′), 136.2 (ArC), 140.0 (ArC1′), 148.7 (ArC1″), 154.1 (COO), 158.5 (ArC7), 159.5 (ArC5); HRMS (ESI) m/z Calcd. for C₂₆H₂₆BrNO₅Na (M + Na)⁺: 534.0892. Found: 534.0881; Anal. Calcd. for C₂₆H₂₆BrNO₅: C, 60.95; H, 5.11; N, 2.73. Found: C, 60.94; H, 5.18; N, 2.69.

• Ethyl 4-hydroxy-5,7-dimethoxy-3,4-bis(4-methoxyphenyl)-3,4-dihydroquinoline-1(2H)-carboxylate (8b)

White solid (1.6 g, 84.5%). M.p. 108–110 °C; UV (MeOH): λ_max 220 (ε 56,085 cm⁻¹M⁻¹), 276 (3365), 337 (5608) nm; IR (KBr): ν_max 3464, 2934, 1677, 1610, 1582, 1509, 1172, 1144, 1062, 1027, 956, 891, 826, 765 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.24 (t, J = 6.0 Hz, 3H, CH₃CH₂), 3.06 (dd, J = 3.0, 12.0 Hz, 1H, H2a), 3.36 (s, 3H, OMe), 3.77 (s, 6H, 2 × OMe), 3.83 (dd, J = 3.0, 9.0 Hz, 1H, H2b), 3.84 (s, 3H, OMe), 4.19 (q, J = 6.0 Hz, 2H, CH₂CH₃), 4.28 (dd, J = 3.0, 12.0 Hz, 1H, H3), 6.23 (d, J = 3.0 Hz, 1H, ArH6), 6.69 (d, J = 9.0 Hz, 2H, ArH3′, ArH5′), 6.73–6.82 (m, 4H, ArH2″, ArH3″, ArH5″, ArH6″), 6.90 (d, J = 9.0 Hz, 2H, ArH2′, ArH6′), 7.16 (d, J = 3.0 Hz, 1H, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.4 (Me), 46.5 (CH₂N), 54.3 (OMe), 55.0 (OMe), 55.3 (2 × OMe), 55.6 (CHAr′), 61.9 (OCH₂), 74.5 (C-OH), 97.0 (ArC6, ArC8), 100.0 (ArC), 112.4 (ArC3′, ArC5′), 112.7 (ArC3″, ArC5″), 117.0 (ArC), 126.3 (ArC2′, ArC6′), 130.7 (ArC2″, ArC6″), 140.1 (ArC1″), 141.4 (ArC1′), 154.2 (COO), 157.7 (ArC4″), 158.2 (ArC4′), 158.6 (ArC7), 159.3 (ArC5); HRMS (ESI) m/z Calcd. for C₂₈H₃₁NO₇Na (M + Na)⁺: 516.1998. Found: 516.1981.

• Ethyl 4-hydroxy-5,7-dimethoxy-3-(4-methoxyphenyl)-4-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate (8c)

White solid (1.5 g, 85%). M.p. 140–142 °C; UV (MeOH): λ_max 219 (ε 41,395 cm⁻¹M⁻¹), 337 (3255) nm; IR (KBr): ν_max 3561, 2971, 1699, 1607, 1577, 1385, 1302, 1237, 1178, 1042, 1008, 829, 765, 752, 736, 703 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.26 (t, J = 6.0 Hz, 3H, CH₃CH₂), 3.08 (dd, J = 3.0, 9.0 Hz, 1H, H2a), 3.32 (s, 3H, OMe), 3.77 (s, 3H, OMe), 3.83 (dd, J = 3.0 Hz, 9.0 Hz, 1H, H2b), 3.84 (s, 3H, OMe), 4.21 (q, J = 6.0 Hz, 2H, CH₂CH₃), 4.33 (dd, J = 3.0 Hz, 12.0 Hz, 1H, H3), 6.23 (d, J = 3.0 Hz, 1H, ArH6), 6.72–6.79 (m, 4H, ArH3′, ArH5′, ArH3″, ArH5″), 6.97–7.00 (m, 2H, ArH4″, ArH8), 7.13–7.18 (m, 4H, ArH2′, ArH6′, ArH2″, ArH6″); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.4 (Me), 54.2 (CH₂N), 54.9 (CHAr′), 55.0 (OMe), 55.3 (OMe), 55.5 (OMe), 61.9 (OCH₂), 74.7 (C-OH), 96.5 (ArC6), 97.0 (ArC8), 100.1 (ArC), 112.6 (ArC3′, ArC5′), 125.2 (ArC3″), 125.5 (ArC5″), 125.9 (ArC4″), 127.1 (ArC2′, ArC6′), 129.2 (ArC2″), 129.6 (ArC6″), 140.1 (ArC), 140.6 (ArC1′), 149.1 (ArC1″), 154.2 (COO), 157.4 (ArC4′), 157.7 (ArC7), 158.3 (ArC5); HRMS (ESI) m/z Calcd. for C₂₇H₂₉NO₆Na (M + Na)⁺: 486.1893. Found: 486.1881; Anal. Calcd. for C₂₇H₂₉NO₆: C, 69.96; H, 6.31; N, 3.02. Found: C, 69.75; H, 6.37; N, 3.01.

• Ethyl 4-(4-(tert-butyl)phenyl)-4-hydroxy-5,7-dimethoxy-3-(4-methoxyphenyl)-3,4-dihydroquinoline-1(2H)-carboxylate (8d)

White solid (1.6 g, 80%). M.p. 118–120 °C; UV (MeOH): λ_max 202 (ε 102,479 cm⁻¹M⁻¹), 222 (113,813) nm; IR (KBr): ν_max 3551, 2957, 1703, 1584, 1515, 1237, 1140, 1060, 1037, 827, 756, 736 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.23 (t, J = 6.0 Hz, 3H, CH₃CH₂), 1.27 (s, 9H, 3 × Me), 3.13 (dd, J = 2.1, 10.2 Hz, 1H, H2a), 3.35 (s, 3H, OMe), 3.79 (s, 3H, OMe), 3.86 (s, 3H, OMe), 4.10–4.19 (m, 3H, CH₂CH₃, H2b), 4.24 (dd, J = 2.7, 12.9 Hz,1H, H3), 6.26 (d, J = 3.0 Hz, 1H, ArH6), 6.76 (d, J = 9.0 Hz, 2H, ArH2′, ArH6′), 6.84 (d, J = 9.0 Hz, 2H, ArH3′, ArH5′), 6.94 (d, J = 8.4 Hz, 2H, ArH2″, ArH6″), 7.17–7.20 (m, 3H, ArH8, ArH3″, ArH5″); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.5 (Me), 31.3 (MeC), 31.4 (MeC), 34.3 (MeC), 46.7 (CMe), 54.0 (CH₂N), 55.1 (OMe), 55.4 (OMe), 55.7 (OMe), 60.4 (CHAr′), 62.9 (OCH₂), 74.8 (C-OH), 97.2 (ArC6, ArC8), 100.3 (ArC), 112.8 (ArC3′, ArC5′), 124.0 (ArC3″, ArC5″), 125.0 (ArC2′, ArC6′), 129.7 (ArC), 130.7 (ArC2″, ArC6″), 140.2 (ArC1′), 146.2 (ArC1″), 148.9 (ArC4″), 154.4 (COO), 158.3 (ArC4′), 158.8 (ArC7), 159.4 (ArC5); HRMS (ESI) m/z Calcd. for C₃₁H₃₇NO₆Na (M + Na)⁺: 542.2519. Found: 542.2496.

• Ethyl 4-hydroxy-5,7-dimethoxy-3-(4-methoxyphenyl)-4-(p-tolyl)-3,4-dihydroquinoline-1(2H)-carboxylate (8e)

White solid (1.5 g, 82%). M.p. 108–110 °C; UV (MeOH): λ_max 220 (ε 47,281 cm⁻¹M⁻¹), 336 (5673) nm; IR (KBr): ν_max 3470, 2935, 2838, 1684, 1611, 1584, 1511, 1374, 1313, 1179, 1143, 1057, 1029, 956, 829, 817, 764 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.16 (t, J = 6.0 Hz, 3H, CH₃CH₂), 2.22 (s, 3H, MeAr″), 2.99 (dd, J = 1.8, 10.8 Hz, 1H, H2a), 3.27 (s, 3H, OMe), 3.69 (s, 3H, OMe), 3.71 (s, 1H, OH), 3.76 (s, 3H, OMe), 3.77 (dd, J = 2.1, 10.5 Hz, 1H, H2b), 4.11 (q, J = 6.0 Hz, 2H, CH₂CH₃), 4.19 (dd, J = 2.7, 12.6 Hz, 1H, H3), 6.15 (d, J = 3.0 Hz, 1H, ArH6), 6.65–6.75 (m, 4H, ArH3′, ArH5′, ArH3″, ArH5″), 6.79 (d, J = 8.1 Hz, 2H, ArH2′, ArH6′), 6.88 (d, J = 8.1 Hz, 2H, ArH2″, ArH6″), 7.08 (d, J = 3.0 Hz, 1H, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.5 (Me), 21.0 (MeAr″), 46.6 (CH₂N), 55.3 (OMe), 55.4 (OMe), 55.6 (OMe), 55.7 (CHAr′), 62.0 (OCH₂), 74.8 (C-OH), 97.1 (ArC6), 97.2 (ArC8), 100.2 (ArC), 112.8 (ArC3′, ArC5′), 125.3 (ArC2′, ArC6′), 128.0 (ArC2″, ArC6″), 129.4 (ArC3″, ArC5″), 130.7 (ArC4″), 135.4 (ArC), 140.2 (ArC1′), 144.8 (ArC1″), 154.4 (COO), 158.7 (ArC4′), 159.1 (ArC7), 159.4 (ArC5); HRMS (ESI) m/z Calcd. for C₂₈H₃₁NO₆Na (M + Na)⁺: 500.2049. Found: 500.2035.

• Ethyl 4-hydroxy-5,7-dimethoxy-3,4-diphenyl-3,4-dihydroquinoline-1(2H)-carboxylate (8f)

White solid (1.55 g, 85%). M.p. 142–144 °C; UV (MeOH): λ_max 219 (ε 42,936 cm⁻¹M⁻¹), 243 (12,881), 337 (4293) nm; IR (KBr): ν_max 3232, 1614, 1511, 1449, 1239, 1203, 1150, 1040, 1030, 840, 832, 811, 719, 582 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.29 (t, J = 6.0 Hz, 3H, CH₃CH₂), 3.17 (dd, J = 2.1, 10.8 Hz, 1H, H2a), 3.35 (s, 3H, OMe), 3.85 (d, J = 1.3 Hz, 1H, H2b), 3.88 (s, 3H, OMe), 3.93 (s, 1H, OH), 4.25 (q, J = 7.2 Hz, 2H, CH₂CH₃), 4.40 (dd, J = 2.7, 12.6 Hz, 1H, H3), 6.27 (d, J = 3.0 Hz, 1H, ArH6), 6.88–6.91 (m, 2H, ArH′), 7.02–7.05 (m, 2H, ArH″), 7.18–7.24 (m, 7H, ArH′, ArH″, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.5 (Me), 46.4 (CH₂N), 55.1 (OMe), 55.4 (OMe), 55.6 (CHAr′), 62.1 (OCH₂), 74.9 (C-OH), 97.1 (ArC6, ArC8), 100.2 (ArC), 117.2 (ArC4′), 125.3 (ArC4″), 126.1 (ArC6′), 126.7 (ArC2′), 127.1 (ArC6″), 127.2 (ArC2″), 127.3 (ArC5′), 127.7 (ArC3′), 129.3 (ArC5″), 129.9 (ArC3″), 137.3 (ArC), 140.3 (ArC1′), 149.2 (ArC1″), 154.3 (COO), 158.6 (ArC7), 159.5 (ArC5); HRMS (ESI) m/z Calcd. for C₂₆H₂₈NO₅ (M + H)⁺: 434.1967. Found: 434.1949; Anal. Calcd. for C₂₆H₂₇NO₅: C, 72.04; H, 6.28; N, 3.23. Found: C, 72.20; H, 6.34; N, 3.19.

• Ethyl 4-hydroxy-5,7-dimethoxy-3-phenyl-4-(p-tolyl)-3,4-dihydroquinoline-1(2H)-carboxylate (8g)

White solid (1.5 g, 78%). M.p. 170–172 °C; UV (MeOH): λ_max 219 (ε 66,666 cm⁻¹M⁻¹) nm; IR (KBr): ν_max 3585, 2956, 2939, 2905, 1697, 1581, 1453, 1397, 1320, 1280, 1225, 1146, 1080, 1057, 1030, 953, 845, 813, 762, 700 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.27 (t, J = 6.0 Hz, 3H, CH₃CH₂), 2.34 (s, 3H, MeAr″), 3.17 (dd, J = 2.7, 10.2 Hz, 1H, H2a), 3.29 (s, 1H, OH), 3.39 (s, 3H, OMe), 3.88 (s, 3H, OMe), 3.90 (dd, J = 2.1, 10.5 Hz, 1H, H2b), 4.22 (q, J = 7.2 Hz, 2H, CH₂CH₃), 4.35 (dd, J = 2.7, 12.9 Hz, 1H, H3), 6.28 (d, J = 3.0 Hz, 1H, ArH6), 6.89–7.02 (m, 6H, ArH′, ArH″), 7.21–7.24 (m, 4H, ArH′, ArH″, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.5 (Me), 21.2 (MeAr″), 46.5 (CH₂N), 55.1 (OMe), 55.4 (OMe), 55.7 (CHAr′), 62.1 (OCH₂), 74.8 (C-OH), 97.1 (ArC6, ArC8), 100.2 (ArC), 126.6 (ArC4′), 127.3 (ArC2′, ArC6′), 127.7 (ArC2″, ArC6″), 127.8 (ArC5′), 128.5 (ArC3′), 129.1 (ArC5″), 129.9 (ArC3″), 135.5 (ArC4″), 137.5 (ArC), 140.2 (ArC1″), 146.2 (ArC1′), 154.4 (COO), 158.7 (ArC7), 159.4 (ArC5); HRMS (ESI) m/z Calcd. for C₂₇H₂₉NO₅Na (M + Na)⁺: 470.1943. Found: 470.1927; Anal. Calcd. for C₂₇H₂₉NO₅: C, 72.46; H, 6.53; N, 3.13. Found: C, 72.66; H, 6.61; N, 3.09.

• Ethyl 3-(4-bromophenyl)-5,7-dimethoxy-4-phenylquinoline-1(2H)-carboxylate (9a)

White solid (0.8 g, 55%). M.p. 188–190 °C; UV (MeOH): λ_max 215 (ε 55,234 cm⁻¹M⁻¹), 247 (19,910), 329 (14,129) nm; IR (KBr): ν_max 2977, 1699, 1597, 1568, 1402, 1325, 1204, 1152, 1045, 1008, 831, 818, 766, 755, 701 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.29 (t, J = 6.0 Hz, 3H, CH₃CH₂), 3.23 (s, 3H, OMe), 3.84 (s, 3H, OMe), 4.24 (q, J = 6.0 Hz, 2H, CH₂CH₃), 4.54 (s, 2H, CH₂N), 6.19 (d, J = 3.0 Hz, 1H, ArH6), 6.80 (d, J = 6.0 Hz, 2H, ArH2′, ArH6′), 6.95 (d, J = 3.0 Hz, 1H, ArH8), 6.97–6.99 (m, 2H, Ph), 7.12–7.14 (m, 3H, Ph), 7.24 (d, J = 6.0 Hz, 2H, ArH3′, ArH5′); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.4 (Me), 48.5 (CH₂N), 55.3 (OMe), 55.4 (OMe), 62.1 (OCH₂), 96.5 (ArC6, ArC8), 100.3 (ArC), 113.8 (Ar′C4), 120.1 (ArC3), 125.9 (ArC2′, ArC6′), 127.2 (ArC3″, ArC5″), 129.0 (ArC2″, ArC6″), 130.1 (ArC4″), 130.8 (ArC3′, ArC5′), 133.3 (ArC4), 138.6 (ArC1′), 139.8 (ArC), 140.0 (ArC1″), 153.4 (COO), 157.6 (ArC7), 159.9 (ArC5); HRMS (ESI) m/z Calcd. for C₂₆H₂₄BrNO₄Na (M + Na)⁺: 516.0786. Found: 516.0766; Anal. Calcd. for C₂₆H₂₄BrNO₄: C, 63.17; H, 4.89; N, 2.83. Found: C, 63.37; H, 4.98; N, 2.80.

• Ethyl 5,7-dimethoxy-3,4-bis(4-methoxyphenyl)quinoline-1(2H)-carboxylate (9b)

White solid (0.75 g, 52%). M.p. 148–150 °C; UV (MeOH): λ_max 251 (ε 16,507 cm⁻¹M⁻¹), 325 (11,279) nm; IR (KBr): ν_max 2966, 2935, 2841, 1704, 1607, 1569, 1508, 1446, 1324, 1244, 1219, 1150, 1050, 831, 819, 758 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.28 (t, J = 6.0 Hz, 3H, CH₃CH₂), 3.28 (s, 3H, OMe), 3.74 (s, 3H, OMe), 3.76 (s, 3H, OMe), 3.83 (s, 3H, OMe), 4.23 (q, J = 6.0 Hz, 2H, CH₂CH₃), 4.53 (s, 2H, CH₂N), 6.20 (d, J = 3.0 Hz, 1H, ArH6), 6.68 (d, J = 9.0 Hz, 4H, ArH3′, ArH5′, ArH3″, ArH5″), 6.88 (d, J = 9.0 Hz, 4H, ArH2′, ArH6′, ArH2″, ArH6″), 6.98 (d, J = 3.0 Hz, 1H, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.4 (Me), 48.9 (CH₂N), 55.0 (2 × OMe), 55.3 (OMe), 55.4 (OMe), 61.9 (OCH₂), 96.6 (ArC6, ArC8), 100.2 (ArC), 112.5 (ArC3′, ArC5′), 113.0 (ArC3″, ArC5″), 114.3 (CHAr′), 129.6 (ArC2″, ArC6″), 130.2 (ArC2″, ArC6″), 131.3 (ArC4), 132.3 (ArC1′), 132.9 (ArC1″), 139.7 (ArC), 153.5 (COO), 157.5 (ArC4′, ArC4″), 157.6 (ArC7), 159.4 (ArC5); HRMS (ESI) m/z Calcd. for C₂₈H₃₀NO₆ (M + H)⁺: 476.2073. Found: 476.2059.

• Ethyl 5,7-dimethoxy-3-(4-methoxyphenyl)-4-phenylquinoline-1(2H)-carboxylate (9c)

White solid (0.8 g, 54%). M.p. 148–150 °C; UV (MeOH): λ_max 215 (ε 57,573 cm⁻¹M⁻¹), 247 (20,562), 327 (14,393) nm; IR (KBr): ν_max 2964, 2901, 2840, 1707, 1601, 1573, 1365, 1307, 1216, 1172, 1144, 1041, 1028, 825, 748, 703 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.28 (t, J = 6.0 Hz, 3H, CH₃CH₂), 3.22 (s, 3H, OMe), 3.73 (s, 3H, OMe), 3.84 (s, 3H, OMe), 4.24 (q, J = 6.0 Hz, 2H, CH₂CH₃), 4.55 (s, 2H, CH₂N), 6.19 (d, J = 3.0 Hz, 1H, ArH6), 6.65 (d, J = 9.0 Hz, 2H, ArH2′, ArH6′), 6.85 (d, J = 9.0 Hz, 2H, ArH3′, ArH5′), 6.99–7.01 (m, 3H, Ph, ArH8), 7.10–7.13 (m, 3H, Ph); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.4 (Me), 55.0 (2 × OMe), 55.3 (OMe), 61.9 (CH₂N), 65.8 (OCH₂), 96.5 (ArC6, ArC8), 100.2 (ArC), 113.0 (ArC5′), 114.2 (ArC3′), 125.5 (ArC3), 127.1 (ArC4″, ArC4), 129.2 (ArC3″, ArC5″), 129.6 (ArC2″, ArC6″), 131.7 (ArC2′, ArC6′), 132.1 (ArC1′), 139.6 (ArC), 140.6 (ArC1″), 153.5 (COO), 157.4 (ArC4′), 157.7 (ArC7), 159.5 (ArC5); HRMS (ESI) m/z Calcd. for C₂₇H₂₇NO₅Na (M + Na)⁺: 468.1787. Found: 468.1773; Anal. Calcd. for C₂₇H₂₇NO₅: C, 72.79; H, 6.11; N, 3.14. Found: C, 72.84; H, 6.18; N, 3.19.

• Ethyl 4-(4-(tert-butyl)phenyl)-5,7-dimethoxy-3-(4-methoxyphenyl)quinoline-1(2H)-carboxylate (9d)

White solid (0.8 g, 57%). M.p. 118–120 °C; UV (MeOH): λ_max 212 (ε 67,271 cm⁻¹M⁻¹), 245 (22,589), 325 (15,303) nm; IR (KBr): ν_max 2936, 1693, 1606, 1513, 1451, 1329, 1248, 1202, 1168, 1138, 1032, 858, 831, 811, 760, 656 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.27 (s, 9H, 3 × Me), 1.28 (t, J = 7.2 Hz, 3H, CH₃CH₂), 3.19 (s, 3H, OMe), 3.74 (s, 3H, OMe), 3.83 (s, 3H, OMe), 4.24 (q, J = 7.2 Hz, 2H, CH₂CH₃), 4.54 (s, 2H, CH₂N), 6.18 (d, J = 3.0 Hz, 1H, ArH6), 6.65 (d, J = 8.7 Hz, 2H, ArH3′, ArH5′), 6.87 (d, J = 6.3 Hz, 2H, ArH3″, ArH5″), 6.90 (d, J = 5.7 Hz, 2H, ArH2″, ArH6″), 6.99 (d, J = 3.0 Hz, 1H, ArH8), 7.13 (d, J = 8.3 Hz, 2H, ArH2′, ArH6′); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.6 (Me), 31.4 (3 × MeC), 34.4 (CMe), 49.0 (CH₂N), 55.1 (OMe), 55.4 (OMe), 55.5 (OMe), 62.1 (OCH₂), 96.9 (ArC6, ArC8), 100.4 (ArC), 113.0 (ArC3′, ArC5′), 114.7 (CHAr′), 124.0 (ArC3″, ArC5″), 128.9 (ArC4), 129.8 (ArC2′, ArC6′), 131.8 (ArC1′), 132.5 (ArC2″, ArC6″), 137.7 (ArC1″), 139.8 (ArC), 148.5 (ArC4″), 153.7 (COO), 157.7 (ArC4′) 157.8 (ArC7), 159.5 (ArC5); HRMS (ESI) m/z Calcd. for C₃₁H₃₆NO₅ (M + H)⁺: 502.2593. Found: 502.2579.

• Ethyl 5,7-dimethoxy-3-(4-methoxyphenyl)-4-(p-tolyl)quinoline-1(2H)-carboxylate (9e)

White solid (0.8 g, 60.5%). M.p. 124–126 °C; UV (MeOH): λ_max 214 (ε 41,875 cm⁻¹M⁻¹), 248 (17,296), 326 (11,834) nm; IR (KBr): ν_max 2957, 2837, 1702, 1599, 1507, 1443, 1241, 1148, 1109, 1051, 1021, 824, 806, 775, 762, 720 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.30 (t, J = 6.0 Hz, 3H, CH₃CH₂), 2.30 (s, 3H, MeAr″), 3.26 (s, 3H, OMe), 3.76 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.26 (q, J = 6.0 Hz, 2H, CH₂CH₃), 4.55 (s, 2H, CH₂N), 6.21 (d, J = 3.0 Hz, 1H, ArH6), 6.69 (d, J = 9.0 Hz, 2H, ArH3′, ArH5′), 6.87–6.92 (m, 4H, ArH2″, ArH3″, ArH5″, ArH6″), 6.95 (d, J = 9.0 Hz, 2H, ArH2′, ArH6′), 7.01 (d, J = 3.0 Hz, 1H, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.5 (Me), 21.2 (MeAr″), 49.0 (CH₂N), 55.1 (OMe), 55.4 (OMe), 55.5 (OMe), 62.0 (OCH₂), 96.8 (ArC6, ArC8), 100.4 (ArC), 113.1 (ArC3′, ArC5′), 114.6 (CHAr′), 127.9 (ArC3″, ArC5″), 129.1 (ArC4′), 129.7 (ArC2′, ArC6′), 131.8 (ArC1′), 132.5 (ArC2″, ArC6″), 135.0 (ArC1″), 137.5 (ArC), 139.8 (ArC4″), 153.6 (COO), 157.7 (ArC4′), 157.8 (ArC7), 159.5 (ArC5); HRMS (ESI) m/z Calcd. for C₂₈H₂₉NO₅Na (M + Na)⁺: 482.1943. Found: 482.1930; Anal. Calcd. for C₂₈H₂₉NO₅: C, 73.18; H, 6.36; N, 3.05. Found: C, 73.29; H, 6.47; N, 3.01.

• Ethyl 5,7-dimethoxy-3,4-diphenylquinoline-1(2H)-carboxylate (9f)

White solid (0.8 g, 58%). M.p. 112–114 °C; UV (MeOH): λ_max 216 (ε 65,759 cm⁻¹M⁻¹), 248 (27,210), 324 (15,873) nm; IR (KBr): ν_max 2973, 2840, 1698, 1595, 1567, 1443, 1396, 1323, 1259, 1146, 1133, 1049, 1031, 1014, 885, 848, 832, 765, 699 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.32 (t, J = 6.0 Hz, 3H, CH₃CH₂), 3.26 (s, 3H, OMe), 3.88 (s, 3H, OMe), 4.28 (q, J = 7.2 Hz, 2H, CH₂CH₃), 4.61 (s, 2H, CH₂N), 6.23 (d, J = 3.0 Hz, 1H, ArH6), 6.96–7.04 (m, 5H, ArH′, Ar″H), 7.11–7.19 (m, 6H, ArH′, ArH″, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.5 (Me), 48.9 (CH₂N), 55.4 (2 × OMe), 62.1 (OCH₂), 96.7 (ArC6, ArC8), 100.4 (ArC), 114.2 (CHAr′), 125.7 (ArC6′), 126.3 (ArC2′), 127.1 (ArC4′, ArC4″), 127.7 (ArC2″, ArC6″), 128.5 (ArC3′, ArC5′), 129.3 (ArC3″, ArC5″), 132.7 (ArC4), 139.8 (ArC), 139.9 (ArC1′), 140.5 (ArC1″), 153.6 (COO), 157.7 (ArC7), 159.8 (ArC5); HRMS (ESI) m/z Calcd. for C₂₆H₂₅NO₄Na (M + Na)⁺: 438.1681. Found: 438.1667; Anal. Calcd. for C₂₆H₂₅NO₄: C, 75.16; H, 6.06; N, 3.37. Found: C, 75.19; H, 6.16; N, 3.33.

• Ethyl 5,7-dimethoxy-3-phenyl-4-(p-tolyl)quinoline-1(2H)-carboxylate (9g)

White solid (0.7 g, 53%). M.p. 118–120 °C; UV (MeOH): λ_max 203 (ε 100,357 cm⁻¹M⁻¹), 252 (54,057), 317 (30,190) nm; IR (KBr): ν_max 2938, 1708, 1599, 1574, 1443, 1397, 1320, 1265, 1203, 1151, 1136, 1047, 1034, 968, 939, 899, 808, 762, 699 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.28 (t, J = 6.0 Hz, 3H, CH₃CH₂), 2.28 (s, 3H, MeAr″), 3.23 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.24 (q, J = 7.2 Hz, 2H, CH₂CH₃), 4.55 (s, 2H, CH₂N), 6.20 (d, J = 3.0 Hz, 1H, ArH6), 6.82–7.00 (m, 7H, ArH′, ArH″), 7.08–7.11 (m, 3H, ArH′, ArH″, ArH8′); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.5 (Me), 21.2 (MeAr″), 48.9 (CH₂N), 55.4 (OMe), 55.5 (OMe), 62.1 (OCH₂), 96.8 (ArC6, ArC8), 114.4 (ArC), 126.2 (CHAr′), 127.7 (ArC6′), 127.8 (ArC2′), 127.9 (ArC4′), 128.0 (ArC5′), 128.3 (ArC3′), 128.5 (ArC5″), 129.1 (ArC3″), 132.5 (ArC4), 135.1 (ArC2″, ArC6″), 137.3 (ArC, ArC4″), 140.0 (ArC1″), 140.2 (ArC1′), 153.6 (COO), 157.8 (ArC7), 159.7 (ArC5); HRMS (ESI) m/z Calcd. for C₂₇H₂₇NO₄Na (M + Na)⁺: 452.1838. Found: 452.1828; Anal. Calcd. for C₂₇H₂₇NO₄: C, 75.50; H, 6.34; N, 3.26. Found: C, 75.56; H, 6.51; N, 3.14.

• Ethyl cis-5,7-dimethoxy-3,4-bis(4-methoxyphenyl)-3,4-dihydroquinoline-1(2H)-carboxylate (10b)

White solid (0.6 g, 92%). M.p. 122–124 °C; UV (MeOH): λ_max 216 (ε 454,959 cm⁻¹M⁻¹), 284 (31,847), 336 (50,045) nm; IR (KBr): ν_max 2971, 2905, 2841, 1703, 1607, 1584, 1511, 1375, 1239, 1169, 1154, 1039, 1023, 936, 889, 811, 763 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.33 (t, J = 9.0 Hz, 3H, CH₃CH₂), 3.31 (dt, J = 3.0, 12.0 Hz, 1H, H3), 3.60 (s, 3H, OMe), 3.61–3.70 (m, 1H, H2a), 3.72 (s, 3H, OMe), 3.79 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.06 (ddd, J = 3.0, 3.0, 12.0 Hz, 1H, H2b), 4.29 (q, J = 9.0 Hz, 2H, CH₂CH₃), 4.42 (dd, J = 3.0, 6.0 Hz, 1H, H4), 6.22 (d, J = 3.0 Hz, 1H, ArH6), 6.48 (d, J = 9.0 Hz, 2H, ArH3′, ArH5′), 6.59 (d, J = 9.0 Hz, 2H, ArH3″, ArH5″), 6.70–6.77 (m, 4H, ArH2′, ArH6′, ArH2″, ArH6″), 7.44 (d, J = 3.0 Hz, 1H, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.5 (Me), 42.8 (ArC4), 42.9 (ArC3), 44.8 (CH₂N), 55.0 (OMe), 55.1 (OMe), 55.3 (OMe), 55.6 (OMe), 61.9 (OCH₂), 94.4 (ArC6, ArC8), 99.2 (ArC), 112.5 (ArC3′, ArC5′), 113.2 (ArC3″, ArC5″), 129.2 (ArC2′, ArC6′), 130.4 (ArC2″, ArC6″), 131.6 (ArC), 132.2 (ArC1″), 138.8 (ArC1′), 154.9 (COO), 156.9 (ArC5), 157.8 (ArC5), 158.2 (ArC4′), 158.7 (ArC4″); HRMS (ESI) m/z Calcd. for C₂₈H₃₁NO₆Na (M + Na)⁺: 500.2049. Found: 500.2034; Anal. Calcd. for C₂₈H₃₁NO₆: C, 70.42; H, 6.54; N, 2.93. Found: C, 70.58; H, 6.72; N, 2.88.

• Ethyl cis-5,7-dimethoxy-3-(4-methoxyphenyl)-4-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate (10c)

White solid (0.6 g, 95%). M.p. 160–162 °C; UV (MeOH): λ_max 216 (ε 54,328 cm⁻¹M⁻¹), 283 (2388), 336 (5970) nm; IR (KBr): ν_max 3001, 2977, 2950, 2837, 1710, 1590, 1516, 1251, 1239, 1060, 1043, 830, 758, 701 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.33 (t, J = 6.0 Hz, 3H, CH₃CH₂), 3.36 (dt, J = 3.0, 12.0 Hz, 1H, H3), 3.58 (s, 3H, OMe), 3.67 (t, J = 12.0 Hz, 1H, H2a), 3.78 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.09 (ddd, J = 3.0, 6.0, 12.0 Hz, 1H, H2b), 4.29 (q, J = 6.0 Hz, 2H, CH₂CH₃), 4.45 (d, J = 3.0, 1H, H4), 6.21 (d, J = 3.0 Hz, 1H, ArH6), 6.56–6.59 (m, 2H, Ph), 6.68–6.75 (m, 4H, ArH2′, ArH3′, ArH5′, ArH6′), 7.01–7.10 (m, 3H, Ph), 7.45 (d, J = 3.0 Hz, 1H, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.5 (Me), 42.9 (ArC4), 43.7 (ArC3), 44.8 (CH₂N), 55.1 (OMe), 55.3 (OMe), 55.6 (OMe), 61.9 (OCH₂), 94.4 (ArC6, ArC8), 99.2 (ArC), 113.2 (ArC3′, ArC5′), 125.9 (ArC4″), 127.1 (ArC2′, Ar′C6), 129.1 (ArC2″, ArC6″), 129.5 (ArC3″, ArC5″), 132.1 (ArC), 138.9 (ArC1″), 139.7 (ArC1′), 154.9 (COO), 157.0 (ArC5), 158.3 (ArC5), 158.8 (ArC4′); HRMS (ESI) m/z Calcd. for C₂₇H₂₉NO₅Na (M + Na)⁺: 470.1943. Found: 470.1927; Anal. Calcd. for C₂₇H₂₉NO₅: C, 72.46; H, 6.53; N, 3.13. Found: C, 72.65; H, 6.45; N, 3.19.

• Ethyl cis-4-(4-(tert-butyl)phenyl)-5,7-dimethoxy-3-(4-methoxyphenyl)-3,4-dihydroquinoline-1(2H)-carboxylate (10d)

White solid (0.65 g, 91.5%). M.p. 116–118 °C; UV (MeOH): λ_max 203 (ε 71,732 cm⁻¹M⁻¹), 220 (74,830) nm; IR (KBr): ν_max 3154, 2959, 1712, 1590, 1512, 1373, 1267, 1240, 1060, 1042, 838, 812, 762 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.28 (s, 9H, 3 × Me), 1.38 (t, J = 6.0 Hz, 3H, CH₃CH₂), 3.36 (dt, J = 6.0, 12.0 Hz, 1H, H3), 3.64 (s, 3H, OMe), 3.72 (t, J = 15.0 Hz, 1H, H2a), 3.82 (s, 3H, OMe), 3.89 (s, 3H, OMe), 4.08 (ddd, J = 3.0, 6.0, 12.0 Hz, 1H, H2b), 4.34 (q, J = 6.0 Hz, 2H, CH₂CH₃), 4.48 (d, J = 6.0, 1H, H4), 6.26 (d, J = 3.0 Hz, 1H, ArH6), 6.54 (d, J = 9.0 Hz, 2H, ArH3′, ArH5′), 6.71–6.78 (m, 4H, ArH2′, ArH6′, ArH2″, ArH6″), 7.09 (d, J = 9H, 2H, ArH3″, ArH5″), 7.47 (d, J = 3.0 Hz, 1H, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.6 (Me), 31.4 (3 × MeC), 34.3 (CMe), 43.2 (ArC4, ArC3), 45.2 (CH₂N), 55.2 (OMe), 55.4 (OMe), 55.7 (OMe), 62.0 (OCH₂), 94.5 (ArC6, ArC8), 99.5 (ArC), 113.2 (ArC3′, ArC5′), 124.1 (ArC3″, ArC5″), 129.2 (ArC2′, ArC6′), 129.3 (ArC2″, ArC6″), 132.3 (ArC), 136.3 (ArC1″), 138.9 (ArC1′), 148.8 (ArC4″), 155.1 (COO), 157.0 (ArC5), 158.4 (ArC7), 158.8 (ArC4′); HRMS (ESI) m/z Calcd. for C₃₁H₃₇NO₅Na (M + Na)⁺: 526.2569. Found: 526.2555; Anal. Calcd. for C₃₁H₃₇NO₅: C, 73.93; H, 7.41; N, 2.78. Found: C, 73.65; H, 7.45; N, 2.74.

• Ethyl cis-5,7-dimethoxy-3-(4-methoxyphenyl)-4-(p-tolyl)-3,4-dihydroquinoline-1(2H)-carboxylate (10e)

White solid (0.65 g, 95.5%). M.p. 140–142 °C; UV (MeOH): λ_max 217 (ε 61,337 cm⁻¹M⁻¹), 283 (2067), 336 (7581) nm; IR (KBr): ν_max 2978, 1704, 1586, 1513, 1376, 1241, 1169, 1058, 1042, 1024, 937, 889, 809, 761 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.36 (t, J = 7.2 Hz, 3H, CH₃CH₂), 2.26 (s, 3H, MeAr″), 3.35 (dt, J = 4.2, 13.5 Hz, 1H, H3), 3.62 (s, 3H, OMe), 3.69 (t, J = 13.5 Hz, 1H, H2a), 3.81 (s, 3H, OMe), 3.87 (s, 3H, OMe), 4.08 (ddd, J = 1.5, 4.50, 12.3 Hz, 1H, H2b), 4.31 (q, J = 7.2 Hz, 2H, CH₂CH₃), 4.46 (d, J = 3.6 Hz, 1H, H4), 6.23 (d, J = 2.4 Hz, 1H, ArH6), 6.47 (d, J = 8.1 Hz, 2H, ArH3′, ArH5′), 6.76 (s, 4H, ArH2″, ArH3″, ArH5″, ArH6″), 6.86 (d, J = 7.8 Hz, 2H, ArH2′, ArH6′), 7.47 (d, J = 2.1 Hz, 1H, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.6 (Me), 21.0 (MeAr″), 43.0 (ArC4), 43.3 (ArC3), 45.0 (CH₂N), 55.2 (OMe), 55.4 (OMe), 55.7 (OMe), 62.0 (OCH₂), 94.5 (ArC6, ArC8), 99.3 (ArC), 113.3 (ArC3′, ArC5′), 128.0 (ArC2′, ArC6′), 129.3 (ArC2″, ArC6″), 129.5 (ArC3″, ArC5″), 132.2 (ArC), 135.5 (ArC4″), 136.4 (ArC1′), 138.9 (ArC1″), 155.0 (COO), 157.0 (ArC5), 158.4 (ArC7), 158.8 (ArC4′); HRMS (ESI) m/z Calcd. for C₂₈H₃₁NO₅Na (M + Na)⁺: 484.2100. Found: 484.2087; Anal. Calcd. for C₂₈H₃₁NO₅: C, 72.86; H, 6.77; N, 3.03. Found: C, 72.89; H, 6.93; N, 2.98.

• Ethyl cis-5,7-dimethoxy-3,4-diphenyl-3,4-dihydroquinoline-1(2H)-carboxylate (10f)

White solid (0.65 g, 93%). M.p. 90–92 °C; UV (MeOH): λ_max 215 (ε 49,140 cm⁻¹M⁻¹), 247 (20,147), 337 (10,319) nm; IR (KBr): ν_max 3001, 2939, 2839, 1687, 1579, 1489, 1454, 1368, 1307, 1214, 1202, 1173, 1063, 1039, 1022, 949, 882, 836, 823, 758, 656 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.37 (t, J = 7.2 Hz, 3H, CH₃CH₂), 3.46 (dt, J = 4.2, 13.2 Hz, 1H, H3), 3.61 (s, 3H, OMe), 3.77 (t, J = 12.9 Hz, 1H, H2a), 3.89 (s, 3H, OMe), 4.20 (ddd, J = 1.5, 4.2, 12.6 Hz, 1H, H2b), 4.33 (q, J = 7.2 Hz, 2H, CH₂CH₃), 4.55 (d, J = 4.8 Hz, 1H, H4), 6.26 (d, J = 2.4 Hz, 1H, ArH6), 6.57–6.61 (m, 2H, ArH′), 6.82–6.85 (m, 2H, ArH″), 7.03–7.14 (m, 3H, ArH′), 7.21–7.25 (m, 3H, ArH″), 7.50 (d, J = 2.4 Hz, 1H, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.6 (Me), 43.7 (ArC4), 43.9 (ArC3), 44.5 (CH₂N), 55.4 (OMe), 55.7 (OMe), 62.0 (OCH₂), 94.6 (ArC6), 99.3 (ArC8), 113.5 (ArC), 126.0 (ArC4′), 126.8 (ArC4″), 127.2 (ArC2″, ArC6″), 127.9 (ArC3′, ArC5′), 128.2 (ArC2′, ArC6′), 129.6 (ArC3″, ArC5″), 139.1 (ArC), 139.9 (ArC1″), 140.1 (ArC1′), 155.0 (COO), 157.2 (ArC5), 159.0 (ArC7); HRMS (ESI) m/z Calcd. for C₂₆H₂₇NO₄Na (M + Na)⁺: 440.1838. Found: 440.1822; Anal. Calcd. for C₂₆H₂₇NO₄: C, 74.80; H, 6.52; N, 3.35. Found: C, 74.96; H, 6.66; N, 3.32.

• Ethyl cis-5,7-dimethoxy-3-phenyl-4-(p-tolyl)-3,4-dihydroquinoline-1(2H)-carboxylate (10g)

White solid (0.6 g, 95%). M.p. 122–124 °C; UV (MeOH): λ_max 216 (ε 134,352 cm⁻¹M⁻¹) nm; IR (KBr): ν_max 2939, 1723, 1690, 1589, 1455, 1373, 1325, 1287, 1243, 1170, 1140, 1057, 1044, 940, 885, 821, 808, 761, 698 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.33 (t, J = 6.9 Hz, 3H, CH₃CH₂), 2.23 (s, 3H, MeAr″), 3.38 (dt, J = 4.2, 13.2 Hz, 1H, H3), 3.59 (s, 3H, OMe), 3.72 (t, J = 13.2 Hz, 1H, H2a), 3.85 (s, 3H, OMe), 4.12 (ddd, J = 1.5, 4.2, 12.3 Hz, 1H, H2b), 4.29 (q, J = 6.9 Hz, 2H, CH₂CH₃), 4.48 (d, J = 4.2 Hz, 1H, H4), 6.21 (d, J = 2.4 Hz, 1H, ArH6), 6.43 (d, J = 8.1 Hz, 2H, ArH3″, ArH5″), 6.81–6.84 (m, 4H, Ph), 7.18–7.21 (m, 3H, ArH2″, ArH6″, Ph), 7.45 (d, J = 2.4 Hz, 1H, ArH8); ¹³C NMR (75.6 MHz, CDCl₃): δ 14.6 (Me), 21.0 (MeAr″), 43.3 (ArC4), 43.7 (ArC3), 44.7 (CH₂N), 55.4 (OMe), 55.7 (OMe), 62.0 (OCH₂), 94.5 (ArC6), 99.3 (ArC8), 113.9 (ArC), 126.7 (ArC4′), 127.9 (ArC2′, ArC6′), 128.0 (Ar″C2, Ar″C6), 128.3 (ArC3′, ArC5′), 129.4 (ArC3″, ArC5″), 135.5 (ArC4″), 136.4 (ArC), 139.0 (ArC1″), 140.2 (ArC1′), 155.0 (COO), 157.1 (ArC5), 158.9 (ArC7); HRMS (ESI) m/z Calcd. for C₂₇H₂₉NO₄Na (M + Na)⁺: 454.1994. Found: 454.1980; Anal. Calcd. for C₂₇H₂₉NO₄: C, 75.15; H, 6.77; N, 3.25. Found: C, 75.40; H, 6.87; N, 3.22.

• cis-5,7-Dimethoxy-3,4-bis(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline (3b)

White solid (0.35 g, 82%). M.p. 102–104 °C; UV (MeOH): λ_max 214 (ε 62,383 cm⁻¹M⁻¹), 246 (23,705), 337 (13,100) nm; IR (KBr): ν_max 2935, 1703, 1608, 1583, 1511, 1234, 1204, 1168, 1143, 1032, 953, 826, 763 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 3.21 (ddd, J = 3.0, 6.0, 9.0 Hz, 1H, H2b), 3.31 (dt, J = 6.0, 12.0 Hz, 1H, H3), 3.53–3.60 (m, 1H, H2a), 3.57 (s, 3H, OMe), 3.72 (s, 3H, OMe), 3.77 (s, 3H, OMe), 3.78 (s, 3H, OMe), 4.13 (bs, 1H, NH), 4.31 (dd, J = 3.0, 6.0 Hz, 1H, H4), 5.82 (d, J = 3.0 Hz, 1H, ArH6), 5.84 (d, J = 3.0 Hz, 1H, ArH8), 6.54–6.58 (m, 4H, ArH3′, ArH5′, ArH3″, ArH5″), 6.63 (d, J = 9.0 Hz, 2H, ArH2″, ArH6″), 6.70 (d, J = 9.0 Hz, 2H, ArH2′, ArH6′); ¹³C NMR (75.6 MHz, CDCl₃): δ 40.9 (ArC4), 42.0 (ArC3), 42.4 (CH₂N), 54.9 (OMe), 55.0 (OMe), 55.1 (OMe), 55.4 (OMe), 87.9 (ArC6), 90.7 (ArC8), 105.5 (ArC), 112.1 (ArC3′, ArC5′), 113.0 (ArC3″, ArC5″), 129.0 (ArC2′, ArC6′), 130.6 (ArC2″, ArC6″), 133.4 (ArC1″), 134.3 (ArC1′), 145.0 (ArC), 157.4 (ArC5), 157.9 (ArC7), 158.3 (ArC4′), 159.9 (ArC1″); HRMS (ESI) m/z Calcd. for C₂₅H₂₈NO₄ (M + H)⁺: 406.2018. Found: 406.2006; Anal. Calcd. for C₂₅H₂₇NO₄.0.25 H₂O: C, 73.24; H, 6.76; N, 3.42. Found: C, 73.48; H, 6.82; N, 3.38.

• cis-5,7-Dimethoxy-3-(4-methoxyphenyl)-4-phenyl-1,2,3,4-tetrahydroquinoline (3c)

White solid (0.4 g, 87%). M.p. 166–168 °C; UV (MeOH): λ_max 203 (ε 51,440 cm⁻¹M⁻¹), 216 (51,440), 337 (5144) nm; IR (KBr): ν_max 3425, 3006, 2964, 2906, 2838, 2877, 1603, 1503, 1402, 1207, 1111, 1134, 1090, 1054, 810, 796, 728 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 3.21 (ddd, J = 3.0, 3.0, 9.0 Hz, 1H, H2b), 3.35 (dt, J = 3.0, 12.0 Hz, 1H, H3), 3.56 (s, 3H, OMe), 3.59–3.64 (m, 1H, H2a), 3.76 (s, 3H, OMe), 3.78 (s, 3H, OMe), 4.14 (bs, 1H, NH), 4.35 (d, J = 3.0, 1H, H4), 5.82 (d, J = 3.0 Hz, 1H, ArH6), 5.85 (d, J = 3.0 Hz, 1H, ArH8), 6.60–6.71 (m, 6H, ArH3′, ArH5′, ArH2″, ArH4″, ArH5″, ArH6″), 7.01–7.06 (m, 3H, ArH2′, ArH6′, ArH3″); ¹³C NMR (75.6 MHz, CDCl₃): δ 40.9 (ArC4), 41.9 (ArC3), 43.3 (CH₂N), 55.0 (OMe), 55.1 (OMe), 55.3 (OMe), 87.9 (ArC6), 90.6 (ArC8), 105.2 (ArC), 113.0 (ArC3′, ArC5′), 125.5 (ArC4″), 126.7 (ArC2′, ArC6′), 128.9 (ArC2″, ArC6″), 129.8 (ArC3″, ArC5″), 133.3 (ArC), 142.1 (ArC1″), 145.1 (ArC1′), 157.9 (ArC5), 158.4 (ArC7), 159.9 (ArC4′); HRMS (ESI) m/z Calcd. for C₂₄H₂₆NO₃ (M + H)⁺: 376.1913. Found: 376.1902; Anal. Calcd. for C₂₄H₂₅NO₃: C, 76.77; H, 6.71; N, 3.73. Found: C, 77.00; H, 6.98; N, 3.70.

• cis-4-(4-(tert-Butyl)phenyl)-5,7-dimethoxy-3-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline (3d)

White solid (0.4 g, 90.5%). M.p. 118–120 °C; UV (MeOH): λ_max 203 (ε 85,611 cm⁻¹M⁻¹), 216 (80,755) nm; IR (KBr): ν_max 3427, 2960, 1609, 1509, 1222, 1211, 1133, 1109, 1050, 1023, 831, 805, 704 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 1.23 (s, 9H, 3 × Me), 3.24 (ddd, J = 3.0, 6.0, 15.0 Hz, 1H, H2b), 3.35 (dt, J = 3.0, 15.0 Hz, 1H, H3), 3.56–3.63 (m, 1H, H2a), 3.57 (s, 3H, OMe), 3.76 (s, 3H, OMe), 3.77 (s, 3H, OMe), 3.84 (bs, 1H, NH), 4.32 (d, J = 3.0, 1H, H4), 5.89 (d, J = 3.0 Hz, 1H, ArH6), 5.97 (d, J = 3.0 Hz, 1H, ArH8), 6.53–6.57 (m, 4H, ArH3′, ArH5′, ArH2″, ArH4″), 6.65 (d, J = 9.0 Hz, 2H, ArH2′, ArH6′), 7.03 (d, J = 9.0 Hz, 2H, ArH3″, ArH5″); ¹³C NMR (75.6 MHz, CDCl₃): δ 31.4 (3 × Me), 34.2 (CMe), 41.2 (ArC4, ArC3), 42.7 (CH₂N), 55.2 (2 × OMe), 55.5 (OMe), 89.5 (ArC6), 91.8 (ArC8), 106.9 (ArC), 113.0 (ArC3′, ArC5′), 123.7 (Ar″C3, Ar″C5), 129.1 (ArC2′, ArC6′), 129.3 (ArC2″, ArC6″), 133.3 (ArC), 138.6 (ArC1″, ArC1′), 148.4 (ArC4″), 158.1 (ArC5), 158.5 (ArC7), 160.0 (Ar′C4); HRMS (ESI) m/z Calcd. for C₂₅H₂₄NO₄ (M + H)⁺: 402.1705. Found: 402.1692.

• cis-5,7-Dimethoxy-3-(4-methoxyphenyl)-4-(p-tolyl)-1,2,3,4-tetrahydroquinoline (3e)

White solid (0.4 g, 87%). M.p. 170–172 °C; UV (MeOH): λ_max 203 (ε 54,535 cm⁻¹M⁻¹), 212 (55,648), 246 (21,702), 336 (11,686) nm; IR (KBr): ν_max 3418, 3002, 2918, 2837, 1613, 1511, 1223, 1110, 1099, 1049, 1030, 822, 767 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.16 (s, 3H, MeAr″), 3.13 (ddd, J = 1.5, 3.6, 10.8 Hz, 1H, H2a), 3.25 (dt, J = 3.9, 12.3 Hz, 1H, H3), 3.41–3.54 (m, 1H, H2b), 3.49 (s, 3H, OMe), 3.69 (s, 3H, OMe), 3.70 (s, 3H, OMe), 4.05 (bs, 1H, NH), 4.26 (d, J = 3.6, 1H, H4), 5.74 (d, J = 2.4 Hz, 1H, ArH6), 5.77 (d, J = 2.1 Hz, 1H, ArH8), 6.46 (d, J = 8.1 Hz, 2H, ArH3′, ArH5′), 6.55 (d, J = 8.7 Hz, 2H, ArH2″, ArH6″), 6.63 (d, J = 9.0 Hz, 2H, ArH3″, ArH5″), 6.77 (d, J = 8.4 Hz, 2H, ArH2′, ArH6′); ¹³C NMR (75.6 MHz, CDCl₃): δ 21.0 (MeAr″), 41.1 (ArC4), 42.0 (ArC3), 42.9 (CH₂N), 55.1 (OMe), 55.2 (OMe), 55.5 (OMe), 88.0 (ArC6), 90.8 (ArC8), 105.6 (ArC), 113.1 (ArC3′, ArC5′), 127.6 (ArC2′, ArC6′), 129.1 (ArC2″, ArC6″), 129.8 (ArC3″, ArC5″), 133.6 (ArC), 134.9 (ArC4″), 139.0 (ArC1″), 145.1 (ArC1′), 158.0 (ArC5), 158.5 (ArC7), 160.0 (ArC4′); HRMS (ESI) m/z Calcd. for C₂₅H₂₈NO₃ (M + H)⁺: 390.2069. Found: 390.2054; Anal. Calcd. for C₂₅H₂₇NO₃: C, 77.09; H, 6.99; N, 3.60. Found: C, 76.97; H, 7.09; N, 3.54.

• cis-5,7-Dimethoxy-3,4-diphenyl-1,2,3,4-tetrahydroquinoline (3f)

White solid (0.4 g, 86.5%). M.p. 180–182 °C; UV (MeOH): λ_max 214 (ε 43,196 cm⁻¹M⁻¹), 337 (6479) nm; IR (KBr): ν_max 3424, 2873, 1598, 1507, 1451, 1401, 1367, 1219, 1203, 1132, 1095, 1078, 1046, 936, 796, 764, 662 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 3.27 (ddd, J = 1.5, 3.6, 11.1 Hz, 1H, H2a), 3.41 (dt, J = 3.9, 12.6 Hz, 1H, H3), 3.56 (s, 3H, OMe), 3.66 (t, J = 12.3 Hz, 1H, H2b), 3.78 (s, 3H, OMe), 4.05 (bs, 1H, NH), 4.41 (dd, J = 1.2, 4.8 Hz, 1H, H4), 5.83 (d, J = 2.4 Hz, 1H, ArH6), 5.87 (d, J = 2.1 Hz, 1H, ArH8), 6.62–6.65 (m, 2H, ArH′), 6.70–6.74 (m, 2H, ArH″), 6.99–7.07 (m, 3H, ArH′), 7.12–7.16 (m, 3H, ArH″); ¹³C NMR (75.6 MHz, CDCl₃): δ 40.7 (ArC4), 42.8 (ArC3), 43.4 (CH₂N), 55.1 (OMe), 55.4 (OMe), 88.2 (ArC6), 90.9 (ArC8), 105.4 (ArC), 125.7 (ArC4″), 126.3 (ArC4′), 126.8 (ArC2′, ArC6′), 127.7 (ArC2″, ArC6″), 128.1 (ArC3′, ArC5′), 129.8 (ArC3″, ArC5″), 141.3 (ArC), 142.2 (ArC1″), 145.0 (ArC1′), 158.5 (ArC5), 160.1 (ArC7); HRMS (ESI) m/z Calcd. for C₂₃H₂₄NO₂ (M + H)⁺: 346.1807. Found: 346.1794; Anal. Calcd. for C₂₃H₂₃NO₂: C, 79.97; H, 6.71; N, 4.05. Found: C, 80.00; H, 6.82; N, 4.02.

• cis-5,7-Dimethoxy-3-phenyl-4-(p-tolyl)-1,2,3,4-tetrahydroquinoline (3g)

White solid (0.4 g, 91%). M.p. 184–186 °C; UV (MeOH): λ_max 216 (ε 110,601 cm⁻¹M⁻¹) nm; IR (KBr): ν_max 3395, 2850, 1617, 1589, 1514, 1470, 1351, 1315, 1222, 1170, 1130, 1096, 1046, 945, 755, 695 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.23 (s, 3H, MeAr″), 3.26 (ddd, J = 1.8, 3.6, 11.1 Hz, 1H, H2a), 3.38 (dt, J = 3.9, 12.3 Hz, 1H, H3), 3.57 (s, 3H, OMe), 3.65 (t, J = 11.1 Hz, 1H, H2b), 3.78 (s, 3H, OMe), 4.39 (dd, J = 1.2, 4.2 Hz, 1H, H4), 5.83 (d, J = 2.1 Hz, 1H, ArH6), 5.86 (d, J = 2.1 Hz, 1H, ArH8), 6.51 (d, J = 8.1 Hz, 2H, ArH3″, ArH5″), 6.73–6.76 (m, 2H, Ph), 6.83 (d, J = 7.8 Hz, 2H, ArH2″, ArH6″), 7.15–7.17 (m, 3H, Ph); ¹³C NMR (75.6 MHz, CDCl₃): δ 21.0 (MeAr″), 40.7 (ArC4), 42.8 (ArC3), 42.9 (CH₂N), 55.1 (OMe), 55.5 (OMe), 88.2 (ArC6), 90.9 (ArC8), 105.6 (ArC), 126.3 (ArC4′), 127.6 (ArC2′, ArC6′), 127.7 (ArC2″, ArC6″), 128.2 (ArC3′, ArC5′), 129.7 (ArC3″, ArC5″), 135.0 (ArC4″), 139.0 (ArC), 142.5 (ArC1″), 145.0 (ArC1′), 158.5 (ArC5), 160.0 (ArC7); HRMS (ESI) m/z Calcd. for C₂₄H₂₆NO₂ (M + H)⁺: 360.1964. Found: 360.1952; Anal. Calcd. for C₂₄H₂₅NO₂: C, 80.19; H, 7.01; N, 3.90. Found: C, 80.00; H, 7.13; N, 3.85.

• 4-(4-(tert-Butyl)phenyl)-3-(4-hydroxyphenyl)-5-hydroxy-7-methoxy-1,2,3,4-tetrahydroquinoline (13d)

Yellow solid (0.06 g, 30%). M.p. 232–234 °C; UV (MeOH): λ_max 203 (ε 63,067 cm⁻¹M⁻¹), 216 (65,388) nm; IR (KBr): ν_max 3470, 3383, 2959, 2925, 2853, 1619, 1512, 1461, 1376, 1218, 1197, 1179, 1125, 1106, 1076, 1054, 825, 798, 726 cm⁻¹; ¹H NMR (300 MHz, Acetone-d₆): δ 1.31 (s, 9H, 3 × Me), 3.22–3.36 (m, 2H, H2a, H3), 3.68–3.82 (m, 1H, H2b), 3.72 (s, 3H, OMe), 4.20 (dd, J = 0.9, 4.5 Hz, 1H, H4), 5.33 (bs, 1H, NH), 5.80 (d, J = 2.4 Hz, 1H, ArH6), 5.91 (d, J = 2.1 Hz, 1H, ArH8), 6.62–6.73 (m, 6H, ArH2′, ArH3′, ArH5′, ArH6′, ArH2″, ArH6″), 7.14 (d, J = 8.4 Hz, 2H, ArH3″, ArH5″), 7.71 (s, 1H, OH), 8.16 (s, 1H, OH); ¹³C NMR (75.6 MHz, CDCl₃): δ 30.9 (3 × MeC), 33.9 (CMe), 40.9 (ArC4), 43.1 (ArC3), 43.2 (CH₂N), 54.1 (OMe), 90.2 (ArC6, ArC8), 104.1 (ArC), 114.6 (ArC3′, ArC5′), 123.4 (ArC3″, ArC5″), 128.9 (ArC2″, ArC6″), 129.6 (ArC2′, ArC6′), 139.8 (ArC1″), 139.8 (ArC1′), 147.9 (ArC), 148.0 (ArC4″), 155.5 (ArC4′), 158.2 (ArC5), 160.1 (ArC7); HRMS (ESI) m/z Calcd. for C₂₆H₃₀NO₃ (M + H)⁺: 404.2226. Found: 404.2209.

• 5-Hydroxy-7-methoxy-3,4-diphenyl-1,2,3,4-tetrahydroquinoline (13f)

Yellow solid (0.07 g, 38.5%). M.p. 198–200 °C; UV (MeOH): λ_max 216 (ε 53,867 cm⁻¹M⁻¹), 246 (14,304), 337 (7152) nm; IR (KBr): ν_max 3675, 3377, 2971, 2901, 1625, 1597, 1490, 1450, 1410, 1375, 1231, 1212, 1153, 1118, 1080, 1050, 798, 764, 662 cm⁻¹; ¹H NMR (300 MHz, Acetone-d₆): δ 3.24–3.31 (m, 1H, H2a), 3.38 (dt, J = 3.9, 12.3 Hz, 1H, H3), 3.62–3.80 (m, 1H, H2b), 3.69 (s, 3H, OMe), 4.45 (dd, J = 1.2, 4.8 Hz, 1H, H4), 5.39 (bs, 1H, NH), 5.76 (d, J = 2.4 Hz, 1H, ArH6), 5.89 (d, J = 2.1 Hz, 1H ArH8), 6.67–6.70 (m, 2H, ArH′), 6.79–6.82 (m, 2H, ArH″), 6.99–7.06 (m, 3H, ArH′), 7.14–7.18 (m, 3H, ArH″), 7.78 (s, 1H, OH); ¹³C NMR (75.6 MHz, Acetone-d₆): δ 40.3 (ArC4), 42.7 (ArC3), 43.7 (CH₂N), 54.1 (OMe), 90.1 (ArC6), 90.2 (ArC8), 103.6 (ArC), 125.4 (ArC4″), 126.1 (ArC4′), 126.6 (ArC2′, ArC6′), 127.6 (ArC2″, ArC6″), 128.0 (ArC3′, ArC5′), 130.0 (ArC3″, ArC5″), 141.9 (ArC), 142.7 (ArC1″), 146.3 (ArC1′), 155.6 (ArC5), 160.0 (ArC7); HRMS (ESI) m/z Calcd. for C₂₂H₂₂NO₂ (M + H)⁺: 332.1951. Found: 332.1636.

• 5-Hydroxy-7-methoxy-3-phenyl-4-(p-tolyl)-1,2,3,4-tetrahydroquinoline (13g)

Yellow solid (0.06 g, 32%). M.p. 128–130 °C; UV (MeOH): λ_max 203 (ε 25,755 cm⁻¹M⁻¹) nm; IR (KBr): ν_max 2922, 2852, 1610, 1510, 1451, 1366, 1330, 1286, 1238, 1202, 1111, 1028, 826, 802, 722, 697 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.22 (s, 3H, MeAr″), 3.24 (ddd, J = 1.2, 3.3, 10.8 Hz, 1H, H2a), 3.43 (dt, J = 4.8, 12.3 Hz, 1H, H3), 3.63 (t, J = 12.3 Hz, 1H, H2b), 3.73 (s, 3H, OMe), 4.25 (d, J = 4.8 Hz, 1H, H4), 5.78 (d, J = 2.1 Hz, 1H, ArH6), 5.85 (d, J = 2.1 Hz, 1H, ArH8), 6.55 (d, J = 8.1 Hz, 2H, ArH3″, ArH5″), 6.71–6.74 (m, 2H, Ph), 6.84 (d, J = 7.80 Hz, 2H, ArH2″, ArH6″), 7.12–7.15 (m, 3H, Ph); ¹³C NMR (75.6 MHz, CDCl₃): δ 21.0 (MeAr″), 40.6 (ArC4), 43.3 (ArC3), 43.5 (CH₂N), 54.1 (OMe), 91.6 (ArC6), 91.9 (ArC8), 104.2 (ArC), 126.4 (ArC4′), 127.8 (ArC2′, ArC6′), 128.1 (ArC2″, ArC6″), 128.2 (ArC3′, ArC5′), 129.8 (ArC3″, ArC5″), 136.0 (ArC4″), 137.7 (ArC), 140.9 (ArC1″), 145.6 (Ar′C1), 154.7 (ArC5), 160.1 (ArC7); HRMS (ESI) m/z Calcd. for C₂₃H₂₄NO₂ (M + H)⁺: 346.1807. Found: 346.1791.

4. Conclusions

Attempts to synthesize 3,4-disubstituted 1,2-dihydroquinolines by a Grignard reaction approach were unsuccessful and resulted in the formation of the more stable quinoline moiety.

However, hydrogenation of N-protected 1,2-dihydroquinolines resulted in the formation of the 1,2,3,4-tetrahydroquinolines with cis configuration. Demethylation of these 5,7-dimethoxy tetrahydroquinolines in the presence of two equivalents of BBr₃ for each methoxy group resulted in the formation of the corresponding hydroxyl compounds, though the compounds were seen to have a low stability. The use of one equivalent of BBr₃ for each methoxy group resulted in the formation of 5-hydroxy analogues in good yields.

The biological activity of compound 3c offers opportunities for further SAR studies on various C4 and aromatic substituents of our 1,2,3,4-tetrahydroquinoline scaffold, which could result in lead compounds with improved anticancer potency. Testing of the mono-deprotected analogues 13 would also provide insight into the role of the methoxy groups in the activity of our compounds.