Synthesis and in Vitro Antifungal Activities of New 2-Aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromides

Abstract

2-Aryl-3,4-dihydroisoquinolin-2-iums might be considered as a class of simple analogues of natural quaternary benzo[c]phenanthridine alkaloids. In this paper, 26 new 2-aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium bromides with various substituents in N-aromatic ring were synthesized from commercially available 1,3-benzodioxole in good to excellent yields. All the compounds were elucidated by MS, high resolution (HR)-MS, IR, ¹H- and ¹³C-NMR analysis, and evaluated for antifungal activities in vitro against Alternaria alternate, Curvularia lunata and Fusarium oxysporum sp. niveum at 50 µg/mL. Most of the compounds showed higher activities against all the test fungi than their natural model compounds sanguinarine and chelerythrine. For A. alternate and Curvularia lunata, most of them were also more active than thiabendazole, a commercial fungicide standard. The structure–activity relationship indicated that the substituent in N-aromatic ring and its position had significant effect on the activity. The general trend was that halogen atoms and CF₃ remarkably enhanced the activity while CH₃ and OCH₃ decreased the activity. Generally, o-substituted isomers were more active than m- and p-substituted isomer. The present results suggest that the title compounds are potential for the development of new isoquinoline antimicrobial agents.

Alkaloids represent a very extensive group of secondary metabolites with diverse structures, distribution in nature, and biological effects. Natural isoquinolines are one of the largest groups of alkaloids. Among them, there is a relatively small but important class of iminium moiety-containing isoquinoline alkaloids, such as quaternary benzo[c]phenanthridine alkaloids (QBAs), quaternary N-naphthyl isoquinolines, berberines and so on^1,2) (Fig. 1). In the past decades, these compounds have aroused interests of both chemists and pharmacologists for their chemical reactivity and extensive bioactivities including antitumor,^3–5) antimicrobial,^6–12) anti-inflammation,¹³⁾ anti-platelet aggregation,¹⁴⁾ anti-angiogenesis,¹⁵⁾ anti-acetylcholinesterase,¹⁶⁾ and antiparasite activities.^17–20)

Our previous studies demonstrated that sanguinarine and chelerythrine (Fig. 1) might serve as ideal lead compounds to develop new isoquinoline antimicrobial and acaricidal agents. Meanwhile, the iminium moiety (C=N⁺) was their determinant for their bioactivities.^11,12,17) The similar cases were also found for antitumor activity of 7-demethyl chelerythrine (NK109)²¹⁾ and antibacterial activity of berberine.⁹⁾ In addition, the molecular planarity was also proven to be an important factor for the activity.²¹⁾ Based on understanding of the structure–activity relationship above and the aim of developing more potent QBAs-like drugs, we intended to design a class of structurally simple C=N⁺-containing isoquinoliniums by imitating structural characteristics of sanguinarine or chelerythrine, and know their bioactivities. We expected that the structural similarity between the designed compounds and their model compounds can lead to discovery of new compounds which might have higher activity than the model compounds.

Fig. 1. Natural Quaternary Iminium Isoquinoline Alkaloids

2-Aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-iums, i.e., the title compounds, are just one class of the compounds designed by us, which possess similar isoquinoline framework, iminium moiety (C=N⁺) and molecular length to QBAs (Fig. 2). It was worth noting that they had different stereo structures. Unlike QBAs, the designed compounds had an approximately plane molecular framework but not complete planarity. There exists a dihedral angle between two phenyl rings, which may change as the type and position of substituents on N-aromatic ring change. The molecular flexibility result from the changeable dihedral angle was expected to make the molecules better match the environment of the binding site of their biotarget and have higher bioactivity.

Fig. 2. Molecular Frameworks of the Title Compounds and Their Model Compounds

In literatures, a few methodologies have been developed to synthesize 2-aryl-3,4-dihydroisoquinolin-2-iums.^22–26) Among them, the most common method was the cyclocondensation of 2-(2-bromoethyl)benzaldehyde from isochroman with primary amine (Chart 1). However, we found that the synthetic route in Chart 1 was not suited to the preparation of the title compounds because the synthesis of the desired key intermediate i.e., 2-(2-bromoethyl)-4,5-dimethoxybenzaldehyde was difficult. Bromination of 6,7-methylenedioxy isochroman followed by treatment with aqueous hydrobromic acid did not afford the desired bromoaldehyde but an unidentified polymer. A similar case was also observed in the preparation of 2-(2-bromoethyl)-4,5-dimethoxybenzaldehyde by bromination of 6,7-dimethoxy isochroman.²⁷⁾ For the reason above, Yamato et al. established a two-step approach to 2-(2-bromoethyl)-4,5-dimethoxybenzaldehyde involving the treatment of 6,7-dimethoxyisochroman with ethyl orthoformate in the presence of BF₃ at −78°C followed by treatment with acetyl bromide, but the total yield was only 13%.²⁷⁾

Chart 1. The Bromoaldehyde Method for the Preparation of Dihydroisoquinolinium Salts

Recently, a new approach to dihydroisoquinolinium salts was reported involving N-arylation of tetrahydroisoquinoline followed by N-bromosuccinimide (NBS) mediated oxidation²⁶⁾ (Chart 2). However, this method was only limited to unsubstituted tetrahydroisoquinoline and monobromo- or monoiodo-substituted arenes.^26,28,29) To our best knowledge, few reports on synthesis and bioactivity of the title compounds were found until now.

Chart 2. N-Arylation Method for the Preparation of Dihydroisoquinolinium Salts

The objective of the present research was to synthesize a series of the new title compounds, search for related compounds which might have antifungal activity superior to sanguinarine and chelerythrine, and establish their structure–activity relationship.

Results and Discussion

Chemistry

The synthesis route of the title compounds was outlined in Chart 3. The intermediate 1 was obtained from commercially available 1,3-benzodioxole via five steps consisting of chloromethylation,³⁰⁾ cyanation of chlorine atom,³¹⁾ hydrolysis of cyano group,^29,31) reduction of carboxyl group,³²⁾ and bromination of hydroxyl group.^32,33)

Chart 3. Synthetic Route of the Title Compounds

Compound 1 reacted with paraformaldehyde in concentrated hydrochloric acid containing small amount of POCl₃ at room temperature for 4–5 h to afford 2 in 95% yield. Compounds 3-n (n=1, 2 ··· 26) were formed via a bis-SN2 cyclization of 2 with aniline or substituted anilines in aqueous solution of NaHCO₃ containing a small amount of sodium dodecyl sulfate (SDS) as phase transfer catalyst. The desired products 3-n were obtained in yields of 75–99%.

The preparation of 4-n from 3-n was a key step. It was reported that NBS was able to selectively and effectively oxidize some N-substituted tetrahydroisoquinolines to form the corresponding 3,4-dihydroisoquinolinium salts.²⁶⁾ However, when the same method was used for preparation of 4-1 from 3-1, the reaction only gave less than 10% yield, and most of 3-1 was recovered. Next, the iodine oxidation³⁴⁾ was also tested but without encouraging result.

Our recent research found that dihydrosanguinarine and dihydrochelerythrine in alcohol solution might be converted into the corresponding 6-alkoxy dihydro derivatives with nearly quantitative yields by a CuCl₂-catalyzed oxidative coupling reaction.¹⁷⁾ Considering the fact that 6-alkoxy dihydrosanguinarine and 6-alkoxy dihydrochelerythrine may be easily converted into their iminium forms in an acidic condition, we further inspected CuCl₂-catalyzed oxidation of 3-n. Gratifyingly, all the compounds 3-n were oxidized by CuCl₂·2H₂O to the corresponding 1-ethoxy-2-aryl-1,2,3,4-tetrahydroisoquinolines in ethanol solution in nearly quantitative yields after reflux for 10 h (Chart 3, Path A). After the solvent was removed, the residue was dissolved in dioxane or diethyl ether and then filtered. The filtrate was treated with hydrobromic acid aqueous solution to afford high-purity 4-n as solids in 93–99% yields (Table 1).

Table 1. The Substitution Patterns and Synthesis of Compounds 3-n and 4-n

Compound		Yield (%)a)	Compound		Yield (%)a)
No.	R		No.	R
3-1	H	99	4-1	H	97 (94)b)
3-2	o-F	97	4-2	o-F	98 (86)
3-3	m-F	91	4-3	m-F	96 (88)
3-4	p-F	99	4-4	p-F	97 (95)
3-5	o-Cl	92	4-5	o-Cl	95 (95)
3-6	m-Cl	92	4-6	m-Cl	95 (91)
3-7	p-Cl	94	4-7	p-Cl	96 (92)
3-8	o-Br	95	4-8	o-Br	95 (95)
3-9	m-Br	95	4-9	m-Br	94 (88)
3-10	p-Br	94	4-10	p-Br	98 (96)
3-11	o-I	86	4-11	o-I	94 (87)
3-12	m-I	97	4-12	m-I	96 (82)
3-13	p-I	96	4-13	p-I	98 (98)
3-14	3,5-diCl	90	4-14	3,5-diCl	99 (80)
3-15	o-CF3	79	4-15	o-CF3	96 (63)
3-16	m-CF3	87	4-16	m-CF3	96 (84)
3-17	p-CF3	98	4-17	p-CF3	97 (92)
3-18	o-NO2	81	4-18	o-NO2	95 (71)
3-19	m-NO2	75	4-19	m-NO2	94 (85)
3-20	p-NO2	93	4-20	p-NO2	96 (83)
3-21	o-Me	99	4-21	o-Me	95 (87)
3-22	m-Me	99	4-22	m-Me	93 (82)
3-23	p-Me	97	4-23	p-Me	96 (90)
3-24	o-MeO	86	4-24	o-MeO	95 (85)
3-25	m-MeO	89	4-25	m-MeO	94 (74)
3-26	p-MeO	98	4-26	p-MeO	97 (89)

a) Isolated yield. b) The data outside the parentheses were the yields (%) of CuCl₂·2H₂O oxidation method. The data in the parentheses were the yields (%) of DDQ oxidation method.

In addition, we also developed another alternative method for preparation of 4-n from 3-n, i.e., 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) selective oxidation reaction of 3-n. Recently, Tsang et al. reported DDQ-mediated oxidative addition reactions between 2-phenyl tetrahydroisoquinoline and nitromethane, acetone etc., and demonstrated that N-phenyl-3,4-dihydroisoquinolin-2-ium ion was their reactive intermediate.³⁵⁾ This finding inspired us to examine DDQ oxidation reaction of 3-n. Pleasingly, stoichiometric DDQ could easily and regioselectively oxidize 3-n to 4-n in methanol at room temperature in several minutes (Chart 3, Path B). After the solvent removal, the residue was treated with ethyl acetate followed by addition of aqueous solution of hydrobromic acid to afford 4-n as solids in good to excellent yields (Table 1). Another work-up procedure was as follows. The residue was treated with 5% HCl by extraction with ethyl acetate. The remaining water phase was adjusted to pH 11 by 10% NaOH followed by extraction with ethyl acetate. The resulted extracts dissolved in dioxane followed by addition of 40% HBr solution to yield 4-n as solids.

Compared with the literature methods,^22–25) the present methods had obvious advantages such as excellent yields, simple work-up operation and easily obtaining high-purity products.

Antifungal Activity

According to mycelium linear growth rate method reported by us,¹²⁾ the antifungal activity in vitro of 4-1–4-26 were screened on Alternaria alternate, Curvularia lunata and Fusarium oxysporum sp. niveum at 50 µg/mL. Triabendazole (TBZ, ≥99.1%), a commercial fungicide standard, sanguinarine iodide and chelerythrine iodide were used as positive controls. Mean inhibition rates of all the test compounds against the same fungus were pairwise compared by Duncan’s multiple test. When any two compounds have not significant difference of activity (p<0.05), a same letter was given after their inhibition rates. On the contrary, when any two compounds have significant difference of activity, two different letters was given after their inhibition rates, respectively. Here, the alphabetical order was consistent with the order of the activity from high to low, i.e. the letter “a” was given to the highest active compounds and the last letter was given to the lowest active compounds. The results were listed in Table 2.

Table 2. The Substituent Patterns and Antifungal Activities of 4-n (50 µg/mL, 72 h)

Compound		Inhibition rate (%)
No.	R	A. alternate	C. lunata	F. oxysporum sp. niveum
4-1	H	33.7±0.9ija)	63.3±2.8gh	2.7±6.4jk
4-2	o-F	81.6±2.4a	94.3±1.4a	86.3±1.9b
4-3	m-F	85.9±1.9a	95.3±1.6a	30.6±5.4e
4-4	p-F	35.9±2.5i	61.2±4.2gh	1.7±5.8jk
4-5	o-Cl	54.3±1.6ef	84.9±3.6bcde	47.0±0.9d
4-6	m-Cl	69.7±1.9c	92.6±0.9ab	16.3±0.0hi
4-7	p-Cl	48.5±4.7g	67.1±1.4g	17.8±4.8ghi
4-8	o-Br	76.3±3.2b	94.3±1.4a	95.6±6.3a
4-9	m-Br	63.7±2.5d	91.1±0.9abc	23.8±3.1efgh
4-10	p-Br	40.2±3.9h	88.6±3.2abcd	15.5±8.1i
4-11	o-I	67.4±3.3cd	92.4±1.6ab	82.0±2.8b
4-12	m-I	57.8±1.6e	84.2±1.6cde	25.9±2.4ef
4-13	p-I	40.7±2.2h	90.0±0.8abc	5.5±4.6j
4-14	3,5-diCl	50.5±1.5fg	51.2±1.5j	16.0±2.0i
4-15	o-CF3	56.0±3.1e	85.3±0.9bcde	18.0±4.0ghi
4-16	m-CF3	58.0±2.6e	79.2±3.8ef	14.0±2.0i
4-17	p-CF3	55.5±3.5e	75.1±4.7f	20.7±1.2fghi
4-18	o-NO2	6.4±3.5m	10.6±2.3n	−4.0±0.0k
4-19	m-NO2	64.6±1.5d	44.6±5.5ijk	24.7±4.2efg
4-20	p-NO2	63.9±1.7d	81.3±1.4def	60.0±5.7c
4-21	o-Me	15.9±0.9l	24.9±16.5m	3.9±4.2j
4-22	m-Me	57.9±1.8e	48.2±0.9ijk	26.1±1.2ef
4-23	p-Me	31.3±0.9jk	41.0±10.2ijk	17.3±5.3ghi
4-24	o-MeO	27.5±1.5k	47.9±2.3ijk	3.3±5.5jk
4-25	m-MeO	31.0±3.7jk	40.4±0.9kl	7.1±4.0j
4-26	p-MeO	27.5±3.0k	33.9±2.6l	2.0±2.9jk
Sanguinarine		47.7±1.2g	58.7±1.5h	50.5±1.8d
Chelerythrine		50.3±1.8fg	48.7±1.3ij	63.2±1.3c
Thiabendazole		28.6±5.4k	20.3±2.5m	93.9±5.3a

a) The differences between data with the different lower-case letters within a column are significant for the same tested fungus (p<0.05), which were carried out by Duncan’s multiple comparison.

Almost all the target compounds (4-1–4-26) displayed activities against each the fungus at 50 µg/mL in varying degrees. Generally, three o-halogenated compounds (4-2, 4-8, 4-11) showed the highest activities. For each the test fungus, most of the compounds were more active than both sanguinarine and chelerythrine. For A. alternate, 13, 14 and 20 of the 26 compounds showed higher activity than chelerythrine, sanguinarine and thiabendazole (TBZ), respectively. 4-2 and 4-3 gave the highest activity with inhibition rates of 81.6% and 85.9%. As to C. lunata, 17, 15 and 24 of the 26 compounds were more active than chelerythrine, sanguinarine and TBZ, respectively. Eight compounds (4-2, 4-3, 4-6, 4-8–4-11, 4-13) exhibited the highest with inhibition rates of 88.6–95.3%. As far as F. oxysporum sp. niveum was concerned, 4-2, 4-8 and 4-11 displayed higher activity than chelerythrine and sanguinarine, of which 4-8 gave the highest activity (95.6%) comparable with TBZ (93.9%) (p<0.05).

Structure–Activity Relationship

By comparison of 4-1 with the other compounds (4-2–4-26), it was clearly seen that introduction of substituents to N-aromatic ring made significant effects on the activity. In general, the introduction of electron-withdrawing substituents like halogen atoms (4-2–4-14) and trifluoromethyl group (4-15–4-17) remarkably enhanced the activity. On the contrary, electron-donating substituents like CH₃ (4-21–4-23) and OCH₃ (4-24–4-26) led to the decrease of activity. In addition, it was worth noting that dichlorinated compound (4-14) did not give higher activities than monochlorinated compounds (4-5, 4-6).

On the other hand, by comparison of the activity of various isomers, the significant position effect of the substituents on the activity was observed. For halogenated isomers (4-2–4-13), o- and m-halogenated isomers showed more activity increment than their corresponding p-halogenated isomer. However, for nitro-substituted isomers (4-18–4-20), the general order of the activity was p-nitro isomer (4-20)>m-nitro isomer (4-19)>o-nitro isomer (4-18). An exception was trifluoromethyl-substituted isomers (4-15–4-17). In most cases, no significant difference was observed among them (p<0.05).

In conclusion, we established an efficient and practical approach to 2-aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium bromides from commercially available 1,3-benzodioxole and synthesized 26 new title compounds 4-n (n=1, 2, ···, 26) with various substituents in N-aromatic ring. The present methods had good to excellent yields and simple work-up operation. Most of the compounds (4-1–4-26) displayed higher antifungal activities against A. alternate, C. lunata and F. oxysporum sp. niveum at 50 µg/mL than their model compounds sanguinarine and chelerythrine. Significant effect of type and position of substituents on the activity was observed. The present results suggest that some of the title compounds are potential for the development of new isoquinoline antimicrobial agents.

Experimental

General and Analytical Methods

Solvents and chemicals were reagent grade and used without purification unless otherwise specified. All arylamines were purchased from J&K Chemical. NaBH₄ and CuCl₂·2H₂O were purchased from AstaTech, China. Column chromatography was performed on silica gel 60 G (Qingdao Haiyang Chemical, China). TBZ, ≥9.1%, a commercial fungicide standard, was purchased from Sigma-Aldrich Trading Co., Ltd. (Shanghai, China). Sanguinarine iodide (>98%) and chelerythrine iodide (>99%) were obtained in our laboratory by isolation from the whole plant of M. microcarpa (MAXIM) FEDDE.¹¹⁾ The fungi A. alternate, C. lunata and F. oxysporum sp. niveum were isolated, identified and provided by the Center of Pesticide Research, Northwest A&F University, Yangling, China. These fungi were grown on potato-dextrose-agar (PDA) plates at 28°C and maintained by periodic subculturing at 4°C.

Melting points were determined on XT-4 micro-melting point apparatus and were uncorrected. Infrared (IR) spectra were recorded in wave numbers (cm⁻¹) on a Bruker TENSOR 27 transform infrared spectrophotometer with KBr disks. ¹H- NMR spectra at 500 MHz and ¹³C-NMR spectra at 125 MHz were recorded with Bruker AVANCE III spectrometer as solutions in CD₃OD unless otherwise noted. Coupling constants were reported in hertz (Hz). Electrospray ionization (ESI)-MS was measured on 4000 QTRAP LC-MS instrument (Thermo Finnigan Co.). MS spectra were obtained from a 4000 QTRAP LC-MS in MS mode. High-resolution mass spectra (HR-MS) were determined on Thermo LTQ XL Orbitrap instrument.

Experimental Procedures

5-(2-Bromoethyl)-6-chloromethyl-1,3-benzodioxole (2): Paraformaldehyde (2.7 g, 90 mmol) and concentrated hydrochloric acid (24 mL) were added in a round bottom flask and stirred at 50°C for 30 min to provide a clear solution, and then cooled to 5°C. Compound 1 (6.9 g, 30 mmol) and POCl₃ (3 mL) were sequently added to the solution above. The reaction solution was stirred at 20–28°C for 4 h. The desired product was collected as solid by filtration and repeatedly washed with water. The crude product was purified through a short column of silica gel using a mixture of ethyl acetate and petroleum ether (1 : 20) as eluent to afford 2 as white solids (7.9 g, 95% yield, mp 51–52°C). ¹H-NMR (500 MHz, CDCl₃) δ: 3.19 (2H, t, J=7.7 Hz), 3.56 (2H, t, J=7.7 Hz), 4.57 (2H, s), 5.96 (2H, s), 6.71 (1H, s), 6.82 (1H, s). ¹³C-NMR (125 MHz, CDCl₃) δ: 32.2, 35.7, 44.3, 101.5 (OCH₂O), 110.0, 110.5, 128.9, 131.9, 146.8, 148.3. Positive ESI-MS: m/z (%)=277.5 [M+1]⁺ (100), 279.3 [M+3]⁺ (97), 281.1 [M+5]⁺ (31).

2-Aryl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-n)

General Procedure: Aniline or substituted aniline (5.0 mmol), sodium hydrogencarbonate (0.84 g, 10 mmol) and sodium dodecyl sulfate (ca. 20 mg) and compound 2 (1.39 g, 5 mmol) were added to 20 mL of water and then heated at 80°C for 1 h while stirring. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. After removing the solvent, the crude product was subjected to SiO₂ column chromatography eluting with a mixture of ethyl acetate and petroleum ether (1 : 20) to give the title compounds 3-n as solids.

2-Aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromides (4-n)

General Procedure A: To the solution of 3-n (2.75 mmol) in ca. 60 mL of ethanol was added 11 mg (0.55 mmol) of CuCl₂·2H₂O at room temperature. The resulting solution was refluxed at 80°C for 10 h using an oil bath under an oxygen atmosphere. After the solvent removal, the residue was dissolved in ca. 40 mL of 1,4-dioxane and then filtered to remove insoluble copper salts. The filtrate was treated with 0.44 mL (ca. 3.0 mmol) of 40% HBr aqueous solution to afford 4-n bromides as solids in 93–99% yields from 3-n.

General Procedure B: To a solution of compound 3-n (2.5 mmol) in MeOH (20 mL) was added DDQ (0.57 g, 2.75 mmol). After the mixture was stirred at room temperature for 0.5 h, the solvent was evaporated to dryness. To the residue, 20 mL of ethyl acetate and 0.5 mL of 40% hydrobromic acid were added. The resulting mixture was treated for 20 min with ultrasonic wave at room temperature. The desired compound as solids was obtained by filtration and repeatedly washed with a small volume of diethyl ether. Another work-up procedure was as follows. The residue was treated with 5% HCl by extraction with ethyl acetate. The remaining water phase was adjusted to pH 11 by 10% NaOH followed by extraction with ethyl acetate. The resulted extracts dissolved in dioxane followed by addition of 40% HBr solution to yield 4-n as solids.

Assay of Antifungal Activity in Vitro

The antifungal activity in vitro of the target compounds was tested by the growth rate method.¹²⁾ The test fungi maintained on PDA medium slants were subcultured for 48 h in Petri dishes prior to testing and used for inoculation of fungal strains on PDA plates. The tested compounds were completely dissolved in dimethyl sulfoxide (DMSO), and then diluted by water to provide the stock solution (1.2 µg/mL) in 5% DMSO aqueous solution. Thiabendazole (1.2 µg/mL), sanguinarine (1.2 µg/mL) and chelerythrine (1.2 µg/mL) in 5% DMSO aqueous solution were used positive drug control and reference controls at the same time, respectively. Five percent DMSO aqueous solution were used as blank control. The stock solution (10 mL) was completely mixed with the autoclaved PDA medium (230 mL) to provide a medium containing 50 µg/mL of test compounds and then poured into the Petri dishes in a laminar flow chamber. When the medium in the plate was partially solidified, a 5-mm thick and 4-mm diameter disc of fungus cut from earlier subcultured Petri dishes was placed at the centre of the semi-solid medium. The dishes were kept in an incubator at 28°C for 72 h. Each experiment was carried out in triplicate. The diameters (in mm) of inhibition zones were measured in three different directions and the growth inhibition rates were calculated according to the following formula and express as means±S.D.:

  

where d₀: diameter of the fungus cut, d_c: diameter of the blank control fungus, d_s: diameter of the compound-treated fungus.

Spectroscopic Characterization of Compounds

2-Phenyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-1): White solid, 1.25 g, 99% yield, mp 71–72°C. ¹H-NMR (CDCl₃) δ: 2.86 (2H, t, J=5.8 Hz), 5.51 (2H, t, J=5.8 Hz), 4.29 (2H, s), 5.90 (2H, s), 6.60 (1H, s), 6.61 (1H, s), 6.83 (1H, t, J=7.3 Hz), 6.95 (2H, d, J=8.0 Hz), 7.26 (2H, dd, J=8.0, 7.3 Hz). ¹³C-NMR (CDCl₃) δ: 29.0, 46.7, 50.8, 100.7, 106.5, 108.4, 115.3, 118.8, 127.3, 127.9, 129.2, 146.0, 146.2. Positive ESI-MS m/z: 254.2 [M+1]⁺.

2-(2-Fluorophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-2): Colorless liquid, 1.31 g, 97% yield. ¹H-NMR (CDCl₃) δ: 6.84–6.98 (4H, m), 6.51 (1H, s), 6.48 (1H, s), 5.83 (2H, s), 4.11 (2H, s), 3.31 (2H, t, J=5.8 Hz), 2.78 (2H, t, J=5.8 Hz). ¹³C-NMR (CDCl₃) δ: 156.7 (d, J=244.4 Hz), 146.2 (d, J=32.0 Hz), 139.7 (d, J=8.8 Hz), 127.4 (d, J=17.5 Hz), 124.4 (d, J=3.5 Hz), 122.4 (d, J=7.6 Hz), 119.5 (d, J=2.71 Hz), 116.3 (d, J=20.4 Hz), 108.7, 106.3, 104.5, 100.7 (C-9), 68.0 (d, J=336.5 Hz), 52.6 (d, J=1.7 Hz), 47.0 (d, J=4.5 Hz), 28.8 (d, J=58.6 Hz). Positive ESI-MS m/z: 272.1 [M+1]⁺.

2-(3-Fluorophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-3): White solid, 1.23 g, 91% yield, mp 95–97°C. ¹H-NMR (CDCl₃) δ: 7.20 (1H, q, J=7.9 Hz), 6.69 (1H, d, J=8.4 Hz), 6.61 (3H, m), 6.48 (1H, t, J=8.1 Hz), 5.92 (2H, s), 4.30 (2H, s), 3.51 (2H, t-like, J=5.5 Hz), 2.87 (2H, t-like, J=5.5 Hz). ¹³C-NMR (CDCl₃) δ: 165.0 (d, J=241.0 Hz), 151.9 (d, J=10.2 Hz), 146.3 (d, J=20.8 Hz), 130.2 (d, J=10.3 Hz), 127.9, 126.86, 110.0, 108.4, 106.5, 104.7 (d, J=21.3 Hz), 101.5, 101.3, 100.8, 50.2, 46.0, 28.9. Positive ESI-MS m/z: 272.1 [M+1]⁺.

2-(4-Fluorophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-4): White solid, 1.34 g, 99% yield, mp 105–106°C. ¹H-NMR (CDCl₃) δ: 6.91–6.99 (4H, m), 6.60 (2H, d, J=6.3 Hz), 5.91 (2H, s), 4.22 (2H, s), 3.44 (2H, t, J=5.8 Hz), 2.87 (2H, t, J=5.8 Hz). ¹³C-NMR (CDCl₃) δ: 157.9 (d, J=236.8 Hz,), 147.09, 146.3 (d, J=24.5 Hz), 127.5, 127.0, 117.4 (d, J=7.7 Hz), 115.7 (d, J=21.8 Hz), 108.7, 106.4, 104.5, 100.8, 50.0, 48.0, 28.8. Positive ESI-MS m/z: 272.1 [M+1]⁺.

2-(2-Chlorophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-5): White solid, 1.32 g, 92% yield, mp 93–94°C. ¹H-NMR (CDCl₃) δ: 7.39 (1H, d, J=7.9 Hz), 7.21 (1H, t, J=7.6 Hz), 7.10 (1H, d, J=7.9 Hz), 6.98 (1H, t, J=7.6 Hz), 6.62 (1H, s), 6.57 (1H, s), 5.91 (2H, s), 4.17 (2H, s), 3.36 (2H, t, J=5.8 Hz), 2.90 (2H, t, J=5.8 Hz). ¹³C-NMR (CDCl₃) δ: 148.9, 146.2, 145.9, 130.7, 128.8, 127.52, 126.90, 123.7, 120.7, 118.1, 108.8, 106.3, 100.7, 53.3, 49.8, 25.8. Positive ESI-MS m/z: 288.2 [M+1]⁺, 290.1 [M+3]⁺.

2-(3-Chlorophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-6): White solid, 1.32 g, 92% yield, mp 86–87°C. ¹H-NMR (CDCl₃) δ: 7.17 (1H, t, J=8.0 Hz), 6.88 (1H, s), 6.81 (2H, dd, J=8.0 Hz), 6.62 (2H, s), 5.92 (2H, s), 4.29 (2H, s), 3.51 (2H, t, J=5.5 Hz), 2.87 (2H, t, J=5.5 Hz). ¹³C-NMR (CDCl₃) δ: 151.3, 146.3, 146.1, 135.1, 130.1, 127.8, 126.8, 118.1, 114.5, 112.7, 108.4, 106.5, 100.8, 50.2, 46.1, 28.9. Positive ESI-MS m/z: 288.2 [M+1]⁺, 290.2 [M+3]⁺.

2-(4-Chlorophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-7): White solid, 1.35 g, 94% yield, mp 148–149°C. ¹H-NMR (CDCl₃) δ: 7.22 (2H, d, J=9.0 Hz), 6.87 (2H, d, J=9.0 Hz), 6.61 (2H, s), 5.92 (2H, s), 4.26 (2H, s), 3.48 (2H, t, J=5.9 Hz), 2.86 (2H, t, J=5.9 Hz). ¹³C-NMR (CDCl₃) δ: 149.0, 146.3, 146.1, 129.0, 127.7, 126.9, 123.5, 116.3, 108.4, 106.4, 100.8, 50.7, 46.7, 28.8. Positive ESI-MS m/z: 288.2 [M+1]⁺, 290.1 [M+3]⁺.

2-(2-Bromophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-8): White solid, 1.57 g, 95% yield, mp 117–119°C. ¹H-NMR (CDCl₃) δ: 7.58 (1H, d, J=7.9 Hz), 7.25 (1H, t, J=7.7 Hz), 7.10 (1H, d, J=7.9 Hz), 6.92 (1H, t, J=7.6 Hz), 6.61 (1H, s), 6.55 (1H, s), 5.89 (2H, s), 4.13 (2H, s), 3.32 (2H, t, J=5.7 Hz), 2.91 (2H, t-like, J=5.7 Hz). ¹³C-NMR (CDCl₃) δ: 150.4, 146.2, 145.8, 134.0, 128.2, 127.6, 127.5, 124.3, 121.2, 119.8, 108.8, 106.3, 100.7, 53.6, 50.4, 29.1. Positive ESI-MS m/z: 332.0 [M+1]⁺, 334.1 [M+3]⁺.

2-(3-Bromophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-9): White solid, 1.57 g, 95% yield, mp 97–98°C. ¹H-NMR (CDCl₃) δ: 7.11 (1H, t, J=8.1 Hz), 7.04 (1H, t, J=2.0 Hz), 6.92 (1H, d, J=7.9 Hz), 6.84 (1H, dd, J=8.4, 2.3 Hz), 6.62 (2H, s), 5.92 (2H, s), 4.29 (2H, s), 3.50 (2H, t, J=5.8 Hz), 2.86 (2H, t, J=5.8 Hz). ¹³C-NMR (CDCl₃) δ: 151.4, 146.3, 146.1, 130.4, 127.8, 126.8, 123.4, 121.0, 117.4, 113.1, 108.4, 106.5, 100.8, 50.1, 46.0, 28.9. Positive ESI-MS m/z: 332.2 [M+1]⁺, 334.2 [M+3]⁺.

2-(4-Bromophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-10): White solid, 1.56 g, 94% yield, mp 158–159°C. ¹H-NMR (CDCl₃) δ: 7.35 (2H, d, J=9.0 Hz), 6.81 (2H, d, J=9.0 Hz), 6.61 (2H, s), 5.91 (2H, s), 4.26 (2H, s), 3.48 (2H, t, J=5.8 Hz), 2.86 (2H, t, J=5.8 Hz). ¹³C-NMR (CDCl₃) δ: 149.3, 146.3, 146.1, 131.9, 127.7, 126.9, 116.6, 110.6, 108.4, 106.5, 100.8, 50.7, 46.7, 28.8. Positive ESI-MS m/z: 332.2 [M+1]⁺, 334.1 [M+3]⁺.

2-(2-Iodophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-11): White solid, 1.63 g, 86% yield, mp 157–158°C. ¹H-NMR (CDCl₃) δ: 7.89 (1H, d, J=7.8 Hz), 7.32 (1H, t, J=7.5 Hz), 7.12 (1H, d, J=7.8 Hz), 6.81 (1H, t, J=7.5 Hz), 6.64 (1H, s), 6.56 (1H, s), 5.91 (2H, s), 4.10 (2H, s), 3.27 (2H, t-like, J=5.3 Hz), 2.97 (2H, br s). ¹³C-NMR (CDCl₃) δ: 153.3, 146.2, 145.8, 140.2, 129.2, 127.7, 127.5, 125.4, 121.1, 108.8, 106.3, 100.7, 97.8, 54.2, 51.1, 29.4. Positive ESI-MS m/z: 380.1 [M+1]⁺.

2-(3-Iodophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-12): White solid, 1.84 g, 97% yield, mp 79–80°C. ¹H-NMR (CDCl₃) δ: 7.25 (1H, d-like, J=7.9 Hz), 7.12 (1H, d, J=7.6 Hz), 6.96 (1H, t, J=7.9 Hz), 6.87 (1H, d, J=8.4 Hz), 6.61 (2H, s), 5.91 (2H, s), 4.26 (2H, s), 3.47 (2H, t, J=5.6 Hz), 2.85 (2H, t-like, J=5.6 Hz). ¹³C-NMR (CDCl₃) δ: 151.4, 146.3, 146.1, 130.6, 127.8, 127.1, 126.8, 123.4, 113.9, 108.4, 106.5, 100.8, 95.5, 50.1, 46.0, 28.9. Positive ESI-MS m/z: 380.2 [M+1]⁺.

2-(4-Iodophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-13): White solid, 1.82 g, 96% yield, mp 159–160°C. ¹H-NMR (CDCl₃) δ: 7.52 (2H, d, J=8.9 Hz), 6.71 (2H, d, J=8.9 Hz), 6.61 (2H, s, H-5), 5.91 (2H, s), 4.26 (2H, s), 3.48 (2H, t, J=5.8 Hz), 2.85 (2H, t, J=5.8 Hz). ¹³C-NMR (CDCl₃) δ: 149.8, 146.3, 146.1, 137.8, 127.8, 126.8, 117.0, 108.4, 106.5, 100.8, 79.8, 50.2, 46.2, 28.8. Positive ESI-MS m/z: 380.0 [M+1]⁺.

2-(3,5-Dichlorophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-14): White solid, 1.44 g, 90% yield, mp 119–120°C. ¹H-NMR (CDCl₃) δ: 6.73 (3H, m), 6.63 (2H, d, J=3.9 Hz), 5.92 (2H, s), 4.28 (2H, s), 3.49 (2H, t, J=5.9 Hz), 2.86 (2H, t, J=5.9 Hz). ¹³C-NMR (CDCl₃) δ: 151.4, 146.5, 146.3, 135.5, 127.8, 126.4, 117.4, 112.2, 108.3, 106.5, 100.9, 49.6, 45.6, 28.8. Positive ESI-MS m/z: 322.1 [M+1]⁺, 324.0 [M+3]⁺.

2-(2-(Trifluoromethyl)phenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-15): White solid, 1.27 g, 79% yield, mp 105–106°C. ¹H-NMR (CDCl₃) δ: 7.80 (1H, d, J=7.8 Hz), 7.53 (1H, t, J=7.6 Hz), 7.41 (1H, d, J=8.0 Hz), 7.24 (1H, d, J=7.6 Hz), 6.63 (1H, s), 6.51 (1H, s), 5.91 (2H, s), 4.04 (2H, s), 3.19 (2H, t-like, J=5.5 Hz), 2.90 (2H, br s). ¹³C-NMR (CDCl₃) δ: 152.4, 146.1, 145.7, 132.8, 127.9, 127.4 (q-like, J=4.6), 127.3, 127.1, 124.7, 124.0, 121.1, 108.7, 106.21, 100.7, 55.6, 51.8, 29.6. Positive ESI-MS m/z: 322.1 [M+1]⁺.

2-(3-(Trifluoromethyl)phenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-16): White solid, 1.40 g, 87% yield, mp 84–85°C. ¹H-NMR (CDCl₃) δ: 7.35 (1H, t, J=8.0 Hz), 7.02–7.11 (3H, m), 6.64 (2H, d, J=2.6 Hz), 5.92 (2H, s, H-9), 4.33 (2H, s), 3.55 (2H, t-like, J=5.6 Hz), 2.89 (2H, t-like, J=5.6 Hz,). ¹³C-NMR (CDCl₃) δ: 150.3, 146.4, 146.2 131.6, 129.6, 127.8, 126.7, 117.4, 114.6, 110.8 (d, J=3.8 Hz,), 110.7, 108.4, 106.5, 100.8, 50.1, 46.0, 28.9. Positive ESI-MS m/z: 322.1 [M+1]⁺.

2-(4-(Trifluoromethyl)phenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-17): White solid, 1.57 g, 98% yield, mp 196–198°C. ¹H-NMR (CDCl₃) δ: 7.50 (2H, d, J=8.5 Hz), 6.92 (2H, d, J=8.5 Hz), 6.64 (2H, s), 5.93 (2H, s), 4.37 (2H, s), 3.58 (2H, t, J=5.8 Hz), 2.88 (2H, t-like, J=5.8 Hz). ¹³C-NMR (CDCl₃) δ: 152.1, 146.4, 146.2, 128.0, 126.7, 126.5 (q-like, J=3.7 Hz), 126.5, 126.5, 113.0, 108.3, 106.5, 100.9, 49.5, 45.4, 28.8. Positive ESI-MS m/z: 322.1 [M+1]⁺.

2-(2-Nitrophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-18): Orange solid, 1.21 g, 81% yield, mp 121–122°C. ¹H-NMR (CDCl₃) δ: 8.22 (1H, d, J=8.5 Hz), 7.45 (1H, t, J=7.6 Hz), 6.70–6.84 (4H, m), 5.97 (2H, s), 4.43 (2H, d, J=4.9 Hz), 3.54 (2H, t, J=7.5 Hz), 3.16 (2H, t, J=7.5 Hz). ¹³C-NMR (CDCl₃) δ: 147.6, 147.1, 144.8, 136.4, 132.6, 130.6, 128.3, 127.0, 116.0, 114.0, 110.0, 108.9, 101.4, 44.9, 35.5, 32.4. Positive ESI-MS m/z: 299.1 [M+1]⁺.

2-(3-Nitrophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-19): Orange solid, 1.12 g, 75% yield, mp 143–144°C. ¹H-NMR (CDCl₃) δ: 7.70 (1H, s), 7.61 (1H, d, J=8.0 Hz), 7.38 (1H, t, J=8.0 Hz), 7.18 (1H, d, J=8.0 Hz), 6.66 (2H, d, J=5.1 Hz), 5.94 (2H, s), 4.38 (2H, s), 3.60 (2H, t, J=5.7 Hz), 2.90 (2H, t-like, J=5.7 Hz). ¹³C-NMR (CDCl₃) δ: 150.6, 149.4, 146.5, 146.3, 129.7, 127.8, 126.3, 119.6, 112.3, 108.4, 108.1, 106.5, 100.9, 49.8, 45.7, 28.8. Positive ESI-MS m/z: 299.1 [M+1]⁺.

2-(4-Nitrophenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-20): Orange solid, 1.39 g, 93% yield, mp 211–212°C. ¹H-NMR (CDCl₃) δ: 8.17 (2H, d, J=9.4 Hz), 6.81 (2H, d, J=9.4 Hz), 6.75 (1H, s), 6.54 (1H, s), 5.96 (2H, s), 4.64 (2H, s), 3.65 (2H, t, J=5.8 Hz), 2.93 (2H, t, J=5.8 Hz). ¹³C-NMR (CDCl₃) δ: 153.7, 146.7, 146.5, 129.8, 128.1, 126.4, 126.0, 111.2, 108.2, 106.6, 101.4, 48.8, 44.8, 28.9. Positive ESI-MS m/z: 299.2 [M+1]⁺.

2-(2-Methylphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-21): White solid, 1.32 g, 99% yield, mp 94–95°C. ¹H-NMR (CDCl₃) δ: 7.16–7.21 (2H, m), 7.08 (1H, d, J=7.9 Hz), 7.00 (1H, t, J=7.2 Hz), 6.63 (1H, s), 6.55 (1H, s), 5.90 (2H, s), 4.02 (2H, s), 3.17 (2H, t-like, J=5.5 Hz), 2.89 (2H, br s), 2.34 (3H, s). ¹³C-NMR (CDCl₃) δ: 151.4, 146.1, 145.8, 132.8, 131.2, 128.3, 127.5, 126.6, 123.2, 119.3, 108.7, 106.3, 100.7, 54.2, 50.2, 29.6, 18.1. Positive ESI-MS m/z: 268.2 [M+1]⁺.

2-(3-Methylphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-22): Colorless liquid, 1.32 g, 99% yield. ¹H-NMR (CDCl₃) δ: 7.16 (1H, t, J=7.6 Hz), 6.75–6.77 (2H, m), 6.66 (1H, d, J=7.3 Hz), 6.61 (2H, d, J=2.8 Hz), 5.89 (2H, s), 4.27 (2H, s), 3.49 (2H, t, J=5.8 Hz), 2.86 (2H, t, J=5.8 Hz), 2.37 (3H, s). ¹³C-NMR (CDCl₃) δ: 150.6, 146.1, 146.0, 138.9, 129.1, 127.9, 127.4, 119.7, 116.1, 112.5, 108.4, 106.5, 100.7, 50.9, 46.7, 29.1, 21.9. Positive ESI-MS m/z: 268.1 [M+1]⁺.

2-(4-Methylphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-23): White solid, 1.30 g, 97% yield, mp 114–115°C. ¹H-NMR (CDCl₃) δ: 7.09 (2H, d, J=8.4 Hz), 6.89 (2H, d, J=8.4 Hz), 6.59 (2H, s), 5.89 (2H, s), 4.23 (2H, s), 3.45 (2H, t, J=5.8 Hz), 2.85 (2H, t, J=5.8 Hz), 2.27 (3H, s). ¹³C-NMR (CDCl₃) δ: 148.5, 146.1, 146.0, 129.7, 128.5, 127.7, 127.4, 116.0, 108.5, 106.5, 100.7, 51.6, 47.4, 29.0, 20.4. Positive ESI-MS m/z: 268.1 [M+1]⁺.

2-(2-Methoxyphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-24): White solid, 1.22 g, 86% yield, mp 84–85°C. ¹H-NMR δ: 7.18 (1H, t, J=8.2 Hz), 6.61 (2H, s), 6.58 (1H, dd, J=8.2, 2.0 Hz), 6.49 (1H, br s), 6.40 (1H, dd, J=8.2, 2.0 Hz), 5.90 (2H, s), 4.29 (2H, s), 3.80 (3H, s), 3.50 (2H, t, J=5.8 Hz), 2.86 (2H, t, J=5.8 Hz). ¹³C-NMR (CDCl₃) δ: 160.7, 151.8, 146.2, 146.0, 129.9, 127.9, 127.3, 108.4, 108.0, 106.5, 103.4, 101.6, 100.7, 55.2, 50.7, 46.5, 29.0. Positive ESI-MS m/z: 284.2 [M+1]⁺.

2-(3-Methoxyphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-25): White solid, 1.26 g, 89% yield, mp 55–56°C. ¹H-NMR (CDCl₃) δ: 7.19 (1H, t, J=8.2 Hz), 6.56–6.61 (3H, m), 6.49 (1H, s), 6.40 (1H, d, J=8.1 Hz), 5.90 (2H, s), 4.29 (2H, s), 3.81 (3H, s), 3.52 (2H, br s), 2.86 (2H, br s). ¹³C-NMR (CDCl₃) δ: 160.7, 151.8, 146.2, 146.0, 129.9, 127.9, 127.3, 108.4, 106.5, 103.4, 101.6, 100.7, 100.7, 55.2, 50.7, 46.5, 29.0. Positive ESI-MS m/z: 284.2 [M+1]⁺.

2-(4-Methoxyphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3-26): Pale yellow solid, 1.39 g, 98% yield, mp 126–127°C. ¹H-NMR (CDCl₃) δ: 6.97 (2H, d, J=9.0 Hz), 6.87 (2H, d, J=9.0 Hz), 6.60 (2H, d, J=9.0 Hz), 5.90 (2H, s), 4.18 (2H, s), 3.77 (3H, s), 3.40 (2H, t, J=5.8 Hz), 2.87 (2H, t, J=5.8 Hz). ¹³C-NMR (CDCl₃) δ: 153.6, 146.1, 145.9, 145.2, 127.5, 127.4, 118.1, 114.6, 108.5, 106.4, 100.7, 55.6, 52.7, 48.5, 27.9. Positive ESI-MS m/z: 284.1 [M+1]⁺.

2-Phenyl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-1): White solid, 1.61 g, 97% yield, mp 229–231°C. IR, ν (KBr) cm⁻¹: 1572 (s, C=N). ¹H-NMR δ: 3.42 (2H, t, J=8.2 Hz), 4.54 (2H, t, J=8.2 Hz), 6.24 (2H, s), 7.11 (1H, s), 7.41 (1H, s), 7.62–7.67 (3H, m), 7.75 (2H, d, J=7.5 Hz), 9.20 (1H, s). ¹³C-NMR δ: 27.1, 51.8, 105.2, 110.1, 113.9, 120.7, 123.4, 131.4, 131.9, 138.4, 144.6, 149.7, 159.0, 165.9 (C-1). HR-MS [M−Br]⁺: Calcd for C₁₆H₁₄NO₂⁺ 252.1019, Found 252.1016.

2-(2-Fluorophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-2): Pale yellow solid, 1.71 g, 98% yield, mp 224–226°C. IR, ν (KBr) cm⁻¹: 1578 (s, C=N). ¹H-NMR δ: 9.17 (1H, s), 7.80 (1H, t, J=7.9 Hz), 7.67 (1H, q, J=5.6 Hz), 7.46–7.51 (2H, m), 7.40 (1H, s), 7.14 (1H, s), 6.26 (2H, s), 4.45 (2H, t, J=8.0 Hz), 3,42 (2H, t, J=8.2 Hz). ¹³C-NMR δ: 167.6, 158.3, 156.1 (d, J=250.6 Hz), 148.4, 137.8, 132.7 (d, J=8.2 Hz), 130.7, 125.8, 125.7 (d, J=3.7 Hz), 119.0, 117.3 (d, J=19.5 Hz), 112.6, 108.9, 103.9, 51.4 (d, J=3.5 Hz), 25.7. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃FNO₂⁺ 270.0925, Found 270.0913.

2-(3-Fluorophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-3): Pale yellow solid, 1.68 g, 96% yield, mp 258–260°C. IR, ν (KBr) cm⁻¹: 1579 (s, C=N). ¹H-NMR δ: 9.28 (1H, s), 7.64–7.74 (3H, m), 7.41–7.46 (2H, m), 7.15 (1H, s), 6.28 (2H, s), 4.56 (2H, t, J=8.1 Hz), 3.46 (2H, t, J=8.1 Hz). ¹³C-NMR δ: 165.1, 164.0 (d, J=246.9 Hz), 157.9, 148.3, 144.21, 137.5, 131.8, 119.2, 118.1 (d, J=3.8 Hz), 117.3 (d, J=21.1 Hz), 112.6, 110.1 (d, J=26.4 Hz), 108.7, 103.8, 50.4, 25.6. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃FNO₂⁺ 270.0925, Found 270.0912.

2-(4-Fluorophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-4): Pale yellow solid, 1.69 g, 97% yield, mp 225–227°C. IR, ν (KBr) cm⁻¹: 1578 (s, C=N). ¹H-NMR δ: 9.20 (1H, s), 7.82–7.85 (2H, q-like, J=8.9 Hz), 7.42–7.45 (3H, m, J=5.5 Hz), 7.15 (1H, s), 6.27 (2H, s), 4.54 (2H, t, J=8.1 Hz), 3.44 (2H, t, J=8.1 Hz). ¹³C-NMR δ: 164.7, 164.4 (d, J=250.1 Hz), 157.6, 148.3. 139.4, 137.0, 124.6 (d, J=9.2 Hz), 119.2, 116.9 (d, J=23.9 Hz), 112.4, 108.7, 103.8, 50.6, 25.6. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃FNO₂⁺ 270.0925, Found 270.0920.

2-(2-Chlorophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-5): Yellow solid, 1.73 g, 95% yield, mp 224–225°C. IR, ν (KBr) cm⁻¹: 1572 (s, C=N). ¹H-NMR δ: 9.19 (1H, s), 7.89 (1H, d, J=7.3 Hz), 7.80 (1H, d, J=7.9 Hz), 7.65–7.67 (2H, m), 7.45 (1H, s), 7.19 (1H, s), 6.30 (2H, s), 4.43 (2H, t, J=8.1 Hz), 3.51 (2H, t, J=8.1 Hz). ¹³C-NMR δ: 168.3, 158.4, 148.4, 140.3, 137.8, 132.3, 130.9, 128.9, 128.4, 127.0, 118.7, 112.7, 109.0, 104.0, 51.5, 25.8. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃ClNO₂⁺ 286.0629, Found 286.0624.

2-(3-Chlorophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-6): Pale yellow solid, 1.73 g, 95% yield, mp 226–228°C. IR, ν (KBr) cm⁻¹: 1573 (s, C=N). ¹H-NMR δ: 9.23 (1H, s), 7.89 (1H, s), 7.64–7.72 (3H, m), 7.41 (1H, s), 7.12 (1H, s), 6.25 (2H, s), 4.52 (2H, t, J=8.1 Hz), 3.41 (2H, t, J=8.1 Hz). ¹³C-NMR δ: 166.6, 159.4, 149.7, 145.5, 138.9, 136.9, 132.7, 131.8, 123.9, 122.0, 120.6, 114.0, 110.1, 105.3, 51.8, 27.0. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃ClNO₂⁺ 286.0629, Found 286.0624.

2-(4-Chlorophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-7): Orange, lustrous and acicular crystal, 1.75 g, 96% yield, mp 211–212°C. IR, ν (KBr) cm⁻¹: 1569 (s, C=N). ¹H-NMR δ: 9.26 (1H, s), 7.82 (2H, d, J=8.8 Hz), 7.70 (2H, d, J=8.8 Hz), 7.45 (1H, s), 7.15 (1H, s), 6.27 (2H, s), 4.55 (2H, t, J=8.1 Hz), 3.45 (2H, t, J=8.1 Hz). ¹³C-NMR δ: 164.6, 157.7, 148.2, 141.6, 137.2, 136.2, 130.0, 123.8, 119.2, 112.6, 108.7, 103.8, 50.5, 25.7. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃ClNO₂⁺ 286.0629, Found 286.0621.

2-(2-Bromophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-8): Pale yellow solid, 1.94 g, 95% yield, mp 138–140°C. IR, ν (KBr) cm⁻¹: 1571 (s, C=N). ¹H-NMR δ: 9.18 (1H, s), 7.97 (1H, d, J=8.1 Hz), 7.88 (1H, d, J=7.9 Hz), 7.70 (1H, t, J=7.6 Hz), 7.61 (1H, t, J=7.6 Hz), 7.44 (1H, s), 7.19 (1H, s), 6.30 (2H, s), 4.42 (2H, t, J=8.1 Hz), 3.53 (2H, t, J=8.1 Hz). ¹³C-NMR δ: 168.3, 158.4, 148.4, 142.0, 137.7, 134.1, 132.4, 129.5, 127.05, 118.6, 117.7, 112.6, 109.1, 104.0, 51.6, 25.8. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃BrNO₂⁺ 330.0124, Found 330.0120.

2-(3-Bromophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-9): Yellow solid, 1.92 g, 94% yield, mp 230–232°C. IR, ν (KBr) cm⁻¹: 1569 (s, C=N). ¹H-NMR δ: 9.25 (1H, s), 8.06 (1H, t, J=2.0 Hz), 7.83 (1H, d, J=8.1 Hz), 7.78 (1H, d, J=8.1 Hz), 7.61 (1H, t, J=8.1 Hz), 7.43 (1H, s), 7.15 (1H, s), 6.28 (2H, s), 4.54 (2H, t, J=8.2 Hz), 3.44 (2H, t, J=8.2 Hz). ¹³C-NMR δ: 166.5, 159.4, 149.7, 145.5, 138.8, 134.8, 132.9, 126.8, 124.4, 122.4, 120.5, 114.0, 110.1, 105.3, 51.7, 27.0. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃BrNO₂⁺ 330.0124, Found 330.0119.

2-(4-Bromophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-10): Yellow solid, 2.00 g, 98% yield, mp 209–210°C. IR, ν (KBr) cm⁻¹: 1566 (s, C=N). ¹H-NMR δ: 9.25 (1H, s), 7.86 (2H, d, J=8.8 Hz), 7.73 (2H, d, J=8.8 Hz), 7.44 (1H, s), 7.15 (1H, s), 6.28 (2H, s), 4.55 (2H, t, J=8.0 Hz), 3.44 (2H, t, J=8.0 Hz). ¹³C-NMR δ: 164.6, 157.8, 148.3, 142.1, 137.3, 133.1, 124.2, 123.9, 119.2, 112.5, 108.7, 103.8, 50.3, 25.6. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃BrNO₂⁺ 330.0124, Found 330.0118.

2-(2-Iodophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-11): Yellow solid, 2.15 g, 94% yield, mp 258–260°C. IR, ν (KBr) cm⁻¹: 1586 (s, C=N). ¹H-NMR δ: 9.17 (1H, s), 8.15 (1H, d, J=7.9 Hz), 7.87 (1H, d, J=7.9 Hz), 7.69 (1H, t, J=7.6 Hz), 7.48 (1H, s), 7.41 (1H, t, J=7.6 Hz), 7.18 (1H, s), 6.29 (2H, s), 4.39 (2H, s), 3.60 (2H, s). ¹³C-NMR (CDCl₃–CD₃OD=2 : 8) δ: 168.2, 158.3, 148.3, 145.5, 140.5, 137.5, 132.2, 130.2, 126.4, 118.7, 112.8, 109.2, 104.0, 93.2, 51.9, 26.1. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃INO₂⁺ 377.9985, Found 377.9975.

2-(3-Iodophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-12): Yellow solid, 2.19 g, 96% yield, mp 231–233°C. IR, ν (KBr) cm⁻¹: 1565 (s, C=N). ¹H-NMR δ: 9.24 (1H, s), 8.20 (1H, s), 8.02 (1H, d, J=8.0 Hz), 7.81 (1H, d, J=8.2 Hz), 7.42–7.46 (2H, m), 7.15 (1H, s), 6.28 (2H, s), 4.53 (2H, t, J=8.1 Hz), 3.44 (2H, t, J=8.1 Hz). ¹³C-NMR δ: 165.0, 157.9, 148.3, 143.9, 139.5, 137.4, 131.3, 131.1, 121.5, 119.2, 112.6, 108.7, 103.8, 94.0, 50.4, 25.6. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃INO₂⁺ 377.9985, Found 377.9973.

2-(4-Iodophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-13): Yellow solid, 2.24 g, 98% yield, mp 253–254°C. IR, ν (KBr) cm⁻¹: 1579 (s, C=N). ¹H-NMR δ: 9.24 (1H, s), 8.05 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.43 (1H, s), 7.15 (1H, s), 6.27 (2H, s), 4.54 (2H, t, J=8.2 Hz), 3.43 (2H, t, J=8.2 Hz). ¹³C-NMR δ: 164.5, 157.8, 148.3, 142.7, 139.2, 137.3, 123.7, 119.3, 112.5, 108.7, 103.8, 95.7, 50.2, 25.6. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃INO₂⁺ 377.9985, Found 377.9975.

2-(3,5-Dichlorophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-14): Orange, lustrous and acicular crystal; 1.97 g, 99% yield, mp 168–170°C. IR, ν (KBr) cm⁻¹: 1570 (s, C=N). ¹H-NMR δ: 9.31 (1H, s), 7.91 (2H, s), 7.77 (1H, s), 7.45 (1H, s), 7.16 (1H, s), 6.29 (2H, s), 4.53 (2H, t, J=8.1 Hz), 3.45 (2H, t, J=8.1 Hz). ¹³C-NMR δ: 165.7, 158.3, 148.4, 144.6, 138.0, 136.2, 130.1, 121.4, 119.1, 112.8, 108.8, 104.0, 50.3, 25.6. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₂Cl₂NO₂⁺ 320.0240, Found 320.0235.

2-((2-Trifluoromethyl)phenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-15): Pale yellow, lustrous and acicular crystal, 1.92 g, 96% yield, mp 239–240°C. IR, ν (KBr) cm⁻¹: 1579 (s, C=N), 1345 (vs, C–F). ¹H-NMR δ: 9.25 (1H, s), 8.08 (1H, d, J=7.7 Hz), 7.90–8.02 (3H, m), 7.42 (1H, s), 7.20 (1H, s), 6.31 (2H, s), 4.55 (1H, s), 4.35 (1H, s), 3.48 (2H, t, J=8.2 Hz). ¹³C-NMR δ: 168.7, 158.8, 148.5, 139.9, 137.8, 134.6, 131.6, 127.8 (q, J=4.65), 127.6, 124.9 (d, J=31.5 Hz), 122.0, 118.3, 112.7, 109.2, 104.1, 52.5, 25.6. HR-MS [M−Br]⁺: Calcd for C₁₇H₁₃F₃NO₂⁺ 320.0893, Found 320.0885.

2-((3-Trifluoromethyl)phenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-16): Yield, 96%; Pale yellow, lustrous and acicular crystal; 1.92 g, 96% yield, mp 181–183°C. IR, ν (KBr) cm⁻¹: 1610 (s, C=N), 1328 (vs, C–F). ¹H-NMR δ: 9.33 (1H, s), 8.19 (1H, s), 8.09 (1H, d, J=7.9 Hz), 7.99 (1H, d, J=7.9 Hz), 7.91 (1H, t-like, J=7.9 Hz), 7.45 (1H, s), 7.17 (1H, s), 6.29 (2H, s), 4.59 (2H, t, J=8.1 Hz), 3.47 (2H, t, J=8.1 Hz). ¹³C-NMR δ: 165.6, 158.1, 148.4, 143.6, 137.6, 131.2, 127.0 (t-like, J=3.8 Hz), 126.3 (d, J=38.9 Hz), 126.0, 122.3, 119.6 (q, J=14.5 Hz), 119.2, 112.6, 108.8, 103.9, 50.4, 25.6. HR-MS [M−Br]⁺: Calcd for C₁₇H₁₃F₃NO₂⁺ 320.0893, Found 320.0889.

2-((4-Trifluoromethyl)phenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-17): Yellow solid, 1.90 g, 97% yield, mp 196–198°C. IR, ν (KBr) cm⁻¹: 1578 (s, C=N), 1323 (vs, C–F). ¹H-NMR δ: 9.35 (1H, s), 8.01 (4H, s), 7.47 (1H, s), 7.18 (1H, s), 6.29 (2H, s), 4.62 (2H, t, J=8.2 Hz), 3.48 (2H, t, J=8.2 Hz). ¹³C-NMR δ: 165.4, 158.2, 148.4, 145.8, 137.8, 131.9 (d, J=32.9 Hz), 127.1 (q, J=3.7 Hz), 124.6 (d, J=270.0 Hz), 123.1, 119.2, 112.8, 108.8, 103.9, 50.3, 25.7. HRMS [M-Br]⁺: Calcd for C₁₇H₁₃F₃NO₂⁺ 320.0893, Found 320.0889.

2-(2-Nitrophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-18): Pale yellow, lustrous and acicular crystal, 1.79 g, 95% yield, mp 157–159°C. IR, ν (KBr) cm⁻¹: 1524 (s, C=N), 1344 (s, –NO₂). ¹H-NMR δ: 9.17 (1H, s), 8.52 (1H, d, J=8.4 Hz), 8.07 (1H, t, J=7.7 Hz), 7.96–7.97 (2H, m), 7.37 (1H, s, H-8), 7.19 (1H, s), 6.30 (2H, s), 4.47 (2H, t, J=8.1 Hz), 3.53 (2H, br s). ¹³C-NMR δ: 167.7, 158.5, 148.4, 142.8, 137.7, 136.0, 135.9, 132.3, 128.4, 126.7, 118.6, 112.6, 109.1, 104.0, 52.2, 25.9. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃N₂O₄⁺ 297.0870, Found 297.0868.

2-(3-Nitrophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-19): Yellow solid, 1.77 g, 94% yield, mp 271–273°C. IR, ν (KBr) cm⁻¹: 1538 (s, C=N), 1352 (s, –NO₂). ¹H-NMR δ: 9.36 (1H, s), 8.68 (1H, s), 8.48 (1H, d, J=8.2 Hz), 8.20 (1H, d, J=8.2 Hz), 7.92 (1H, t, J=8.2 Hz), 7.45(1H, s), 7.12 (1H, s), 6.27 (2H, s), 4.59 (2H, t, J=8.2 Hz), 3.47 (2H, t, J=8.2 Hz). ¹³C-NMR δ: 165.7, 158.5, 149.0, 148.5, 143.6, 137.8, 131.5, 128.2, 124.8, 119.1, 117.7, 112.99, 109.0, 104.0, 50.5, 25.8. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃N₂O₄⁺ 297.0870, Found 297.0867.

2-(4-Nitrophenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-20): Orange solid, 1.80 g, 96% yield, mp 227–229°C. IR, ν (KBr) cm⁻¹: 1569 (s, C=N), 1342 (s, –NO₂). ¹H-NMR δ: 9.38 (1H, s), 8.50 (2H, d, J=8.9 Hz), 8.04 (2H, d, J=8.9 Hz), 7.46 (1H, s), 7.13 (1H, s), 6.28 (2H, s), 4.59 (2H, t, J=8.1 Hz), 3.47 (2H, t, J=8.1 Hz). ¹³C-NMR δ: 165.6, 158.7, 148.5, 147.1, 141.1, 138.2, 125.3, 123.4, 119.2, 113.1, 109.0, 104.0, 50.3, 25.8. HR-MS [M−Br]⁺: Calcd for C₁₆H₁₃N₂O₄⁺ 297.0870, Found 297.0866.

2-(2-Methylphenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-21): Pale yellow solid, 1.64 g, 95% yield, mp 251–252°C. IR, ν (KBr) cm⁻¹: 1567 (s, C=N). ¹H-NMR δ: 9.74 (1H, s, H-1), 7.94 (1H, s), 7.87 (1H, d, J=7.6 Hz), 7.35–7.43 (3H, m), 6.93 (1H, s), 6.17 (2H, s), 4.31 (2H, t, J=7.6 Hz), 3.49 (2H, t, J=7.6 Hz), 2.46 (3H, s). ¹³C-NMR δ: 166.5, 157.2, 148.0, 142.0, 135.7, 132.1, 131.7, 131.0, 128.2, 125.4, 119.3, 114.6, 109.0, 103.4, 52.1, 26.6, 18.1. HR-MS [M−Br]⁺: Calcd for C₁₇H₁₆NO₂⁺ 266.1176, Found 266.1167.

2-(3-Methylphenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-22): Yellow acicular crystal, 1.60 g, 93% yield, mp 244–247°C. IR, ν (KBr) cm⁻¹: 1579 (s, C=N). ¹H-NMR δ: 9.23 (1H, s, H-1), 7.63 (1H, s), 7.55 (2H, q-like, J=7.5 Hz), 7.45–7.48 (2H, m), 7.14 (1H, s), 6.27 (2H, s), 4.55 (2H, t, J=8.2 Hz), 3.44 (2H, t, J=8.2 Hz), 2.51 (3H, s). ¹³C-NMR δ: 164.2, 157.4, 148.2, 143.1, 140.8, 136.9, 131.1, 129.8, 122.4, 119.3, 119.0, 112.4, 108.6, 103.7, 50.4, 25.6, 19.9. HR-MS [M−Br]⁺: Calcd for C₁₇H₁₆NO₂⁺ 266.1176, Found 266.1171.

2-(4-Methylphenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-23): Golden, lustrous and acicular crystal, 1.66 g, 96% yield, mp 235–236°C. IR, ν (KBr) cm⁻¹: 1573 (s, C=N). ¹H-NMR δ: 9.20 (1H, s), 7.68 (2H, d, J=8.0 Hz), 7.50 (2H, d, J=8.0 Hz), 7.44 (1H, s), 7.14 (1H, s), 6.26 (2H, s), 4.54 (2H, t, J=8.2 Hz), 3.43 (2H, t, J=8.2 Hz), 2.48 (3H, s). ¹³C-NMR δ: 163.8, 157.3, 148.2, 141.3, 140.7, 136.7, 130.4, 121.7, 119.3, 112.3, 108.6, 103.67, 50.4, 25.6, 19.8. HR-MS [M−Br]⁺: Calcd for C₁₇H₁₆NO₂⁺ 266.1176, Found 266.1169.

2-(2-Methoxyphenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-24): Golden solid, 1.71 g, 95% yield, mp 230–231°C. IR, ν (KBr) cm⁻¹: 1574 (s, C=N). ¹H-NMR δ: 9.07 (1H, s), 7.62–7.66 (2H, m), 7.41 (1H, s), 7.36 (1H, d, J=8.4 Hz), 7.21 (1H, t, J=8.5 Hz), 7.15 (1H, s), 6.27 (2H, s), 4.38 (2H, t, J=8.2 Hz), 4.02 (3H, s), 3.41 (2H, t, J=8.2 Hz). ¹³C-NMR δ: 166.9, 157.5, 152.5, 148.2, 137.1, 132.3, 131.7, 125.3, 121.1, 119.0, 112.8, 112.2, 108.8, 103.7, 55.6, 51.3, 25.8. HR-MS [M−Br]⁺: Calcd for C₁₇H₁₆NO₃⁺ 282.1125, Found 282.1116.

2-(3-Methoxyphenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-25): Pale yellow solid, 1.70 g, 94% yield, mp 185–186°C. IR, ν (KBr) cm⁻¹: 1576 (s, C=N). ¹H-NMR δ: 9.24 (1H, s), 7.57 (1H, t, J=8.2 Hz), 7.45 (1H, s), 7.32–7.38 (2H, m), 7.21 (1H, d, J=8.2 Hz), 7.14 (1H, s), 6.27 (2H, s), 4.56 (2H, t, J=8.1 Hz), 3.94 (3H, s), 3.44 (2H, t, J=8.1 Hz). ¹³C-NMR δ: 164.4, 161.0, 157.5, 148.2, 144.2, 137.0, 130.9, 119.2, 116.2, 113.8, 112.5, 108.7, 107.8, 103.7, 55.1, 50.5, 25.7. HR-MS [M−Br]⁺: Calcd for C₁₇H₁₆NO₃⁺ 282.1125, Found 282.1117.

2-(4-Methoxyphenyl)-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromide (4-26): Pale yellow solid, 1.75 g, 97% yield, mp 184–185°C. IR, ν (KBr) cm⁻¹: 1573 (s, C=N). ¹H-NMR δ: 9.17 (1H, s), 7.75 (2H, d, J=8.3 Hz), 7.44 (1H, s), 7.20 (2H, d, J=8.3 Hz), 7.13 (1H, s), 6.26 (2H, s), 4.53 (2H, t, J=8.0 Hz), 3.92 (3H, s), 3.43 (2H, t, J=8.0 Hz). ¹³C-NMR δ: 165.2, 163.6, 159.3, 150.4, 138.6, 138.2, 125.7, 121.58, 117.2, 114.4, 110.8, 105.8, 57.3, 52.8, 27.9. HR-MS [M−Br]⁺: Calcd for C₁₇H₁₆NO₃⁺ 282.1125, Found 282.1120.

Acknowledgment

This work was supported by the National Natural Science Foundation of China (NNSF; No. 31000865, 31172365, 31101469).

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