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Article

Synthesis of 5,6-Dihydrophenanthridines via Palladium-Catalyzed Intramolecular Dehydrogenative Coupling of Two Aryl C−H Bonds

by
Meng-Yue Wang
†,
Xue-Qing Zhu
†,
Bao-Yin Zhao
,
Hong-Xia Zhang
,
Yong-Qiang Wang
* and
Qiong Jia
*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, School of Foreign Languages, College of Chemistry & Materials Science, Northwest University, Xi’an 710069, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2023, 28(6), 2498; https://doi.org/10.3390/molecules28062498
Submission received: 14 February 2023 / Revised: 4 March 2023 / Accepted: 7 March 2023 / Published: 9 March 2023
(This article belongs to the Special Issue Chemical Synthesis of Natural Products)
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Versions Notes

Abstract

:
5,6-Dihydrophenanthridines are common aza heterocycle frameworks of natural products and pharmaceuticals. Herein, we reported the first palladium-catalyzed intramolecular C−H/C−H dehydrogenative coupling reaction of two simple arenes to generate 5,6-dihydrophenanthridines. The approach features a broad substrate scope and good tolerance of functional groups, offering an efficient alternative synthesis route for important 5,6-dihydrophenanthridine compounds.

1. Introduction

5,6-Dihydrophenanthridines are common aza heterocycle frameworks of natural products and pharmaceuticals [1,2,3,4,5,6,7,8,9,10,11,12], exhibiting various biological activities including antibiotic, anti-inflammatory, and anticancer activity (Figure 1) [13,14,15,16,17,18,19]. More recently, studies have shown that the current COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and 5,6-dihydrophenanthridine derivatives can interact tightly with SARS-CoV-2 nucleocapsid protein and inhibit the replication of SARS-CoV-2 in vitro [20,21]. Owing to the synthetic challenges in their unique polycyclic skeleton structures, as well as their potential druggability, 5,6-dihydrophenanthridines have aroused considerable interest in synthetic chemists [22,23]. In view of the structural feature of 5,6-dihydrophenanthridines, the formation of their aryl−aryl bond is undoubtedly the key step. To date, there are three main strategies to forge the aryl−aryl bond of 5,6-dihydrophenanthridines (Scheme 1): (1) transition-metal-catalyzed cross-couplings of organometallic aryls with aryl halides (path A) [24,25,26,27,28,29,30]; (2) annulation via benzyne intermediates (path B) [31,32,33]; and (3) the direct arylation of nonactivated aryl C−H bonds with aryl halides (path C) [34,35,36,37,38,39,40,41,42,43,44,45]. Compared to paths A and B, the biggest advantage of path C is that the more expensive and difficult-to-prepare organometallic coupling partner is replaced in this transformation. Nevertheless, the simplest and ideal approach to access 5,6-dihydrophenanthridines is the dehydrogenative coupling of two nonactivated aryl C−H bonds (path D), particularly when aryl halides are not readily available. However, so far there has been no report on using the ideal strategy in the construction of 5,6-dihydrophenanthridine. The major hindrance to the ideal strategy lies in three challenges: (1) the low reactivity of the aryl C−H bond [46]; (2) the regioselectivity issue, especially when there are several reactive sites; and (3) the strong coordinative nitrogen atom of the substrate and product that can easily poison the metal catalyst [23]. In order to accomplish the ideal approach, we hypothesized that an appropriate directing group could be introduced into the substrate to control the regioselectivity whilst at the same time enhancing the reactivity of the aryl C−H bond. Meanwhile, the nitrogen atom of the substrate should be protected by a proper protecting group. In addition, an efficient catalytic system should undoubtedly be sought. Herein, we document the successful execution of this hypothesis to realize the first palladium-catalyzed intramolecular dehydrogenative coupling of two aryl C−H bonds to construct 5,6-dihydrophenanthridines.

2. Results and Discussion

2.1. Optimization of Reaction Conditions

We commenced this research by investigating the phenol-protecting group, which had the potential directing feature for the ortho-functionalization of arenes. A series of phenol-protecting groups were tested with 10 mol% Pd(OAc)2 as the catalyst and acetyl as the protecting group of the nitrogen atom in dimethyl sulfoxide (DMSO) under an air atmosphere (Table 1). The reaction did not occur without the phenol-protecting group (entry 1). The protecting groups CONMe2 and O-(2-pyridyl)carbonyl are excellent directing groups in many C-H functionalization reactions of arenes, but they almost did not work in this reaction (entries 2 and 3). Gratifyingly, when the O-(2-pyridyl)sulfonyl group was used as the protecting group, the desired aryl C−H/C−H coupling product 2a was generated with a 9% yield (entry 4). The structure of 2a was confirmed by single-crystal X-ray diffraction. We considered that the reactivity of the O-(2-pyridyl)-sulfonyl group should lie in it being not only a great directing group but also a good activating group to facilitate the formation of a phenyl−Pd complex through the ortho C−H bond activation of phenol [47,48]. Encouraged by the preliminary result, we then carefully examined other parameters of the reaction. The influence of the solvent showed that CF3CH2OH was the best option, providing 2a with a 12% yield (entries 5–7). After screening the oxidant, copper(II) trifluoroacetate hydrate provided the highest yield (31%, entries 8–12). Note that without any oxidant the reaction gave 2a with a 8% yield under an argon atmosphere (entry 13). Next, the reaction temperature was checked (entries 14–17). Increasing the temperature benefitted the reaction, and the yield was increased to 45% at 100 °C. It turned out that the N-protecting group was crucial for this reaction. As speculated, the replacement of the N-protecting group with Ts, Boc, methyl, or phenyl all led to inferior results (entries 18–21). Then, the palladium source was investigated, indicating that Pd(TFA)2 was the best catalyst (entries 22–25). The investigation of the amount of Pd(TFA)2 and Cu(TFA)2·H2O indicated that Pd(TFA)2 (15 mol%) and Cu(TFA)2·H2O (2.2 equiv.) were the best choices (entries 26–31). It is noteworthy that the reaction proceeded similarly under an argon atmosphere (entry 31). Accordingly, the optimized reaction conditions were identified as the following: Pd(TFA)2 (15 mol%) and Cu(TFA)2·H2O (2.2 equiv.) in CF3CH2OH at 100 °C under an air atmosphere for 20 h (entry 29).

2.2. Substrate Scope

With the optimal conditions in hand, we first examined the effect of the substituents on the right aromatic ring for the aryl C−H/C−H coupling (Scheme 2). A variety of aryls with both electron-donating and electron-withdrawing groups could be engaged in this transformation, providing the desired 5,6-dihydrophenanthridines with good-to-excellent yields. A broad range of functional groups such as alkyls (2b−g), halides (F, Cl, Br, 2h−j), trifluoromethoxy (2k), nitro (2l), trifluoromethyl (2m), and methyl sulfonyl group (Ms, 3n) were compatible with this process. These provided synthetically interesting results because such substituents acted as versatile handles for further transformations. The position of the substituent on the aromatic rings had almost no effect on the reactivity (2o−q). Next, we investigated the substituents on the left phenol ring. Again, the aryl C−H/C−H dehydrogenative coupling reaction was insensitive to the electronic property of the substituent groups such as electron-donating methyl and methoxy, and electron-withdrawing ester groups; all reactions proceeded successfully, affording the desired products with 75–82% yields (2r−t).

2.3. Large-Scale Experiment and Synthetic Application

To test the practicality of this dehydrogenative coupling, a large-scale experiment was carried out. With the above standard reaction conditions, 1a (1.146 g, 3.0 mmol) provided 5,6-dihydrophenanthridine 2a (832 mg) with a 73% yield (Figure 2).
To demonstrate the synthetic application of this methodology, we employed dehydrogenative coupling as the key step to synthesize an inhibitor of potassium channels KV1.3 and IK-1 (7) (Scheme 3) [6]. First, the 2-pyridysulfonyl group was readily removed by zinc in NH4Cl (aq)/THF (1:1) at room temperature, affording 3 in a quantitative yield. Then, the hydroxy group was transformed into a benzenesulfonate group (4), which was further removed to give product 5 [49,50]. Next, the acetyl group in product 5 could be readily eliminated using H2SO4 in MeOH, affording the product phenanthridine 6 with a 76% yield. Finally, the inhibitor dihydrophenanthridine 7 was achieved by the activation of the imine structure in phenanthridine with acyl chlorides to give an intermediary imminium ion followed by in situ nucleophilic attack with indole [6].

2.4. Mechanistic Investigations

To gain insight into the mechanism of this intramolecular dehydrogenative coupling of the two aryl C−H bonds, a kinetic isotope effect (KIE) experiment was performed. The KIE value of the two parallel competition reactions of 1a and [D7]-1a was found to be 3.04 (Figure 3). This implied that an electrophilic aromatic palladation mechanism was unlikely, and the cleavage of the C−H bond on the right aromatic ring should be involved in the rate-determining step. In addition, a radical-trapping experiment was performed. In the presence of 1.0 equiv. of 2,2,6,6-tetramethylpiperidine oxide (TEMPO), under the above standard conditions, the reaction of 1a proceeded well to give 2a with almost the same yield, illustrating a low possibility for a free radical pathway.
On the basis of the above results and the relevant literature [51,52,53,54,55], a plausible mechanism is proposed in Scheme 4. Initially, the O-(2-pyridyl)sulfonyl group-directed palladation formed complex I, which then underwent an intramolecular concerted metalation−deprotonation (CMD) step assisted by trifluoroacetate via a six-membered transition state (II) to afford intermediate III. Finally, the reductive elimination of intermediate III produced the 5,6-dihydrophenanthridine product along with Pd(0), which was reoxidized by Cu2+ to regenerate the Pd(II) species to complete the catalytic cycle.

3. Materials and Methods

3.1. General Information

All reactions were carried out under an air atmosphere. Unless noted otherwise, commercially available chemicals were used without further purification. Flash chromatography was performed with silica gel (200–300 mesh). An oil bath served as the heat source. NMR spectra were acquired on either a Bruker 400 MHz (1H at 400 MHz, 13C at 100 MHz) or Jeol 400 MHz (1H at 400 MHz, 13C at 100 MHz) device, and NMR spectra were recorded in CDCl3 (TMS, δ = 0.00 ppm for 1H and δ = 77.10 ppm for 13C), DMSO-d6 (δ = 2.50 ppm for 1H and δ = 39.52 ppm for 13C), or CD3OD (δ = 3.31 ppm for 1H and δ = 49.00 ppm for 13C) using the solvent residue peaks as the internal references. Coupling constants were reported in hertz (Hz). Data for 1H NMR spectra were reported as follows: chemical shift (ppm, referenced to protium, s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, ddd = doublet of doublet of doublets, m = multiplet, coupling constant (Hz), and integration). Infrared (IR) data were acquired on a Bruker Invenio-RFT-IR spectrometer. Absorbance frequencies were reported in reciprocal centimeters (cm−1). Mass spectra were acquired on a BrukerDaltonics S2 MicroTof-Q II mass spectrometer. X-ray crystal structure analyses were measured on a Bruker Smart APEXIICCD instrument using Mo-Kα radiation. The structures were solved and refined using the SHELXTL software package.

3.2. General Procedure A for Preparation of Substrates

To a solution of N-(3-hydroxyphenyl)acetamide (30.0 mmol, 4.51g) in CH2Cl2 (50 mL), Et3N (40.0 mmol, 4.04 g) was added. The mixture was stirred at room temperature for 30 min, and then pyridine-2-sulfonyl chloride (30.0 mmol, 5.31 g) was added. The mixture was stirred overnight. The solvent was removed by distillation, and then EtOAc (50 mL) was added. The resulting solution was washed with water (3 × 10 mL) and brine (3 × 5 mL), dried over MgSO4, and concentrated. The residue was used without further purification in the next step.
To a solution of residue (1 mmol) in anhydrous tetrahydrofuran (10 mL), NaH (60 mg, 1.5 mmol, 60%) was added. The mixture was stirred at room temperature for 30 min, and then benzyl bromide (1.2 mmol) was added. The mixture was stirring at room temperature until completion of the reaction (monitored by TLC). Then, the reaction mixture was filtered and purified by column chromatography (eluent: PET (petroleum ether):EA (ethyl acetate) = 2:1).

3.3. General Procedure B for Preparation of Substrates

To a solution of 3-aminophenol (30.0 mmol, 4.51 g) in CH2Cl2 (50 mL), NEt3 (40.0 mmol, 4.04 g) was added. The mixture was stirred at room temperature for 30 min, and then pyridine-2-sulfonyl chloride (30.0 mmol, 5.31 g) was added. The mixture was stirred overnight. The solvent was removed by distillation, and then EtOAc (50 mL) was added. The resulting solution was washed with water (3 × 10 mL) and brine (3 × 5 mL), dried over MgSO4, and concentrated. The residue was used without further purification in the next step.
To a solution of residue (1 mmol) in CH2Cl2 (10 mL), acetic anhydride (122 mg, 1.2 mmol) was added. The mixture was stirred overnight. The solvent was removed by distillation, and then CH2Cl2 (15 mL) was added. The resulting solution was washed with water (3 × 5 mL) and brine (3 × 5 mL), dried over MgSO4, and concentrated. The residue was purified by column chromatography (eluent: PET:EA = 2:1) to give the product.
To a solution of above product (1 mmol) in anhydrous tetrahydrofuran (10 mL), NaH (60 mg, 1.5 mmol, 60%) was added. The mixture was stirred at room temperature for 30 min, and then benzyl bromide (1.2 mmol) was added. The mixture was stirring at room temperature until completion of the reaction (monitored by TLC). Then, the reaction mixture was filtered and purified by column chromatography (eluent: PET:EA = 2:1).

3.4. General Procedure C for Preparation of Products

3-(N-benzylacetamido)phenyl pyridine-2-sulfonate derivatives 1 (0.2 mmol), Pd(TFA)2 (15 mol %), and Cu(TFA)2·H2O (2.2 equiv.) were added to a 10 mL round-bottom flask in CF3CH2OH, and these were held at 100 °C under an air atmosphere until completion of the reaction (monitored by TLC). Then, purification by flash chromatography afforded product 2.

3.5. The Synthesis of Immunosuppressant 7

1-Hydroxyphenanthridin-5(6H)-yl)ethan-1-one (3): A suspension of 5-acetyl-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate 2 (152mg, 0.4 mmol) and Zn powder (not activated, 1.3 g, 20 mmol) in a 1:1 mixture of THF and saturated NH4Cl solution in water (20 mL) was stirred at 30 °C until consumption of the starting material (monitored by TLC). The mixture was filtered over a pad of celite to remove the Zn. The filtrate was extracted with EA (15 mL) and washed with a saturated aqueous solution of ammonium chloride and brine. The combined organic phase was dried over MgSO4 and concentrated. The residue was purified by flash chromatography to afford the corresponding product 3 (eluent: PET:EA = 1:1, Rf = 0.2) as a white solid. Quant.: m. p. = 212–213 °C; 1H NMR (400 MHz, CD3OD) δ 8.46 (d, J = 7.9 Hz, 1H), 7.33–7.29 (m, 1H), 7.28–7.19 (m, 2H), 7.16–7.12 (m, 1H), 6.86 (d, J = 7.4 Hz, 2H), 4.61 (d, J = 9.8 Hz, 2H), 2.09 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 170.4, 155.3, 139.7, 135.2, 130.5, 128.1, 127.7, 126.9, 126.6, 125.0, 117.0, 115.8, 114.2, 45.3, 20.9; HRMS (ESI) m/z calculated for C15H13NO2Na [M+Na]+: 262.0838; found 262.0830.
5-Acetyl-5,6-dihydrophenanthridin-1-yl benzenesulfonate (4): The compound 3 (0.4 mmol, 96 mg) was dissolved in DCM (10 mL) in a bottle filled under an argon atmosphere. The solution was cooled to 0 °C. Then, NEt3 (0.078 mL, 0.56 mmol, 1.4 equiv) was added dropwise to the solution, which was followed by the addition of benzenesulfonyl chloride (84.5 mg, 0.48 mmol, 1.2 equiv). After 5 min, the ice bath was removed, and the reaction was monitored by TLC. Once the phenol was completely consumed, the reaction was stopped. The solvent was evaporated under a vacuum, and the residue was purified by flash column chromatography to give 4 as a colorless gel (144mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 7.9, 1.3 Hz, 1H), 7.32–7.41 (m, 5H), 7.29–7.25 (m, 1H), 7.24–7.19 (m, 2H), 7.14–7.07 (m, 3H), 4.27 (s, 2H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 146.39, 140.2, 136.1, 133.9, 129.3, 128.4, 128.3 (3C), 128.2 (2C), 127.8, 127.7, 125.7, 123.5, 122.0, 45.0, 21.7.
1-(Phenanthridin-5(6H)-yl)ethan-1-one (5) [56]: To a bottle were added 4 (144 mg, 0.38 mmol), Pd(OAc)2 (8.84 mg 0.039 mmol), DPPF (7.3 mg, 0.039 mmol), Et3N (119 mg 1.18 mmol), HCOOH (36 mg 0.78 mmol), and DMF (4 mL). The atmosphere was replaced by an argon atmosphere. The mixture was stirred at 80 °C for 6 h. After the usual workup, the residue was purified by flash column chromatography to give 5 as a yellow gel (58.5 mg, 69%). H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.6, 6.1 Hz, 2H), 7.45–7.14 (m, 6H), 4.90 (s, 2H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.3, 137.8, 135.0, 131.6, 129.6, 127.9 (2C), 127.6, 126.2, 126.0, 124.5, 124.3, 123.2, 44.8, 22.0.
Phenanthridin (6) [57]: A stock solution was prepared by dropwise addition of concentrated sulfuric acid (1 mL) to reagent-grade methanol (5 mL) in a scintillation vial (20 mL in volume). The stock solution was stirred for 5 min, and then the solution was cooled to room temperature. A bottle equipped with a spin bar was charged with 1-(phenanthridin-5(6H)-yl)ethan-1-one 5 (0.26 mmol). A fraction of the stock solution (0.5 mL) was added slowly to the solid reagent, and the reaction mixture was stirred at 60 °C for 15 min. Then, the reaction mixture was cooled to room temperature, and distilled water (2 mL), EtOAc (5 mL), and saturated Na2CO3 solution (2 mL) were added dropwise to the reaction mixture. The aqueous phase was extracted with EA (2 × 8 mL), and the combined organic fractions were dried over anhydrous Na2SO4 or MgSO4. The combined organic fractions were filtered through celite, and the filtrate was concentrated. The residue was purified by flash column chromatography to give phenanthridine 6 as a white solid (35.7 mg, 76%). m. p. = 106–109 °C; 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.61 (dd, J = 12.6, 7.4 Hz, 2H), 8.20 (d, J = 9.5 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.90–7.85 (m, 1H), 7.79–7.67 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 153.7, 144.5, 132.6, 131.1, 130.2, 128.9, 128.8, 127.6, 127.2, 126.5, 124.1, 122.3, 122.0.
Immunosuppressant (7) [58]: Phenanthridine (0.2 mmol) was dissolved in dry tetrahydrofuran (2.0 mL) under an argon atmosphere. After cooling to 0°C, the appropriate acetyl chloride (1.2 mmol) was added dropwise. The mixture was stirred for 2 h at room temperature and then cooled to 0 °C again. Triethylamine (0.3 mmol) was added followed by 1H-indole (1.5 mmol). After stirring for 3 h at room temperature, water was added, and the mixture was extracted several times with ethyl acetate. After washing the combined organic phases with brine and drying over Na2SO4, the solvent was removed in vacuo. The residue was purified by flash column chromatography to give immunosuppressant 7 as a white solid (35.7 mg, 76%). m. p. = 211–213 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.99 (dd, J = 26.9, 7.7 Hz, 2H), 7.73 (d, J = 7.7 Hz, 1H), 7.52–7.47 (m, 2H), 7.41–7.37 (m, 1H), 7.33 (s, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.17 (d, J = 4.4 Hz, 2H), 7.05–7.01 (m, 2H), 6.11 (s, 1H), 2.19 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 168.6, 137.4, 136.3, 135.7, 130.8, 128.8, 128.2, 128.0, 127.8, 126.9, 126.00, 125.96, 125.8, 124.6, 124.2, 123.8, 121.4, 119.0 (2C), 113.9, 111.6, 49.7, 22.6; IR (KBr): 3016, 2961, 2927, 1662, 1455, 1426, 1455, 1426, 1378.9, 1213, 1186, 1118, 1049, 1049, 987, 874, 753, 667, 594 cm−1; HRMS (ESI) m/z calculated for C23H18N2ONa [M+Na]+: 361.1311; found 361.1307.

3.6. Characterization Data of Substrates and Products

3-(N-Benzylacetamido)phenyl pyridine-2-sulfonate (1a): The product was synthesized by general method A (eluent: EA:PE = 1:2, Rf = 0.23); 278.9 mg, 73% yield; white solid; m. p. = 78–79 °C; 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.92–7.88 (m, 2H), 7.58 (d, J = 3.0 Hz, 1H), 7.38–7.18 (m, 4H), 7.15–7.07 (m, 3H), 6.99–6.71 (m, 2H), 4.80 (s, 2H), 1.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9, 153.2, 150.6, 149.9, 143.9, 138.3, 136.9, 130.5, 128.5 (2C), 128.3, 127.5, 127.0, 124.2, 122.4, 121.9, 52.7, 22.7; IR (KBr): 3063, 2924, 1658, 1601, 1581, 1485, 1428, 1376, 1196, 1117, 938, 616, 593 cm−1; HRMS (ESI) m/z calculated for C20H18N2O4SNa [M+Na]+: 405.0879; found 405.0871.
3-(N-(4-Methylbenzyl)acetamido)phenyl pyridine-2-sulfonate (1b): The product was synthesized by general method A (eluent: EA:PE = 1:2, Rf = 0.22); 332.7 mg, 84% yield; white solid; m. p. = 83–94 °C; 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.92–7.88 (m, 2H), 7.58 (d, J = 3.3 Hz, 1H), 7.34–7.21 (m, 1H), 7.11 (d, J = 7.0 Hz, 1H), 7.01 (dd, J = 16.4, 7.4 Hz, 4H), 6.88 (d, J = 7.3 Hz, 1H), 6.83 (s, 1H), 4.75 (s, 2H), 2.28 (s, 3H), 1.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 153.2, 150.6, 149.9, 143.9, 138.3, 137.1, 133.9, 130.5, 129.2, 128.5, 128.3, 127.1, 124.2, 122.5, 121.9, 52.4, 22.8, 21.1; IR (KBr): 2924, 1731, 1620, 1572, 1490, 1467, 1378, 1195, 1067, 1032, 840 cm−1; HRMS (ESI) m/z calculated for C21H20N2O4SNa [M+Na]+: 419.1036; found 419.1033.
3-(N-(4-Ethylbenzyl)acetamido)phenyl pyridine-2-sulfonate (1c): The product was synthesized by general method A (eluent: EA:PE = 1:1, Rf = 0.25); 369.9 mg, 91% yield; colorless gel; 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.6 Hz, 1H), 7.85 (d, J = 2.1 Hz, 2H), 7.54 (ddd, J = 6.7, 4.7, 2.4 Hz, 1H), 7.25–7.19 (m, 1H), 7.12–6.94 (m, 5H), 6.86 (d, J = 8.1 Hz, 1H), 6.80 (s, 1H), 4.72 (s, 2H), 2.54 (q, J = 7.6 Hz, 2H), 1.74 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 152.9, 150.4, 149.7, 143.8, 143.2, 138.2, 133.9, 130.3, 128.3, 128.1, 127.8, 126.9, 124.0, 122.3, 121.7, 52.2, 28.3, 22.5, 15.3; IR (KBr): 3057, 2926, 1914, 1854, 1806, 1529, 1428, 1379, 1197, 1139, 1118, 926, 867, 772, 594, 553 cm−1; HRMS (ESI) m/z calculated for C22H23N2O4S [M+H]+: 411.1373; found 411.1384.
3-(N-(4-Isopropylbenzyl)acetamido)phenyl pyridine-2-sulfonate (1d): The product was synthesized by general method A (eluent: EA:PE = 1:1, Rf = 0.25); 361.3 mg, 85% yield; colorless gel; 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 4.7 Hz, 1H), 7.93 (d, J = 7.9 Hz, 2H), 7.61 (ddd, J = 6.8, 4.6, 2.2 Hz, 1H), 7.32–7.26 (m, 1H), 7.19–7.03 (m, 5H), 6.94 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H), 4.79 (s, 2H), 2.87 (p, J = 7.0 Hz, 1H), 1.81 (s, 3H), 1.21 (d, J = 2.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 13C NMR (101 MHz, CDCl3) δ 169.6, 152.8, 150.4, 149.7, 147.8, 143.8, 138.2, 134.0, 130.3, 128.2, 128.1, 126.9, 126.3, 124.0, 122.2, 121.6, 52.2, 33.5, 23.8, 22.5; IR (KBr): 3551, 2959, 1643, 1601, 1485, 1428, 1380, 1197, 1138, 1117, 1085, 1017, 926, 865, 768, 751, 592, 548 cm−1; HRMS (ESI) m/z calculated for C23H25N2O4S [M+H]+: 425.1530; found 425.1546.
3-(N-(4-(tert-Butyl)benzyl)acetamido)phenyl pyridine-2-sulfonate (1e): The product was synthesized by general method A (eluent: EA:PE = 1:2, Rf = 0.28); 363.7 mg, 83% yield; white solid; m. p. = 82–93 °C; 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 4.5 Hz, 1H), 7.93 (d, J = 4.5 Hz, 2H), 7.60 (dd, J = 8.8, 4.6 Hz, 1H), 7.29 (dd, J = 11.3, 5.4 Hz, 3H), 7.15 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 7.5 Hz, 1H), 6.89 (s, 1H), 4.78 (s, 2H), 1.81 (s, 3H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.9, 153.3, 150.6, 150.4, 149.9, 144.1, 138.2, 133.8, 130.4, 128.2 (2C), 127.1, 125.4, 124.2, 122.5, 121.8, 52.4, 34.5, 31.3, 22.7; IR (KBr): 2960, 1660, 1601, 1513, 1428, 1377, 1295, 1196, 1117, 926, 865, 801, 722, 550 cm−1; HRMS (ESI) m/z calculated for C24H26N2O4SNa [M+Na]+: 461.1505; found 461.1515.
3-(N-(4-Isobutylbenzyl)acetamido)phenyl pyridine-2-sulfonate (1f): The product was synthesized by general method A (eluent: EA:PE = 1:1, Rf = 0.25); 403.9 mg, 92% yield; colorless gel; 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 4.6 Hz, 1H), 7.93 (d, J = 3.6 Hz, 2H), 7.63–7.57 (m, 1H), 7.29–7.25 (m, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.06–7.00 (m, 4H), 6.93–6.84 (m, 2H), 4.79 (s, 2H), 2.43 (d, J = 7.2 Hz, 2H), 1.81 (s, 3H), 0.87 (d, J = 6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 169.7, 153.1, 150.5, 149.8, 143.8, 140.8, 138.2, 134.0, 130.3, 129.1, 128.2, 128.1, 127.0, 124.1, 122.4, 121.7, 52.3, 44.9, 30.0, 22.6, 22.2; IR (KBr): 2955, 2925, 1659, 1601, 1581, 1485, 1428, 1379, 1197, 1138, 1117, 926, 866, 771, 736, 594, 550 cm−1; HRMS (ESI) m/z calculated for C24H27N2O4S [M+H]+: 439.1686; found 439.1683.
3-(N-([1,1’-Biphenyl]-4-ylmethyl)acetamido)phenyl pyridine-2-sulfonate (1g): The product was synthesized by general method A (eluent: EA:PE = 1:2, Rf = 0.24); 348.2 mg, 76% yield; white solid; m. p. = 102–103 °C; 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.6 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.85–7.81 (m, 1H), 7.63–7.54 (m, 2H), 7.50 (dd, J = 8.2, 4.6 Hz, 3H), 7.43–7.39 (m, 2H), 7.33–7.26 (m, 2 H), 7.21 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 7.9 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.91 (s, 1H), 4.86 (s, 2H), 1.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 153.0, 150.4, 149.8, 143.8, 140.3, 140.0, 138.1, 135.8, 130.4, 128.8, 128.6, 128.1, 127.2, 127.0, 126.9, 126.8, 123.9, 122.3, 121.8, 52.2, 22.6; IR (KBr): 3058, 2926, 1661, 1601, 1581, 1486, 1428, 1379, 1294, 1197, 801, 766, 616, 594 cm−1; HRMS (ESI) m/z calculated for C26H22N2O4SNa [M+Na]+: 481.1192; found 481.1190.
3-(N-(4-Fluorobenzyl)acetamido)phenyl pyridine-2-sulfonate (1h): The product was synthesized by general method A (eluent: EA:PE = 1:2, Rf = 0.27); 336.1 mg, 84% yield; white solid; m. p. = 83–84 °C; 1H NMR (400 MHz, CDCl3) δ 8.81–8.74 (m, 1H), 8.04–7.90 (m, 2H), 7.62 (ddd, J = 6.8, 4.7, 2.1 Hz, 1H), 7.33–7.28 (m, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.16–7.10 (m, 2H), 6.93 (dd, J = 17.8, 9.0 Hz, 3H), 6.86 (s, 1H), 4.80 (s, 2H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9, 162.2 (JC-F = 244.0 Hz), 153.6, 150.7, 150.1, 143.8, 138.3, 132.8 (JC-F = 3.0 Hz), 130.62, 130.58, 130.5, 128.2, 127.1, 124.1, 122.4 (JC-F = 45.0 Hz), 115.4 (JC-F = 22.0 Hz), 51.9, 22.7; IR (KBr): 2922, 1660, 1602, 1581, 1509, 1428, 1378, 1303, 1197, 1139, 1086, 945, 773 cm−1; HRMS (ESI) m/z calculated for C20H17FN2O4SNa [M+Na]+: 423.0785; found 423.0795.
3-(N-(4-Chlorobenzyl)acetamido)phenyl pyridine-2-sulfonate (1i): The product was synthesized by general method A (eluent: EA: PE = 1:2, Rf = 0.23); 332.8 mg, 80% yield; white solid; m. p. = 84–85 °C; 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 4.3 Hz, 1H), 7.93 (d, J = 3.7 Hz, 2H), 7.60 (dd, J = 8.9, 4.3 Hz, 1H), 7.32–7.28 (m, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 7.7 Hz, 1H), 6.85 (s, 1H), 4.77 (s, 2H), 1.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9, 153.3, 150.6, 150.0, 143.6, 138.3, 135.5, 133.2, 130.6, 130.0, 128.6, 128.2, 126.9, 124.1, 122.4, 122.0, 51.9, 22.6; IR (KBr): 2923, 1661, 1601, 1486, 1428, 1379, 1291, 1197, 1139, 1117, 925, 802, 773 cm−1; HRMS (ESI) m/z calculated for C20H17ClN2O4SNa [M+Na]+: 439.0490; found 439.0492.
3-(N-(4-Bromobenzyl)acetamido)phenyl pyridine-2-sulfonate (1j): The product was synthesized by general method A (eluent: EA:PE = 1:1, Rf = 0.23); 291.1 mg, 76% yield; yellow gel; 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 4.7 Hz, 1H), 7.95 (d, J = 6.5 Hz, 2H), 7.75–7.54 (m, 1H), 7.52–7.26 (m, 3H), 7.16 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9, 153.1, 150.5, 149.9, 143.5, 138.2, 135.9, 131.4, 130.6, 130.2, 128.2, 126.8, 124.0, 122.2, 121.9, 121.3, 51.9, 22.5; IR (KBr): 2959, 2920, 1660, 1602, 1582, 1486, 1428, 1379, 1197, 1139, 1118, 926, 866, 801, 773, 594, 551 cm−1; HRMS (ESI) m/z calculated for C20H17BrN2O4SNa [M+Na]+: 482.9985; found 482.9979.
3-(N-(4-(Trifluoromethoxy)benzyl)acetamido)phenyl pyridine-2-sulfonate (1k): The product was synthesized by general method A (eluent: EA:PE = 1:2, Rf = 0.24); 358.8 mg, 77% yield; white solid; m. p. = 77–78 °C; 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 4.4 Hz, 1H), 8.03–7.84 (m, 2H), 7.67–7.58 (m, 1H), 7.35–7.30 (m, 1H), 7.19 (d, J = 8.5 Hz, 3H), 7.11 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 4.82 (s, 2H), 1.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1, 153.4, 150.6, 150.1, 148.5, 143.8, 138.3, 135.7, 130.7, 130.1, 128.2, 126.9, 124.1, 122.5, 122.1, 120.9, 120.4 (JC-F = 255.0 Hz), 52.0, 22.7; IR (KBr): 2924, 1662, 1602, 1582, 1429, 1380, 1255, 1227, 1196, 991, 867, 801 cm−1; HRMS (ESI) m/z calculated for C21H17F3N2O5SNa [M+Na]+: 489.0702; found 489.0700.
3-(N-(4-Nitrobenzyl)acetamido)phenyl pyridine-2-sulfonate (1l): The product was synthesized by general method A (eluent: EA:PE = 1:2, Rf = 0.20); 354.5 mg, 83% yield; white solid; m. p. = 100–101 °C; 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 4.6 Hz, 1H), 8.11 (d, J = 8.6 Hz, 2H), 8.01–7.93 (m, 2H), 7.66–7.57 (m, 1H), 7.36–7.32 (m, 3H), 7.16 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 6.5 Hz, 2H), 4.92 (s, 2H), 1.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 153.4, 150.6, 150.2, 147.3, 144.4, 143.5, 138.4, 130.8, 129.3, 128.3, 126.7, 124.1, 123.8, 122.4, 122.2, 52.2, 22.6; IR (KBr): 3077, 2923, 1662, 1601, 1518, 1428, 1378, 1344, 1197, 1140, 931, 861 cm−1; HRMS (ESI) m/z calculated for C20H17N3O6SNa [M+Na]+: 450.0730; found 450.0731.
3-(N-(4-(Trifluoromethyl)benzyl)acetamido)phenyl pyridine-2-sulfonate (1m): The product was synthesized by general method A (eluent: EA:PE = 1:2, Rf = 0.26); 342.1 mg, 76% yield; white solid; m. p. = 85–86 °C; 1H NMR (400 MHz, CDCl3) δ 8.78–8.65 (m, 1H), 7.99–7.87 (m, 2H), 7.71–7.56 (m, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.36–7.25 (m, 3H), 7.16 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 8.2 Hz, 2H), 4.88 (s, 2H), 1.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1, 153.4, 150.6, 150.1, 143.7, 141.0, 138.3, 130.7, 129.7 (JC-F = 32.0 Hz), 128.8, 128.2, 126.8, 125.5, 124.08, 124.07 (JC-F = 270.0 Hz), 122.4, 122.1, 52.4, 22.6; IR (KBr): 2925, 1663, 1602, 1486, 1380, 1324, 1198, 1115, 1066, 930, 802, 593 cm−1; HRMS (ESI) m/z calculated for C21H17F3N2O4SNa [M+Na]+: 473.0753; found 473.0750.
3-(N-(4-(Methylsulfonyl)benzyl)acetamido)phenyl pyridine-2-sulfonate (1n): The product was synthesized by general method A (eluent: EA:PE = 1:1, Rf = 0.22); 358.8 mg, 78% yield; yellow solid; m. p. = 132–137 °C; 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 4.6 Hz, 1H), 8.00–7.95 (m, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.67–7.59 (m, 1H), 7.44–7.35 (m, 3H), 7.18 (d, J = 8.9 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.91 (s, 1H), 4.93 (s, 2H), 3.06 (s, 3H), 1.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.0, 152.7, 150.4, 149.7, 143.2, 143.0, 139.3, 138.3, 130.6, 129.0, 128.3, 127.3, 126.5, 123.9, 122.1, 121.9, 52.0, 44.2, 22.3; IR (KBr): 2954, 2923, 1659, 1600, 1548, 1378, 1302, 1197, 1147, 1089, 958, 931, 764, 594, 553, 523 cm−1; HRMS (ESI) m/z calculated for C21H20N2O6S2Na [M+Na]+: 483.0655; found 483.0652.
3-(N-(3-Methylbenzyl)acetamido)phenyl pyridine-2-sulfonate (1o): The product was synthesized by general method A (eluent: EA:PE = 1:2, Rf = 0.22); 281.2 mg, 71% yield; white solid; m. p. = 68–69 °C; 1H NMR (400 MHz, CDCl3) δ 8.78–8.74 (m, 1H), 7.95–7.88 (m, 2H), 7.64–7.56 (m, 1H), 7.29 (dd, J = 9.8, 6.4 Hz, 1H), 7.16–7.12 (m, 2H), 7.05 (d, J = 7.5 Hz, 1H), 6.98 (s, 1H), 6.90 (dd, J = 14.3, 6.7 Hz, 3H), 4.79 (s, 2H), 2.30 (s, 3H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9, 153.4, 150.6, 149.9, 144.0, 138.2 (2C), 136.8, 130. 4, 129.3, 128.3 (2C), 128.2, 127.1, 125.6, 124.2, 122.5, 121.9, 52.7, 22.7, 21.4; IR (KBr): 2923, 1660, 1602, 1515, 1486, 1428, 1294, 1197, 1139, 1117, 1039, 948, 801, 773cm−1; HRMS (ESI) m/z calculated for C21H20N2O4SNa [M+Na]+: 419.1036; found 419.1026.
3-(N-([1,1’-Biphenyl]-3-ylmethyl)acetamido)phenyl pyridine-2-sulfonate (1p): The product was synthesized by general method A (eluent: EA:PE = 1:1, Rf = 0.24); 394.7 mg, 86% yield; yellow gel; 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 4.1 Hz, 1H), 7.84–7.72 (m, 2H), 7.48 (dd, J = 19.3, 7.3 Hz, 4H), 7.42–7.22 (m, 6H), 7.01–6.86 (m, 2H), 7.15–7.07(m, 2H), 4.89 (s, 2H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 153.2, 150.6, 150.0, 143.8, 141.3, 140.7, 138.2, 137.4, 130.6, 129.0, 128.8, 128.2, 127.5, 127.4, 127.3, 127.1(2C), 126.4, 124.2, 122.5, 122.1, 52.7, 22.8; IR (KBr): 2920, 2851, 1660, 1601, 1582, 1484, 1428, 1378, 1261, 1197, 1139, 1117, 936, 761, 737, 699, 593, 550 cm−1; HRMS (ESI) m/z calculated for C26H23N2O4S [M+H]+: 459.1373; found 459.1357.
3-(N-(2-Methylbenzyl)acetamido)phenyl pyridine-2-sulfonate (1q): The product was synthesized by general method A (eluent: EA:PE = 1:2, Rf = 0.24); 308.9 mg, 78% yield; white solid; m. p. = 104–105 °C; 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 4.5 Hz, 1H), 7.94–7.87 (m, 2H), 7.59 (dd, J = 8.5, 4.9 Hz, 1H), 7.27–7.23 (m, 1H), 7.18–6.98 (m, 5H), 6.90–6.86 (m, 2H), 4.87 (s, 2H), 2.13 (s, 3H), 1.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 153.3, 150.6, 149.9, 143.7, 138.2, 136.3, 134.5, 130.3 (2C), 129.2, 128.2, 127.5, 127.0, 125.9, 124.2, 122.4, 121.9, 49.9, 22.7, 19.0; IR (KBr): 2924, 1662, 1602, 1486, 1379, 1302, 1198, 1140, 1117, 925, 803, 770, 738, 617 cm−1; HRMS (ESI) m/z calculated for C21H20N2O4SNa [M+Na]+: 419.1036; found 419.1046.
5-(N-Benzylacetamido)-2-methylphenyl pyridine-2-sulfonate (1r): The product was synthesized by general method B (eluent: EA:PE = 1:1, Rf = 0.22); 333.5 mg, 84% yield; yellow gel; 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 4.6 Hz, 1H), 7.93 (d, J = 3.4 Hz, 2H), 7.64–7.58 (m, 1H), 7.26 (d, J = 6.7 Hz, 3H), 7.19–7.11 (m, 3H), 6.90 (s, 1H), 6.80 (d, J = 8.1 Hz, 1H), 4.82 (s, 2H), 2.22 (s, 3H), 1.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 153.4, 150.5, 148.2, 141.1, 138.2, 136.9, 132.0, 131.3, 128.4, 128.3, 128.1, 127.2, 126.6, 123.8, 122.0, 52.4, 22.5, 16.0; IR (KBr): 2955, 2924, 2853, 1659, 15613, 1579, 1504, 1428, 1197, 1104, 1087, 941, 867, 801, 751, 715, 596, 552cm−1; HRMS (ESI) m/z calculated for C21H21N2O4S [M+H]+: 397.1217; found 397.1207.
5-(N-Benzylacetamido)-2-methoxyphenyl pyridine-2-sulfonate (1s): The product was synthesized by general method B (eluent: EA:PE = 1:1, Rf = 0.22); 370.8 mg, 90% yield; yellow gel; 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 5.1 Hz, 1H), 8.03–7.86 (m, 2H), 7.62 (dd, J = 4.4, 1.9 Hz, 1H), 7.36–7.11 (m, 5H), 6.96–6.92 (m, 1H), 6.86–6.77 (m, 2H), 4.82 (s, 2H), 3.59 (s, 3H), 1.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 154.0, 151.2, 150.2, 138.3, 138.0, 137.0, 135.0, 128.6, 128.3, 127.9, 127.8, 127.3, 124.1, 123.7, 112.7, 55.8, 52.6, 22.6; IR (KBr): 2925, 2850, 1654, 1509, 1380, 1295, 1271, 1197, 1112, 780, 764, 599, 545 cm−1; HRMS (ESI) m/z calculated for C21H20N2O5SNa [M+Na]+: 435.0985; found 435.0984.
Methyl 4-(N-benzylacetamido)-2-((pyridin-2-ylsulfonyl)oxy)benzoate (1t): The product was synthesized by general method B (eluent: EA:PE = 1:1, Rf = 0.22); 295.5 mg, 67% yield; colorless gel; 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.7 Hz, 1H), 8.03–7.93 (m, 2H), 7.88 (d, J = 8.3 Hz, 1H), 7.63–7.57 (m, 1H), 7.26 (d, J = 6.8 Hz, 3H), 7.18–7.08 (m, 3H), 7.04 (d, J = 8.3 Hz, 1H), 4.89 (s, 2H), 3.80 (s, 3H), 1.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 164.3, 154.0, 150.4, 148.8, 147.1, 138.4, 136.6, 132.8, 128.6, 128.3, 128.1, 127.6, 126.4, 124.3, 123.9, 123.8, 52.7, 52.5, 22.9; IR (KBr): 2954, 2924, 2853, 1726, 1665, 1462, 1378, 1264, 1199, 1153, 740, 593 cm−1; HRMS (ESI) m/z calculated for C22H21N2O6S [M+H]+: 441.1115; found 441.1104.
5-Acetyl-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2a): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.22); 63.9 mg, 83% yield; white solid; m. p. = 151–152 °C; 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 3.1 Hz, 1H), 8.00 (d, J = 7.4 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.66–7.62 (m, 1H), 7.11–7.52 (m, 7H), 4.43 (s, 2H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.8, 153.0, 149.6, 146.8, 140.3, 137.5, 135.9, 131.9, 128.2, 128.1, 127.9, 127.8, 127.8 (2C), 125.7, 123.8, 123.7, 121.9, 45.1, 22.1; IR (KBr): 2924, 2853, 1663, 1444, 1377, 1218, 1187, 1048, 960, 765, 735, 553 cm−1; HRMS (ESI) m/z calculated for C20H16N2O4SNa [M+Na]+: 403.0723; found 403.0720.
5-Acetyl-9-methyl-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2b): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.24); 67.8 mg, 84% yield; white solid; m. p. = 145–146 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 2.4 Hz, 1H), 7.83–7.72 (m, 2H), 7.69–7.65 (m, 1H), 7.46–7.19 (m, 4H), 6.99 (dd, J = 20.2, 7.5 Hz, 2H), 4.40 (s, 2H), 2.28 (s, 3H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.8, 153.3, 149.6, 146.7, 140.4, 137.5, 137.1, 133.1, 128.7, 128.6, 127.8, 127.7, 125.5, 123.8, 123.7, 123.5, 121.9, 120.4, 44.8, 22.1, 21.4; IR (KBr): 2824, 1664, 1608, 1454, 1427, 1378, 1340, 1207, 1190, 1086, 1058, 767 cm−1; HRMS (ESI) m/z calculated for C21H18N2O4SNa [M+Na]+: 417.0879; found 417.0887.
5-Acetyl-9-ethyl-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2c): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.20); 66.3 mg, 81% yield; white solid; m. p. = 123–125 °C; 1H NMR (400 MHz, CDCl3) 8.31 (s, 1H), 7.77 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.60–7.53 (m, 1H), 7.36–7.12 (m, 4H), 6.99–6.90 (m, 2H), 4.33 (s, 2H), 2.52 (q, J = 7.6 Hz, 2H), 2.04 (s, 3H), 1.17 (t, J = 7.6 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 168.8, 153.1, 149.6, 146.8, 143.5, 140.3, 137.4, 133.3, 128.0, 127.8, 127.7, 127.6 (2C), 125.6, 124.0, 123.6 (2C), 121.8, 44.8, 28.8, 22.1, 15.6; IR (KBr): 3055, 2958, 2854, 1662, 1454, 1426, 1375, 1188, 1118, 1044, 948, 902, 878, 826, 810, 765, 724, 593, 564 cm−1; HRMS (ESI) m/z calculated for C22H21N2O4S [M+H]+: 409.1217; found 409.1201
5-Acetyl-9-isopropyl-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2d): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.3); 72.6mg, 79% yield; yellow solid; m. p. = 163–165 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.91 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.67–7.59 (m, 1H), 7.46–7.13 (m, 4H), 7.09–7.01 (m, 2H), 4.39 (s, 2H), 2.89 (p, J = 7.1, 5.8 Hz, 1H), 2.12 (s, 3H), 1.27 (d, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 168.8, 152.9, 149.5, 148.1, 146.7, 140.3, 137.4, 133.4, 127.8, 127.7 (2C), 126.4, 126.3, 125.5, 124.1, 123.7, 123.6, 121.6, 44.8, 33.9, 23.9, 22.1; IR (KBr): 3016, 2961, 2927, 1662, 1455, 1426, 1379, 1213, 1186, 1118, 1049, 987, 949, 753, 667, 594 cm−1; HRMS (ESI) m/z calculated for C22H22N2O4SNa [M+Na]+: 445.1192; found 445.1188.
5-Acetyl-9-(tert-butyl)-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2e): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.21); 73.3 mg, 84% yield; white solid; m. p. = 181–182 °C; 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.11 (s, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.66–7.56 (m, 1H), 7.48–7.20 (m, 5H), 7.06 (d, J = 7.9 Hz, 1H), 4.37 (s, 2H), 2.12 (s, 3H), 1.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.8, 152.9, 150.6, 150.5, 149.5, 146.8, 140.3, 138.2, 137.4, 133.1, 127.7 (2C), 125.4, 125.3, 124.4 123.8, 123.6, 121.5, 44.8, 34.8, 31.3, 22.2; IR (KBr): 2960, 1664, 1455, 1427, 1377, 1340, 1207, 1187, 1085, 1055, 882, 766 cm−1; HRMS (ESI) m/z calculated for C24H24N2O4SNa [M+Na]+: 459.1349; found 459.1345.
5-Acetyl-9-isobutyl-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2f): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.22); 64.5 mg, 74% yield; yellow solid; m. p. = 148–152 °C; 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.80 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.69–7.62 (m, 1H), 7.40–7.29 (m, 3H), 7.22 (s, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 4.49 (s, 2H), 2.42 (d, J = 7.1 Hz, 2H), 2.13 (s, 3H), 2.01–1.59 (m, 1H), 0.91 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 168.9, 153.4, 149.7, 146.8, 141.2, 140.4, 137.5, 133.3, 129.0, 128.8, 127.9, 127.7 (2C), 125.4, 124.1, 123.7 (2C), 121.7, 45.3, 44.9, 30.1, 22.4, 22.2; IR (KBr): 2955, 2925, 2868, 1663, 1579, 1455, 1418, 1377, 1340, 1206, 1190, 1118, 1052, 987, 950, 909, 871, 812, 768, 727, 593, 555 cm−1; HRMS (ESI) m/z calculated for C24H24N2O4SNa [M+Na]+: 459.1349; found 459.1345.
5-Acetyl-9-phenyl-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2g): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.20); 76.5 mg, 82% yield; white solid; m. p. = 141–142 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 3.3 Hz, 1H), 8.24 (d, J = 1.2 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.3 Hz, 2H), 7.55–7.49 (m, 1H), 7.51–7.36 (m, 6H), 7.31–7.19 (m, 3H), 4.52 (s, 2H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 153. 1, 149.7, 146.7, 140.5, 140.3, 137.5, 134.9, 128.9 (2C), 128.5, 128.2, 127.9, 127.7, 127.5, 127.1, 126.9, 126.7, 126.2, 123.8, 123.5, 121.9, 44.8, 22.2; IR (KBr): 3057, 2924, 1664, 1605, 1452, 1376, 1340, 1217, 1205, 1186, 765, 742 cm−1; HRMS (ESI) m/z calculated for C26H20N2O4SNa [M+Na]+: 479.1036; found 479.1030.
5-Acetyl-9-fluoro-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2h): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.26); 53.7 mg, 69% yield; white solid; m. p. = 151–152 °C; 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 3.4 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.80–7.76 (m, 1H), 7.75–7.64 (m, 1H), 7.52–7.37 (m, 3H), 7.30 (s, 1H), 7.13 (dd, J = 8.0, 5.9 Hz, 1H), 6.90–6.86 (m, 1H), 4.58 (s, 2H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 161.6 (JC-F = 243.0 Hz), 153.2, 149.8, 146.7, 140.2, 137.9, 131.7, 129.7 (JC-F = 5.0 Hz), 128.7, 128.0, 126.9 (JC-F = 4.0 Hz), 123.7 (2C), 122.8, 122.0, 115.0 (JC-F = 16.2 Hz), 114.8 (JC-F = 13.3 Hz), 44.4, 22.0; IR (KBr): 3728, 2361, 2341, 1665, 1606, 1591, 1454, 1420, 1381, 1340, 1219, 1184, 814 cm−1; HRMS (ESI) m/z calculated for C20H15FN2O4SNa [M+Na]+: 421.0629; found 421.0620.
5-Acetyl-9-chloro-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2i): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.22); 63.8 mg, 81% yield; white solid; m. p. = 172–173 °C; 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 3.9 Hz, 1H), 7.92 (d, J = 7.7 Hz, 2H), 7.81–7.77 (m, 1H), 7.39 (ddd, J = 12.4, 11.3, 6.3 Hz, 3H), 7.27 (d, J = 7.3 Hz, 1H), 7.18–7.06 (m, 2H), 4.60 (s, 2H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.8, 153.5, 149.9, 146.7, 140.4, 137.9, 134.4, 133.3, 129.8, 128.8, 128.0, 127.9 (2C), 126.9, 123.8, 123.7, 122.5, 122.2, 44.5, 22.1; IR (KBr): 2923, 2852, 2361, 1665, 1606, 1467, 1452, 1403, 1380, 1338, 1218, 1186, 816,764 cm−1; HRMS (ESI) m/z calculated for C20H15ClN2O4SNa [M+Na]+: 437.0333; 437.0330.
5-Acetyl-9-bromo-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2j): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.22); 68.5mg, 75% yield; white solid; m. p. = 167–169 °C; 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 3.3 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.82–7.74 (m, 1H), 7.46–7.30 (m, 3H), 7.29–7.18 (m, 2H), 7.01 (d, J = 8.1 Hz, 1H), 4.42 (s, 2H), 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 153.7, 149.9, 146.8, 140.4, 138.1, 134.9, 130.9, 130.8, 130.3 128.8, 128.0, 127.2 (2C), 123.8 (2C), 122.3 (2C), 121.4, 44.7, 22.2; IR (KBr): 3055, 2924, 2853, 1661, 1578, 1451, 1373, 1337, 1217, 1185, 1117, 871, 842, 763, 735, 721, 592, 556 cm−1; HRMS (ESI) m/z calculated for C20H15N2O4SBrNa [M+Na]+: 480.9828; found 480.9827.
5-Acetyl-9-(trifluoromethoxy)-5,6-dihydrophenanthridin-1-yl pyridine- 2-sulfonate (2k): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.21); 77.0 mg, 83% yield; white solid; m. p. = 145–146 °C; 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 4.1 Hz, 1H), 7.87 (d, J = 7.7 Hz, 2H), 7.78–7.74 (m, 1H), 7.50–7.37 (m, 3H), 7.30 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 4.59 (s, 2H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.8, 153.2, 149.7, 148.2, 146.8, 140.2, 137.9, 134.5, 134.4, 129.9, 128.9, 127.9, 126.9, 123.7, 122.5, 121.8, 120.8, 120.4, 120.3 (JC-F = 255.0 Hz), 44.5, 22.1; IR (KBr): 2923, 2360, 1666, 1455, 1427, 1382, 1340, 1253, 1215, 1118, 872, 811, 765 cm−1; HRMS (ESI) m/z calculated for C21H15F3N2O5SNa [M+Na]+: 487.0546; found 487.0556.
5-Acetyl-9-nitro-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2l): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.23); 60.9 mg, 68% yield; white solid; m. p. = 167–168 °C; 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 1.8 Hz, 1H), 8.47 (d, J = 3.9 Hz, 1H), 8.09–8.03 (m, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.89–7.77 (m, 1H), 7.51–7.41 (m, 4H), 7.37–7.26 (m, 1H), 4.82 (s, 2H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 153.6, 150.1, 147.4, 146.8, 142.7, 140.4, 138.2, 129.8, 129.5, 128.3, 126.7, 123.9, 123.8, 123.0, 122.8, 122.1, 121.9, 44.9, 22.1; IR (KBr): 2922, 2852, 2361, 1667, 1608, 1524, 1383, 1347, 1219, 1187, 872, 835, 811 cm−1; HRMS (ESI) m/z calculated for C20H15N3O6SNa [M+Na]+: 448.0574; found 448.0581.
5-Acetyl-9-(trifluoromethyl)-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2m): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.22); 65.4 mg, 73% yield; white solid; m. p. = 153–154 °C; 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 4.1 Hz, 1H), 8.24 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.78–7.74 (m, 1H), 7.45 (dd, J = 16.0, 8.3 Hz, 3H), 7.40–7.35 (m, 1H), 7.34–7.27 (m, 2H), 4.70 (s, 2H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 153.4, 149.8, 146.9, 140.4, 139.6, 138.0, 129.8 (JC-F = 32.4 Hz), 129.1, 129.0, 128.0, 126.3 (JC-F = 1.8 Hz), 124.8 (JC-F = 4.2 Hz, 2C), 123.8 (2C), 123.7 (JC-F = 270.8 Hz), 122.4, 122.0, 44.9, 22.1; IR (KBr): 2924, 2361, 1667, 1455, 1422, 1382, 1331, 1254, 1167, 1119, 1078, 810, 764 cm−1; HRMS (ESI) m/z calculated for C21H15F3N2O4SNa [M+Na]+: 471.0597; found 471.0591.
5-Acetyl-9-(methylsulfonyl)-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2n): The product was synthesized by general method C (eluent: EA:PE = 1.5:1, Rf = 0.20); 64.1 mg, 70% yield; yellow solid; m. p. = 132–137 °C; 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.49 (d, J = 4.7 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.94–7.76 (m, 2H), 7.51–7.37 (m, 4H), 7.29 (s, 1H), 4.77 (s, 2H), 3.17 (s, 3H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.0, 153.0, 149.9, 146.9, 141.4, 140.4, 140.1, 138.4, 129.7, 129.3, 128.2, 127.2, 126.7 (2C), 124.4, 123.8, 122.5, 121.8, 44.9, 44.3, 22.1; IR (KBr): 3019, 2925, 1664, 1377, 1317, 1214, 1148, 1118, 745, 667, 562 cm−1; HRMS (ESI) m/z calculated for C21H18N2O6S2Na [M+Na]+: 481.0498; found 481.0496.
5-Acetyl-8-methyl-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2o): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.23); 62.3 mg, 79% yield; white solid; m. p. = 190–191 °C; 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.68–7.64 (m, 1H), 7.39–7.30 (m, 3H), 7.22 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 4.48 (s, 2H), 2.32 (s, 3H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.0, 153.2, 149.7, 146.7, 140.2, 138.4, 137.5, 135.9, 128.5, 128.1, 127.7, 127.5, 126.4, 125.3, 123.9 (2C), 123.7, 121.9, 45.2, 22.2, 21.2; IR (KBr): 2923, 2853, 1664, 1456, 1378, 1212, 1188, 1118, 1054, 986, 959, 866 cm−1; HRMS (ESI) m/z calculated for C21H18N2O4SNa [M+Na]+: 417.0879; found 417.0883.
5-Acetyl-8-phenyl-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2p): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.22); 75.9mg, 83% yield; white solid; m. p. = 209–210 °C; 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 4.7 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.60 (dd, J = 19.8, 7.8 Hz, 3H), 7.42 (ddd, J = 30.2, 13.9, 7.7 Hz, 7H), 7.30–7.21 (m, 2H), 4.48 (s, 2H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.1, 153.1, 149.7, 146.9, 140.8, 140.3, 139.8, 137.5, 136.5, 129.0, 128.7, 128.0, 127.9, 127.8, 127.0, 126.9, 126.3, 124.1, 124.0, 123.7 (2C), 122.2, 45.2, 22.2; IR (KBr): 3010, 2924, 2853, 1660, 1466, 1377, 1336, 1214, 1188, 1118, 986, 957, 866, 809, 748, 699, 594, 557, 541cm−1; HRMS (ESI) m/z calculated for C26H21N2O4S [M+H]+: 457.1217; found 457.1198.
5-Acetyl-7-methyl-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2q): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.25); 63.1 mg, 80% yield; white solid; m. p. = 159–160 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.74–7.56 (m, 2H), 7.48–7.21 (m, 4H), 7.13–7.09 (m, 1H), 7.03 (d, J = 7.3 Hz, 1H), 4.43 (s, 2H), 2.34 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 153.1, 149.5, 146.7, 140.3, 137.4, 135.2, 133.5, 129.9, 127.9, 127.4, 127.1, 125.9 (2C), 124.4, 123.9, 123.5, 122.0, 41.7, 22.1, 19.1; IR (KBr): 2924, 1664, 1480, 1454, 1427, 1377, 1339, 1189, 1118, 813, 766, 621 cm−1; HRMS (ESI) m/z calculated for C21H18N2O4SNa [M+Na]+: 417.0879; found 417.0870.
5-Acetyl-2-methyl-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2r): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.22); 71.7 mg, 91% yield; white solid; m. p. = 206–208 °C; 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.76–7.69 (m, 1H), 7.47–7.32 (m, 1H), 7.22–7.07 (m, 3H), 7.04–6.97 (m, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.54 (s, 2H), 3.76 (s, 3H), 2.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.0, 153.8, 151.1, 149.6, 145.6, 138.1, 137.4, 135.7, 131.8, 130.3, 128.9, 127.9, 127.7, 127.4, 125.6, 124.1, 123.5, 123.0, 45.3, 22.1, 17.7; IR (KBr): 3019, 2361, 1654, 1481, 1452, 1377, 1214, 1117, 1049, 868, 743, 667, 591, 546 cm−1; HRMS (ESI) m/z calculated for C21H19N2O4S [M+H]+: 395.1060; found 395.1061.
5-Acetyl-2-methoxy-5,6-dihydrophenanthridin-1-yl pyridine-2-sulfonate (2s): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.22); 65.9 mg, 80% yield; yellow solid; m. p. = 210–213 °C; 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 4.7 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.59 (dd, J = 16.3, 7.7 Hz, 2H), 7.27 (d, J = 7.7 Hz,2H), 7.15 (s, 1H), 7.10–7.00 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H), 4.62 (s, 2H), 2.55 (s, 3H), 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.0, 153.8, 149.6, 145.7, 138.2, 137.4, 135.8, 131.8, 130.4, 128.9, 127.9, 127.7 (2C), 127.4, 125.7, 124.1, 123.5, 123.0, 45.3, 22.2, 17.8; IR (KBr): 3008, 2926, 2848, 1652, 1481, 1429, 1376, 1236, 1196, 1111, 1049, 1019, 986, 964, 867, 790, 746, 703, 666, 587, 553 cm−1; HRMS (ESI) m/z calculated for C21H20N2O5SNa [M+Na]+: 435.0985; found 435.0984.
Methyl 5-acetyl-1-((pyridin-2-ylsulfonyl)oxy)-5,6-dihydrophenanthridine-2-carb- oxylate (2t): The product was synthesized by general method C (eluent: EA:PE = 1:1, Rf = 0.22); 65.7 mg, 75% yield; white solid; m. p. = 200–203 °C; 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 4.7, 1.9 Hz, 1H), 7.97 (dd, J = 14.3, 8.9 Hz, 2H), 7.68 (d, J = 7.8 Hz, 1H), 7.61–7.57 (m, 1H), 7.29 (s, 1H), 7.20 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 7.12 (dd, J = 5.8, 3.3 Hz, 2H), 7.08–7.01 (m, 1H), 4.53 (s, 2H), 4.01 (s, 3H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 165.5, 153.3, 149.6, 145.6, 143.3, 137.5, 135.5, 130.7, 128.5, 128.4, 128.1, 127.9, 127.7, 125.5, 124.9 (2C), 123.6, 123.1, 52.7, 45.0, 22.4; IR (KBr): 2925, 2851, 1656, 1496, 1481, 1452, 1429, 1376, 1237, 1197, 1164, 1112, 1050, 1019, 988, 965, 867, 808, 790, 725, 702, 615, 587, 554 cm−1; HRMS (ESI) m/z calculated for C22H18N2O6SNa [M+Na]+: 461.0778; found 461.0772.

4. Conclusions

In summary, we developed the first palladium-catalyzed intramolecular C−H/C−H dehydrogenative coupling between two simple arenes to construct 5,6-dihydrophenanthridines. The approach featured a broad substrate scope and good tolerance of functional groups, and it offers an efficient alternative synthesis route for the important 5,6-dihydrophenanthridine compounds. Further application and mechanistic studies are currently ongoing in our laboratory.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28062498/s1, Reference [59] is cited in the Supplementary Materials.

Author Contributions

Y.-Q.W. conceived and designed the experiments; M.-Y.W. and X.-Q.Z. performed the experiments; B.-Y.Z. and H.-X.Z. analyzed the data; M.-Y.W., Y.-Q.W. and Q.J. wrote the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC-21971206).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 28 02498 g001 550
Figure 1. Natural products and drugs containing 5,6-dihydrophenidine skeleton.
Figure 1. Natural products and drugs containing 5,6-dihydrophenidine skeleton.
Molecules 28 02498 g001
Molecules 28 02498 sch001 550
Scheme 1. The main strategies to forge aryl−aryl bond of 5,6-dihydrophenanthridines.
Scheme 1. The main strategies to forge aryl−aryl bond of 5,6-dihydrophenanthridines.
Molecules 28 02498 sch001
Molecules 28 02498 sch002 550
Scheme 2. Scope of the two-aryl C−H/C−H coupling reaction. Reaction conditions: 1 (0.5 mmol), Pd(TFA)2 (15 mol%) and Cu(TFA)2·H2O (1.1 mmol) in CF3CH2OH (2 mL) under air atmosphere at 100 °C for 20 h.
Scheme 2. Scope of the two-aryl C−H/C−H coupling reaction. Reaction conditions: 1 (0.5 mmol), Pd(TFA)2 (15 mol%) and Cu(TFA)2·H2O (1.1 mmol) in CF3CH2OH (2 mL) under air atmosphere at 100 °C for 20 h.
Molecules 28 02498 sch002
Molecules 28 02498 g002 550
Figure 2. Large-scale experiment.
Figure 2. Large-scale experiment.
Molecules 28 02498 g002
Molecules 28 02498 sch003 550
Scheme 3. The synthesis of immunosuppressant 7.
Scheme 3. The synthesis of immunosuppressant 7.
Molecules 28 02498 sch003
Molecules 28 02498 g003 550
Figure 3. KIE experiment.
Figure 3. KIE experiment.
Molecules 28 02498 g003
Molecules 28 02498 sch004 550
Scheme 4. Plausible mechanism.
Scheme 4. Plausible mechanism.
Molecules 28 02498 sch004
Table
Table 1. Optimization of conditions for the synthesis of 5,6-dihydrophenanthridine a.
Table 1. Optimization of conditions for the synthesis of 5,6-dihydrophenanthridine a.
Molecules 28 02498 i001
EntryDGPGPd cat.OxidantT
/°C		SolventYield
(%) b
1-HAcPd(OAc)2air70DMSO0
2-CONMe2AcPd(OAc)2air70DMSOtrace
3-CO(2-Py)AcPd(OAc)2air70DMSOtrace
4-SO2(2-Py)AcPd(OAc)2air70DMSO9
5-SO2(2-Py)AcPd(OAc)2air70HFIP11
6-SO2(2-Py)AcPd(OAc)2air70CF3CH2OH12
7 c-SO2(2-Py)AcPd(OAc)2air70Other solvents<6
8-SO2(2-Py)AcPd(OAc)2Cu(TFA)2·H2O70CF3CH2OH31
9-SO2(2-Py)AcPd(OAc)2Cu(OAc)2·H2O70CF3CH2OH22
10-SO2(2-Py)AcPd(OAc)2Cu(OAc)270CF3CH2OH21
11-SO2(2-Py)AcPd(OAc)2CuF2·2H2O70CF3CH2OH29
12 c-SO2(2-Py)AcPd(OAc)2Other oxidants70CF3CH2OH<20
13-SO2(2-Py)AcPd(OAc)2Argon70CF3CH2OH8
14-SO2(2-Py)AcPd(OAc)2Cu(TFA)2·H2O60CF3CH2OH23
15-SO2(2-Py)AcPd(OAc)2Cu(TFA)2·H2O80CF3CH2OH35
16-SO2(2-Py)AcPd(OAc)2Cu(TFA)2·H2O100CF3CH2OH45
17-SO2(2-Py)AcPd(OAc)2Cu(TFA)2·H2O120CF3CH2OH46
18-SO2(2-Py)TsPd(OAc)2Cu(TFA)2·H2O100CF3CH2OHtrace
19-SO2(2-Py)BocPd(OAc)2Cu(TFA)2·H2O100CF3CH2OHtrace
20-SO2(2-Py)MePd(OAc)2Cu(TFA)2·H2O100CF3CH2OH3
21-SO2(2-Py)PhPd(OAc)2Cu(TFA)2·H2O100CF3CH2OH18
22-SO2(2-Py)AcPd(PPh3)4Cu(TFA)2·H2O100CF3CH2OH53
23-SO2(2-Py)AcPd(TFA)2Cu(TFA)2·H2O100CF3CH2OH62
24 c-SO2(2-Py)AcOther [Pd]Cu(TFA)2·H2O100CF3CH2OHtrace
25-SO2(2-Py)AcPd(PPh3)2Cl2Cu(TFA)2·H2O100CF3CH2OH36
26 d-SO2(2-Py)AcPd(TFA)2Cu(TFA)2·H2O100CF3CH2OH74
27 e-SO2(2-Py)AcPd(TFA)2Cu(TFA)2·H2O100CF3CH2OH75
28 d,f-SO2(2-Py)AcPd(TFA)2Cu(TFA)2·H2O100CF3CH2OH16
29 d,g-SO2(2-Py)AcPd(TFA)2Cu(TFA)2·H2O100CF3CH2OH83
30 d,h-SO2(2-Py)AcPd(TFA)2Cu(TFA)2·H2O100CF3CH2OH82
31 d,i-SO2(2-Py)AcPd(TFA)2Cu(TFA)2·H2O100CF3CH2OH83
a Reaction conditions: 1 (0.5 mmol), catalyst (10 mol%), and oxidant (0.55 mmol) in solvent (2 mL) for 20 h. b Isolated yield. c Others, see Table S1 in the Supplementary Materials. d Pd(TFA)2 (15 mol%) was used. e Pd(TFA)2 (30 mol%) was used. f Cu(TFA)2·H2O (0.25 mmol) was used. g Cu(TFA)2·H2O (1.1 mmol) was used. h Cu(TFA)2·H2O (2.0 mmol) was used. i Under argon atmosphere.
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MDPI and ACS Style

Wang, M.-Y.; Zhu, X.-Q.; Zhao, B.-Y.; Zhang, H.-X.; Wang, Y.-Q.; Jia, Q. Synthesis of 5,6-Dihydrophenanthridines via Palladium-Catalyzed Intramolecular Dehydrogenative Coupling of Two Aryl C−H Bonds. Molecules 2023, 28, 2498. https://doi.org/10.3390/molecules28062498

AMA Style

Wang M-Y, Zhu X-Q, Zhao B-Y, Zhang H-X, Wang Y-Q, Jia Q. Synthesis of 5,6-Dihydrophenanthridines via Palladium-Catalyzed Intramolecular Dehydrogenative Coupling of Two Aryl C−H Bonds. Molecules. 2023; 28(6):2498. https://doi.org/10.3390/molecules28062498

Chicago/Turabian Style

Wang, Meng-Yue, Xue-Qing Zhu, Bao-Yin Zhao, Hong-Xia Zhang, Yong-Qiang Wang, and Qiong Jia. 2023. "Synthesis of 5,6-Dihydrophenanthridines via Palladium-Catalyzed Intramolecular Dehydrogenative Coupling of Two Aryl C−H Bonds" Molecules 28, no. 6: 2498. https://doi.org/10.3390/molecules28062498

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