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Article

Electrochemical Radical Tandem Difluoroethylation/Cyclization of Unsaturated Amides to Access MeCF2-Featured Indolo/Benzoimidazo [2,1-a]Isoquinolin-6(5H)-ones

by
Yunfei Tian
1,*,
Dongyu Guo
2,
Luping Zheng
1,
Shaolu Yang
1,
Ningning Zhang
1,
Weijun Fu
1 and
Zejiang Li
2
1
Key Laboratory of Fuction-Oriented Porous Materials of Henan Province, College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471934, China
2
Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry & Materials Science, Hebei University, Baoding 071002, China
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(5), 973; https://doi.org/10.3390/molecules29050973
Submission received: 12 January 2024 / Revised: 15 February 2024 / Accepted: 19 February 2024 / Published: 22 February 2024
(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)
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Abstract

:
A metal-free electrochemical oxidative difluoroethylation of 2-arylbenzimidazoles was accomplished, which provided an efficient strategy for the synthesis of MeCF2-containing benzo[4,5]imidazo[2,1-a]-isoquinolin-6(5H)-ones. In addition, the method also enabled the efficient construction of various difluoroethylated indolo[2,1-a]isoquinolin-6(5H)-ones. Notably, this electrochemical synthesis protocol proceeded well under mild conditions without metal catalysts or exogenous additives/oxidants added.

1. Introduction

Organofluorine compounds are very useful and attractive organic molecules, which play pivotal roles in pharmaceuticals, agrochemicals, and performance materials [1,2,3,4,5,6]. Among various fluorine-containing groups, the difluoroethyl group (CF2Me) is receiving more and more attention due to its special chemical and biological properties [7,8,9]. In particular, the introduction of a difluoroethyl group can improve the metabolic stability and potency of a target molecule [10,11]. Therefore, the development of new and efficient protocols for the rapid introduction of the difluoroethyl group to target compounds is in high demand. In this context, the radical strategy has emerged as a powerful approach for the synthesis of CF2Me-containing compounds. However, recent developments in this direction have always involved peroxides or photoredox catalysts [12,13,14,15,16]. On the other hand, electrochemical synthesis has also attracted much attention due to the advantages of avoiding the usage of chemical oxidants and reductants [17,18,19,20,21,22,23]. Very recently, much progress in electrochemical difluoroethylation has been made by Hu [24] and our group [25,26]. Although these methods have provided innovative transformations, the preparation of CF2Me-substituted polycyclic compounds has not been achieved.
Benzo[4,5]imidazo[2,1-a]isoquinolines and indolo [2,1-a]isoquinolines, which are significant classes of fused polycyclic nitrogen-containing scaffolds, widely exist in natural products and pharmaceuticals (Figure 1(1)) [27,28,29,30,31]. Although substantial efforts have been contributed to the construction of these polycyclic compounds [32,33,34,35,36,37,38,39], the CF2Me-containing target polycycles remain a great challenge to date (Figure 1(2)). As part of our continuing interest in difluoroethylation functionalizations, we anticipated that the radical cyclization process would provide a feasible platform for the synthesis of CF2Me-revised target polycycles. Herein, we report an electrochemical-induced radical cascade cyclization strategy, whereby a series of CF2Me-substituted indolo [2,1-a]isoquinolines and benzo[4,5]imidazo[2,1-a]isoquinolines could be efficiently prepared under mild and chemical oxidant-free conditions (Figure 1(3)).

2. Results and Discussion

We began our investigation by examining the electrochemical difluoroethylation reaction of N-methacryloyl-2-phenylbenzoimidazole (1a) with NaSO2CF2Me (2a) (Table 1). To our delight, the electrolysis furnished an 86% yield of the desired cyclization product 3a at a constant voltage of 2.1 V in an undivided cell equipped with a carbon plate anode and a Pt plate cathode (Table 1, entry 1). Then, the various conditions, such as voltage, electrode material, electrolyte, and solvent, were measured. Neither lower voltage nor higher voltage led to a higher efficiency (entries 2,3). C(+)|Pt(−) was proved to be the optimal electrode material combination compared to others (entries 4–6). A switch of the electrolytes LiClO4 to other electrolytes such as Et4NClO4, nBu4NClO4, or nBu4NPF6 significantly restrained the reaction (entries 7–9). The change in solvent proportion failed to improve the yield of 3a (entries 10, 11). The cyclization product 3a could not be observed without electricity (entry 12).
With the above-optimized conditions in hand, we investigated the substrate scopes (Scheme 1). It can be seen that a wide range of 2-arylbenzoimidazoles with either electron-donating or electron-withdrawing substituents worked well and afforded the corresponding products in good to high yields (3a–3h). The ortho-substituted 2-arylbenzoimidazoles were also tolerated in the reaction, and the desired products were obtained at 70–88% yields (3i–3m), among which the single crystal structure of product 3m was obtained. When utilizing meta-substituted 2-arylbenzoimidazoles as the starting materials, the reactions demonstrated good site-selectivity with no regioisomers detected (3n). It also occurred smoothly on disubstituted substrates to produce the cyclization products in good yields (3o and 3p). The 3, 5-di substituent was successfully converted to the target product 3q at 72% yield without the interference of steric hindrance. For Ar1 substituents, the dimethyl-substituted N-methacryloyl-2-phenylbenzoimidazoles gave the desired products 3r in good yields. The substrates with phenyl- or benzyl-substitution of the terminal olefin were also able to produce the relevant products (3s and 3t). The substrates containing naphthalene or thiophene were all compatible with this reaction mode, delivering the corresponding products 3u and 3v at 74% and 67% yields, respectively.
Subsequently, we turned our attention to the synthesis of indolo[2,1-a]isoquinoline derivatives, which are key structural skeletons of various pharmaceuticals. As shown in Scheme 2, the desired CF2Me-substituted indolo[2,1-a]isoquinoline derivatives were obtained in moderate to excellent yields. The halosubstituted (F−, Cl−, Br−) substrates also smoothly underwent a cyclization process to provide the corresponding products with good efficiency (5b–5e). Moreover, the substrates with an ethyl group at the C3 position of the indole ring were demonstrated to be suitable substrates to provide the final products at 65–75% yield (5f–5h). Notably, this method also enabled the access to cyclopropyldifluoromethylated indolo[2,1-a]isoquinoline (5i), which was further confirmed by X-ray crystallography.
Then, some control experiments were carried out to investigate the mechanism of this reaction (Scheme 3). When the radical scavenger 2,6-di-tert-butyl-4-methylphenol (BHT) was added to the standard reaction system, the reaction was significantly suppressed, and the desired product was not detected by TLC. When adding 1,1-diphenylethylene into the system, only 16% yield of the target product was obtained and the radical adduct was found by HRMS. The two experiments suggested that the reaction may involve a radical pathway. To further understand the details of this reaction mechanism, cyclic voltammetry (CV) experiments were performed. As shown in Figure 2, the oxidation peaks of 1a and 2a were at 1.47 V and 0.67 V, respectively. These results indicated that 2a was more easily oxidized than 1a.
Based on the above results, a plausible mechanism of this reaction was proposed (Scheme 4). First, the anodic oxidation of MeCF2SO2Na generated the MeCF2SO2 radical, which then liberated SO2 to afford the MeCF2 radical. Subsequently, the addition of the MeCF2 radical to the double bond of 1a yielded a carbon-centered radical A. The intermediate A underwent further intramolecular radical cyclization to afford the aryl radical B. The intermediate B was oxidized at the anode to give aryl cation C, which resulted in the expected product 3a via a deprotonation process.

3. Materials and Methods

3.1. General Methods

1H and 13C NMR and 19F NMR spectra were recorded on a Bruker advance Ⅲ 400 or 500 spectrometer (Billerica, MA, USA) in CDCl3 with TMS as the internal standard. High-resolution mass spectral analysis (HRMS (TOF)) data were measured on a Bruker Apex II. All products were identified by 1H, 19F, 13C NMR, and HRMS. The starting materials were purchased from Energy, J&K Chemicals (Beijing, China) or Aldrich (St. Louis, MO, USA) and used without further purification. The conversion was monitored by thin-layer chromatography (TLC). Flash column chromatography was performed over silica gel (200–300 mesh). Cyclic voltammetry experiments were carried out in an electrochemical workstation (CHI660E, Shanghai, China). 2-arylbenzimidazoles/2-arylindoles were prepared according to the reported procedures [35].

3.2. General Procedure for the Reaction

A 20 mL test tube with a stir bar was charged with, 2-arylbenzimidazoles/2-arylindoles (1 equiv., 0.2 mmol), MeCF2SO2Na, or sodium cyclopropyldifluoromethylsulfinate (3 equiv., 0.6 mmol), LiClO4 (0.3 M), MeCN (4.5 mL), H2O (1.5 mL). The tube was equipped with a carbon plate (10 mm × 10 mm × 3 mm) as the anode and a platinum plate (10 mm × 10 mm × 0.2 mm) as the cathode. The reaction mixture was electrolyzed in an undivided cell at room temperature under a constant voltage of 2.1 V for 3h. Upon completion, the mixture was extracted with EtOAc (10 mL × 3). The combined organic phases were dried over Na2SO4 and condensed under vacuum. The residue was purified by silica gel column chromatography to afford the final products (1H NMR, 19F NMR, and 13C NMR of compounds (3a–v and 5a–i) are shown in Supplementary Materials).
5-(2,2-Difluoropropyl)-5-methylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3a) [39]. A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 153–154 °C, 56.1 mg, 86 % yield. 1H NMR (400 MHz, CDCl3): δ 8.52–8.49 (m, 1H), 8.37–8.35 (m, 1H), 7.84–7.82 (m, 1H), 7.59–7.55 (m, 1H), 7.50 (t, J = 7.2 Hz, 2H), 7.47–7.40 (m, 2H), 3.30–3.18 (m, 1H), 2.79–2.67 (m, 1H), 1.72 (s, 3H), 1.34 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 172.2, 149.6, 144.0, 140.0, 131.5, 131.3, 127.9, 126.8, 126.0, 125.9, 125.6, 122.6 (t, J = 240.5 Hz), 122.3, 119.8, 115.7, 48.2 (t, J = 23.9 Hz), 45.5, 31.1, 24.7 (t, J = 27.3 Hz). 19F NMR (471 MHz, CDCl3): δ −86.07–−86.30 (m, 2F). HRMS (ESI-TOF) m/z: Calcd for C19H16F2N2O (M + H)+ 327.1303; found 327.1306. IR (KBr) ν 3402, 3057, 2931, 1943, 1840, 1700, 1619, 1547, 985, 803, 644, 549 cm−1.
5-(2,2-Difluoropropyl)-3,5-dimethylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3b). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 132–133 °C, 55.7 mg, 82 % yield. 1H NMR (500 MHz, CDCl3): δ 8.37 (d, J = 8.0 Hz, 1H), 8.35–8.33 (m, 1H), 7.80–7.79 (m, 1H), 7.44–7.38 (m, 2H), 7.30 (d, J = 8.5 Hz, 1H), 7.26 (s, 1H), 3.21 (q, J = 15.0 Hz, 1H), 2.70 (q, J = 15.5 Hz, 1H), 2.45 (s, 3H), 1.70 (s, 3H), 1.32 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 172.3, 149.8, 144.1, 141.8, 140.1, 131.4, 129.0, 127.1, 126.0, 125.8, 125.3, 122.5 (t, J = 240.6 Hz), 119.7, 119.6, 115.6, 48.2 (t, J = 24.1Hz), 45.5, 31.0, 24.7(t, J = 27.4 Hz), 21.8. 19F NMR (471 MHz, CDCl3): δ −86.01–−86.20 (m, 2F). HRMS (ESI-TOF) m/z: Calcd for C20H18F2N2O (M + H)+ 341.1460; found 341.1461. IR (KBr) ν 3415, 3068, 2964, 2361, 1909, 1715, 1613, 1557, 1238, 915, 801, 615 cm−1.
5-(2,2-Difluoropropyl)-3-fluoro-5-methylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3c). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate =10/1), mp 134–135 °C, 58.5 mg, 85 % yield. 1H NMR (400 MHz, CDCl3): δ 8.50 (dd, J = 8.4, 6.0 Hz, 1H), 8.34 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.46–7.39 (m, 2H), 7.22–7.15 (m, 2H), 3.29–3.17 (m, 1H), 2.71–2.59 (m, 1H), 1.70 (s, 3H), 1.40 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.6, 164.6 (d, J = 252.5 Hz), 148.8, 144.0, 142.9 (d, J = 7.9 Hz), 131.4, 128.5 (d, J = 9.1Hz), 125.7 (d, J = 37.5 Hz), 122.4 (t, J = 240.6 Hz), 119.7, 118.89, 118.87, 115.9 (d, J = 22.4 Hz), 115.6, 113.7 (d, J = 23.2 Hz), 48.3 (t, J = 23.7 Hz), 45.7, 30.9, 24.7 (t, J = 27.3Hz). 19F NMR (471 MHz, CDCl3): δ −85.51–−86.22 (m, 1F), −87.32–−88.02 (m, 1F), −106.94–-106.99 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C19H15F3N2O (M + H)+ 345.1209; found 345.1211. IR (KBr) ν 3380, 3111, 3068, 2988, 2920, 2877, 2620, 2370, 1956, 1913, 1802, 1715, 1625, 1566, 1008, 986, 786, 655, 578 cm−1.
3-Chloro-5-(2,2-difluoropropyl)-5-methylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3d). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 174–175 °C, 62.6 mg, 87 % yield. 1H NMR (400 MHz, CDCl3): δ 8.43 (d, J = 8.4 Hz, 1H), 8.34 (d, J = 6.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.47–7.42 (m, 4H), 3.28–3.16 (m, 1H), 2.73–2.61 (m, 1H), 1.71 (s, 3H), 1.40 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.5, 148.7, 143.9, 141.8, 137.5, 131.4, 128.5, 127.4, 127.0, 126.0, 125.8, 122.5 (t, J = 239.0 Hz), 120.9, 119.8, 115.6, 48.2 (t, J = 23.6 Hz), 45.5 (d, J = 3.3Hz), 30.9, 24.8 (t, J = 27.2 Hz). 19F NMR (471 MHz, CDCl3): δ −85.56–−86.27 (m, 1F), −87.33–−88.03 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C19H15ClF2N2O (M + H)+ 361.0914; found 361.0915. IR (KBr) ν 3355, 3005, 2923, 2851, 2369, 1916, 1720, 1577, 1450, 1356, 1076, 902, 835, 765, 619 cm−1.
3-Bromo-5-(2,2-difluoropropyl)-5-methylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3e). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 207–208 °C, 64.0 mg, 79 % yield. 1H NMR (500 MHz, CDCl3): δ 8.37–8.33 (m, 2H), 7.82–7.80 (m, 1H), 7.63–7.61 (m, 2H), 7.46–7.41 (m, 2H), 3.27–3.17 (m, 1H), 2.72–2.63 (m, 1H), 1.71 (s, 3H), 1.41 (t, J = 18.5 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 171.4, 148.7, 143.9, 141.9, 131.4, 131.3, 129.9, 127.5, 126.0, 125.8, 122.5 (t, J = 238.5 Hz), 121.4, 119.9, 115.6, 48.2 (t, J = 23.7 Hz), 45.5 (d, J = 3.3Hz), 30.8, 24.8 (t, J = 27.2 Hz). 19F NMR (471 MHz, CDCl3): δ −85.57–−86.28 (m, 1F), −87.26–−87.96 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C19H15BrF2N2O (M + H)+ 405.0408; found 405.0409. IR (KBr) ν 3420, 3074, 3004, 2946, 2713, 2359, 1910, 1793, 1725, 1543, 1420, 1292, 1072, 983, 905, 832, 716, 654 cm−1.
5-(2,2-Difluoropropyl)-5-methyl-3-(trifluoromethyl)benzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3f). A light-yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 151–152 °C, 63.0 mg, 80 % yield. 1H NMR (500 MHz, CDCl3): δ 8.63 (d, J = 8.0 Hz, 1H), 8.38–8.36 (m, 1H), 7.86–7.85 (m, 1H), 7.75–7.72 (m, 2H), 7.49–7.45 (m, 2H), 3.33–3.24 (m, 1H), 2.80–2.71 (m, 1H), 1.75 (s, 3H), 1.43 (t, J = 18.5 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.4, 148.1, 143.9, 140.7, 132.8 (q, J = 32.8 Hz), 131.5, 126.7, 126.24, 126.20, 125.6, 124.7 (q, J = 3.6 Hz), 124.0–123.9 (m), 122.5 (t, J = 240.1Hz), 120.2, 115.8, 48.1 (t, J = 23.5 Hz), 45.7 (d, J = 3.3Hz), 30.8, 24.8 (t, J = 27.2 Hz). 19F NMR (471 MHz, CDCl3): δ −62.91 (s, 3F), −85.44–−86.13 (m, 1F), −87.85–−88.51 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C20H15F5N2O (M + H)+ 395.1177; found 395.1179. IR (KBr) ν 3418, 3065, 2975, 2946, 2874, 2357, 1927, 1802, 1723, 1613, 1555, 1456, 1076, 991, 905, 839, 694, 546 cm−1.
Methyl 5-(2,2-difluoropropyl)-5-methyl-6-oxo-5,6-dihydrobenzo [4,5]imidazo [2,1-a]isoquinoline-3-carboxylate (3g). A light-yellow liquid after purification by flash column chromatography (petroleum ether/ethyl acetate = 7/1), 57.6 mg, 75 % yield. 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 8.0 Hz, 1H), 8.38–8.36 (m, 1H), 8.18 (s, 1H), 8.13 (dd, J = 8.4, 1.6 Hz, 1H), 7.86–7.84 (m, 1H), 7.49–7.44 (m, 2H), 3.98 (s, 3H), 3.31–3.19 (m, 1H), 2.87–2.75 (m, 1H), 1.76 (s, 3H), 1.40 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 171.7, 166.1, 148.6, 144.1, 140.3, 132.4, 131.5, 128.7, 128.3, 126.18, 126.16, 126.14, 126.12, 122.6 (t, J = 238.6 Hz), 120.1, 115.8, 52.5, 48.3 (t, J = 23.5 Hz), 45.7 (d, J = 3.4 Hz), 30.8, 24.8 (t, J = 27.2 Hz). 19F NMR (471 MHz, CDCl3): δ −85.83–−86.54 (m, 1F), −87.26–−87.96 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C21H18F2N2O3 (M + H)+ 385.1358; found 385.1360. IR (thin film) ν 3417, 3080, 2980, 2848, 2354, 1922, 1843, 1717, 1614, 1550, 1475, 1359, 982, 903, 758, 565 cm−1.
5-(2,2-Difluoropropyl)-5-methyl-6-oxo-5,6-dihydrobenzo [4,5]imidazo [2,1-a]isoquinoline-3-carbonitrile (3h). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 7/1), mp 243–244 °C, 43.5 mg, 62% yield. 1H NMR (500 MHz, CDCl3): δ 8.59 (d, J = 8.0 Hz, 1H), 8.36–8.34 (m, 1H), 7.86–7.84 (m, 1H), 7.78 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.48–7.46 (m, 2H), 3.31–3.21 (m, 1H), 2.76–2.66 (m, 1H), 1.73 (s, 3H), 1.46 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 170.9, 147.6, 143.9, 141.0, 131.4, 131.04, 131.03, 130.9, 126.7, 126.5, 126.3, 122.5 (t, J = 238.6 Hz), 120.3, 118.0, 115.8, 114.5, 48.1 (t, J = 23.3 Hz), 45.5 (d, J = 3.1 Hz), 30.6, 29.6, 24.8 (t, J = 27.1Hz). 19F NMR (471 MHz, CDCl3): δ −85.22–−85.93 (m, 1F), −88.52–−89.22 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C20H15F2N3O (M + H)+ 352.1256; found 352.1260. IR (KBr) ν 3414, 3088, 2991, 2943, 2733, 2351, 2224, 1942, 1816, 1723, 1615, 1573, 1552, 1479, 1449, 1243, 1126, 1081, 911, 846, 741, 662 cm−1.
5-(2,2-Difluoropropyl)-1,5-dimethylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3i). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 149–150 °C, 55.1 mg, 81% yield. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, J = 8.0 Hz, 1H), 8.36–7.34 (m, 1H), 7.81–7.79 (m, 1H), 7.45–7.38 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 3.22 (q, J = 15.2 Hz, 1H), 2.72 (q, J = 15.2 Hz, 1H), 2.47 (s, 3H), 1.71 (s, 3H), 1.34 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 172.3, 149.8, 144.0, 141.8, 140.0, 131.4, 129.1, 127.2, 125.9, 125.8, 125.3, 122.6 (t, J = 240.6 Hz), 119.7, 119.6, 115.6, 48.2 (t, J = 23.9 Hz), 45.5, 31.1, 24.7 (t, J = 27.3 Hz), 21.9. 19F NMR (471 MHz, CDCl3): δ −85.99–−86.18 (m, 2F). HRMS (ESI-TOF) m/z: Calcd for C20H18F2N2O (M + H)+ 341.1460; found 341.1462. IR (KBr) ν 3410, 3065, 2991, 2963, 2854, 2720, 2361, 1909, 1843, 1796, 1716, 1619, 1559, 1242, 985, 915, 802, 659 cm−1.
5-(2,2-Difluoropropyl)-1-methoxy-5-methylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3j). A brown solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 165–166 °C, 49.8 mg, 70% yield. 1H NMR (500 MHz, CDCl3): δ 8.39–8.37 (m, 1H), 7.91–7.89 (m, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.43–7.39 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 4.14 (s, 3H), 3.23 (q, J = 15.0 Hz, 1H), 2.71 (q, J = 15.5 Hz, 1H), 1.72 (s, 3H), 1.32 (t, J = 18.5 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 172.1, 158.7, 147.7, 144.3, 142.6, 131.7, 130.3, 125.6, 125.5, 122.5 (t, J = 240.6 Hz), 120.5, 119.1, 115.5, 111.8, 110.4, 56.6, 48.6 (t, J = 23.9 Hz), 45.4, 31.5, 24.7 (t, J = 27.4 Hz). 19F NMR (471 MHz, CDCl3): δ −85.88–−86.06 (m, 2F). HRMS (ESI-TOF) m/z: Calcd for C20H18F2N2O2 (M + H)+ 357.1409; found 357.1410. IR (KBr) ν 3395, 3198, 3063, 3007, 2923, 2848, 2684, 2544, 2369, 2226, 1936, 1792, 1703, 1612, 1540, 1480, 1242, 1098, 1055, 935, 861, 803, 594 cm−1.
5-(2,2-Difluoropropyl)-1-fluoro-5-methylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3k). A yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 153–154 °C, 55.0 mg, 80% yield. 1H NMR (500 MHz, CDCl3): δ 8.38–8.37 (m, 1H), 7.94–7.92 (m, 1H), 7.51 (td, J = 8.0, 5.0 Hz, 1H), 7.47–7.43 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.24–7.21 (m, 1H), 3.29–3.19 (m, 1H), 2.76–2.67 (m, 1H), 1.72 (s, 3H), 1.39 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.6, 160.4 (d, J = 262.1Hz), 145.8 (d, J = 8.4 Hz), 144.2, 142.5, 131.8 (d, J = 9.6 Hz), 130.4, 126.0 (d, J = 14.0 Hz), 122.8, 122.5 (t, J = 240.6 Hz), 120.5, 115.8, 115.6, 115.5, 111.8 (d, J = 9.9 Hz), 48.5 (t, J = 23.7 Hz), 45.4, 31.3, 24.8 (t, J = 27.3 Hz). 19F NMR (471 MHz, CDCl3): δ −85.44–−86.11 (m, 1F), −87.00–−87.69 (m, 1F), −107.12–−107.16 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C19H15F3N2O (M + H)+ 345.1209; found 345.1211. IR (KBr) ν 3358, 3115, 3065, 2918, 2848, 2681, 2360, 1943, 1800, 1705, 1625, 1580, 1525,1452, 1345, 1240, 932, 896, 799, 765, 602 cm−1.
1-Chloro-5-(2,2-difluoropropyl)-5-methylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3l). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 210–211 °C, 63.4 mg, 88% yield. 1H NMR (400 MHz, CDCl3): δ 8.39 (dd, J = 6.0, 3.2 Hz, 1H), 7.93 (dd, J = 6.0, 3.2 Hz, 1H), 7.58–7.56 (m, 1H), 7.47–7.42 (m, 4H), 3.30–3.19 (m, 1H), 2.77–2.65 (m, 1H), 1.72 (s, 3H), 1.38 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.4, 147.0, 143.9, 142.9, 133.5, 131.5, 130.6, 130.4, 126.3, 125.9, 125.7, 122.5 (t, J = 238.8 Hz), 120.7, 120.5, 115.7, 48.49 (t, J = 23.7 Hz), 45.76 (d, J = 3.5 Hz), 31.43 (s), 24.80 (t, J = 27.3Hz). 19F NMR (471 MHz, CDCl3): δ −85.21–−85.92 (m, 1F), −86.99–−87.70 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C19H15ClF2N2O (M + H)+ 361.0914; found 361.0916. IR (KBr) ν 3410, 3064, 3003, 2944, 2848, 2363, 2112, 1956, 1802, 1726, 1610, 1573, 1532,1456, 1239, 1093, 1045, 951, 902, 755, 575 cm−1.
1-Bromo-5-(2,2-difluoropropyl)-5-methylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3m). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 196–197 °C, 63.2 mg, 78% yield. 1H NMR (500 MHz, CDCl3): δ 8.38 (dd, J = 6.0, 3.0 Hz, 1H), 7.93 (dd, J = 6.0, 3.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.49–7.44 (m, 3H), 7.33 (t, J = 8.0 Hz, 1H), 3.29–3.20 (m, 1H), 2.76–2.67 (m, 1H), 1.72 (s, 3H), 1.38 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.3, 147.1, 143.5, 143.1, 135.3, 130.8, 130.6, 126.4, 126.3, 125.9, 122.5 (t, J = 240.7 Hz), 121.8, 121.3, 120.8, 115.7, 48.4 (t, J = 23.5 Hz), 45.9 (d, J = 3.2 Hz), 31.5, 24.8 (t, J = 27.3Hz). 19F NMR (471 MHz, CDCl3): δ −85.15–−85.86 (m, 1F), −86.99–−87.69 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C19H15BrF2N2O (M + H)+ 405.0408; found 405.0412. IR (KBr) ν 3415, 3090, 3063, 3000, 2924, 2848, 2680, 2363, 1957, 1803, 1726, 1610, 1565, 1535, 1450, 1236, 1092, 1039, 951, 898, 755, 569 cm−1.
5-(2,2-Difluoropropyl)-2,5-dimethylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3n). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 116–117 °C, 51.7 mg, 76% yield. 1H NMR (500 MHz, CDCl3): δ 8.37–8.35 (m, 1H), 8.32 (s, 1H), 7.83–7.81 (m, 1H), 7.45–7.40 (m, 2H), 7.37 (s, 2H), 3.22 (q, J = 15.5 Hz, 1H), 2.70 (q, J = 15.5 Hz, 1H), 2.46 (s, 3H), 1.69 (s, 3H), 1.33 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 172.4, 149.8, 143.9, 137.9, 137.2, 132.4, 131.5, 126.7, 126.1, 125.8, 125.5, 122.6 (t, J = 240.5 Hz), 122.0, 119.7, 115.6, 48.2 (t, J = 24.0 Hz), 45.3 (d, J = 2.2 Hz), 31.1, 24.7 (t, J = 27.3Hz), 20.9. 19F NMR (471 MHz, CDCl3): δ −86.02–−86.20 (m, 2F). HRMS (ESI-TOF) m/z: Calcd for C20H18F2N2O (M + H)+ 341.1460; found 341.1462. IR (KBr) ν 3417, 3115, 3073, 2923, 2850, 2671, 2369, 1943, 1716, 1613, 1547, 1495, 1335, 1238, 1172, 1012, 878, 826, 763, 555 cm−1.
5-(2,2-Difluoropropyl)-1,3,5-trimethylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3o). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 150–151 °C, 58.0 mg, 82% yield. 1H NMR (500 MHz, CDCl3): δ 8.39–8.38 (m, 1H), 7.83–7.81 (m, 1H), 7.44–7.39 (m, 2H), 7.15 (s, 2H), 3.27–3.18 (m, 1H), 3.02 (s, 3H), 2.76–2.67 (m, 1H), 2.42 (s, 3H), 1.71 (s, 3H), 1.32 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 172.5, 150.0, 144.2, 141.1, 140.2, 139.7, 132.3, 130.6, 125.5, 125.4, 125.3, 122.7 (t, J = 240.6 Hz), 119.9, 118.4, 115.6, 48.5 (t, J = 24.1Hz), 45.4, 31.7, 24.7 (t, J = 27.3Hz), 24.6, 21.6. 19F NMR (471 MHz, CDCl3): δ −85.66–−85.96 (m, 2F). HRMS (ESI-TOF) m/z: Calcd for C21H20F2N2O (M + H)+ 355.1616; found 355.1619. IR (KBr) ν 3394, 3115, 3061, 3001, 2924, 2853, 2746, 2359, 1953, 1914, 1805, 1716, 1615, 1533, 1462, 1229, 1081, 905, 803, 615, 544 cm−1.
1,3-Dichloro-5-(2,2-difluoropropyl)-5-methylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3p). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 216–217 °C, 58.5 mg, 74% yield. 1H NMR (500 MHz, CDCl3): δ 8.38–8.36 (m, 1H), 7.92–7.91 (m, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.48–7.44 (m, 2H), 7.40 (d, J = 1.5 Hz, 1H), 3.29–3.20 (m, 1H), 2.72–2.63 (m, 1H), 1.73 (s, 3H), 1.45 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.7, 146.3, 144.1, 143.8, 136.2, 134.4, 131.3, 130.5, 126.5, 126.1, 122.4 (t, J = 240.8 Hz), 120.8, 119.2, 115.6, 48.4 (t, J = 23.4 Hz), 45.8 (d, J = 3.0 Hz), 31.3, 24.9 (t, J = 27.1 Hz). 19F NMR (471 MHz, CDCl3): δ −85.15–−85.86 (m, 1F), −87.94–−88.64 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C19H14Cl2F2N2O (M + H)+ 395.0524; found 395.0527. IR (KBr) ν 3418, 3144, 3070, 3007, 2947, 2781, 2369, 1954, 1919, 1803, 1725, 1612, 1577, 1446, 1230, 1083, 1033, 983, 911, 802, 755, 618, 555 cm−1.
5-(2,2-Difluoropropyl)-2,4,5-trimethylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3q). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 170–171 °C, 51.0 mg, 72% yield. 1H NMR (400 MHz, CDCl3): δ 8.35–8.33 (m, 2 H), 7.46–7.38 (m, 1H), 7.42 (pd, J = 7.2, 1.6 Hz, 2H), 7.18 (s, 1H), 3.34–3.11 (m, 2H), 2.62 (s, 3H), 2.41 (s, 3H), 1.80 (s, 3H), 1.38 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 173.5, 150.4, 144.1, 137.7, 137.5, 136.4, 134.6, 131.5, 125.9, 125.2, 122.9 (t, J = 240.3Hz), 122.9, 119.6, 115.7, 46.6, 44.9 (t, J = 23.5 Hz), 27.2, 24.5 (t, J = 27.5 Hz), 22.8, 20.6. 19F NMR (471 MHz, CDCl3): δ −88.43–−88.61 (m, 1F), −88.66–−88.85 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C21H20F2N2O (M + H)+ 355.1616; found 355.1619. IR (KBr) ν 3385, 3060, 3010, 2917, 2851, 2357, 1994, 1909, 1795, 1706, 1612, 1542, 1455, 1228, 1152, 1026, 946, 888, 799, 765, 656, 561 cm−1.
3-Bromo-5-(2,2-difluoropropyl)-5,9,10-trimethylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3r). A yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 226–227 °C, 72.7 mg, 84% yield. 1H NMR (500 MHz, CDCl3): δ 8.31 (d, J = 9.0 Hz, 1H), 8.12 (s, 1H), 7.60–7.58 (m, 2H), 7.56 (s, 1H), 3.26–3.16 (m, 1H), 2.70–2.61 (m, 1H), 2.41 (s, 3H), 2.39 (s, 3H), 1.70 (s, 3H), 1.39 (t, J = 18.5 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 171.3, 148.0, 142.4, 141.7, 135.2, 135.0, 131.2, 129.9, 129.7, 127.2, 125.3, 122.4 (t, J = 240.7 Hz), 121.7, 120.0, 115.9, 48.2 (t, J = 23.8 Hz), 45.4 (d, J = 3.3Hz), 30.8, 24.7 (t, J = 27.2 Hz), 20.5, 20.4. 19F NMR (471 MHz, CDCl3): δ −85.57–−86.28 (m, 1F), −87.17–−87.87 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C21H19BrF2N2O (M + H)+ 433.0721; found 433.0723. IR (KBr) ν 3402, 3090, 2978, 2737, 2586, 2361, 2193, 1933, 1720, 1596, 1539, 1458, 1230, 1082, 948, 859, 698, 654, 562 cm−1.
5-(2,2-Difluoropropyl)-5-phenylbenzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3s). A yellow liquid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 44.2 mg, 57% yield. 1H NMR (400 MHz, CDCl3): δ 8.58 (dd, J = 8.0, 1.2 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.56–7.37 (m, 4H), 7.32–7.24 (m, 3H), 7.22–7.17 (m, 3H), 3.98–3.07 (m, 1H), 3.18–3.07 (m, 1H), 1.47 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 170.3, 149.7, 144.1, 142.3, 139.8, 131.6, 131.2, 129.3, 129.1, 128.2, 128.1, 126.8, 125.93, 125.87, 125.7, 123.6, 122.8 (t, J = 239.8 Hz), 119.9, 115.7, 53.4, 46.0 (t, J = 23.5 Hz), 25.3 (t, J = 27.5 Hz). 19F NMR (471 MHz, CDCl3): δ −84.84–−85.02 (m, 1F), −85.04–−85.22 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C24H18F2N2O (M + H)+ 389.1460; found 389.1463. IR (thin film) ν 3427, 3064, 2921, 2847, 2720, 2350, 1943, 1829, 1717, 1612, 1552, 1445, 1366, 1108, 1043, 942, 848, 701, 624 cm−1.
5-Benzyl-5-(2,2-difluoropropyl)benzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one (3t). A white solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 160–161 °C, 52.3 mg, 65% yield. 1H NMR (500 MHz, CDCl3): δ 8.36–8.34 (m, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.68–7.66 (m, 1H), 7.63–7.62 (m, 2H), 7.49–7.46 (m, 1H), 7.41–7.36 (m, 2H), 6.87 (t, J = 7.5 Hz, 1H), 6.77 (t, J = 7.5 Hz, 2H), 6.49 (d, J = 7.5 Hz, 2H), 3.53 (d, J = 12.5 Hz, 1H), 3.49–3.41 (m, 1H), 3.17 (d, J = 12.5 Hz, 1H), 2.99–2.90 (m, 1H), 1.43 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.2, 149.2, 143.6, 137.4, 133.2, 130.9, 130.8, 129.1, 128.0, 127.8, 127.3, 125.72, 125.69, 125.4, 124.1, 122.6 (t, J = 240.8 Hz), 119.6, 115.4, 51.9, 50.7, 46.5 (t, J = 23.8 Hz), 25.1 (t, J = 27.3Hz). 19F NMR (471 MHz, CDCl3): δ −83.32–−84.00 (m, 1F), −84.83–−85.51 (m, 1F). HRMS (ESI-TOF) m/z: C25H20F2N2O (M + H)+ 403.1616; found 403.1617. IR (KBr) ν 3398, 3033, 3001, 2960, 2934, 2851, 2678, 2366, 2054, 1792, 1712, 1606, 1585, 1555, 1495, 1448, 1263, 1242, 1175, 1113, 1045, 946, 833, 694, 536 cm−1.
7-(2,2-Difluoropropyl)-7-methylbenzo[h]benzo [4,5]imidazo [2,1-a]isoquinolin-8(7H)-one (3u). A yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 195–196 °C, 55.6 mg, 74% yield. 1H NMR (500 MHz, CDCl3): δ 10.56 (d, J = 8.5 Hz, 1H), 8.47–8.45 (m, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.96–7.94 (m, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.84– 7.81 (m, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.50–7.46 (m, 2H), 3.37–3.27 (m, 1H), 2.90–2.81 (m, 1H), 1.78 (s, 3H), 1.33 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 172.3, 149.7, 144.0, 140.6, 132.7, 132.0, 130.4, 130.3, 128.7, 128.4, 128.2, 126.9, 125.9, 125.8, 122.5 (d, J = 240.5 Hz), 123.7, 120.1, 117.6, 115.7, 47.9 (t, J = 24.1Hz), 45.9, 31.0, 24.6 (t, J = 27.3Hz). 19F NMR (471 MHz, CDCl3): δ −86.07–−86.30 (m, 1F), −86.32–−86.46 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C23H18F2N2O (M + H)+ 377.1460; found 377.1462. IR (KBr) ν 3405, 3104, 3058, 3003, 2940, 2726, 2356, 1940, 1789, 1715, 1619, 1572, 1526, 1453, 1305, 1266, 1182, 1078, 975, 939, 905, 823, 749, 606, 586 cm−1.
4-(2,2-Difluoropropyl)-4-methylbenzo [4,5]imidazo [1,2-a]thieno [2,3-c]pyridin-5(4H)-one (3v). A yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), mp 187–188 °C, 44.5 mg, 67% yield. 1H NMR (400 MHz, CDCl3): δ 8.33–8.30 (m, 1H), 7.78–7.75 (m, 1H), 7.59 (d, J = 4.8 Hz, 1H), 7.44–7.38 (m, 2H), 7.11 (d, J = 5.2Hz, 1H), 3.24–3.12 (m, 1H), 2.66–2.54 (m, 1H), 1.67 (s, 3H), 1.38 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 172.6, 146.4, 145.9, 143.9, 130.9, 130.4, 125.9, 125.8, 125.5, 123.6, 122.4 (t, J = 240.5 Hz), 119.7, 115.2, 48.2 (t, J = 24.3Hz), 45.6–45.5 (m), 29.9, 24.5 (t, J = 27.3Hz). 19F NMR (471 MHz, CDCl3): δ −86.86–−87.18 (m, 2F). HRMS (ESI-TOF) m/z: Calcd for C17H14F2N2OS (M + H)+333.0868; found 333.0870. IR (KBr) ν 3358, 3117, 3065, 2921, 2851, 2681, 2357, 1942, 1866, 1706, 1619, 1579, 1525, 1455, 1425, 1348, 1248, 1168, 1098, 935, 895, 831, 802, 768, 674, 599 cm−1.
5-(2,2-Difluoropropyl)-3,5,12-trimethylindolo [2,1-a]isoquinolin-6(5H)-one (5a). A white gummy after purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1), 46.6 mg, 66% yield. 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 7.2Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.60–7.58 (m, 1H), 7.41–7.34 (m, 3H), 7.23 (d, J = 8.4 Hz, 1H), 3.28–3.16 (m, 1H), 2.71–2.60 (m, 1H), 2.65 (s, 3H), 2.44 (s, 3H), 1.69 (s, 3H), 1.31 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 172.0, 137.3, 137.0, 134.0 (d, J = 30.9 Hz), 132.6, 129.6 (d, J = 24.5 Hz), 128.3, 127.7, 125.4, 124.9, 124.2, 123.2, 122.9 (t, J = 240.2Hz), 118.2, 116.7, 113.6, 48.1 (t, J = 24.2Hz), 45.0–44.8 (m), 31.4, 24.5 (t, J = 27.4 Hz), 21.5, 11.5. 19F NMR (471 MHz, CDCl3): δ −84.11–−84.82 (m, 1F), −85.19–-85.89 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C22H21F2NO (M + H)+ 354.1664; found 354.1666. IR (thin film) ν 3358, 3184, 3071, 3001, 2923, 2850, 2567, 2363, 1919, 1716, 1627, 1570, 1489, 1392, 1320, 1158, 1091, 1012, 839, 766, 672 cm−1.
5-(2,2-Difluoropropyl)-3-fluoro-5,12-dimethylindolo [2,1-a]isoquinolin-6(5H)-one (5b). A yellow liquid after purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1), 51.4 mg, 72 % yield. 1H NMR (500 MHz, CDCl3): δ 8.61 (d, J = 8.0 Hz, 1H), 8.03 (dd, J = 8.8, 6.0 Hz, 1H), 7.59 (d, J = 7.0 Hz, 1H), 7.42–7.35 (m, 2H), 7.17–7.11 (m, 2H), 3.28–3.18 (m, 1H), 2.63 (s, 3H), 2.62–2.55 (m, 1H), 1.69 (s, 3H), 1.38 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 171.2, 161.8 (d, J = 248.4 Hz), 139.8 (d, J = 6.9 Hz), 134.2, 132.4, 128.9, 126.9 (d, J = 8.3Hz), 125.7, 124.3, 122.7 (t, J = 240.6 Hz), 122.4 (d, J = 2.5 Hz), 118.3, 116.7, 114.9 (d, J = 21.8 Hz), 114.1, 113.9, 48.1 (t, J = 24.1Hz), 45.1, 31.2, 24.6 (t, J = 27.4 Hz), 11.4. 19F NMR (471 MHz, CDCl3): δ −84.17–−84.88 (m, 1F), −86.70–-87.41 (m, 1F), −112.80–−112.85 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C21H18F3NO (M + H)+ 358.1413; found 358.1415. IR (thin film) ν 3355, 3043, 3014, 2973, 2867, 2747, 2591, 2470, 2360, 1940, 1903, 1787, 1702, 1569, 1502, 1016, 975, 819, 755, 625, 589, 531 cm−1.
3-Chloro-5-(2,2-difluoropropyl)-5,10,12-trimethylindolo [2,1-a]isoquinolin-6(5H)-one (5c). A yellow liquid after purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1), 56.8 mg, 76 % yield. 1H NMR (400 MHz, CDCl3): δ 8.62–8.59 (m, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.61–7.58 (m, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.41–7.35 (m, 3H), 3.28–3.16 (m, 1H), 2.63 (s, 3H), 2.67–2.55 (m, 1H), 1.69 (s, 3H), 1.38 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.2, 138.9, 134.2, 133.1, 132.3, 128.6, 127.6, 127.4, 126.2, 125.9, 124.5, 124.4, 122.8 (t, J = 240.4 Hz), 118.4, 116.7, 114.9, 48.0 (t, J = 23.9 Hz), 44.9, 31.2, 24.7 (t, J = 27.3Hz), 11.5. 19F NMR (471 MHz, CDCl3): δ −84.35–−85.06 (m, 1F), −86.79–-87.49 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C21H18ClF2NO (M + H)+ 374.1118; found 374.1120. IR (thin film) ν 3343, 3195, 3124, 3054, 2983, 2921, 2873, 2727, 2360, 2226, 1939, 1793, 1686, 1602, 1560, 1458, 1285, 1233, 1082, 1013, 978, 902, 811, 711, 619, 546 cm−1.
3-Bromo-5-(2,2-difluoropropyl)-5,12-dimethylindolo [2,1-a]isoquinolin-6(5H)-one (5d). A yellowish liquid after purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1), 57.7 mg, 69% yield. 1H NMR (500 MHz, CDCl3): δ 8.60 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.60–7.58 (m, 2H), 7.52 (dd, J = 8.5, 2.0 Hz, 1H), 7.43–7.35 (m, 2H), 3.27–3.17 (m, 1H), 2.63 (s, 3H), 2.65–2.56 (m, 1H), 1.68 (s, 3H), 1.38 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 171.1, 139.2, 134.3, 132.3, 130.5, 130.3, 128.7, 126.4, 126.0, 124.9, 124.4, 122.7 (t, J = 240.5 Hz), 121.2, 118.5, 116.8, 115.1, 48.1 (t, J = 23.9 Hz), 44.9, 31.2, 24.7 (t, J = 27.3Hz), 11.5. 19F NMR (471 MHz, CDCl3): δ −84.40–-85.07 (m, 1F), −86.79–-87.47 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C21H18BrF2NO (M + H)+ 420.0594; found 420.0598. IR (thin film) ν 3340, 3188, 3124, 3054, 2868, 2727, 2357, 1940, 1902, 1870, 1789, 1693, 1603, 1553, 1289, 1238, 1079, 1015, 973, 903, 803, 761, 701, 618 cm−1.
3-Chloro-5-(2,2-difluoropropyl)-5,10,12-trimethylindolo [2,1-a]isoquinolin-6(5H)-one (5e). A yellow liquid after purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1), 56.6 mg, 73% yield. 1H NMR (500 MHz, CDCl3): δ 8.34 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.30 (s, 1H), 7.25 (d, J = 9.0 Hz, 1H), 7.15 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 3.14–3.04 (m, 1H), 2.50 (s, 3H), 2.52–2.43 (m, 1H), 2.38 (s, 3H), 1.56 (s, 3H), 1.25 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 170.9, 139.0, 134.1, 133.0, 132.5, 132.5, 128.8, 127.6, 127.4, 127.2, 126.1, 124.6, 122.7 (t, J = 240.4 Hz), 118.5, 116.4, 114.7, 48.1 (t, J = 24.0 Hz), 44.9, 31.2, 24.6 (t, J = 27.4 Hz), 21.6, 11.5. 19F NMR (471 MHz, CDCl3): δ −84.19–-84.90 (m, 1F), −86.72–−87.42 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C22H20ClF2NO (M + H)+ 388.1274; found 388.1275. IR (thin film) ν 3357, 3094, 2980, 2938, 2861, 2733, 2359, 1877, 1692, 1592, 1556, 1492, 1462, 1296, 1242, 1172, 1073, 939, 901, 801, 714, 664, 619, 591 cm−1.
5-(2,2-Difluoropropyl)-12-ethyl-5-methylindolo [2,1-a]isoquinolin-6(5H)-one (5f). A yellow liquid after purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1), 52.9 mg, 75% yield. 1H NMR (500 MHz, CDCl3): δ 8.64 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.0 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.44–7.35 (m, 4 H), 3.26–3.13 (m, 3H), 2.70–2.61 (m, 1H), 1.70 (s, 3H), 1.42 (t, J = 7.5 Hz, 3H), 1.31 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 172.0, 137.1, 134.5, 131.8, 128.8, 127.5, 127.4, 127.3, 125.7, 124.7, 124.3, 122.9 (t, J = 240.2Hz), 121.1, 118.2, 116.9, 48.1 (t, J = 24.3Hz), 44.9, 31.3, 24.5 (t, J = 27.4 Hz), 18.6, 13.3. 19F NMR (471 MHz, CDCl3): δ −84.21–−84.92 (m, 1F), −85.41–−86.12 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C22H21F2NO (M + H)+ 354.1664; found 354.1667. IR (thin film) ν 3364, 3118, 3068, 2973, 2931, 2878, 2681, 2367, 1845, 1720, 1700, 1677, 1606, 1559, 1456, 1395, 1335, 1262, 1128, 1085, 903, 805, 736, 702, 552 cm−1.
5-(2,2-Difluoropropyl)-12-ethyl-5,10-dimethylindolo [2,1-a]isoquinolin-6(5H)-one (5g). A yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1), mp 151–152 °C, 47.7 mg, 65% yield. 1H NMR (500 MHz, CDCl3): δ 8.50 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.45–7.35 (m, 3H), 7.22 (d, J = 8.0 Hz, 1H), 3.25–3.16 (m, 1H), 3.13 (q, J =7.5 Hz, 2H), 2.69–2.60 (m, 1H), 2.51 (s, 3H), 1.69 (s, 3H), 1.41 (t, J = 7.5 Hz, 3H), 1.30 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 171.7, 137.0, 133.9, 132.6, 131.9, 128.9, 127.4, 127.3, 127.0, 125.8, 124.6, 122.9 (t, J = 240.2Hz), 121.0, 118.2, 116.6, 48.1 (t, J = 24.4 Hz), 44.8, 31.2, 24.4 (t, J = 27.4 Hz), 21.6, 18.6, 13.3. 19F NMR (471 MHz, CDCl3): δ −84.10–−84.77 (m, 1F), −85.39–−86.06 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C23H23F2NO (M + H)+ 368.1820; found 368.1824. IR (KBr) ν 3358, 3121, 3068, 2968, 2936, 2871, 2733, 2369, 2249, 1917, 1770, 1693, 1592, 1560, 1493, 1466, 1309, 1238, 1122, 1079, 943, 896, 816, 734, 561 cm−1.
5-(2,2-Difluoropropyl)-12-ethyl-10-fluoro-5-methylindolo [2,1-a]isoquinolin-6(5H)-one (5h). A yellow liquid after purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1), 51.9 mg, 70% yield. 1H NMR (500 MHz, CDCl3): δ 8.57 (dd, J = 9.0, 5.0 Hz, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.44–7.37 (m, 2H), 7.23 (dd, J = 9.0, 2.5 Hz, 1H), 7.09 (td, J = 9.0, 2.5 Hz, 1H), 3.24–3.15 (m, 1H), 3.12–3.07 (m, 2H), 2.69–2.60 (m, 1H), 1.69 (s, 3H), 1.40 (t, J = 7.5 Hz, 3H), 1.31 (t, J = 19.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 171.8, 160.4 (d, J = 241.1Hz), 137.3, 133.2 (d, J = 9.4 Hz), 130.7, 130.4, 127.65 (d, J = 41.6 Hz), 127.3, 125.4, 124.8, 122.8 (d, J = 240.4 Hz), 120.6 (d, J = 4.1Hz), 118.0 (d, J = 9.0 Hz), 113.1 (d, J = 24.6 Hz), 104.0 (d, J = 24.0 Hz), 48.3 (t, J = 24.2Hz), 44.8, 31.2, 24.6 (t, J = 27.4 Hz), 18.7, 13.2. 19F NMR (471 MHz, CDCl3): δ −84.78–−85.42 (m, 1F), −85.86–−86.52 (m, 1F), −118.11–−118.16 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C22H20F3NO (M + H)+ 372.1570; found 372.1575. IR (thin film) ν 3360, 3124, 3075, 3038, 2960, 2928, 2877, 2850, 2764, 2367, 2249, 2172, 2039, 1967, 1940, 1889, 1826, 1692, 1616, 1562, 1399, 1340, 1173, 976, 902, 846, 734, 691,652, 595 cm−1.
3-Chloro-5-(2-cyclopropyl-2,2-difluoroethyl)-5,12-dimethylindolo [2,1-a]isoquinolin-6(5H)-one (5i). A yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1), mp 155–156 °C, 50.4 mg, 63% yield. 1H NMR (500 MHz, CDCl3): δ 8.61 (d, J = 7.5 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.42–7.36 (m, 3H), 3.40–3.30 (m, 1H), 2.76–2.67 (m, 1H), 2.63 (s, 3H), 1.69 (s, 3H), 1.02–0.95 (m, 1H), 0.44–0.23 (m, 4 H). 13C{1H} NMR (125 MHz, CDCl3): δ 171.2, 139.2, 134.3, 133.1, 132.3, 128.8, 127.5, 126.1, 125.9, 124.4, 124.3, 122.4 (t, J = 242.3Hz), 118.4, 116.8, 114.7, 47.7 (t, J = 25.9 Hz), 45.0, 31.7, 16.6 (t, J = 28.9 Hz), 11.5, 1.3–1.2 (m). 19F NMR (471 MHz, CDCl3): δ −94.49–−95.10 (m, 1F), −99.95–−100.56 (m, 1F). HRMS (ESI-TOF) m/z: Calcd for C23H20ClF2NO (M + H)+ 400.1274; found 400.1279. IR (KBr) ν 3341, 3190, 3110, 3053, 3021, 2985, 2948, 2911, 2860, 2724, 2630, 2350, 2080, 1939, 1869, 1789, 1679, 1609, 1563, 1459, 1430, 1280, 1245, 1135, 1059, 1016, 925, 895, 813, 714, 639, 539 cm−1.

4. Conclusions

In summary, a novel electrochemical tandem cyclization/difluoroethylation reaction of 2-arylbenzimidazoles/2-arylindoles was reported by our group. Various CF2Me-substituted benzimidazo [2,1-a]isoquinolin-6(5H)-ones and indolo [2,1-a]isoquinolin-6(5H) ones could be readily synthesized in good to high yield. Additionally, it also offered a convenient protocol for the preparation of cyclopropyldifluoromethylated indolo [2,1-a]isoquinolin-6(5H) ones. Further investigation to construct other useful substituted heterocycles by electrochemical oxidative difluoroethylation is currently underway in our laboratory as well.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29050973/s1, Figure S1: HRMS analysis of adduct products; Figure S2: Cyclic voltammograms of substrates; Figure S3: Structure of product 3m; Figure S4: Structure of product 5i; Tables S1 and S2: crystal and structure refinement data for 3m and 5i; 1H NMR, 19F NMR, and 13C NMR of compounds 3a–v and 5a–i.

Author Contributions

Conceptualization, Y.T.; methodology, D.G. and Y.T.; investigation, Y.T., L.Z., D.G., S.Y. and N.Z.; writing—original draft preparation, Y.T.; writing—review and editing, Y.T. and Z.L.; supervision, W.F.; funding acquisition, Y.T. and Z.L. All authors have read and agreed to the published version of the manuscript.

Funding

This project is supported by the National Natural Science Foundation of China (22302088 and 21702044), the Natural Science Foundation of Hebei Province (B2022201059), the Key Scientific Research Project of Higher Education of Henan Province (24B150022), and the Key Laboratory of Photochemical Conversion and Optoelectronic Materials, TIPC, CAS (PCOM202304).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data underlying this study are available in the published article and its Supplementary Materials. Deposition Numbers 2303467 (for 3m) and 2307007 (for 5i) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif (accessed on 25 October 2023 and 10 November 2023), by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 00973 g001
Figure 1. Strategies for radical difluoroethylated heterocycles.
Figure 1. Strategies for radical difluoroethylated heterocycles.
Molecules 29 00973 g001
Molecules 29 00973 sch001
Scheme 1. Scope of the substrates 2-arylbenzimidazoles. Reaction conditions: carbon plate (10 mm × 10 mm × 3 mm) as the anode, platinum plate (10 mm × 10 mm × 0.20 mm) as the cathode, undivided cell, 2.1 V, 1 (0.2 mmol), 2a (0.6 mmol), LiClO4 (0.3 M), CH3CN (4.5 mL), H2O (1.5 mL), rt, 3h, isolated yields.
Scheme 1. Scope of the substrates 2-arylbenzimidazoles. Reaction conditions: carbon plate (10 mm × 10 mm × 3 mm) as the anode, platinum plate (10 mm × 10 mm × 0.20 mm) as the cathode, undivided cell, 2.1 V, 1 (0.2 mmol), 2a (0.6 mmol), LiClO4 (0.3 M), CH3CN (4.5 mL), H2O (1.5 mL), rt, 3h, isolated yields.
Molecules 29 00973 sch001
Molecules 29 00973 sch002
Scheme 2. Scope of the substrates 2-arylindoles. Reaction conditions: carbon plate (10 mm × 10 mm × 3 mm) as the anode, platinum plate (10 mm × 10 mm × 0.20 mm) as the cathode, undivided cell, 2.1 V, 4 (0.2 mmol), 2 (0.6 mmol), LiClO4 (0.3 M), CH3CN (4.5 mL), H2O (1.5 mL), rt, 3h, isolated yields.
Scheme 2. Scope of the substrates 2-arylindoles. Reaction conditions: carbon plate (10 mm × 10 mm × 3 mm) as the anode, platinum plate (10 mm × 10 mm × 0.20 mm) as the cathode, undivided cell, 2.1 V, 4 (0.2 mmol), 2 (0.6 mmol), LiClO4 (0.3 M), CH3CN (4.5 mL), H2O (1.5 mL), rt, 3h, isolated yields.
Molecules 29 00973 sch002
Molecules 29 00973 sch003
Scheme 3. Reactions for mechanistic determination: (a) a radical trapping experiment involved BHT; (b) a radical trapping experiment involved 1,1-diphenylethylene.
Scheme 3. Reactions for mechanistic determination: (a) a radical trapping experiment involved BHT; (b) a radical trapping experiment involved 1,1-diphenylethylene.
Molecules 29 00973 sch003
Molecules 29 00973 g002
Figure 2. Cyclic voltammograms of substrates in 0.1 M LiClO4/(CH3CN/H2O), using glassy carbon working electrode, platinum wire counter electrode, and Ag/AgNO3 reference electrode at 50 mVs−1 scan rates: a—background, b—1a (5 mM), c—2a (5 mM), d—1a (5 mM) and 2a (5 mM).
Figure 2. Cyclic voltammograms of substrates in 0.1 M LiClO4/(CH3CN/H2O), using glassy carbon working electrode, platinum wire counter electrode, and Ag/AgNO3 reference electrode at 50 mVs−1 scan rates: a—background, b—1a (5 mM), c—2a (5 mM), d—1a (5 mM) and 2a (5 mM).
Molecules 29 00973 g002
Molecules 29 00973 sch004
Scheme 4. Proposed reaction mechanism.
Scheme 4. Proposed reaction mechanism.
Molecules 29 00973 sch004
Table 1. Optimization of the typical conditions a.
Table 1. Optimization of the typical conditions a.
Molecules 29 00973 i001
EntryVariations from Standard ConditionsYield (%) b
1None86
21.8 V52
32.5 V65
4C (+)|Ni (−)62
5C (+)|C (−)56
6Pt (+)|Pt (−)39
7nBu4NClO4 as the electrolyte37
8Et4NClO4 as the electrolyte61
9nBu4NPF6 as the electrolyte26
10CH3CN/H2O (9:1)47
11CH3CN/H2O (1:1)66
12No electricityn.d
a Reaction conditions: carbon plate (10 mm × 10 mm × 3 mm) as the anode, platinum plate (10 mm × 10 mm × 0.20 mm) as the cathode, undivided cell, 2.1 V, 1a (0.2 mmol), 2a (0.6 mmol), LiClO4 (0.3 M), CH3CN (4.5 mL), H2O (1.5 mL), rt, 3 h. b Isolated yields.
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Tian, Y.; Guo, D.; Zheng, L.; Yang, S.; Zhang, N.; Fu, W.; Li, Z. Electrochemical Radical Tandem Difluoroethylation/Cyclization of Unsaturated Amides to Access MeCF2-Featured Indolo/Benzoimidazo [2,1-a]Isoquinolin-6(5H)-ones. Molecules 2024, 29, 973. https://doi.org/10.3390/molecules29050973

AMA Style

Tian Y, Guo D, Zheng L, Yang S, Zhang N, Fu W, Li Z. Electrochemical Radical Tandem Difluoroethylation/Cyclization of Unsaturated Amides to Access MeCF2-Featured Indolo/Benzoimidazo [2,1-a]Isoquinolin-6(5H)-ones. Molecules. 2024; 29(5):973. https://doi.org/10.3390/molecules29050973

Chicago/Turabian Style

Tian, Yunfei, Dongyu Guo, Luping Zheng, Shaolu Yang, Ningning Zhang, Weijun Fu, and Zejiang Li. 2024. "Electrochemical Radical Tandem Difluoroethylation/Cyclization of Unsaturated Amides to Access MeCF2-Featured Indolo/Benzoimidazo [2,1-a]Isoquinolin-6(5H)-ones" Molecules 29, no. 5: 973. https://doi.org/10.3390/molecules29050973

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