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. 2023 Feb 14;8(8):7517–7528. doi: 10.1021/acsomega.2c06689

Synthesis of Difluoroarymethyl-Substituted Benzimidazo[2,1-a]isoquinolin-6(5H)-ones under Mild Conditions

Kaixia Sui 1, Yuting Leng 1,*, Yangjie Wu 1,*
PMCID: PMC9979369  PMID: 36872989

Abstract

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A highly efficient method for synthesis of difluoroarymethyl-substituted benzimidazo[2,1-a]isoquinolin-6(5H)-ones using 2-arylbenzoimidazoles with α,α-difluorophenylacetic acid as reaction substrates has been developed through radical cascade cyclization. The advantage of this strategy lies in excellent functional group tolerance to generate the corresponding products in good yields under base- and metal-free conditions.

Introduction

Benzimidazo-fused polycyclic motifs, especially benzimidazo-isoquinolin-6(5H)-one derivatives, are important N-heterocyclic moieties, which have been frequently found in natural products and pharmaceuticals.1,2 This kind of polycyclic compound also exhibited an amazingly wide spectrum of biological properties, including anti-inflammatory,3 antidiabetic,4 antitumor,5 and anti-HIV-1 properties (Figure 1).6 Therefore, a great number of synthetic methods have been developed for the preparation of various functionalized novel benzimidazo-isoquinolin-6(5H)-one compounds, such as condensation and metal-free-catalyzed cross-couplings.7,8 Recently, radical cascade cyclization has emerged as a powerful strategy for assembling these frameworks because of its simplicity, efficiency, and atom economy.9−11 In 2019, Yu and co-workers realized the construction of benzimidazo[2,1-a]isoquinolin-6(5H)-ones via silver-catalyzed decarboxylative radical cascade cyclization (Scheme 1a).12 At the same time, Guan’s laboratory has devoted effort to the development of photocatalysis radical cascade cyclization reaction toward the preparation of benzimidazo[2,1-a]isoquinolin-6(5H)-ones (Scheme 1b).13 In addition, Li and co-workers reported a facile cascade cyclization reaction for the construction of carbamoylated benzimidazo[2,1-a]isoquinolin-6(5H)-ones.14 Moreover, Pan’s group constructed the indolo[2,1-a]isoquinolin derivatives via metal-free radical cascade cyclization.15 Recently, Chen’s group published a similar type of work.16 Despite these achievements, the development of an efficient method for the novel benzimidazo[2,1-a]isoquinolin-6(5H)-one derivatives is still highly desirable and valuable.

Figure 1.

Figure 1

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Selected examples containing a benzimidazo-isoquinolin-6(5H)-one unit.

Scheme 1. Synthesis of Benzimidazo-Isoquinoline Fused Frameworks.

Scheme 1

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On the other hand, fluorine-containing compounds, as the most important organic compounds, have been widely presented in the fields of pharmaceutical, chemical, agrochemical, and materials science.17 Among these fluorine-containing groups, the benzylic difluoromethylene groups (ArCF2) are versatile and valuable moieties for the development of potential pharmaceuticals owing to their unique stability, and an isosteric property as an ethereal oxygen atom or a carbonyl group, as well as a lipophilic hydrogen-bond donor.18 In recent years, the decarboxylative radical difluoromethylation reaction has usually been considered one of the most efficient methods for the preparation of C–CF2 bonds.19 In addition, α,α-difluoroarylacetic acids have received particular interest due to their beneficial properties, such as easy to store and accessible building blocks for the construction of fluorinated compounds.20

In this context, the preparation of ArCF2-substituted benzimidazo[2,1-a]isoquinolin-6(5H)-ones is an attractive task. With our ongoing interest in radical chemistry, we, herein, designed metal-free and base-free-catalyzed radical cascade cyclization for the construction of difluoroarymethyl-substituted benzimidazo[2,1-a]isoquinolin-6(5H)-ones (Scheme 1c).

Results and Discussion

Initially, we examined the feasibility of the oxidative coupling reaction of N-methacryloyl-2-phenylbenzoimidazole 1a with α,α-difluorophenylacetic acid 2a using (NH4)2S2O8 as an oxidant (Table 1). To our delight, the desired product 3aa was obtained in 89% yield using 3.0 equiv of (NH4)2S2O8 as an oxidant in dimethyl sulfoxide (DMSO) at 80 °C under an Ar atmosphere (Table 1, entry 1). The structure of 3aa was unambiguously confirmed by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). Based on this result, different control experiments were carried out to evaluate the factors that influence reaction efficiency. Other conditions, such as catalysts, oxidants, the loading of oxidants, solvents, the molar ratio of reactants, temperatures, and times, were further conducted. It is extraordinarily effective with the Ag(I)–peroxydisulfate combination in many decarboxylative and related oxidative transformations.21 Therefore, we tried different silver carbonates as the catalyst for this transformation. Nevertheless, the yield of 3aa could not be improved but decreased slightly when the typical AgNO3 or Ag2CO3 was employed (Table 1, entries 2 and 3). Next, various oxidants were tested, and the results showed that (NH4)2S2O8 turned out to be the most effective oxidant (Table 1, entries 4–8), especially, the reaction could not proceed without it. In addition, we evaluated the effect of the loading of the oxidant on the reaction. The results showed that 3.0 equiv of (NH4)2S2O8 was the optimal one (Table S1, entries 1–5). Subsequently, the equivalent ratios of 1a and 2a were examined. When the equivalent ratio was 1.5:1, the best yield could be gained (Table S2, entries 1–5). Screening of the temperature revealed that 80 °C was the optimal one, increasing or decreasing the temperature showed a negative effect (Table S3, entries 1–5). It is possible that the reaction produced other byproducts under high temperatures and lower oxidation activity under the lower temperature, thus reducing the yield of the desired products. Several other solvents were tried in the reaction (Table S4, entries 1–9), and it was found that none of them had a good effect. The results indicated that DMSO is the best solvent. Finally, the effect of reaction time was also investigated, and the results showed that 8 h was the optimal time (Table 1, entries 9–11). Unfortunately, a slightly decreased yield was obtained when the reaction was exposed to air (Table 1, entry 12). After rigorous experiments, the optimal conditions were established as follows: 1a (0.3 mmol, 1.5 equiv), 2a (0.2 mmol, 1.0 equiv), (NH4)2S2O8 (0.6 mmol, 3.0 equiv), and DMSO (2 mL) at 80 °C for 8 h under an Ar atmosphere.

Table 1. Optimization of Reaction Conditionsa.

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entry oxidant solvent time (h) yieldb (%)
1 (NH4)2S2O8 DMSO 12 89
2c (NH4)2S2O8 DMSO 12 81
3d (NH4)2S2O8 DMSO 12 84
4 K2S2O8 DMSO 12 32
5e TBHP DMSO 12 nr
6 DTBP DMSO 12 nr
7 TBPB DMSO 12 nr
8   DMSO 12 nr
9 (NH4)2S2O8 DMSO 8 94
10 (NH4)2S2O8 DMSO 6 87
11 (NH4)2S2O8 DMSO 4 59
12f (NH4)2S2O8 DMSO 8 78
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a

Reaction conditions: 1a (0.3 mmol, 1.5 equiv), 2a (0.2 mmol, 1.0 equiv), oxidant (0.6 mmol, 3.0 equiv), and solvent (2.0 mL) was allowed to stir at 80 °C for T h under an Ar atmosphere.

b

Isolated yield.

c

10 mol % AgNO3 was used.

d

10 mol % Ag2CO3 was used.

e

70% tert-butyl hydroperoxide (TBHP) in H2O.

f

Under air. nr: no reaction.

Having identified the optimal conditions, we further explored the applicability of this reaction. First, the suitability of a series of α,α-difluoroarylacetic acids 2 was investigated (Scheme 2). As anticipated, substrates 2 with electron-donating or electron-withdrawing substituents on the phenyl rings could react well with 1a, affording products in moderate to good yields (46–94%). In general, α,α-difluoroarylacetic acids bearing electron-donating groups showed better reactivity than those attached with electron-withdrawing groups. To our delight, electron-withdrawing substituents, such as F, Br, and CN, at the para position, proved to be well-tolerated under the standard conditions to afford the corresponding difluorobenzyl benzimidazo[2,1-a]isoquinolin-6(5H)-ones in good yields (56–75%). Br atom at the meta or ortho position led to a slight drop in yields (3ak, 3an), which might be caused by the low stability of the difluoromethyl radicals and steric hindrance. Notably, when 2,2-difluoro-2-(naphthalen-1-yl)acetic acid 2o and 2,2-difluoro-2-(thiophen-2-yl)acetic acid 2p were employed, the transformation could also proceed smoothly, and the products (3ao, 3ap) were obtained in (74%, 39%) yields, respectively. Gratifyingly, aliphatic difluoroacetic acid and α,α-difluoropropanoic acid 2q could also react well to deliver the desired product 3aq (62%) under the current reaction conditions.

Scheme 2. Substrate Scope with Difluoroarylacetic Acid,

Scheme 2

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Reaction conditions: 1a (0.3 mmol, 1.5 equiv), 2a (0.2 mmol. 1.0 equiv), and (NH4)2S2O8 (0.6 mmol, 2.0 equiv) in DMSO (2.0 mL) at 80 °C for 8 h under an Ar atmosphere.

Isolated yield.

Encouraged by the above results, we then examined the scope of N-methacryloyl-2-phenylbenzoimidazole 1 (Scheme 3). Pleasingly, N-methacryloyl-2-arylbenzoimidazoles bearing different substituents on the aromatic ring also could react well with 2a to give the corresponding target products (3ba-3ma) in good yields (59–87%). Benzimidazole derivatives with an electron-donating group or an electron-withdrawing group at different positions of the 2-phenyl moiety in substrate 1 readily could react, providing the desired benzimidazo[2,1-a]isoquinolin-6(5H)-ones 3 in moderate to good yields. This transformation also proceeded well when the ortho-substituted or meta-substituted 2-phenyl ring benzimidazole derivatives were employed, affording the corresponding products (3ia–3la, 66–74%) in a relatively high yield. The results showed that the reaction was not affected by the steric hindrance of the substrate. When the benzene ring of benzimidazole was substituted with 4,5-di(Me), it could also react well to give the corresponding products (3ma) in satisfactory yield (59%). To our great delight, it could also accomplish this transformation in the presence of a naphthyl group or a thienyl group on the 2-phenyl ring of benzimidazole derivatives, the cyclization products were isolated in good yields (3na, 3oa). Specifically, when N-phenylacryloyl-2-phenylbenzoimidazole 1p was employed as the corresponding product 3pa was obtained in 52% yield. Among all of the new synthetic products, the structure of 3ea was further confirmed by X-ray crystallography.

Scheme 3. Substrate Scope with 2-Arylbenzoimidazoles,

Scheme 3

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Reaction conditions: 1a (0.3 mmol, 1.5 equiv), 2a (0.2 mmol, 1.0 equiv), and (NH4)2S2O8 (0.6 mmol, 2.0 equiv) in DMSO (2.0 mL) at 80 °C for 8 h under an Ar atmosphere.

Isolated yield.

To gain further insight into the reaction mechanism, several control experiments were carried out. First, the oxidative decarboxylation reaction of N-methacryloyl-2-phenylbenzoimi dazole 1a with phenylacetic acid 2r could proceed under standard conditions (Scheme 4a). These results indicate that the CF2 group of α,α-difluorophenylacetic acid has little influence on the transformation process, and corresponding products 3ar can be obtained in a relatively high yield (68%). When the radical scavengers 2,2,6,6-tetramethylpiperidin-1-yl-oxidanyl (TEMPO) and 2,6-di-tert-butyl-butyl-4-methylphenol (BHT) were added to the optimized reactions of 1a and 2a, respectively, the desired product 3aa was not observed (Scheme 4b,c). Instead, the generation of a TEMPO adduct 4 was detected by liquid chromatography–mass spectrometry (LC-MS). This result indicates that a radical pathway might be engaged in.

Scheme 4. Control Experiments,

Scheme 4

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Reaction conditions: (a) 1a (0.3 mmol, 1.5 equiv), 2r (0.2 mmol, 1.0 equiv), and (NH4)2S2O8 (0.6 mmol, 2.0 equiv) in DMSO (2.0 mL) at 80 °C for 8 h under an Ar atmosphere. (b) 2r was changed to 2a, 1,1-dlphenylethylene (2.0 equiv) or BHT (2.0 equiv) was used. (c) 2r was changed to 2a, TEMPO (2.0 equiv) was used.

Isolated yield.

Based on the above experimental results as well as previous literature reports,22 a plausible reaction pathway is proposed (Scheme 5). Initially, in the presence of (NH4)2S2O8, a radical intermediate A is generated from α,α-difluorophenylacetic acid 2avia a decarboxylation process, with the release of carbon dioxide. Next, the intermediate A attacks the alkenyl moiety in substrate 1a to deliver a more stable tertiary radical B. Subsequently, intramolecular cyclization of radical B occurs quickly to form intermediate C. Finally, intermediate C undergoes SET oxidation to produce the corresponding carbocation D, followed by deprotonation to give the product 3aa.

Scheme 5. Plausible Mechanism of Reaction between 1a and 2a.

Scheme 5

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Reaction conditions: (a) 1a (0.3 mmol, 1.5 equiv), 2a (0.2 mmol, 1.0 equiv), and (NH4)2S2O8 (0.6 mmol, 2.0 equiv) in DMSO (2.0 mL) at 80 °C for 8 h under an Ar atmosphere. A, B were the radicals produced in the reaction. C, D were the intermediates produced in the reaction. 3aa was the desired product.

Conclusions

In summary, we developed an efficient and simple synthesis scheme for the construction of difluoroarymethyl-substituted benzimidazo[2,1-a]isoquinolin-6(5H)-ones through direct decarboxylative coupling of 2-arylbenzoimidazoles with α,α-difluorophenylacetic acid. Remarkably, the merits of this method make this reaction particularly beneficial for further transformation with the wide reactant scope under the transition-metal-free and base-free conditions. Moreover, mechanistic studies confirmed that difluoroarylmethylation occurs via a radical mechanism. Further synthetic application of this strategy is ongoing in our laboratory.

Experimental Section

General Information

Unless otherwise mentioned, solvents and reagents were purchased from commercial sources and were used as received. All air- and moisture-sensitive manipulations were performed using oven-dried glassware (120 °C for a minimum of 15 h), including standard Schlenk techniques under an atmosphere of argon. Flash column chromatography was performed using 100–200 mesh silica gel. Analytical thin-layer chromatography was performed using glass plates precoated with silica gel (GF254). Visualization was done by ultraviolet fluorescence (λ = 254 nm). 1H NMR and 13C NMR spectra were recorded on a Bruker DPX-400 spectrometer with CDCl3 as the solvent and TMS as an internal standard. Melting points were measured using a WC-1 microscopic apparatus and were uncorrected. X-ray analysis was performed with a single-crystal X-ray diffractometer (Gemini E) purchased from Agilent. The mass spectra were indicated by GC-MS (Thermo Fisher Scientific DSQ II). High-resolution mass spectrometry (HRMS) data were obtained on an Agilent Technologies 1290–6540 UHPLC/accurate mass quadrupole time-of flight (Q-TOF) LC/MS using ESI as an ion source. Measured values were reported to 4 decimal places of the calculated value.

General Procedure for the Construction of 3aa–3aq and 3ba–3oa

To a 25 mL oven-dried Schlenk tube containing a magneton were added 1 (0.3 mmol, 1.5 equiv), 2 (0.2 mmol, 1.0 equiv), (NH4)2S2O8 (0.6 mmol, 3.0 equiv), DMSO (2mL). Then, the mixture was charged with Ar and stirred at 80 °C. After 8 h, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed under vacuum, and the residue was subjected to column chromatography on silica gel (petroleum ether/ethyl acetate = 8/1∼5/1) to get the desired products 3aa–3ar and 3ba–3oa.

5-(2,2-Difluoro-2-phenylethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3aa)

White solid (yield 72.97 mg, 94%), mp 102–103 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.50–8.43 (m, 1H), 8.27–8.20 (dd, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.48–7.33 (m, 5H), 7.08–6.96 (m, 5H), 3.58–3.41 (m, 1H), 3.02–2.88 (m, 1H), 1.66 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.4, 149.2, 143.6, 139.2, 135.3 (t, JC–F = 26.3 Hz), 131.1, 130.9, 129.3 (t, JC–F = 2.0 Hz), 127.7, 127.5, 126.8, 125.5, 125.4, 125.1, 124.4 (t, JC–F = 6.1 Hz), 123.5, 122.1, 121.1, 119.4, 118.6, 115.4, 49.2 (t, JC–F = 27.3 Hz), 45.3 (t, JC–F = 3.0 Hz), 30.9. 19F NMR (376 MHz, chloroform-d) δ −89.29 (d, J = 248.5 Hz, 1F), −90.76 (d, J = 248.5 Hz, 1F). HRMS (ESI) m/z: calcd for C24H18F2N2O [M + H]+ 389.1460, found: 389.1462.

5-(2,2-Difluoro-2-(p-tolyl)ethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ab)

White solid (yield 63.54 mg, 79%), mp 156–157 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.52–8.44 (m, 1H), 8.17–8.12 (m, 1H), 7.82–7.75 (m, 1H), 7.59–7.47 (m, 3H), 7.44–7.34 (m, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.0 Hz, 2H), 3.57–3.42 (m, 1H), 3.09–2.97 (m, 1H), 1.87 (s, 3H), 1.69 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.5, 149.3, 143.5, 140.0, 139.3, 131.7 (t, JC–F = 26.3 Hz), 131.2, 131.0, 128.3, 127.7, 127.2, 125.5, 125.2, 124.7 (q, JC–F = 6.1 Hz), 123.8, 122.3, 121.3, 119.4, 118.9, 115.45, 49.4 (t, JC–F = 26.3 Hz), 49.1, 45.5 (d, JC–F = 5.1Hz), 31.4, 20.5. 19F NMR (376 MHz, chloroform-d) δ −84.89 (d, J = 247.8 Hz, 1F), −92.82 (d, J = 247.8 Hz, 1F). HRMS (ESI) m/z: calcd for C25H20F2N2O [M + H]+ 403.1617, found: 403.1618.

5-(2-(4-Ethylphenyl)-2,2-difluoroethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ac)

White solid (yield 75.74 mg, 91%), mp 130–131 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.48–8.44 (m, 1H), 8.21–8.08 (m, 1H), 7.84–7.72 (m, 1H), 7.55–7.45 (m, 3H), 7.42–7.33 (m, 2H), 6.91 (d, J = 8.0Hz, 2H), 6.82 (d, J = 8.0Hz, 2H), 3.59–3.45 (m, 1H), 3.12–2.94 (m, 1H), 2.22 (q, J = 8.0 Hz, 2H), 1.69 (s, 3H), 0.93 (t, J = 8.0 Hz, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.4, 149.2, 146.0 (t, JC–F = 2.0 Hz), 143.5, 139.2, 132.1 (t, JC–F = 26.3 Hz), 131.1, 130.9, 127.6, 127.1 (d, JC–F = 8.1 Hz), 125.5 (t, JC–F = 5.1 Hz), 125.1, 124.7 (t, JC–F = 6.1 Hz), 123.7, 122.2, 121.3 (d, JC–F = 2.0 Hz), 119.4, 118.9, 115.4, 49.2 (q, JC–F = 27.3 Hz), 45.5 (d, JC–F = 5.1 Hz), 31.4, 27.8, 14.5. 19F NMR (376 MHz, chloroform-d) δ −85.64 (d, J = 247.8 Hz, 1F), −91.68 (d, J = 247.4 Hz, 1F). HRMS (ESI) m/z: calcd for C26H22F2N2O [M + H]+ 417.1773, found: 417.1769.

5-(2,2-Difluoro-2-(4-methoxyphenyl)ethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ad)

White solid (yield 70.25 mg, 84%), mp 141–142 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.47–8.44 (m, 1H), 8.16–8.11 (m, 1H), 7.80–7.74 (m, 1H), 7.55–7.45 (m, 3H), 7.44–7.34 (m, 2H), 6.89 (d, J = 8.0 Hz, 2H), 6.43 (d, J = 8.0 Hz, 2H), 3.57–3.40 (m, 1H), 3.38 (s, 3H), 3.08–2.88 (m, 1H), 1.67 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.6, 160.5, 149.5, 143.8, 139.6, 131.3 (d, JC–F = 16.2 Hz), 127.9, 127.4, 127.3, 127.0, 126.8, 126.5 (t, JC–F = 6.1 Hz), 125.7, 125.4, 124.0, 122.5, 121.6, 119.6, 119.1, 115.7, 113.2, 54.9, 49.7 (dd, JC–F = 26.3Hz, 4.0 Hz), 45.7 (d, JC–F = 5.1 Hz), 31.5. 19F NMR (376 MHz, chloroform-d) δ −83.63 (d, J = 247.8 Hz, 1F), −91.86 (d, J = 247.8 Hz, 1F). HRMS (ESI) m/z: calcd for C25H20F2N2O2 [M + H]+ 419.1566, found: 419.1567.

5-(2,2-Difluoro-2-(4-fluorophenyl)ethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ae)

White solid (yield 60.92 mg, 75%), mp 118–119 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.49–8.43 (m, 1H), 8.27–8.14 (m, 1H), 7.84–7.78 (m, 1H), 7.53–7.37 (m, 5H), 7.08–7.00 (m, 2H), 6.74 (t, J = 8.0 Hz, 2H), 3.57–3.44 (m, 1H), 3.07–2.94 (m, 1H), 1.72 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.4, 164.3, 161.8, 149.2, 143.6, 139.1, 131.0 (d, JC–F = 2.0 Hz), 127.8, 126.9 (t, JC–F = 3.0 Hz), 126.8 (q, JC–F = 3.0 Hz), 126.6, 125.7 (t, JC–F = 11.1 Hz), 125.3, 123.3, 122.2, 120.8, 119.5, 118.4, 115.3, 115.0, 114.8, 49.4 (t, JC–F = 28.3 Hz), 45.4 (q, JC–F = 2.0 Hz), 31.1 19F NMR (376 MHz, chloroform-d) δ −87.93 (d, J = 250.0 Hz, 1F), −90.13 (d, J = 250.9 Hz, 1F), −110.75 (s, 1F). HRMS (ESI) m/z: calcd for C24H17F3N2O [M + H]+ 407.1366, found: 407.1368.

5-(2-(4-Bromophenyl)-2,2-difluoroethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3af)

White solid (yield 71.77 mg, 77%), mp 146–147 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.48–8.43 (m, 1H), 8.21–8.15 (m, 1H), 7.84–7.77 (m, 1H), 7.50–7.49 (m, 2H), 7.48–7.40 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 3.55–3.42 (m, 1H), 3.06–2.94 (m, 1H), 1.71 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.4, 149.1, 143.6, 139.0, 134.2 (t, JC–F = 26.3 Hz), 131.1,131.0, 127.8, 127.0, 126.3 (t, JC–F = 6.1 Hz), 125.6, 125.5, 124.3 (t, JC–F = 2.0 Hz), 123.2, 122.2, 120.8, 119.6, 118.4, 115.3, 49.2 (q, JC–F = 27.3 Hz), 45.4 (q, JC–F = 2.0 Hz), 31.1. 19F NMR (376 MHz, chloroform-d) δ −88.25 (d, J = 250.42 Hz, 1F), −91.67 (d, J = 250.42 Hz, 1F). HRMS (ESI) m/z: calcd for C24H17BrF2N2O [M + H]+ 467.0565, found: 467.0564.

4-(1,1-Difluoro-2-(5-methyl-6-oxo-5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinolin-5-yl)ethyl)benzonitrile (3ag)

White solid (yield 46.27 mg, 56%), mp 169–170 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.50–8.43 (m, 1H), 8.18–8.12 (m, 1H), 7.85–7.80 (m, 1H), 7.52–7.40 (m, 5H), 7.34 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 3.50 (m, 1H), 3.03 (m, 1H), 1.73 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.5, 149.2, 143.8, 139.9 (t, JC–F = 26.3 Hz), 139.0, 131.8, 131.4, 131.1, 128.3, 127.1, 126.4, 126.0, 125.9, 125.7 (t, JC–F = 6.1 Hz), 123.0, 122.5, 120.5, 120.0, 118.1, 117.5, 115.5, 113.8 (d, JC–F = 2.0 Hz), 49.3 (t, JC–F = 26.3 Hz), 45.6 (q, JC–F = 2.0 Hz), 31.3. 19F NMR (376 MHz, chloroform-d) δ −89.18 (d, J = 253.0 Hz, 1F), −92.46 (d, J = 250.4 Hz, 1F). HRMS (ESI) m/z: calcd for C25H17F2N3O [M + H]+ 414.1413, found: 414.1427.

5-(2-([1,1′-Biphenyl]-4-yl)-2,2-difluoroethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ah)

White solid (yield 76.12 mg, 82%), mp 186–187 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.50–8.44 (m, 1H), 8.19–8.14 (m, 1H), 7.78–7.72 (m, 1H), 7.55–7.47 (m, 3H), 7.37–7.28 (m, 5H), 7.24–7.16 (m, 4H), 7.08 (d, J = 8.0 Hz, 2H), 3.66–3.52 (m, 1H), 3.15–3.04 (m, 1H), 1.72 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.7, 149.5, 143.8, 142.9 (d, JC–F = 2.0 Hz), 139.8, 139.5, 134.0 (t, JC–F = 27.3 Hz), 131.3 (d, JC–F = 8.1 Hz), 128.6, 128.0, 127.7, 127.4, 127.1, 126.7, 125.8 (d, JC–F = 2.0 Hz), 125.6, 125.4 (t, JC–F = 7.1 Hz), 124.0, 122.6, 121.5, 119.8, 119.1, 115.6, 49.5 (t, JC–F = 26.3 Hz), 45.8 (d, JC–F = 4.0 Hz), 31.7. 19F NMR (376 MHz, chloroform-d) δ −86.88 (d, J = 248.5 Hz, 1F), −91.20 (d, J = 248.9 Hz, 1F). HRMS (ESI) m/z: calcd for C30H22F2N2O [M + H]+ 465.1773, found: 465.1779.

5-(2,2-Difluoro-2-(m-tolyl)ethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ai)

Yellow oily liquid (yield 61.93 mg, 77%), purified by column chromatography with petroleum ether/ethyl acetate (8:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.55–8.43 (m, 1H), 8.26–8.13 (m, 1H), 7.88–7.72 (m, 1H), 7.56–7.33 (m, 5H), 6.93 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 2H), 3.59–3.42 (m, 1H), 3.10–2.92 (m, 1H), 2.07 (s, 3H), 1.70 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.5, 149.3, 143.6, 139.3, 137.6, 135. 0(t, JC–F = 25.3 Hz), 131.2, 130.9, 130.2 (t, JC–F = 2.0 Hz), 127.7 (t, JC–F = 4.0 Hz), 127.0, 125.5 (d, JC–F = 14.1 Hz), 125.2, 125.2 (t, JC–F = 6.1Hz), 123.7, 122.3, 121.9 (t, JC–F = 6.1 Hz), 121.2, 119.4, 118.8, 115.5, 49.4 (q, JC–F = 28.3 Hz), 45.5 (q, JC–F = 2.0 Hz), 31.24, 20.8. 19F NMR (376 MHz, chloroform-d) δ −87.43 (d, J = 247.8 Hz, 1F), −91.4 (d, J = 247.4 Hz, 1F). HRMS (ESI) m/z: calcd for C25H20F2N2O [M + H]+ 403.1617, found: 403.1617.

5-(2,2-Difluoro-2-(3-methoxyphenyl)ethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3aj)

White solid (yield 66.07 mg, 79%), mp 102–103 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.54–8.43 (m, 1H), 8.27–8.18 (m, 1H), 7.84–7.72 (m, 1H), 7.58–7.32 (m, 5H), 6.96 (t, J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.75–6.42 (m, 2H), 3.5 (s, 3H), 3.57–3.42 (m, 1H), 3.11–2.91 (m, 1H), 1.71 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.5, 158.8, 149.3, 143.6, 139.3, 136.6 (t, JC–F = 26.3 Hz), 131.1 (d, JC–F = 18.2 Hz), 129.0, 127.7, 127.0, 125.6 (d, JC–F = 6.1 Hz), 125.2, 123.4, 122.3, 121.0, 119.4, 118.5, 116.9 (t, JC–F = 6.1 Hz), 115.5, 115.0 (d, JC–F = 2.0 Hz), 110.2 (t, JC–F = 7.1 Hz), 54.8, 49.3 (t, JC–F = 28.3 Hz), 45.5 (q, JC–F = 2.0 Hz), 31.2. 19F NMR (376 MHz, chloroform-d) δ −87.84 (d, J = 247.4 Hz, 1F), −91.37 (d, J = 247.8 Hz, 1F). HRMS (ESI) m/z: calcd for C25H20F2N2O2 [M + H]+ 419.1566, found: 419.1564.

5-(2-(3-Bromophenyl)-2,2-difluoroethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ak)

Yellow oily liquid (yield 39.15 mg, 42%), purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.52–8.44 (m, 1H), 8.29–8.18 (m, 1H), 7.88–7.76 (m, 1H), 7.59–7.32 (m, 5H), 7.22–7.10 (m, 2H), 7.01–6.88 (m, 2H), 3.57–3.42 (m, 1H), 3.06–2.95 (m, 1H), 1.72 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.7, 149.4, 144.0, 139.2, 137.7 (t, JC–F = 26.3 Hz), 132.9 131.4, 131.3, 129.7, 128.3 (t, JC–F = 7.1 Hz), 127.2, 126.1, 126.0, 125.7, 123.6 (t, JC–F = 6.1 Hz), 123.1, 122.6, 122.4, 120.6, 119.9, 115.8, 49.5 (t, JC–F = 27.3 Hz), 45.7 (t, JC–F = 3.0 Hz), 31.4. 19F NMR (376 MHz, chloroform-d) δ −89.60 (d, J = 250.8 Hz, 1F), −90.64 (d, J = 250.4 Hz, 1F). HRMS (ESI) m/z: calcd for C24H17BrF2N2O [M + H]+ 467.0565, found: 467.0567.

5-(2,2-Difluoro-2-(o-tolyl)ethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3al)

White solid (yield 57.10 mg, 71%), mp 126–127 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.52–8.43 (m, 1H), 8.21–8.16 (m, 1H), 7.82–7.75 (m, 1H), 7.54–7.45 (m, 3H), 7.44–7.32 (m, 2H), 6.94 (d, J = 7.6 Hz, 1H), 6.92–6.81 (m, 1H), 6.78–6.68 (m, 2H), 3.64–3.344 (m, 1H), 3.12–2.83 (m, 1H), 2.37 (s, 3H), 1.70 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.4, 149.5, 143.9, 139.7, 135.6 (d, JC–F = 4.0 Hz), 133.4 (t, JC–F = 24.0 Hz), 131.4 (d, JC–F = 31.3 Hz), 129.6, 127.9, 127.1, 125.8 (d, JC–F = 3.0 Hz), 125.3 (d, JC–F = 3.0 Hz), 125.1 (t, JC–F = 9.1 Hz), 124.5, 122.5, 122.1, 119.67, 115.6, 48.3 (d, JC–F = 27.3 Hz), 45.6 (d, JC–F = 4.0 Hz), 31.5, 20.0 (t, JC–F = 3.0 Hz). 19F NMR (376 MHz, chloroform-d) δ −86.91 (d, J = 251.9 Hz, 1F), −89.30 (d, J = 251.9 Hz, 1F). HRMS (ESI) m/z: calcd for C25H20F2N2O [M + H]+ 403.1617, found: 403.1615.

5-(2,2-Difluoro-2-(2-methoxyphenyl)ethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3am)

White solid (yield 61.89 mg, 73%), mp 159–160 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.41–8.32 (m, 1H), 8.21–8.17 (m, 1H), 7.81–7.76 (m, 1H), 7.42–7.32 (m, 5H), 6.99–6.84 (m, 1H), 6.67–6.52 (m, 2H), 6.46–6.32 (m, 1H), 3.86 (s, 3H), 3.77–3.52 (m, 1H), 3.34–3.12 (m, 1H), 1.72 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.7, 156.6 (t, JC–F = 5.0 Hz), 149.7, 143.9, 139.8, 131.4, 131.0, 127.9, 127.2, 125.8 (t, JC–F = 9.1 Hz), 125.6, 125.4, 123.2 (q, JC–F = 9.1 Hz), 122.8, 122.6, 120.7, 120.1, 119.7, 118.3, 115.8, 111.3, 55.7, 47.7 (q, JC–F = 26.3 Hz), 45.7 (q, JC–F = 4.0 Hz), 31.1. 19F NMR (376 MHz, chloroform-d) δ −88.02 (d, J = 253.8 Hz, 1F), −88.87 (d, J = 253.0 Hz, 1F). HRMS (ESI) m/z: calcd for C25H20F2N2O2 [M + H]+ 419.1566, found: 419.1569.

5-(2-(2-Bromophenyl)-2,2-difluoroethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3an)

Colorless oily liquid (yield 42.88 mg, 46%), purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.54–8.37 (m, 1H), 8.32–8.21 (m, 1H), 7.88–7.77 (m, 1H), 7.49–7.32 (m, 6H), 6.99–6.72 (m, 3H), 3.77–3.54 (m, 1H), 3.49–3.33 (m, 1H), 1.75 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.4, 158.8, 149.2, 143.6, 139.2, 136.5(t, JC–F = 26.3 Hz), 134.2, 130.9 (t, JC–F = 19.2 Hz), 128.9, 127.6, 126.9, 125.5 (q, JC–F = 11.1 Hz), 125.1, 123.3, 122.2, 120.9, 119.4 (d, JC–F = 3.0 Hz), 118.5, 116.8(t, JC–F = 6.1 Hz), 115.4 (d, JC–F = 11.1 Hz), 114.9 (t, JC–F = 2.0 Hz), 110.1 (t, JC–F = 7.1 Hz), 49.2 (t, JC–F = 27.3 Hz), 45.4 (q, JC–F = 2.0 Hz), 31.1. 19F NMR (376 MHz, chloroform-d) δ −87.25 (d, J = 255.7 Hz, 1F), −91.09 (d, J = 255.7 Hz, 1F). HRMS (ESI) m/z: calcd for C24H17BrF2N2O [M + H]+ 467.0565, found: 467.0589.

5-(2,2-Difluoro-2-(naphthalen-1-yl)ethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ao)

White solid (yield 62.92 mg, 74%), mp 115–116 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.45–8.42 (m, 1H), 8.09 (d, J = 8.0Hz, 1H), 8.04–7.93 (m, 1H), 7.84–7.76 (m, 1H), 7.69–7.66 (m, 1H), 7.62–7.56 (m, 1H), 7.51–7.28 (m, 8H), 6.97 (t, J = 1.2 Hz, 1H), 3.86–3.74 (m, 1H), 3.34–3.12 (m, 1H), 1.67 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.0, 149.2, 143.5, 139.1, 133.5, 131.0, 130.7 (t, JC–F = 3.0 Hz), 130.4, 130.2, 128.8(t, JC–F = 3.0 Hz), 128.6, 127.6, 126.7 (d, JC–F = 8.1 Hz), 125.6 (t, JC–F = 7.1 Hz), 125.4, 125.1, 124.3, 124.1 (t, JC–F = 4.0 Hz), 123.8, 123.5 (t, JC–F = 10.1 Hz), 122.1, 121.8, 119.3, 115.4, 48.7 (t, JC–F = 26.3 Hz), 45.4 (t, JC–F = 3.0 Hz), 31.1. 19F NMR (376 MHz, chloroform-d) δ −85.24 (d, J = 253.4 Hz, 1F), −87.57 (d, J = 253.4 Hz, 1F). HRMS (ESI) m/z: calcd for C28H20F2N2O [M + H]+ 439.1617, found: 439.1622.

5-(2,2-Difluoro-2-(thiophen-2-yl)ethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ap)

Yellow oily liquid (yield 30.74 mg, 39%), purified by column chromatography with petroleum ether/ethyl acetate (6:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.51–8.42 (m, 1H), 8.35–8.25 (m, 1H), 7.84–7.77 (m, 1H), 7.53–7.37 (m, 5H), 7.16–7.11 (m, 1H), 6.90–6.84 (m, 1H), 6.78–6.62 (m, 1H), 3.72–3.54 (m, 1H), 3.19–3.02 (m, 1H), 1.75 (s, 3H).13C{1H} NMR (101 MHz, chloroform-d) δ 171.7, 149.6, 144.0, 139.5, 138.0 (t, JC–F = 31.3 Hz), 131.3 (t, JC–F = 26.3 Hz), 127.9, 127.2 (t, JC–F = 2.0 Hz), 127.0, 126.6 (t, JC–F = 6.1 Hz), 125.9 (d, JC–F = 5.1 Hz), 125.5, 122.4, 122.1, 119.7 (d, JC–F = 4.0 Hz), 117.3, 115.7, 49.7 (t, JC–F = 26.3 Hz), 45.7 (t, JC–F = 2.0 Hz), 31.1. 19F NMR (376 MHz, chloroform-d) δ −79.30 (dd, J = 312.1 Hz, 255.7 Hz, 1F), −84.28 (dd, J = 627.9 Hz, 255.7 Hz, 1F). HRMS (ESI) m/z: calcd for C22H16F2N2OS [M + H]+ 395.1024, found: 395.1024.

(S)-5-(2,2-Difluoropropyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3aq)

Colorless oily liquid (yield 40.47 mg, 62%), purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.58–8.48 (m, 1H), 8.40–8.31 (m, 1H), 7.87–7.78 (m, 1H), 7.59–7.40 (m, 5H), 3.23 (m, 1H), 2.82–2.56 (m, 1H), 1.72 (s, 3H), 1.33 (t, J = 18.8 Hz, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 172.18, 149.62, 144.08, 140.0, 131.4 (d, JC–F = 23.2 Hz), 127.9, 126.7, 126.0, 125.9, 125.5, 124.9, 122.5(d, JC–F = 17.2 Hz), 120.2, 119.8, 115.7, 48.3 (t, JC–F = 24.2 Hz), 45.6 (t, JC–F = 3.0 Hz), 31.0, 24.7 (t, JC–F = 27.3 Hz). 19F NMR (376 MHz, chloroform-d) δ −86.2 (d, J = 7.5 Hz, 2F). HRMS (ESI) m/z: calcd for C19H16F2N2O [M + H]+ 327.3541, found: 327.3546.

(S)-5-Methyl-5-phenethylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ar)

Yellow oily liquid (yield 47.93 mg, 68%), purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.57–8.48 (m, 1H), 8.35–8.28 (m, 1H), 7.84–7.80 (m, 1H), 7.67–7.59 (m, 1H), 7.55–7.49 (m, 2H), 7.48–7.32 (m, 2H), 7.16–7.05 (m, 2H), 7.03–6.97 (m, 1H), 6.95–6.89 (m, 2H), 2.86–2.75 (m, 1H), 2.35–2.16 (m, 3H), 1.74 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 172.9, 149.7, 144.0, 141.3, 140.2, 132.0, 131.3, 128.2, 128.1, 127.8, 126.0, 126.0, 126.0, 125.8, 125.5, 123.2, 119.7, 115.7, 49.2, 44.2, 31.6, 29.4.

5-(2,2-Difluoro-2-phenylethyl)-3,5-dimethylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ba)

White solid (yield 69.97 mg, 87%), mp 132–133 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.32 (d, J = 8.0 Hz, 1H), 8.23–8.20 (m, 1H), 7.81–7.75 (m, 1H), 7.44–7.38 (m, 2H), 7.28–7.24(m, 1H), 7.16 (s, 1H), 7.08–7.02 (m, 5H), 3.58–3.47 (m, 1H), 3.06–2.96 (m, 1H), 2.38 (s, 3H), 1.69 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.7, 149.5, 143.7, 141.5, 139.1, 135.5 (t, JC–F = 26.3 Hz), 131.1, 129.3 (t, JC–F = 2.0 Hz), 128.8, 127.7, 127.4, 125.5, 124.9, 124.4 (t, JC–F = 6.1Hz), 123.6, 121.1, 119.6, 119.2, 118.7, 115.4, 49.2 (t, JC–F = 28.3 Hz), 45.4 (t, JC–F = 3.0 Hz), 31.2, 21.6. 19F NMR (376 MHz, chloroform-d) δ −89.12 (d, J = 249.7 Hz, 1F), −90.75 (d, J = 249.7 Hz, 1F). HRMS (ESI) m/z: calcd for C25H20F2N2O [M + H]+ 403.1617, found: 403.1625.

5-(2,2-Difluoro-2-phenylethyl)-3-methoxy-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ca)

Colorless oily liquid (yield 69.41 mg, 83%), purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.38 (d, J = 8.0 Hz, 1H), 8.22–8.17 (m, 1H), 7.78–7.72 (m, 1H), 7.77–7.74 (m, 2H), 7.10–6.98 (m, 6H), 6.87 (d, J = 4.0 Hz, 1H), 3.86 (s, 3H), 3.59–3.46 (m, 1H), 3.03–2.92 (m, 1H), 1.69 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.5, 161.8, 149.4, 143.7, 141.2, 135.5 (t, JC–F = 26.3 Hz), 131.0, 129.3 (t, JC–F = 2.0 Hz), 127.8, 127.5, 125.5, 124.7, 124.4 (t, JC–F = 6.1 Hz), 123.5, 121.1, 119.0, 118.7, 115.3, 115.2, 113.6, 112.5, 55.2, 49.4 (t, JC–F = 27.3 Hz), 45.6(t, JC–F = 3.0 Hz), 31.3. 19F NMR (376 MHz, chloroform-d) δ −89.62 (d, J = 248.9 Hz, 1F), −90.50 (d, J = 249.3 Hz, 1F). HRMS (ESI) m/z: calcd for C25H20F2N2O2 [M + H]+ 419.1566, found: 419.1566.

5-(2,2-Difluoro-2-phenylethyl)-3-fluoro-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3da)

White solid (yield 59.29 mg, 73%), mp 134–135 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.46 (m, 1H), 8.25–8.18 (m, 1H), 7.81–7.73 (m, 1H), 7.46–7.33 (m, 2H), 7.22–7.15 (m, 1H), 7.14–7.02 (m, 6H), 3.61–3.44 (m, 1H), 3.02–2.86 (m, 1H), 1.71 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.30, 165.9, 163.4, 148.9, 143.9, 142.4 (d, JC–F = 8.1 Hz), 135.7 (t, JC–F = 26.3 Hz), 131.4, 130.0 (t, JC–F = 2.0 Hz), 128.4 (t, JC–F = 9.1 Hz), 126.1, 125.6, 124.8 (t, JC–F = 6.1Hz), 123.8, 121.4, 119.8, 119.1 (d, JC–F = 2.0 Hz), 118.9, 116.3, 116.1, 115.8, 114.3, 114.1, 49.8 (t, JC–F = 27.3 Hz), 46.0 (q, JC–F = 2.0 Hz), 31.4. 19F NMR (376 MHz, chloroform-d) δ −90.12 (d, J = 248.9 Hz, 1F), −90.98 (d, J = 249.3 Hz, 1F), −107.02 (s, 1F). HRMS (ESI) m/z: calcd for C24H17F3N2O [M + H]+ 407.1366, found: 407.1366.

3-Chloro-5-(2,2-difluoro-2-phenylethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ea)

White solid (yield 62.42 mg, 78%), mp 136–137 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.38 (d, J = 8.0 Hz, 1H), 8.26–8.20 (m, 1H), 7.82–7.76 (m, 1H), 7.47–7.36 (m, 4H), 7.15–7.02 (m, 5H), 3.59–3.45 (m, 1H), 3.01–2.88(m, 1H), 1.70 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.4, 149.0, 144.2, 141.5, 137.9, 135.9(t, JC–F = 25.3 Hz), 131.7, 130.2 (t, JC–F = 2.0 Hz), 128.9, 128.5, 127.8, 127.6, 126.4, 126.1, 125.0 (t, JC–F = 6.1Hz), 124.1, 121.6 (d, JC–F = 15.1Hz), 120.2, 119.2, 116.1, 50.2, 49.9 (t, JC–F = 27.3 Hz), 46.1 (t, JC–F = 3.0 Hz), 31.5. 19F NMR (376 MHz, chloroform-dchloroform-d) δ −89.58 (d, J = 250.0 Hz, 1F), −91.02 (d, J = 249.7 Hz, 1F). HRMS (ESI) m/z: calcd for C24H17ClF2N2O [M + H]+ 423.1070, found: 423.1073.

3-Bromo-5-(2,2-difluoro-2-phenylethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3fa)

White solid (yield 70.84 mg, 76%), mp 147–148 °C, purified by column chromatography with petroleum ether/ethyl acetate (8:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 12.0 Hz, 1H), 8.26–8.20 (m, 1H), 7.83–7.76 (m, 1H), 8.01–7.56 (m, 1H), 7.53 (d, J = 4.0 Hz, 1H), 7.48–7.38 (m, 2H), 7.14–7.06 (m, 5H), 3.61–3.47 (m, 1H), 8.26–8.20 (m, 1H), 1.71 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 170.8, 148.4, 143.6, 141.0, 135.3 (t, JC–F = 25.3 Hz), 131.1(d, JC–F = 8.1 Hz), 130.1, 129.6 (t, JC–F = 2.0 Hz), 127.9, 127.0, 125.8, 125.5 (t, JC–F = 11.1 Hz), 124.4 (t, JC–F = 6.1 Hz), 123.4, 121.3, 121.0, 119.5, 118.5, 115.5, 49.3 (t, JC–F = 27.3 Hz), 45.4 (t, JC–F = 3.0 Hz), 30.9. 19F NMR (376 MHz, chloroform-d) δ −89.29 (d, J = 250.0 Hz, 1F), −91.25 (d, J = 249.7 Hz, 1F). HRMS (ESI) m/z: calcd for C24H17BrF2N2O [M + H]+ 467.0565, found: 467.0581.

5-(2,2-Difluoro-2-phenylethyl)-5-methyl-6-oxo-5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline-3-carbonitrile (3ga)

White solid (yield 61.97 mg, 75%), mp 196–197 °C, purified by column chromatography with petroleum ether/ethyl acetate (5:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.55 (d, J = 8.0 Hz, 1H), 8.30–8.25 (m, 1H), 7.87–7.80 (m, 1H), 7.74–7.67 (m, 2H), 7.51–7.43 (m, 2H), 7.18–7.06 (m, 5H), 3.66–3.48 (m, 1H), 3.06–2.72 (m, 1H), 1.74 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 170.3, 147.3, 143.6, 140.1, 135.3 (t, JC–F = 26.3 Hz), 131.2 (d, JC–F = 4.0 Hz), 130.7, 129.8 (t, JC–F = 2.0 Hz), 128.09, 126.3, 126.3, 126.2 (d, JC–F = 3.0 Hz), 124.35(t, JC–F = 6.1 Hz), 123.4, 121.0, 120.1, 118.6, 117.8, 115.7, 114.2, 49.3 (t, JC–F = 27.3 Hz), 45.5 (t, JC–F = 2.0 Hz), 30.7. 19F NMR (376 MHz, chloroform-d) δ −89.58 (d, J = 249.7 Hz, 1F), −91.66 (d, J = 249.7 Hz). HRMS (ESI) m/z: calcd for C25H17F2N3O [M + H]+ 414.1413, found: 414.1392.

5-(2,2-Difluoro-2-phenylethyl)-5-methyl-3-(trifluoromethyl)benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ha)

White solid (yield 62.95 mg, 69%), mp 125–126 °C, purified by column chromatography with petroleum ether/ethyl acetate (7:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.57 (d, J = 8.0 Hz, 1H), 8.30–8.24 (m, 1H), 7.85–7.81 (m, 1H), 7.71–7.63 (m, 2H), 7.50–7.40 (m, 2H), 7.11–7.03 (m, 5H), 3.64–3.50 (m, 1H), 3.09–2.96 (m, 1H), 1.74 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 170.7, 147.8, 143.6, 139.8, 135.2 (t, JC–F = 26.3 Hz), 132.5 (q, JC–F = 32.3 Hz), 131.2, 129.6 (t, JC–F = 2.0 Hz), 128.0, 126.2, 125.9 (d, JC–F = 2.0 Hz), 125.5, 124.7, 124.5 (t, JC–F = 3.0 Hz), 124.4 (t, JC–F = 6.1 Hz), 124.0 (q, JC–F = 4.0 Hz), 123.4, 122.0, 121.0, 119.9, 118.6, 115.6, 49.3 (t, JC–F = 27.3 Hz), 45.6 (t, JC–F = 3.0 Hz), 30.8. 19F NMR (376 MHz, chloroform-d) δ −62.83 (s, 3F), −89.07 (d, J = 250.4 Hz, 1F), −91.33 (d, J = 250.0 Hz, 1F). HRMS (ESI) m/z: calcd for C25H17F5N2O [M + H]+ 457.1334, found: 457.1343.

5-(2,2-Difluoro-2-phenylethyl)-1-fluoro-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ia)

White solid (yield 59.29 mg, 73%), mp 161–162 °C, purified by column chromatography with petroleum ether/ethyl acetate (7:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.27–8.19 (m, 1H), 7.95–7.86 (m, 1H), 7.50–7.39 (m, 3H), 7.28 (d, J = 8.0 Hz, 1H), 7.25–7.17 (m, 1H), 7.12–7.03 (m, 5H), 3.62–3.44 (m, 1H), 3.10–2.88 (m, 1H), 1.73 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.6, 162.0, 159.4, 146.1 (d, JC–F = 8.1 Hz), 144.6 (d, JC–F = 3.0 Hz), 142.5, 136.0 (t, JC–F = 26.3 Hz), 132.2 (d, JC–F = 9.1 Hz), 130.8 (d, JC–F = 2.0 Hz), 130.2 (t, JC–F = 2.0 Hz), 128.6, 126.39 (d, JC–F = 5.1 Hz), 125.08(t, JC–F = 6.1 Hz), 124.14, 123.58(d, JC–F = 3.0 Hz), 121.7, 120.9, 119.3, 116.1 (t, JC–F = 14.1 Hz), 112.4 (d, JC–F = 10.1 Hz), 50.4(d, JC–F = 27.3 Hz), 46.0 (q, JC–F = 2.0 Hz), 32.02. 19F NMR (376 MHz, chloroform-d) δ −89.53 (d, J = 249.3 Hz, 1F), −91.13 (d, J = 248.9 Hz, 1F), −107.45 (s, 1F). HRMS (ESI) m/z: calcd for C24H17F3N2O [M + H]+ 407.1366, found: 407.1367.

5-(2,2-Difluoro-2-phenylethyl)-9-methoxy-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ja)

Yellowish oily liquid (yield 55.20 mg, 66%), purified by column chromatography with petroleum ether/ethyl acetate (7:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.42–8.36 (m, 1H), 7.78 (d, J = 4.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.48–7.41 (m, 3H), 7.15–7.02 (m, 6H), 3.92 (s, 3H), 3.38–3.42 (m, 1H), 3.09–2.95 (m, 1H),1.71 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 172.0, 158.4, 148.4, 138.9, 138.1, 135.7 (t, JC–F = 26.3 Hz), 132.2, 130.7, 129.64, 127.9 (d, JC–F = 17.2 Hz), 127.1, 125.3, 124.8 (t, JC–F = 7.1 Hz), 123.81, 122.7, 121.4, 120.1, 118.9, 114.8, 99.5, 55.9, 49.6 (t, JC–F = 27.3 Hz), 45.7 (d, JC–F = 3.0 Hz), 31.4. 19F NMR (376 MHz, chloroform-d) δ −89.51 (d, J = 248.9 Hz, 1F), −90.93 (d, J = 248.9 Hz, 1F). HRMS (ESI) m/z: calcd for C25H20F2N2O2 [M + H]+ 419.1566, found: 419.1565.

9-Chloro-5-(2,2-difluoro-2-phenylethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ka)

White solid (yield 57.41 mg, 68%), mp 148–149 °C, purified by column chromatography with petroleum ether/ethyl acetate (7:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.45–8.42 (m, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.57–7.45 (m, 3H), 7.36–7.33 (m, 1H), 7.14–6.99 (m, 5H), 3.57–3.44 (m, 1H), 3.08–2.97 (m, 1H), 1.71 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.4, 150.5, 144.7, 139.5, 135.3 (t, JC–F = 26.3 Hz), 131.4, 131.1, 129.7, 129.5 (t, JC–F = 2.0 Hz), 127.8 (d, JC–F = 3.0 Hz), 127.0, 125.7, 125.3, 124.5 (t, JC–F = 6.1Hz), 123.5, 121.8, 121.1, 119.4, 118.6, 116.1, 49.4 (t, JC–F = 27.3 Hz), 45.5 (t, JC–F = 2.0 Hz), 31.1. 19F NMR (376 MHz, chloroform-d) δ −88.87 (d, J = 248,5 Hz, 1F), −91.36 (d, J = 248.5 Hz, 1F). HRMS (ESI) m/z: calcd for C24H17ClF2N2O [M + H]+ 423.1070, found: 423.1074.

9-Bromo-5-(2,2-difluoro-2-phenylethyl)-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3la)

White solid (yield 68.98 mg, 74%), mp 104–105 °C, purified by column chromatography with petroleum ether/ethyl acetate (7:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.44–8.42(m, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 4.0 Hz, 1H), 7.56–7.44 (m, 4H), 7.12–7.01 (m, 5H), 3.56–3.43 (m, 1H), 3.08–2.96 (m, 1H), 1.71 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.4, 150.3, 145.0, 139.5, 135.2 (t, JC–F = 25.3 Hz), 131.4, 130.1, 129.5 (t, JC–F = 2.0 Hz), 128.0, 127.8 (d, JC–F = 2.0 Hz), 127.0, 125.7, 124.5 (t, JC–F = 7.1 Hz), 123.5, 122.4, 121.8, 121.1, 118.6, 116.5, 49.4 (t, JC–F = 28.3 Hz), 45.5 (q, JC–F = 2.0 Hz), 31.1. 19F NMR (376 MHz, chloroform-d) δ −88.91 (d, J = 248.9 Hz, 1F), −91.35 (d, J = 248.9 Hz, 1F). HRMS (ESI) m/z: calcd for C24H17BrF2N2O [M + H]+ 467.0565, found: 467.0584.

5-(2,2-Difluoro-2-phenylethyl)-5,9,10-trimethylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ma)

White solid (yield 49.11 mg, 59%), mp 181–182 °C, purified by column chromatography with petroleum ether/ethyl acetate (7:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.46–8.36 (m, 1H), 8.03 (s, 1H), 7.56 (s, 1H), 7.48–7.40 (m, 3H), 7.17–7.02 (m, 5H), 3.61–3.44 (m, 1H), 3.08–2.92 (m, 1H), 2.42 (d, J = 4.0 Hz, 6H), 1.70 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.6, 148.6, 142.2, 139.1, 135.7 (t, JC–F = 26.3 Hz), 134.6 (d, JC–F = 3.0 Hz), 130.6, 129.5 (t, JC–F = 9.1 Hz), 127.9, 127.6, 126.9, 125.4, 124.5 (t, JC–F = 6.1 Hz), 123.6, 122.5, 121.2, 119.7, 118.8, 115.8, 49.4 (t, JC–F = 28.3 Hz), 45.5 (t, JC–F = 2.0 Hz), 31.2, 29.5, 20.3 (t, JC–F = 2.0 Hz). 19F NMR (376 MHz, chloroform-d) δ −90.19 (d, J = 248.5 Hz, 1F), −90.10 (d, J = 248.5 Hz, 1F). HRMS (ESI) m/z: calcd for C26H22F2N2O [M + H]+ 417.1773, found: 417.1773.

7-(2,2-Difluoro-2-phenylethyl)-7-methylbenzo[h]benzo[4,5]imidazo[2,1-a]isoquinolin-8(7H)-one (3na)

White solid (yield 63.08 mg, 72%), mp 137–138 °C, purified by column chromatography with petroleum ether/ethyl acetate (7:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 10.54 (d, J = 12 Hz, 1H), 8.31 (m, 1H), 7.98–7.88 (m, 3H), 7.85–7.81 (m, 1H), 7.67–7.63 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.50–7.41 (m, 2H), 7.09–6.95 (m, 5H), 3.60–3.42 (m, 1H), 3.12–2.82 (m, 1H), 1.78 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 171.7, 149.5, 143.8, 140.1, 135.3 (t, JC–F = 26.3 Hz), 132.6, 131.7, 130.1 (d, JC–F = 12.1 Hz), 129.4 (t, JC–F = 2.0 Hz), 128.4, 128.17, 127.97, 127.73, 126.68, 125.52(d, JC–F = 4.0 Hz), 124.53(t, JC–F = 6.1 Hz), 123.7, 123.6, 121.2, 119.8, 118.7, 117.6, 115.6, 49.2 (t, JC–F = 27.3 Hz), 45.8 (q, JC–F = 2.0Hz), 31.1. 19F NMR (376 MHz, chloroform-d) δ −89.28 (d, J = 248.5 Hz, 1F), −91.48 (d, J = 248.2 Hz, 1F). HRMS (ESI) m/z: calcd for C28H20F2N2O [M + H]+ 439.1617, found: 439.1612.

4-(2,2-Difluoro-2-phenylethyl)-4-methylbenzo[4,5]imidazo[1,2-a]thieno[2,3-c]pyridin-5(4H)-one (3oa)

Yellow oily liquid (yield 59.90 mg, 76%), purified by column chromatography with petroleum ether/ethyl acetate (7:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.17–8.13 (m, 1H), 7.75–7.71 (m, 1H), 7.48 (d, J = 4.0 Hz, 1H), 7.42–7.32 (m, 2H), 7.07 (d, J = 4.0 Hz, 4H), 7.03–6.99 (m, 2H), 3.52–3.39 (m, 1H), 2.94–2.83 (m, 1H), 1.63 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 172.0, 146.1, 145.1, 143.5, 135.0 (t, JC–F = 26.3 Hz), 130.5, 130.1, 129.5 (t, JC–F = 2.0 Hz), 127.8, 126.0, 125.5, 125.1, 124.5 (t, JC–F = 6.1 Hz), 123.4 (d, JC–F = 5.1 Hz), 121.0 119.3, 118.5, 114.9, 49.2 (t, JC–F = 27.3 Hz), 45.40 (t, JC–F = 2.0 Hz), 29.88. 19F NMR (376 MHz, chloroform-d) δ −89.65 (d, J = 248.9 Hz, 1F), −91.19 (d, J = 249.3 Hz, 1F). HRMS (ESI) m/z: calcd for C22H16F2N2OS [M + H]+ 395.1024, found: 395.1020.

5-(2,2-Difluoro-2-phenylethyl)-5-phenylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3pa)

Yellow oily liquid (yield 46.82 mg, 52%), purified by column chromatography with petroleum ether/ethyl acetate (6:1) as the eluent. 1H NMR (400 MHz, chloroform-d) δ 8.58–8.51 (m, 1H), 8.16–8.11 (m, 1H), 7.84–7.78 (m, 1H), 7.57–7.42 (m, 1H), 7.46–7.33 (m, 2H), 7.38–7.31 (m, 1H), 7.29–7.21 (m, 3H), 7.19–7.09 (m, 8H), 4.29–4.11 (m, 1H), 3.48–3.33 (m, 1H). 13C{1H}NMR (101 MHz, chloroform-d) δ 169.9, 149.7, 144.0, 142.5, 139.3, 136.0 (t, JC–F = 26.3 Hz),131.5, 131.2, 129.7 (d, JC–F = 5.1 Hz), 129.0, 128.2 (t, JC–F = 9.1 Hz), 126.9, 125.9, 125.6 (t, JC–F = 5.1 Hz), 124.8 (t, JC–F = 7.1 Hz), 124.1, 123.7, 121.7, 119.7, 115.8, 53.5, 47.4 (t, JC–F = 27.3 Hz), 29.7.19F NMR (376 MHz, chloroform-d) δ −88.60 (d, J = 248.9 Hz, 1F), −89.68 (d, J = 248.9 Hz, 1F). HRMS (ESI) m/z: calcd for C29H20F2N2O [M + H]+ 451.1617, found: 451.1612.

Acknowledgments

The authors gratefully acknowledge the National Science Foundation of China (51603192, 21172200) for financial support of this research.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c06689.

  • Experimental procedures; mechanistic experiments; characterization data; and NMR spectra (PDF)

  • Data_202208148 (CIF)

Author Contributions

This manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ao2c06689_si_001.pdf (4.7MB, pdf)
ao2c06689_si_002.cif (504KB, cif)

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