Cobalt-Catalyzed C–H Activation/Annulation of Benzamides with Fluorine-Containing Alkynes: A Route to 3- and 4-Fluoroalkylated Isoquinolinones

Abstract

The C–H activation/annulation reaction of various benzamides with fluoroalkylated alkynes in the presence of a Co(acac)₂·2H₂O catalyst proceeded very smoothly to give the corresponding 3- and 4-fluoroalkylated isoquinolinones in excellent yields with approximately 70% regioselectivities. These regioisomers could be successfully separated and obtained in pure form. Major or minor regioisomers were determined as 4- or 3-fluoroalkylated isoquinolinones, respectively, based on X-ray crystallographic analyses.

Graphical Abstract

INTRODUCTION

3,4-Disubstituted isoquinolinone nucleus A as shown in Figure 1 has attracted considerable attention in the pharmaceutical and agrochemical industries as a very important skeleton for expressing interesting biological activities.¹ For example, the isoquinolinone derivative A1, which possesses an aminomethyl and a phenyl group at the 3- and 4-positions, respectively, acts as a dipeptidyl peptidase-4 (DPP-4) inhibitor and suppresses the degradation of incretin hormones, while, compound A2, having a methoxycarbonyl and a phenyl group at the same positions, inhibits c-Jun N-terminal protein kinase (JNK), which is involved in signaling from the cell surface to the nucleus.² In addition, the 3,4-diphenyl isoquinolinone derivative A3 shows high antibacterial activity against Pseudomonas aeruginosa.³

Figure 1.

Various 3,4-disubstituted isoquinolinones with interesting biological activity.

Thus, 3,4-disubstituted isoquinolinones are extremely important molecules of biological interest. Accordingly, enormous interest has also been paid to fluorine-containing 3,4-disubstituted isoquinolinones. The reason is that the introduction of a small number of fluorine atoms into organic substances very often dramatically enhances their biological activities.⁴ Despite such potential utility, there have been quite limited studies on the synthesis of fluorinated isoquinolinones thus far.⁵

Transition-metal-catalyzed sequential C–H activation/annulation with alkynes is one of the most efficient and elegant protocols for the preparation of various heterocyclic compounds due to its high atom and step economy,⁶ and various heterocycles, such as isoquinolines, quinolines, indoles, etc., have been synthesized utilizing this methodology thus far.⁷ Therefore, it is quite promising to apply this synthetic strategy toward fluoroalkylated alkynes to synthesize fluorine-containing heterocycles; however, it has not abstracted little attention thus far. A few precedents include the synthesis of 3-trifluoromethylated indole via C–H activation/annulation of acetanilide with trifluoromethylated alkynes^8a or the synthesis of 3- and 4-fluoroalkylated isocoumarins when benzoic acid is used instead of acetanilide (Scheme 1a).^8b In both cases, significantly expensive metals are required such as a second-row transition metal, rhodium, a third-row transition metal, iridium, and an expensive Cp* ligand. Therefore, the development of the C–H activation/annulation process under the influence of a less expensive transition-metal catalyst for synthesizing fluorinated heterocycles is highly desirable.

Scheme 1.

Synthetic Protocols to Introduce a Fluoroalkyl Group into Heterocyclic Compounds

Herein we describe a first example of Cp*-free and inexpensive cobalt-catalyzed C–H activation/annulation of various amides with fluoroalkylated alkynes to yield fluorine-containing 3,4-disubstituted isoquinolinones (Scheme 1b), with reference to Daugulis’s work.⁹

RESULTS AND DISCUSSION

We initiated the investigation using fluoroalkylated alkyne 1a and benzamide 2A with a quinoline as a directing group to optimize the reaction conditions. The results are summarized in Table 1 (see Supporting Information for detail).

Table 1.

Screening for the Reaction Conditions of the C–H Activation/Annulation Reaction^a

entry	catalyst	base	oxidant	yieldb/% 3aA+4aA	ratiob/3aA:4aA
1	Co(OAc)2·4H2O	KOAc	AgNO3	29	77:23
2	Co(OH)2	KOAc	AgNO3	5	80:20
3	Co(acac)2·2H2O	KOAc	AgNO3	90	66:34
4	CoCl2	KOAc	AgNO3	33	80:20
5	CoBr2	KOAc	AgNO3	43	78:22
6	Co(acac)3	KOAc	AgNO3	69	78:22
7c		KOAc	AgNO3	0
8	Co(acac)2·H2O	Cs2CO3	AgNO3	46	66:34
9	Co(acac)2·2H2O	NaOAc	AgNO3	74	66:34
10	Co(acac)2·2H2O	K2CO3	AgNO3	56	66:34
11d	Co(acac)2·2H2O		AgNO3	18	66:34
12	Co(acac)2·2H2O	KOAc	Ag2O	40	66:34
13	Co(acac)2·2H2O	KOAc	MnO2	18	64:36
14e	Co(acac)2·2H2O	KOAc		0
15f	Co(acac)2·2H2O	KOAc	AgNO3	88	66:34

^aReaction conditions: 1a (0.5 mmol), 2A (0.75 mmol), cobalt catalyst (10 mol %), base (2.0 equiv), oxidant (2.0 equiv), TFE (5.0 mL), 80 °C, 18 h. TFE = 2,2,2-trifluoroethanol.

^bDetermined by ¹⁹F NMR.

^cWithout catalyst.

^dWithout base.

^eWithout oxidant.

^f1.1 equiv of 2A was used.

To a solution of 10 mol % of Co(OAc)₂·4H₂O were added 2.0 equiv each of KOAc and AgNO₃ in TFE (2,2,2-trifluoroethanol), 1.0 equiv of fluoroalkylated alkyne 1a, and 1.5 equiv of benzamide 2A, and the mixture was heated at 80 °C for 18 h. As a result, the C–H activation/annulation reaction took place to give the desired cyclic products 3aA and 4aA in 29% yield as a regioisomeric mixture (77:23) (entry 1). The stereochemical assignments of 3aA and 4aA were carried out based on the X-ray crystallographic analysis. Thus, major regioisomer 3aA formed a single crystal suitable for X-ray crystallographic analysis by recrystallization from hexane/EtOAc. The result shows that major regioisomer 3aA was found to possess a CF₃ group at the 4-position.¹⁰ As shown in entries 2–6, we carried out the reaction using various Cp*-free cobalt catalysts. When Co(OH)₂ was used as catalyst instead of Co(OAc)₂·4H₂O, the lower yield was obtained (entry 2). The yield was dramatically improved to 90% combined yields using Co(acac)₂·2H₂O as a catalyst (entry 3). On the other hand, CoCl₂, CoBr₂, and Co(acac)₃ were less effective for this reaction than Co(acac)₂·2H₂O (entries 4–6). Besides, the cyclic products were not obtained at all in the absence of a cobalt catalyst (entry 7). When the base was switched from KOAc to Cs₂CO₃, NaOAc, or K₂CO₃, the yield and isomeric ratio of the desired products did not change drastically (entries 8–10). As shown in entry 11, the reaction without base produced only 18% of isoquinolinones 3aA and 4aA, indicating that a base is crucial for the achievement of better yield. Subsequently, we carried out the reaction using other oxidants like Ag₂O or MnO₂, giving the cyclic products 3aA and 4aA in lower yields (entries 12 and 13). Additionally, the reaction without an oxidant did not proceed at all (entry 14). Finally, the desired products were obtained in an 88% combined yield as a regioisomeric mixture, even when only 1.1 equiv of benzamide 2A was used (entry 15).

With the optimal reaction conditions (Table 1, entry 15), we carried out C–H activation/annulation reaction using various fluoroalkylated internal alkynes 1 and benzamide 2A.

First of all, it was noteworthy that the regioisomeric ratio of 3A/4A was approximately 70:30 in almost all cases, as shown in Scheme 2. The position of the substituent on the benzene ring in the fluoroalkylated alkynes, like meta- or ortho-positions, did not affect the reaction, leading to desired fluorine-containing isoquinolinones 3bA/4bA in 93% and 3cA/4cA in 71% as combined yields. It is delightful to find that various fluoroalkylated alkynes having both electron-donating (R¹ = p-t-BuC₆H₄, p- or o-MeOC₆H₄) and electron-withdrawing groups (R¹ = o-EtO₂CC₆H₄, p-PhC₆H₄) were well accommodated, delivering corresponding products 3A and 4A in excellent yields (3dA/4dA–3hA/4hA). The reaction using the alkyne 1i bearing a 1-naphthyl group as an R¹ took place smoothly, resulting in 3iA and 4iA in a 93% combined yield as a mixture of atropisomers as well as regioisomers. It should be noted that the alkyne 1j having an aliphatic substituent is also be applicable, giving the corresponding products 3jA/4jA in a 71% yield with the reverse regioselectivity (21:79). In the case of nonafluorobutylated alkyne 1k, the reaction took place smoothly to give the desired isoquinolinones 3kA and 4kA in a 64% combined yield.

Scheme 2. Cobalt-Catalyzed C–H Activation/Annulation of Benzamide 2A with Various Fluoroalkylated Alkynes 1^a.

^aYields are determined by ¹⁹F NMR. Values in parentheses are regioisomeric ratios of 3A/4A. Values in brackets show isolated yields of 3A/4A. ^[a]Combined isolated yield. ^[b]Atropisomers were detected. ^[c]The reaction was carried out on a 3 mmol scale.

Notably, the regioisomers 3A and 4A were easily separated from each other in almost all cases, except for 3bA/4bA and 3fA/4fA, by simple silica gel column chromatography, which is a strong point of this method for the practical application.

Subsequently, we investigated the reaction of various amides 2 with the fluoroalkylated alkyne 1a, as shown in Scheme 3. It was noteworthy that reactions also showed approximately 70:30 regioselectivity (3a/4a) in all cases. Substrates 2 having various substituents on the benzene ring of the amide, such as electron-donating (t-Bu, MeO) or electron-withdrawing (CF₃, NO₂) groups, were applicable in the present cobalt-catalyzed C–H activation/annulation, affording the fluoroalkylated isoquinolinones 3aB/4aB–3aE/4aE in good to excellent yields. The reaction using m-chloro benzamide 2F as a substrate took place smoothly to give the cyclic products 3aF/4aF in an 83% yield. The structure of 3aF was determined based on a single X-ray crystallographic analysis. Sterically hindered o-substituted benzamides 2G and 2H reacted with 1a, giving the cyclized products 3aG/4aG and 3aH/4aH in 78% and 52% yields, respectively. Thiophen-2-carboxamide 2I can also be successfully applied to this reaction, and the corresponding isoquinolinones 3aI and 4aI were formed in an 88% combined yield, whereas the reaction using furan-2-carboxamide 2J took place to give the desired cyclic products 3aJ/4aJ in a lower yield (53%). Naphthalene-1-carboxamide 2K could also participate in this annulation, leading to fluoroalkylated isoquinolinones 3aK/4aK in 54% yields. When the cinnamoyl amide 2L was used, on the other hand, the reaction did not proceed well.

Scheme 3. Cobalt-Catalyzed C–H Activation/Annulation of Various Amides 2 with the Fluoroalkylated Alkyne 1a^a.

^aYields are determined by ¹⁹F NMR. Values in parentheses are regioisomeric ratios of 3a/4a. Values in brackets show isolated yields of 3a/4a. ^[a]Combined isolated yield. ^[b]4aL was not detected based on ¹⁹F NMR.

Subsequently, we examined the C–H activation/annulation reaction using o-halogenated benzamides 2, as shown in Table 2. When the o-chloro benzamide 2M was used, only desired products 3aM/4aM via C–H bond cleavage were obtained in 81% combined yield (entry 1). In the reaction using o-bromobenzamide 2N, however, cyclization products 3aA and 4aA via C–Br cleavage/annulation were given in 13% yield, along with the 3aN/4aN via C–H activation/annulation in 64% yield (entry 2). Furthermore, when the o-iodinated benzamide 2O was used, dehalogenated products 3aA/4aA were obtained in higher yields rather than the desired C–H activation/annulation products 3aO/4aO (entry 3). The reaction of o-iodinated benzamide 2O with fluoroalkylated alkyne 1a in the presence of 2.0 equiv of KOAc and 10 mol % of Co(acac)₃ without an oxidant produced the dehologenated products 3aA/4aA in a 57% yield (entry 4), indicating that an oxidant is not necessary to form dehalogenated products 3aA/4aA.

Table 2.

Cobalt-Catalyzed C–H Activation/Annulation of o-Halogenated Amides 2^a

		C–H cleavage products				C–X cleavage products
entry	X (substrate)	products	yieldb/% of 3+4	ratiob/of 3/4	isolated yield/% of 3, 4	yieldb/% 3aA+4aA	ratiob/3aA/4aA
1	Cl (2M)	3aM/4aM	81	74:26	58, 20	0
2	Br (2N)	3aN/4aN	64	72:28	44, 16	13	84:16
3	I (2O)	3aO/4aO	36	72:28	25, –c	45	82:18
4d	I (2O)	3aO/4aO	17	71:29		57	87:13

^aReaction conditions: 1a (0.5 mmol), 2 (0.55 mmol), Co(acac)₂·2H₂O (10 mol %), KOAc (2.0 equiv), AgNO₃ (2.0 equiv), TFE (5.0 mL), 80 °C, 18 h. TFE = 2,2,2-trifluoroethanol.

^bDetermined by ¹⁹F NMR.

^cHard to be purified.

^dThe reaction was carried out using 10 mol % of Co(acac)₃ and 2.0 equiv of KOAc without AgNO₃.

On the basis of the above results and previous reports,^6,7,9 a proposed reaction mechanism for the cobalt-catalyzed oxidative annulation in the presence of KOAc and AgNO₃ is depicted in Scheme 4. Thus, the C–H activation/annulation reaction presumably proceeds as follows: (1) formation of Co–N bond with benzamide and KOAc, leading to the Int-1, (2) oxidation of cobalt(II) species by AgNO₃, then concerted metalation deprotonation (CMD) process to produce the Int-2 via aminoquinoline-assisted C–H bond functionalization,^11,8b (3) coordinative insertion of fluoroalkylated alkynes 1 into a C–Co bond of the Int-2 affords seven-membered Int-3,¹² (4) reductive elimination of the Int-3 provides desired fluoroalkylated isoquinolinones 3 and 4, together with the generation of Co(I) species, and (5) reoxidation of cobalt(I) to cobalt(II) species by AgNO₃ (Path A). On the other hand, C–X cleavage product 3aA/4aA obtained from 2N and 2O were produced via another process Path B involving the oxidative addition step because dehalogenated products 3aA/4aA were obtained in 57% yields although AgNO₃ as an oxidant was not used, as shown in entry 4 on Table 2. Thus, (1) transmetalation of Co(I) with benzamide 2N/2O produces the Int-1′, and (2) oxidative addition of Co(I) to C–X bond of 2N/2O generates the cobalt(III) species followed by transmetalation with KL (L = acac or OAc), giving the Int-2. The following reaction mechanism is the same as the C–H activation process, (3) coordinative insertion of alkynes 1 into a C–Co bond of the Int-2 affords Int-3, and (4) reductive elimination of the Int-3 provides desired fluoroalkylated isoquinolinones 3aA/4aA. Since C–I bond energy is generally lower than C–Br bond energy, C–I cleavage product 3aA/4aA was obtained in higher yields rather than the C–Br cleavage product, as shown in entries 2 and 3 in Table 2.

Scheme 4.

Proposed Reaction Mechanism

CONCLUSION

In conclusion, we have developed Cp*-free and inexpensive cobalt-catalyzed C–H activation/annulation of various amides with internal fluoroalkylated alkynes to furnish fluoroalkylated isoquinolinones derivatives. The reaction features a broad substrate scope, and therefore, we successfully prepared structurally various heterocyclic amides. Furthermore, to the best of our knowledge, this protocol is a first example of the C–H activation/annulation reaction using fluoroalkylated internal alkynes with an inexpensive cobalt catalyst. Although the reaction does not proceed with excellent regioselectivity, 3-and 4-fluoroalkylated isoquinolinone derivatives could be easily separated by simple silica gel column chromatography. Accordingly, this process would become a practical and efficient synthetic protocol for fluorine-containing isoquinolinones.¹³

EXPERIMENTAL SECTION

General Information.

¹H and ¹³C NMR spectra were obtained using an AVANCE III 400 NMR spectrometer (¹H, 400 MHz; ¹³C, 100 MHz) in chloroform-d (CDCl₃) (Bruker, Germany) at 25 °C, and the chemical shifts are reported in parts per million (ppm) based on the residual proton signal of the NMR solvent. ¹⁹F NMR (376 MHz) spectra were obtained using an AVANCE III 400 NMR spectrometer in CDCl₃ with CFCl₃ (δ_F = 0 ppm) as an internal standard (Bruker, Germany) at 25 °C. The Bruker AVANCE III 400 NMR spectrometer was used for determining the yield of the products with trifluoromethylbenzene (CF₃C₆H₅) or hexafluorobenzene (C₆F₆) as internal references. ¹H, ¹³C, and ¹⁹F NMR data were recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplets of doublets, m = multiplets, dm = doublet of multiplets, tm = doublet of multiplets), coupling constants (Hz), integration. IR spectra were recorded using the KBr method with an FT/IR-4100 type A spectrometer (JASCO, Japan); all spectra are reported in wavenumbers (cm⁻¹). High-resolution mass spectra (HRMS) were recorded on a JMS-700MS spectrometer (Sector MS) (JEOL, Japan) using the fast-atom bombardment (FAB) method.

All reactions were carried out using dried glassware with a magnetic stirrer bar and routinely monitored by ¹⁹F NMR spectroscopy or thin-layer chromatography (TLC). All chemicals were of reagent grade and, if necessary, purified in the usual manner before use. Fluoroalkylated alkynes 1 and amides 2 used in this research were prepared according to the literature.^14,15 Column chromatography was carried out on silica gel (Wako gel 60 N, 38–100 μm), and TLC analysis was performed on silica gel TLC plates (Merck, silica gel 60F₂₅₄).

X-ray Crystallography.

A colorless prismic crystal of 3aA with approximate dimensions of 0.15 mm × 0.13 mm × 0.12 mm was mounted on a glass fiber. All measurements for 3aA were made on a diffractometer with filtered Mo Kα radiation (λ = 0.71073 Å) and a rotating anode generator using a VariMax with PILATUS/DW (Rigaku): compound 3aA triclinic, a = 7.8247(5) Å, b = 10.3737(6) Å, c = 12.4493(6) Å, α = 86.667, β = 84.245, γ = 83.687, V = 998.198(10) ų, T = 173(2) K, space group P1, Z = 2 reflection measured. The final R₁ and wR₂ were 0.0363 and 0.1036 (I > 2σ(I)).

A colorless prismic crystal of 3aF with approximate dimensions of 0.39 mm × 0.24 mm × 0.21 mm was mounted on a glass fiber. All measurements for 3aF were made on a diffractometer with filtered Mo Kα radiation (λ = 0.71073 Å) and a rotating anode generator using a VariMax with PILATUS/DW (Rigaku): compound 3aF triclinic, a = 8.6332(2) Å, b = 9.8737(2) Å, c = 12.3770(4) Å, α = 79.584, β = 85.595, γ = 89.945, V = 1034.5(10) ų, T = 173(2) K, space group P1, Z = 2 reflection measured. The final R₁ and wR₂ were 0.0341 and 0.0954 (I > 2σ(I)).

A colorless prismic crystal of 3aK with approximate dimensions of 0.49 mm × 0.20mm × 0.17 mm was mounted on a glass fiber. All measurements for 3aK were made on a diffractometer with filtered Mo Kα radiation (λ = 0.71073 Å) and a rotating anode generator using a VariMax with PILATUS/DW (Rigaku): compound 3aK monoclinic, a = 15.8753(12) Å, b = 7.0132(5) Å, c = 20.6246(15) Å, α = 90, β = 90.197, γ = 90, V = 2296.3(3) ų, T = 173(2) K, space group P21/c, Z = 4 reflection measured. The final R₁ and wR₂ were 0.0545 and 0.1682 (I > 2σ(I)).

All calculations were performed using the CrystalStructure crystallographic software package. The structure was solved by direct methods and expanded using Fourier techniques. The structural model was refined by a full-matrix least-squares method using SHELXL-2014/6.¹⁶ All calculations were performed using the SHELXL program. Crystallographic data for this compound has been deposited with the Cambridge Crystallographic Data Centre as supplementary data no. CCDC 2027269 (3aA), 2027270 (3aF), and 2027271 (3aK). A copy of the data can be obtained free of charge by applying to The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK (https://summary.ccdc.cam.ac.uk/structure-summary-form).

Typical Procedure for C–H Activation Reaction.

In a 30 mL two-necked round bottomed-flask, equipped with a magnetic stirring bar, were placed fluoroalkylated alkyne 1a (0.102 g, 0.50 mmol), benzamide 2A (0.137 g, 0.55 mmol), Co(acac)₂·2H₂O (0.015 g, 0.050 mmol), KOAc (0.098 g, 1.00 mmol), and AgNO₃ (0.170 g, 1.00 mmol), in TFE (5.00 mL) under argon, and the resulting mixture was stirred at 80 °C using an oil bath. After 18 h, the reaction mixture was cooled to room temperature and subjected to flash column chromatography using silica gel as the stationary phase and EtOAc as the mobile phase. After removal of solvent from the eluent under reduced pressure, the residue was purified by silica gel column chromatography (hexane/AcOEt = 2:1) to give the corresponding 3-(4-chlorophenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)isoquinolin-1(2H)-one (3aA) (0.119 g, 0.264 mmol) and 4-(4-chlorophenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)isoquinolin-1(2H)-one (4aA) (0.061 g, 0.136 mmol).

3-(4-Chlorophenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)-isoquinolin-1(2H)-one (3aA).

Eluent = hexane/EtOAc 2:1. White solid (53% yield, 121 mg). Mp: 199.2–200.0 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.87 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.54 (dd, J = 8.0, 1.2 Hz, 1H, ArH), 8.09 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 8.07–8.01 (m, 1H, ArH), 7.83 (tm, J = 7.8 Hz, 1H, ArH), 7.75–7.69 (m, 1H, ArH), 7.63 (t, J = 7.7 Hz, 1H, ArH), 7.43–7.36 (m, 3H, ArH), 7.13 (dd, J = 8.2, 2.1 Hz, 1H, ArH), 7.08 (dd, J = 8.2, 2.1 Hz, 1H, ArH), 6.83 (dd, J = 8.3, 2.1 Hz, 1H, ArH), 6.66 (dd, J = 8.3, 2.1 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.4 (CO), 151.0 (Ar), 144.8–144.6 (m, Ar), 144.4 (Ar), 136.3–136.1 (m, Ar), 134.6 (Ar), 133.4 (Ar), 133.0 (Ar), 132.4 (Ar), 131.1 (Ar), 130.9–130.7 (m, Ar), 129.7–129.5 (m, Ar), 129.3 (Ar), 128.8 (Ar), 127.9 (Ar), 127.4 (Ar), 127.1 (Ar), 125.8 (Ar), 124.7 (C–F, ³J_C–F = 4.1 Hz, CF₃–C=C), 124.5 (C–F, ¹J_C–F = 273.6 Hz, CF₃), 121.9 (Ar), 106.5 (C–F, ²J_C–F = 30.1 Hz, CF₃–C). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.62 (s, 3F). IR (KBr): 3064, 1673, 1612, 1484, 1366, 1335, 1231, 1175, 1097, 1021, 979, 896, 854, 814, 788 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₅ClF₃N₂O, 451.0820; found, 451.0831.

4-(4-Chlorophenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)-isoquinolin-1(2H)-one (4aA).

Eluent = hexane/EtOAc 2:1. White solid (27% yield, 61 mg). Mp: 215.6–216.2 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.91 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.54–8.49 (m, 1H, ArH), 8.24 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 7.98 (dd, J = 8.2, 1.4 Hz, 1H, ArH), 7.78 (dm, J = 7.3 Hz, 1H, ArH), 7.70–7.60 (m, 3H, ArH), 7.51–7.42 (m, 3H, ArH), 7.40–7.35 (m, 1H, ArH), 7.34–7.29 (m, 1H, ArH), 7.14–7.09 (m, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.5 (C=O), 151.2 (Ar), 145.3 (Ar), 136.9 (Ar), 136.6 (Ar), 136.3 (Ar), 134.3 (Ar), 133.7 (Ar), 133.1 (Ar), 131.9–131.7 (m, Ar), 131.4–131.2 (m, Ar), 130.5–130.3 (m, Ar), 129.7 (Ar), 129.4 (Ar), 129.1 (Ar), 128.9 (Ar), 128.81 (C–F, ²J_C–F = 29.7 Hz, CF₃–C), 128.80 (Ar), 128.6 (Ar), 127.1 (Ar), 126.8 (Ar), 126.0 (Ar), 121.8 (Ar), 120.9–121.1 (m, Ar), 120.76 (C–F, ¹J_C–F = 276.8 Hz, CF₃). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −52.80 (s, 3F). IR (KBr): 3067, 3004, 1667, 1596, 1489, 1450, 1365, 1328, 1260, 1198, 1018, 824, 777 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₅ClF₃N₂O, 451.0820; found, 451.0822.

3-(3-Chlorophenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)-isoquinolin-1(2H)-one (3bA) and 4-(3-Chlorophenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)isoquinolin-1(2H)-one (4bA).

These products were hard to separate each other by silica gel column chromatography because of similar polarity. Eluent = hexane/EtOAc 2:1. White solid (83% yield, 186 mg). Yield: 83%; Eluent of column chromatography: hexane/EtOAc = 2:1. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): (atropisomer 1 + atropisomer 2) δ −51.78 to −51.70 (m, 6F), −52.89 (s, 3F), −52.91 (s, 3F).

3-(2-Chlorophenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)-isoquinolin-1(2H)-one (3cA).

Eluent = hexane/EtOAc 2:1. White solid (47% yield, 106 mg). Mp: 214.8–215.7 °C. ¹H NMR (400 MHz, CDCl₃): (atropisomer 1 + atropisomer 2) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.33 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.62–8.51 (m, 2H, ArH), 8.10–7.99 (m, 4H, ArH), 7.88–7.30 (m, 12H, ArH), 6.72–7.29 (m, 7H, ArH), 6.56 (td, J = 7.6, 1.1 Hz, 1H, ArH). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): (atropisomer 1) δ −54.01 (s, 3F); (atropisomer 2) δ −53.82 (s, 3F). IR (KBr): 3010, 1671, 1600, 1489, 1426, 1376, 1324, 1291, 1218, 1132, 1016, 822, 794, 774, 752, 708 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₅ClF₃N₂O, 451.0820; found, 451.0830.

4-(2-Chlorophenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)-isoquinolin-1(2H)-one (4cA).

Eluent = hexane/EtOAc 2:1. White solid (14% yield, 32 mg). Mp: 214.8–215.7 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.88 (dd, J = 4.2, 1.6 Hz, 1H, ArH), 8.57–8.49 (m, 1H, ArH), 8.23 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 7.98 (dd, J = 8.3, 1.2 Hz, 1H, ArH), 7.85 (dt, J = 7.4, 1.2 Hz, 1H, ArH), 7.71–7.60 (m, 3H, ArH), 7.59–7.53 (m, 1H, ArH), 7.49–7.37 (m, 4H, ArH), 7.04–6.97 (m, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.7 (C=O), 145.4 (Ar), 136.4 (Ar), 136.3 (Ar), 136.1 (Ar), 134.53–134.51 (m, Ar), 134.40 (Ar), 133.3 (Ar), 132.3–132.1 (m, Ar), 131.2–131.0 (m, Ar), 129.84 (Ar), 129.75 (Ar), 129.67 (Ar), 129.4 (Ar), 129.3 (C–F, ²J_C–F = 29.9 Hz, CF₃–C), 129.1 (Ar), 128.7 (Ar), 126.9 (Ar), 126.5 (Ar), 126.0 (Ar), 121.8 (Ar), 120.7 (C–F, ¹J_C–F = 277.0 Hz, CF₃), 119.2 (q, J = 2.4 Hz, Ar). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −55.12 (s, 3F). IR (KBr): 3010, 1671, 1600, 1489, 1426, 1376, 1324, 1291, 1218, 1132, 1016, 822, 794, 774, 752, 708 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₅ClF₃N₂O, 451.0820; found, 451.0830.

3-(4-(tert-Butyl)phenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)-isoquinolin-1(2H)-one (3dA).

Eluent = hexane/EtOAc 2:1. White solid (63% yield, 149 mg). Mp: 255.0–255.6 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.55 (dd, J = 8.0, 1.2 Hz, 1H, ArH), 8.04 (dd, J = 8.3, 1.7 Hz, 2H, ArH), 7.82 (tm, J = 8.7 Hz, 1H, ArH), 7.66–7.58 (m, 2H, ArH), 7.38 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 7.35–7.30 (m, 2H, ArH), 7.08 (s, 2H, ArH), 6.69 (dm, J = 8.4 Hz, 1H, ArH), 6.61 (dm, J = 8.4 Hz, 1H, ArH), 1.06 (s, 9H, C(CH₃)₃). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.6 (C=O)151.5 (Ar), 150.9 (Ar), 146.3 (C–F, ³J_C–F = 2.9 Hz, Ar), 144.6 (Ar), 136.6 (Ar), 136.0 (Ar), 133.4 (Ar), 133.3 (Ar), 131.2 (Ar), 131.0 (Ar), 129.3–129.1 (m, Ar), 128.9 (Ar), 128.8 (Ar), 128.7 (Ar), 128.0–127.8 (m, Ar), 127.6 (Ar), 125.8 (Ar), 125.6 (Ar), 124.69 (C–F, ³J_C–F = 4.1 Hz, CF₃–C=C), 124.68 (C–F, ¹J_C–F = 273.7 Hz, CF₃), 123.9 (Ar), 123.4 (Ar), 121.7 (Ar), 106.3 (C–F, ²J_C–F = 30.0 Hz, CF₃–C), 34.5 (C(CH₃)₃), 31.0 (C(CH₃)₃). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.76 (s, 3F). IR (KBr): 3046, 2962, 2866, 1676, 1609, 1557, 1489, 1367, 1333, 1266, 1231, 1180, 1165, 1134, 1107, 1025, 978, 897, 854, 833, 814, 789, 773, 761, 749, 709 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₉H₂₄F₃N₂O, 473.1835; found, 473.1845.

4-(4-(tert-Butyl)phenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)-isoquinolin-1(2H)-one (4dA).

Eluent = hexane/EtOAc 2:1. White solid (21% yield, 50 mg). Mp: 178.4–179.1 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.91 (dd, J = 4.2, 1.6 Hz, 1H, ArH), 8.55–8.49 (m, 1H, ArH), 8.22 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 7.96 (dd, J = 8.2, 1.2 Hz, 1H, ArH), 7.79 (d, J = 7.3 Hz, 1H, ArH), 7.69–7.58 (m, 3H, ArH), 7.52 (s, 1H, ArH), 7.50 (s, 1H, ArH), 7.43 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 7.40–7.35 (m, 1H, ArH), 7.32–7.28 (m, 1H, ArH), 7.22–7.16 (m, 1H, ArH), 1.41 (s, 9H, C(CH₃)₃). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.6 (C=O), 151.2 (Ar), 151.1 (Ar), 145.4 (Ar), 137.4 (Ar), 136.9 (Ar), 136.3 (Ar), 132.9 (Ar), 132.1 (Ar), 130.5–131.3 (m, Ar), 130.1–130.0 (m, Ar), 129.62 (Ar), 129.56–129.45 (m, Ar), 129.2 (Ar), 129.0 (Ar), 128.42 (C–F, ²J_C–F = 29.8 Hz, CF₃–C), 128.41 (Ar), 127.6 (Ar), 126.8 (Ar), 126.0 (Ar), 125.32 (Ar), 125.29 (Ar), 122.6 (C–F, ³J_C–F = 2.7 Hz, Ar), 121.8 (Ar), 120.9 (C–F, ¹J_C–F = 277.1 Hz, CF₃), 34.8 (C(CH₃)₃), 31.5 (C(CH₃)₃). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −52.83 (s, 3F). IR (KBr): 2963, 1671, 1366, 1328, 1202, 1132, 826, 781, 761, 722, 708 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₉H₂₄F₃N₂O, 473.1835; found, 473.1829.

3-(4-Methoxyphenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)-isoquinolin-1(2H)-one (3eA).

Eluent = hexane/EtOAc 2:1. White solid (41% yield, 92 mg). Mp: 209.6–210.2 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.87 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.55 (dd, J = 8.0, 1.4 Hz, 1H, ArH), 8.05 (dd, J = 8.3, 1.7 Hz, 2H, ArH), 7.81 (tm, J = 8.8, 1.5 Hz, 1H, ArH), 7.67 (dd, J = 6.9, 2.8 Hz, 1H, ArH), 7.60 (tm, J = 7.6 Hz, 1H, ArH), 7.40–7.34 (m, 3H, ArH), 7.10 (dd, J = 8.5, 2.2 Hz, 1H, ArH), 6.78 (dd, J = 8.6, 2.2 Hz, 1H, ArH), 6.63 (dd, J = 8.6, 2.7 Hz, 1H, ArH), 6.20 (dd, J = 8.5, 2.7 Hz, 1H, ArH),3.58 (s, 3H, OCH₃). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.6 (C=O), 159.4 (Ar), 150.9 (Ar), 146.0 (q, J = 2.9 Hz, Ar), 144.5 (Ar), 136.7 (Ar), 136.1 (Ar), 133.34 (Ar), 133.28 (Ar),131.1 (Ar), 130.9–130.7 (m, Ar), 129.6–129.5 (m, Ar), 129.0 (Ar), 128.8 (Ar), 127.6 (Ar), 126.3 (Ar), 125.8 (Ar), 124.70 (C–F, ¹J_C–F = 272.9 Hz, CF₃), 124.69 (C–F, ³J_C–F = 4.2 Hz, CF₃–C=C), 121.8 (Ar), 112.6 (Ar), 112.2 (Ar), 106.6 (C–F, ²J_C–F = 29.8 Hz, CF₃–C), 55.1 (OCH₃),. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.71 (s, 3F). IR (KBr): 3012, 2971, 2357, 2343, 1671, 1511, 1486, 1440, 1365, 1338, 1290, 1251, 1177, 1162, 1126, 1095, 1026, 979, 854, 814, 780, 714 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₆H₁₈F₃N₂O₂, 447.1315; found, 447.1326.

4-(4-Methoxyphenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)-isoquinolin-1(2H)-one (4eA).

Eluent = hexane/EtOAc 2:1. White solid (31% yield, 69 mg). Mp: 126.9–127.8 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.90 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.55–8.50 (m, 1H, ArH), 8.21 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 7.95 (dd, J = 8.3, 1.2 Hz, 1H, ArH), 7.79 (d, J = 7.3 Hz, 1H, ArH), 7.69–7.58 (m, 3H, ArH), 7.42 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 7.38–7.33 (m, 1H, ArH), 7.32–7.27 (m, 1H, ArH), 7.25–7.19 (m, 1H, ArH), 7.06–7.01 (m, 2H, ArH), 3.87 (s, 3H, OCH₃). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.5 (C=O), 159.5 (Ar), 151.1 (Ar), 145.4 (Ar), 137.5 (Ar), 136.9 (Ar), 136.2 (Ar), 132.9 (Ar), 131.6–131.4 (m, Ar), 131.1–130.9 (m, Ar), 130.4–130.2 (m, Ar), 129.6 (Ar), 129.2 (Ar), 129.0 (Ar), 128.6 (C–F, ²J_C–F = 29.5 Hz, CF₃–C), 128.4 (Ar), 127.4 (Ar), 127.2 (Ar), 126.8 (Ar), 125.9 (Ar), 122.2 (C–F, ³J_C–F = 2.7 Hz, Ar), 121.8 (Ar), 120.9 (C–F, ¹J_C–F = 277.1 Hz, CF₃), 114.0 (Ar), 113.9 (Ar), 55.3 (OCH₃). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −52.80 (s, 3F). IR (KBr): 3069, 2368, 2342, 1671, 1606, 1509, 1366, 1327, 1290, 1246, 1199, 1143, 1032, 853, 825, 782, 761, 722, 708 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₆H₁₈F₃N₂O₂, 447.1315; found, 447.1315.

3-(2-Methoxyphenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)-isoquinolin-1(2H)-one (3fA) and 4-(2-Methoxyphenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)isoquinolin-1(2H)-one (4fA).

These products were hard to separate each other by silica gel column chromatography because of similar polarity. Eluent = hexane/EtOAc 2:1. White solid (77% yield, 171 mg). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): (atropisomer 1 + atropisomer 2) δ −53.44 (s, 3F), −53.71 (s, 3F), −54.66 (s, 3F), −55.30 (s, 3F).

3-(2-Ethoxycarbonylphenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)isoquinolin-1(2H)-one (3gA).

Eluent = hexane/EtOAc 2:1. White solid (57% yield, 139 mg). Mp: 192.2–193.0 °C. ¹H NMR (400 MHz, CDCl₃): (atropisomer 1 + atropisomer 2): δ 8.90–8.74 (m, 2H, ArH), 8.58 (d, J = 8.1 Hz, 2H, ArH), 8.11–7.95 (m, 4H, ArH), 7.88–6.78 (m, 20H, ArH), 4.40–3.98 (m, 4H, CH₂), 1.17 (t, J = 7.1 Hz, 3H, CH₃), 0.96 (t, J = 7.2 Hz, 3H, CH₃). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): (atropisomer 1) δ −53.21 (s, 3F); (atropisomer 2) δ −52.88 (s, 3F). IR (KBr): 3063, 2989, 1955, 1709, 1672, 1612, 1572, 1556, 1484, 1368, 1294, 1091, 1081, 978, 853, 823, 791, 771, 718 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₈H₂₀F₃N₂O₃, 489.1421; found, 489.1419.

4-(2-Ethoxycarbonylphenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)isoquinolin-1(2H)-one (4gA).

Eluent = hexane/EtOAc 2:1. White solid (12% yield, 29 mg). Mp: 162.2–162.9 °C. ¹H NMR (400 MHz, CDCl₃): (atropisomer 1 + atropisomer 2) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.51 (dd, J = 4.4, 2.9 Hz, 1H, ArH), 8.55–8.48 (m, 2H, ArH), 8.25–8.18 (m, 4H, ArH), 8.00–7.94 (m, 2H, ArH), 7.86–7.75 (m, 2H, ArH), 7.70–7.53 (m, 10H, ArH), 7.50–7.37 (m, 4H, ArH), 6.96–6.90 (m, 2H, ArH), 4.19–4.07 (m, 4H, CH₂), 1.07 (t, J = 7.14 Hz, 3H, CH₃), 1.01 (t, J = 7.1 Hz, 3H, CH₃). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): (atropisomer 1) δ −54.43 (s, 3F); (atropisomer 2) δ −53.87 (s, 3F). IR (KBr): 3066, 2979, 1705, 1672, 1596, 1497, 1451, 1390, 1363, 1327, 1289, 1258, 1198, 1161, 1120, 1047, 1015, 854, 818, 786, 718 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₈H₂₀F₃N₂O₃, 489.1421; found, 489.1419.

3-(4-Biphenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)isoquinolin-1(2H)-one (3hA).

Eluent = hexane/EtOAc 2:1. White solid (54% yield, 133 mg). Mp: 190.2–190.9 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.91 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.61–8.56 (m, 1H, ArH), 8.11–8.08 (m, 1H, ArH), 8.04 (dd, J = 8.3, 1.7 Hz, 2H, ArH), 7.84 (tm, J = 7.8 Hz, 1H, ArH), 7.68–7.61 (m, 2H, ArH), 7.43 (dd, J = 7.3, 1.4 Hz, 1H, ArH), 7.40–7.27 (m, 8H, ArH), 6.90–6.96 (s, 2H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.6 (C=O), 151.0 (Ar), 145.8 (q, J = 2.7 Hz, Ar), 144.6 (Ar), 141.0 (Ar), 140.0 (Ar), 136.5 (Ar), 136.1 (Ar), 133.37 (Ar), 133.30 (Ar), 133.0 (Ar), 131.2 (Ar), 130.0–129.8 (m, Ar), 129.1 (Ar), 128.9 (Ar), 128.82 (Ar), 128.75–128.60 (m, Ar), 127.76 (Ar), 127.70 (Ar), 126.9 (Ar), 125.82 (Ar), 125.75 (Ar), 125.66 (Ar),125.3 (Ar), 124.8 (C–F, ³J_C–F = 4.2 Hz, CF₃–C=C), 124.7 (C–F, ¹J_C–F = 273.6 Hz, CF₃), 121.8 (Ar), 106.4 (C–F, ²J_C–F = 29.9 Hz, CF₃–C). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.63 (s, 3F). IR (KBr): 3554, 3048, 1955, 1675, 1607, 1557, 1486, 1427, 1365, 1334, 1231, 1096, 1027, 978, 896, 817, 763, 733 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₃₁H₂₀F₃N₂O, 493.1522; found, 493.1537.

4-(4-Biphenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)isoquinolin-1(2H)-one (4hA).

Eluent = hexane/EtOAc 2:1. White solid (19% yield, 51 mg). Mp: 130.8–131.7 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.93 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.60–8.50 (m, 1H, ArH), 8.24 (dd, J = 8.3, 1.7 Hz, 1H, ArH), 7.98 (dd, J = 8.3, 1.3 Hz, 1H, ArH), 7.81 (d, J = 7.2 Hz, 1H, ArH), 7.77–7.67 (m, 5H, ArH), 7.67–7.60 (m, 2H, ArH), 7.54–7.42 (m, 5H, ArH), 7.42–7.37 (m, 1H, ArH), 7.26–7.22 (m, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.5 (C=O), 151.2 (Ar), 145.4 (Ar), 140.9 (Ar), 140.5 (Ar), 137.2 (Ar), 136.8 (Ar), 136.3 (Ar), 134.2 (Ar), 133.0 (Ar), 131.0–130.8 (m, Ar), 130.52–130.41 (m, Ar), 130.41–130.29 (m, Ar), 129.7 (Ar), 129.3 (Ar), 129.1 (Ar), 129.0 (Ar), 128.56 (C–F, ²J_C–F = 29.9 Hz, CF₃–C), 128.52 (Ar),127.7 (Ar), 127.5 (Ar), 127.2 (Ar), 127.13 (Ar), 127.07 (Ar), 126.8 (Ar), 126.0 (Ar), 122.2–122.0 (m, Ar), 121.8 (Ar), 120.9 (C–F, ¹J_C–F = 277.1 Hz, CF₃). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −52.72 (s, 3F). IR (KBr): 3031, 1673, 1598, 1487, 1365, 1328, 1199, 1144, 853, 824, 772, 741, 707 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₃₁H₂₀F₃N₂O, 493.1522; found, 493.1522.

3-(Naphthalen-1-yl)-2-(quinolin-8-yl)-4-(trifluoromethyl)-isoquinolin-1(2H)-one (3iA).

Eluent = hexane/EtOAc 2:1. White solid (70% yield, 163 mg). Mp: 246.0–246.8 °C. ¹H NMR (400 MHz, CDCl₃): (atropisomer 1 + atropisomer 2) δ 8.93 (dd, J = 4.1, 1.6 Hz, 1H, ArH), 8.80–8.60 (m, 3H, ArH), 8.14 (d, J = 7.8 Hz, 2H, ArH), 7.97 (dd, J = 8.3, 1.5 Hz, 1H, ArH), 7.92–7.05 (m, 24H, ArH), 6.96 (t, J = 7.6 Hz, 1H, ArH), 6.89 (t, J = 7.8 Hz, 1H, ArH), 6.76 (t, J = 7.7 Hz, 1H, ArH). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): (atropisomer 1 + atropisomer 2) δ −53.05 (s, 3F), −53.25 (s, 3F). IR (KBr): 3052, 1952, 1675, 1610, 1557, 1487, 1427, 1393, 1362, 1333, 1236, 1198, 1138, 1103, 967, 895, 845, 823, 779, 706 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₉H₁₈F₃N₂O, 467.1366; found, 467.1375.

4-(Naphthalen-1-yl)-2-(quinolin-8-yl)-3-(trifluoromethyl)-isoquinolin-1(2H)-one (4iA).

Eluent = hexane/EtOAc 2:1. White solid (12% yield, 28 mg). Mp: 121.4–122.2 °C. ¹H NMR (400 MHz, CDCl₃): (atropisomer 1 + atropisomer 2) δ 8.99–8.89 (m, 2H, ArH), 8.57 (d, J = 7.9 Hz, 2H, ArH), 8.23 (d, J = 8.3 Hz, 2H, ArH), 8.02–7.41 (m, 26H, ArH), 6.89 (dm, J = 8.1 Hz, 2H, ArH). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): (atropisomer 1 + atropisomer 2) δ −54.49 (s, 3F), −54,58 (s, 3F). IR (KBr): 3052, 1671, 1594, 1497, 1453, 1362, 1324, 1205, 1168, 1130, 826, 781, 731, 708 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₉H₁₈F₃N₂O, 467.1366; found, 467.1373.

3-n-Octyl-2-(quinolin-8-yl)-4-(trifluoromethyl)isoquinolin-1(2H)-one (3jA).

Eluent = hexane/EtOAc 2:1. White solid (12% yield, 20 mg). Mp: 90.9–91.7 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.86 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.44 (dd, J = 8.0, 1.0 Hz, 1H, ArH), 8.25 (dd, J = 8.3, 1.7 Hz, 1H, ArH), 8.03–7.96 (m, 2H, ArH), 7.77–7.67 (m, 3H, ArH), 7.52 (tm, J = 7.6 Hz, 1H, ArH), 7.45 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 2.83–2.66 (m, 1H, –CH₂–C=C), 2.24–2.04 (brs, 1H, –CH₂–C=C), 1.48–1.37 (m, 2H, –CH₂–), 1.23–1.13 (m, 2H, –CH₂–), 1.10–1.01 (m, 2H, –CH₂–), 1.01–0.91 (m, 2H, –CH₂–), 0.88–0.79 (m, 7H, CH₃CH₂CH₂–). 13C{¹H} NMR (100 MHz, CDCl₃): δ 163.2 (C=O), 151.6 (Ar), 148.0–147.8 (m, Ar), 144.6 (Ar), 136.4 (Ar), 133.7 (Ar), 133.1 (Ar), 130.4 (Ar), 129.7 (Ar), 129.4 (Ar), 128.6 (Ar), 127.0 (Ar), 126.3 (Ar), 125.8 (C–F, ¹J_C–F = 273.5 Hz, CF₃), 125.0 (Ar), 124.3 (C–F, ³J_C–F = 4.7 Hz, CF₃–C=C), 122.2 (Ar), 105.1 (C–F, ²J_C–F = 30.3 Hz, CF₃–C), 31.76 (C–F, ⁴J_C–F = 4.2 Hz, C=C–CH₂), 31.71 (CH₂), 30.0 (CH₂), 29.4 (CH₂), 28.9 (CH₂), 28.5 (CH₂), 22.6 (CH₂), 14.1 (CH₃). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −52.56 (s, 3F). IR (KBr): 2926, 2860, 1671, 1607, 1556, 1488, 1372, 1332, 1210, 1153, 1137, 1094, 925, 835, 822, 775, 712 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₇H₂₈F₃N₂O, 453.2148; found, 453.2152.

4-n-Octyl-2-(quinolin-8-yl)-3-(trifluoromethyl)isoquinolin-1(2H)-one (4jA).

Eluent = hexane/EtOAc 2:1. White solid (53% yield, 90 mg). Mp: 118.5–119.4 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.86 (dd, J = 4.2, 1.6 Hz, 1H, ArH), 8.53 (dd, J = 8.0, 1.2 Hz, 1H, ArH), 8.19 (dd, J = 8.3, 1.5 Hz, 1H, ArH), 7.97–7.89 (m, 2H, ArH), 7.80 (tm, J = 7.8 Hz, 1H, ArH), 7.69–7.59 (m, 3H, ArH), 7.39 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 3.07–2.95 (m, 2H, – CH₂–C=C), 1.82–1.71 (m, 2H, – CH₂–), 1.60–1.50 (m, 2H, – CH₂–), 1.46–1.28 (m, 8H, – CH₂–CH₂–CH₂–CH₂–), 0.92 (t, J = 6.8 Hz, 3H, CH₃). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.3 (C=O), 151.0 (Ar), 145.2 (Ar), 137.6 (Ar), 136.2 (Ar), 136.1 (Ar), 133.1 (Ar), 129.7 (Ar), 129.2 (Ar), 129.04 (Ar), 128.99 (Ar), 128.95 (Ar), 128.4 (C–F, ²J_C–F = 30.7 Hz, CF₃–C), 127.4 (Ar), 125.9 (Ar), 124.5 (Ar), 121.70 (C–F, ¹J_C–F = 276.9 Hz, CF₃), 121.67 (Ar), 121.3–121.5 (m, Ar), 31.9 (CH₂), 30.7 (CH₂), 30.1 (CH₂), 29.3 (CH₂), 28.2–28.0 (m, CH₂), 22.7 (CH₂), 14.2 (CH₃). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −53.38 (s, 3F). IR (KBr): 2930, 2857, 1664, 1596, 1498, 1469, 1362, 1321, 1185, 1165, 1129, 1061, 898, 825, 791, 721, 706 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₇H₂₈F₃N₂O, 453.2148; found, 453.2163.

3-(4-Chlorophenyl)-4-(nonafluorobutyl)-2-(quinolin-8-yl)-isoquinolin-1(2H)-one (3kA).

Eluent = hexane/EtOAc 2:1. White solid (29% yield, 87 mg). Mp: 195.2–195.7 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.86 (dd, J = 4.2, 1.6 Hz, 1H, ArH), 8.57 (dd, J = 8.0, 1.3 Hz, 1H, ArH), 8.06 (dd, J = 8.3, 1.6 Hz, 2H, ArH), 7.80 (tm, J = 7.9 Hz, 1H, ArH), 7.69 (dd, J = 6.7, 2.9 Hz, 1H, ArH), 7.62 (t, J = 7.6 Hz, 1H, ArH), 7.41–7.34 (m, 3H, ArH), 7.15–7.09 (m, 1H, ArH), 7.04 (dd, J = 8.3, 2.1 Hz, 1H, ArH), 6.82 (d, J = 8.3 Hz, 1H, ArH), 6.58 (dd, J = 8.3, 2.2 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.5 (C=O), 151.1 (Ar), 147.6 (C–F, ³J_C–F = 3.6 Hz, Ar), 144.4 (Ar), 136.6 (Ar), 136.3 (Ar), 134.5 (Ar), 134.0 (Ar), 133.4 (Ar), 132.5 (Ar), 131.5 (Ar), 131.3 (Ar), 130.2 (Ar), 129.4 (Ar), 129.04 (Ar), 128.95 (Ar), 128.0 (Ar), 126.9 (Ar), 126.5 (Ar), 126.0 (Ar), 125.9 (Ar), 125.69 (m, CF₂–C=C), 122.0 (Ar), 121.2–105.4 (m, 4C, CF₃–CF₂–CF₂–CF₂–), 104.7 (C–F, ²J_C–F = 21.4 Hz, CF₂–C=C). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −81.31 (t, J = 9.9 Hz, 3F, CF₃), − 95.84 to −96.15 (m, 2F, CF₂), −118.85 to −119.12 (m, 2F, CF₂), −126.30 to −126.55 (m, 2F, CF₂). IR (KBr): 3053, 2924, 2853, 1675, 1602, 1551, 1484, 1390, 1352, 1321, 1233, 1134, 1089, 1021, 969, 916, 865, 827, 800, 767, 730 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₈H₁₅ClF₉N₂O, 601.0724; found, 601.0731.

4-(4-Chlorophenyl)-3-(nonafluorobutyl)-2-(quinolin-8-yl)-isoquinolin-1(2H)-one (4kA).

Eluent = hexane/EtOAc 2:1. White solid (28% yield, 84 mg). Mp: 121.2–121.9 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.82 (dd, J = 4.1, 1.7 Hz, 1H, ArH), 8.52–8.46 (m, 1H, ArH), 8.21 (dd, J = 8.3, 1.7 Hz, 1H, ArH), 7.94 (dd, J = 8.2, 1.1 Hz, 1H, ArH), 7.81–7.75 (m, 1H, ArH), 7.69–7.59 (m, 3H, ArH), 7.48–7.43 (m, 3H, ArH), 7.41 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 7.28–7.22 (m, 1H, ArH), 6.97–6.91 (m, 1H, ArH),. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 163.2 (C=O), 151.0 (Ar), 145.8–145.6 (m, Ar), 137.6–137.4 (m, Ar), 137.1–136.9 (m, Ar), 136.2 (Ar), 134.2 (Ar), 133.6–133.4 (m, Ar), 133.21 (Ar), 133.16 (Ar), 131.8 (Ar), 130.6–130.4 (m, Ar), 129.6 (Ar), 129.3 (Ar), 129.0 (Ar), 128.6 (Ar), 128.2 (Ar), 128.1 (Ar), 127.43 (Ar), 127.38 (C–F, ²J_C–F = 21.9 Hz, CF₂–C–N), 126.9 (Ar), 125.8 (Ar), 124.4–124.1 (m, Ar), 121.7 (Ar), 105.0–119.3 (m, 4C, CF₃–CF₂–CF₂–CF₂–). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −81.41 (t, J = 9.9 Hz, 3F, CF₃), − 93.70 to −100.75 (m, 2F, CF₂), −117.96 to −118.24 (m, 2F, CF₂), −125.64 to −128.22 (m, 2F, CF₂). IR (KBr): 3070, 1670, 1600, 1489, 1354, 1321, 1230, 1169, 1139, 1094, 1017, 893, 873, 792, 773, 761, 734 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₈H₁₅ClF₉N₂O, 601.0724; found, 601.0721.

6-(tert-Butyl)-3-(4-chlorophenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)isoquinolin-1(2H)-one (3aB).

Eluent = hexane/EtOAc 2:1. White solid (48% yield, 123 mg). Mp: 313.7–314.7 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.86 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.48 (d, J = 8.5 Hz, 1H, ArH), 8.09–8.03 (m, 2H, ArH), 7.73–7.67 (m, 2H, ArH), 7.41–7.34 (m, 3H, ArH), 7.13 (dd, J = 8.2, 2.0 Hz, 1H, ArH), 7.08 (dd, J = 8.2, 2.0 Hz, 1H, ArH), 6.84 (dd, J = 8.3, 2.0 Hz, 1H, ArH), 6.66 (dd, J = 8.3, 2.0 Hz, 1H, ArH), 1.46 (s, 9H, (CH₃)₃C–Ar). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.3 (C=O), 157.0 (Ar), 151.0 (Ar), 144.72–144.56 (m, Ar), 144.49 (Ar), 136.4 (Ar), 136.2 (Ar), 134.5 (Ar), 132.9 (Ar), 132.6 (Ar), 131.2 (Ar), 130.9–130.7 (m, Ar), 129.8–129.6 (m, Ar), 129.3 (Ar), 128.9 (Ar), 128.6 (Ar), 127.4 (Ar), 127.1 (Ar), 126.0 (Ar), 125.8 (Ar), 124.6 (C–F, ¹J_C–F = 273.3 Hz, CF₃), 123.5 (Ar), 121.9 (Ar), 121.0 (C–F, ³J_C–F = 4.2 Hz, CF₃–C=C), 106.7 (C–F, ²J_C–F = 29.9 Hz, CF₃–C), 35.7 ((CH₃)₃C–Ar), 31.2 ((CH₃)₃C–Ar). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.52 (s, 3F). IR (KBr): 2966, 2870, 1681, 1615, 1557, 1483, 1412, 1394, 1366, 1326, 3111, 1268, 1222, 1169, 1132, 1101, 1034, 1017, 988, 830, 811, 790, 742, 723 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₉H₂₃ClF₃N₂O, 507.1446; found, 507.1444.

6-(tert-Butyl)-4-(4-chlorophenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)isoquinolin-1(2H)-one (4aB).

Eluent = hexane/EtOAc 2:1. White solid (25% yield, 63 mg). Mp: 205.9–206.5 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.46 (d, J = 8.4 Hz, 1H, ArH), 8.21 (dd, J = 8.3, 1.7 Hz, 1H, ArH), 7.95 (dd, J = 8.2, 1.2 Hz, 1H, ArH), 7.77 (dm, J = 7.3 Hz, 1H, ArH), 7.70 (dd, J = 8.4, 1.7 Hz, 1H, ArH), 7.68–7.63 (m, 1H, ArH), 7.53–7.47 (m, 2H, ArH), 7.44–7.38 (m, 2H, ArH), 7.37–7.32 (m, 1H, ArH), 7.11 (d, J = 1.8 Hz, 1H, ArH), 1.25 (s, 9H, (CH₃)₃C–Ar). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.3 (C=O), 156.8 (Ar), 151.1 (Ar), 145.4 (Ar), 136.71 (Ar), 136.67 (Ar), 136.2 (Ar), 134.2 (Ar), 133.9 (Ar), 131.9–131.7 (m, Ar), 131.4–131.2 (m, Ar), 130.6–130.4 (m, Ar), 129.6 (Ar), 129.0 (Ar), 128.73 (Ar), 128.70 (C–F, ²J_C–F = 30.0 Hz, CF₃–C), 128.65 (Ar), 128.4 (Ar), 127.4 (Ar), 125.9 (Ar), 124.5 (Ar), 123.3 (Ar), 121.7 (Ar), 121.4–121.2 (m, Ar), 120.8 (C–F, ¹J_C–F = 276.9 Hz, CF₃), 35.4 ((CH₃)₃C–Ar), 31.0 ((CH₃)₃C–Ar). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −52.73 (s, 3F). IR (KBr): 3066, 2966, 2870, 1663, 1598, 1491, 1361, 1332, 1271, 1196, 1173, 1139, 1090, 1016, 846, 823, 791 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₉H₂₃ClF₃N₂O, 507.1446; found, 507.1455.

3-(4-Chlorophenyl)-6-methoxy-2-(quinolin-8-yl)-4-(trifluoromethyl)isoquinolin-1(2H)-one (3aC).

Eluent = hexane/EtOAc 2:1. White solid (48% yield, 118 mg). Mp: 233.9–234.8 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.87 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.45 (d, J = 9.0 Hz, 1H, ArH), 8.07 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 7.74–7.68 (m, 1H, ArH), 7.42–7.35 (m, 4H, ArH), 7.19 (dd, J = 9.0, 2.4 Hz, 1H, ArH), 7.13 (dd, J = 8.2, 2.0 Hz, 1H, ArH), 7.07 (dd, J = 8.2, 2.0 Hz, 1H, ArH), 6.82 (dd, J = 8.4, 2.0 Hz, 1H, ArH), 6.65 (dd, J = 8.4, 2.0 Hz, 1H, ArH), 3.98 (s, 3H, CH₃O–Ar). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 163.5 (C=O), 162.0 (Ar), 150.9 (Ar), 145.5–145.4 (m, Ar), 144.4 (Ar), 136.3 (Ar), 136.1 (Ar), 136.1 (Ar), 135.0 (Ar), 134.5 (Ar), 132.5 (Ar), 131.2 (Ar), 130.9 (Ar), 130.7 (Ar), 129.5 (Ar), 129.2 (Ar), 128.7 (Ar), 127.4 (Ar), 127.0 (Ar), 125.7 (Ar), 124.5 (C–F, ¹J_C–F = 273.1 Hz, CF₃), 121.8 (Ar), 119.4 (Ar), 116.5 (Ar), 107.0 (C–F, ³J_C–F = 4.1 Hz, Ar), 106.0 (C–F, ²J_C–F = 29.7 Hz, CF₃–C), 55.6 (CH₃O–Ar). ¹⁹NMR (376 MHz, CDCl₃, CFCl₃): δ −51.94 (s, 3F). IR (KBr): 2994, 1663, 1613, 1486, 1385, 1330, 1254, 1216, 1130, 1105, 1017, 941, 853, 824, 774, 751, 723 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₆H₁₇ClF₃N₂O₂, 481.0925; found, 481.0933.

4-(4-Chlorophenyl)-6-methoxy-2-(quinolin-8-yl)-3-(trifluoromethyl)isoquinolin-1(2H)-one (4aC).

Eluent = hexane/EtOAc 2:1. White solid (30% yield, 72 mg). Mp: 128.4–129.2 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.90 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.43 (d, J = 8.9 Hz, 1H, ArH), 8.23 (dd, J = 8.3, 1.7 Hz, 1H, ArH), 7.96 (dd, J = 8.2, 1.4 Hz, 1H, ArH), 7.76 (dm, J = 7.3 Hz, 1H, ArH), 7.68–7.63 (m, 1H, ArH), 7.50–7.45 (m, 2H, ArH), 7.43 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 7.41–7.37 (m, 1H, ArH), 7.33–7.29 (m, 1H, ArH), 7.18 (dd, J = 8.8, 2.5 Hz, 1H, ArH), 6.45 (d, J = 2.4 Hz, 1H, ArH), 3.74 (s, 3H, CH₃O–Ar). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 163.4 (C=O), 162.1 (Ar), 151.1 (Ar), 145.4 (Ar), 138.9 (Ar), 136.7 (Ar), 136.2 (Ar), 134.3 (Ar), 133.8 (Ar), 131.9–131.7 (m, Ar), 131.4–131.2 (m, Ar), 130.8 (Ar), 130.5–130.3 (m, Ar), 129.6 (Ar), 129.4 (C–F, ²J_C–F = 29.7 Hz, CF₃–C), 129.0 (Ar), 128.9 (Ar), 128.8 (Ar), 125.9 (Ar), 121.8 (Ar), 120.7 (C–F, ¹J_C–F = 277.2 Hz, CF₃), 120.60–120.46 (m, Ar), 120.44 (Ar), 117.4 (Ar), 109.7 (Ar), 55.5 (CH₃O–Ar). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −52.87 (s, 3F). IR (KBr): 3010, 1671, 1660, 1490, 1426, 1377, 1325, 1291, 1219, 1133, 1016, 853, 822, 795, 774, 752 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₆H₁₇ClF₃N₂O₂, 481.0925; found, 481.0940.

3-(4-Chlorophenyl)-2-(quinolin-8-yl)-4,6-bis(trifluoromethyl)-isoquinolin-1(2H)-one (3aD).

Eluent = hexane/EtOAc 2:1. White solid (53% yield, 140 mg). Mp: 258.8–259.7 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.86 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.66 (d, J = 8.4 Hz, 1H, ArH), 8.31 (s, 1H, ArH), 8.08 (dd, J = 8.4, 1.5 Hz, 1H, ArH), 7.83 (d, J = 8.4 Hz, 1H, ArH), 7.73 (dd, J = 7.8, 1.7 Hz, 1H, ArH), 7.45–7.63 (m, 3H, ArH), 7.15 (dd, J = 8.2, 2.1 Hz, 1H, ArH),7.10 (dd, J = 8.3, 2.1 Hz, 1H, ArH), 6.83 (dd, J = 8.4, 2.1 Hz, 1H, ArH), 6.69 (dd, J = 8.4, 2.1 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.6 (C=O), 151.1 (Ar), 146.5–146.3 (m, Ar), 144.1 (Ar), 136.3 (Ar), 135.8 (Ar), 135.02 (C–F, ²J_C–F = 32.5 Hz, CF₃–C), 135.00 (Ar), 133.3 (Ar), 131.8 (Ar), 131.1 (Ar), 130.7–130.5 (m, Ar), 130.0 (Ar), 129.6 (Ar), 129.6–129.4 (m, Ar), 128.9 (Ar), 128.0 (Ar), 127.6 (Ar), 127.2 (Ar), 125.8 (Ar), 124.2 (C–F, ¹J_C–F = 273.5 Hz, CF₃), 124.0 (m, Ar), 123.7 (C–F, ¹J_C–F = 272.9 Hz, CF₃), 122.30–122.10 (m, Ar), 122.07 (Ar), 106.3 (C–F, ²J_C–F = 30.7 Hz, CF₃–C). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.66 (s, 3F), −63.55 (s, 3F). IR (KBr): 3056, 1690, 1611, 1565, 1485, 1428, 1376, 1314, 1220, 1173, 1133, 1032, 986, 898, 818, 791, 722 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₆H₁₄ClF₆N₂O, 519.0693; found, 519.0698.

4-(4-Chlorophenyl)-2-(quinolin-8-yl)-3,6-bis(trifluoromethyl)-isoquinolin-1(2H)-one (4aD).

Eluent = hexane/EtOAc 2:1. White solid (29% yield, 75 mg). Mp: 202.9–203.6 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.87 (dd, J = 4.1, 1.5 Hz, 1H, ArH), 8.64 (d, J = 8.3 Hz, 1H, ArH), 8.24 (dm, J = 8.3 Hz, 1H, ArH), 7.99 (dm, J = 8.2 Hz, 1H, ArH), 7.84 (dm, J = 8.3 Hz, 1H, ArH), 7.80 (dm, J = 7.3 Hz, 1H, ArH), 7.69 (t, J = 7.8 Hz, 1H, ArH), 7.55–7.49 (m, 2H, ArH), 7.44 (dd, J = 8.3, 4.4 Hz, 1H, ArH), 7.42–7.37 (m, 2H, ArH), 7.35–7.30 (m, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.7 (C=O), 151.3 (Ar), 145.0 (Ar), 137.2 (Ar), 136.3 (Ar), 136.2 (Ar), 134.92 (Ar), 134.86 (C–F, ²J_C–F = 32.7 Hz, CF₃–C), 132.6 (Ar),131.6–131.8 (m, Ar), 131.1–131.3 (m, Ar), 130.40 (C–F, ²J_C–F = 30.2 Hz, CF₃–C), 130.36 (Ar), 130.0 (Ar), 129.8 (Ar), 129.21 (Ar), 129.20 (Ar), 129.12 (Ar), 129.0 (Ar), 126.0 (Ar), 125.5 (q, J = 3.2 Hz, Ar), 124.2 (C–F, ³J_C–F = 3.9 Hz, CF₃–C=C), 123.5 (C–F, ¹J_C–F = 273.5 Hz, CF₃), 122.0 (Ar), 120.51 (C–F, ¹J_C–F = 277.4 Hz, CF₃), 120.45 (m, Ar). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −53.06 (s, 3F), − 63,53 (s, 3F). IR (KBr): 3051, 1678, 1494, 1428, 1374, 1338, 1313, 1197, 1138, 1018, 823, 793 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₆H₁₄ClF₆N₂O, 519.0693; found, 519.0705.

3-(4-Chlorophenyl)-6-nitro-2-(quinolin-8-yl)-4-(trifluoromethyl)-isoquinolin-1(2H)-one (3aE).

Eluent = hexane/EtOAc 2:1. White solid (57% yield, 141 mg). Mp: 244.8–245.5 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.89 (m, 1H, ArH), 8.86 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.67 (d, J = 8.8 Hz, 1H, ArH), 8.35 (dd, J = 8.8, 2.0 Hz, 1H, ArH), 8.10 (dd, J = 8.3, 1.7 Hz, 1H, ArH), 7.75 (dd, J = 7.0, 2.6 Hz, 1H, ArH), 7.45–7.38 (m, 3H, ArH), 7.16 (dd, J = 8.3, 2.0 Hz, 1H, ArH), 7.11 (dd, J = 8.3, 2.0 Hz, 1H, ArH), 6.82 (dd, J = 8.4, 2.0 Hz, 1H, ArH), 6.69 (dd, J = 8.4, 2.0 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.2 (C=O), 151.2 (Ar), 150.9 (Ar), 147.4–147.2 (m, Ar), 144.0 (Ar), 136.4 (Ar), 135.5 (Ar), 135.2 (Ar), 133.8 (Ar), 131.5 (Ar), 130.96 (Ar), 130.93 (Ar), 130.6–130.4 (m, Ar), 129.8 (Ar), 129.5–129.3 (m, Ar), 128.9 (Ar), 127.7 (Ar), 127.3 (Ar), 125.8 (Ar), 124.0 (C–F, ¹J_C–F = 273.8 Hz, CF₃), 122.2 (Ar), 121.6 (Ar), 120.54 (C–F, ³J_C–F = 4.5 Hz, CF₃–C=C), 106.3 (C–F, ²J_C–F = 30.7 Hz, CF₃–C). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.83 (s, 3F). IR (KBr): 3070, 1682, 1609, 1532, 1476, 1349, 1222, 1175, 1132, 1017, 988, 901, 868, 840, 809, 789, 737 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₄ClF₃N₃O₃, 496.0670; found, 496.0682.

4-(4-Chlorophenyl)-6-nitro-2-(quinolin-8-yl)-3-(trifluoromethyl)-isoquinolin-1(2H)-one (4aE).

Eluent = hexane/EtOAc 2:1. White solid (23% yield, 57 mg). Mp: 122.5–123.2 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.87 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.66 (d, J = 8.7 Hz, 1H, ArH), 8.36 (dd, J = 8.8, 2.1 Hz, 1H, ArH), 8.25 (dd, J = 8.3, 1.7 Hz, 1H, ArH), 8.00 (dd, J = 8.4, 1.3 Hz, 1H, ArH), 7.99 (d, J = 2.2 Hz, 1H, ArH), 7.80 (dm, J = 7.3 Hz, 1H, ArH), 7.72–7.66 (m, 1H, ArH), 7.56–7.51 (m, 2H, ArH), 7.46 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 7.42–7.38 (m, 1H, ArH), 7.31–7.35 (m, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.2 (C=O), 151.3 (Ar), 150.9 (Ar), 144.9 (Ar), 137.9 (Ar), 136.4 (Ar), 135.9 (Ar), 135.2 (Ar), 132.2 (Ar), 131.8–131.6 (m, Ar), 131.24–131.11 (m, Ar), 131.17 (C–F, ²J_C–F = 30.2 Hz, CF₃–C), 130.8 (Ar), 130.35 (Ar), 130.33–130.22 (m, Ar), 130.17 (Ar), 129.4 (Ar), 129.1 (Ar), 126.0 (Ar), 123.1 (Ar), 122.5 (Ar), 122.1 (Ar), 120.43–120.28 (m, Ar), 120.33 (C–F, ¹J_C–F = 277.7 Hz, CF₃). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −53.26 (s, 3F). IR (KBr): 3052, 2368, 1679, 1618, 1531, 1490, 1197, 1150, 1016, 853, 824, 789, 751 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₄ClF₃N₃O₃, 496.0670; found, 496.0686.

7-Chloro-3-(4-chlorophenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)isoquinolin-1(2H)-one (3aF).

Eluent = hexane/EtOAc 2:1. White solid (52% yield, 122 mg). Mp: 235.8–236.7 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.86 (dd, J = 4.2, 1.5 Hz, 1H, ArH), 8.49 (d, J = 2.4 Hz, 1H, ArH), 8.09 (dd, J = 8.2, 1.5 Hz, 1H, ArH), 8.00–7.94 (m, 1H, ArH), 7.77 (dd, J = 8.9, 2.4 Hz, 1H, ArH), 7.73 (dd, J = 7.1 2.6 Hz, 1H, ArH), 7.44–7.36 (m, 3H, ArH), 7.12 (dd, J = 8.2, 1.9 Hz, 1H, ArH), 7.08 (dd, J = 8.2, 1.9 Hz, 1H, ArH), 6.79 (dd, J = 8.3, 1.9 Hz, 1H, ArH), 6.66 (dd, J = 8.3, 1.9 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.3 (C=O), 151.0 (Ar), 145.1–144.9 (m, Ar), 144.2 (Ar), 136.3 (Ar), 135.9 (Ar), 134.8 (Ar), 134.2 (Ar), 133.8 (Ar), 132.0 (Ar), 131.4 (Ar), 131.1 (Ar), 130.8–130.6 (m, Ar), 129.5 (Ar), 128.8 (Ar), 128.2 (Ar), 127.5 (Ar), 127.14 (Ar), 127.11 (Ar), 126.5 (C–F, ³J_C–F = 4.2 Hz, CF₃–C=C), 125.8 (Ar), 124.2 (C–F, ¹J_C–F = 273.6 Hz, CF₃), 122.0 (Ar), 106.2 (C–F, ²J_C–F = 30.3 Hz, CF₃–C). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.58 (s, 3F). IR (KBr): 3090, 3037, 1675, 1608, 1547, 1486, 1423, 1361, 1332, 1288, 1225, 1171, 1138, 1093, 1016, 979, 908, 855, 817, 786, 760, 743, 721 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₄Cl₂F₃N₂O, 485.0430; found, 485.0430.

7-Chloro-4-(4-chlorophenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)isoquinolin-1(2H)-one (4aF).

Eluent = hexane/EtOAc 2:1. White solid (25% yield, 61 mg). Mp: 119.9–120.5 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.48 (d, J = 2.2 Hz, 1H, ArH), 8.23 (dd, J = 8.3, 1.7 Hz, 1H, ArH), 7.98 (dd, J = 8.3, 1.3 Hz, 1H, ArH), 7.78 (dm, J = 7.3 Hz, 1H, ArH), 7.69–7.64 (m, 1H, ArH), 7.57 (dd, J = 8.7, 2.3 Hz, 1H, ArH), 7.51–7.46 (m, 2H, ArH), 7.44 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 7.39–7.34 (m, 1H, ArH), 7.32–7.06 (m, 2H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.4 (C=O), 151.2 (Ar), 145.1 (Ar), 136.34 (Ar), 136.29 (Ar), 135.9 (Ar), 135.3 (Ar), 134.6 (Ar), 133.5 (Ar), 133.3 (Ar), 131.8–131.6 (m, Ar), 131.3–131.1 (m, Ar), 130.5–130.3 (m, Ar), 129.9 (Ar), 129.08 (Ar), 129.04 (C–F, ²J_C–F = 30.1 Hz, CF₃–C), 128.99 (Ar), 128.96 (Ar), 128.85 (Ar), 128.1 (Ar), 127.9 (Ar), 126.0 (Ar), 121.9 (Ar), 120.6 (C–F, ¹J_C–F = 277.3 Hz, CF₃), 120.4 (m, Ar). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −52.89 (s, 3F). IR (KBr): 3068, 1675, 1596, 1489, 1365, 1325, 1278, 1198, 1133, 1089, 1016, 908, 824, 792, 760, 723 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₄Cl₂F₃N₂O, 485.0430; found, 485.0438.

3-(4-Chlorophenyl)-8-methyl-2-(quinolin-8-yl)-4-(trifluoromethyl)isoquinolin-1(2H)-one (3aG).

Eluent = hexane/EtOAc 2:1. White solid (47% yield, 108 mg). Mp: 242.0–242.7 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.89 (dd, J = 4.2, 1.6 Hz, 1H, ArH), 8.06 (dd, J = 8.3, 1.7 Hz, 1H, ArH), 7.94–7.88 (m, 1H, ArH), 7.69 (dd, J = 7.1, 2.6 Hz, 1H, ArH), 7.68–7.63 (m, 1H, ArH), 7.43–7.35 (m, 4H, ArH), 7.11 (dd, J = 8.2, 2.1 Hz, 1H, ArH), 7.07 (dd, J = 8.2, 2.1 Hz, 1H, ArH), 6.85 (dd, J = 8.4, 2.1 Hz, 1H, ArH), 6.66 (dd, J = 8.4, 2.1 Hz, 1H, ArH), 2.90 (s, 3H, CH₃). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 163.0 (C=O), 151.0 (Ar), 144.8–144.6 (m, Ar), 144.5 (Ar), 143.0 (Ar), 136.7 (Ar), 136.2 (Ar), 134.8 (Ar), 134.4 (Ar),132.7 (Ar), 132.5 (Ar), 131.28 (Ar), 131.26 (Ar), 130.8–130.6 (m, Ar), 129.6–129.4 (m, Ar), 129.2 (Ar), 128.9 (Ar), 127.4 (Ar), 127.0 (Ar), 125.8 (Ar), 124.6 (C–F, ¹J_C–F = 273.5 Hz, CF₃), 124.3 (Ar), 122.8 (C–F, ³J_C–F = 4.3 Hz, CF₃–C=C), 121.9 (Ar), 106.4 (C–F, ²J_C–F = 29.6 Hz, CF₃–C), 24.6 (CH₃). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.53 (s, 3F). IR (KBr): 3073, 3037, 2933, 2855, 1670, 1612, 1593, 1562, 1477, 1427, 1362, 1341, 1299, 1246, 1170, 1142, 1099, 1015, 881, 804, 787, 757 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₆H₁₇ClF₃N₂O, 465.0976; found, 465.0982.

4-(4-Chlorophenyl)-8-methyl-2-(quinolin-8-yl)-3-(trifluoromethyl)isoquinolin-1(2H)-one (4aG).

Eluent = hexane/EtOAc 2:1. White solid (25% yield, 58 mg). Mp: 137.5–138.3 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.90 (dd, J = 4.2, 1.6 Hz, 1H, ArH), 8.23 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 7.96 (dd, J = 8.3, 1.2 Hz, 1H, ArH), 7.77 (dm, J = 7.3 Hz, 1H, ArH), 7.70–7.63 (m, 1H, ArH), 7.50–7.41 (m, 4H, ArH), 7.41–7.33 (m, 2H, ArH), 7.32–7.25 (m, 1H, ArH), 6.94 (d, J = 8.0 Hz, 1H, ArH), 2.88 (s, 3H, CH₃). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 163.2 (C=O), 151.3 (Ar), 145.6 (Ar), 143.0 (Ar), 138.7 (Ar), 137.0 (Ar), 136.4 (Ar), 134.5 (Ar), 134.3 (Ar), 132.8 (Ar), 132.3 (Ar), 132.2–132.0 (m, Ar), 131.7–131.5 (m, Ar), 130.9–130.7 (m, Ar), 129.7 (Ar), 129.2 (Ar), 128.92 (Ar), 128.88 (C–F, ²J_C–F = 29.8 Hz, CF₃–C), 126.1 (Ar), 125.7 (Ar), 125.4 (Ar), 121.9 (Ar), 121.1–120.9 (m, Ar), 120.8 (C–F, ¹J_C–F = 277.0 Hz, CF₃), 24.3 (CH₃). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −52.97 (s, 3F). IR (KBr): 3010, 1671, 1660, 1490, 1426, 1377, 1325, 129, 1219, 1133, 1016, 853, 822, 795, 774, 752 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₆H₁₇ClF₃N₂O, 465.0976; found, 465.0970.

3-(4-Chlorophenyl)-8-nitro-2-(quinolin-8-yl)-4-(trifluoromethyl)-isoquinolin-1(2H)-one (3aH) and 4-(4-Chlorophenyl)-8-nitro-2-(quinolin-8-yl)-3-(trifluoromethyl) isoquinolin-1(2H)-one (4aH).

These products were hard to separate each other by silica gel column chromatography because of similar polarity. Eluent = hexane/EtOAc 2:1. Brown solid (43% yield, 106 mg). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.70 (s, 3F), −53.37 (s, 3F).

5-(4-Chlorophenyl)-6-(quinolin-8-yl)-4-(trifluoromethyl)thieno-[2,3-c]pyridin-7(6H)-one (3aI).

Eluent = hexane/EtOAc 2:1. White solid (57% yield, 130 mg). Mp: 226.1–226.6 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.88 (dd, J = 4.2, 1.6 Hz, 1H, ArH), 8.09 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 7.88 (d, J = 5.4 Hz, 1H, ArH), 7.74 (dd, J = 7.0, 2.6 Hz, 1H, ArH), 7.66–7.52 (m, 1H, ArH), 7.45–7.37 (m, 3H, ArH), 7.13 (dd, J = 8.2, 2.1 Hz, 1H, ArH), 7.08 (dd, J = 8.2, 2.1 Hz, 1H, ArH), 6.85 (dd, J = 8.3, 2.1 Hz, 1H, ArH), 6.68 (dd, J = 8.3, 2.1 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 158.4 (C=O), 151.1 (Ar), 145.6–145.5 (m, Ar), 144.3 (Ar), 141.0 (Ar), 136.3 (Ar), 135.8 (Ar), 134.9 (Ar), 134.7 (Ar), 131.5 (Ar), 131.2 (Ar), 131.1 (Ar), 130.0 (Ar), 129.6 (Ar), 128.9 (Ar), 127.5 (Ar), 127.1 (Ar), 125.8 (Ar), 124.8 (C–F, ³J_C–F = 4.0 Hz, CF₃–C=C), 124.3 (C–F, ¹J_C–F = 272.7 Hz, CF₃), 122.0 (Ar), 106.5 (C–F, ²J_C–F = 32.4 Hz, CF₃–C). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −53.59 (s, 3F). IR (KBr): 3061, 1671, 1603, 1524, 1487, 1437, 1411, 1390, 1369, 1338, 1286, 1240, 1173, 1097, 1016, 914, 833, 764, 736 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₃H₁₃ClF₃N₂OS, 457.0384; found, 457.0385.

4-(4-Chlorophenyl)-6-(quinolin-8-yl)-5-(trifluoromethyl)thieno-[2,3-c]pyridin-7(6H)-one (4aI).

Eluent = hexane/EtOAc 2:1. Brown solid (27% yield, 62 mg). Mp: 137.1–137.9 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.89 (dd, J = 4.2, 1.5 Hz, 1H, ArH), 8.22 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 7.97 (dm, J = 8.2 Hz, 1H, ArH), 7.78 (d, J = 7.5 Hz, 1H, ArH), 7.69 (d, J = 5.3 Hz, 1H, ArH), 7.68–7.63 (m, 1H, ArH), 7.49–7.38 (m, 4H, ArH), 7.37–7.31 (m, 1H, ArH), 6.79 (d, J = 5.3 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 158.2 (C=O), 151.3 (Ar), 145.7 (Ar), 145.3 (Ar), 136.3 (Ar), 136.0 (Ar), 134.4 (Ar), 134.2 (Ar), 132.5 (Ar), 131.0–130.8 (m, Ar), 130.70–130.55 (m, Ar), 130.55–130,40 (m, Ar), 130.0 (Ar), 129.6 (C–F, ²J_C–F = 30.5 Hz, CF₃–C), 129.0 (Ar), 128.8 (Ar), 125.9 (Ar), 121.9 (Ar), 120.8 (C–F, ¹J_C–F = 276.4 Hz, CF₃), 119.5–119.3 (m, Ar). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −52.64 (s, 3F). IR (KBr): 3066, 2959, 2853, 2371, 2360, 2340, 1667, 1596, 1572, 1489, 1439, 1387, 1344, 1258, 1198, 1159, 1132, 1014, 809, 780, 725 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₃H₁₃ClF₃N₂OS, 457.0384; found, 457.0399.

5-(4-Chlorophenyl)-6-(quinolin-8-yl)-4-(trifluoromethyl)furo[2,3-c]pyridin-7(6H)-one (3aJ).

Eluent = hexane/EtOAc 2:1. White solid (40% yield, 88 mg). Mp: 203.7–204.2 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.87 (dd, J = 4.2, 1.6 Hz, 1H, ArH), 8.07 (dd, J = 8.3, 1.5 Hz, 1H, ArH), 7.88 (d, J = 2.0 Hz, 1H, ArH), 7.72 (dd, J = 7.9, 1.6 Hz, 1H, ArH), 7.46–7.35 (m, 3H, ArH), 7.12 (dd, J = 8.2, 2.0 Hz, 1H, ArH), 7.07 (dd, J = 8.2, 2.0 Hz, 1H, ArH), 7.00–6.95 (m, 1H, ArH), 6.83 (dd, J = 8.3, 2.1 Hz, 1H, ArH), 6.67 (dd, J = 8.3, 2.0 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 153.4 (C=O), 151.1 (Ar), 149.2 (Ar), 145.3 (C–F, ³J_C–F = 2.9 Hz, Ar), 144.2 (Ar), 142.7 (Ar), 136.3 (Ar), 135.5 (Ar), 135.1 (Ar), 131.5–131.3 (m, Ar), 131.2 (Ar), 130.9 (Ar), 130.4–130.2 (m, Ar), 130.0–129.9 (m, Ar), 129.8 (Ar), 128.9 (Ar), 127.5 (Ar), 127.1 (Ar), 125.8 (Ar), 124.0 (C–F, ¹J_C–F = 271.7 Hz, CF₃), 122.0 (Ar), 108.0 (C–F, ³J_C–F = 3.4 Hz, CF₃–C=C), 104.4 (C–F, ²J_C–F = 33.7 Hz, CF₃–C). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −54.14 (s, 3F). IR (KBr): 3122, 2370, 2359, 1697, 1604, 1556, 1493, 1443, 1379, 1337, 1290, 1253, 1175, 1159, 1139, 1115, 1031, 952, 901, 855, 829, 799 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₃H₁₃ClF₃N₂O₂, 441.0612; found, 441.0615.

4-(4-Chlorophenyl)-6-(quinolin-8-yl)-5-(trifluoromethyl)furo[2,3-c]pyridin-7(6H)-one (4aJ).

Eluent = hexane/EtOAc 2:1. Brown solid (7% yield, 15 mg). Mp: 269.8–270.5 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.90 (dd, J = 4.2, 1.6 Hz, 1H, ArH), 8.24 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 7.99 (dd, J = 8.2, 1.2 Hz, 1H, ArH), 7.80 (d, J = 2.0 Hz, 1H, ArH), 7.78–7.74 (m, 1H, ArH), 7.70–7.64 (m, 1H, ArH), 7.48–7.43 (m, 3H, ArH), 7.43–7.38 (m, 1H, ArH), 7.36–7.31 (m, 1H, ArH), 6.38 (d, J = 2.0 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 153.1 (C=O), 151.3 (Ar), 149.1 (Ar), 145.2 (Ar), 143.4 (Ar), 136.3 (Ar), 135.7 (Ar), 134.5 (Ar), 134.1 (Ar), 133.7 (Ar), 130.7–130.5 (m, Ar), 130.5–130.4 (m, Ar), 130.2 (Ar), 129.07 (Ar), 129.02 (C–F, ²J_C–F = 30.7 Hz, CF₃–C), 128.92 (Ar), 128.91 (Ar), 125.9 (Ar), 122.0 (Ar), 120.6 (C–F, ¹J_C–F = 277.5 Hz, CF₃), 118.0–117.8 (m, Ar), 108.3 (Ar). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −52.66 (s, 3F). IR (KBr): 3118, 3004, 2929, 2855, 1683, 1604, 1574, 1490, 1451, 1426, 1382, 1302, 1200, 1134, 1088, 1032, 1015, 917, 901, 847, 821, 794, 777, 758 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₃H₁₃ClF₃N₂O₂, 441.0612; found, 441.0615.

3-(4-Chlorophenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)benzo-[h]isoquinolin-1(2H)-one (3aK).

Eluent = hexane/EtOAc 2:1. White solid (31% yield, 77 mg). Mp: 293.2–293.8 °C. ¹H NMR (400 MHz, CDCl₃): δ 10.14 (d, J = 8.6 Hz, 1H, ArH), 8.88–8.83 (m, 1H, ArH), 8.20 (d, J = 9.1 Hz, 1H, ArH), 8.11 (dd, J = 9.1, 1.9 Hz, 1H, ArH), 8.07 (d, J = 8.2 Hz, 1H, ArH), 7.95 (d, J = 7.6 Hz, 1H, ArH), 7.76–7.60 (m, 3H, ArH), 7.49–7.39 (m, 2H, ArH), 7.36 (dd, J = 8.2, 4.2 Hz, 1H, ArH), 7.17 (dd, J = 8.1, 1.7 Hz, 1H, ArH), 7.11 (dd, J = 8.1, 1.7 Hz, 1H, ArH), 6.92 (dd, J = 8.2, 1.8 Hz, 1H, ArH), 6.71 (dd, J = 8.2, 1.8 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.7 (C=O), 151.0 (Ar), 145.8–145.6 (m, Ar), 144.4 (Ar), 136.9 (Ar), 136.2 (Ar), 135.4 (Ar), 134.8 (Ar), 134.6 (Ar), 132.6 (Ar), 132.4 (Ar), 131.8 (Ar), 131.0 (Ar), 130.8–130.6 (m, Ar), 129.5–129.3 (m, Ar), 129.3 (Ar), 128.88 (Ar), 128.86 (Ar), 128.2 (Ar), 127.9 (Ar), 127.5 (Ar), 127.3 (Ar), 127.1 (Ar), 125.8 (Ar), 124.7 (C–F, ¹J_C–F = 273.7 Hz, CF₃), 121.9 (Ar), 121.7 (C–F, ³J_C–F = 4.5 Hz, CF₃–C=C), 119.9 (Ar), 106.6 (C–F, ²J_C–F = 29.7 Hz, CF₃–C). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −50.49 (s, 3F). IR (KBr): 2994, 1663, 1613, 1486, 1385, 1330, 1254, 1210, 1131, 1105, 1017, 941, 853, 824, 774, 751 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₉H₁₇ClF₃N₂O, 501.0976; found, 501.0974.

4-(4-Chlorophenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)benzo-[h]isoquinolin-1(2H)-one (4aK).

Eluent = hexane/EtOAc 2:1. White solid (17% yield, 43 mg). Mp: 140.0–140.5 °C. ¹H NMR (400 MHz, CDCl₃): δ 10.12–10.07 (m, 1H, ArH), 8.88 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.25 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 8.03–7.98 (m, 2H, ArH), 7.93–7.89 (m, 1H, ArH), 7.85–7.80 (m, 1H, ArH), 7.74–7.62 (m, 3H, ArH), 7.54–7.49 (m, 2H, ArH), 7.47–7.41 (m, 2H, ArH), 7.38–7.33 (m, 1H, ArH), 7.16 (d, J = 9.0 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 162.7 (C=O), 151.3 (Ar), 145.4 (Ar), 138.4 (Ar), 137.1 (Ar), 136.3 (Ar), 134.48 (Ar), 134.42 (Ar), 134.36 (Ar), 133.3 (Ar), 132.3–132.1 (m, Ar), 131.7 (Ar), 130.5–130.3 (m, Ar), 129.8 (C–F, ²J_C–F = 30.1 Hz, CF₃–C), 129.7 (Ar), 129.13 (Ar), 129.03 (Ar), 128.96 (Ar), 128.94 (Ar), 128.4 (Ar), 128.3 (Ar), 127.8 (Ar), 126.1 (Ar), 123.7 (Ar), 121.9 (Ar), 121.6 (Ar), 120.68 (C–F, ³J_C–F = 2.3 Hz, Ar), 120.64 (C–F, ¹J_C–F = 277.2 Hz, CF₃). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −52.78 (s, 3F). IR (KBr): 2369, 2357, 1662, 1597, 1488, 1371, 1199, 1131, 1016, 854, 834, 802, 761, 706 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₉H₁₇ClF₃N₂O, 501.0976; found, 501.0978.

6-(4-Chlorophenyl)-4-phenyl-1-(quinolin-8-yl)-5-(trifluoromethyl)pyridin-2(1H)-one (3aL).

Eluent = hexane/EtOAc 2:1. Brown solid (3% yield, 7 mg). Mp: 231.2–231.9 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.96 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.10 (dd, J = 8.3, 1.7 Hz, 1H, ArH), 7.76–7.71 (m, 1H, ArH), 7.52–7.40 (m, 8H, ArH), 7.17 (dd, J = 8.3, 2.1 Hz, 1H, ArH), 7.09 (dd, J = 8.3, 2.1 Hz, 1H, ArH), 6.88 (dd, J = 8.3, 2.1 Hz, 1H, ArH), 6.69 (dd, J = 8.3, 2.1 Hz, 1H, ArH), 6.68 (s, 1H, C(=O)–CH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.7 (C=O), 152.4 (Ar), 151.2 (Ar), 150.9–150.7 (m, Ar), 144.0 (Ar), 138.9 (Ar), 136.3 (Ar), 135.8 (Ar), 135.1 (Ar), 131.8 (Ar), 130.8–130.6 (m, Ar), 130.6 (Ar), 129.7 (Ar), 128.9 (Ar), 128.5 (Ar), 128.2 (Ar), 127.8–127.7 (m, Ar), 127.5 (Ar), 127.2 (Ar), 125.9 (Ar), 123.8 (C–F, ¹J_C–F = 273.8 Hz, CF₃), 122.6 (Ar), 122.1 (Ar), 109.4 (C–F, ²J_C–F = 30.3 Hz, CF₃–C). One carbon (CF₃–C) is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −48.13 (s, 3F). IR (KBr): 3062, 1677, 1598, 1483, 1397, 1322, 1306, 1174, 1145, 1075, 1017, 868, 794 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₇H₁₇ClF₃N₂O, 477.0976; found, 477.0974.

8-Chloro-3-(4-chlorophenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)isoquinolin-1(2H)-one (3aM).

Eluent = hexane/EtOAc 2:1. White solid (58% yield, 140 mg). Mp: 271.8–272.3 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.87 (dd, J = 4.2, 1.6 Hz, 1H, ArH), 8.06 (dd, J = 8.3, 1.5 Hz, 1H, ArH), 7.94 (m, 1H, ArH), 7.70 (dd, J = 7.3, 2.3 Hz, 1H, ArH), 7.68–7.60 (m, 2H, ArH), 7.42–7.34 (m, 3H, ArH), 7.11 (dd, J = 8.3, 1.9 Hz, 1H, ArH), 7.07 (dd, J = 8.3, 1.9 Hz, 1H, ArH), 6.83 (dd, J = 8.3, 1.9 Hz, 1H, ArH), 6.66 (dd, J = 8.3, 1.9 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 160.5 (C=O), 151.0 (Ar), 146.0–145.8 (m, Ar), 144.4 (Ar), 136.7 (Ar), 136.3 (Ar), 136.2 (Ar), 134.7 (Ar), 132.9 (Ar), 132.3 (Ar), 131.4 (Ar), 131.3 (Ar), 130.6–130.4 (m, Ar), 129.4 (Ar), 128.9 (Ar), 127.6 (Ar), 127.1 (Ar), 125.8 (Ar), 124.4 (C–F, ¹J_C–F = 274.0 Hz, CF₃), 123.7 (C–F, ³J_C–F = 4.5 Hz, CF₃–C=C), 122.4 (Ar), 122.0 (Ar), 105.8 (C–F, ²J_C–F = 30.1 Hz, CF₃–C). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.61 (s, 3F). IR (KBr): 3065, 3006, 1674, 1614, 1593, 1545, 1488, 1468, 1426, 1360, 1294, 1233, 1206, 1170, 1099, 1038, 1015, 895, 870, 826, 809, 787, 759, 728 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₄Cl₂F₃N₂O, 485.0430; found, 485.0432.

8-Chloro-4-(4-chlorophenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)isoquinolin-1(2H)-one (4aM).

Eluent = hexane/EtOAc 2:1. White solid (20% yield, 48 mg). Mp: 169.0–169.8 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H, ArH), 8.22 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 7.95 (dd, J = 8.3, 1.2 Hz, 1H, ArH), 7.79–7.74 (m, 1H, ArH), 7.68–7.59 (m, 2H, ArH), 7.50–7.43 (m, 4H, ArH), 7.38–7.33 (m, 1H, ArH), 7.31–7.26 (m, 1H, ArH), 7.01 (dm, J = 7.3 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 160.6 (C=O), 151.2 (Ar), 145.3 (Ar), 140.0 (Ar), 136.8 (Ar), 136.4 (Ar), 136.3 (Ar), 134.6 (Ar), 133.7 (Ar), 132.7 (Ar), 132.5 (Ar), 132.1–131.9 (m, Ar), 131.6–131.4 (m, Ar), 130.7–130.6 (m, Ar), 129.9 (C–F, ²J_C–F = 30.1 Hz, CF₃–C), 129.7 (Ar), 129.1 (Ar), 129.0 (Ar), 126.4 (Ar), 126.0 (Ar), 123.5 (Ar), 121.9 (Ar), 120.4 (C–F, ¹J_C–F = 277.0 Hz, CF₃), 120.1–119.9 (m, Ar). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −53.30 (s, 3F). IR (KBr): 3052, 1680, 1590, 1488, 1387, 1358, 1327, 1269, 1201, 1128, 1089, 1016, 980, 854, 810, 790, 732 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₄Cl₂F₃N₂O, 485.0430; found, 485.0439.

8-Bromo-3-(4-chlorophenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)isoquinolin-1(2H)-one (3aN).

Eluent = hexane/EtOAc 2:1. Light yellow solid (44% yield, 116 mg). Mp: 232.6–233.4 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.87 (dd, J = 4.2, 1.2 Hz, 1H, ArH), 8.07 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 8.03–7.97 (m, 1H, ArH), 7.90 (dm, J = 7.8 Hz, 1H, ArH), 7.70 (dd, J = 7.1, 2.4 Hz, 1H, ArH), 7.56 (tm, J = 8.2 Hz, 1H, ArH), 7.43–7.35 (m, 3H, ArH), 7.10 (dd, J = 8.3, 1.9 Hz, 1H, ArH), 7.07 (dd, J = 8.3, 1.9 Hz, 1H, ArH), 6.83 (dd, J = 8.3, 1.9 Hz, 1H, ArH), 6.65 (dd, J = 8.3, 1.9 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 160.4 (C=O), 151.0 (Ar), 145.9–145.7 (m, Ar), 144.3 (Ar), 136.22 (Ar), 136.20 (Ar), 136.17 (Ar), 135.2 (Ar), 134.7 (Ar), 133.0 (Ar), 132.2 (Ar), 131.2 (Ar), 130.6–130.4 (m, Ar), 129.4 (Ar), 128.9 (Ar), 127.5 (Ar), 127.1 (Ar), 125.8 (Ar), 124.39 (C–F, ³J_C–F = 4.4 Hz, CF₃–C=C), 124.33 (C–F, ¹J_C–F = 273.0 Hz, CF₃), 124.1 (Ar), 123.2 (Ar), 121.9 (Ar), 105.8 (C–F, ²J_C–F = 29.8 Hz, CF₃–C). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.58 (s, 3F). IR (KBr): 3064, 1676, 1611, 1588, 1489, 1462, 1340, 1292, 1205, 1168, 1101, 807 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₄BrClF₃N₂O, 528.9930; found, 528.9942.

8-Bromo-4-(4-chlorophenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)isoquinolin-1(2H)-one (4aN).

Eluent = hexane/EtOAc 2:1. Light yellow solid (16% yield, 42 mg). Mp: 220.1–220.9 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.87 (dd, J = 4.2, 1.6 Hz, 1H, ArH), 8.21 (dd, J = 8.2, 1.4 Hz, 1H, ArH), 7.95 (dm, J = 8.2 Hz, 1H, ArH), 7.87 (d, J = 7.8 Hz, 1H, ArH), 7.78 (dm, J = 7.3 Hz, 1H, ArH), 7.76 (tm, J = 7.8 Hz, 1H, ArH), 7.05–7.45 (m, 2H, ArH), 7.42 (dd, J = 8.3, 4.2 Hz, 1H, ArH), 7.39–7.32 (m, 2H, ArH), 7.31–7.26 (m, 1H, ArH), 7.06 (d, J = 8.4 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 160.6 (C=O), 151.2 (Ar), 145.2 (Ar), 140.0 (Ar), 136.5 (Ar), 136.4 (Ar), 136.3 (Ar), 134.5 (Ar), 133.7 (Ar), 132.6 (Ar), 132.1–131.9 (m, Ar), 131.6–131.4 (m, Ar), 130.7 (Ar), 129.78 (C–F, ²J_C–F = 30.0 Hz, CF₃–C), 129.73 (Ar), 129.1 (Ar), 129.0 (Ar), 127.2 (Ar), 126.0 (Ar), 124.4 (Ar), 124.2 (Ar), 121.9 (Ar), 120.4 (C–F, ¹J_C–F = 277.2 Hz, CF₃), 120.2–120.0 (m, Ar). One carbon is missing due to overlapping with the other signals. ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −53.26 (s, 3F). IR (KBr): 3056, 2923, 2366, 2344, 1672, 1586, 1485, 1426, 1389, 1356, 1327, 1273, 1193, 1165, 1125, 1085, 1015, 789 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₄BrClF₃N₂O, 528.9930; found, 528.9942.

4-(4-Chlorophenyl)-8-iodo-2-(quinolin-8-yl)-4-(trifluoromethyl)-isoquinolin-1(2H)-one (3aO).

Eluent = hexane/EtOAc 2:1. White solid (25% yield, 72 mg). Mp: 270.3–271.1 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.85 (dd, J = 4.1, 1.4 Hz, 1H, ArH), 8.31 (d, J = 7.6 Hz, 1H, ArH), 8.07–8.00 (m, 2H, ArH), 7.69 (dd, J = 7.8, 1.5 Hz, 1H, ArH), 7.43–7.31 (m, 4H, ArH), 7.08 (dd, J = 8.2, 1.7 Hz, 1H, ArH), 7.05 (dd, J = 8.2, 1.7 Hz, 1H, ArH), 6.82 (dd, J = 8.4, 1.5 Hz, 1H, ArH), 6.64 (dd, J = 8.4, 1.5 Hz, 1H, ArH). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 160.1 (C=O), 151.0 (Ar), 145.5–145.3 (m, Ar), 144.2 (Ar), 143.0 (Ar), 136.23 (Ar), 136.21 (Ar), 135.3 (Ar), 134.7 (Ar), 133.2 (Ar), 132.2 (Ar), 131.2 (Ar), 130.6–130.4 (m, Ar), 129.43 (Ar), 129.39 (Ar), 128.9 (Ar), 127.5 (Ar), 127.0 (Ar), 125.8 (Ar), 125.3 (C–F, ³J_C–F = 4.4 Hz, CF₃–C=C), 124.32 (C–F, ¹J_C–F = 273.6 Hz, CF₃), 124.26 (Ar), 122.0 (Ar), 106.0 (C–F, ²J_C–F = 30.0 Hz, CF₃–C), 94.6 (Ar). ¹⁹F NMR (376 MHz, CDCl₃, CFCl₃): δ −51.56 (s, 3F). IR (KBr): 3036, 1677, 1613, 1590, 1541, 1488, 1465, 1340, 1292, 1204, 1139, 1099 cm⁻¹. HRMS (FAB) m/z: [M + H]⁺ calcd for C₂₅H₁₄ClF₃IN₂O, 576.9791; found, 576.9788.

Typical Procedure for C–H Activation Reaction on a 3 mmol Scale.

In a 100 mL two-necked round bottomed-flask, equipped with a magnetic stirring bar, were placed fluoroalkylated alkyne 1h (0.733 g, 2.98 mmol), benzamide 2A (0.819 g, 3.30 mmol), Co(acac)₂·2H₂O (0.088 g, 0.300 mmol), KOAc (0.592 g, 6.03 mmol), and AgNO₃ (1.020 g, 6.00 mmol), in TFE (30 mL) under argon, and the resulting mixture was stirred at 80 °C using an oil bath. After 18 h, the reaction mixture was cooled to room temperature and subjected to flash column chromatography using silica gel as the stationary phase and EtOAc as the mobile phase. After the removal of the solvent from the eluent under reduced pressure, the residue was purified by silica gel column chromatography (hexane/AcOEt = 2:1) to give the corresponding 3-(4-biphenyl)-2-(quinolin-8-yl)-4-(trifluoromethyl)isoquinolin-1(2H)-one (3hA) (0.780 g, 1.58 mmol) and 4-(4-biphenyl)-2-(quinolin-8-yl)-3-(trifluoromethyl)-isoquinolin-1(2H)-one (4hA) (0.326 g, 0.662 mmol).