ones with Î±-Bromo Ketones and Benzamides via Pd-catalyzed CH

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Cascade One-pot Method to Synthesize Isoquinolin-1(2H)-ones with #-Bromo Ketones and Benzamides via Pd-catalyzed C-H Activation Caixia Xie, Zhen Dai, Yadi Niu, and Chen Ma J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03224 • Publication Date (Web): 25 Jan 2018 Downloaded from http://pubs.acs.org on January 26, 2018

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The Journal of Organic Chemistry

Cascade One-pot Method to Synthesize Isoquinolin-1(2H)-ones with α-Bromo Ketones and Benzamides via Pd-catalyzed C-H Activation Caixia Xie, a Zhen Dai, a Yadi Niu, a and Chen Ma a,b* a

School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P. R. China. b

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, P. R. China Email: [email protected]

ABSTRACT: A cross-coupling strategy of palladium-catalyzed ortho-C-H bond activation and intramolecular addition of N-C annulation to synthesize isoquinolin-1(2H)-ones has been developed. A wide range of α-bromo ketones with different substituents proceeded smoothly in this reaction and varieties of isoquinolin-1(2H)-one derivatives were obtained in moderate to good yields. INTRODUCTION Isoquinolin-1(2H)-one derivatives are very important structure units of alkaloids. They exist extensively in naturally and biologically interesting molecules such as thalifoline,1 doryphorine,2 ruprechstyril,3 isocarbostyril,4 and pancratistatin.5 These isoquinoline-1(2H)-ones exhibit superior qualities in the discovery and development of drugs for the treatment of human diseases. And their biological and medicinal activities such as tachykinin recepters,6 antifungal activities,7 5-HT3 antagonists,8 hypolipidemic,9 and CPARPs inhibitors,10 have been reported in detail. On account of these activities, the syntheses of isoquinolin-1(2H)-ones has attracted widely attention. Many approaches to this structure have been developed.11 they can be obtained effectively by the cyclization of 2-halobenzamides with alkynes,12 β-ketoesters,13 ketones,14 and 1,3-indandiones15 catalyzed by copper or zinc catalysts. In addition to these classical methods, transition metal-catalyzed C-H bond

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activation and annulation of N-substituted benzamides provided efficient methods for the construction of isoquinolin-1(2H)-ones.16 Among these, the ortho-C-H bond functionalization of N-(quinolin-8-yl)benzamides and intramolecular cyclization have been explored widely with alkynes,17 allenes,18 arynes,19 and ortho-nitrobenzoic acids20 (Scheme 1). However, although transition metal-catalyzed C-H bond activation and annulation to synthesize isoquinolin-1(2H)-ones has been significantly advanced,16-20 the direct activation of C-H bond of N-(quinolin-8-yl)benzamides with organic halides to promote the annulation has not yet been reported as far as we study. The halide coupling partner in Pd-catalyzed C-H alkylation has emerged as a powerful method for generating C-C bond.21 Thus we envisioned that α-bromo ketones would be cheap, available and functional-group-tolerant substrates to synthesize isoquinolin-1(2H)-ones directly and effectively. Scheme 1. Different Protocols for the Syntheses of Isoquinolin-1(2H)-ones.

RESULTS AND DISCUSSION Our initial investigations commenced by exploring the optimal reaction conditions using 2-methyl-N-(quinolin-8-yl)benzamide (1a) and 2-bromo-1-phenylethanone (2a) as model substrates under Pd-catalyzed conditions (Table 1). The desired product 8-methyl-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3a) was obtained with a yield of 75% when the reaction proceeded in the presence of 10 mol% Pd(OAc)2, 20 mol% PivOH and 2.5 equiv K2CO3 at 110 oC for 36 h in t-AmOH (entry 1). Then, screening of solvents indicated that t-AmOH was the most appropriate solvent (entries


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Table 1. Optimization of Reaction Conditions a, e

Ligand Additive Solvent Temp/oC Yield/%b PivOH K2CO3 t-AmOH 110 75 PivOH K2CO3 o-Xylene 110 N.D. PivOH K2CO3 DCE/t-BuOH 110 trace PivOH K2CO3 i-Octyl-OH 110 N.D. PivOH K2CO3 t-BuOH 110 70 PivOH K2CO3 i-PrOH 110 59 PivOH K2CO3 i-BuOH 110 37 PivOH K2CO3 DME 110 N.D. PivOH K2CO3 HFIP 110 21 PivOH Na2CO3 t-AmOH 110 33 PivOH Cs2CO3 t-AmOH 110 31 PivOH K3PO4 t-AmOH 110 36 PivOH KOH t-AmOH 110 16 PivOH t-BuONa t-AmOH 110 33 ----K2CO3 t-AmOH 110 N.D. L-Proline K2CO3 t-AmOH 110 62 Dibenzyl K2CO3 t-AmOH 110 N.D. phosphite 18 Pd(OAc)2 L-Alanine K2CO3 t-AmOH 110 79 19 Pd(OAc)2 Valine K2CO3 t-AmOH 110 67 20 Pd(OAc)2 L-Alanine K2CO3 t-AmOH 100 17 21 Pd(OAc)2 L-Alanine K2CO3 t-AmOH 120 81 22 Pd(OAc)2 L-Alanine K2CO3 t-AmOH 130 83 23 Pd(TFA)2 L-Alanine K2CO3 t-AmOH 130 64 24 Pd(acac)2 L-Alanine K2CO3 t-AmOH 130 53 25 PdCl2(PPh3)2 L-Alanine K2CO3 t-AmOH 130 63 d 26 Pd(OAc)2 L-Alanine K2CO3 t-AmOH 130 77 a Reaction conditions: 1a (0.5 mmol), Pd catalyst (0.05 mmol), ligand (0.1 mmol), 2a (2.0 mmol), additive (1.25 mmol), solvent (2 mL), 130 °C, 36 h. bIsolated yields. c DCE/t-BuOH = 2:1. dUnder N2 atmosphere. eA supplement can be seen in Supporting Information. 1-9). And various additives were examined, revealing that K2CO3 was the best choice in this reaction (entries 1 and 10-14). Subsequently, a control experiment without ligand was carried out and no desired product was detected (entry 15). Thus, several ligands were also investigated (entries 16-19), and the use of L-Alanine was more efficient than others. Additionally, lowering the temperature did not increase the yield of 3a (entry 20), but increasing it to 130 oC resulted in the best yield of 83% (entry Entry 1 2 3c 4 5 6 7 8 9 10 11 13 13 14 15 16 17

Catalyst (mol%) 2 Pd(OAc) Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2



22). No satisfactory yield of the desired product 3a was obtained catalyzed by other palladium catalysts such as Pd(TFA)2, PdCl2(PPh3)2 and Pd(acac)2 (entries 23-25). Finally, no improvement occurred when the reaction proceeded under N2 atmosphere (entry 26). Table 2. Substrate Scope a ,b

a

Reaction condition A: 1 (0.5 mmol), Pd(OAc)2 (0.05 mmol), L-Alanine (0.1 mmol), 2 (2.0 mmol), K2CO3 (1.25 mmol), t-AmOH (2 mL), 130 °C, TLC monitored the end of the reaction. bIsolated yields. cCondition B: 1 (0.5 mmol), Pd(OAc)2 (0.05 mmol), L-Alanine (0.1 mmol), 2 (1.0 mmol), K2CO3 (1.25 mmol), NaI (0.1 mmol), t-AmOH (2 mL), 130 °C, TLC monitored the end of the reaction. Equipped with a set of optimized conditions (Table 1, entry 22), we assessed the scopes of the method by varying the substituents of N-(quinolin-8-yl)benzamides (1) and α-bromo ketones (2), as shown in Table 2. It is noteworthy that the substituents on the aromatic ring of compound 1 have a significant influence on the efficiency of the reaction. The N-(quinolin-8-yl)benzamides bearing electron-donating groups at ortho-position gave better yields than these with electron-withdrawing groups (3a, 3n and 3o). And the yield increased when NaI was added in the reaction of 2-fluoro-N-(quinolin-8-yl)benzamide (3n, condition B), which was similar to the reported results.21b Meanwhile, the substituents at meta-position and para-position of


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compounds 1 were also compatible to this reaction, giving the corresponding products (3p and 3v). However, when N-(quinolin-8-yl)benzamides bearing electron-neutral (H) and para-substituent group, a mixture of separable mono-substituted and bis-substituted was obtained by roughly 1 to 2 (3v, 3v’ - 3aa, 3aa’). We next examined the influence of the α-bromo ketones. Much to our satisfaction, α-bromo ketones bearing electron-donating groups (4-Me, 4-OMe, 3-Me and 3-OMe) and electron-withdrawing groups (4-F, 4-Cl, 4-CF3, 4-NO2, 3-Cl and 3-F) transformed smoothly into corresponding products in moderate to good yields (56%-80%, 3b-3j). 2-Bromo-1-(naphthalen-2-yl)ethanone also participated well in the reaction to afford the desired product 3k in a yield of 69%. In addition, when the substituents were alkyl groups (-Me, -cyclopropyl), the desired products 3l and 3m were obtained in the yield of 62% and 51%, respectively. Finally, the substituents of the compounds 2 have no obvious influence on the ratio of the products when reacting with N-(quinolin-8-yl)benzamide (3w, 3w’-3aa, 3aa’). Based on the above data and the previous reports on bidentate directing group-assisted C-H activation, a possible mechanism was proposed (See the Supporting information). Processes of C-H activation catalyzed by Palladium complexes and intramolecular additions promoted by K3CO3 were included. CONCLUSION In summary, we have developed a Pd-catalyzed, bidentate-auxiliary-directed methodology for the synthesis of isoquinolin-1(2H)-one derivatives with α-bromo ketones. Reactants with different substituents were competent in this transformation. And a broad range of products were obtained in moderate to good yields, providing an effective synthetic method for the isoquinolin-1(2H)-one derivatives. Besides, the detachment of the directing group of the reaction and the precise origin of its monoalkylation selectivity are under study in our laboratory. EXPERIMENTAL SECTION General information N-(quinolin-8-yl)benzamide were prepared according to literature procedures. 22 Other reagents were commercially available and were used without further purification. All reactions were monitored by thin-layer chromatography (TLC). 1H NMR and 13C NMR spectra were recorded on a Bruker Avance 400 (400 MHz) or 300 (300 MHz) spectrometer, using CDCl3 as solvent and tetramethylsilane (TMS) as internal standard. HRMS spectra (ESI) were determined on a Q-TOF6510 spectrograph (Agilent). Melting points were determined on an XD-4 digital micro melting point apparatus. General experimental procedures for the synthesis of compounds 3 A mixture of compound 1 (0.5 mmol), compound 2 (2.0 mmol), Pd(OAc)2 (0.05 mmol), K2CO3 (1.25 mmol), L-Alanine (0.1 mmol) in t-AmOH (2 mL) was stirred in



a sealed tube at 130 oC. TLC monitored the end of the reaction. Then the mixture was cooled to room temperature and brine (100 ml) was poured into the solution. The mixture was extracted with EtOAc (5 × 30 mL). The organic layers were combined and dried using anhydrous Na2SO4. The product was purified using flash chromatography on silica gel (petroleum ether / EtOAc = 3: 1). Lastly, the desired product was obtained after vacuum-rotary evaporation. 8-Methyl-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3a) White solid (150 mg, 83%). Mp: 169–170 °C. 1H NMR (300 MHz, CDCl3): δ = 8.90 (dd, J = 5.7 Hz, 1.8 Hz, 1H), 8.05 (dd, J = 8.4 Hz, 1.5 Hz, 1H), 7.69 (dd, J = 8.1 Hz, 1.5 Hz, 1H), 7.53-7.48 (m, 2H), 7.43-7.38 (m, 2H), 7.34 (q, J = 4.2 Hz, 1H), 7.25 (t, J = 3.6 Hz, 1H), 7.11-7.08 (m, 2H), 7.01-6.89 (m, 3H), 6.57 (s, 1H), 2.90 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 164.1, 150.9, 144.9, 144.3, 142.5, 139.1, 137.8, 136.4, 136.1, 131.99, 130.9, 129.9, 128.9, 128.7, 128.6, 127.9, 127.3, 125.9, 124.6, 123.9, 121.6, 107.9, 24.01. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H19N2O 363.1492; found 363.1489. 8-Methyl-2-(quinolin-8-yl)-3-(p-tolyl)isoquinolin-1(2H)-one (3b) Off white solid (134 mg, 71%). Mp: 199–201 °C.1H NMR (400 MHz, CDCl3): δ = 8.95 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.10 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.74 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.56-7.52 (m, 2H), 7.48-7.43 (m, 2H), 7.39 (q, J = 4.0 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.04 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 6.60 (s, 1H), 2.95 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 164.1, 150.9, 145.0, 144.4, 142.5, 139.2, 138.0, 137.7, 136.1, 133.6, 131.9, 130.9, 129.7, 128.9, 128.6, 128.5, 128.0, 125.9, 124.6, 123.9, 121.5, 107.8, 24.0, 21.1. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C26H21N2O 377.1648; found 377.1650. 3-(4-Methoxyphenyl)-7-methyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3c) White solid (143 mg, 73%). Mp: 157–159 °C. 1H NMR (400 MHz, CDCl3): δ = 8.90 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.08 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.71 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.52-7.48 (m, 2H), 7.45-7.38 (m, 2H), 7.36 (q, J = 4.0 Hz, 1H), 7.25 (t, J = 5.6 Hz, 1H), 7.03 (dt, J = 9.6 Hz, 2.8 Hz, 2H), 6.54 (s, 1H), 6.47-6.44 (m, 2H), 3.60 (s, 3H), 2.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 164.2, 159.0, 150.9, 144.9, 144.1, 142.5, 139.1, 138.0, 136.1, 131.9, 130.9, 130.0, 129.7, 128.9, 128.5, 126.0, 124.5, 123.8, 121.5, 112.7, 107.8, 55.0, 23.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C26H21N2O2 393.1598; found 393.1591. 3-(4-Chlorophenyl)-8-methyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3d) Light yellow solid (143 mg, 72%). Mp: 204-206 °C. 1H NMR (400 MHz, CDCl3): δ = 8.89 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.09 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.74 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.55-7.40 (m, 2H), 7.45-7.40 (m, 2H), 7.36 (q, J = 4.0 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.07-7.05 (m, 2H), 6.92-6.90 (m, 2H), 6.54 (s, 1H), 2.90 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 164.0, 151.0, 145.0, 143.1, 142.6, 138.8, 137.5, 136.2, 134.9, 133.90, 132.07, 130.9, 130.1, 130.1, 129.0, 128.8, 127.6, 126.0, 124.7, 124.0, 121.7, 108.0, 23.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H18N2OCl 397.1102; found 397.1117.


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3-(4-Fluorophenyl)-8-methyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3e) Light yellow solid (150 mg, 79%). Mp: 219–221 °C. 1H NMR (400 MHz, CDCl3): δ = 8.89 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.08 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.73 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.46-7.39 (m, 2H), 7.36 (q, J = 4.0 Hz, 1H), 7.26-7.24 (m, 1H), 7.10-7.06 (m, 2H), 6.60 (t, J = 8.8 Hz, 2H), 6.54 (s, 1H), 2.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 164.0, 163.4 (d, 1JC,F = 247 Hz, 1C), 150.9, 144.7, 143.2, 142.6, 138.9, 137.6, 136.2, 132.5 (d, 4JC,F = 4 Hz, 1C), 132.0, 131.0, 130.6 (d, 3JC,F = 8 Hz, 1C), 130.0, 129.0, 128.7, 125.9, 124.6, 124.0, 121.6, 114.4 (d, 2 JC,F = 2 Hz, 1C), 107.9, 23.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H18N2OF 381.1398; found 381.1387. 8-Methyl-2-(quinolin-8-yl)-3-(4-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one (3f) White solid (142 mg, 66%). Mp: 218–220 °C. 1H NMR (400 MHz, CDCl3): δ = 8.90 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.10 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.75 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.47 (m, 2H), 7.38 (q, J = 4.4 Hz, 1H), 7.29 (m, 3H), 7.21 (d, J = 8.4 Hz, 2H), 6.57 (s, 1H), 2.90 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 163.9, 151.0, 144.7, 142.8, 139.9, 138.7 (d, 1JC,F = 242 Hz, 1C), 137.3, 132.2, 130.9, 130.3, 130.0 (d, 2JC,F = 33 Hz, 1C), 129.0, 128.9, 126.0, 125.1, 124.8, 124.3 (d, 3JC,F = 4 Hz, 1C), 124.3, 124.2, 124.1, 122.4, 121.7, 108.3, 23.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C26H18N2OF3 431.1360; found 431.1369. 8-Methyl-3-(4-nitrophenyl)-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3g) Yellow solid (163 mg, 80%). Mp: 284–286 °C. 1H NMR (400 MHz, CDCl3): δ = 8.89 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.10 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.81-7.74 (m, 3H), 7.61-7.54 (m, 2H), 7.50 (q, J = 8.0 Hz, 2H), 7.39 (q, J =4.0 Hz, 1H), 7.33-7.26 (m, 3H), 6.59 (s, 1H), 2.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 163.7, 151.1, 147.1, 144.5, 142.7, 142.7, 142.1, 138.4, 137.1, 136.3, 132.3, 131.0, 130.7, 129.6, 129.1, 129.1, 126.0, 124.9, 124.2, 122.5, 121.8, 108.6, 23.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H18N3O3 408.1343; found 408.1351. 3-(3-Chlorophenyl)-8-methyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3h) White solid (147 mg, 74%). Mp: 179–181 °C. 1H NMR (400 MHz, CDCl3): δ = 8.91 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.09 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.73 (dd, J = 8.0 Hz, 1.0 Hz, 1H), 7.54-7.40 (m, 2H), 7.47-7.40 (m, 2H), 7.37 (q, J = 4.4 Hz, 1H), 7.27-7.25 (m, 1H), 7.17 (t, J = 1.2 Hz, 1H), 6.97-6.94 (m, 2H), 6.84 (t, J = 8.0 Hz, 1H), 6.56 (s, 1H), 2.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 163.9, 151.0, 144.7, 142.8, 142.6, 138.8, 137.9, 137.5, 136.2, 133.2, 132.1, 130.9, 130.2, 129.0, 128.9, 128.8, 128.5, 128.0, 126.9, 126.0, 124.7, 124.1, 121.7, 108.1, 24.0. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H18N2OCl 397.1102; found 397.1101. 3-(3-Fluorophenyl)-8-methyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3i) Off white solid (150 mg, 79%). Mp: 148–150 °C. 1H NMR (400 MHz, CDCl3): δ = 8.91 (d, J = 2.8 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.2 Hz, 2H), 7.47 (q, J =8.0 Hz, 2H), 7.38 (q, J =8.0 Hz, 1H), 7.27 (d, J =8.0 Hz, 1H), 6.90-6.83 (m, 3H), 6.71-6.67 (m, 1H), 6.57 (s, 1H), 2.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 163.9, 162.8 (d, 1JC,F = 244 Hz, 1C), 151.0, 144.7, 142.9, 142.6, 138.8,



138.4 (d, 3JC,F = 8 Hz, 1C), 137.5, 136.2, 132.1, 130.9, 130.2, 129.0 (d, 3JC,F = 14 Hz, 1C), 128.7, 126.0, 124.7, 124.6 (d, 4JC,F = 3 Hz, 1C), 124.1, 121.7, 116.0 (d, 2JC,F = 23 Hz, 1C), 115.0 (d, 2JC,F = 21 Hz, 1C), 108.0, 23.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H18N2OF 381.1394; found 381.1391. 3-(3-Methoxyphenyl)-8-methyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3j) Light yellow solid (114 mg, 58%). Mp: 216–218 °C. 1H NMR (400 MHz, CDCl3): δ = 8.94 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.10 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.72 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.51-7.35 (m, 5H), 7.25-7.24 (m, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H), 6.60 (s, 2H), 6.57-6.55 (m, 1H), 3.28 (s, 3H), 2.90 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 164.0, 158.4, 150.9, 145.2, 144.0, 142.5, 139.0, 138.1, 137.6, 136.2, 132.0, 130.7, 129.9, 128.9, 128.6, 128.5, 126.1, 124.6, 123.9, 121.5, 121.1, 114.7, 113.3, 107.8, 54. 8, 23.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C26H21N2O2 393.1598; found 393.1593. 8-Methyl-3-(naphthalen-2-yl)-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3k) Light yellow solid (142 mg, 69%). Mp: 111–113 °C. 1H NMR (400 MHz, CDCl3): δ = 8.96 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.02 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.72 (s, 1H), 7.62-7.50 (m, 5H), 7.44 (d, J = 7.6 Hz, 2H), 7.37-7.31 (m, 5H), 7.26-7.24 (m, 1H), 7.11 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.66 (s, 1H), 2.91 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 164.1, 150.9, 144.9, 144.2, 142.6, 139.1, 137.8, 136.2, 133.9, 132.5, 132.4, 132.0, 131.0, 130.0, 128.9, 128.6, 128.1, 128.0, 127.4, 126.7, 126.4, 126.0, 124.7, 124.0, 121.6, 108.4, 24.0. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C29H21N2O 413.1648; found 413.1646. 3-Cyclopropyl-8-methyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3l) Light yellow solid (83 mg, 51%). Mp: 178-180 °C. 1H NMR (400 MHz, CDCl3): δ = 8.89 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.22 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 7.94 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.74-7.68 (m, 2H), 7.48-7.39 (m, 2H), 7.35 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 6.35 (s, 1H), 2.87 (S, 3H), 1.17-1.13 (m, 1H), 0.69-0.55 (m, 1H), 0.47-0.43 (m, 1H), 0.31-0.30 (m, 1H), 0.30-0.28 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 164.5, 151.2, 144.9, 142.3, 139.4, 137.6, 136.2, 131.7, 130.4, 129.2, 128.8, 126.4, 124.2, 123.6, 121.7, 103.5, 23.8, 14.5, 7.9, 6.5. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C22H19N2O 327.1492; found 327.1498. 3,8-Dimethyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3m) White solid (93 mg, 62%). Mp: 196–198 °C. 1H NMR (400 MHz, CDCl3): δ = 8.90 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.24 (dd, J = 8.3 Hz, 1.6 Hz, 1H), 7.95 (dd, J = 7.0 Hz, 2.7 Hz, 1H), 7.70-7.65 (m, 2H), 7.48-7.41 (m, 2H), 7.34 (d, J = 8.0, 1H), 7.17 (d, J = 4.0, 1H), 6.45 (s, 1H), 2.85 (s, 3H), 1.86 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 164.6, 151.4, 144.6, 142.3, 139.9, 139.4, 137.4, 136.3, 131.8, 130.1, 129.5, 129.1, 129.0, 126.5, 123.8, 123.4, 121.9, 105.9, 23.9, 20.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C20H17N2O 301.1335; found 301.1331. 8-Fluoro-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3n) Light yellow solid (A: 33 mg, 18%, B: 86 mg, 47%). Mp: 224–226 °C. 1H NMR (300 MHz, CDCl3): δ = 8.89 (dd, J = 6.0 Hz, 3.0 Hz, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.69 (d, J = 6.0 Hz, 1H),


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7.61-7.54 (m, 1H), 7.50 (dd, J = 9.0 Hz, 3.0 Hz, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.35-7.30 (m, 2H), 7.12-6.58 (m, 6H), 6.57 (d, J = 2.1 Hz, 1H), 5.26 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 164.7 (d, 1JC,F = 263 Hz, 1C), 160.5 (d, 3JC,F = 5 Hz, 1C), 150.9, 145.7, 144.7, 140.1, 137.0, 136.1 (d, 3JC,F = 10 Hz, 1C), 133.7 (d, 3JC,F = 10 Hz, 1C), 130.9, 128.9, 128.6, 128.182, 127.4, 125.8, 122.1 (d, 4JC,F = 5 Hz, 1C), 121. 6, 114.6, 114. 6, 113.6 (d, 2JC,F = 22 Hz, 1C), 106.7 (d, 4JC,F = 3 Hz, 1C). HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C24H16N2OF 367.1241; found 367.1239. 8-Chloro-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3o) White solid (46 mg, 24%). Mp: 247–249 °C. 1H NMR (400 MHz, CDCl3): δ = 8.90 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.08 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.72 (dd, J = 8.4 Hz, 0.8 Hz, 1H), 7.53-7.48 (m, 4H), 7.44 (t, J = 8.0 Hz, 1H), 7.37 (q, J = 4.0 Hz, 1H), 7.12-7.10 (m, 1H), 7.04-7.00 (m, 1H), 6.96 (t, J = 8.0 Hz, 2H), 6.57 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 161.5, 150. 9, 145.5, 144.7, 140.4, 137.2, 136.2, 136.0, 135.9, 132.3, 130.9, 129.8, 128.9, 128.7, 128.6, 128.1, 127.3, 125.8, 125.4, 121.9, 121.6, 106.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C24H16N2OCl 383.0946; found 383.0949. 7-Methyl-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3p) Off-white solid (138 mg, 76%). Mp: 233–235 °C. 1H NMR (400 MHz, CDCl3): δ = 8.87 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.28 (s, 1H), 8.03 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.67 (dd, J = 8.0 Hz, 0.8 Hz, 1H), 7.48 (s, 2H), 7.47 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.31 (q, J = 4.4 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 7.2 Hz, 1H), 6.93 (t, J = 7.6 Hz, 2H), 6.59 (s, 1H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 163.2, 150. 9, 144.9, 143.6, 137.6, 136.7, 136.5, 136.1, 135.0, 134.2, 130.7, 128.9, 128.8, 128.7, 128.0, 127.9, 127.3, 126.1, 125.8, 125.4, 121.5, 107.3, 21.6. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H19N2O 363.1492; found 363.1490. 7-Methyl-2-(quinolin-8-yl)-3-(p-tolyl)isoquinolin-1(2H)-one (3q) Light yellow solid (132 mg, 70%). Mp: 231–233 °C. 1H NMR (400 MHz, CDCl3): δ = 8.89 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 8.26 (s, 1H), 8.09 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.72 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.50 (s, 2H), 7.50-7.45 (m, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.36 (q, J = 4.4 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 8.0 Hz, 2H), 6.59 (s, 1H), 2.49 (s, 3H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 163.3, 150.9, 144.9, 143.7, 137.7, 137.6, 136.6, 136.1, 135.0, 134.1, 133.7, 130.7, 128.8, 128.7, 128.6, 128.0, 128.0, 126.0, 125.9, 125.3, 121.4, 107.3,21.6, 21.1. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C26H21N2O 377.1648; found 377.1644. 3-(4-Chlorophenyl)-7-methyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3r) Yellow solid (157 mg, 79%). Mp: 270–271 °C. 1H NMR (400 MHz, CDCl3): δ = 8.87 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.26 (s, 1H), 8.09 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.74 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.53-7.48 (m, 3H), 7.44 (t, J = 8.0 Hz, 1H), 7.36 (q, J = 4.4 Hz, 1H), 7.05 (d, J = 12 Hz, 2H), 6.92 (d, J = 12 Hz, 2H), 6.57 (s, 1H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 163.1 151.0, 144.7, 142.4, 137.3, 137.0, 136.2, 135.0, 134.7, 134.3, 133.9, 130.7, 130.1, 128.9, 128.1, 127.6, 126.2, 125.9, 125.5, 121.6, 107.5,



21.6. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H18N2OCl 397.1102; found 397.1102. 3-(4-Fluorophenyl)-7-methyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3s) Off white solid (160 mg, 84%). Mp: 199–201 °C. 1H NMR (400 MHz, CDCl3): δ = 8.87 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.27 (s, 1H), 8.08 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.73 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.51-7.47 (m, 3H), 7.44 (t, J = 7.6 Hz, 1H), 7.35 (q, J = 4.0 Hz, 1H), 7.09-7.05 (m, 2H), 6.64-6.58 (m, 3H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 163.4 (d, 1JC,F = 247 Hz, 1C), 163.2, 150.9, 144.7, 142.5, 137.4, 136.9, 136.1, 134.8, 134.2, 132.6 (d, 4JC,F = 3 Hz, 1C), 130.7 (d, 3JC,F = 8 Hz, 1C), 128.9, 128.8, 128.0, 126.1, 125.9, 125.56, 121.6, 114.4 (d, 2JC,F = 21 Hz, 1C), 107.4, 21.6. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H18N2OF 381.1398; found 381.1376. 7-Methyl-3-(4-nitrophenyl)-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3t) Yellow solid (157 mg, 77%). Mp: 244-246 °C. 1H NMR (400 MHz, CDCl3): δ = 8.88 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.28 (s, 1H), 8.12 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.81-7.75 (m, 3H), 7.57-7.52 (m, 3H),7.48 (t, J = 8.0 Hz, 1H), 7.39 (q, J = 4.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.63 (s, 1H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 162.9, 151.0, 147.1, 144.3, 142.9, 141.3, 137.8, 136.7, 136.4, 134.5, 134.3, 130.9, 129. 7, 129.2, 129.0, 128.2, 126.4, 126.0, 125.8, 122.6, 121.8, 108.2, 21.6. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H18N3O3 408.1343; found 408.1349. 3,7-Dimethyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3u) Yellow solid (103 mg, 69%). Mp: 258–260 °C. 1H NMR (400 MHz, CDCl3): δ = 8.86 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.23-8.18 (m, 2H), 7.95 (dd, J = 7.2 Hz, 2.0 Hz, 1H), 7.70-7.64 (m, 2H), 7.47-7.45 (m, 1H), 7.42-7.39 (m, 2H), 6.49 (s, 1H), 2.46 (s, 3H), 1.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 163.7, 151.4, 144.6, 139.1, 137.1, 136.3, 135.8, 135.3, 134.0, 123.0, 129.4, 129.1, 127.8, 126.4, 125.3, 124.8, 121.8, 105.3, 21.5, 21.0. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C20H17N2O 301.1335; found 301.1332. 6-Methyl-8-(2-oxo-2-phenylethyl)-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2H)-on e (3v) Light yellow solid (43 mg, 18%). Mp: 202-203 °C. 1H NMR (400 MHz, CDCl3): δ = 8.86 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.01 (t, J = 7.2 Hz, 3H), 7.62 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.37-7.32 (m, 4H), 7.30 (q, J = 4.4 Hz, 1H), 7.06 (d, J = 7.6 Hz, 3H), 6.97-6.88 (m, 3H), 6.54 (s, 1H), 5.51 (d, J = 16.8 Hz, 1H), 4.69 (d, J = 17.2 Hz, 1H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 198.0, 163.5, 150.6, 144.5, 142.3, 139.3, 138.0, 137.5, 136.5, 136.0, 132.4, 132.3, 131.2, 128.8, 128.4, 127.7, 127.1, 126.0, 125.8, 121.8, 121.3, 107.7, 45.8, 21.6. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C33H25N2O2 481.1838; found 481.1838. 6-Methyl-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3v’) Light yellow solid (74 mg, 41%). Mp: 199-202 °C. 1H NMR (400 MHz, CDCl3): δ = 8.89 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.07 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.70-7.68 (m, 1H), 7.49-7.47 (m, 1H), 7.41-7.31 (m, 4H), 7.11 (d, J = 6.4 Hz, 2H), 7.01-6.99 (m, 1H), 6.95-6.92 (m, 2H), 6.57 (s, 1H), 2.51 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 163.2, 150.9, 144.8, 144.6, 243.2, 137.5, 137.4, 136.5, 136.1, 130.8, 128.8, 128.6,


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128.4, 128.4, 127.9, 127.3, 125.9, 125.8, 123.3, 121.5, 107.3, 21.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H19N2O 363.1492; found 363.1492. (3w) 8-(2-Oxo-2-phenylethyl)-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one 1 Yellow solid (47 mg, 20%). Mp: 204–206 °C. H NMR (400 MHz, CDCl3): δ = 8.86 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.00-7.97 (m, 3H), 7.62-7.58 (m, 2H), 7.54-7.50 (m, 2H), 7.46 (t, J = 7.2 Hz, 1H), 7.37-7.33 (m, 3H), 7.30-7.27 (q, J = 4.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 7.06-7.04 (m, 2H), 6.99-6.95 (m, 1H), 6.99-6.88 (m, 2H), 6.60 (s, 1H), 5.54 (d, J = 17.2 Hz, 1H), 4.73 (d, J = 17.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 197.8, 163.5, 150.6, 144.6, 144.5, 139.2, 138.2, 137.5, 137.5, 136.3, 135.9, 132.4, 131.9, 131.1, 130.7, 128.8, 128.5, 128.4, 128.3, 127.8, 127.1, 126.2, 125.8, 124.0, 121.4, 107.8, 45.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C32H23N2O2 467.1754; found 467.1757. 3-Phenyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3w’) White solid (59 mg, 34%). Mp: 203–205 °C. 1H NMR (400 MHz, CDCl3): δ = 8.89 (d, J = 2.8 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.71 (t, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.2 Hz, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.35 (q, J = 4.4 Hz, 1H), 7.11 (d, J = 7.2 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.64 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 163.2, 150.9, 144.8, 144.6, 137.4, 137.3, 136.4, 136.0, 132.7, 130.7, 128.8, 128.7, 128.5, 128.0, 127.3, 126.7, 126.1, 125.8, 125.5, 121.5, 107.4. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C24H17N2O 349.1335; found 349.1334. 8-(2-oxo-2-(p-tolyl)ethyl)-2-(quinolin-8-yl)-3-(p-tolyl)isoquinolin-1(2H)-one (3x) Off-white solid (42 mg, 17%). Mp: 224–226 °C. 1H NMR (400 MHz, CDCl3): δ = 8.85 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 7.97 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.61 (m, 2H), 7.50 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.28 (q, J = 4.0 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 8.0 Hz, 2H), 6.57 (s, 1H), 5.49 (d, J = 16.8 Hz, 1H), 4.71 (d, J = 17.2 Hz, 1H), 2.30 (s, 3H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 197.6, 163.6, 150.6, 144.7, 144.5, 143.1, 139.2, 138.4, 137.6, 136.0, 135.0, 133.5, 131.8 131.1, 130.5, 129.0, 128.8, 128.6, 128.6, 128.4, 127.9, 126.0, 125.8, 123.9, 121.4, 107.9, 45.8, 21.6, 21.1. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C34H27N2O2 495.2067; found 495.2068. 2-(quinolin-8-yl)-3-(p-tolyl)isoquinolin-1(2H)-one (3x’) Yellow solid (53 mg, 29%). Mp: 92–94 °C. 1H NMR (400 MHz, CDCl3): δ = 8.90 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.10 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.73-7.66 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.50-7.46 (m, 2H), 7.43 (t, J = 8.0 Hz, 1H), 7.37 (q, J = 4.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 7.6 Hz, 2H), 6.62 (s, 1H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 163.3, 150.9, 144.9, 144.6, 137.8, 137.4, 136.1, 133.6, 132.6, 130.7, 128.8, 128.7, 128.6, 128.5, 128.0, 126.6, 126.1, 125.9, 125.4, 121.5, 107.4, 21.1. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H19N2O 363.1492; found 363.1495. 3-(4-methoxyphenyl)-8-(2-(4-methoxyphenyl)-2-oxoethyl)-2-(quinolin-8-yl)isoqui nolin-1(2H)-one (3y) White solid (58 mg, 22%). Mp: 221–223 °C. 1H NMR (400



MHz, CDCl3): δ = 8.84 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 7.98-7.95 (m, 3H), 7.60-7.54 (m, 2H), 7.50-7.48 (m, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.28 (q, J = 4.0 Hz, 1H), 7.20 (d, J = 6.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.56 (s, 1H), 6.44 (d, J = 8.8 Hz, 2H), 5.48 (d, J = 16.8 Hz, 1H), 4.70 (d, J = 17.2 Hz, 1H), 3.76 (s, 3H), 3.58 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 196.6, 163.7, 163.0, 159.0, 150.6, 144.7, 144.2, 139.3, 138.5, 137.6, 136.0, 131.8, 131.1, 130.7, 130.6, 130.4, 130.1, 128.9, 128.5, 126.0, 125.8, 123.9, 121.4, 113.4, 112.6, 107.8, 55.3, 55.0, 45.4. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C34H27N2O4 527.1967; found 527.1967. 3-(4-Methoxyphenyl)-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3y’) Light yellow solid (81 mg, 43%). Mp: 178–180 °C. 1H NMR (400 MHz, CDCl3): δ = 8.90 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.10 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.73-7.66 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.50-7.42 (m, 3H), 7.37 (q, J = 4.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.62 (s, 1H), 6.48 (d, J = 8.8 Hz, 2H), 3.61 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 163.4, 159.1, 150.9, 144.8, 144.3, 137.5, 137.4, 136.1, 132.6, 130.7, 130.1, 128.9, 128.8, 128.7, 128.5, 126.5, 126.1, 125.9, 125.4, 121.5, 112.7, 107.4, 55.1. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C25H19N2O2 379.1441; found 379.1448. 3-(4-Chlorophenyl)-8-(2-(4-chlorophenyl)-2-oxoethyl)-2-(quinolin-8-yl)isoquinoli n-1(2H)-one (3z) White solid (59 mg, 22%). Mp: 228–230 °C. 1H NMR (400 MHz, CDCl3): δ = 8.83 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.02 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.66-7.58 (m, 2H), 7.54-7.48 (m, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.31-7.28 (m, 3H), 7.00 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6,57 (s, 1H), 5.40 (d, J = 17.2 Hz, 1H), 4.66 (d, J = 17.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 196.6, 163.4, 150.68, 144.4, 143.3, 139.0, 138.7, 137.9, 137.1, 136.2, 135.9, 134.7, 133.9, 132.1, 131.1, 130.9, 130.1, 129.8, 128.9, 128.8, 128.6, 127.5, 126.3, 125.9, 124.0, 121.5, 108.0, 45.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C32H21N2O2Cl2 535.0974; found 535.0972. 3-(4-Chlorophenyl)-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3z’) Light yellow solid (86 mg, 45%). Mp: 209–211 °C. 1H NMR (400 MHz, CDCl3): δ = 8.89 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.12 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.77 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.70-7.68 (m, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.53-7.45 (m, 3H), 7.39 (q, J = 4.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.61 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 163.2, 150.9, 144.6, 143.3, 137.7, 137.1, 136.3, 134.9, 134.0, 132.8, 130.8, 130.1, 128.9, 128.5, 127.6, 126.94, 126.2, 125.9, 125.6, 121.6, 107.6. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C24H16N2OCl 383.0946; found 383.0946. 3-(4-Fluorophenyl)-8-(2-(4-fluorophenyl)-2-oxoethyl)-2-(quinolin-8-yl)isoquinoli n-1(2H)-one (3aa) White solid (63 mg, 25%). Mp: 241–242 °C. 1H NMR (400 MHz, CDCl3): δ = 8.84 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 8.02-7.99 (m, 3H), 7.66-7.59 (m, 2H), 7.54-7.49 (m, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.31 (q, J = 4.0 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.05-6.98 (m, 4H), 6.61-6.57 (m, 3H), 5.45 (d, J = 16.8 Hz, 1H), 4.68 (d, J = 16.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 196.2, 166.7 (d, 1JC,F = 252 Hz, 1C),


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163.5, 163.3 (d, 1JC,F = 247 Hz, 1C), 150.7, 144.4, 143.5, 139.1, 138.0, 137.2, 136.1, 133.9 (d, 4JC,F = 3 Hz, 1C), 132.3 (d, 4JC,F = 3 Hz, 1C), 132.0, 131.1 (d, 3JC,F = 7 Hz, 1C), 130.9 (d, 3JC,F = 8 Hz, 1C), 130.7 (d, 3JC,F = 8 Hz, 1C), 128.9, 128.7, 126.3, 125.8, 124.0, 121.5, 115.4 (d, 2JC,F = 21 Hz, 1C), 114.3 (d, 2JC,F = 22 Hz, 1C), 45.9. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C32H21N2O2F2 503.1566; found 503.1565. 3-(4-Fluorophenyl)-2-(quinolin-8-yl)isoquinolin-1(2H)-one (3aa’) Off white solid (93 mg, 51%). Mp: 178–180 °C. 1H NMR (400 MHz, CDCl3): δ = 8.88 (dd, J = 4.4 Hz, 1.2 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.10 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.75-7.68 (m, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.53-7.49 (m, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.37 (q, J = 4.0 Hz, 1H), 7.11-7.07 (m, 2H), 6.65-6.61 (m, 3H); 13C NMR (100 MHz, CDCl3): δ = 163,4 (d, 1JC,F = 247 Hz, 1C), 163.2, 151.0, 144.67, 143.5, 137.2 (d, 3JC,F = 7 Hz, 1C), 136.1, 132.8, 132.5, 132.4, 130.8, 130.7, 130.6, 128.9 (d, 4JC,F = 3 Hz, 1C), 128.5, 126.9, 126.1, 125.9, 125.6, 121.6, 114.5 (d, 2JC,F = 21 Hz, 1C), 107.5. HRMS (ESI-TOF) m/z: [(M + H)+] calcd for C24H16N2OF 367.1241; found 367.1243.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

ACKNOWLEDGMENT We are grateful to the National Science Foundation of China (No. 21572117) and State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (No. GTZK201707) for financial support of this research.

ASSOCIATED CONTENT Supporting Information Available: The copies of 1H NMR and 13C NMR spectra of all compounds is available free of charge via the Internet:// pubs. acs. org.

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