Oxidative Aromatization of 3,4-Dihydroquinolin-2(1H)-ones to Quinolin

Jun 7, 2019 - Inorganic persulfate salts were identified as efficient reagents for the oxidative aromatization of 3,4-dihydroquinolin-2(1H)-ones throu...
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Oxidative Aromatization of 3,4-Dihydroquinolin-2(1H)‑ones to Quinolin-2(1H)‑ones Using Transition-Metal-Activated Persulfate Salts Weiming Chen,†,‡,⊥ Changliang Sun,§,⊥ Yan Zhang,∥ Tianwen Hu,§ Fuqiang Zhu,§ Xiangrui Jiang,∥ Melkamu Alemu Abame,‡,∥ Feipu Yang,∥ Jin Suo,∥ Jing Shi,§ Jingshan Shen,*,∥ and Haji A. Aisa*,†

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†

Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, South Beijing Road 40-1, Urumqi, Xinjiang 830011, People’s Republic of China ‡ University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, People’s Republic of China § Topharman Shanghai Co., Ltd., Building 1, No. 388 Jialilue Road, Zhangjiang Hitech Park, Shanghai 201209, People’s Republic of China ∥ CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People’s Republic of China S Supporting Information *

ABSTRACT: Inorganic persulfate salts were identified as efficient reagents for the oxidative aromatization of 3,4dihydroquinolin-2(1H)-ones through the activation of readily available transition metals, such as iron and copper. The feasible protocol conforming to the requirement of green chemistry was utilized in the preparation of the key intermediate (7-(4chlorobutoxy)quinolin-2(1H)-one 2) of brexpiprazole in 80% isolated yield on a 100 g scale, and different quinolin-2(1H)-one derivatives with various functional groups were demonstrated in 52−89% yields.

Q

The frequently used oxidative methods for the aromatization of dihydroquinolin-2(1H)-one derivative 1, such as oxygen, MnO2, Dess−Martin periodinane,14 PhI(OAc)2, PhI(OAc)2/ KBr, I2/MeOH, I2/DMSO, FeCl3/AcOH,15 Pd/C/AcOH,16,32 and TBHP/CuSO4,20 were attempted but provided unsatisfactory results with fairly low conversation rates or a complicated reaction mixture. By our further trials, easily accessible potassium persulfate (K2S2O8) presented encouraging results in comparison with potassium peroxymonosulfate (Oxone), as shown in Table 1 (entries 1 and 2). No remarkable improvement was observed regardless of the reaction temperature and solvents that were optimized. In further trials, the combination of NaBr and persulfate salt did not accelerate the oxidation, and more impurities were generated by TLC. As known, transition-metal-activated persulfate salts were utilized widely for organic-pollutant degradation,33,34 but they have not been used for this oxidative aromatization. Therefore, we attempted initially to use iron salt as the activator for the oxidative aromatization of 3,4-dihydroquinolin-2(1H)ones.33−35 When a catalytic amount of FeSO4·7H2O was employed, a significant improvement was observed with up to

uinolin-2(1H)-ones, as a typical sort of quinoline and coumarin derivatives,1−11 are an important class of nitrogen heterocycles and exist broadly in the molecular structures of nature products12,13 and clinical drugs, such as brexpiprazole, cilostamide, indacaterol, rebamipide, and tipifanib (Figure 1). With respect to the preparation of quinolin-2(1H)-one derivatives, one widely used strategy is the oxidative aromatization of their corresponding 3,4-dihydroquinolin-2(1H)-one derivatives. Although a number of methods for the oxidative aromatization of heterocyclic compounds have been developed,14−23 they are rarely reported for the oxidative aromatization of 3,4-dihydroquinolin-2(1H)-one derivatives except using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).24−26 In our previous work, the oxidative aromatization of 3,4dihydroquinolin-2(1H)-one derivative 1 to quinolin-2(1H)one derivative 2, a key intermediate of an antipsychotic drug substance brexpiprazole,27−29 was performed using DDQ.30 In this method, the oxidant is highly efficient for this chemical transformation, but it is uneconomical, harmful, and potentially genotoxic as well as its byproduct 4,5-dichloro-3,6-dihydroxyphthalonitrile (DDHQ).31 Therefore, we herein describe our efforts to develop an alternative method for the oxidative aromatization of 3,4-dihydroquinolin-2(1H)-one derivatives. © 2019 American Chemical Society

Received: March 17, 2019 Published: June 7, 2019 8702

DOI: 10.1021/acs.joc.9b00756 J. Org. Chem. 2019, 84, 8702−8709

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The Journal of Organic Chemistry

Figure 1. Natural products and clinical drugs containing quinolin-2(1H)-ones.

Table 1. Selected Screening Experiments of Oxidative Aromatization of 1a

HPLC results of reaction mixtured entry

oxidants

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19h

Oxone K2S2O8 Oxone K2S2O8 (NH4)2S2O8 Na2S2O8 Na2S2O8 Na2S2O8 Na2S2O8 Na2S2O8 Na2S2O8 Na2S2O8 Na2S2O8 Na2S2O8 Na2S2O8 Na2S2O8 Na2S2O8 Na2S2O8 Na2S2O8

b

c

activator

solvent

FeSO4·7H2O FeSO4·7H2O FeSO4·7H2O FeSO4·7H2O MnCl2 FeCl3·6H2O Fe(acac)2 Fe powder Co(OAc)2 NiCl2 CuSO4 Pd/C (10%) CuSO4 CuSO4 CuSO4 CuSO4 CuSO4

MeCN/water MeCN/water MeCN/water MeCN/water MeCN/water MeCN/water MeCN/water MeCN/water MeCN/water MeCN/water MeCN/water MeCN/water MeCN/water MeCN/water toluene/waterf acetone/waterg MeCN water MeCN/water

reaction time (h)

conv of 1 (%)e

purity of 2 (%)

6 6 6 1 1 1 6 1 2.5 1 6 6 0.5 2 6 6 6 1 0.5

42 90 71 99 99 ∼100 99 ∼100 95 ∼100 96 90 99 99 43 40 53 95 ∼100

25 64 40 90 89 92 72 82 73 90 54 45 93 84 22 25 36 89 94

a

The reactions were performed on a 1−5 g scale under the conditions (0.1 equiv of activator and 2.0 equiv of persulfate salt in 20 V solvent) unless otherwise noted. bThe ratio of mixed solvent was 1:1 by volume. cThe sampling time was 6 h unless the reaction end point was monitored by TLC. d Calculated for the reaction mixture from the HPLC area percentage at 230 nm. eCalculated by 100% minus remaining 1 from the HPLC area percentage. fPerformed at about 100 °C. gPerformed at about 65 °C. hThe reaction was performed on a 100 g scale to give the purified product in 80% isolated yield and with 98% HPLC purity.

used (Table 1, entries 7, 11, and 12). In the following research, CuSO4 was chosen as the activator considering its shorter reaction time. In the screening of several solvents (toluene/water, acetone/ water, and MeCN), bad results were given in the aspects of conversion rate andor HPLC purity (Table 1, entries 15−17). Though the reaction mixture in water gave a high conversion rate and purity level, the starting material, 1, was not consumed completely because of its poor solubility in water (Table 1, entry 18); therefore, the combination of MeCN/water was a good choice.

a 99% conversion rate and 90% of HPLC purity (Table 1, entries 3 and 4). During our following studies, sodium persulfate (Na 2 S 2 O 8 ) and ammonium persulfate ((NH4)2S2O8) gave similar results to K2S2O8, but Na2S2O8 was selected for further research due to its relatively higher thermal stability and solubility (Table 1, entries 5 and 6).36,37 Subsequently, different transition metals were employed to activate the persulfate salt. The significant improvements were observed using Fe, Cu, and Pd (Table 1, entries 8−10, entries 13 and 14) in comparison with the results without metal activation (entry 2). Lower HPLC purities along with a longer reaction time were indicated when Mn, Co, and Ni salts were 8703

DOI: 10.1021/acs.joc.9b00756 J. Org. Chem. 2019, 84, 8702−8709

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The Journal of Organic Chemistry Table 2. Preparation of Quinolin-2(1H)-ones by CuSO4-Activated Oxidative Aromatizationa

a The reaction was performed on 1−5 g scale by “the standard method” (0.1 equiv of CuSO4 and 2.0 equiv of Na2S2O8 in 10 V acetonitrile and 10 V water) unless otherwise noted. bThe isolated yields were calculated after purified by column chromatography unless otherwise mentioned. cThe reaction was performed by “the modified method” (0.1 equiv of CuSO4 and 2.0 equiv of Na2S2O8 in 10 V acetonitrile, 10 V water, and 5 equiv of hydrochloride acid). dObtained as a dihydrochloride salt. e21% of brexpiprazole was observed in the reaction mixture by HPLC, but it was not isolated. f4.0 equiv of Na2S2O8 was utilized. gIn the reaction mixture, a large amount of 3s was not consumed, and crude 4s was obtained in 20% yield after workup.

complicated reaction mixture by TLC.39 However, when hydrochloride acid (5 equiv) was preadded into the reaction mixture (as the modified method), potential oxidations on Natoms of the piperazine ring in 3c were inhibited to afford the oxidative aromatization product 4c with a moderate yield. However, for the oxidative aromatization of 3,4-dihydrobrexpiprazole 3d by the modified method,40 the low purity of brexpiprazole was observed in the reaction mixture by HPLC analysis, as the S-atom in thiophene was prone to be oxidized. Contrastively, aripiprazole (3e) without the S-atom, a structural analogue of brexpiprazole, afforded the desired product 4e in a good yield by the modified method. The scope of the oxidative aromatization of 3,4-dihydroquinolin-2(1H)-one derivatives was further investigated. 5-Ethyloxy derivative 4f and 7-ethyloxy derivative 4g were obtained in

As a result, the economical combination of stoichiometric persulfate salts and a catalytic amount of transition metals in MeCN/water was feasible and defined for the oxidative aromatization. The key intermediate 2 was obtained in 80% isolated yield and with 98% purity on a 100 g scale by the standard method of 2.0 equiv of Na2S2O8 and 0.1 equiv of CuSO4 (Table 1, entry 19). To further investigate the oxidative aromatization, first, several intermediates in the synthetic route of brexpiprazole were prepared (Table 2). Bromo derivative 4a was obtained with a similar isolated yield as 2,38 but compound 3b did not react well, potentially due to the oxidizable phenolic hydroxyl group.28 In order to survey the tolerance of N-atoms in the piperazine ring, the base form of 3c was used initially for the oxidative aromatization as in the standard method to provide a 8704

DOI: 10.1021/acs.joc.9b00756 J. Org. Chem. 2019, 84, 8702−8709

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89% and 88% yields, respectively, while more equivalents of the oxidant were necessary for trifluoromethanesulfonylprotected derivatives 4h and 4i. The benzyl groups in 4j and 4k were tolerated even in the in situ acidic ambient reaction mixture at MeCN/water refluxing temperature.41 The alkylsubstituted quinolin-2(1H)-ones (4l−4n) bearing aliphatic hydroxyl, benzoyl, and methylsulfonyl groups were obtained in 78%, 74% and 85% yields, respectively. However, for the vinyland bromo-substituted quinolin-2(1H)-ones (4o and 4p), 4 equiv of persulfate salt was required to complete the oxidative aromatization but even so with the decreased yields (62% and 66%, respectively). The fluoro- and nitro-substituted derivatives (4q and 4r) were isolated in 50−60% yields; however cyano-derivative 4s was obtained in 20% yield because a large amount of substrate 3s was not consumed. Generally, from the results, quinolin-2(1H)-ones with electron-donating groups were relatively easy to be obtained by the oxidative aromatization. On the basis of reported literatures and the experimental facts above,35,42,43 transition-metal-activated persulfate salts are proposed to be a single-electron-transfer (SET) process (Figure 2).20 As being presented in the mechanistic hypothesis

Note

EXPERIMENTAL SECTION

General Information. All commercially available materials and solvents were used directly without further purification unless otherwise noted. TLC analyses were performed on silica gel 60 F254 plates. The ESI mass spectra were determined on a THERMO LTQ. All high-resolution mass spectra (HRMS) were measured on a mass spectrometer (Agilent Technologies 6520) by using electrospray ionization (ESI) quadrupole time-of-flight (Q-TOF). 1H NMR and 13 C{1H} NMR data were recorded on 400 or 500 MHz instruments using TMS as an internal standard and are reported relative to their residual solvent signals. 1H NMR data are presented as the chemical shift in ppm (multiplicity, coupling constant, and integration). The multiplicities are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The 3,4-dihydroquinolin-2(1H)-ones 1,30 3a,44 3d,45 3j,46 3l,47 3n,47 and 3p48 were prepared according to published procedures. Besides, apart from commercially available 3b, 3e (aripiprazole), 3q, and 3r, the substrates 3c, 3f, 3g, 3h, 3i, 3k, 3m, 3o, and 3s were prepared as the following experiments. 7-(4-Bromobutoxy)-3,4-dihydroquinolin-2(1H)-one (3a). White solid. 1H NMR (500 MHz, DMSO-d6): δ 9.98 (s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.48 (dd, J = 8.2, 2.5 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H), 3.92 (t, J = 6.3 Hz, 2H), 3.59 (t, J = 6.7 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.41 (dd, J = 8.2, 6.8 Hz, 2H), 2.00−1.89 (m, 2H), 1.86−1.74 (m, 2H). The 1H NMR data are consistent with the literature.44 7-(4-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (3d). White solid. 1H NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 7.69 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 5.5 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 7.4 Hz, 1H), 6.49 (dd, J = 8.2, 2.5 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.06 (brs, 4H), 2.77 (t, J = 7.5 Hz, 2H), 2.61 (brs, 4H), 2.41 (dt, J = 8.6, 6.0 Hz, 4H), 1.80−1.68 (m, 2H), 1.67−1.54 (m, 2H). The 1H NMR data are consistent with the literature.45 7-(Benzyloxy)-3,4-dihydroquinolin-2(1H)-one (3j). White solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.02 (s, 1H), 7.46−7.27 (m, 5H), 7.05 (d, J = 8.2 Hz, 1H), 6.56 (dd, J = 8.2, 2.5 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 5.03 (s, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.44−2.38 (m, 2H). The 1H NMR data are consistent with the literature.46 7-(2-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one (3l). Off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.86 (dd, J = 7.6, 1.3 Hz, 1H), 6.68 (s, 1H), 3.85 (t, J = 6.5 Hz, 2H), 2.96−2.87 (m, 2H), 2.82 (t, J = 6.4 Hz, 2H), 2.65−2.59 (m, 2H). The 1H NMR data are consistent with the literature.47 2-(2-Oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethylmethanesulfonate (3n). Off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.05 (s, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.84 (dd, J = 7.6, 1.4 Hz, 1H), 6.74 (d, J = 1.1 Hz, 1H), 4.35 (t, J = 6.7 Hz, 2H), 3.12 (s, 3H), 2.91 (t, J = 6.6 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.42 (dd, J = 8.3, 6.8 Hz, 2H). The 1 H NMR data are consistent with the literature.47 7-Bromo-3,4-dihydroquinolin-2(1H)-one (3p). White solid. 1H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 8.0, 1.9 Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H), 2.83 (t, J = 7.6 Hz, 2H), 2.47−2.40 (m, 2H). The 1H NMR data are consistent with the literature.49 7-(4-(Piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (3c). The substrate 3a (3.0 g, 10.1 mmol), tert-butyl piperazine-1carboxylate (2.2 g, 11.8 mmol), and potassium carbonate (2.0 g, 14.5 mmol) were added into acetonitrile (20 mL). The resulted suspension was heated to reflux for 4 h and monitored by TLC. The reaction mixture was added into water with stirring, and the precipitate was isolated to obtain the N-Boc intermediate in 98% yield as a white solid (4.0 g, 9.9 mmol). The intermediate was added into the solution of hydrochloric acid (2 mol/L, 10 mL) and ethanol (10 mL), which was heated to reflux for 2 h and monitored by TLC. The reaction mixture was basified with NaOH (2 mol/L) and extracted with dichloromethane to give the base form of 3c as an offwhite solid (2.8 g, 9.2 mmol) in 91% yield. 1H NMR (400 MHz, DMSO-d6): δ 9.97 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.47 (dd, J = 8.2,

Figure 2. Proposed mechanism of the oxidative aromatization to quinolin-2(1H)-ones.

with copper as an example, the sulfate free radical (SO4−•) is formed by the activation of a transition metal and promotes 3,4-dihydroquinolin-2(1H)-ones 3 to generate the species 5, and later, the benzyl cation 6 is formed and the oxidative aromatization is achieved to the corresponding quinolin2(1H)-one derivatives 4. The derivatives with electrondonating groups gave better results as presented in Table 2, which indicated a consistence with this probable pathway via benzyl cation 6. In conclusion, the oxidative aromatizations of 3,4dihydroquinolin-2(1H)-ones to quinolin-2(1H)-ones were performed in the presence of transition-metal-activated persulfate salts. This valid protocol was economical and environmentally benign and was utilized for the synthesis of the key intermediate of brexpiprazole, 7-(4-chlorobutoxy)quinolin-2(1H)-one 2, on a 100 g scale. Furthermore, quinolin-2(1H)-one derivatives with various functional groups were synthesized by the oxidative aromatization in 52−89% yields. 8705

DOI: 10.1021/acs.joc.9b00756 J. Org. Chem. 2019, 84, 8702−8709

Note

The Journal of Organic Chemistry 2.4 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 3.88 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.66 (t, J = 4.7 Hz, 4H), 2.45−2.33 (m, 2H), 2.25 (t, J = 7.1 Hz, 5H), 1.74−1.45 (m, 4H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 170.3, 157.9, 139.2, 128.4, 115.4, 107.5, 101.7, 67.3, 58.2, 54.1, 45.6, 30.8, 26.6, 24.0, 22.5. ESI-MS: m/z 304.34 [M + H]. 5-Ethoxy-3,4-dihydroquinolin-2(1H)-one (3f). Bromoethane (5.0 g, 45.9 mmol) and 5-hydroxy-3,4-dihydroquinolin-2(1H)-one (5.0 g, 30.6 mmol) were added into the mixture of potassium carbonate (8.8 g, 63.7 mmol) and N,N-dimethylformamide (30 mL). The mixture was heated to 70 °C for 5 h and monitored by TLC. The reaction mixture was added into water (90 mL) with stirring. The resulted precipitate was filtered and dried to obtain 3f as a white solid (4.4 g, 23.0 mmol) in 75% yield. 1H NMR (400 MHz, DMSO-d6): δ 10.00 (s, 1H), 7.06 (t, J = 8.1 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 6.47 (d, J = 7.9 Hz, 1H), 4.01 (q, J = 7.0 Hz, 2H), 2.79 (t, J = 7.7 Hz, 2H), 2.39 (t, J = 7.7 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 170.0, 155.6, 139.2, 127.6, 111.0, 108.0, 105.7, 63.3, 29.8, 18.3, 14.7. ESI-MS: m/z 192.24 [M + H]. 7-Ethoxy-3,4-dihydroquinolin-2(1H)-one (3g). The product 3g (4.6 g, 24.1 mmol) was obtained in 79% yield by the same method as the above 3f from 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (5.0 g, 30.6 mmol). 1H NMR (400 MHz, DMSO-d6): δ 9.97 (s, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.50−6.39 (m, 2H), 3.93 (q, J = 7.0 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.46−2.36 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H). 13 C{1H} NMR (125 MHz, DMSO-d6): δ 170.2, 157.7, 139.2, 128.4, 115.4, 107.5, 101.6, 62.9, 30.7, 24.0, 14.6. ESI-MS: m/z 192.19 [M + H]. 2-Oxo-1,2,3,4-tetrahydroquinolin-7-yl Trifluoromethanesulfonate (3h). Trifluoromethanesulfonic anhydride (7.6 g, 26.9 mmol) was added into the mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)one (3.0 g,18.4 mmol), pyridine (4.0 g, 50.6 mmol), and dichloromethane (30 mL) below 10 °C. The mixture was warmed naturally to 20−30 °C and stirred for 3 h. After TLC analysis indicated the reaction end point, the reaction mixture was extracted with dichloromethane and water. By a general workup, crude product was purified by column chromatography to afford 3h (4.6 g, 15.6 mmol) as a white solid in 85% yield. 1H NMR (400 MHz, DMSOd6): δ 10.28 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.01 (dd, J = 8.3, 2.6 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 2.93 (t, J = 7.6 Hz, 2H), 2.59−2.40 (m, 3H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 170.0, 147.8, 140.2, 129.6, 124.5, 118.2 (J = 318.7 Hz), 114.1, 107.4, 29.8, 24.2. ESI-MS: m/z 294.04 [M − H]. Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl Trifluoromethanesulfonate (3i). Sodium hydride (60% dispersion in mineral oil, 0.4 g, 10 mmol) was added in portions into the mixture of 3h (2.0 g, 6.8 mmol) in dried N,N-dimethylformamide (10 mL) below 0 °C. After the mixture was stirred for 30 min, benzyl bromide (1.4 g, 8.2 mmol) was added successively into the solution and stirred at ambient temperature overnight. The reaction mixture was quenched carefully with saturated ammonium chloride solution (10 mL) and extracted with dichloromethane (50 mL). After general workup, purified product 3i (1.9 g, 4.9 mmol) was obtained in 72% yield as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.40 (d, J = 8.3 Hz, 1H), 7.35−7.27 (m, 2H), 7.27−7.20 (m, 3H), 7.07 (dd, J = 8.3, 2.3 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 5.17 (s, 2H), 3.00 (t, J = 7.4 Hz, 2H), 2.75 (dd, J = 8.4, 6.4 Hz, 2H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 169.6, 148.1, 140.9, 136.5, 129.4, 128.6, 127.3, 127.0, 126.5, 118.0 (J = 318.7 Hz), 114.9, 108.7, 44.3, 30.6, 24.1. HRMS (ESI): calcd for C17H15F3NO4S [M − H]−, 386.0668; found, 386.0676. 7-((2-Fluorobenzyl)oxy)-3,4-dihydroquinolin-2(1H)-one (3k). Crude 3k was obtained by the same method of 3f from 2-fluorobenzyl bromide (8.7 g, 46.0 mmol) and 7-hydroxy-3,4-dihydroquinolin2(1H)-one (5.0 g, 30.6 mmol). After purification by column chromatography, 3k (5.1 g, 18.8 mmol) was obtained in 61% yield as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.00 (s, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.41 (td, J = 7.4, 1.6 Hz, 1H), 7.24 (dd, J = 14.7, 7.8 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.59 (dd, J = 8.2, 2.5 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 5.07 (s, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.46−2.36 (m, 2H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 170.3, 160.3 (J = 245.0 Hz), 157.4, 139.3, 130.5 (J = 3.7 Hz), 130.3 (J = 7.5

Hz), 128.5, 124.5 (J = 3.7 Hz), 123.8 (J = 13.7 Hz), 116.1, 115.4 (J = 20.0 Hz), 107.7, 102.0, 63.5 (J = 3.7 Hz), 30.7, 24.0. ESI-MS: m/z 272.29 [M + H]. 2-(2-Oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl Benzoate (3m). To a suspension of 3l (3.0 g, 15.7 mmol), triethylamine (2.3 g, 22.7 mmol), and 4-dimethylaminopyridine (0.2 g, 1.6 mmol) in dichloromethane (30 mL) was added benzoic anhydride (4.2 g, 18.6 mmol) below 10 °C. The reaction mixture was warmed naturally and stirred at an ambient temperature to obtain a solution. After the end point was identified by TLC, water (30 mL) was added. By a general extraction workup, the crude product was purified by column chromatography and slurried with acetone and petroleum ether (30 mL, 1:1 by volume) to obtain 3m (2.6 g, 8.8 mmol) in 56% yield as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 7.94 (d, J = 7.1 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.09 (d, J = 7.6 Hz, 1H), 6.86 (dd, J = 7.6, 1.3 Hz, 1H), 6.81 (s, 1H), 4.42 (t, J = 6.7 Hz, 2H), 2.95 (t, J = 6.6 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.46−2.37 (m, 2H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 170.2, 165.6, 138.3, 137.0, 133.3, 129.7, 129.1, 128.7, 127.7, 122.4, 121.6, 115.4, 65.2, 34.1, 30.5, 24.4. HRMS (ESI): calcd for C18H16NO3 [M + H]+, 294.1136; found, 294.1133. 7-Vinyl-3,4-dihydroquinolin-2(1H)-one (3o). To the solution of 3n (3.0 g, 11.2 mmol) in N,N-diethylacetamide (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU. 3.4 g, 22.4 mmol) was added, and the mixture was heated to reflux for 4 h. After the reaction end point was monitored by TLC, the reaction mixture was extracted with dichloromethane (100 mL) and water (100 mL). After general washings, the crude product was purified by column chromatography to obtain vinyl derivative 3o (1.5 g, 8.7 mmol) in 78% yield as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.01 (dd, J = 7.7, 1.4 Hz, 1H), 6.92 (d, J = 1.3 Hz, 1H), 6.65 (dd, J = 17.6, 10.9 Hz, 1H), 5.68 (d, J = 17.4 Hz, 1H), 5.21 (d, J = 11.1 Hz, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.47−2.39 (m, 2H). 13 C{1H} NMR (125 MHz, DMSO-d6): δ 170.2, 138.6, 136.4, 136.1, 128.0, 123.5, 119.9, 113.7, 112.3, 30.4, 24.6. ESI-MS: m/z 174.26 [M + H]. 2-Oxo-1,2,3,4-tetrahydroquinoline-7-carbonitrile (3s). The substrate 3h (1.5 g, 5.1 mmol), cyanide zinc (0.89 g, 7.6 mmol), 1,1′bis(diphenylphosphino)ferrocene (0.56 g, 1.0 mmol), and tris(dibenzylideneacetone)dipalladium (0.5 g, 0.6 mmol) were mixed in DMF (10 mL). The mixture was heated to 120 °C for 4 h under a nitrogen atmosphere. After 3h, consumed by TLC, the insoluble materials were filtered off and the residue was poured into water (30 mL). The isolated solid was reslurried in ethyl acetate (10 mL) and filtered to obtain 3s (610 mg, 3.5 mmol) in 70% yield as a gray-yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 7.42−7.33 (m, 2H), 7.15 (s, 1H), 2.96 (t, J = 7.6 Hz, 2H), 2.47 (d, J = 7.5 Hz, 2H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 170.0, 139.3, 129.7, 129.0, 125.6, 118.8, 117.4, 109.6, 29.6, 24.9. HRMS (ESI): calcd for C10H7N2O [M − H]−, 171.0564; found, 171.0561. The 1H NMR data are consistent with the literature.50 Standard Method for Oxidative Aromatization. The substrate 3 (1.0 g unless otherwise noted, 1.0 equiv), Na2S2O8 (2.0 equiv), and CuSO4 (0.1 equiv) were added into MeCN (10 mL, 10 V) and water (10 mL, 10 V) with stirring. The resulted suspension was heated to reflux (about 76 °C). The reaction end point was monitored generally by TLC with the developing solvent of 5% methanol in dichloromethane, visualized at UV254 nm. The reaction mixture was extracted with dichloromethane. The separated organic phase was washed with water and brine and later dried over anhydrous sodium sulfate. After being filtered and concentrated, the residue was purified by column chromatography with 2−10% methanol in dichloromethane to obtain the oxidative product. 7-(4-Bromobutoxy)quinolin-2(1H)-one (4a).51 Compound 3a (33.5 mmol, 10.0 g) was used for the reaction to give 4a as an offwhite solid (8.2 g, 83% yield). 1H NMR (500 MHz, DMSO-d6): δ 11.59 (s, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.54 (d, J = 9.4 Hz, 1H), 6.85−6.70 (m, 2H), 6.29 (d, J = 9.4 Hz, 1H), 4.03 (t, J = 6.2 Hz, 2H), 3.60 (t, J = 6.6 Hz, 2H), 2.04−1.92 (m, 2H), 1.90−1.80 (m, 2H). 13 C{1H}NMR (125 MHz, DMSO-d6): δ 162.2, 160.3, 140.6, 140.0, 8706

DOI: 10.1021/acs.joc.9b00756 J. Org. Chem. 2019, 84, 8702−8709

Note

The Journal of Organic Chemistry

1H), 4.51 (t, J = 6.5 Hz, 2H), 3.11 (t, J = 6.5 Hz, 2H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 165.6, 162.0, 141.0, 140.0, 139.0, 133.4, 129.6, 129.1, 128.8, 127.9, 122.9, 121.3, 117.7, 115.1, 64.9, 34.53. HRMS (ESI): calcd for C18H16NO3 [M + H]+, 294.1125; found, 294.1128. 2-(2-Oxo-1,2-dihydroquinolin-7-yl)ethylmethanesulfonate (4n).47 Compound 3n (7.4 mmol, 3.0 g) was used for the reaction to give 4n as an off-white solid (1.68 g, 85% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.72 (s, 1H), 7.86 (d, J = 9.5 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.12 (dd, J = 8.0, 1.3 Hz, 1H), 6.45 (d, J = 9.5 Hz, 1H), 4.44 (t, J = 6.5 Hz, 2H), 3.13 (s, 3H), 3.06 (t, J = 6.5 Hz, 2H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 162.0, 139.9, 139.8, 139.0, 127.9, 122.7, 121.4, 117.8, 115.2, 70.2, 36.6, 34.8. LRMS (ESI): m/z 268.21 [M + H]. 7-Vinylquinolin-2(1H)-one (4o). Compund 3o (2.9 mmol, 500 mg) was used for the reaction to afford 4o as a white solid (305 mg, 62% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.73 (s, 1H), 7.87 (d, J = 9.5 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.34 (dd, J = 8.2, 1.4 Hz, 1H), 7.29 (s, 1H), 6.79 (dd, J = 17.6, 10.9 Hz, 1H), 6.46 (d, J = 9.5 Hz, 1H), 5.90 (d, J = 17.5 Hz, 1H), 5.39 (d, J = 11.0 Hz, 1H). 13 C{1H} NMR (125 MHz, DMSO-d6): δ 162.0, 139.8, 139.2, 138.9, 136.1, 128.1, 121.7, 119.4, 118.8, 116.3, 112.7. HRMS (ESI): calcd for C11H10NO [M + H]+, 172.0757; found, 172.0759. 7-Bromoquinolin-2(1H)-one (4p).53 Off-white solid (650 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 7.90 (d, J = 9.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.33 (dd, J = 8.4, 1.8 Hz, 1H), 6.52 (d, J = 9.6 Hz, 1H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 161.6, 140.0, 139.8, 129.8, 124.6, 123.4, 122.4, 118.2, 117.3. LRMS (ESI): m/z 224.08 and 226.09 [M + H]. 7-Fluoroquinolin-2(1H)-one (4q). Light-yellow solid (568 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.82 (s, 1H), 7.90 (d, J = 9.6 Hz, 1H), 7.73 (dd, J = 9.4, 6.2 Hz, 1H), 7.10−6.95 (m, 2H), 6.45 (d, J = 9.6 Hz, 1H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 164.0, 162.0 (J = 12.2 Hz), 140.4 (J = 12.5 Hz), 139.8, 130.4 (J = 10.6 Hz), 120.9 (J = 2.5 Hz), 116.2, 109.9 (J = 23.0 Hz), 101.0 (J = 25.5 Hz). HRMS (ESI): calcd for C9H5FNO [M − H]−, 162.0361; found, 162.0361. The 1H NMR and 13C{1H}NMR data are consistent with the literature.54 6-Nitroquinolin-2(1H)-one (4r). Yellow solid (520 mg, 52% yield). 1 H NMR (400 MHz, DMSO-d6): δ 12.31 (s, 1H), 8.69 (s, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.12 (d, J = 9.6 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 6.67 (d, J = 9.5 Hz, 1H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 162.0, 143.3, 141.5, 140.2, 125.1, 124.3, 123.8, 118.6, 116.1. HRMS (ESI): calcd for C9H5N2O3 [M − H]−, 189.0306; found, 189.0307. The 1H NMR and 13C{1H}NMR data are consistent with the literature.55 2-Oxo-1,2-dihydroquinoline-7-carbonitrile (4s). Compound 3s (2.3 mmol, 400 mg) was used for the reaction. After 6 h, TLC indicated a large amount of substrate was not consumed and the reaction was filtered to afford crude 4s (80 mg, 0.5 mmol) in 20% yield as a gray-yellow solid. The sample for 1H NMR and 13C{1H} NMR was obtained by preparative TLC. 1H NMR (400 MHz, DMSO-d6): δ 12.03 (s, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 4.4 Hz, 1H), 7.58 (dd, J = 8.1, 1.6 Hz, 1H), 6.69 (d, J = 9.6 Hz, 1H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 161.5, 139.5, 138.6, 129.3, 125.2, 124.3, 122.3, 118.9, 118.5, 112.0. HRMS (ESI): calcd for C10H5N2O [M − H]−, 169.0407; found, 169.0407. The 1H NMR data are consistent with the literature.56 Modified Method for Oxidative Aromatization. The substrate (1.51 g of 3c or 2.24 g of 3e aripiprazole, 5 mmol), Na2S2O8 (2.38 g, 10 mmol), and CuSO4 (80 mg, 0.5 mmol) were added into the solution of hydrochloride acid (ca. 2 mL, 25 mmol) in MeCN (10 V) and water (10 V) with stirring. The resulted suspension was heated to reflux (about 76 °C) and monitored by TLC. 7-(4-(Piperazin-1-yl)butoxy)quinolin-2(1H)-one dihydrochloride (4c).57 The reaction mixture was concentrated to dryness, and the residue was suspended in the solution of dichloromethane and methanol. After stirring for 2 h, the inorganic salts were filtered off. The filtrate was concentrated, and the resulting solid was purified with hot methanol to obtain 4c (1.34 g, 72% yield) as a dihydrochloride

129.2, 118.5, 113.3, 110.7, 98.6, 66.8, 34.8, 29.0, 27.3. LRMS (ESI): m/z 296.18 and 298.17 [M + H]. 7-Hydroxyquinolin-2(1H)-one (4b).26 Off-white solid (610 mg, 62% yield). 1H NMR (500 MHz, DMSO-d6): δ 11.62 (s, 1H), 10.31 (brs, 1H), 7.75 (d, J = 9.4 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 2.1 Hz, 1H), 6.67 (dd, J = 8.5, 2.2 Hz, 1H), 6.22 (d, J = 9.4 Hz, 1H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 162.4, 159.8, 140.8, 140.3, 129.3, 117.2, 112.5, 111.8, 99.9. LRMS (ESI): m/z 162.21 [M + H]. 5-Ethoxyquinolin-2(1H)-one (4f). Compound 3f (26.2 mmol, 5.0 g) was used for the reaction to give 4f as a white solid (4.4 g, 89% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.70 (s, 1H), 8.03 (d, J = 9.7 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 6.41 (d, J = 9.7 Hz, 1H), 4.14 (q, J = 6.8 Hz, 2H), 1.40 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 161.9, 154.8, 140.1, 134.2, 131.3, 120.4, 109.4, 107. 6, 103.4, 63.8, 14.51. HRMS (ESI): calcd for C11H12NO2 [M + H]+, 190.0863; found, 190.0861. 7-Ethoxyquinolin-2(1H)-one (4g). White solid (870 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.56 (s, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 6.93−6.67 (m, 2H), 6.29 (d, J = 9.4 Hz, 1H), 4.05 (q, J = 6.9 Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H). 13 C{1H} NMR (125 MHz, DMSO-d6): δ 162.2, 160.3, 140.6, 140.0, 129.2, 118.4, 113.2, 110.8, 98.5, 63.3, 14.5. HRMS (ESI): calcd for C11H12NO2 [M + H]+ 190.0863, found 190.0858. 2-Oxo-1,2-dihydroquinolin-7-yl Trifluoromethanesulfonate (4h). Off-white solid (773 mg, 78% yield). 1H NMR (400 MHz, DMSOd6): δ 11.93 (s, 1H), 7.97 (d, J = 9.6 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.42−7.20 (m, 2H), 6.59 (d, J = 9.6 Hz, 1H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 161.6, 149.6, 139.9, 139.4, 130.5, 123.3, 119.1, 118.2 (J = 318.7 Hz), 114.8, 107.5. HRMS (ESI): calcd for C10H7F3NO4S [M + H]+ 294.0067, found 294.0071. 1-Benzyl-2-oxo-1,2-dihydroquinolin-7-yl Trifluoromethanesulfonate (4i). Off-white solid (742 mg, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.07 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 6.4 Hz, 1H), 7.52 (s, 1H), 7.46−7.05 (m, 6H), 6.83 (d, J = 10.1 Hz, 1H), 5.53 (s, 2H). 13 C{1H} NMR (125 MHz, DMSO-d6): δ 161.2, 150.0, 140.0, 139.2, 136.2, 131.3, 128.6, 127.2, 126.6, 122.4, 120.47, 118.1 (J = 318.7 Hz), 115.3 (J = 12.5 Hz), 108.5 (J = 12.5 Hz), 44.8. HRMS (ESI): calcd for C17H13F3NO4S [M + H]+ 384.0512, found 384.0517. 7-(Benzyloxy)quinolin-2(1H)-one (4j).52 White solid (810 mg, 82% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.60 (s, 1H), 7.80 (d, J = 9.5 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.48−7.34 (m, 5H), 6.97−6.79 (m, 2H), 6.30 (d, J = 9.5 Hz, 1H), 5.15 (s, 2H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 162.2, 160.0, 140.6, 140.0, 136.5, 129.3, 128.4, 128.0, 127.8, 118.7, 113.5, 110.9, 99.1, 69.4. LRMS (ESI): m/z 252.20 [M + H]. 7-((2-Fluorobenzyl)oxy)quinolin-2(1H)-one (4k). White solid (830 mg, 84% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.61 (s, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.46−7.38 (dd, J = 13.5, 6.2 Hz, 1H), 7.31−7.20 (m, 2H), 6.96−6.82 (m, 2H), 6.31 (d, J = 9.5 Hz, 1H), 5.19 (s, 2H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 162.2, 160.4 (J = 245.0 Hz), 159.8, 140.6, 139.9, 130.6 (J = 5.0 Hz), 130.5 (J = 8.7 Hz), 129.3, 124.6 (J = 3.7 Hz), 123.3 (J = 15.0 Hz), 118.8, 115.4 (J = 20.0 Hz), 113.6, 110.8, 99.1, 63.7 (J = 3.7 Hz). HRMS (ESI): calcd for C16H13FNO2 [M + H]+ 270.0925, found 270.0931. 7-(2-Hydroxyethyl)quinolin-2(1H)-one (4l). Off-white solid (770 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.65 (s, 1H), 7.84 (d, J = 9.5 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.42 (d, J = 9.5 Hz, 1H), 4.68 (t, J = 5.2 Hz, 1H), 3.63 (m, 2H), 2.77 (t, J = 6.8 Hz, 2H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 162.0, 142.5, 140.0, 138.9, 127.6, 123.0, 120.9, 117.4, 115.0, 61.8, 39.8. HRMS (ESI): calcd for C11H12NO2 [M + H]+ 190.0863, found 190.0858. 2-(2-Oxo-1,2-dihydroquinolin-7-yl)ethyl Benzoate (4m). Offwhite solid (735 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.72 (s, 1H), 7.92 (d, J = 7.1 Hz, 2H), 7.85 (d, J = 9.5 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.24 (s, 1H), 7.15 (dd, J = 8.0, 1.2 Hz, 1H), 6.44 (d, J = 9.5 Hz, 8707

DOI: 10.1021/acs.joc.9b00756 J. Org. Chem. 2019, 84, 8702−8709

The Journal of Organic Chemistry

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salt and a light-yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 11.79 (brs, 1H, D2O exchangeable), 11.63 (s, 1H. D2O exchangeable), 9.76 (brs, 2H, D2O exchangeable), 7.80 (d, J = 9.5 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 6.86−7.74(m, 2H), 6.29 (d, J = 9.5 Hz, 1H), 4.03 (t, J = 5.9 Hz, 2H), 3.80−3.05 (m, 10H), 1.95−1.73 (m, 4H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 162.3, 160.2, 140.6, 140.0, 129.3, 118.6, 113.4, 110.8, 98.7, 67.0, 55.2, 47.7, 39.8, 25.7, 20.0. LRMS (ESI): m/z 302.34 [M + H] for the base. Dehydro-aripiprazole (4e).58 The reaction mixture was basified with dilute sodium hydroxide aqueous solution and extracted with dichloromethane. After general washings, the purified product was obtained by column chromatography with methanol and dichloromethane as a light-yellow solid (1.54 g, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.57 (s, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.54 (d, J = 9.3 Hz, 1H), 7.33−7.24 (m, 2H), 7.14−7.09 (m, 1H), 6.83−6.75 (m, 2H), 6.29 (d, J = 9.5 Hz, 1H), 4.04 (t, J = 6.4 Hz, 2H), 2.96 (brs, 4H), 2.53 (brs, 4H), 2.40 (t, J = 7.1 Hz, 2H), 1.82−1.72 (m, 2H), 1.68−1.55 (m, 2H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 162.2, 160.4, 151.2, 140.7, 140.0, 132.6, 129.2, 128.2, 126.0, 124.3, 119.5, 118.5, 113.2, 110.9, 98.6, 67.6, 57.3, 52.8, 51.0, 26.5, 22.6. LRMS (ESI): m/z 446.34 [M + H]. Preparation of 7-(4-Chlorobutoxy)quinolin-2(1H)-one (2) on a 100 g Scale. The oxidant Na2S2O8 (187.0 g, 0.785 mol) and CuSO4 (6.3 g, 0.039 mol) were added into the suspension of 7-(4chlorobutoxy)-3,4-dihydroquinolin-2(1H)-one 1 (100.0 g, 0.394 mol) in MeCN (1000 mL) and water (1000 mL) with stirring. The resulted mixture was heated to reflux (about 76 °C) for 0.5 h and monitored by TLC prior to HPLC analysis. The reaction showed a two-layer heterogeneous mixture and was quenched with sodium sulfite aqueous solution. The two layers were separated, and the organic phase was decolorized with activated carbon (5.0 g). After being filtered, the filtrate was concentrated and the residue was dispersed into water (500 mL). The crude product was collected after filtration and slurried with ethyl acetate (200 mL). After being filtered and dried, the oxidative product 2 (79.2 g, 0.314 mol, 80% mole yield and 79% weight yield) was obtained as an offwhite solid with 98% of HPLC purity.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00756.

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Note

Spectroscopic copies of 3,4-dihydroquinolin-2(1H)-ones and quinolin-2(1H)-ones (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Fuqiang Zhu: 0000-0001-9075-6474 Jingshan Shen: 0000-0001-9679-9934 Haji A. Aisa: 0000-0003-4652-6879 Author Contributions ⊥

W.C. and C.S. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Special Foundation of Chinese Academy of Sciences for strategic pilot technology (XDA12040105). The authors thank Dongye Shen for his contribution to English editing and polishing this manuscript. 8708

DOI: 10.1021/acs.joc.9b00756 J. Org. Chem. 2019, 84, 8702−8709

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DOI: 10.1021/acs.joc.9b00756 J. Org. Chem. 2019, 84, 8702−8709