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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 Akber Aisa J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00756 • Publication Date (Web): 07 Jun 2019 Downloaded from http://pubs.acs.org on June 7, 2019
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The Journal of Organic Chemistry
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*,† †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, P. R. China ‡University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, P. R. China §Topharman Shanghai Co., Ltd., Building 1, No.388 Jialilue Road, Zhangjiang Hitech Park, Shanghai 201209, P. R. China ∥CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China These authors contributed equally to this work. *Corresponding Author. E-mail:
[email protected] (J. Shen);
[email protected] (H. A. Aisa).
TOC R O
Persulfate Salt (Na2S2O8, ...) Transition-metal (Fe, Cu, ...)
N H
R = alkyl, O-alkyl, OTf, vinyl, Br, F, NO2, CN, etc.
MeCN/Water Reflux
R O
N H
- Economical and non-toxic oxidant - Readily available transition-metal - Avoidable environmental issues
19 samples 52-89% isolated yield
_____________________________________________________________________ Abstract Inorganic persulfate salts were identified as efficient reagents for the oxidative aromatization of 3,4-dihydroquinolin-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-(4-chlorobutoxy)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. _______________________________________________________________________________
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Quinolin-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 been 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 OMe O N Me
O
N
O O
N H
Daurine
S
N
O
O N H
O
Cilostamide
Brexpiprazole O
N H
Cl
Cl
HN
HO
N
HO
H2N
Cl O
O
N H
O
N H Rebamipide
O
OH Indacaterol
N
N
N
Tipifarnib
Figure 1. Natural products and clinical drugs containing quinolin-2(1H)-ones In our previous work, the oxidative aromatization of 3,4-dihydroquinolin-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. 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/AcOH16,
32
and TBHP/CuSO4,20 were attempted but
provided un-satisfactory results with fairly low conversation rates or 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). But no remarkable improvement was observed whatever reaction temperature and solvents were optimized. In the further trials, the combination of NaBr and persulfate salt didn’t accelerate the oxidation, and more impurities were generated by TLC.
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The Journal of Organic Chemistry
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 99% conversion rate and 90% of HPLC purity (Table 1, entries 3 and 4). During our following studies, sodium persulfate (Na2S2O8) and ammonium persulfate ((NH4)2S2O8) gave the 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 Table 1. Selected Screening Experiments of Oxidative Aromatization of 1a O
N H
Cl
O 1
Entry
Oxidants
Oxidant (2.0 equiv) Activator (0.1 equiv) O Solvent (20 V) Reflux
Solventb
Activator
N H
Reaction
O
Cl
2
HPLC results of reaction mixtured
time (h)c
Conv. of 1 (%)e
Purity of 2 (%)
1
Oxone
-
MeCN/Water
6
42
25
2
K2S2O8
-
MeCN/Water
6
90
64
3
Oxone
FeSO4.7H2O
MeCN/Water
6
71
40
4
K2S2O8
FeSO4.7H2O
MeCN/Water
1
99
90
5
(NH4)2S2O8
FeSO4.7H2O
MeCN/Water
1
99
89
6
Na2S2O8
FeSO4.7H2O
MeCN/Water
1
~100
92
7
Na2S2O8
MnCl2
MeCN/Water
6
99
72
8
Na2S2O8
FeCl3.6H2O
MeCN/Water
1
~100
82
9
Na2S2O8
Fe(acac)2
MeCN/Water
2.5
95
73
10
Na2S2O8
Fe powder
MeCN/Water
1
~100
90
11
Na2S2O8
Co(OAc)2
MeCN/Water
6
96
54
12
Na2S2O8
NiCl2
MeCN/Water
6
90
45
13
Na2S2O8
CuSO4
MeCN/Water
0.5
99
93
14
Na2S2O8
Pd/C (10%)
MeCN/Water
2
99
84
15
Na2S2O8
CuSO4
Toluene/Waterf
6
43
22
16
Na2S2O8
CuSO4
Acetone/Waterg
6
40
25
17
Na2S2O8
CuSO4
MeCN
6
53
36
18
Na2S2O8
CuSO4
Water
1
95
89
19h
Na2S2O8
CuSO4
MeCN/Water
0.5
~100
94
a
The reactions were performed on 1–5 g scale under the conditions (0.1 equiv activator and 2.0 equiv
persulfate salt in 20 V solvent) unless otherwise noted. b The ratio of mixed solvent was 1:1 by volume. c The
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d
Calculated for the reaction
mixture from HPLC area percentage at 230 nm. eCalculated by 100% minus remained 1 from HPLC area percentage. f Performed at about 100 oC. g Performed at about 65 oC. h The reaction was performed on a 100 g scale to give purified product in 80% isolated yield and with 98% HPLC purity.
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 longer reaction time were indicated when Mn, Co, and Ni salts were used (Table 1, entries 7, 11 and 12). In the following research, CuSO4 was chosen as the activator considering its shorter reaction time. We attempted several solvents for the oxidative aromatization, however, inferior results were showed whatever in the aspect of conversion rate or 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 wasn’t consumed completely because of its poor solubility in water (Table 1, entry 18), therefore, the combination of MeCN/water was a good choice. As a result, the economical combination of stoichiometric persulfate salts and 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, firstly, several intermediates in the synthetic route of brexpiprazole were prepared (Table 2). Bromo- derivative 4a was obtained with 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 complicated reaction mixture by TLC.39 However, when hydrochloride acid (5 equiv) was pre-added into the reaction mixture (as the modified method), potential oxidations on N-atoms of piperazine ring in 3c were inhibited to afford the oxidative aromatization product 4c with moderate yield. But for the oxidative aromatization of 3,4-dihydrobrexpiprazole 3d by the modified method,40 low purity of brexpiprazole was observed in reaction mixture by HPLC analysis, as the S-atom in thiophene was prone to be oxidized. Contrastively, aripiprazole (3e) without S-atom, a structural analogue of brexpiprazole, afforded the desired product 4e in 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 89 and 88% yields, respectively, while more equivalents of the oxidant were necessary for
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The Journal of Organic Chemistry
trifluoromethanesulfonyl-protected derivatives 4h and 4i. The benzyl groups in 4j and 4k were tolerated even in the in-situ acidic ambient of reaction mixture at MeCN/water refluxing temperature.41 The alkyl-substituted 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 vinyl- and bromo-substituted quinolin-2(1H)-ones (4o and 4p), 4 equiv of persulfate salt were 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% yield, however cyano-derivative 4s was obtained in 20% yield because a large amount of substrate 3s wasn’t consumed. Generally, from the results, quinolin-2(1H)-ones with electron-donating groups were relatively easy to be obtained by the oxidative aromatization. Table 2. Preparation of Quinolin-2(1H)-ones by CuSO4-Activatted Oxidative Aromatizationa Na2S2O8 (2.0 equiv)
R
R
CuSO4 (0.1 equiv) MeCN/Water (10 V/10 V) Reflux 3,4-Dihydroquinolin-2(1H)-ones O
N H
O
N H
Quinolin-2(1H)-ones
3a-p
N H
O
4a-p
NH
Br
O
N H
O
4a, 83%b
N N H
O
4d
O 4cc,d , 72%
N O
(Brexpiprazole)c,
N H
S
N
O
O
OH 4b, 62%
N
N H
N
O
Cl Cl
4ec, 69%
e
21%
OEt
N H
O
N H 4f, 89%
O
OEt
O
N H
N Bn
O
OTf
4hf , 78%
4g, 88%
OTf
4if , 75%
F N H
O
OBn
O
N H
4j, 82%
N H
O
O
O
O
4n, 85%
OH
O
N H
O
N H 4pf , 66%
4of , 62%
N H
OBz
4m, 74%
4l, 78%
4k, 84%
OMs
N H
Br
O
N H
F
4qf , 57%
NO2 N H
O
4rf , 52%
a
O
N H
CN
4sf , 20%g
The reaction was performed on 1–5 g scale by “the standard method” (0.1 equiv CuSO4 and
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2.0 equiv Na2S2O8 in 10 V acetonitrile and 10 V water) unless otherwise noted. b The isolated yields were calculated after purified by column chromatography unless otherwise mentioned.
c
The reaction was performed by “the modified method” (0.1 equiv CuSO4 and 2.0 equiv Na2S2O8 in 10 V acetonitrile, 10 V water, and 5 equiv of hydrochloride acid). d Obtained as a dihydrochloride salt. e 21% of brexpiprazole was observed in reaction mixture by HPLC, but it was not isolated. f 4.0 equiv of Na2S2O8 were utilized. g In the reaction mixture, a large amount of 3s was not consumed, and crude 4s was obtained in 20% yield after workup.
On
the
basis
of
reported
literatures
and
the
experimental
above,35,
facts
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 with copper as an example, the sulfate free radical (SO4-.) is formed by the activation of 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 quinolin-2(1H)-one derivatives 4. The derivatives with electron-donating groups gave better results as presented in Table 2, which indicated a consistence with this probable pathway via benzyl cation 6. Cu(II) + SO42-
H
+ SO4-
H R O
S2O82-
N H 3
H
Cu(I)
R N H
O
R O
N H
+ H+
+ HSO45
Cu(II)
H R O
4
N H
6
Figure 2. Proposed mechanism of the oxidative aromatization to quinolin-2(1H)-ones In
conclusion,
the
oxidative
aromatizations
of
3,4-dihydroquinolin-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.
Experimental Section General Information. All commercially available materials and solvents were used directly
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The Journal of Organic Chemistry
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
13C{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.
1H
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)ethyl methanesulfonate (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 1H NMR data are consistent with the
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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-1-carboxylate (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 base form of 3c as an off-white 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, 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 oC 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).
13C{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
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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) at below 10 oC. The mixture was warmed naturally to 20-30 oC and stirred for 3 h. After TLC analysis indicated the reaction endpoint, the reaction mixture was extracted with dichloromethane and water. By 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, DMSO-d6) 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) at below 0 oC. After the mixture was stirred for 30 minutes, 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-dihydroquinolin-2(1H)-one (5.0 g, 30.6 mmol). After purified 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), benzoic anhydride (4.2 g, 18.6 mmol) was added into the mixture below 10 oC. The reaction mixture was warmed naturally and stirred at ambient temperature to
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obtain a solution. After the endpoint was identified by TLC, water (30 mL) was added. By general extraction workup, the crude product was purified by column chromatography and slurried with acetone and petroleum ether (30 mL, 1:1 by volume) obtained 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), 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 endpoint 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). 13C{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 oC for 4 h under nitrogen atomosphere. After 3h was 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 grey-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 The Standard Method for Oxidative Aromatization of 3 to 4. The substrate (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 oC). The reaction endpoint was monitored generally by TLC with the developing solvent of 5% methanol in dichloromethane, visualized at UV254 nm. The reaction mixture was
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The Journal of Organic Chemistry
extracted with dichloromethane. The separated organic phase was washed with water and brine, 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 10.0 g of 3a (33.5 mmol) was used for the reaction to give 4a as an off-white 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). 13C{1H}NMR (125 MHz, DMSO-d6) δ 162.2, 160.3, 140.6, 140.0, 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). 5.0 g of 3f (26.2 mmol) 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). 13C{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, DMSO-d6) 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). 13C{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,
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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). Off-white 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, 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)ethyl methanesulfonate (4n).47 2.0 g of 3n (7.4 mmol) 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). 500 mg of 3o (2.9 mmol) 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,
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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). 13C{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). 1H 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). 400 mg of 3s (2.3 mmol) was used for the reaction. After 6 h, TLC indicated a large amount of substrate was no consumed and the reaction was filtered to afford crude 4s (80 mg, 0.5 mmol) in 20% yield as a grey-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 The Modified Method for Oxidative Aromatization. The substrate (1.51 g 3c or 2.24 g 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 oC) 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
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concentrated, and the resulting solid was purified with hot methanol to obtain 4c (1.34 g, 72% yield) as a dihydrochloride 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 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-(4-chlorobutoxy)-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 oC) 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 off-white solid with 98% of HPLC purity.
Acknowledgments This work was supported by Special Foundation of Chinese Academy of Sciences for strategic pilot technology (Grant No. XDA12040105). The authors thank Dongye Shen for his contribution to English editing and polishing of this manuscript.
Supporting Information
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Spectroscopic copies of 3,4-dihydroquinolin-2(1H)-ones and quinolin-2(1H)-ones associated with this article can be found online at http://pubs.acs.org/.
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