A regioselective SNAr reaction of poly-halo-quinoline-3- carboxylates with phenol, thiophenol, or N-methylaniline

Article abstract of DOI:10.1080/00397910903531656

By S_NAr reaction, poly-halo-quinoline-3-carboxylates such as ethyl 4-chloro-2-cyclopropyl-6,7-difluoro-quinoline-3-carboxylate and ethyl 4-chloro-2-cyclopropyl-5,6-difluoro-quinoline-3-carboxylate were transformed into the 4-phenoxy or 4-phenyl

Full text of DOI:10.1080/00397910903531656

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A Regioselective SNAr Reaction of Poly-
halo-quinoline-3-carboxylates with
Phenol, Thiophenol, or N-Methylaniline
Shikui Zhao a b & Weicheng Zhou a
a State Key Lab of New Drug & Pharmaceutical Process, Shanghai
Institute of Pharmaceutical Industry , Shanghai, China
b Center of Technology, Jiangsu Nhwa Pharma. Corporation , Xuzhou,
China
Published online: 14 Dec 2010.
To cite this article: Shikui Zhao & Weicheng Zhou (2010) A Regioselective SNAr Reaction of Poly-halo-
quinoline-3-carboxylates with Phenol, Thiophenol, or N-Methylaniline, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:1, 20-32, DOI:
10.1080/00397910903531656
To link to this article: http://dx.doi.org/10.1080/00397910903531656
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Synthetic Communications1, 41: 20–32, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903531656
A REGIOSELECTIVE SNAr REACTION OF POLY-HALO-
QUINOLINE-3-CARBOXYLATES WITH PHENOL,
THIOPHENOL, OR N-METHYLANILINE
Shikui Zhao1,2 and Weicheng Zhou1
1State Key Lab of New Drug & Pharmaceutical Process, Shanghai Institute
of Pharmaceutical Industry, Shanghai, China
2Center of Technology, Jiangsu Nhwa Pharma. Corporation, Xuzhou, China
By SNAr reaction, poly-halo-quinoline-3-carboxylates such as ethyl 4-chloro-2-cyclopropyl-6,
7-difluoro-quinoline-3-carboxylate and ethyl 4-chloro-2-cyclopropyl-5,6-difluoro-quinoline-3-
carboxylate were transformed into the 4-phenoxy or 4-phenylthio or 4-(N-methyl)
phenylamino-6,7 (or 5,6)-difluoro-quinoline-3-carboxylates or the 4,7-disubstituted, 4,5-
disubstituted, 4,6,7-trisubstituted and 4,5,6-trisubstituted products under mild conditions in
moderate to excellent yields. Highly regioselective mono- or multi-substitution was observed.
Keywords: N-Methylaniline; phenol; poly-halo-quinoline-3-carboxylates; SNAr reaction; synthesis; thiophenol
INTRODUCTION
The structural modifications on the quinoline scaffold may result in a variety of
compounds possessing antimalarial, antibacterial, antihypertensitive or antihyperli-
pidemic activities.[1,2] The fluoroquinolones have become the mainstay of totally
synthesized antibacterials in the infectious treatment, and the antihyperlipidemic
Pitavastatin, a quinoline compound is a new kind of hydroxymethylglutaryl-
coenzyme A (HMG CoA) inhibitors. As part of our investigations on quinoline
derivatives with pharmacological interests, we required a series of quinoline-3-
carboxylates substituted with phenylthio, phenoxy or N-methylphenylamino groups
at position 4, 5, 6, or 7 which would expedite the discovery of new potential HMG
CoA inhibitors. A very straight forward method for this synthesis could be the direct
nucleophilic substitution of halogen in the poly-halo-quinoline-3-carboxylates by
phenol, thiophenol or N-methylaniline. It is well known that the SNAr of 1-alkyl-6-
fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with some secondary
amines such as piperazine afforded the fluoroquinolone antibacterials, e.g.,
Ciprofloxacin and Norfloxacin.[3] The 4-substitued-aminoquinoline-3-carboxylates
might be synthesized from 4-chloroquinoline-3-carboxylates[4] In continuation of
our interest in the structural modifications on the quinoline scaffold,[5] we report
Received August 8, 2009.
Address correspondence to Shikui Zhao, Center of Technology, Jiangsu Nhwa Pharma.
Corporation, Xuzhou 221007, China. E-mail: zhaosk2002@163.com
20

A REGIOSELECTIVE SNAr REACTION
21
here a regioselective SNAr reaction of 4-chloro-6,7-difluoro-quinoline-3-carboxylates
or 4-chloro-5,6-difluoro-quinoline-3-carboxylates with thiophenol, phenol or
N-methylaniline to give a series of novel quinoline-3-carboxylates substituted with
phenylthio, phenoxy or N-methylphenylamino groups at position 4, 5, 6, or 7.
RESULTS AND DISCUSSION
3,4-Difluoroaniline (1) was reacted with diethyl [chloro(cyclopropyl)methylene]
malonate (2, prepared from diethyl malonate and cyclopanecarboxylic acid
chloride)[6] to form diethyl [cyclopropyl(3,4-difluorophenylamino)methylene]
malonate (3) in high yield (Scheme 1), which underwent by thermal cyclization to
give 4, mixed with a trace of isomer 5. The mixture of 4 and 5 was refluxed in
acetonitrile with phosphous oxychloride to give 6 and 7, which were separated by
flash chromatography.
The monosubstitution of 6 with phenol was investigated at first, and the reac-
tion was contaminated with 4-monosubstituted and 4,7-disubstituted products when
it was carried out in DMF with K2CO3 as base. Fortunately, it worked well with 1.1
equiv of the nucleophile mixed with NaH (60%, 1.1 equiv) in THF at reflux to give
4-monsubstitution 9a in 91% yield (Scheme 2, entry 1 in Table 1). The similar reac-
tions with 4-fluorophenol and 4-methoxylphenol gave the satisfactory results
(Table 1, entries 2 and 3). When 4-fluorothiophenol or 4-methoxythiophenol was
served as the nucleophile, the reaction condition was a bit milder than the phenol
case (entries 4 and 5). However, the reaction was harsher for the N-methylanilines
case. The reaction of 6 with N-methyl-4-fluoroaniline or N-methyl-4-methoxyaniline
was failed in NaH=THF and finally it worked well when BuLi was employed in the
THF at ice bath (Table 1, entries 6 and 7).
The investigation on 4,7-disubstitution of substrate 6 were easier than the
4-monosubstitution. For phenols and thiophenols, the amounts of nucleophile
were increased to 2.1 equivalents and the reaction functioned well in K2CO3=DMF
in an excellent yield (entries 8–12 in Table 1). However, compound 10f and 10g were
obtained in moderate yield even with BuLi as the base (entries 13 and 14 in Table 1).
Scheme 1. Synthesis of 6 and 7 from 3,4-difluoroaniline.

22
S. ZHAO AND W. ZHOU
ꢀ
=
Scheme 2. When X O, (A) NaH, THF, reflux, 6 h; (B) K2CO3, DMF, 100 C, 16 h; (C) NaH, DMSO,
ꢀ
ꢀ
=
100 ꢀC, 12 h. When X S, (A) NaH, THF, ice bath, 4 h; (B) K2CO3, DMF, 50 C, 16 h; (C) NaH, DMSO,
=
130 C, 24 h. When X NCH3, (A) BuLi, THF, ice bath, 2 h. (B) BuLi, THF, r.t., 4 h.
It is difficult to prepare 4,6,7-trisubstituted products. For phenols and thiophe-
nols, the ardent reaction conditions such as NaH and DMSO were employed, while
the yields were only 30–50% when the amounts of nucleophile and base were
increased to 3.5 or 4 equivalents (entries 15–19), and it was failed to get the
4,6,7-tri-(N-methylphenylamino) products although many tests were tried.
Encouraged by the above results, we investigated the SNAr reaction with 7 as
the substrate. It was showed that the 4-monosubstitutions with three series of
nucleophilic agents might go in the same condition as the subtract 6. The disubstitu-
tion gave 4,5-disubstituted products in the lower yield, indicating that in compound
7,5-fluoro was a better leaving group than the 6-fluoro, but the leaving ability was
not as good as the 7-fluoro in compound 6 (Scheme 3).
1
The H NMR data (in CDCl3, 400 MHz) were very helpful to identify the
4-substituted, 4,6,7-trisubstituted, 4,5-disubstituted and 4,5,6-trisubstituted pro-
1
ducts. For example, in the H NMR spectrum of 9b, the double double peak at
7.68 ppm was assigned to 8-H at quinoline ring and the coupling constants of JH-F (o)
,
JH-F(m) were calculated as 11.2 Hz and 7.2 Hz, respectively, another double double
peak at 7.56 ppm was assigned to 5-H with the coupling constants of JH-F (o), JH-F(m)
10.4 Hz and 8.4 Hz. In the spectrum of 11b, the two sharp single peaks at 7.26 and
7.16 could be assigned to be the signal of 8-H and 5-H, respectively, indicating the
absence of fluorine at position 6 and 7. In the spectrum of 13a, the triple peak at
7.57 could be assigned to be the signal of 7-H, indicating the presence of fluorine
at position 6. In the spectrum of 14a, the two double peaks at 7.85 and 7.38 could
be assigned to be the signal of 7-H and 8-H, indicating the absence of fluorine at
position 5 and 6. It was difficult to identify 4,7-disubstituted or 4,6-disubstituted
1
products only by the H NMR and MS. The structure of 10a was confirmed by
X-ray crystallography and the data (Figure 1) shows that it was a 4,7-disubstituted
product.[7]
In summary, we have shown a systematic study on the SNAr reaction of ethyl
4-chloro-2-cyclopropyl-6,7-difluoro-quinoline-3-carboxylate or ethyl 4-chloro-2-
cyclopropyl-5,6-difluoro-quinoline-3-carboxylate with phenols, thiophenols or

A REGIOSELECTIVE SNAr REACTION
23
Table 1. Substitutions of 6
Ratio of
Product 8 to 6
Yield
Sovent Time=h Temp.=ꢀC (%)ꢁ Mp=ꢀC
Entry
Nucleophile 8
Base
NaH
NaH
NaH
NaH
NaH
1
2
3
4
5
9a
9b
9c
9d
9e
1.1
1.1
1.1
1.1
1.1
THF
THF
THF
THF
THF
6
6
6
4
4
67
67
91
88
88
89
87
110–2
120–2
86–88
114–6
110–2
67
0ꢂ5
0ꢂ5
6
7
9f
1.1
1.1
BuLi
BuLi
THF
THF
2
2
0ꢂ5
0ꢂ5
79
80
139–40
100–2
9g
8
9
10a
10b
10c
10d
10e
2.1
2.1
2.1
2.1
2.1
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
16
16
16
16
16
100
100
100
50
87
85
92
93
94
102–4
143–5
oil
10
11
12
oil
50
oil
13
14
10f
3
3
BuLi
BuLi
THF
THF
4
4
25
25
42
56
177–9
oil
10g
15
16
17
18
19
11a
11b
11c
11d
11e
3.5
3.5
3.5
4
NaH
NaH
NaH
NaH
NaH
DMSO
DMSO
DMSO
DMSO
DMSO
12
12
12
24
24
100
100
100
130
130
42
50
39
36
31
72–4
oil
150–2
166–8
170–2
4
ꢁThe products 9a–10b were recrystallized from n-hexane; 10c–11e were isolated by flash chromatography.

24
S. ZHAO AND W. ZHOU
ꢀ
=
Scheme 3. When X O, (A) NaH, THF, reflux, 6 h; (B) K2CO3, DMF, 100 C, 16 h; (C) NaH, DMSO,
ꢀ
ꢀ
=
100 ꢀC, 10 h. When X S, (A) NaH, THF, ice bath, 4 h; (B) K2CO3, DMF, 50 C, 16 h; (C) NaH, DMSO,
=
130 C, 24 h. When X NCH3, (A) BuLi, THF, ice bath, 2 h.
N-methylanilines, revealing that the substitution is highly regioselective, which
would afford 4-monosubstituted, 4,7-disubstituted, 4,5-disubstituted, 4,6,7-trisubsti-
tuted or 4,5,6-trisubstituted quinoline-3-carboxylates by controlling the reaction
temperature, the type of the base, the solvents as well as the ratio of the substrate
to the nucleophile.
Figure 1. X-ray crystallographic structure of compound 10a.

A REGIOSELECTIVE SNAr REACTION
25
EXPERIMENTAL
Melting points were determined on an Electrothermal Melting Point Appara-
1
tus and were uncorrected. H NMR spectra were recorded at 400 MHz on a Varian
Inova-400 spectrometer in deuterated chloroform or deuterated dimethylsulfoxide
with chemical shifts (d) given in ppm relative to TMS as an internal standard.
High-resolution mass spectra (HRMS) were recorded on an Agilent 6210 TOF
instrument. X-Ray crystallography data were collected on a SMART APEX-II
˚
diffractometer with CCD detector using Cu-Ka radiation (k ¼ 1.54178 A).
Preparation of Diethyl[cyclopropyl(3,4-difluorophenylamino)
methylene]malonate (3)
A mixture of 1 (31.0 g, 0.24 mol), 2 (49.4 g, 0.2 mol), anhydrous K2CO3 (33.1 g,
0.24 mol), and DMF (300 ml) was stirred at 100 ꢀC (oil bath temperature) for 16 h.
When it was cooled to room temperature, the inorganic material was removed by
filtration and washed with ethyl acetate. The resulting solution was transferred to
a separatory funnel, and ethyl acetate and water were added. The organic layer
was separated, washed with brine, dried over Na2SO4, and concentrated to give
yellow oil (61.0 g, yield 90%) which was used for the next step without further
purification. It was purified by silica gel chromatography (petroleum ether—ethyl
acetate, 10:1) to provide 3 as an analytical sample: colorless oil; 1H NMR
(400 MHz, CDCl3): d 10.96 (s, 1H), 7.13–6.84 (m, 3H), 4.26 (q, J ¼ 7.2 Hz, 2H),
4.18 (q, J ¼ 7.2 Hz, 2H), 1.92–1.84 (m, 1H), 1.33 (t, J ¼ 7.2 Hz, 3H), 1.28 (q,
J ¼ 7.2 Hz, 3H), 0.77–0.72 (m, 2H), 0.47–0.43 (m, 2H).
Preparation of Ethyl 2-Cyclopropyl-6,7-difluoro-4-hydroxyquinoline-
3-carboxylate (4)
The crude 3 (60 g, 0.18 mol) was added to diphenyl ether (500 ml) and heated at
220 ꢀC for 0.5 h. After the solution cooled, the precipitate was filtered off, washed
with petroleum ether, and dried. The obtained solid (47.4 g, 91.4%) was used for
the next step without further purification. It was recrystallized from 95% ethanol
to give 4 as an analytical sample: Colorless crystal, mp 280–282 ꢀC; 1H NMR
(400 MHz, CDCl3 þ D2O): d 7.99 (dd, J ¼ 10.8, 8.8 Hz, 1H), 7.53 (dd, J ¼ 10.8,
6.8 Hz, 1H), 4.37 (q, J ¼ 7.2 Hz, 2H), 2.23–1.99 (m, 1H), 1.37 (t, J ¼ 7.2 Hz, 3H),
1.10–1.06 (m, 4H).
Preparation of Ethyl 4-Chloro-2-cyclopropyl-6,7-difluoroquinoline-3-
carboxylate (6) and Ethyl 4-Chloro-2-cyclopropyl-5,6-
difluoroquinoline-3-carboxylate (7)
Phosphorus oxychloride (26.0 ml, 0.28 mol) was added to a suspension of crude
4 (46.0 g, 0.16 mol) in acetonitrile (400 ml) and the mixture was heated at 75 ꢀC for 6 h.
The resulting light brown solution was poured into the aqueous solution saturated
with sodium bicarbonate (500 ml); the suspension was extracted with ethyl acetate
twice. The organic extracts were dried over Na2SO4 and concentrated to dryness to

26
S. ZHAO AND W. ZHOU
give an off-white solid, which was purified by silica gel chromatography (petroleum
ether–ethyl acetate, 100:1) to give 6 (32.5 g, 66.5%) and 7 (4.4 g, 9.6%). 6: white solid,
mp 68–70 ꢀC; 1H NMR (400 MHz, CDCl3): d 7.90 (dd, J ¼ 10.8, 8.4 Hz, 1H), 7.68 (dd,
J ¼ 11.2, 7.6 Hz, 1H), 4.53 (q, J ¼ 7.2 Hz, 2H), 2.10–2.06 (m, 1H), 1.45 (t, J ¼ 7.2 Hz,
3H), 1.31–1.27 (m, 2H), 1.09–1.04 (m, 2H). MS (ESI): m=z ¼ 312, 314 (MþH)þ.
HRMS: m=z calcd. for C15H13ClF2NO2 (MþH)þ 312.0603, found: 312.0623. 7: white
solid, mp 88–90 ꢀC; 1H NMR (400 MHz, CDCl3): d 7.78–7.74 (m, 1H), 7.61–7.54 (m,
1H), 4.57 (q, J ¼ 7.2 Hz, 2H), 2.11–2.05 (m, 1H), 1.49 (t, J ¼ 7.2 Hz, 3H), 1.34–1.31
(m, 2H), 1.11–1.07 (m, 2H). MS (ESI): m=z ¼ 312, 314 (M þ H)þ.
SNAr of 6 or 7 Ethyl 2-Cyclopropyl-6,7-difluoro-4-phenoxyquinoline-
3-carboxylate (9a)
Phenol (0.66 g, 7.0 mmol) was added to a mixture of NaH (60%, 0.28 g,
7.0 mmol) in THF (20 ml) at 0 ꢀC. The resulting mixture was stirred at 0 ꢀC for
0.5 h, and then 6 (2.0 g, 6.4 mmol) was added. The mixture was refluxed for 6 h. the
reaction mixture was transferred to a separatory funnel, then ethyl acetate and water
were added. The organic layer were separated, washed with brine, dried over Na2SO4
and concentrated to dryness to give a white solid, which was recrystallized from
n-hexane to give 9a (2.16 g, 91%) as a colorless powder. 1H NMR (400 MHz, CDCl3):
d 7.69 (dd, J ¼ 11.2, 7.2 Hz, 1H), 7.59 (dd, J ¼ 10.4, 8.8 Hz, 1H), 7.32–7.27 (m, 2H),
7.09 (t, J ¼ 7.6 Hz, 1H), 6.92–6.89 (m, 2H), 4.16 (q, J ¼ 7.2 Hz, 2H), 2.26–2.20 (m,
1H), 1.36–1.32 (m, 2H), 1.14 (t, J ¼ 7.2 Hz, 3H), 1.09–1.05 (m, 2H).
Compounds 9b–9e and 12a–12b were prepared in the similar manner otherwise
the reaction temperature mentioned in Tables 1 and 2.
Table 2. Substitutions of 7
Ratio of
8 to 7
Yield
Sovent Time=h Temp.=ꢀC (%)ꢁ Mp=ꢀC
Entry Product
Nucleophiles 8
Base
1
2
12a
12b
1.1
1.1
NaH
NaH
THF
THF
6
4
67
83
88
105–7
123–5
0ꢂ5
3
12c
1.1
BuLi
THF
2
ice bath
88
137–9
4
5
6
7
13a
13b
14a
14b
2.1
2.1
4
K2CO3 DMF
K2CO3 DMF
16
16
24
24
100
100
130
130
58
39
38
32
oil
oil
NaH
NaH
DMSO
DMSO
101–3
163–5
4
ꢁThe products 12a–c were recrystallized from n-hexane; 13a–14b were isolated by flash chromatography.

A REGIOSELECTIVE SNAr REACTION
27
Ethyl 2-Cyclopropyl-6,7-difluoro-4-(4-fluorophenyloxy)quinoline-3-
carboxylate (9b)
1
Colorless powder, H NMR (400 MHz, CDCl3): d 7.68 (dd, J ¼ 11.2, 7.2 Hz,
1H), 7.56 (dd, J ¼ 10.4, 8.4 Hz, 1H), 7.0–6.96 (m, 2H), 6.87–6.84 (m, 2H), 4.17
(q, J ¼ 7.2 Hz, 2H), 2.21–2.17 (m, 1H), 1.34–1.30 (m, 2H), 1.16 (t, J ¼ 7.2 Hz, 3H),
1.08–1.03 (m, 2H).
Ethyl 2-Cyclopropyl-6,7-difluoro-4-(4-methoxyphenyloxy)quinoline-
3-carboxylate (9c)
Colorless powder, 1H NMR (400 MHz, CDCl3): d 7.69–7.59 (m, 2H), 6.86–6.90
(m, 4H), 4.14 (q, J ¼ 7.2 Hz, 2H), 3.77 (s, 3H), 2.20–2.16 (m, 1H), 1.33–1.29 (m, 2H),
1.17 (t, J ¼ 7.2 Hz, 3H), 1.06–1.02 (m, 2H).
Ethyl 2-Cyclopropyl-6,7-difluoro-4-(4-fluorophenylthio)quinoline-
3-carboxylate (9d)
1
Lightly yellow powder. H NMR (400 MHz, CDCl3): d 7.96 (dd, J ¼ 11.6,
8.4 Hz, 1H), 7.69 (dd, J ¼ 11.2, 8.0 Hz, 1H), 7.26–7.22 (m, 2H), 6.96–6.92 (m, 2H),
4.46 (q, J ¼ 7.2 Hz, 2H), 2.13–2.08 (m, 1H), 1.36 (t, J ¼ 7.2 Hz, 3H), 1.38–1.31 (m,
2H), 1.12–1.07 (m, 2H).
Ethyl 2-Cyclopropyl-6,7-difluoro-4-(4-methoxyphenylthio)quinoline-
3-carboxylate (9e)
1
Lightly yellow powder. H NMR (400 MHz, CDCl3): d 7.95 (dd, J ¼ 11.6,
8.8 Hz, 1H), 7.59 (dd, J ¼ 11.2, 7.6 Hz, 1H), 7.22–7.18 (m, 2H), 6.73–6.70 (m, 2H),
4.39 (q, J ¼ 7.2 Hz, 2H), 3.68 (s, 3H), 2.05–2.01 (m, 1H), 1.32 (t, J ¼ 7.2 Hz, 3H),
1.27–1.23 (m, 2H), 1.03–0.98 (m, 2H).
Ethyl 2-Cyclopropyl-5,6-difluoro-4-(4-methoxyphenyloxy)quinoline-
3-carboxylate (12a)
Colorless powder. 1H NMR (400 MHz, CDCl3): d 7.78–7.74 (m, 1H), 7.56–7.51
(m, 1H), 6.83–6.81 (m, 4H), 4.26 (q, J ¼ 7.2 Hz, 2H), 3.78 (s, 3H), 2.21–2.17 (m, 1H),
1.38–1.34 (m, 2H), 1.19 (t, J ¼ 7.2 Hz, 3H), 1.12–1.07 (m, 2H).
Ethyl 2-Cyclopropyl-5,6-difluoro-4-(4-methyloxyphenylthio)quinoline-
3-carboxylate (12b)
1
Lightly yellow powder. H NMR (400 MHz, CDCl3): d 7.74–7.72 (m, 1H),
7.50–7.46 (m, 1H), 7.34–7.32 (m, 2H), 6.80–6.78 (m, 2H), 4.50 (q, J ¼ 7.2 Hz, 2H),
3.77 (s, 3H), 2.13–2.10 (m, 1H), 1.42 (t, J ¼ 7.2 Hz, 3H), 1.36–1.32 (m, 2H),
1.13–1.09 (m, 2H).

28
S. ZHAO AND W. ZHOU
Ethyl 2-Cyclopropyl-6,7-difluoro-4-(N-methyl-4-fluorophenylamino)-
quinoline-3-carboxylate (9f)
BuLi (2.7 mol=L, 1.25 mL, 3.37 mmol) was added to a mixture of N-methyl-4-
fluoroaniline (0.41 g, 3.27 mmol) in THF (15 ml) at 0 ꢀC. The resulting mixture was
stirred at 0 ꢀC for 0.5 h, and then 6 (1.0 g, 3.21 mmol) was added. The mixture was
stirred for 2 h below 5 ꢀC. The reaction mixture was transferred to a separatory
funnel, then ethyl acetate and water were added. The organic layer were separated,
washed with brine, dried over Na2SO4 and concentrated to dryness to give a yellow
solid, which was recrystallized from n-hexane to give 9f (1.01 g, 79%) as a yellow pow-
1
der. H NMR (400 MHz, CDCl3): d 7.86–7.81 (m, 1H), 7.47 (dd, J ¼ 10.4, 8.8 Hz,
1H), 6.95–6.90 (m, 2H), 6.61–6.57 (m, 2H), 4.15 (q, J ¼ 7.2 Hz, 2H), 3.34 (s, 3H),
2.19–2.14 (m, 1H), 1.15 (t, J ¼ 7.2 Hz, 3H), 1.39–1.36 (m, 2H), 1.14–1.07 (m, 2H).
Compounds 9g, 10f, 10g, and 12c were prepared in the similar manner
otherwise the reaction temperature and the molecular ratio mentioned in Tables 1
and 2.
Ethyl 2-Cyclopropyl-6,7-difluoro-4-(N-methyl-4-
methyloxyphenylamino)quinoline-3-carboxylate (9g)
1
Yellow powder. H NMR (400 MHz, CDCl3): d 7.79–7.76 (m, 1H), 7.48 (dd,
J ¼ 10.8, 8.8 Hz, 1H), 6.79–6.76 (m, 2H), 6.62–6.59 (m, 2H), 4.11 (q, J ¼ 7.2 Hz,
2H), 3.75 (s, 3H), 3.31 (s, 3H), 2.17–2.13 (m, 1H), 1.15 (t, J ¼ 7.2 Hz, 3H),
1.35–1.32 (m, 2H), 1.07–1.03 (m, 2H).
Ethyl 2-Cyclopropyl-6-difluoro-4,7-di-(N-methyl-4-
fluorophenylamino)quinoline-3-carboxylate (10f)
1
Yellow solid. H NMR (400 MHz, CDCl3): d 7.63 (b, 1H), 7.30–7.27 (m, 1H),
7.01–6.57 (m, 8H), 4.12 (q, J ¼ 7.2 Hz, 2H), 3.45 (s, 3H), 3.35 (s, 3H), 2.20 (b, 1H),
1.20 (t, J ¼ 7.2 Hz, 3H), 1.35 (m, 2H), 1.12–1.08 (m, 2H).
Ethyl 2-Cyclopropyl-6difluoro-4,7-(N-methyl-4-
methyloxyphenylamino)quinoline-3-carboxylate (10g)
1
Yellow oil. H NMR (400 MHz, CDCl3): d 7.57 (b, 1H), 7.26 (d, J ¼ 9.2 Hz,
1H), 7.01–6.60 (m, 8H), 4.08 (q, J ¼ 7.2 Hz, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.38 (s,
3H), 3.30 (s, 3H), 2.19–2.17 (m, 1H), 1.14 (t, J ¼ 7.2 Hz, 3H), 1.29–1.26 (m, 2H),
1.02–0.98 (m, 2H).
Ethyl 2-Cyclopropyl-5,6-difluoro-4-(N-methyl-4-
methyloxyphenylamino)quinoline-3-carboxylate (12c)
1
Yellow powder. H NMR (400 MHz, CDCl3): d 7.84–7.80 (m, 1H), 7.56–7.49
(m, 1H), 6.81–6.77 (m, 2H), 6.56–6.53 (m, 2H), 4.20 (q, J ¼ 7.2 Hz, 2H), 3.76 (s, 3H),
3.28 (s, 3H), 2.16–2.12 (m, 1H), 1.17 (t, J ¼ 7.2 Hz, 3H), 1.38–1.36 (m, 2H), 1.11–1.08
(m, 2H).

A REGIOSELECTIVE SNAr REACTION
29
Ethyl 2-Cyclopropyl-6-fluoro-4,7-diphenyloxyquinoline-3-
carboxylate (10a)
A mixture of phenol (0.95 g, 10.1 mmol), 6 (1.5 g, 4.81 mmol), anhydrous
K2CO3 (1.39 g, 10.1 mmol), and DMF (15 ml) was stirred at 100 ꢀC for 16 h. When
it was cooled to room temperature, the solid was isolated by filtration and washed
with ethyl acetate. The resulting mixture was transferred to a separatory funnel,
and ethyl acetate and water were added. The organic layer was separated, washed
with brine, dried over Na2SO4, and concentrated to dryness to give an off-white
solid, which was recrystallized from n-hexane to give 10a (1.85 g, 87%) as a colorless
1
powder. H NMR (400 MHz, CDCl3): d 7.56 (d, J ¼ 11.6 Hz, 1H), 7.44–6.89 (m,
11H), 4.17–4.12 (m, 2H), 2.24–2.18 (m, 1H), 1.25–1.20 (m, 2H), 1.12 (td, J ¼ 7.2,
1.2 Hz, 3H), 1.02–0.97 (m, 2H). HRMS: m=z calcd for C27H23FNO4 (M þ H)þ
444.1611, found: 444.1613.
Compounds 10b–10e and 13a–b were prepared in the similar manner otherwise
the reaction temperature mentioned in Tables 1 and 2.
Ethyl 2-Cyclopropyl-6-fluoro-4,7-di-(4-fluorophenyloxy)quinoline-3-
carboxylate (10b)
1
Colorless powder. H NMR (400 MHz, CDCl3): d 7.53 (d, J ¼ 11.2 Hz, 1H),
7.25 (d, J ¼ 7.6 Hz, 1H), 7.12–7.10 (m, 4H), 7.01–6.96 (m, 2H), 6.88–6.84 (m, 2H),
4.17 (q, J ¼ 7.2 Hz, 2H), 2.20–2.16 (m, 1H), 1.26–1.21 (m, 2H), 1.15 (t, J ¼ 7.2 Hz,
3H), 1.03–0.99 (m, 2H).
Ethyl 2-Cyclopropyl-6-fluoro-4,7-di-(4-methoxyphenyloxy)
quinoline-3-carboxylate (10c)
Colorless oil. 1H NMR (400 MHz, CDCl3): d 7.57 (d, J ¼ 10.8 Hz, 1H), 7.19 (d,
J ¼ 8.4 Hz, 1H), 7.10–7.08 (m, 2H), 6.96–6.94 (m, 2H), 6.86–6.80 (m, 4H), 4.18 (q,
J ¼ 7.2 Hz, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 2.18–2.16 (m, 1H), 1.26–1.19 (m, 2H),
1.16 (t, J ¼ 7.2 Hz, 3H), 1.00–0.96 (m, 2H).
Ethyl 2-Cyclopropyl-6-fluoro-4,7-di-(4-fluorophenylthio)quinoline-3-
carboxylate (10d)
Lightly yellow solid. 1H NMR (400 MHz, CDCl3): d 7.83 (d, J ¼ 10.8 Hz, 1H),
7.58–7.54 (m, 2H), 7.43 (d, J ¼ 7.2, Hz, 1H), 7.28–7.24 (m, 2H), 7.19–7.15 (m, 2H),
6.98–6.93 (m, 2H), 4.45 (q, J ¼ 7.2 Hz, 2H), 2.11–2.07 (m, 1H), 1.37 (t, J ¼ 7.2 Hz,
3H), 1.29–1.25 (m, 2H), 1.07–1.02 (m, 2H).
Ethyl 2-Cyclopropyl-6-fluoro-4,7-di-(4-methoxyphenylthio)quinoline-
3-carboxylate (10e)
1
Yellow oil. H NMR (400MHz, CDCl3): d 7.83 (d, J ¼ 10.8Hz, 1H), 7.49 (d,
J ¼ 8.8 Hz, 2H), 7.27–7.22 (m, 3H), 6.97 (d, J ¼ 9.2 Hz, 2H), 6.75 (d, J ¼ 9.2 Hz, 2H),
4.42 (q, J ¼ 7.2 Hz, 2H), 3.86 (s, 3H), 3.74 (s, 3H), 2.05–2.03 (m, 1H), 1.37 (t, J ¼ 7.2 Hz,
3H), 1.20–1.17 (m, 2H), 0.99–0.96 (m, 2H). MS (ESI): m=z ¼ 536(M þ H)þ.

30
S. ZHAO AND W. ZHOU
Ethyl 2-Cyclopropyl-6-fluoro-4,5-di-(4-methoxyphenoxy)quinoline-3-
carboxylate (13a)
1
Colorless oil. H NMR (400 MHz, CDCl3): d 7.95 (dd, J ¼ 9.2, 4.4 Hz, 1H),
7.57 (t, J ¼ 9.6 Hz, 1H), 6.83–6.54 (m, 8H), 4.16 (q, J ¼ 7.2 Hz, 2H), 3.79 (s, 3H),
3.76 (s, 3H), 2.20–2.17 (m, 1H), 1.43–1.40 (m, 2H), 1.12–1.08 (m, 5H).
Ethyl 2-Cyclopropyl-6-fluoro-4,5-di-(4-methoxyphenylthio)-
quinoline-3-carboxylate (13b)
Yellow oil. 1H NMR (400MHz, CDCl3): d 8.08–8.04 (m, 1H), 7.41 (t,
J ¼ 8.8 Hz, 1H), 7.08–6.69 (m, 8H), 4.33 (q, J ¼ 7.2 Hz, 2H), 3.75 (s, 3H), 3.74 (s,
3H), 2.14–2.09 (m, 1H), 1.28 (t, J ¼ 7.2 Hz, 3H), 1.40–1.35 (m, 2H), 1.12–1.07 (m, 2H).
Ethyl 2-Cyclopropyl-4,6,7-triphenoxyquinoline-3-carboxylate (11a)
Phenol (2.12 g, 22.5 mmol) was added to a mixture of NaH (60%, 0.85 g,
21.2 mmol) in DMSO (20 ml) at room temperature. The resulting mixture was stirred
at room temperature for 0.5 h after which, 6 (2.0 g, 6.42 mmol) was added. The mix-
ture was stirred at 100 ꢀC for 12 h. When TLC indicated that the reaction was com-
plete, the reaction mixture was transferred to a separatory funnel, then ethyl acetate
and water were added. The organic layer were separated, washed with brine, dried
over Na2SO4 and concentrated to dryness. The residue was purified by silica gel
column chromatography (petroleum ether—ethyl acetate, 80:1) to provide 11a
1
(1.4 g, 42.2%) as a white solid. H NMR (400 MHz, CDCl3): d 7.38–7.33 (m, 4H),
7.25–7.15 (m, 5H), 7.06–7.00 (m, 4H), 6.87–6.80 (m, 4H), 4.15 (q, J ¼ 7.2 Hz, 2H),
2.23–2.19 (m, 1H), 1.26–1.22 (m, 2H), 1.12 (t, J ¼ 7.2 Hz, 3H), 1.01–0.96 (m, 2H).
Compounds 11b and 11c were prepared in the manner analogous to the
method described above. Compounds 11d, 11e, 14a, and 14b were prepared in the
above method, but the reaction temperature were raised up to 130 ꢀC and reacted
for 24 h.
Ethyl 2-Cyclopropyl-4,6,7-tri-(4-fluorophenoxy)quinoline-3-
carboxylate (11b)
White solid. 1H NMR (400MHz, CDCl3): d 7.26 (s, 1H), 7.16 (s, 1H), 7.10–7.01
(m, 4H), 6.97–6.89 (m, 4H), 6.86–6.82 (m, 2H), 6.78–6.74 (m, 2H), 4.21 (q, J ¼ 7.2 Hz,
2H), 2.21–2.16 (m, 1H), 1.25–1.21 (m, 2H), 1.16 (t, J ¼ 7.2 Hz, 3H), 1.02–0.97 (m, 2H).
HRMS: m=z calcd for C33H25F3NO5 (M þ H)þ 572.1685, found: 572.1688.
Ethyl 2-Cyclopropyl-4,6,7-tri-(4-methoxyphenoxy)quinoline-3-
carboxylate (11c)
White solid. 1H NMR (400 MHz, CDCl3): d 7.23 (s, 1H), 7.19 (s, 1H),
7.10–7.07 (m, 2H), 6.97–6.94 (m, 2H), 6.90–6.87 (m, 2H), 6.82–6.80 (m, 2H), 6.76
(s, 4H), 4.20 (q, J ¼ 7.2 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 2.21–2.18
(m, 1H), 1.25–1.22 (m, 2H), 1.20 (t, J ¼ 7.2 Hz, 3H), 1.01–0.98 (m, 2H).

A REGIOSELECTIVE SNAr REACTION
31
Ethyl 2-Cyclopropyl-4,6,7-tri-(4-fluorophenylthio)quinoline-3-
carboxylate (11d)
1
Lightly yellow solid. H NMR (400 MHz, CDCl3): d 7.81 (s, 1H), 7.54–7.49
(m, 3H), 7.32–7.28 (m, 2H), 7.18–7.14 (m, 2H), 7.06–7.02 (m, 2H), 7.00–7.97
(m, 2H), 7.89–6.84 (m, 2H), 4.44 (q, J ¼ 7.2 Hz, 2H), 2.10–2.06 (m, 1H), 1.35
(t, J ¼ 7.2 Hz, 3H), 1.33–1.28 (m, 2H), 1.08–1.03 (m, 2H).
Ethyl 2-Cyclopropyl-4,6,7-tri-(4-methoxyphenylthio)quinoline-3-
carboxylate (11e)
1
Yellow solid. H NMR (400MHz, CDCl3): d 7.83 (s, 1H), 7.49–7.47 (m, 2H),
7.35–7.32 (m, 2H), 7.26 (s, 1H), 6.99–6.90 (m, 6H), 6.67–6.64 (m, 2H), 4.42 (q,
J ¼ 7.2 Hz, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.74 (s, 3H), 2.04–2.01 (m, 1H), 1.35 (t,
J ¼ 7.2 Hz, 3H), 1.21–1.16 (m, 2H), 0.98–0.94 (m, 2H). MS (ESI): m=z ¼ 656
(M þ H)þ.
Ethyl 2-Cyclopropyl-4,5,6-tri-(4-methoxyphenoxy)quinoline-3-
carboxylate (14a)
1
White solid. H NMR (400 MHz, CDCl3): d 7.85 (d, J ¼ 8.8 Hz, 1H), 7.38 (t,
J ¼ 9.2 Hz, 1H), 6.79–6.47 (m, 12H), 4.16 (q, J ¼ 7.2 Hz, 2H), 3.77 (s, 3H), 3.75 (s,
3H), 3.74 (s, 3H), 2.19–2.16 (m, 1H), 1.39–1.35 (m, 2H), 1.11–1.06 (m, 5H).
Ethyl 2-Cyclopropyl-4,6,7-tri-(4-methoxyphenylthio)quinoline-3-
carboxylate (14b)
1
Yellow solid. H NMR (400 MHz, CDCl3): d 7.83 (b, 1H), 7.39–7.36 (m, 2H),
7.07 (d, J ¼ 9.2 Hz, 1H), 7.05–7.03 (m, 2H), 6.97–6.72 (m, 8H), 4.25 (q, J ¼ 7.2 Hz,
2H), 3.87 (s, 3H), 3.76 (s, 6H), 2.08–2.06 (m, 1H), 1.25 (t, J ¼ 7.2 Hz, 3H),
1.34–1.31 (m, 2H), 1.07–1.03 (m, 2H).
ACKNOWLEDGMENT
This work was supported by ‘‘New Drug Innovation 2009 ꢃ 9301–007’’ by
Ministry of Science and Technology of China.
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