Investigation of amination in 4-chloro-2-phenylquinoline derivatives with amide solvents

Article abstract of DOI:10.1016/j.tet.2008.09.100

Novel 4-amino-2-phenylquinoline derivatives were synthesized by reacting various 4-chloro-2-arylquinoline compounds having activated chloro group with the corresponding amide solvents at reflux for overnight. The activity of amination by the amide solvent

Full text of DOI:10.1016/j.tet.2008.09.100

Tetrahedron 64 (2008) 11751–11755
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Investigation of amination in 4-chloro-2-phenylquinoline derivatives
with amide solvents
,
a
a
b
Jui-Ying Tsai a, Chih-Shiang Chang a , Yi-Fan Huang , Hua-Shin Chen , Shao-Kai Lin ,
*
Fung Fuh Wong a, Li-Jiau Huang a , Sheng-Chu Kuo
,
a
*
a Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh Shih Road, Taichung, Taiwan 40402, ROC
b Sustainable Environment Research Center, National Cheng Kung University, No. 500, Sec. 3, An-ming Road, Tainan City, Taiwan 709, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 4-amino-2-phenylquinoline derivatives were synthesized by reacting various 4-chloro-2-aryl-
quinoline compounds having activated chloro group with the corresponding amide solvents at reflux for
overnight. The activity of amination by the amide solvents depended on the competition between the
steric and electronic effect of the N-substituents on the amino group. Their activities were shown as N,N-
dimethylformamide>N,N-diethylformamide>N-methylformamide>formamide>N,N-dimethylacetamide>
N,N-dimethylpropionamide. The yields for the amination products seemed proportional to the ease of
the dissociation of the amides.
Received 25 August 2008
Received in revised form
22 September 2008
Accepted 26 September 2008
Available online 8 October 2008
Keywords:
Dialkylformamide
Amination
Ó 2008 Published by Elsevier Ltd.
4-Chloro-2-phenylquinoline
4-Amino-2-phenylquinoline
1. Introduction
solvents to prepare a series of 4-amino-2-arylquinoline for en-
hancing the biological activities.
The preparation of amino-containing heterocyclic and aromatic
compounds, such as aminopyrine (antipyretic),1 ampyzine (central
stimulant),2 6-dimethylamino-8-azaadenosine (antitumor),3 dimeth-
thirimol (fungicide),4 diphenhydramine (antihistamine),2 metha-
done (narcotic analgesic),5 and various other drugs,6 have been
extensively studied owing to their importance as biologically active
compounds. In addition to their usefulness as drugs, the reactivity
of their amino group also makes them popular starting components
in organic synthesis.7
2-Phenylquinoline derivatives are the effective pharmacophore
in medicinal chemistry as illustrated by its application in pharma-
ceutical agents in fields as novel antitumor promoters,8 antiplatelet
agents,9 and DNA-intercalator agents10–12 according to the mod-
erate effective binding ability with DNA. 2-Phenylquinoline con-
taining an additional basic N-4-aminoalkyl function would strongly
increase the biological activity of immunostimulatory CpG-oligo-
deoxynucleotides.13 In 2006, the 4-aminoquinoline derivatives
were also explored as the melanin-concentrating hormone 1-re-
ceptor (MCH1R) antagonist by DeVita et al.14 Therefore, we planned
to develop a convenient amination methodology using amide
In the literature, the structural parameters, and energy barrier
for rotational about C–N bond, of a series of amides with varying
substituents, have been experimentally determined.15 They agreed
quite well with theoretical values calculated by ab initio calcula-
tions (MP2 level with the 6-31þG(d) basis)16 and hybrid QM/MM
calculations (IMOMM method).17 Thus, it is a great interest to us to
relate the amination ability of amides to their dissociation activity
and resonance structure parameter.18 In this work, we also
attempted to relate the amination yield of a series of substituted
4-chloro-2-arylquinoline to the ease of dissociation of various
substituted amide solvents that were used as amination agents.
2. Results and discussion
2-Phenylquinoline derivatives (1) were prepared by following
the previous published procedure using condensation and tandem
thermal cyclization approaches.19 2-Phenylquinoline derivatives
(1a–1e) were efficiently transformed into the corresponding
4-chloro-2-arylquinoline 2a–2e in 77–92% yields by using thionyl
chloride in CH2Cl2 solution at reflux (see Scheme 1).20
For the model amination studies, 4-chloro-2-phenylquinoline
(2a) was treated with N,N-dimethylformamide (DMF) or N,N-
diethylformamide (DEF) at reflux. The reaction gave the corre-
sponding amination products in 75% and 51% yield, respectively (3a
* Corresponding authors. Tel.: þ886 4 2205 3366x5615; fax: þ886 4 2207 8083.
E-mail address: chihshiang@mail.cmu.edu.tw (C.-S. Chang).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.09.100

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J.-Y. Tsai et al. / Tetrahedron 64 (2008) 11751–11755
O
R1
O
Cl
R3
N
5
SOCl2
X1
R2
X1
R1 , R2 = H, Me
CH2Cl2
7
N
H
N
X2
X2
R
3 = Me, n-Pr
1a. X1 = H, X2 = H
2a. X1 = H, X2 = H, 91%
2b. X1 = H, X2 = o-F, 92%
2c. X1 = H, X2 =p-OMe, 88%
2d. X1 = 6-F, X2 = H, 82%
2e. X1 = 7-F, X2 = H, 80%
2f. X1 = 8-F, X2 = H, 77%
1b. X1 = H, X2 = o-F
1c. X1 = H, X2 = p-OMe
1d. X1 = 6-F, X2 = H
1e. X1 = 7-F, X2 = H
1f. X1 = 8-F, X2 = H
3. X1 = H, X2 = H
5. X1 = H, X2 = p-OMe
3a. R1 = R2 = Me
5a. R1 = R2 = Me
3b. R1 = R2 = Et
3c. R1 = H, R2 = Me
3d. R1 = R2 = H
5b. R1 = R2 = Et
R2
R1
N
N
5c. R1 = H, R2 = Me
5d. R
1 = R2 = H
X1
4. X1 = H, X2 = o-F
6. X1 = 6-F, X2 = H, R1 = R2 = Me
7. X1 = 7-F, X2 = H, R1 = R2 = Me
8. X1 = 8-F, X2 = H, R1 = R2 = Me
X2
4a. R1 = R2 = Me
4b.R1 = R2 = Et
4c. R1 = H, R2 = Me
4d. R1 = R2 = H
Scheme 1.
and 3b, see Scheme 1 and Table 1). Due to the balance of electronic
and steric contributions, both N,N-dimethylformamide (DMF) and
N,N-diethylformamide (DEF) were assumed as planar or nearly
planar nitrogen bond configuration to promote the nucleophilicity
of lone-pair on nitrogen (B, see Scheme 2).16
4-Chloro-2-phenylquinoline (2a) was treated with other am-
ide solvents, including formamide and N-methylformamide un-
der the same condition. Relatively low isolated yields were
obtained (3c and 3d, 32–43%, see Table 1). Theoretically, both
formamide and N-methylformamide favored the C(Oꢀ)]Nþ
configuration (A, see Scheme 2) than N,N-dimethylformamide
(DMF) and N,N-diethylformamide (DEF). As a consequence, the
electron density and nucleophilicity of its nitrogen group were
somewhat suppressed.21,22 In the case of N,N-dimethylacetamide
(DMA) and N,N-dimethylpropionamide (DMP), large distortions
away from planar configuration (C, see Scheme 2) caused by
repulsion between relatively bulky substituents on carbon and
nitrogen groups are expected.23 The sterical hindrance of sub-
stituents on amide likely reduced the nucleophilicity of electron
lone-pair on nitrogen group and resulted in poor amination
yields (10–11%). Nevertheless, our synthetic yields for amination
products seemed to vary with dissociation activity of amides
reported in the literatures.16,17
For the further demonstration investigation, we applied the
various substituents 2-phenylquinolines involving 4-chloro-2-(2-
fluorophenyl)quinoline (2b), 4-chloro-2-(4-methoxylphenyl)quinoline
Table 1
The results of the amination of 4-chloro-2-arylquinolines with amides
2-Phenylquinolines (2a–2f)
Amides R1R2NC(]O)R3
4-Amino-2-phenylquinolines (3–8)
S.M.
X1
H
X2
H
R1
R2
R3
Products
X1
X2
R1
R2
Yields (%)
2a
Me
Et
Me
H
Me
Me
Me
Et
H
H
Me
Me
H
H
H
H
Me
n-Pr
3a
3b
3c
3d
3a
3a
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
Me
H
Me
Me
Me
Et
H
H
Me
Me
75
51
43
32
11
10
2b
2c
2d
H
o-F
Me
Et
Me
H
Me
Et
H
H
H
H
H
4a
4b
4c
4d
H
H
H
H
o-F
o-F
o-F
o-F
Me
Et
Me
H
Me
Et
H
83
49
16
13
H
H
H
p-OMe
Me
Et
Me
H
Me
Et
H
H
H
H
H
5a
5b
5c
5d
H
H
H
H
p-OMe
p-OMe
p-OMe
p-OMe
Me
Et
Me
H
Me
Et
H
58
27
23
14
H
H
6-F
H
Me
Me
H
6
6-F
H
Me
Me
91
2e
2f
7-F
8-F
H
H
Me
Me
Me
Me
H
H
7
8
7-F
8-F
H
H
Me
Me
Me
Me
87
56

J.-Y. Tsai et al. / Tetrahedron 64 (2008) 11751–11755
11753
small substituting groups
O
R1
R2
R1, R2 = H or Me
3 = H
C
N
R3
R
A
mild substituting groups
bulky substituting groups
O
R1
R1, R2 = Me
3 = Me or i-Pr
R1, R2 = Me or Et
3 = H
R1
R2
O
R3
N
C
C
N
R
R
R3
R2
B
C
Scheme 2.
(2c), 4-chloro-6-fluoro-2-phenylquinoline (2d), 4-chloro-7-fluoro-
2-phenylquinoline (2e), and 4-chloro-8-fluoro-2-phenylquinoline
(2f) with a series of amide solvents including N,N-dimethylforma-
mide, N,N-diethylformamide, N-methylformamide, and formamide
under the same condition to obtain the corresponding amination
products in 13–91% yields (4a–4d, 5a–5d, 6, 7, and 8 see Table 1).
The better isolation yields were obtained by using N,N-dime-
thylformamide (DMF) as reaction solvent (58–91%, 4a, 5a, 6, 7, and
3.2. Standard procedure for the synthesis of 4-chloro-2-
phenylquinoline derivatives (2a–2f)
A
solution of 2-phenyl-4-quinolone derivatives (1a–1f,
15 mmol, 1.0 equiv) and thionyl chloride (SOCl2, 0.15 mol, 10 equiv,
w10 mL) in CH2Cl2 solution (100 mL) was reflux for 12 h. When the
reaction was completed, the reaction mixture was concentrated,
added to water (200 mL), and extracted with ethyl acetate
(4ꢁ200 mL). The organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue solution was
purified by column chromatography on silica gel or re-crystalliza-
tion to give the corresponding 4-chloro-2-phenylquinoline prod-
ucts (2a–2g) in 77–92% yields.
8
see Table 1). However, these experimental results could
supported our model conversion studies of 4-chloro-2-phenyl-
quinoline (2a) to the corresponding amination products (3a–3f).
In conclusion, we have developed the newly amination method
by treating substituted 4-chloro-2-arylquinoline derivatives (2a–2f)
with various substituent amides, including N,N-dimethylacetamide,
N,N-dimethylpropionamide, formamide, N,N-diethylformamide,
and N-methylformamide. Based on our experimental data, the
order of dissociation activity is N,N-dimethylformamide>N,N-
diethylformamide>N-methylformamide>formamide>N,N-dime-
thylacetamide>N,N-dimethylpropionamide. Our experimental
results were consistent with the previous literature reported data
and theoretical calculations.
3.2.1. 4-Chloro-2-phenylquinoline (2a)
1H NMR (DMSO-d6, 200 MHz)
d
7.49–7.52 (m, 3H, H-30, 40, 50),
7.52 (t, 1H, J¼6.7 Hz, H-6), 7.84 (t, 1H, J¼6.7 Hz, H-7), 8.07–8.12 (m,
2H, H-5, 8), 8.23–8.28 (m, 2H, H-20, 60), 8.33 (s, 1H, H-3); 13C NMR
(DMSO-d6, 50 MHz)
d
119.31, 123.98, 124.99, 127.82 (Cꢁ2), 128.40,
129.37 (Cꢁ2), 130.11, 130.62, 131.61, 137.87, 142.78, 148.69, 156.77;
IR (KBr) 1613 (C]N) cmꢀ1. Anal. Calcd for C15H10ClN: C: 75.16; H:
4.21; N: 5.84. Found: C: 75.21; H: 4.33; N: 5.81.
3. Experimental section
3.1. General procedure
3.2.2. 4-Chloro-2-(2-fluorophenyl)quinoline (2b)
1H NMR (DMSO-d6, 200 MHz)
d
7.35–7.57 (m, 3H, H-40, 50, H-3),
7.74–7.78 (dd,1H, J¼1.3, 6.9 Hz, H-30), 7.92 (t,1H, J¼8.2 Hz, H-6), 7.80
– 8.05 (m, 2H, H-7, 8), 8.09–8.13 (d,1H, J¼8.9, H-60), 8.16–8.20 (d,1H,
All chemicals were of reagent grade. Analytical thin-layer
chromatography (TLC) was performed on precoated plates (silica
gel 60 F-254) purchased from Merck Inc. Purification by gravity
column chromatography was carried out by use of Merck Reagents
Silica Gel 60 (particle size 0.063–0.200 mm, 70–230 mesh ASTM).
Infrared (IR) spectra were measured on a Bomem Michelson Series
FT-IR spectrometer. The wave numbers reported are referenced to
the polystyrene 1601 cmꢀ1 absorption. Absorption intensities are
recorded by the following abbreviations: s, strong; m, medium; w,
weak. Proton NMR spectra were obtained on a Bruker (200 MHz)
spectrometer by use of CDCl3 and DMSO-d6 as solvent. Carbon-13
NMR spectra were obtained on a Bruker (50 MHz) spectrometer by
use of CDCl3 as solvent. Carbon-13 chemical shifts are referenced to
J¼8.2 Hz, H-5); 13C NMR (DMSO-d6, 50 MHz)
d 117.10, 122.5, 124.00,
124.91, 125.41, 128.91, 130.20, 131.71 (Cꢁ3), 132.50, 142.05, 148.73,
153.75,162.40; IR (KBr) 1618 (C]N) cmꢀ1. Anal. Calcd for C15H9ClFN:
C: 69.91; H: 3.52; N: 5.44. Found: C: 70.12; H: 4.01; N: 5.31.
3.2.3. 4-Chloro-2-(4-methoxylphenyl)quinoline (2c)
1H NMR (DMSO-d6, 200 MHz)
d 3.80 (s, 3H, OCH3), 7.03–7.08 (d,
2H, J¼8.4 Hz, H-30, 50), 7.69 (t, 1H, J¼8.2 Hz, H-6), 7.82 (t, 1H,
J¼8.2 Hz, H-7), 8.03–8.22 (m, 2H, H-5, 8), 8.26–8.30 (d, 2H,
J¼8.4 Hz, H-20, 60), 8.32 (s, 1H, H-3); 13C NMR (DMSO-d6, 50 MHz)
d
55.8, 114.74 (Cꢁ2), 118.82, 123.96, 124.67, 127.91, 129.35 (Cꢁ2),
129.91, 130.31, 131.49, 142.55, 148.77, 156.47, 161.50; IR (KBr) 1622
(C]N) cmꢀ1. Anal. Calcd for C16H12ClNO: C: 71.25; H: 4.48; N: 5.19.
Found: C: 71.14; H: 4.33; N: 5.34.
the center of the CDCl3 triplet (
d 77.0 ppm). Multiplicities are
recorded by the following abbreviations: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; J, coupling constant (Hz). Ele-
mental analyses were carried out on a Heraeus CHN–O RAPID el-
ement analyzer.
3.2.4. 4-Chloro-6-fluoro-2-phenylquinoline (2d)
1H NMR (DMSO-d6, 200 MHz)
d
7.47–7.51 (m, 3H, H-30, 40, 50),
7.73–7.81 (m, 2H, H-3, 7), 8.12–8.23 (m, 3H, H-20, 60, 8), 8.33 (s, 1H,

11754
J.-Y. Tsai et al. / Tetrahedron 64 (2008) 11751–11755
H-5); 13C NMR (DMSO-d6, 50 MHz)
d
107.51, 108.00, 119.96, 121.34,
157.17; IR (KBr) 1612 (C]N) cmꢀ1. Anal. Calcd for C16H14N2: C:
121.85, 125.95, 127.72 (Cꢁ2), 129.36 (Cꢁ2), 130.62, 133.35, 137.65,
82.02; H: 6.02; N: 11.96. Found: C: 82.32; H: 6.08; N: 11.54.
142.11, 145.87; IR (KBr) 1614 (C]N) cmꢀ1
.
Anal. Calcd for
C15H9ClFN: C: 69.91; H: 3.52; N: 5.44. Found: C: 69.95; H: 3.55; N:
5.38.
3.3.4. 2-Phenylquinolin-4-amine (3d)
1H NMR (DMSO-d6, 200 MHz)
d 6.80 (s, 2H, NH2), 7.07 (s, 1H,
H-3), 7.33–7.62 (m, 5H, H-30, 40, 50, 6, 7), 7.76–7.77 (dd, 1H, J¼1.0,
3.2.5. 4-Chloro-7-fluoro-2-phenylquinoline (2e)
8.3 Hz, H-5), 8.01–8.05 (m, 2H, H-20, 60), 8.06–8.09 (d, 1H, J¼6.1 Hz,
1H NMR (DMSO-d6, 200 MHz)
d
7.51–7.54 (m, 3H, H-30, 40, 50),
H-8); 13C NMR (DMSO-d6, 50 MHz)
d 99.51, 118.26, 122.64, 123.96,
7.76–7.85 (m, 2H, H-3, 6), 8.11–8.27 (m, 3H, H-20, 60, 5), 8.34 (s, 1H,
H-8); 13C NMR (DMSO-d6, 50 MHz)
113.42, 113.82, 118.22, 118.86,
122.33, 126.88, 127.08, 127.94 (Cꢁ2), 129.39 (Cꢁ2), 130.89, 137.59,
142.91, 158.11; IR (KBr) 1622 (C]N) cmꢀ1
Anal. Calcd for
127.22 (Cꢁ2), 128.99 (Cꢁ2), 129.27, 129.62, 129.72, 140.42, 149.22,
152.82, 156.66; IR (KBr) 1633 (C]N) cmꢀ1. Anal. Calcd for C15H12N2:
C: 81.79; H: 5.49; N: 12.72. Found: C: 81.35; H: 5.25; N: 12.64.
d
.
C15H9ClFN: C: 69.91; H: 3.52; N: 5.44. Found: C: 70.21; H: 3.64; N:
5.40.
3.3.5. 2-(2-Fluorophenyl)-N,N-dimethylquinolin-4-amine (4a)
1H NMR (DMSO-d6, 200 MHz)
d
2.99 (s, 6H, NCH3ꢁ2), 7.14 (s, 1H,
H-3), 7.31–7.35 (m, 2H, H-40, 50), 7.44–7.51 (m, 2H, H-30, 6), 7.65 (t,
3.2.6. 4-Chloro-8-fluoro-2-phenylquinoline (2f)
1H, J¼8.3 Hz, H-7), 7.90–7.95 (m, 2H, H-60, 8), 8.02–8.07 (d, 1H,
1H NMR (DMSO-d6, 200 MHz)
d
7.44–7.50 (m, 3H, H-30, 40, 50),
J¼8.4 Hz, H-5); 13C NMR (DMSO-d6, 50 MHz)
43.95 (Cꢁ2), 108.46,
d
7.69–8.21 (m, 6H, H-3, 5, 6, 7, 20, 60); 13C NMR (DMSO-d6, 50 MHz)
116.92, 121.69, 124.89, 125.15, 125.29, 128.41, 129.66, 130.15, 131.45,
d
111.37, 112.01, 119.17, 120.13, 122.41, 127.15, 127.93 (Cꢁ2), 129.33
131.76, 145.85, 149.75, 153.33, 157.60; IR (KBr) 1607 (C]N) cmꢀ1
.
(Cꢁ2), 130.11, 132.45, 137.72, 142.55, 158.21; IR (KBr) 1624 (C]N)
cmꢀ1. Anal. Calcd for C15H9ClFN: C: 69.91; H: 3.52; N: 5.44. Found:
C: 68.03; H: 3.65; N: 5.58.
Anal. Calcd for C17H15FN2: C: 76.67; H: 5.68; N: 10.52. Found: C:
76.87; H: 5.78; N: 10.46.
3.3.6. N,N-Diethyl-2-(2-fluorophenyl)quinolin-4-amine (4b)
1H NMR (DMSO-d6, 200 MHz)
d
1.06–1.13 (t, 6H, J¼7.0 Hz,
3.3. Standard procedure for the synthesis of 4-amino-2-
phenylquinoline derivatives (3a–3f, 4a–4d, 5a–5d, 6, 7, and 8)
NCH3ꢁ2), 3.31–3.37 (q, 4H, J¼7.0 Hz, CH2ꢁ2), 7.22–7.36 (m, 3H, H-
30, 40, 50), 7.45–7.50 (m, 2H, H-3, 6), 7.64 (t, 1H, J¼8.2 Hz, H-7), 7.92–
7.97 (m, 3H, H-5, 60, 8); 13C NMR (DMSO-d6, 50 MHz)
d
12.43 (Cꢁ2),
4-Chloro-2-phenylquinoline derivatives (2a–2f, 15 mmol,
1.0 equiv) were dissolved in the various amide solutions (100 mL)
including N,N-dimethylformamide, N,N-diethylformamide, N-methyl-
formamide, formamide, N,N-dimethylacetamide, and N,N-dimethyl-
propionamide at reflux for overnight. When the reaction was
completed, the reaction mixture was added to water (100 mL) and
extracted with ethyl acetate (3ꢁ100 mL). The organic extracts were
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue solution was purified by column chromatography
on silica gel to give the corresponding 4-amino-2-phenylquinoline
products (3a–3f, 4a–4d, 5a–5d, 6, 7, and 8) in 11–91% yields.
46.49 (Cꢁ2), 111.42, 111.56, 116.49, 116.95, 123.27, 124.33, 125.21,
125.63, 129.72, 130.22, 131.37, 131.69, 149.85, 153.58, 155.53; IR
(KBr) 1608 (C]N) cmꢀ1. Anal. Calcd for C19H19FN2: C: 77.52; H:
6.51; N: 9.52. Found: C: 77.53; H: 6.49; N: 9.48.
3.3.7. N-Methyl-2-(2-fluorophenyl)quinolin-4-amine (4c)
1H NMR (DMSO-d6, 200 MHz)
d 2.99 (s, 3H, NCH3), 7.16 (s, 1H, H-
3), 7.30–7.36 (m, 3H, H-40, 50, NH), 7.45–7.52 (m, 2H, H-30, 6), 7.66–
7.74 (t, 1H, J¼8.9 Hz, H-7), 7.90–7.95 (m, 2H, H-60, 8), 8.03–8.04 (d,
1H, J¼2.2 Hz, H-5); 13C NMR (DMSO-d6, 50 MHz)
d 30.11, 116.71,
121.33, 123.21, 124.92, 125.17, 125.89, 126.33, 131.82, 132.34, 132.55,
134.41, 147.76, 155.38, 156.72, 158.49; IR (KBr) 1618 (C]N) cmꢀ1
.
3.3.1. N,N-Dimethyl-2-phenylquinoline-4-amine (3a)
Anal. Calcd for C16H13FN2: C: 76.17; H: 5.19; N: 11.10. Found: C:
76.37; H: 5.02; N: 11.23.
1H NMR (DMSO-d6, 200 MHz)
d
3.05 (s, 6H, NCH3ꢁ2), 7.36
(s, 1H, H-3), 7.47–7.52 (m, 4H, H-30, 40, 50, 6), 7.67 (t, 1H, J¼8.2 Hz,
H-7), 7.95–7.99 (d, 1H, J¼8.3 Hz, H-5), 8.03–8.08 (d, 1H, J¼8.3 Hz,
H-8), 8.20–8.24 (dd, 2H, J¼1.8, 6.0 Hz, H-20, 60); 13C NMR (DMSO-
3.3.8. 2-(2-Fluorophenyl)quinolin-4-amine (4d)
1H NMR (DMSO-d6, 200 MHz)
d
7.32–7.40 (m, 4H, H-3, 40, NH2),
d6, 50 MHz)
d
43.84 (Cꢁ2), 104.88, 121.67, 124.66, 124.68, 127.47
7.62–7.67 (m, 6H, H-30, 5, 50, 6, 60, 7), 8.05–8.11 (d, 1H, J¼8.6 Hz, H-
(Cꢁ2), 128.83 (Cꢁ2), 129.05, 129.19, 129.96, 139.76, 149.49,
8); 13C NMR (DMSO-d6, 50 MHz)
d 100.01, 119.27, 122.73, 123.97,
156.56, 158.04; IR (KBr) 1602 (C]N) cmꢀ1
.
Anal. Calcd for
127.29, 130.52, 133.44, 133.78, 138.25, 140.08, 140.44, 141.42, 157.42,
C17H16N2: C: 82.22; H: 6.49; N: 11.28. Found: C: 82.15; H: 6.55;
N: 11.14.
159.77, 162.31; IR (KBr) 1621 (C]N) cmꢀ1
.
Anal. Calcd for
C15H11FN2: C: 75.62; H: 4.65; N: 11.76. Found: C: 75.21; H: 4.81; N:
11.83.
3.3.2. N,N-Diethyl-2-phenylquinolin-4-amine (3b)
1H NMR (DMSO-d6, 200 MHz)
d
1.05–1.12 (t, 6H, J¼2.9 Hz,
3.3.9. 2-(4-Methoxyphenyl)-N,N-dimethylquinolin-4-amine (5a)
NCH3ꢁ2), 3.31–3.42 (q, 4H, J¼6.9 Hz, –CH2ꢁ2), 7.41–7.49 (m, 5H, H-
1H NMR (DMSO-d6, 200 MHz)
d
3.01 (s, 6H, NCH3ꢁ2), 3.79 (s,
3, 6, 30, 40, 50), 7.63 (t, 1H, J¼7.0 Hz, H-7), 7.92–7.95 (m, 2H, H-5, 8),
3H, OCH3), 7.01–7.05 (d, 2H, J¼8.0 Hz, H-30, 50), 7.29 (s, 1H, H-3),
7.41–7.45 (t, 1H, J¼7.0 Hz, H-6), 7.61 (dd, 1H, J¼1.2 Hz, H-7), 7.87–
7.91 (d, 1H, J¼8.6 Hz, H-5), 7.98–8.02 (d, H, J¼8.4 Hz, H-8), 8.13–8.17
8.18–8.19 (m, 2H, H-20, 60); 13C NMR (DMSO-d6, 50 MHz)
d 12.51
(Cꢁ2), 46.37 (Cꢁ2), 108.13, 123.50, 124.35, 125.26, 127.70 (Cꢁ2),
129.11 (Cꢁ2), 129.33, 129.68, 130.23, 139.89, 149.84, 156.38, 156.59;
IR (KBr) 1621 (C]N) cmꢀ1. Anal. Calcd for C19H20N2: C: 82.57; H:
7.29; N: 10.14. Found: C: 82.42; H: 7.11; N: 10.31.
(d, 2H, J¼8.0 Hz, H-20, 60); 13C NMR (DMSO-d6, 50 MHz)
d 44.08
(Cꢁ2), 55.71, 104.66, 114.42 (Cꢁ2), 121.71, 124.58, 124.80, 129.06
(Cꢁ2), 129.49, 129.97, 132.33, 149.68, 156.41, 158.15, 160.79; IR (KBr)
1623 (C]N) cmꢀ1. Anal. Calcd for C18H18N2O: C: 77.67; H: 6.52; N:
10.06. Found: C: 77.35; H: 6.57; N: 10.37.
3.3.3. N-Methyl-2-phenylquinolin-4-amine (3c)
1H NMR (DMSO-d6, 200 MHz)
d
2.96–2.98 (d, 3H, J¼4.4 Hz,
NCH3), 6.87 (1H, s, NH), 7.33–7.47 (m, 6H, H-3, 30, 40, 50, 6, 7), 7.82–
3.3.10. N,N-Diethyl-2-(4-methoxyphenyl)quinolin-4-amine (5b)
7.86 (d, 1H, J¼9.0 Hz, H-5), 8.15–8.19 (m, 2H, H-20, 60); 13C NMR
1H NMR (DMSO-d6, 200 MHz)
d
1.05–1.12 (t, 6H, J¼7.1 Hz,
(DMSO-d6, 50 MHz)
d
29.87, 95.26, 118.54, 121.79, 124.29, 127.58
CH3ꢁ2), 3.32–3.42 (q, 4H, J¼7.1 Hz, CH2ꢁ2), 3.79 (s, 3H, OCH3),
(Cꢁ2), 128.89 (Cꢁ2), 129.33, 129.54, 129.77, 140.66, 148.56, 152.17,
7.01–7.06 (dd, 2H, J¼2.0, 8.9 Hz, H-30, 50), 7.38 (s, 1H, H-3), 7.41–7.46

J.-Y. Tsai et al. / Tetrahedron 64 (2008) 11751–11755
11755
(t, 1H, J¼8.3 Hz, H-6), 7.61–7.66 (t, 1H, J¼8.3 Hz, H-7), 7.88–7.97 (dd,
2H, J¼2.1, 8.6 Hz, H-5, 8), 8.12–8.16 (d, 2H, 8.9 Hz, H-20, 60); 13C NMR
H-20, 60, 5); 13C NMR (DMSO-d6, 50 MHz)
d
44.12 (Cꢁ2), 111.65,
114.22, 118.53, 126.33, 127.62, 128.01, 129.45 (Cꢁ2), 131.94 (Cꢁ2),
(DMSO-d6, 50 MHz)
d
12.52 (Cꢁ2), 46.35 (Cꢁ2), 55.72,107.71,114.47
140.32, 156.65, 158.38, 162.11, 163.04; IR (KBr) 1633 (C]N) cmꢀ1
.
(Cꢁ2), 123.30, 124.30, 124.90, 129.08 (Cꢁ2), 129.56, 130.00, 132.26,
149.82, 156.22 (Cꢁ2), 160.82; IR (KBr) 1610 (C]N) cmꢀ1. Anal. Calcd
for C20H22N2O: C: 78.40; H: 7.24; N: 9.14. Found: C: 78.52; H: 7.56;
N: 9.18.
Anal. Calcd for C17H15FN2: C: 76.67; H: 5.68; N: 10.52. Found: C:
76.72; H: 5.75; N: 10.25.
Acknowledgements
3.3.11. N-Methyl-2-(4-methoxyphenyl)quinolin-4-amine (5c)
1H NMR (DMSO-d6, 200 MHz)
d 3.10 (s, 3H, NCH3), 3.77 (s, 3H,
We are grateful to the National Science Council of Republic of
China for financial support.
OCH3), 6.68 (s, 1H, H-3), 6.72–6.88 (m, 3H, H-30, 50, NH), 7.41–8.03
(m, 2H, H-6, 7), 8.11–8.22 (m, 4H, H-20, 60, 5, 8); 13C NMR (DMSO-d6,
50 MHz)
d
31.15, 55.81, 114.78 (Cꢁ2), 117.89, 122.34, 125.81, 128.20,
Supplementary data
131.41 (Cꢁ2), 132.57, 132.88, 144.12, 149.73, 156.48, 161.52, 161.87;
IR (KBr) 1610 (C]N) cmꢀ1. Anal. Calcd for C17H16N2O: C: 77.25; H:
6.10; N: 10.60. Found: C: 77.15; H: 6.19; N:10.24.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.09.100.
3.3.12. 2-(4-Methoxyphenyl)quinolin-4-amine (5d)
1H NMR (DMSO-d6, 200 MHz)
d 3.89 (s, 3H, OCH3), 6.45 (s, 2H,
References and notes
NH2), 6.99 (s, 1H, H-3), 7.04–7.06 (d, 2H, J¼7.8 Hz, H-30, 50), 7.64–
7.78 (m, 2H, H-6, 7), 8.09–8.13 (m, 2H, H-5, 8), 8.22–8.23 (m, 2H, H-
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20, 60); 13C NMR (DMSO-d6, 50 MHz)
d
55.91, 114.79 (Cꢁ2), 117.22,
124.96, 127.35, 129.41 (Cꢁ2), 130.32, 131.05, 141.28, 143.38, 149.66,
154.38, 160.29, 162.39; IR (KBr) 1623 (C]N) cmꢀ1. Anal. Calcd for
C16H14N2O: C: 76.78; H: 5.64; N: 11.19. Found: C: 76.75; H: 5.68; N:
11.23.
3.3.13. 6-Fluoro-N,N-dimethyl-2-phenylquinolin-4-amine (6)
1H NMR (DMSO-d6, 200 MHz)
d
3.40 (s, 6H, NCH3ꢁ2), 7.13 (s, 1H,
H-3), 7.60–7.63 (m, 3H, H-30, 40, 50), 7.82–7.83 (m, 1H, H-7), 8.03–
8.09 (m, 3H, H-20, 60, 8), 8.25–8.27 (m,1H, H-5); 13C NMR (DMSO-d6,
50 MHz)
d
43.77 (Cꢁ2), 107.31, 114.30, 121.97, 125.12, 129.92, 130.51
10. Atwell, G. J.; Bos, C. D.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1988, 31, 1048.
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jarski, A. J. J. Med. Chem. 2003, 46, 1242.
(Cꢁ2), 131.28, 134.53 (Cꢁ2), 138.76, 149.10, 154.31, 161.38, 162.21; IR
(KBr) 1621 (C]N) cmꢀ1. Anal. Calcd for C17H15FN2: C: 76.67; H:
5.68; N: 10.52. Found: C: 76.61; H: 5.69; N: 10.49.
14. Jiang, J.; Lin, P.; Hoang, M.; Chang, L.; Tan, C.; Feighner, S.; Palyha, O. C.; Hreniuk,
D. L.; Pan, J.; Sailer, A. W.; Morin, N. R.; MacNeil, D. J.; Howard, A. D.; Van der
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3.3.14. 7-Fluoro-N,N-dimethyl-2-phenylquinolin-4-amine (7)
1H NMR (DMSO-d6, 200 MHz)
d
3.43 (s, 6H, NCH3ꢁ2), 7.52 (s,1H,
H-3), 7.63–7.67 (m, 3H, H-30, 40, 50), 7.78–7.80 (m, 1H, H-6), 8.01–
8.13 (m, 1H, H-5), 8.32–8.38 (m, 3H, H-20, 60, 8); 13C NMR (DMSO-d6,
50 MHz)
d
43.53 (Cꢁ2), 112.31,114.56, 121.32, 125.47, 125.88, 126.35,
128.01 (Cꢁ2), 130.41 (Cꢁ2), 136.51, 147.65, 156.34, 159.87, 161.22; IR
(KBr) 1620 (C]N) cmꢀ1. Anal. Calcd for C17H15FN2: C: 76.67; H:
5.68; N: 10.52. Found: C: 76.57; H: 5.42; N: 10.68.
3.3.15. 8-Fluoro-N,N-dimethyl-2-phenylquinolin-4-amine (8)
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1H NMR (DMSO-d6, 200 MHz)
d
3.45 (s, 6H, NCH3ꢁ2), 7.46–7.53
(m, 3H, H-30, 40, 50), 7.66–7.79 (m, 3H, H-3, 6, 7), 8.21–8.23 (m, 3H,