Facile and efficient synthesis of 2-aminoquinoline derivatives reduced by Zn/AcOH

Article abstract of DOI:10.3987/COM-15-13368

In this paper, a simple and efficient method for one-pot synthesis of 2-aminoquinolines was accomplished in good yields via reductive cyclization of nitro and cyano groups mediated by zinc/acetic acid is reported.

Full text of DOI:10.3987/COM-15-13368

HETEROCYCLES, Vol. 92, No. 3, 2016
521
HETEROCYCLES, Vol. 92, No. 3, 2016, pp. 521 - 527. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 16th November, 2015, Accepted, 27th January, 2016, Published online, 5th February, 2016
DOI: 10.3987/COM-15-13368
FACILE AND EFFICIENT SYNTHESIS OF 2-AMINOQUINOLINE
DERIVATIVES REDUCED BY Zn/AcOH
a,
a
b
Guolan Dou, * Deming Wang, and Daqing Shi
aSchool of Safety Engineering, China University of Mining & Technology,
Xuzhou 221116, P. R. China. E-mail: gldoucumt@163.com
bKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou
2
15123, P. R. China
Abstract – In this paper, a simple and efficient method for one-pot synthesis of
-aminoquinolines was accomplished in good yields via reductive cyclization of
nitro and cyano groups mediated by zinc/acetic acid is reported.
2
Nitrogen-containing heterocycles are abundant in nature and are of great significance to life because their
structural subunits exist in many natural products. Quinoline derivatives occur in a large number of
1
2
natural products and drug-like compounds. 2-Aminoquinoline derivatives are especially important
3
4
because of their pharmaceutical activities and applications, including antiprotozals, antidepressants,
antihypertensives,5 anti-HIV,6 anti-Alzheimer disease,7 melanin-concentrating hormone receptor
8
9
antagonists and Src kinase inhibitors.
There has been a large amount of effort devoted to developing efficient methods for the preparation of
substituted 2-aminoquinolines. Srinivasan et reported the synthesis of
al.10
-aminoquinoline-3-carbonitrile from the reaction of arylidenemalononitriles with enaminone. Wilson et
2
al.11 described the synthesis of 2-aminoquinolines using microwave-assisted synthesis. Basic
condensations of aromatic ketones with (dimethylamino)propionitrile,12 Frielander’s approach13 and
nucleophilic substitution of chloroquinoline14 have also been used to synthesize 2-aminoquinolines.
However, these methods have disadvantages such as forcing conditions, unsatisfactory yields, long
reaction times, high temperatures, complex manipulations, and commercially unavailable starting
materials. Zhou et al.15,16 obtained 2-aminoquinoline-3-carboxylic acid derivatives rapidly in good yields
by treating nitrocyano olefins with a low-valent titanium reagent in dry THF at room temperature. The
same group also reported the intramolecular reductive coupling of cyano and nitro groups induced by

522
HETEROCYCLES, Vol. 92, No. 3, 2016
SmI
2
to produce 2-aminoquinoline in good yields.17 However, the requirement of anhydrous and/or
anaerobic conditions detracts from the usefulness of these methods. Coupling between cyano and nitro
1
8
groups can also be achieved using tin dichloride, however, the reaction time is long, involving heating
under reflux for 6 h. Reductive coupling of cyano and nitro groups can be achieved using iron and acetic
acid, but yields are generally moderate.19-21 Therefore, more efficient methods to prepare these kinds of
compounds with mild reaction conditions and high yields are desirable. The zinc-acetic acid (Zn/AcOH)
couple is a well-known reducing reagent, capable of a wide range of reactions,22,23 among which
reductions of nitro, carbonyl and activated alkenes are the most common. We found that
2-amino-3-cyanoquinoline can be obtained by Zn/AcOH-mediated cyano–nitrile coupling in a study
24
optimizing the synthesis of substituted quinoline-1-oxides. In this study, we further explore the potential
of Zn/AcOH-mediated cyano–nitrile coupling and describe a convenient one-pot reductive cyclization
protocol for the synthesis of 2-aminoquinolines.
i
CO Pr
2
H
C
i
CO Pr
2
Zn-AcOH
Solvent
CN
N
NH2
NO2
1a
2a
Scheme 1
Table 1. Conditions trialed to optimize for the reductive cyclization reduction
○
Ratioa
1:1
1:2
1:3
1:4
1:5
1:4
1:4
1:4
1:4
1:4
1:4
Yield (%)b
Entry
Temperature ( C)
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
THF
1
2
3
4
5
6
7
8
9
60
39
57
72
83
75
33
60
86
67
53
57
60
60
60
60
rt
40
reflux
reflux
reflux
reflux
1
1
0
1
MeCN
CHCl
3
a
Ratio of 1a and the zinc
Isolated yield after recrystallization of the product
b

HETEROCYCLES, Vol. 92, No. 3, 2016
523
Isopropyl-2-cyano-3-(2-nitrophenyl)acrylate (1a) was used as a model substrate to optimize the
experimental conditions for the proposed reductive cyclization reaction (Scheme 1). The results are
summarized in Table 1.
The ratio of 1a to Zn/AcOH was evaluated between the range of 1:1 and 1:5. The yield of
2
-aminoquinoline 2a increased as the ratio of 1a to Zn/AcOH was increased from 1:1 to 1:4 (Table 1,
entries 1–4). Further increasing this ratio to 1:5 resulted in a decrease in yield compared with that
obtained using a ratio of 1:4 (Table 1, entry 5). Therefore, 1:4 was chosen for all further reactions.
Reaction temperature was investigated next; heating to reflux resulted in the highest yield (Table 1,
entries 6–8). Solvent screening revealed that EtOH was preferable to the other solvents tested (Table 1,
entries 8–11). We concluded that the optimal conditions are 4 equivalents of Zn/AcOH in EtOH heated at
reflux.
With the optimized conditions in hand, we then examined the applicability of the process for the synthesis
of other 2-aminoquinolines (Scheme 2).
R
H
Z
Y
R
Z
Y
C
Zn-AcOH
CN
EtOH, reflux
N
NH2
NO2
X
X
1
2
Scheme 2
Table 2. Synthesis of 2-aminoquinolines by Zn/AcOH reduction
Entry
X
H
H
H
H
H
H
H
H
H
H
Y
Z
R
Product
2a
Yield (%)a
1
2
3
4
5
6
7
8
9
H
H
CO
2
2
iPr
86
82
79
87
90
83
82
84
80
86
H
H
CO
Me
2b
2c
H
H
4-ClC
6
H
4
H
H
CO
CO
CO
CO
2
2
2
2
Et
2d
2e
H
Cl
Cl
Cl
OMe
Me
Et
iPr
5
H
2f
H
2g
OMe
OCH
OCH
C
6
H
2h
2i
2
2
O
O
4-BrC
6
H
4
1
0
C
6
H
5
2j
aIsolated yield after recrystallization of the product

524
HETEROCYCLES, Vol. 92, No. 3, 2016
We found that the method was applicable to a broad selection of substrates (Table 2), with a range of
groups in the R position tolerated including esters and substituted phenyls. Good or acceptable yields
were obtained when a 5-Cl-, 4,5-OCH
2
O- or 4,5-dimethoxy-substituted phenyl ring was present (entries
1
5
–10). All the products were characterized by IR, HRMS and H NMR spectroscopy.
In summary, a series of 2-aminoquinolines were synthesized by Zn/AcOH reaction of nitro and cyano
groups. This protocol is advantageous compared with other published methods because it uses readily
accessible materials, requires simple manipulations, and allows facile isolation of products via simple
recrystallization.
EXPERIMENTAL
Commercial solvents and reagents were used as received. Melting points are uncorrected. IR spectra were
-1 1
recorded on Varian F-1000 spectrometer in KBr with absorptions in cm . H NMR was determined on
Varian-300 MHz spectrometer in DMSO-d solution. J values are in Hz. Chemical shifts are expressed in
ppm downfield from internal standard TMS. MS data were obtained using microma GCT-TOF instrument
6
+
25
(
EI ). The synthesis of the reactant 1 is according to the report literature.
General procedure for the synthesis of 2 is represented as follows.
To a solution of 3-(2-nitrophenyl)acrylonitriles 1 (1 mmol) and Zn (4 mmol) in 5 mL of EtOH was added
.2 mL AcOH, then the mixture was stirred at reflux for 1-2 h. After this period, the TLC analysis of the
mixture showed the reaction to be completed. The reaction mixture was quenched with 30 mL of water
and extracted with CHCl (3 × 20 mL). The combined extracts were washed with water (3 × 20 mL) and
dried over anhydrous Na SO . After evaporation of the solvent under reduced pressure, the crude product
was purified by recrystallization from 95% EtOH.
Isopropyl 2-aminoquinoline-3-carboxylate (2a): white solid, mp 156-158 C. IR (KBr) ν: 3417, 3146,
0
3
2
4
o
-1
1
2
831, 1669, 1611, 1515, 1446, 1409, 1267, 1163, 986, 828, 715, 688 cm . H NMR (300 MHz,
DMSO-d ) (δ, ppm): 1.36 (6H, d, J = 6.0 Hz, 2×CH ), 5.18 (1H, m, OCH), 7.19 (3H, br s, NH + ArH),
.48 (1H, d, J = 8.4 Hz, ArH), 7.61 (1H, t, J = 7.8 Hz, ArH) 7.84 (1H, d, J = 8.1 Hz, ArH), 8.71 (1H, s,
6
3
2
7
+
ArH). HRMS [Found: m/z 230.1058 (M ), calcd for C13
H
14
N
2
2
O : M, 230.1055]. Anal. Calcd for
C
13
H
14
N
2
O
2
: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.71; H, 6.29; N, 12.28%.
o
Methyl 2-aminoquinoline-3-carboxylate (2b): white solid, mp 120-122 C. IR (KBr) ν: 3427, 3157,
-1 1
2
956, 1701, 1631, 1565, 1437, 1291, 1203, 1132, 1078, 954, 800, 748, 597 cm . H NMR (300 MHz,
DMSO-d
6
) (δ, ppm): 3.88 (3H, s, OCH
3
), 7.19 (3H, br s, NH
2
+ ArH), 7.48 (1H, s, ArH), 7.62 (1H, s,
+
ArH), 7.83 (1H, s, ArH), 8.75 (1H, s, ArH). HRMS [Found: m/z 202.0743 (M ), calcd for C11
H
10
N
2
O : M,
2
2
02.0742]. Anal. Calcd for C11
3.97%.
H
10
N
2
2
O : C, 65.34; H, 4.98. N, 13.85; Found: C, 65.45; H, 4.87; N,
1

HETEROCYCLES, Vol. 92, No. 3, 2016
525
o
3
-(4-Chlorophenyl)quinolin-2-amine (2c): white solid, mp 206-208 C. IR (KBr) ν: 3438, 3126, 2757,
-1
1
1
643, 1568, 1496, 1434, 1200, 1126, 1089, 1016, 906, 838, 755, 688 cm . H NMR (300 MHz,
DMSO-d
6
) (δ, ppm): 6.09 (2H, s, NH
2
), 7.18 (1H, m, ArH), 7.51 (5H, m, ArH), 7.68 (2H, d, J = 7.8 Hz,
+
N
35Cl: M, 254.0611]. Anal.
ArH), 7.82 (1H, s, ArH). HRMS [Found: m/z 254.0612 (M ), calcd for C15
H
11
2
Calcd for C15
H11ClN
2
: C, 70.73; H, 4.35; N, 11.00. Found: C, 70.61; H, 4.48; N, 11.15%.
o
Ethyl 2-aminoquinoline-3-carboxylate (2d): white solid, mp 124-126 C. IR (KBr) ν: 3418, 3275, 3148,
-1 1
2
979, 1697, 1626, 1566, 1482, 1439, 1290, 1204, 1137, 1083, 1015, 960, 802, 750 cm . H NMR (300
MHz, DMSO-d ) (δ, ppm): 1.34 (3H, t, J = 4.2 Hz, CH ), 4.34 (2H, m, OCH ), 7.19 (3H, br s, NH +
6
3
2
2
ArH), 7.48 (1H, d, J = 8.1 Hz, ArH), 7.61 (1H, t, J = 6.0 Hz, ArH), 7.83 (1H, d, J = 7.2 Hz, ArH), 8.73
+
(
1H, s, ArH). HRMS [Found: m/z 216.0901 (M ), calcd for C12
H
12
N
2
2
O : M, 216.0899]. Anal. Calcd for
C
12
H
12
N
2
O
2
: C, 66.65; H, 5.59; N, 12.96. Found: C, 66.78; H, 5.45; N, 12.84%.
o
Methyl 2-amino-6-chloroquinoline-3-carboxylate (2e): white solid, mp 184-186 C. IR (KBr) ν: 3427,
-1 1
3
268, 3127, 2900, 1705, 1628, 1561, 1483, 1440, 1362, 1273, 1185, 1082, 930, 822, 792, 667 cm . H
NMR (300 MHz, DMSO-d ) (δ, ppm): 3.88 (3H, s, OCH ), 7.30 (2H, s, NH ), 7.47 (1H, d, J = 8.7 Hz,
6
3
2
ArH), 7.60 (1H, d, J = 7.8 Hz, ArH), 7.97 (1H, s, ArH), 8.75 (1H, s, ArH). HRMS [Found: m/z 236.0351
+
35Cl: M, 236.0353]. Anal. Calcd for C11
(
M ), calcd for C11
H
9
2
N O
2
H
9
ClN O
2 2
: C, 55.83; H, 3.83; N, 11.84.
Found: C, 55.96; H, 3.71; N, 11.72%.
o
Ethyl 2-amino-6-chloroquinoline-3-carboxylate (2f): white solid, mp 186-188 C. IR (KBr) ν: 3422,
-
1 1
3
274, 3141, 2993, 1701, 1633, 1563, 1490, 1360, 1277, 1191, 1086, 963, 827, 798, 696, 668 cm . H
NMR (300 MHz, DMSO-d ) (δ, ppm): 1.34 (3H, t, J = 7.2 Hz, CH ), 4.34 (2H, m, OCH ), 7.32 (2H, s,
NH ), 7.46 (1H, d, J = 9.0 Hz, ArH), 7.59 (1H, dd, J = 2.1 Hz, J = 9.0 Hz, ArH), 7.98 (1H, s, ArH), 8.74
1H, s, ArH). HRMS [Found: m/z 250.0508 (M ), calcd for C12
35Cl: M, 250.0509]. Anal. Calcd
: C, 57.49; H, 4.42; N, 11.17. Found: C, 57.60; H, 4.37; N, 11.31%.
Isopropyl 2-amino-6-chloroquinoline-3-carboxylate (2g): white solid, mp 206-208 C. IR (KBr) ν:
6
3
2
2
1
2
+
(
H
11
N
2
O
2
for C12
H11ClN
2
O
2
o
-
1 1
3
423, 3274, 3149, 2974, 1700, 1636, 1560, 1486, 1412, 1276, 1238, 1190, 1070, 820, 799, 668 cm . H
NMR (300 MHz, DMSO-d ) (δ, ppm): 1.34 (6H, d, J = 6.0 Hz, 2×CH ), 5.16 (1H, m, OCH), 7.32 (2H, s,
NH ), 7.47 (1H, d, J = 9.0 Hz, ArH), 7.60 (1H, dd, J = 9.0 Hz, ArH), 7.99 (1H, d, J = 2.1 Hz,
35Cl: M, 264.0666].
6
3
2
1
= 2.4 Hz, J
2
+
ArH), 8.72 (1H, s, ArH). HRMS [Found: m/z 264.0663 (M ), calcd for C13
H
13
N
2
O
2
Anal. Calcd for C13
H13ClN
2
O
2
: C, 58.99; H, 4.95; N, 10.58. Found: C, 58.89; H, 5.06; N, 10.69%.
o
6
,7-Dimethoxy-3-phenylquinolin-2-amine (2h): white solid, mp 204-206 C. IR (KBr) ν: 3451, 3294,
-1 1
3
164, 2999, 1637, 1624, 1500, 1460, 1395, 1247, 1166, 1013, 849, 785, 755, 610 cm . H NMR (300
) (δ, ppm): 3.79 (3H, s, OCH ), 3.84 (3H, s, OCH ), 5.61 (2H, s, NH ), 6.94 (1H, s, ArH),
.13 (1H, s, ArH), 7.40 (1H, s, ArH), 7.48 (4H, d, J = 3.6 Hz, ArH), 7.69 (1H, s, ArH). HRMS [Found:
MHz, DMSO-d
6
3
3
2
7
+
m/z 280.1209 (M ), calcd for C17
H
16
N
2
2
O : M, 280.1212]. Anal. Calcd for C17
H
16
N
2
2
O : C, 72.84; H, 5.75;

526
HETEROCYCLES, Vol. 92, No. 3, 2016
N, 9.99. Found: C, 72.72; H, 5.88; N, 9.87%.
o
7
-(4-Bromophenyl)-[1,3]dioxolo[4,5-g]quinolin-6-amine (2i): brown solid, mp 192-194 C. IR (KBr) ν:
-
1 1
3
477, 3457, 3161, 2923, 1630, 1602, 1490, 1410, 1226, 1034, 937, 829, 744, 589 cm . H NMR (300
) (δ, ppm): 6.11 (2H, s, OCH O), 6.31 (2H, s, NH ), 7.00 (1H, s, ArH), 7.19 (1H, s, ArH),
.44 (2H, d, J = 7.5 Hz, ArH), 7.68 (2H, d, J = 7.5 Hz, ArH), 7.80 (1H, s, ArH). HRMS [Found: m/z
MHz, DMSO-d
6
2
2
7
3
3
7
3
+
79Br: M, 342.0004]. Anal. Calcd for C16
42.0003 (M ), calcd for C16
.23; N, 8.16. Found: C, 56.12; H, 3.11; N, 8.27%.
-Phenyl-[1,3]dioxolo[4,5-g]quinolin-6-amine (2j): white solid, mp 114-116 C. IR (KBr) ν: 3445, 3299,
H
11
N
2
O
2
H11BrN
2
O
2
: C, 56.00; H,
o
-1 1
151, 2892, 1632, 1602, 1485, 1410, 1231, 1122, 1040, 946, 836, 779, 701, 587 cm . H NMR (300 MHz,
DMSO-d
6
) (δ, ppm): 5.71 (2H, s, NH
2
), 6.06 (2H, s, OCH
2
O), 6.92 (1H, s, ArH), 7.12 (1H, s, ArH), 7.45
+
(
5H, m, ArH), 7.68 (1H, s, ArH). HRMS [Found: m/z 264.0898 (M ), calcd for C16
H
12
N
2
O : M,
2
2
64.0899]. Anal. Calcd for C16
0.69%.
H
12
N
2
2
O : C, 72.72; H, 4.58; N, 10.60. Found: C, 72.84; H, 4.44; N,
1
ACKNOWLEDGEMENTS
We are grateful to financial support from the Fundamental Research Funds for the Central Universities
2014QNB01).
(
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