Synthesis of mono-substituted derivatives of 6-aminoquinoline

Article abstract of DOI:10.1016/j.cclet.2010.10.005

Several 6-aminoquinoline derivatives, which could be used in drug design, have been synthesized. The reaction conditions were comparatively studied, and the p-chloroaniline was used as optimum oxidant in Skraup-Doebner-Von Miller reaction. The nitro group was reduced effectively by SnCl₂ with no halo-removed occurred.

Full text of DOI:10.1016/j.cclet.2010.10.005

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 253–255
www.elsevier.com/locate/cclet
Synthesis of mono-substituted derivatives of 6-aminoquinoline
a,c
a
a
Tian Lan a,b, Xian Xia Yuan a, , Jiang Hong Yu , Chao Jia , Yu Shi Wang ,
*
Hui Juan Zhang a, Zi Feng Ma a, Wei Dong Ye c
a School of Chemistry and Chemical Engineering, Shanghai Jiaotong University, Shanghai 200240, China
b School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China
c Xinchang Pharmaceutical Factory, Zhejiang Pharmaceutics Co. Ltd., Xinchang 312500, China
Received 17 June 2010
Available online 22 December 2010
Abstract
Several 6-aminoquinoline derivatives, which could be used in drug design, have been synthesized. The reaction conditions were
comparatively studied, and the p-chloroaniline was used as optimum oxidant in Skraup–Doebner–Von Miller reaction. The nitro
group was reduced effectively by SnCl2 with no halo-removed occurred.
# 2010 Xian Xia Yuan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 6-Aminoquinoline; 6-Nitroquinoline; Skraup reaction; Oxidant
Aminoquinoline derivatives are useful moieties in drug discovery, such as choloroquine [1] and primaquine [2]
against malaria. Although many aminoquinoline compounds have been synthesized in recent years, the systematical
description of the 6-aminoquinolines is still not so comprehensive.
In general, aminoquinoline could be prepared from the corresponding nitroquinoline by reduction reaction, because
of the easier availability of the nitroquinoline [3]. And the 6-nitroquinoline derivatives could be synthesized from two
routes (Scheme 1): modification directly on 6-nitroquinoline for pyridine-substituted quinolines (route 1) and Skraup
ring-closing reaction for benzene-substituted structures (route 2).
In the present paper, several 6-aminoquinoline derivatives, as listed in Table 1, had been obtained. The conditions of
Skraup reaction and the reduction reaction have been examined in detail. And the target compounds could be obtained
effectively from the modified method.
6-Nitroquinoline was stable with halogenation reagents because the benzene was passivated by the strong
electrowithdrawing group NO2. The pyridine ring could be activated by N-oxide group, and then could be chlorinated
by POCl3 (route 1). The 2- and 4-substituted quinolines (entries a and b, Table 1) were obtained respectively, which
was after the process of column chromatography. But the 3-substituted compound could not be obtained because of the
much lower yield than expected [4]. The N-oxide could be removed when the NO2 was reduced to NH2.
Skraup reaction (route 2) was useful for the synthesis of quinoline, especially for the benzene-substituted
compounds. And the oxidants played key role in the reaction. In general, nitrobenzene was used in the reaction as
* Corresponding author.
E-mail address: yuanxx@sjtu.edu.cn (X.X. Yuan).
1001-8417/$ – see front matter # 2010 Xian Xia Yuan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.10.005

[()TD$FIG]
254
T. Lan et al. / Chinese Chemical Letters 22 (2011) 253–255
O N
2
route 1
O N
2
H N
2
reduction
R
N
O
R
R
OH
O N
2
N
N
route 2
+
OH
a: R= 2-Cl; b: R=4-Cl
c: R= 5-Cl; d: R=5-OMe
e: R= 7-Cl; f: R=8-Cl
g: R= 8-Br; h: R=8-Me
i: R=8-OMe
OH
NH
2
Skraup-Doebner-Von Miller reaction
Scheme 1. The synthesis of 6-animoquinolines.
Table 1
The synthesis of 6-nitroquinolines and 6-aminoquinolines.
Entry
R
6-Nitroquinolines
Entry
6-Aminoquinolines
Route
Yielda (%)
Entry
Reductant
Yielda (%)
a
b
c
d
e
f
2-Cl
1a
1b
1
1
2
2
2
2
2
2
24
52
48
22
44
51
61
66
32
2a [10]
2b
2d
SnCl2/HCl
SnCl2/HCl
SnCl2/HCl
SnCl2/HCl
SnCl2/HCl
SnCl2/HCl
H2/Pd-C
89
92
85
87
90
91
78
94
81
4-Cl
5-Cl
1d [9]
1e [9]
1f
7-Cl
2e
8-Cl
2f
2g
8-Br
1g
1h
g
h
i
8-Me
8-OMe
5-OMe
2h
1i
1c
2i
2c
H2/Pd-C
b
–
H2/Pd-C
a
Isolate yields.
b
Directly substituted reaction between MeOK and 6-nitroquinoline.
oxidant [5–7], but the yield was low (Table 2) and it was difficult to be removed out. So, several oxidants were
examined when using 8-chloro-6-nitroquinoline as model reaction. Because quinolines were not stable for strong
oxidants, the weak oxidants should be chosen carefully. It was proved that the inorganic oxidants exhibited higher
activity than nitrobenzene, although the yields were still low. The highest yields were obtained using the 1,4-
benzoquinone and p-chloroaniline as oxidants, probably because that they could dissolve well in the organic solvent.
And the p-chloroaniline was chosen as the best oxidant in this reaction.
It was unusual for the 5-methoxy-6-nitroquinoline (entry i, Table 1) that could not be prepared by the 2 routes
discussed above. It could be synthesized from 6-nitroquinoline directly by electrophilic substitution, because the NO2
could activate the adjacent 5-position [8].
Pd/C and H2 were wildly used for the reductive conversion of NO2 to NH2, and the 6-aminoquinolines (entries g–i,
Table 1) were prepared with high yields. But the halo-substituted compounds were not obtained because the halogens
were removed under this condition. And several reductive conditions were screened carefully (Table 3). It indicated
that the catalyst always induced the remove of halogen. Both Fe and Zn could form the corresponding compounds, but
it was difficult to remove the residues. So, the SnCl2Á2H2O/HCl was the best reagent for the reductive reaction, and
halo-substituted 6-aminoquinolines (entry a–f, Table 1) were effectively obtained.
Table 2
Effects of oxidants on the 8-chloro-6-nitroquinoline yield.
Oxidant
8-Chloro-6-nitroquinoline yield (%)a
Oxidant
8-Chloro-6-nitroquinoline yield (%)a
Nitrobenzene
FeCl3
24
38
55
CuCl2
33
46
1,4-Benzoquinone
p-Chloroaniline
a
Isolated yield.

T. Lan et al. / Chinese Chemical Letters 22 (2011) 253–255
255
Table 3
Reduction of 1f and 1i via different methods.
Reductant
O2N
O2N
[DT$INLE]
[DT$INLE]
N
N
OCH3
Cl
Product
Yield (%)
Product
Yield (%)
NH2NH2ÁH2O/C
NH2NH2ÁH2O/Pd–C
H2/Pd–C
2f + 6-AQa
–
96
92
42
56
90
2i
2i
2i
2i
2i
2i
96
95
94
53
58
92
6-AQ
6-AQ
2f
Fe/HCl
Zn/HAc
2f
SnCl2Á2H2O/HCl
2f
a
6-AQ: 6-aminoquinoline.
In conclusion, several 6-aminoquinolines had been synthesized effectively. The oxidants in Skraup reaction were
examined carefully, and the soluble p-chloroaniline was used as the optimal reagent. The problem of halogen removal
by Pd catalyst could be overcame by using SnCl2Á2H2O/HCl as reductant.
Acknowledgments
The authors are grateful for the financial support of this work by the National Science Foundation of China (No.
20776085), the 973 Program of China (No. 2007CB209700), the STCSM of China (Nos. 10JC1406900 and
09XD1402400), the Foundation of Zhejiang Pharmaceutics Co. Ltd. and the Opening Foundation of Zhejiang
Provincial Top Key Discipline.
References
[1] B. Priohit, A. Mahapatra, Stud. Ethno-Med. 3 (2009) 33.
[2] A.M. Dondorp, S. Yeung, L. White, et al. Nat. Rev. Microbiol. 8 (2010) 272.
[3] F.A. Carey, R.J. Sundberg, Adv. Org. Chem., 4th ed., New York, 2000.
[4] G.B. Bachman, D.E. Cooper, J. Org. Chem. 9 (1944) 302.
[5] R.E. Lutz, P.S. Bailey, T.A. Martin, J. Am. Chem. Soc. 68 (1946) 1324.
[6] M.V. Ramana, S.S. Malik, J.A. Parihar, Tetrahedron Lett. 45 (2004) 8681.
[7] Z. Song, M. Mertzman, D.L. Hughes, J. Heterocycl. Chem. 30 (1993) 17.
[8] T. Kawakami, H. Suzuki, J. Chem. Soc., Perkin Trans. 1 8 (2000) 1259.
[9] 5- and 7-chloro-6-nitroquinolines: To stirred liquid of m-chloroaniline (20 mL) was added acetic anhydride dropwise at room temperature until
all the starting material consumed. The resulted mixture was neutralized by aqueous ammonia, and the obtained solid was filtered, washed
thoroughly with water. After vacuum drying, 28 g nearly pure m-chloroacetanilide was obtained. To a well-stirred mixture of m-
chloroacetanilide (18 g) and concentrated sulfuric acid (180 mL) was slowly added guanidinium nitrate (16 g) while maintaining the
temperature at 5–10 8C. After the addition completed, the reaction mixture was poured into ice water (800 mL), and the solid obtained was
filtered, washed with water and dried in vacuum oven for 8 h, a yellow product weighted 22 g was obtained, which was then purified through
recrystallization to get 3-chloro-4-nitroacetanilide. A mixture of 3-chloro-4-nitroacetanilide (1.0 g), water (3.0 mL), concentrated sulfuric acid
(4.0 mL), glycerol (2.5 mL), and p-chloroaniline (1.5 g) was boiled gently under reflux for 3 h. The product was cooled, diluted to 50 mL and
filtered, the residue was disposed and the filtrate was adjusted to alkaline with aqueous ammonia. The precipitate was filtered off, washed and
dried. Purification of the product by column chromatography gave the corresponding products. 5-Chloro-6-nitroquinolines: 1H NMR
(400 MHz, DMSO-d6): d 9.14 (dd, 1H, J = 4.4, 1.6 Hz), 8.75 (d, 1H, J = 8.8 Hz), 8.28 (d, 1H, J = 8.8 Hz), 8.19 (d, 1H, J = 8.8 Hz), 7.84 (dd, 1H,
J = 8.8, 4.4 Hz), 35%. 7-Chloro-6-nitroquinolines: 1H NMR (400 MHz, DMSO-d6): d 9.09 (dd, 1H, J = 4.4, 1.6 Hz), 8.87 (s, 1H), 8.58 (d, 1H, J
= 8.8 Hz), 8.33 (s, 1H), 7.72 (dd, 1H, J = 8.8, 4.4 Hz), 27%.
[10] General procedure for 6-aminoquinolines: The 6-nitroquinoline derivative (0.1 g) was added slowly with stirring to 1.0 g stannous chloride in
5 mL of 6 mol/L hydrochloric acid with gently heating for 1 h. After neutralizing the reaction mixture by aqueous ammonia, the precipitate was
extracted with CH2Cl2 (4 Â 20 mL). The combined CH2Cl2 layer was dried with anhydrous MgSO4. Evaporating and chromatographing the
extraction gave corresponding pure 6-aminoquinoline. 2-chloro-6-aminoquinoline: 1H NMR (400 MHz, DMSO-d6): d 8.99 (d, 1H, J = 8.4 Hz),
7.61 (d, 1H, J = 8.8 Hz), 7.27 (d, 1H, J = 8.4 Hz), 7.17 (dd, 1H, J = 8.8, 2.8 Hz), 7.03 (d, 1H, J = 2.8 Hz), 5.71 (s, 2H); Anal. Calcd. for
C9H7N2Cl: C, 60.33; H, 3.91; N, 15.64. Found: C, 60.56; H, 3.74; N, 15.31.