Facile and Efficient Synthesis of 2-Aminoquinoline-3-carboxylic Acid Derivatives via Reductive Cyclization of Nitro and Cyano Groups Induced by Low-valent Titanium

Article abstract of DOI:10.1039/a800588e

A short and facile synthesis of a series of 2-aminoquinoline-3-carboxylic acid derivatives was accomplished in good yields via the intramolecular reductive cyclization of nitrocyano olefins promoted by TiCl4/Zn.

Full text of DOI:10.1039/a800588e

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398 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 398±399$
Facile and Efficient Synthesis of 2-Aminoquinoline-
3-carboxylic Acid Derivatives via Reductive
Cyclization of Nitro and Cyano Groups Induced
by Low-valent Titanium$
Longhu Zhou,* Sujiang Tu, Daqin Shi and Guiyuan Dai
Department of Chemistry, Xuzhou Normal University, Xuzhou, 221009, P.R. China
A short and facile synthesis of a series of 2-aminoquinoline-3-carboxylic acid derivatives was accomplished in good
yields via the intramolecular reductive cyclization of nitrocyano olefins promoted by TiCl4/Zn.
Low-valent titanium reagents have an exceedingly high
ability to promote reductive coupling of carbonyl com-
pounds and are attracting increasing interest in organic
synthesis. Many other functional groups can also be
coupled.1 Recently, we reported the cyclodimerization of
a,b-unsaturated ketones and a,b-unsaturated nitrile com-
pounds promoted by this reagent, yield functional cyclo-
pentanes2 and cyclopentenes3 respectively.
2-Aminoquinoline derivatives have attracted much
concern due to their biological properties.4 For instance,
simple molecules such as 2-aminoquinoline have been iso-
lated from a North American mushroom known for its anti-
Scheme 1
bacterial and antihelminthic activity.5 It has been reported
that 2-aminoquinoline analogues have antiprotozal,6 anti-
In conclusion, with its high yields, mild conditions as well
depressent7 and antihypertensive8 properties. Recently, there
as straightforward procedure, we think that the present
has been considerable interest in the development of
method may be useful for the preparation of 2-amino-
methodology for accessing these compounds. In most
quinoline-3-carboxylic acid derivatives. Further studies to
reported methods for the synthesis of 2-aminoquinoline
develop other new uses of this reagent are now in progress.
derivatives strong basic solvents as well as harsh thermal
conditions are employed, e.g. basic condensations of
aromatic ketones with (dimethylamino)propionitrile,9a,b
Experimental
Melting points were uncorrected. 1H NMR spectra were obtained
Frielander's approach9c and nucleophilic substitution on
the previously formed chloroquinoline under strong basic
for solutions in CDCl3 with Me4Si as internal standard using
a Bruker AC-80 spectrometer, mass spectra on a ZAB-HS or
conditions.9d
Finnigan MAT GC-MS spectrometer. Microanalyses were carried
out using a Perkin-Elmer 240C analyser. IR spectra were recorded
on a FTIR-8101 spectrometer in KBr.
The cyano group is relatively more stable to low-valent
titanium reagents than carbonyl and cannot be reduced
unless the reaction mixture is re¯uxed for a long time, and
giving only low yield.10 The nitro group, however, is rela-
tively more easily reduced.11 We considered that the inter-
mediate derived from a more active functional group by
treatment with low-valent titanium could perhaps attack a
more stable functional group which otherwise would not
react with low-valent titanium. Therefore, we have studied
the behaviour of a molecule containing both cyano and
nitro groups, 3, when treated with titanium(IV) chloride and
zinc in tetrahydrofuran at room temperature.
As expected, 2-aminoquinoline-3-carboxylic acid deriva-
tives 4 were rapidly obtained in good yields by treatment of
nitrocyano ole®ns 3 with TiCl4±Zn in dry THF at room
temperature (Scheme 1). Our synthetic strategy was based
on the use of KF±Al2O3 as catalyst for preparing key inter-
mediates 3 from readily available starting materials and use
of low-valent titanium to promote reductive cyclization
of nitrocyano ole®ns 3 to produce products 4 under mild
conditions.
General Procedure for Synthesis of Nitrocyano Ole®ns 3.Ð
Aromatic aldehyde (10 mmol), ethyl cyanoacetate or malononitrile
12
(10 mmol), KF±Al2O3 (200 mg) and dry ethanol (5 cm3) were
added to a dry ¯ask. The mixture was allowed to react at 30 8C
during 2±3 h. On completion of the reaction the mixture was poured
into water (50 cm3) and extracted with diethyl ether (3 Â 30 ml).
The combined extracts were washed with water (2Â 20 ml, dried
(Na2SO4) and the solvent was removed to give the crude product,
which was further puri®ed by recrystallization from ethanol.
1
3a: light tan needles, mp 139±140 8C; ꢀ~max/cm 2250 (CN); dH
7.61±7.70 (3 H, m, ArH), 8.31±8.40 (1 H, m, ArH), 8.47 (1 H, s,
0CH1) (Found: C, 60.2; H, 2.4; N, 14.3. C10H5N3O2 requires
C, 60.3; H, 2.5; N, 14.1%).
1
3b: orange needles, mp 138±140 8C; ꢀ~max/cm 2240 (CN), 1735
(CO); dH 3.98 (3 H, s, CH3), 7.72±7.89 (3 H, m, ArH), 8.23±8.27
(1 H, m, ArH), 8.74 (1 H, s, 0CH1) (Found: C, 57.0; H, 3.4;
N, 12.2. C11H8N2O4 requires C, 56.9; H, 3.5; N, 12.1%).
Table 1 Yields of the products
Yield of 3
(%)
Yield of 4
(%)
Entry
R1, R2
X
Table 1 summarizes the results. All reactions could be
carried out under mild conditions. However, treating amino-
cyano ole®ns derived from nitrocyano ole®ns 3 under the
same reaction conditions gave no reaction.
a
b
c
d
e
f
g
h
i
H, H
H, H
H, H
H, H
H, H
OCH2O
OCH2O
OCH2O
OCH2
OCH2O
CN
95
91
88
79
86
96
93
91
84
90
81
91
89
85
87
78
85
90
79
86
CO2CH3
CO2C2H5
CO2C3H7-i
CO2C4H9-n
CN
CO2CH3
CO2C2H5
CO2C3H7-i
CO2C4H9-n
*To receive any correspondence.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
j

View Article Online
J. CHEM. RESEARCH (S), 1998 399
1
‡
3c: orange needles, mp 102±103 8C; ꢀ~max/cm 2230 (CN), 1735
ArH); m/z 245 (M ‡ 1, 11), 244 (M , 68), 188 (6), 171 (15), 144
(CO); dH 1.40 (3 H, t, J ˆ 7.1, CH3), 4.42 (2 H, q, J ˆ 7.1 Hz,
OCH2), 7.64±8.28 (4 H, m, ArH), 8.71 (1 H, s, CH1) (Found:
C, 58.4; H, 4.2; N, 11.5. C12H10N2O4 requires C, 58.5; H, 4.2;
N, 11.4%).
(100), 143 (52), 117 (23), 116 (35%) (Found: C, 69.0; H, 6.7;
N, 11.4. C14H16N2O2 requires C, 68.8; H, 6.6; N, 11.5%).
4f: tan crystals, mp 280 8C (decomp.) (from ethyl acetate and
1
EtOH); ꢀ~max/cm 3400 (NH2), 3160 (NH2), 2230 (CN); dH 6.14
1
3d: orange tiny needles, mp 81 8C; ꢀ~max/cm 2250 (CN), 1725
(2 H, s, OCH2O), 6.66 (2 H, br s, NH2), 6.91 (1 H, s, ArH), 7.12
(1 H, s, ArH), 8.37 (1 H, s, hetero ArH) (Found: C, 62.2; H, 3.2;
N, 19.5. C11H7N3O2 requires C, 62.0; H, 3.3; N, 19.7%).
(CO); dH 1.38 (3 H, d, J ˆ 6.2, CH3), 1.40 (3 H, d, J ˆ 6.2, CH3),
5.26 (1 H, t, J ˆ 6.2 Hz, OCH), 7.61±7.94 (3 H, m, ArH), 8.24±8.36
(1 H, m, ArH), 8.72 (1 H, s, 0CH1) (Found: C, 60.2; H, 4.5; N,
1
4g: yellow crystals, mp 225±227 8C (from EtOH); ꢀ~max/cm 3400
10.7. C13H12N2O4 requires C, 60.0; H, 4.7; N, 10.8%).
(NH2), 3150 (NH2), 1680 (CO); dH 3.93 (3 H, s, OCH3), 6.05 (2 H,
s, OCH2), 6.67 (2 H, br, s, NH2), 6.92 (1 H, s, ArH), 6.99 (1 H, s,
1
3e: orange prisms, mp 44±46 8C; ꢀ~max/cm
2230 (CN), 1730
‡
(CO); dH 0.99 (3 H, t, J ˆ 6.2, CH3), 1.43±1.78 (4 H, m, CH2CH2),
4.37 (2 H, J ˆ 6.4 Hz, OCH2), 7.72±7.89 (3 H, m, ArH), 8.23±8.26
(1 H, m, ArH), 8.73 (1 H, s, 0CH1) (Found: C, 61.5; H, 5.0;
N, 10.4. C14H14N2O4 requires C, 61.3; H, 5.1; N, 10.2%).
ArH), 8.49 (1 H, s, hetero ArH); m/z 247 (M ‡ 1, 21), 246 (M ,
44), 215 (27), 214 (45), 188 (44), 187 (100), 161 (12), 160 (30%)
(Found: C, 58.4; H, 4.2; N, 11.5. C12H10N2O4 requires C, 58.5;
H, 4.1; N, 11.4%).
1
1
3f: light tan tiny needles, mp 111±113 8C; ꢀ~max/cm 2240 (CN),
4h: yellow crystals, mp 204±205 8C (from ethyl acetate); ꢀ~max/cm
dH 6.30 (2 H, s, OCH2O), 7.21 (1 H, s, ArH), 7.77 (1 H, s, ArH),
8.35 (1 H, s, 0CH1) (Found: C, 54.1; H, 2.1; N, 17.4. C11H5N3O4
requires C, 54.3; H, 2.1; N, 17.3%).
3440 (NH2), 3280 (NH2), 1680 (CO); dH 1.41 (3 H, t, J ˆ 7.1, CH3),
4.38 (2 H, q, J ˆ 7.1 Hz, OCH2), 6.03 (2 H, s, OCH2O), 6.56 (2 H,
br s, NH2), 6.90 (1 H, s, ArH), 6.95 (1 H, s, ArH), 8.46 (1 H, s,
1
‡
3g: yellow needles, mp 162±164 8C; ꢀ~max/cm 2230 (CN), 1740
hetero ArH); m/z 261 (M ‡ 1, 20), 276 (M , 100), 232 (6), 215 (9),
(CO); dH 3.97 (3 H, s, OCH3), 6.26 (2 H, s, OCH2O), 7.27 (1 H, s,
ArH), 7.72 (1 H, s, ArH), 8.85 (1 H, s, 0CH1) (Found: C, 52.3;
H, 2.8; N, 10.4. C12H8N2O6 requires C, 52.2; H, 2.9; N, 10.1%).
214 (11), 188 (72), 161 (7), 160 (20%) (Found: C, 60.3; H, 4.5;
N, 10.7. C13H12N2O4 requires C, 60.0; H, 4.6; N, 10.8%).
1
4i: yellow crystals, mp 215±217 8C (from EtOH); ꢀ~max/cm 3380
1
3h: yellow tiny needles, mp 139±140 8C; ꢀ~max/cm 2240 (CN),
(NH2), 3200 (NH2), 1680 (CO); dH 1.38 (6 H, d, J ˆ 6.2, 2 CH3),
5.26 (1 H, J ˆ 6.2 Hz, OCH), 6.03 (2 H, s, OCH2O), 6.54 (2 H, br
s, NH2), 6.91 (1 H, s, ArH), 6.95 (1 H, s, ArH), 8.44 (1 H, s, hetero
1730 (CO); dH 1.42 (3 H, t, J ˆ 7.1, CH3), 4.42 (2 H, q, J ˆ 7.1 Hz,
OCH2), 6.26 (2 H, s, OCH2O), 7.25 (1 H, s, ArH), 7.72 (1 H, s,
ArH), 8.64 (1 H, s, 0CH1) (Found: C, 53.7; H, 3.6; N, 9.6.
‡
ArH); m/z 275 (M ‡ 1, 6), 274 (M , 94), 232 (9), 215 (11), 214 (9),
C
13H10N2O6 requires C, 53.8; H, 3.5; N, 9.7%).
3i: light tan needles, mp 112±113 8C; ꢀ~max/cm 2250 (CN), 1725
188 (100), 187 (38), 161 (6), 160 (25%) (Found: C, 61.4; H, 5.1;
N, 10.3. C14H14N2O4 requires C, 61.3; H, 5.1; N, 10.2%).
1
1
(CO); dH 1.40 (6 H, d, J ˆ 6.4, 2 ÂCH3), 5.22 (1 H, J ˆ 6.4 Hz,
OCH), 6.25 (2 H, s, OCH2O), 7.25 (1 H, s, ArH), 7.70 (1 H, s,
ArH), 8.60 (1 H, s, 0CH1) (Found: C, 55.3; H, 4.1; N, 9.1.
4j: yellow crystals, mp 148±149 8C (from EtOH); ꢀ~max/cm 3480
(NH2), 3200 (NH2), 1680 (CO); dH 1.00 (3 H, t, J ˆ 6.8, CH3),
1.21±1.78 (4 H, m, CH2CH2), 4.32 (2 H, t, J ˆ 6.4 Hz, OCH2), 6.02
(2 H, s, OCH2O), 6.55 (2 H, br s, NH2), 6.89 (1 H, s, ArH), 6.93
(1 H, s, ArH), 8.42 (1 H, s, hetero ArH); m/z 289 (M ‡ 1, 17), 288
C
14H12N2O6 requires C, 55.3; H, 4.0; N, 9.2%).
3j: light tan tiny needles, mp 98±99 8C; ꢀ~max/cm 2250 (CN),
1
‡
1725 (CO); dH 0.99 (3 H, t, J ˆ 6.4, CH3), 1.31±1.81 (4 H, m,
CH2CH2), 4.35 (2 H, t, J ˆ 6.4 Hz, OCH2), 6.25 (2 H, s, OCH2O),
7.30 (1 H, s, ArH), 7.71 (1 H, s, ArH), 8.62 (1 H, s, 0CH1)
(Found: C, 56.8; H, 4.3; N, 8.7. C15H14N2O6 requires C, 56.6;
H, 4.4; N, 8.8%).
(M , 90), 232 (11), 216 (7), 215 (11), 188 (100), 187 (31), 161 (8),
160 (23) (Found: C, 62.4; H, 5.7; N, 9.6. C15H16N2O4 requires
C, 62.5; H, 5.6; N, 9.7%).
We are grateful to the Education Committee Nature
Science Foundation of Jiangsu province for ®nancial
support.
General Procedure for Synthesis of 2-Aminoquinoline-3-carboxylic
Acid Derivatives 4.ÐTiCl4 (1.65 ml, 15 mmol) was added dropwise
using a syringe to a stirred suspension of zinc power (1.95 g,
30 mmol) in freshly distilled dry THF (20 ml) at RT under a N2
atmosphere. The mixture was re¯uxed for 2 h. The suspension of
the low-valent titanium reagent formed was cooled to RT and a
solution of nitrocyano ole®n 3 (5 mmol) in THF (3 ml) was added
carefully. On completion of the reaction most of the solvent was
removed in vacuum. The residue was poured into 10% K2CO3
(100 ml) and extracted with CHCl3 (4Â 30 ml). The combined
organic layer was washed with water (2 Â20 ml), dried (Na2SO4),
and the solvent removed to give the crude product, which was
puri®ed by recrystallization from an appropriate solvent.
Received, 21st January 1998; Accepted, 12th April 1998
Paper E/8/00588E
References
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4a: Light tan prisms, mp 226±227 8C (from ethyl acetate and
1
acetone); ꢀ~max/cm 3400 (NH2), 3160 (NH2), 2230 (CN); dH 5.46
(2 H, br s, NH2), 7.32±7.71 (4 H, m, ArH), 8.30 (1 H, s, hetero
‡
ArH); m/z 170 (M ‡ 1, 22), 169 (M , 100), 144 (73), 143 (34), 117
(20), 116 (33%) (Found: C, 70.9; H, 4.4; N, 24.8. C10H7N3 requires
C, 71.0; H, 4.2, N, 24.8%).
4b: yellow crystals, mp 139±140 8C (from EtOH, lit.13 140±
1
141 8C); ꢀ~max/cm 3380 (NH2), 3200 (NH2), 1700 (CO); dH 3.93
(3 H, s, OCH3), 6.80 (2 H, br s, NH2), 7.03±7.68 (4 H, m, ArH),
8.66 (1 H, s, hetero ArH).
7 A. A. Alhaider, M. A. Abdelkader and E. J. Lien, J. Med.
Chem., 1985, 28, 1398; K. Hino, Y. Nagai and H. Uno, Chem.
Pharm. Bull., 1987, 35, 2819.
4c: yellow needles, mp 134±135 8C (from EtOH lit.13 135 8C);
1
ꢀ~max/cm 3450 (NH2), 3180 (NH2), 1700 (CO); dH 1.41 (3 H, t,
J ˆ 7.2, CH3), 4.40 (2 H, q, J ˆ 7.2 Hz, OCH2), 6.68 (2 H, br s,
8 S. F. Campbell, J. D. Hardstone and M. J. Palmer, J. Med.
Chem., 1988, 31, 1031.
NH2), 7.10±7.82 (4 H, m, ArH), 8.69 (1 H, s, hetero ArH); m/z 217
(M ‡ 1, 14), 216 (M , 100), 171 (18), 170 (32), 144 (75), 143 (65),
‡
9 (a) S. Gorbadjiev, Ch. Ivanov and B. Moskova, Synth. Commun.,
1985, 15, 451; (b) S. Gorbadjiev, Ch. Ivanov and B. Moskova,
Synth. Commun., 1987, 17, 1363; (c) A. A. Sayed, Synth.
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10 W. X. Chen, J. H. Zhang, M. Y. Hu and X. C. Wang,
Synthesis, 1990, 701; J. X. Chen, J. P. Jiang, W. X. Chen and
T. Y. Gao, Heterocycles, 1991, 32, 2339.
116 (36). 89 (23%).
4d: orange prisms, mp 160±161 8C (from EtOH); ꢀ~max/cm 3415
1
(NH2), 3150 (NH2), 1690 (CO); dH 1.41 (6 H, d, J ˆ 6.2, 2 CH2),
5.28 (1 H, J ˆ 6.2 Hz, OCH), 6.66 (2 H, br s, NH2), 7.24±7.70 (4 H,
‡
m, ArH), 8.65 (1 H, s, hetero ArH); m/z 231 (M ‡ 1, 15), 230 (M ,
81), 188 (5), 171 (14), 144 (100), 143 (51), 117 (21), 116 (32%)
(Found: C, 67.6; H, 6.2; N, 12.3. C13H14N2O2 requires C, 67.8; H,
6.1; N, 12.2%).
11 J. George and S. Chandrascharan, Synth. Commun., 1983, 13,
495.
1
4e: yellow crystals, mp 104±106 8C (from EtOH); ꢀ~max/cm 3380
(NH2), 3150 (NH2), 1690 (CO); dH 1.00 (3 H, t, J ˆ 6.9, CH3),
1.44±1.68 (4 H, m, CH2CH2), 4.35 (2 H, t, J ˆ 6.4 Hz, OCH2), 6.79
(2 H, br s, NH2), 7.20±7.71 (4 H, m, ArH), 8.66 (1 H, s, hetero
12 G. Y. Dai, D. Q. Shi and L. H. Zhou, Chin. J. Appl. Chem.,
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13 J. M. Tyler, J. Chem. Soc., 1955, 203.