Synthesis derivatives of 2-amino-4-quinolones from 1,2,3,4- tetrahydroquinoline-8-carboxylic acids

Article abstract of DOI:10.1002/jhet.1702

A simple and efficient method is developed. Novel 2-amino-4-quinolone derivatives are synthesized. The products that have several functional groups for possible future modifications are described.

Full text of DOI:10.1002/jhet.1702

660
Synthesis Derivatives of 2-Amino-4-quinolones from
1,2,3,4-Tetrahydroquinoline-8-carboxylic acids
Vol 50
*
Dimitriy Listunov , Kirill Popov, Tetyana Tkachuk, and Yulian Volovenko
Organic Synthesis Laboratory, Kyiv National University, Kyiv 01033, Ukraine
*
E-mail: listunov_d@meta.ua
Received January 13, 2012
DOI 10.1002/jhet.1702
Published online in Wiley Online Library (wileyonlinelibrary.com).
O
N
O
R2
OH
NH
R1
NH2
R1
A simple and efficient method is developed. Novel 2-amino-4-quinolone derivatives are synthesized. The
products that have several functional groups for possible future modifications are described.
J. Heterocyclic Chem., 50, 660 (2013).
INTRODUCTION
For starting, quinoline-8-carboxylic acid was used a
modified method [9]. As oxidant, we used iodine in the
Skraup’s reaction. Esters were obtained by standard
methods using thionylchloride and the corresponding
absolute alcohol.
The 4-quinolines were formed when esters were heated
with arylacetonitriles with t-BuONa in pyridine.
In IR, there are absorption bands of the synthesized com-
pounds, the primary amino groups (3440 and 3340 cmÀ1),
and conjugations keto-group (1505–1512 cmÀ1, depending
of the substituent). The amino group’s signal is observed as
two-proton singlet (exchangeable with D2O) at 5.6–6.9 ppm
in 1H NMR.
The interest in synthesis of enaminoketones series based on
quinoline core is explained by the fact that these compounds
have multiple reaction sites and can serve as precursors for
the synthesis of new heterocyclic systems, 2-aminoquinolone
can easily be converted to 4-hydroxyquinolone-2, which are
used as a diuretic [1]. Also, amino group in their system
conjugate with keto group; that is why, it is like the amide
group in these systems. That is why, it could serve as an
isosteric analogue of amide group. Recent publication of
Erb and coworkers showed that 2-amino-4-quinolones
could be a potential potassium channel openers [2]. The
system of benzo[e,f]quinolizine is a structural component
of Lycopodium alkaloids, which show pronounced stimu-
latory effect on the respiratory center, as well as increased
blood pressure [3].
In summary, we describe the products that have several
functional groups for possible future modifications. The
structure of the synthesized compounds was proved by
methods of NMR, IR spectroscopy, and elemental analysis.
RESULTS AND DISCUSSION
EXPERIMENTAL
There are many methods for synthesis of 4-quinolones,
we used one of them. It is based on the interection of
N-methylanthranilate and arylacetonitriles [4] in the basic
case. This route permits the synthesis of a condensed system
with desired substitutes in aromatic ring and in system of
4-quinolone. We started from 1,2,3,4-tetrahydroquinoline-
8-carboxylic acid methyl ester to 2-methyl-1,2,3,
4-tetrahydroquinoline-8-carboxylic acid ethyl ester (Scheme 1).
The synthesis of 1,2,3,4-tetrahydroquinoline-8-carboxylic
acid in two alternative routes is described in literature
(Scheme 2). Synthesis is possible either from the
corresponding isatin [5] or from quinoline-8-carboxylic acid
[6],[7]. The path through the isatin was described for acid
with substituent in C-2 position. We used Raney nickel for
reduction of both acids [8].
General data. Solvents were purified according to standard
methods [10]. All commercially available chemicals were
purchased from Aldrich and Merck. The1H NMR (400MHz) and
13C NMR (100 MHz) spectra were recorded on a Varian Gemini
spectrometer, using DMSO-d6. All chemical shifts are reported in
ppm relative to TMS. IR spectra were recorded on spectrometer
Nicolet Nexus 470 in tablets KBr. Mass spectra were recorded on
a VG micromass 7070H spectrometer in chemical ionization
mode (atmospheric pressure chemical ionisation). Melting points
were determined through a Fisher–Johns apparatus and are
uncorrected. Elemental analyses (C, H, N) determined by means
of a Perkin–Elmer 240 CHN elemental analyzer
8-Quinolinecarboxylic acid(5a).
Anthranilic acid, 54.8 g
(0.4 mol), was dissolved in 140-mL 80% H2SO4. The reaction
mixture was heated with stirring until 140ꢀ, then added a
catalytic amount of NaI and added dropwise 35.8 mL
© 2013 HeteroCorporation

May 2013
Synthesis Derivatives of 2-Amino-4-quinolones from
1,2,3,4-Tetrahydroquinoline-8-carboxylic acids
661
Scheme 1. Synthesis of 2-amino-4-quinolones derivatives.
3-Amіno-2-phenyl-6,7-dihydro-1H, 5H-pyrido [3,2,1-ij]-quіnolіn-
1-on (3a). This compound was obtained as white powder.
O
O
Yield: 80%; mp 287–288ꢀC; 1H NMR (400.4 MHz, DMSO-d6):
2.17 (2H, m), 2.98 (2H, t, J = 6 Hz), 4.01 ( 2H, t, J = 5.6 Hz ), 5.67
(2H, s), 7.06 (1H, t, J= 7.6 Hz), 7.2 (5H, m), 7.4 ( 1H, t, J=7.2Hz),
7.94 (1Н, d, J=7.6Hz).
R2
R3
O
t-BuONa
Py, reflux
+
N
NH2
R2
CN
NH
R1
13C NMR(100.7MHz, DMSO-d6): 21.33; 27.1, 45.5, 104.37,
121.74, 124.10, 125.29, 126.48, 126.90, 128.94, 130.12, 132.13,
136.16, 136.37, 152.89, 171.87, IR (KBr) n: 3428, 3303, 1647,
R1
3a-h, 4a,b
1
2
1600, 1524 cmÀ1
;
MS: m/z 277 (M+); Anal. Calcd for
R1=H (3a-h),R3=Me; R1= Me (4a, 4b), R3=Et
R2= 3a, 4a:C6H5-, 3b: 4-FC6H4-,
3c: 3-ClC6H4-, 3d, 4b:3-CF3C6H4-
C18H16N2O: C, 78.24; H, 5.84; N,10.14. Found: C, 78.19; H,
5.79; N, 10.11.
3-Amіno-2-(4-fluorophenyl)-6,7-dihydro-1H, 5H-pyrido [3,2,1-
ij]-quіnolіn-1-on (3b). This compound was obtained as white
powder.
3e: 4-MeOC6H4-, 3f: 3,4-(MeO)2 C6H3-
H
N
O
*
3g:
3h:
1
Yield: 85%; mp 283–284ꢀC; H NMR (400.4 MHz, DMSO-
*
N
O
d6): 2,15 (2H, m), 2.96 (2H, t, J = 5.6 Hz), 4.0 (2H, t, J = 6 Hz),
5.74 (2H, s), 6.95 (2H, d, J = 8.8 Hz), 7.06 (1H,t, J = 7.6 Hz),
7.14 (2H, d, J = 8.4 Hz), 7.26 (1H, m), 7.92 (1Н, d, J = 7.6 Hz).
13C NMR (100.7 MHz, DMSO-d6): 21.32; 27.10, 45.51, 103.24,
115.60, 115.76, 121.74, 124.06, 125.17, 126.48, 130.15, 132.53,
134.07, 134.14, 136.18, 152.44, 160.49, 171.89, IR (KBr) n:
3445, 3310, 1647, 1611, 1523cmÀ1 ; MS: m/z 295 (M+); Anal.
Calcd for C18H15FN2O: C, 73,45; H, 5,14; N, 9,52. Found: C,
73.39; H, 5.08; N, 9.47.
Scheme 2. Two alternative routes for synthesis of 1,2,3,4-tetrahydroqui-
noline-8-carboxylic acids and their esters.
[H]
SOCl2
N
R
N
R
R1OH
N
R
H
O
OH
5a,b
O
OH
O
O
3-Amіno-2-(3-chlorophenyl)-6,7-dihydro-1H, 5H-pyrido [3,2,1-
R1
ij]-quіnolіn-1-on (3c).
This compound was obtained as white
1. (COCl)2, THF
2. AlCl3, CS2
powder.
a, b
Yield: 67%; mp 277–278ꢀC; 1H NMR (400.4 MHz, DMSO-d6):
2.15 (2H, m), 2.96 (2H, t, J = 5.2 Hz), 3.99 (2H, t, J = 5.2 Hz), 5,9
(2H, s), 7.07 (1H, d, J = 8.8 Hz), 7.2 (1H, d, J = 7.6Hz), 7.27
(3H, m), 7.4 (1H, t, J = 7.2 Hz), 7.92 (1Н, d, J = 7.6 Hz).
3. H2O2, NaOH
O
OH
NH2
N
R
H
13C NMR (100.7 MHz, DMSO-d6): 22.8; 27.3, 45.8, 97,
113.9, 117, 123.7, 126.5, 127, 127.1, 128, 130, 133.7, 134.1, 137.1,
R= H, Me
a: R=H, glycerole, H2SO4, NaI, 5a
b; R=Me, crotonic aldehyde, HCI, 5b
R1=Me (6a), Et (6b)
142.5, 156.8, 175.4, IR (KBr) n: 3446, 3324, 1644, 1611, 1518 cmÀ1
;
MS: m/z 311 (M+); Anal. Calcd for C18H15ClN2O: C, 69.57; H,
4.86; N,9.01. Found: C, 69.51; H, 4.81; N, 8.99.
3-Amіno-2-(3-trifluoromethylphenyl)-6,7-dihydro-1H, 5H-pyrido
[3,2,1-ij]-quіnolіn-1-on (3d). This compound was obtained as
white powder.
Yield: 90%; mp 231–232ꢀC; 1H NMR (400.4 MHz, DMSO-d6):
2.2 (2H, m), 3.03 (2H, m), 4.1 (2H, m), 6.9 (2H, s), 7.23 (1H, t,
J = 8 Hz), 7.43 (1H, d, J = 6.8 Hz), 7.57 (2H, m), 7.67 (2H, m),
8.06 (1Н, d, J = 8 Hz).
13C NMR (100.7 MHz, DMSO-d6): 20.97, 26.76, 46.67, 104.8,
118.52, 121.46, 123.15, 123.44, 124.93, 125.97, 127.23, 128.81,
130.45, 131.43, 134.62, 135.72, 136.15, 153.82, 171,82, IR (KBr)
n: 3465, 3279, 1637, 1617, 1518cmÀ1 ; MS: m/z 345 (M+); Anal.
Calcd for C19H15F3N2O: C, 66.28; H, 4.39; N,8.14. Found: C,
66.21; H, 4.35; N, 8.11.
(0.486 mol) of glycerol, maintaining a constant temperature. The
mixture was heated at this temperature for 6.5 h, сooled to room
temperature and neutralized with an alkali, and the precipitate
was filtered. The product was purified by recrystallization from
ethanol. Yield 60%, mp 186–188ꢀC (literature 183–185ꢀC).
Synthesis of esters of 1,2,3,4-tetrahydroquinoline-8-carboxylic
acids (6a,b).
To a 0.02 mole of the corresponding acid, that
dissolved in absolute alcohol, was added dropwise 0.035mol
SOCl2. Then, mixture was boiled for 2–3 days, concentrated
under reduced pressure, added with a small amount of water, and
neutralized with NaHCO3. The ester was extracted with toluene
and dried over Na2SO4. Solvent was distilled away. Boiling
point = 99ꢀC/0.06 mmHg. (not substituted), 102ꢀC/0.06 mmHg
(with methyl in the 2-position)).
3-Amіno-2-(4-methoxyphenyl-6,7-dihydro-1H, 5H-pyrido [3,2,1-
ij]-quіnolіn-1-on (3e).
This compound was obtained as white
powder.
General method for the synthesis of 3-amіno-2-aryl-6,
7-dihydro-1H, 5H-pyrido [3,2,1-ij]-1-quіnolіnones (3a–h, 4a,b).
Ester, 3.5 mmol, was mixed with 3.5 mmol farylacetonitrile, added
with 5 mL of dry pyridine, and 4.1 mmol t-BuONa, after which
the mixture was heated for 6 h. The solvent was evaporated, and
the residue was dissolved in a little water and neutralized with
hydrochloric acid. The precipitate was filtered, washed with water,
and crystallized from 2-propanol
1
Yield: 75%; mp 279–280ꢀC; H NMR (400.4 MHz, DMSO-
d6): 2.17 (2H, m), 2.97 (2H, t, J = 5.6 Hz), 3.82(3H, s), 4.0
(2H, t, J = 6 Hz), 5.71 (2H, s), 6.95 (2H, d, J = 8.8 Hz), 7.06 (1H,
t, J = 7.6 Hz), 7.16 (2H, d, J = 8.4 Hz), 7.26 (1H, d, J = 6.8Hz),
7.93 (1Н, d, J = 7.2 Hz).
13C NMR (100.7 MHz, DMSO-d6): 21.32; 27.1, 45.55, 55.51,
104.02, 114.52, 121.72, 124.05, 125.07, 126.44, 128.13, 130.06,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

662
D. Listunov, K. Popov, T. Tkachuk and Y. Volovenko
Vol 50
133.14, 136.07, 152.55, 158.38, 171.73. IR (KBr) n: 3428, 3330,
1653, 1626, 1516 cmÀ1; MS: m/z 307 (M+); Anal. Calcd for
C19H18N2O2: C, 74,49; H, 5,92; N,9,14. Found: C, 74,41; H,
5,86; N, 9,11.
3-Amіno-5-methyl-2-phenyl-6,7-dihydro-1H, 5H- pyrido[3,2,1-ij]-
quіnolіn-1-on (4a). This compound was obtained as white powder.
1
Yield: 67%; mp 150–151ꢀC; H NMR (400.4 MHz, DMSO-
d6): 1.4 (3H, d, J = 6.4 Hz), 1.5 (1H, m), 1.91 (1H, m), 2.77
(2H, m), 3.52 ( 1H, m), 5.87 (2H, s), 7.12 (1H, t, J = 7.2 Hz),
7.34 (1H, d, J = 6.4 Hz), 7.45 (5H, m), 7.97 (1Н, d, J = 7.6 Hz).
13C NMR (100.7 MHz, DMSO-d6): 17.1, 21.2, 29.9, 57.5,
97.3, 113.7, 117.8, 123.4, 126.8, 127.7, 128.5, 128.7, 128.7,
128.9, 134.6, 137.4, 142.7, 156.8, 175.4. IR (KBr) n:
3425, 3300, 1645, 1603, 1525 cmÀ1 ; MS: m/z 291 (M+); Anal.
Calcd for C19H18N2O): C, 78.59; H, 6.25, N, 9.65. Found: C,
78.55; H, 6.21; N, 9.59.
3-Amіno-2-(3,4-dimethoxyphenyl)-6,7-dihydro-1H, 5H-pyrido
[3,2,1-ij]-quіnolіn-1-on (3f).
This compound was obtained
as white powder.
Yield: 70%; mp 269–270ꢀC; 1H NMR (400.4 MHz, DMSO-d6):
2.14 (2H, m), 2.96 (2H, t, J = 6 Hz ), 3.73 (3H, s), 3.8 (3H, s), 3.99
(2H, t, J = 5.6 Hz), 5.71 (2H, s), 6,77 (2H, m), 6.94 (1H, d, J = 8 Hz),
7.06 (1H, t, J = 7.2 Hz), 7.25 (1H, d, J = 6.8 Hz), 7.94 (1Н, d,
J = 7.6 Hz).
13C NMR (100.7MHz, DMSO-d6): 21.35, 27.12, 45.48, 55.89,
56.04, 104.29, 112.69, 115.96, 121.64, 124.11, 124.17, 126.38,
125.30, 128.75, 130.01, 136.10, 148.02, 149.29, 152.5, 171.95;
IR (KBr) n: 3450, 3329, 1654, 1627, 1516 cmÀ1 ;MS: m/z 337
(M+); Anal. Calcd for C20H20N2O3: C, 71.41; H, 5.99; N,8.34.
Found: C, 71.36; H, 5.95; N, 8.29.
3-Amіno-5-methyl-2-(3-trifluoromethylphenyl)-6,7-dihydro-1H,
5H-pyrido[3,2,1-ij]-quіnolіn-1-on (4b).
This compound was
obtained as white powder.
1
Yield: 72%; mp 180–181ꢀC; H NMR (400.4 MHz, DMSO-
d6): 1.4 (3H, d, J = 6.4 Hz), 1.5 (1H, m), 1.92 (1H, m), 2.77
(2H, m), 3,51 ( 1H, m), 6.0 (2H, s), 7.11 (1H, t, J = 7.6 Hz),
7.34 (1H, d, J = 6.8 Hz), 7.6 (3H, m), 7.96 (1Н, d, J = 7.2 Hz).
3-Amіno-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6,7-dihydro-1H,
13C NMR (100.7 MHz, DMSO-d6): 17, 24.1, 29.8, 57.7, 97.1,
113.4, 117.6, 122.6, 123.6, 124.5, 124.8, 126.9, 128.5, 130.6, 132.5,
132.9, 137.3, 142.5, 156.8, 175.4. IR (KBr) n: 3430, 3305, 1646,
1605, 1528 cmÀ1; MS: m/z 359 (M+); Anal. Calcd for C20H17F3N2O:
C, 67.03; H, 4.78; N,7.82. Found: C, 66.98; H, 4.72; N, 7.78.
5H-pyrido [3,2,1-ij]-quіnolіn-1-on (3g).
This compound was
obtained as white powder.
1
Yield: 65%; mp 258–259ꢀC; H NMR (400.4 MHz, DMSO-
d6): 2.1 (2H, m), 2.96 (2H, m), 3.99 (2H, t, J = 6 Hz), 4.2
(4H, s), 5.7 (2H, s), 6.68 (2H, m), 6.84 (1H, d, J = 8 Hz), 7.06
(1H, t, J = 8 Hz), 7.25 (1H, d, J = 6.8 Hz), 7.92 (1Н, d, J = 8 Hz).
13C NMR (100.7 MHz, DMSO-d6): 22.9, 27.4, 45.9, 64.2,
64.3, 97, 111.4, 112.6, 113.7, 117, 121.3, 123.6, 124.8,
127.1, 137.3, 142.7, 149.3, 149.8, 156.8, 175.5, IR (KBr) n:
3429, 3329, 1646, 1612, 1518 cmÀ1 ; MS: m/z 335 (M+); Anal.
Calcd for C20H18N2O3: C, 71.84; H, 5.43; N,8.38. Found: C,
71.77; H, 5.37; N, 8.30.
3-Amіno-2-(1H-benzimidazol-2-yl)-6,7-dihydro-1H, 5H-pyrido
[3,2,1-ij]-quіnolіn-1-on (3h). This compound was obtained as
white powder.
Yield: 65%; mp more than 300ꢀC; 1H NMR (400.4 MHz, DMSO-
d6): 2.2 (2H, m ), 2.98 (2H, t, J= 6 Hz), 4.06 (2H, t, J= 5.2 Hz), 7.11
(2H, m), 7.15 (1H, t, J= 7.6 Hz), 7.33 (1H, d, J=6.8Hz), 7.57
(2H, m), 8.15 (1Н, d, J= 7.2 Hz), 11.52 (1H, s), 13.72 (1H, s).
13C NMR (100.7 MHz, DMSO-d6): 21.12, 26.96, 45.20,
91.02, 96.08, 111.48, 117.09, 121.30, 122.12, 123.78, 124.43,
125.86, 130.79, 132.12, 135.13, 141.8, 153.11, 154.80, 173.23.
IR (KBr) n: 3448, 3280,1643, 1541, 1523 cmÀ1 ; MS: m/z 317
(M+); Anal. Calcd for C19H16N4O: C, 72.14; H, 5.10; N, 17.71.
Found: C, 72.08; H, 5.04; N, 17.68.
REFERENCES AND NOTES
[1] Hardtmann, G. E. US 4192876; C07D215/22 – (1980).
[2] Erb, B.; Rigo, B.; Pirotte, B.; Couturier, D. J Heterocycl Chem
2002, 39, 15–28.
[3] Heathcock, C. H.; Kleinman, E. F.; Binkley, E. С. JACS 1982,
104, 1054.
[4] Kutrov, G. P.; Kovalenko, N. V.; Volovenko, Y. M. Russ J
Org Chem 2008, 44, 257.
[5] Kojima, E.; Fujimori, S.; Awano, K. US 4956372, C07D215/
48 (1990).
[6] Coppola G. M. J Heterocycl Chem 1978, 15, 645.
[7] Li X.-G.; Cheng X.; Zhou Q.-L. Synth Commun 2002,
32, 2477.
[8] Graeheva, I. N.; Tochilkin, A. I. Chem Heterocycl Comp 1988, 65.
[9] Campbell, K. N.; Kerwin, J. F.; La Forge, R. A.; Campbell, B. K.
JACS 1946, 68, 1844.
[10] Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory
Chemicals; Elsevier: Oxford, 2003; 609.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet