4-Hydroxyquinol-2-ones. 87. Unusual synthesis of 1-R-4-hydroxy-1-oxo-1,2- dihydroquinoline-3-carboxylic acid pyridylamides

Article abstract of DOI:10.1007/s10593-005-0296-z

4-Chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acids and their esters react with aminopyridines in refluxing DMF to give the corresponding 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pyridylamides. Their structures were proved by ¹

Full text of DOI:10.1007/s10593-005-0296-z

Chemistry of Heterocyclic Compounds, Vol. 41, No. 9, 2005
4-HYDROXYQUINOL-2-ONES. 87*. UNUSUAL
SYNTHESIS OF 1-R-4-HYDROXY-2-OXO-1,2-DIHYDRO-
QUINOLINE-3-CARBOXYLIC ACID PYRIDYLAMIDES
1
1
2
3
3
I. V. Ukrainets , L. V. Sidorenko , S. V. Slobodzyan , V. B. Rybakov , and V. V. Chernyshev
4
-Chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acids and their esters react with aminopyridines in
refluxing DMF to give the corresponding 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
1
pyridylamides. Their structures were proved by H NMR and mass spectroscopy, counter synthesis, and
by X-ray analysis. A possible mechanism is proposed for the indicated chemical reaction.
Keywords: aminopyridine, 4-chloro-2-oxoquinoline-3-carboxylic acids, amidation, X-ray analysis.
We have previously shown that 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate esters 1 react readily
with primary and secondary amines to give high yields of the corresponding 4-N-substituted 3-carbalkoxy-1,2-
dihydroquinolin-2-ones [2].
4
-Chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 2 also form similar products of "normal"
nucleophilic addition but with the difference that alternate compounds can be obtained depending on the reaction
conditions. Hence when the reaction is carried out in ethanol the 4-alkyl(aryl)amino-substituted acids 3 are
formed whereas the reaction in refluxing DMF gives 4-alkyl(aryl)aminoquinolin-2-ones 4. In the latter case the
decarboxylation evidently occurs after the formation of the 4-amino derivatives since 4-chloro-1,2-
dihydroquinolin-2-ones, free from activation of the chlorine atom by electron-acceptor substituents in position 3
of the quinoline ring, are inert towards N-nucleophiles [3].
The reaction with aminopyridines, however, occurs quite differently. Thus the reaction of the 4-chloro-
substituted acids 2 with α-, β-, or γ-aminopyridines under reflux in both anhydrous and ordinary DMF
unexpectedly gave the corresponding 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pyridylamides 5,
1
whose structures were confirmed by H NMR and mass-spectroscopic data and by chromatography-mass
spectrometry. X-ray analysis was used also in the case of the pyridyl-4-amide 5c.
The reaction of the aminopyridines with the 4-chloro esters 1 was just as unexpected. Hence the
4
-hydroxy amides 5 are formed immediately in aqueous DMF. However, in anhydrous solvent the reaction stops
at the stage of formation of the N-(3-alkoxycarbonyl-2-oxo-1,2-dihydroquinolin-4-yl)pyridinium chlorides 6
which can then be converted to the 4-hydroxy amides 5. It was of interest that, in aqueous DMF, the 1-N-alkyl-
_
*
_
______
For Communication 86 see [1].
_________________________________________________________________________________________
1
2
National University of Pharmacy, Kharkov 61002, Ukraine; e-mail: uiv@kharkov.ua. Ohio Northern
3
University, Ada 45810, Ohio, USA; e-mail: s-slobodzian@onu.edu. M. V. Lomonosov State University,
Moscow 119899, Russia; e-mail: rybakov@biocryst.phys.msu.su. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 9, pp. 1362-1371, September, 2005. Original article submitted June 17, 2004.
1
158
0009-3122/05/4109-1158©2005 Springer Science+Business Media, Inc.

R'
R"
OH
O
O
OH
N
N
OH
H
2
N–Py
aq. DMF
N
Et
9
N
O
O
Et
R
8
4a–c
R'
NH
aq. DMF
R"
DMF
OH
O
Cl
O
O
H N–Py,
DMF
2
R'
N
N
HN
R'
OH
, EtOH
H
R"
N
N
O
N
R
R"
O
R
5
a–e
2
OH
H N–Py
aq. DMF
N
R
O
2
aq. DMF
3
a,b
Cl
O
OAlk
NH2
NH2
N
R
O
+
+
–
1
–
Cl
N
O
O
Cl
N
O
H N–Py,
2
dry DMF
OEt
OEt
N
H
N
OH
6
7
3
a R = R' = H, R'' = CH
2
–Ph; b R = Pr, R' = H, R'' = 4-Cl-Ph; 4 a R = R' = H, R'' = CH
2
–Ph;
b R = H, R' = R'' = Pr; c R = Pr, R' = H, R'' = 4-Cl–Ph; 5 a R = H, 4-Py; b R = Et, 4-Py;
c R = Pr, 4-Py; d R = Pr, 3-Py; e R = Pr, 2-Py
substituted esters 1 were converted to the amides 5 in the presence of the aminopyridines in the course of 30 min
whereas the same reaction for the 1H derivative along with the 1H-pyridinium chloride 6 needs many hours
reflux.
The 4-chloro acids 2 are hydrolyzed when simply worked up with refluxing aqueous DMF to the
4
-hydroxy-1,2-dihydroquinolin-2-one 8. None the less, the 4-hydroxyamides 5 should hardly be considered as a
result of aminolysis by the aminopyridine acids 2 or their possible 4-hydroxy acid derivatives 9. In the first
place, as shown above, even with alkylamines (i.e. with stronger bases than the aminopyridines) the 4-chloro
acids 2 form only the quinolin-2-ones 3 or 4. In the second, 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic
acids 9 are actually amidated in refluxing DMF but only using alkylamines [4]. Attempts to carry out such a
reaction with anilines [5] or with 4-aminopyridine were unsuccessful. In other words, for the formation of the
hetarylamides directly from the amines and acids 2 or 9, the electrophilic properties of the latter are clearly
insufficient. It undoubtedly needs some kind of activation of the carbonyls in their carboxyl groups.
1
159

Correlation of the data given allows us to conclude that the initial products of the reaction of the
4
-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 2 with the aminopyridines are the quaternary
pyridinium salts 10. The formation of the amides of the 4-hydroxy acids 5 in anhydrous DMF shows that the
source of the 4-OH substituent can only be the carboxyl group in this instance. Hence the subsequent course of
the reaction must include a nucleophilic attack of carboxylate ion at the carbon atom in position 4 of the
quinolone ring (route A) which leads to the cyclic intermediate 11. Following from this SN2Ar type reaction
mode, fission of the bond to the leaving group liberates the aminopyridine which then reacts with lactone 12 to
NH2
N
H N
H N
2
2
+
N
+
H N–Py,
2
N
O
O
DMF
Route А
O
O
O
2
O
O
–
H N–Py
2
N
R
N
R
O
N
R
O
1
0
1
1
1
2
R
O
O
N
R
O
O
O
N
O
O
+
N
O
NH2
H N
2
+
N
O
Route В
2 H N–Py
2
H N–Py
O
2
O
5
–
2
N
R
N
R
O
1
3
1
0
10
8
–
CO2
O
+
N
Route С
OH
O
N
O
N
H
+
R
N
R
9
O
N
O
N
O
O
R
15
O
H N
2
+
N
N
H N
2
O
O
O
N
R
14
1
160

give the final 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbalkoxylic acid pyridylamide 5. It is likely that the
-carbalkoxypyridinium chloride 6 is converted to the 4-hydroxyamide 5a by a similar scheme after initial
3
hydrolysis of the ester group since the reaction only occurs in the presence of water. A marked decrease in the
rate of reaction in the case of the 1H-derivatives may be due to their ability to form the more hydrolytically
stable aromatic 2-hydroxy tautomer 7 via lactam-lactim tautomerism. We have noted this feature during the
alkylation in DMF of 4-hydroxy- [6] and 4-amino-1H-2-oxo-1,2-dihydroquinoline-3-carboxylate esters [1].
Of course, it is in principle impossible to exclude an intermolecular character for the reaction of the
pyridinium salts 10 to the amides 5. However, the realization of such a mechanism demands an additional
condition for the successful occurrence of the reaction involving the formation of the symmetrical diester (route
B) and coming about only as the result of a synchronous attack of the C(4) atoms by both carboxylate ions.
Otherwise, the separated amine will react with the mono ester 14 (route C) thus liberating the 1-R-4-hydroxy-2-
oxo-1,2-dihydroquinoline-3-carboxylic acids 9 the participation of which in further chemical reactions is
unlikely due to its high tendency towards decarboxylation under the described conditions. As a result the yield of
the 4-hydroxyamide 5 would be markedly lowered due to the formation of the 4-hydroxyquinolin-2-one 8 and
this does not agree with experimental data.
Hence comparison of the positive and negative aspects of each of the discussed variants of the formation
of the 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pyridylamides 5 in the reactions of the 4-chloro
acids 2 with the aminopyridines led us to conclude that route A appears to be preferred.
We have not considered inter- or intramolecular reaction of the pyridinium salts 10 involving acylation
of a primary amino group as one possible route to the formation of the 4-hydroxyamides 5. The pyridinium
nitrogen atom is a powerful electron acceptor, exceeding the majority of other functional groups [7]. This leads
1
to a marked lowering of the electron density and, consequently, to the reactivity of the amino group. H NMR
spectroscopic data is a persuasive confirmation of this. A singlet signal for the amino group protons in the
Fig. 1. Atomic numbering and spatial structure of the amide 5c molecule. The thermal vibration ellipsoids
are given with a 50% probability. The intramolecular hydrogen bonds are shown by dashed lines.
1
161

4
-amino-1-(3-ethoxycarbonyl-2-oxo-1,2-dihydroquinolin-4-yl)pyridinium chloride (6) is found at 9.25 ppm.
Such a chemical shift is typical of amides rather than amines [8]. Hence acylation of the amino group in the
pyridinium salts 10 is not possible under these conditions.
TABLE 1. Specific Interatomic Distances (d) in the Structure of Compound
5
c
Bond
d, Å
Bond
d, Å
Bond
d, Å
N
N
N
(1)–C(2)
(1)–C(10)
(1)–C(11)
1.389(4)
1.391(4)
1.453(4)
1.247(4)
1.438(4)
1.364(4)
1.465(4)
1.340(4)
1.445(5)
C
C
C
C
C
C
C
C
C
(5)–C(10)
(5)–C(6)
1.396(5)
1.397(4)
1.370(5)
1.380(5)
1.370(5)
1.410(5)
1.507(4)
1.515(4)
1.265(4)
C
(15)–N(16)
1.350(4)
1.413(4)
1.368(4)
1.381(5)
1.383(5)
1.323(5)
1.329(5)
1.382(5)
N
C
C
C
(16)–C(17)
(17)–C(18)
(17)–C(22)
(18)–C(19)
(6)–C(7)
C
C
C
C
C
C
(2)–O(2)
(2)–C(3)
(3)–C(4)
(3)–C(15)
(4)–O(4)
(4)–C(5)
(7)–C(8)
(8)–C(9)
(9)–C(10)
(11)–C(12)
(12)–C(13)
(15)–O(15)
C(19)–N(20)
N
(20)–C(21)
(21)–C(22)
C
TABLE 2. Specific Valence Angles (ω) in the Structure of Compound 5c
Angle
ω, deg.
Angle
ω, deg.
C
C
C
(2)–N(1)–C(10)
(2)–N(1)–C(11)
(10)–N(1)–C(11)
121.6(3)
116.7(3)
121.5(3)
118.1(4)
123.4(4)
118.5(4)
119.6(4)
119.0(4)
121.4(4)
123.0(4)
115.3(4)
121.8(4)
108(2)
N
(1)–C(10)–C(5)
(1)–C(10)–C(9)
120.8(4)
120.9(4)
118.4(4)
112.4(3)
112.8(3)
122.0(4)
119.9(4)
118.1(4)
128.5(4)
109(2)
N
C
(5)–C(10)–C(9)
(1)–C(11)–C(12)
(11)–C(12)–C(13)
O
O
N
(2)–C(2)–N(1)
(2)–C(2)–C(3)
(1)–C(2)–C(3)
N
C
O(15)–C(15)–N(16)
O(15)–C(15)–C(3)
N(16)–C(15)–C(3)
C
C
C
(4)–C(3)–C(2)
(4)–C(3)–C(15)
(2)–C(3)–C(15)
C
C
C
C
C
C
C
(15)–N(16)–C(17)
(15)–N(16)–H(16)
(17)–N(16)–H(16)
(18)–C(17)–C(22)
(18)–C(17)–N(16)
(22)–C(17)–N(16)
(17)–C(18)–C(19)
O
(4)–C(4)–C(3)
(4)–C(4)–C(5)
O
123(2)
C
C
C
C
C
C
C
C
C
(3)–C(4)–C(5)
(4)–O(4)–H(4)
(10)–C(5)–C(6)
(10)–C(5)–C(4)
(6)–C(5)–C(4)
(7)–C(6)–C(5)
(6)–C(7)–C(8)
(9)–C(8)–C(7)
(8)–C(9)–C(10)
118.8(4)
124.9(4)
116.3(4)
117.5(4)
126.2(4)
114.3(4)
125.3(4)
118.0(4)
120.5(4)
117.5(4)
122.0(4)
120.4(4)
119.0(4)
122.2(4)
119.5(4)
N
(20)–C(19)–C(18)
(19)–N(20)–C(21)
(20)–C(21)–C(22)
(17)–C(22)–C(21)
C
N
C
TABLE 3. Hydrogen Bonds in the Structure of the Studied Amide 5c*
D–H
d (D–H), Å
d (D···A), Å
d (H···A), Å ϕ (D–H···A), deg.
A
O
(4)–H(4)
(16)–H(16)
1.02(4)
1.00(4)
2.479(4)
2.599(4)
1.57(4)
1.70(3)
145(4)
147(3)
O
(15)
N
O
(2)
_
*
______
D = donor atom; A = acceptor atom; H = hydrogen atom, d = distance, ϕ =
angle.
1
162

EXPERIMENTAL
1
H NMR spectra for the synthesized compounds were recorded on a Bruker WM-360 (360 MHz)
instrument using DMSO-d solvent and TMS internal standard. Mass spectra were recorded on a Finnigan MAT
6
Incos 50 quadrupole spectrometer in the full scanning mode over the range 33-700 m/z with an electron
ionization strength of 70 eV, direct introduction of the sample, and a heating rate of about 5°C/s. 4-Chloro-2-
oxo-1,2-dihydroquinoline-3-carboxylic acids 2 and their esters were synthesized by a known method [6, 9].
4
-Benzylamino-2-oxo-1,2-dihydroquinoline-3-carboxylic Acid (3a). Benzylamine (1.09 ml, 0.01 mol)
was added to a solution of 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (2, R = H, 2.23 g, 0.01 mol)
in alcohol (15 ml) and refluxed for 2 h. The acid 3a began to crystallized from the refluxing reaction mixture
after just 20-30 min. After cooling, the crystals of the 4-benzylaminoacid 3a were filtered off, washed with
1
alcohol, and dried to give 2.79 g (95%); mp 246-248°C (decomp.). H NMR spectrum, δ, ppm (J, Hz): 16.70
(
1Н, s, СООН); 12.00 (1H, s, NH); 11.42 (1H, t, J = 6.9, NH); 8.25 (1Н, d, J = 8.0, Н-5); 7.66 (1Н, t, J = 7.2,
Н-7); 7.45-7.30 (6Н, m, Н-8 + C H ); 7.21 (1H, t, J = 7.2, H-6); 5.10 (2Н, d, J = 6.9, СН ). Found, %: C 69.56;
6
5
2
H 4.94; N 9.70. C H N O . Calculated, %: C 69.38; H 4.79; N 9.52.
1
7
14
2
3
4
-(4-Chlorophenylamino)-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxylic Acid (3b). Obtained
1
similarly. Yield 93%; mp 191-193°C. H NMR spectrum, δ, ppm (J, Hz): 16.58 (1Н, s, СООН); 11.97 (1H, s,
NH); 7.73 (2Н, m, Н-5,7); 7.46 (1Н, d, J = 7.9, Н-8); 7.39 (2Н, d, J = 8.0, Н-3,5 C H ); 7.18 (2Н, d, J = 8.0,
6
5
Н-2,6 Ph); 7.09 (1H, t, J = 7.0, H-6); 4.24 (2Н, t, J = 7.1, NCH ); 1.67 (2H, m, СН Ме); 0.93 (3Н, t, J = 7.1,
2
2
СН ). Found, %: C 63.84; H 4.70; N 7. 93. C H ClN O . Calculated, %: C 63.96; H 4.80; N 7.85.
3
19 17
2
3
4
-Benzylamino-1H-quinolin-2-one (4a). Benzylamine (1.09 ml, 0.01 mol) was added to a solution of
compound 2 (R = H, 2.23 g, 0.01 mol) in DMF (10 ml) and refluxed with a reflux condenser for 2 h. After
cooling, the crystals of the aminoquinolone 4a were filtered off, washed with water, and dried. Yield 1.85 g
1
(
74%); mp 250-251°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 10.77 (1H, s, NH); 8.00 (1Н, d, J = 8.1,
Н-5); 7.65 (1H, t, J = 6.9, NH); 7.43 (1Н, t, J = 7.3, Н-7); 7.36-7.28 (5Н, m, C H ); 7.19 (1Н, d, J = 7.6, Н-8);
6
5
7
.10 (1H, t, J = 7.3, H-6); 5.11 (1Н, s, Н-3); 4.44 (2Н, d, J = 6.9, СН ). Found, %: C 76.62; H 5.75; N 11.22.
2
C H N O. Calculated, %: C 76.78; H 5.64; N 11.19.
1
6
14
2
Compounds 4b,c were prepared by the same method.
1
4
-Dipropylamino-1H-quinolin-2-one (4b). Yield 77%; mp 133-135°C (ethanol). H NMR spectrum,
δ, ppm (J, Hz): 11.20 (1H, s, NH); 7.67 (1Н, d, J = 8.2, Н-5); 7.41 (1H, t, J = 7.2, Н-7); 7.25 (1Н, d, J = 8.2,
Н-8); 7.11 (1H, t, J = 7.2, Н-6); 5.80 (1Н, s, Н-3); 3.11 (4H, t, J = 7.0, 2NCH ); 1.50 (4H, m, 2CH Me); 0.79
2
2
(
6Н, t, J = 7.0, 2СН ). Found, %: C 73.53; H 8.37; N 11.32. C H N O. Calculated, %: C 73.74; H 8.25;
3 15 20 2
N 11.46.
4
-(4-Chlorophenylamino)-1-propyl-1H-quinolin-2-one (4c). Yield 79%; mp 240-242°C (DMF).
H NMR spectrum, δ, ppm (J, Hz): 8.55 (1H, s, NH); 8.13 (1Н, d, J = 7.8, Н-5); 7.62 (1H, t, J = 7.1, Н-7); 7.49
1Н, d, J = 7.8, Н-8); 7.42 (2H, d, J = 8.2, Н-3,5 Ph); 7.31 (2H, d, J = 8.2, Н-2,6 Ph); 7.23 (1H, t, J = 7.1, Н-6);
1
(
5
.88 (1Н, s, Н-3); 4.14 (2H, t, J = 7.1, NCH ); 1.60 (2H, m, CH Me); 0.92 (3Н, t, J = 7.1, СН ). Found, %:
2 2 3
C 69.24; H 5.53; N 8.90. C H ClN O. Calculated, %: C 69.12; H 5.48; N 8.96.
1
8
17
2
4
-Hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxylic Acid Pyrid-4-yl Amide (5c).
4
-Aminopyridine (0.94 g, 0.01 mol) was added to a solution of 4-chloro-2-oxo-1-propyl-1,2-dihydroquinoline-3-
carboxylic acid (2, R = Pr, 2.65 g, 0.01 mol) in dry or ordinary DMF (10 ml) and refluxed for 1 h. The reaction
mixture was cooled and the separated amide 5c was filtered off, washed with alcohol, and dried. Yield 2.74 g
1
(
(
85%); mp 190-192°C (DMF). H NMR spectrum, δ, ppm (J, Hz): 16.48 (1Н, s, ОН); 12.94 (1H, s, NH); 8.44
2H, d, J = 6.3, Н-2,6 Py); 8.20 (1Н, d, J = 7.9, Н-5); 7.74 (1H, t, J = 7.9, Н-7); 7.60 (2H, d, J = 6.3, Н-3,5 Py);
7
.50 (1Н, d, J = 9.4, Н-8); 7.33 (1H, t, J = 7.9, Н-6); 4.33 (2H, t, J = 7.2, NCH ); 1.70 (2H, m, CH Me); 1.00
2 2
+
+
+
(
3Н, t, J = 7.2, СН ). Mass spectrum, m/z (I , %): 323 [M] (100), 281 [M–C H ] (20), 230 [M–NHPy] (25),
3
rel
3
6
2
02 (1.2), 187 (77), 121 (0.9), 94 (26).
1
163

X-Ray Analysis of Amide 5c. The experimental intensities of the diffracted reflections were obtained
at room temperature (293(2) K) on a CAD4 [10] diffractometer (MoKα irradiation, graphite monochromator,
ω-scanning). The parameters for the unit cells were measured and refined for 25 reflexes in the range of
1
θ angles 15-16°. The amide 5c crystallized in the monoclinic crystal system with the space group P2 /n
3
3
(
a = 7.912(2), b = 10.274(2), c = 19.210(5) Å; β = 98.11(2)°; V = 1545.9(6) Å ; Z = 4; dcalc = 1.389 g/cm ;
-1
µ = 0.097 mm ). The diffraction experiment was carried out on a crystal with the linear dimensions
.3 × 0.3 × 0.3 mm (2.14 ≤ θ ≤ 25.98°, index range h, k, l: -9 ≤ h ≤ 9, 0 ≤ k ≤ 12, 0 ≤ l ≤ 23). In all 3034
independent reflexes were collected (Rint = 0.0303). The number of refined parameters was 226. Results for the
refined structure: GOF = 0.787, R /wR [I > 2σ (I)] 0.0485 / 0.0460, R /wR (all reflexes) 0.1909 / 0.0765,
0
1
2
1
2
-
3
∆
ρmax / ∆ρmin: 0.151 / -0.153 e·Å .
Since the crystal of the investigated compound has a low linear absorption coefficient and small size a
correction for absorption was not carried out. Initial treatment of the body of experimental data was performed
using the WinGX program package [11]. All subsequent calculations were carried out using the SHELX97
program package [12]. The crystal structure was determined by a direct method with refinement of positional
and thermal parameters then carried out in the anisotropic approximation for all non hydrogen atoms. The H
atoms were calculated from geometric considerations and refined using the “riding atom” model. The hydrogens
of the hydroxyl and amide group were excluded and they were directly localized from electron density
difference synthesis. These hydrogen atoms were refined independently in the isotropic approximation.
Individual interatomic distances and valence angles are presented in Tables 1 and 2. The parameters for the
intramolecular hydrogen bonds are given in Table 3. The crystallographic information for the amide 5c has been
placed in the Cambridge Structural Database (reference CCDC No. 249895) [13]. The steric positioning of the
atoms in the molecule of the compound studied with their numbering are shown in Figure 1 and were obtained
using the ORTEP3 program [14]. The parameters for the H bonds were calculated using the PARST95 program
[15].
The 1,2-dihydroquinoline system of the amide 5c N(1)···C(10) is planar to an accuracy of 0.019(3) Å. The
atoms O(2), O(4), C(11), and C(15) attached to it also lie in this plane. The amide group is virtually coplanar with the
ring (torsional angle C(4)–C(3)–C(15)–O(15) 0.7(6)°), the plane of the pyridine ring making a dihedral angle of
7
.3(1)° with the plane of the hydroxydihydroquinoline bicycle. This amide substituent orientation is stabilized
by a weak intramolecular hydrogen bond O(15)···H(18)–C(18) (O···H 2.26 Å, O···H–C 120°) and a strong
intramolecular hydrogen bond O(15)···H(4)–O(4) (O···H 1.57 Å, O···H–O 145°).
The C(4)–O(4) and C(3)–C(4) bond lengths of 1.340(5) and 1.364(4) Å are typical of enols. The significant
lengthening of the C(15)–O(15) bond to 1.265(4) Å (mean value 1.202 Å [16]) is evidently due to the strong
O
(15)···H(4)–O(4) intramolecular hydrogen bond.
The propyl substituent on the N
(1)–C(11)–C(12)–C(13) 172.7(3)°) and is turned almost perpendicularly to the plane of the quinoline ring (torsional
1
atom has an antiperiplanar conformation (torsional angle
N
angle C(2)–N(1)–C(11)–C(12) 92.4(4)°). This position for the alkyl group is likely due to the intramolecular
shortening of contact H(11a)···H(9) (1.85 Å) and the weak intramolecular hydrogen bond O(2)···H(11b)–C(11) (O···H
2
.26 Å, O···H–C 102°).
In the crystal the molecules of the amide 5c form a stack along the crystallographic (1 0 0) axis. In each
stack dimers are formed via interaction between the dihydroquinoline fragments with the dihydropyridine rings
placed over the benzenes. The distance between the centers of the rings is 3.61 Å and the planes of the
dihydropyridine and benzene rings subtend an angle of 1.3°. The dimers are orientated such that the pyridine
ring amide fragments are placed over the benzene rings of the associated dimers with a distance of 3.79 Å
between the centers of the rings and an angle between the planes of 7.2°.
Compounds 5d,e were prepared by the preceding method.
4
-Hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxylic Acid Pyrid-3-yl Amide (5d).
1
Yield 89%; mp 161-163°C (DMF). H NMR spectrum, δ, ppm (J, Hz): 16.55 (1Н, s, ОН); 13.02 (1H, s, NH);
8
.74 (1H, s, Н-2 Py); 8.30 (1H, d, J = 4.3, Н-6 Py); 8.20 (2Н, d, J = 8.3, Н-5 + Н-4 Py); 7.74 (1H, t, J = 7.6,
1
164

Н-7); 7.52 (1Н, d, J = 9.0, Н-8); 7.33 (1H, t, J = 7.6, H-6); 7.30 (1H, t, J = 7.9, Н-5 Py); 4.29 (2H, t, J = 7.2,
+
NCH ); 1.74 (2H, m, CH Me); 1.09 (3Н, t, J = 7.2, СН ). Mass spectrum, m/z (I , %): 323 [M] (60), 281 [M–
2
+
2
3
rel
+
C H ] (12), 230 [M–NHPy] (53), 187 (38), 94 (100).
3
6
4
-Hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxylic Acid Pyrid-2-yl Amide (5e).
1
Yield 76%; mp 178-179°C (DMF). H NMR spectrum, δ, ppm (J, Hz): 16.50 (1Н, s, ОН); 12.88 (1H, s, NH);
8
7
4
.35 (1H, d, J = 5.0, Н-6 Py); 8.24 (1H, d, J = 7.9, Н-3 Py); 8.19 (1Н, d, J = 7.9, Н-5); 7.75 (1H, t, J = 7.6, Н-7);
.70 (1H, t, J = 8.2, Н-4 Py); 7.45 (1Н, d, J = 8.6, Н-8); 7.30 (1H, t, J = 7.9, H-6); 7.08 (1H, t, J = 5.4, Н-5 Py);
.30 (2H, t, J = 7.2, NCH ); 1.72 (2H, m, CH Me); 1.01 (3Н, t, J = 7.2, СН ). Mass spectrum, m/z (I , %): 323
2
+
2
3
rel
+
+
[M] (100), 281 [M–C H ] (75), 230 [M–NHPy] (4.7), 202 (3.5), 187 (58), 121 (8), 94 (54).
3 6
4
-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic Acid Pyrid-4-yl Amide (5a). Water (2 ml) was
added to a suspension of compound 6 (3.45 g, 0.01 mol) in DMF (20 ml) and refluxed for 15 h. The reaction
mixture was cooled and the precipitate was filtered off, washed several times on the filter with hot water to
1
remove the starting pyridinium chloride 6, and dried. Yield 1.60 g (57%); mp 360-362°C (DMR). H NMR
spectrum, δ, ppm (J, Hz): 16.43 (1Н, s, ОН); 12.91 (1H, s, NH–Py); 12.00 (1H, s, NH); 8.33 (2H, d, J = 4.8,
Н-2,6 Py); 8.16 (1Н, d, J = 7.9, Н-5); 7.63 (1H, t, J = 7.0, Н-7); 7.52 (2H, d, J = 4.8, Н-3,5 Py); 7.44 (1Н, d,
+
+
J = 7.9, Н-8); 7.27 (1H, t, J = 7.0, Н-6). Mass spectrum, m/z (I , %): 281 [M] (100), 188 [M–NHPy] (70), 94
rel
(
37).
1
-Ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic Acid Pyrid-4-yl Amide (5b).
-Aminopyridine (0.94 g, 0.01 mol) and 2-3 drops of water were added to a solution of methyl 4-chloro-1-ethyl-
-oxo-1,2-dihydroquinoline-3-carboxylate (1, R = Et, Alk = Me, 2.65 g, 0.01 mol) in DMF (10 ml) and refluxed
4
2
for 30 min. The reaction mixture was cooled and the precipitated amide 5b was filtered off, washed on the filter
1
with ethanol, and dried. Yield 2.53 g (82%); mp 187-189°C (DMF). H NMR spectrum, δ, ppm (J, Hz): 16.56
(
1Н, s, ОН); 12.97 (1H, s, NH); 8.45 (2H, d, J = 6.5, Н-2,6 Py); 8.21 (1Н, d, J = 8.3, Н-5); 7.76 (1H, t, J = 7.9,
Н-7); 7.61 (2H, d, J = 6.5, Н-3,5 Py); 7.53 (1Н, d, J = 8.6, Н-8); 7.34 (1H, t, J = 7.3, H-6); 4.35 (2H, q, J = 7.2,
+
+
NCH ); 1.31 (3Н, t, J = 7.2, СН ). Mass spectrum, m/z (I , %): 309 [M] (100), 281 [M–C H ] (18), 216 [M–
NHPy] (33), 187 (60), 94 (32).
2
3
rel
2
4
+
A mixed sample of the pyridylamides 5a-e with a known sample obtained by treating the ethyl
1
R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates with the aminopyridines [17] did not cause a
1
depression in melting points. The H NMR and chromatography mass spectra for these materials were identical.
4
-Amino-1-(3-ethoxycarbonyl-2-oxo-1,2-dihydroquinolin-4-yl)pyridinium Chloride (6). 4-Amino-
pyridine (0.94 g, 0.01 mol) was added to a solution of ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate
1, R = H, Alk = Et, 2.51 g, 0.01 mol) in anhydrous DMF (10 ml) and refluxed for 1 h. The reaction mixture was
cooled and the precipitated pyridinium chloride 6 was filtered off, washed with acetone, and dried. Yield 3.11 g
(
1
(
90%); mp 290-292°C. H NMR spectrum, δ, ppm (J, Hz): 12.91 (1H, s, NH); 9.25 (2H, s, NH ); 8.32 (2H, d,
2
J = 5.1, Н-2,6 Py); 7.69 (1H, t, J = 7.2, Н-7); 7.55 (1Н, d, J = 7.8, Н-8); 7.25 (1H, t, J = 7.2, H-6); 7.15-7.05
(
3H, m, Н-5 + Н-3,5 Py); 4.10 (2H, q, J = 7.0, ОCH ); 1.00 (3Н, t, J = 7.0, СН ). Found, %: C 59.18; H 4.54;
2
3
N 12.29. C H ClN O . Calculated, %: C 59.05; H 4.66; N 12.15.
1
7
16
3
3
1
-Ethyl-4-hydroxy-1H-quinolin-2-one (8). A.
A
solution of 4-chloro-1-ethyl-2-oxo-1,2-
dihydroquinoline-3-carboxylic acid (2, R = Et, 2.51 g, 0.01 mol) in aqueous DMF (10 ml) was refluxed for 2 h.
After cooling, the reaction mixture was diluted with water. The precipitated solid was filtered off, washed with
1
water, and dried. Yield 1.41 g (75%); mp 274-276°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 11.35 (1H, s,
ОH); 7.88 (1Н, d, J = 8.0, Н-5); 7.60 (1H, t, J = 7.1, Н-7); 7.47 (1Н, d, J = 8.0, Н-8); 7.19 (1H, t, J = 7.1, H-6);
5
.84 (1Н, s, Н-3); 4.19 (2H, q, J = 7.1, NCH ); 1.12 (3Н, t, J = 7.1, СН ). Found, %: C 69.96; H 5.72; N 7.33.
2 3
C H NO . Calculated, %: C 69.83; H 5.86; N 7.40.
1
1
11
2
B. A mixture of 1-ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (9, 2.33 g, 0.01 mol)
and 4-aminopyridine (0.94 g, 0.01 mol) in anhydrous DMF (10 ml) was treated by the method described above.
Yield 1.51 g (80%).
1
165

A mixed sample with a sample of the quinolin-2-one 8 prepared by method A did not give a depression
1
of melting point and the H NMR spectra of the compounds were identical.
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