4-Hydroxyquinol-2-ones. 86. Synthesis of methyl (ethyl) esters of 1-substituted 4-amino-2-oxoquinoline-3-carboxylic acids

Article abstract of DOI:10.1007/s10593-005-0295-0

Several variants of the synthesis of esters of 1-N-substituted 4-amino-2-oxoquinoline-3-carboxylic acids have been studied, one of which is recommended as preparative. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0295-0

Chemistry of Heterocyclic Compounds, Vol. 41, No. 9, 2005
4-HYDROXYQUINOL-2-ONES. 86*. SYNTHESIS
OF METHYL (ETHYL) ESTERS OF 1-SUBSTITUTED
4-AMINO-2-OXOQUINOLINE-3-CARBOXYLIC ACIDS
I. V. Ukrainets, L. V. Sidorenko, and O. V. Gorokhova
Several variants of the synthesis of esters of 1-N-substituted 4-amino-2-oxoquinoline-3-carboxylic acids
have been studied, one of which is recommended as preparative.
Keywords:
3-alkoxycarbonyl-4-aminoquinolin-2-one,
4-chloroquinolin-2-one,
alkylation,
N-debenzylation.
Esters of 1-substituted 4-amino-2-oxoquinoline-3-carboxylic acids 1 are of interest as potentially
biologically active substances and also as a basis for further chemical conversions with an adequately broad
synthetic potential.
The usual method of obtaining compounds of this family comprises acylation of anthranilonitrile 2 with
the acid chloride of an appropriate acid, containing a fairly reactive methylene group, with subsequent closure of
the 4-aminoquinoline ring under the action of basic catalysts [2, 3]. This method gives good results in the
synthesis of 3-alkoxycarbonyl-1H-4-amino-2-oxoquinolines 3 [4] and, in principle, may be used for obtaining
1-N-alkyl derivatives 1 (Scheme 1, method A). Regretably alkylation of anthranilonitrile 2 does not occur
quantitatively and the N-alkyl derivatives obtained always contain contamination by the starting material,
effective elimination of which is only possible by chromatography (especially in the case of the lower N-alkyl
substituents). Using the available N-alkylanthranilic acids in the synthesis of anthranilonitriles 4 [5] may exclude
chromatographic purification, but such a modification introduces several additional stages, esterification,
amidation in an autoclave, dehydration of the amide, and removal of the N-protecting group [2,3], which is not
always justified by far.
A second possible variant for obtaining esters of 1-substituted 4-amino-2-oxoquinoline-3-carboxylic
acids 1 is the alkylation of the previously isolated 1H-derivatives 3 (method B). As a result of lactam–lactim,
enamine–imine, and keto–enol tautomerism for esters 3 it is possible that five tautomeric forms exist (Scheme 2),
in which both nitrogen atoms, the oxygen of the 2-C=O group, or the carbon atom at position 3 of the quinoline
ring may potentially be nucleophilic centers.
We noted previously [4] that the properties of the 4-amino group in esters 3, judging by the chemical
1
shift of its protons in the H NMR spectrum (8.3 ppm), are far closer to an amide than to a normal amine (for
example, for anilines the mean value is ~4 ppm [6]). It is also known that in 1H-4-amino-2-oxo-3-
phenylquinolines alkylation of the 4-amino group (chemical shift 5.9 ppm) is successfully effected only in the
_______
* For Part 85 see [1].
__________________________________________________________________________________________
National University of Pharmacy, Kharkov 61002, Ukraine; e-mail: uiv@kharkov.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1355-1361, September, 2005. Original article submitted
April 6, 2004.
0009-3122/05/4109-1151©2005 Springer Science+Business Media, Inc.
1151

Scheme 1
–
Cl
NH2
Cl
O
O
N
O
O
+
OR2
OR2
+
1
N
R
12
O
N
H
N
R
R-I (Br),
DMF, K2CO3
9
10
HCl,
100°C,
15 min
Py, reflux 8 h
OH
O
O
OR 2
C:
POCl3
NH
Cl
O
O
N
OR2
OR2
R
H2N-Bzl
R1
7
N
R
O
N
R
O
R1
R1
8
11
NH3, 70°C, 5 h
HCl, 100°C, 2 min
NH2
O
O
NH2
O
NH2
O
B: R-I (Br),
OR2
OR2
DMF, K2CO3
OR 2
+
N
H
N
OR
N
R
O
3
R1
6
1a–g
A: R-I, DMF,
K2CO3
EtONa, EtOH
N
NH2
N
N
ClOCCH2COOEt
2
NH
NCOCH2COOEt
R
R
5
4
1 a R = Me, b R = C3H7, c R = C6H13, d R = C7H15, e R = C8H17, f R = Ph, g R+R1 = –(CH2)3–;
a-f R1 = H; a, b, f, g R2 = Et, c-e R2 = Me
presence of very strong bases (potassium hexamethyldisilazide) and only after introducing a 1-N protecting
group [2]. Consequently on alkylating esters 3 in the system DMF–K2CO3 the 4-amino group may be excluded
from the number of probable targets for electrophilic attack. Due to steric difficulties the formation of 3-alkyl
derivatives is also not very likely. Experiments carried out by us show that on interacting esters 3 with alkyl
halides the 4-amino group is indeed not affected. Two types of reaction product are formed, viz. the desired
1152

Scheme 2
NH2
O
O
NH2
O
NH
O
OR2
OR2
OH
OR2
N
H
OH
N
N
3
3b
3a
NH
O
NH
O
OR2
OR2
OH
O
N
H
N
H
3c
3d
1-N-alkyl derivatives 1 and esters of 4-amino-2-alkoxyquinoline-3-carboxylic acids 6 isomeric with them. The
higher yields of the latter indicate the significant contribution of the 4-amino-2-hydroxy form 3a to the
resonance hybrid of esters 3 in an alkaline medium.
In view of the above arguments a different approach to the synthesis of amino esters 1 seemed of
interest, based on the use of the easily accessible ethyl esters of 1-substituted 4-hydroxy-2-oxoquinoline-3-
carboxylic acids 7 [7]. Modification of the 4-hydroxy substituent of such compounds into a primary amino
group, theoretically at least, is not inconsistent. Several practical procedures are known for such a conversion.
First of all, there is direct replacement of a 4-hydroxy group by NH2 by the reaction of 3-R-4-hydroxyquinol-2-
ones with benzylammonium chloride at 300°C [8]. With benzylamine a similar reaction occurs under
comparatively mild conditions (180°C), but leads only to 4-benzylaminoquinolone and only subsequent catalytic
hydrogenation gives 4-amino derivatives [9]. It is evident that the methods given are unsuitable for obtaining
amino esters 1 because of the thermal instability of the initial 4-hydroxy derivatives 7 [10] in the first case, and
the high reactivity of their ester groupings [11] in the second, and consequently were not considered by us.
TABLE 1. Characteristics of Esters of 1-R-4-Amino-2-oxoquinoline-3-
carboxylic Acids 1a-g
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °С
C
H
N
1a
1b
1c
1d
1e
1f
C13H14N2O3
63.31
63.40
5.85
5.73
11.51
11.38
173-175
(ethanol)
83 (C)
46 (A)
72 (C)
70 (C)
35 (B)
87 (C)
81 (C)
C15H18N2O3
C17H22N2O3
C18H24N2O3
C19H26N2O3
C18H16N2O3
C14H14N2O3
65.50
65.68
6.79
6.61
10.10
10.21
154-156
(ethanol)
67.66
67.53
7.47
7.33
9.15
9.26
137-139
(methanol)
68.28
68.33
7.54
7.65
8.93
8.85
133-135
(methanol)
69.22
69.06
7.81
7.93
8.62
8.48
136-138
(methanol)
70.29
70.12
5.34
5.23
9.16
9.09
215-217
(ethanol)
1g
65.18
65.11
5.37
5.46
10.76
10.85
237-239
(ethanol)
1153

1
TABLE 2. H NMR Spectra of Esters of 1-R-4-Amino-2-oxoquinoline-3-
carboxylic Acids 1a-g
Chemical shifts, δ, ppm
Com-
pound
Н arom.
Н-8 Н-7
(1Н, d) (1Н, d) (1Н, t) (1Н, t)
4-NH2
(2H, s)
R
R2
Н-5
Н-6
1a
1b
1c
8.00
7.99
8.06
8.15
8.14
8.17
7.41
7.41
7.39
7.64
7.62
7.65
7.21
7.22
7.20
3.46 (3Н, s, NCH3)
4.21 (2Н, q,
ОСН2); 1.19
(3Н, t, CH3)
4.02 (2Н, t, NCH2);
1.54 (2Н, m, NCH2СН2);
0.90 (3Н, t, CH3)
4.20 (2Н, q,
ОСН2); 1.20
(3Н, t, CH3)
4.09 (2Н, t, NCH2);
1.53 (2Н, q, NCH2СН2);
1.30 (6H, m, CH2)3CH3);
0.85 (3Н, t, CH3)
3.73 (3Н, s,
ОСН3)
1d
1e
8.07
8.07
8.16
8.16
7.39
7.39
7.63
7.64
7.19
7.20
4.07 (2Н, t, NCH2);
3.71 (3Н, s,
ОСН3)
1.52 (2Н, q, NCH2СН2);
1.21 (8H, m, (CH2)4CH3);
0.80 (3Н, t, CH3)
4.06 (2Н, t, NCH2);
3.77 (3Н, s,
ОСН3)
1.51 (2Н, q, NCH2СН2);
1.22 (10H, m, (CH2)5CH3);
0.83 (3Н, t, CH3)
1f
8.36
7.98
8.20
7.93
6.36
7.64-7.10
(7Н, m,
Н-7,6 + N–C6H5)
see. Н-7 and Н-6
4.18 (2Н, q,
ОСН2); 1.21
(3Н, t, CH3)
1g
—
7.38 (d)
7.07
3.87 (2Н, t, NCH2);
2.84 (2Н, t,
NCH2CH2СН2);
1.87 (2H, q,
4.20 (2Н, q,
ОСН2); 1.23
(3Н, t, CH3)
NCH2CH2СН2)
It is more preferred to convert the 4-hydroxy esters 7 into chloro derivatives 8, the synthesis of which is
also possible by alkylating 1H-4-chloro-2-oxoquinolines 9 [12]. Nucleophilic substitution of the chlorine atom in
these compounds under the action of primary and secondary alkyl- and arylamines occurs readily [13]. However
ammonia does not react, after passing dry gaseous ammonia into a solution of chloro-substituted ester 8 in
alcohol or DMF for 5 h only the starting material was isolated. At atmospheric pressure such a replacement was
successfully effected only for the highly reactive 4-chloro-3-nitroquinol-2-ones [14], while in the remaining
cases treatment with ammonia in an autoclave is necessary [8]. This is not acceptable for the synthesis of amino
esters 1 due to the inevitable amidation of the alkoxycarbonyl group.
Another method giving no positive result is that used successfully by us for the synthesis of esters of 1H-
4-amino-2-oxoquinoline-3-carboxylic acids 2, which was the treatment of N-(1H-3-alkoxycarbonyl-2-
oxoquinolin-4-yl)pyridinium chlorides with alkyl- or arylamines [4]. It turned out that, unlike the 1H-derivative,
the ethyl esters of 1-alkyl-4-chloro-2-oxoquinoline-3-carboxylic acids 8 did not form the corresponding
quaternary salts 10 with pyridine.
Nevertheless replacement of a chlorine atom in esters 8 by a primary amino group was successfully
effected, although indirectly, through the 4-benzylamino derivatives 11. Catalytic hydrogenation [9, 15] or
catalyzed acid hydrolysis [16, 17] are most frequently used in organic chemistry to remove benzyl
protection.The first method as a rule is fairly extended in time (6-12 h) and moreover unsafe. On the other hand
hydrolysis of 1-R-3-alkoxycarbonyl-4-benzylamino-2-oxoquinolines 11 with conc. HCl occurs in 2 min. It is
interesting to note that the ester group is not affected by this. It is however necessary to take into account the fact
that too extended a treatment of 4-benzylaminoquinolones 11 with boiling conc. HCl is accompanied not
1154

only by debenzylation but also by decomposition of the alkoxycarbonyl group with the formation of
1
1-R-4-amino-2-oxoquinolines 12. After 15 min their content in the mixture, judging by the H NMR spectrum,
amounted to ~40% in relation to esters 1. The whole chain of conversions of 4-hydroxy esters 7 into the final
4-amino derivatives 1 (method C) is readily effectable without isolating the intermediate 4-chloro- and
4-benzylaminoquinolones. Apart from the mentioned hydrogenation and acid hydrolysis used by us the final
stage where necessary may be carried out by any other suitable method. Choices of N-debenzylating agent and
the conditions for using them are fairly wide [18-25], which on the whole makes the proposed method practically
universal and enables it to be recommended as a practical method.
EXPERIMENTAL
1
The H NMR spectra of the synthesized compounds were recorded on a Varian Mercury VX 200
(200 MHz) instrument, solvent was DMSO-d6, internal standard TMS.
4-Amino-2-oxo-1-propylquinoline-3-carboxylic Acid Ethyl Ester (1b). 1-Iodopropane (6.83 ml,
0.07 mol) was added to a mixture of anthranilonitrile 2 (5.91 g, 0.05 mol) and anhydrous K2CO3 (13.8 g,
0.1 mol) in DMF (80 ml) and the mixture stirred for 5 h at 90°C. The mixture was cooled, and diluted with
water. The precipitated oily residue of N-propylanthranilonitrile 4 was extracted with CH2Cl2 (3 × 50 ml). The
organic extracts were combined, the solvent distilled off, and the residue chromatographed on a column (silica
gel L 100/250) in the solvent system CH2Cl2–hexane, 3:1.
N-Propylanthranilonitrile 4 Rf 0.60; (Silufol UV 254, CH2Cl2–hexane, 3:1); initial anthranilonitrile 2
(under the same conditions) Rf 0.31. The obtained N-propylanthranilonitrile 4 (4.25 g, 0.026 mol) was dissolved
in CH2Cl2 (50 ml), triethylamine (4.2 ml, 0.03 mol) was added, and then ethoxymalonyl chloride (4.52 g,
0.03 mol) was added in small portions with stirring and cooling. After 4-5 h the reaction mixture was poured into
cold water (100 ml), thoroughly stirred, and transferred to a separating funnel. The organic layer was separated,
dried over CaCl2, and the solvent removed, finally at reduced pressure. A solution of sodium ethylate, from
metallic sodium (1.15 g, 0.05 mol) and absolute ethanol (50 ml), was added to the residue of anilide 5 and the
mixture boiled for 1 h (use of sodium methylate in methanol as basic catalyst is accompanied by
transesterification). The mixture was cooled, and poured into water (200 ml). The precipitated solid amino ester
1b was filtered off, washed with water, and dried. Yield 6.34 g (46% calculated on anthranilonitrile 2).
4-Amino-1-octyl-2-oxoquinoline-3-carboxylic Acid Methyl Ester (1e). B. Amino ester 3 (R2 = Me)
was alkylated with 1-bromooctane by the procedure in the previous experiment, reaction time was 8 h. At the
end of the reaction the mixture was poured into water, and the alkylation products extracted with CH2Cl2. The
unreacted amino ester 3 (~7%) is separated in the residue insoluble in CH2Cl2. It was filtered off and dried. The
solvent was distilled from the filtrate, hexane was added to the residue, the mixture was rubbed thoroughly, and
filtered. The solid on the filter (amino ester 1e) was washed several times with hexane, and dried. Yield was
35%.
4-Amino-2-octyloxyquinoline-3-carboxylic Acid Methyl Ester (6, R = C8H17, R2 = Me). The hexane
filtrate remaining after separation of amino ester 1e (see previous experiment) was purified with carbon, after
1
which the solvent was removed. Ester 6 was obtained as a light yellow oily liquid. Yield 52%. H NMR
spectrum, δ, ppm: 8.14 (1H, d, H-5); 7.71 (2H, s, NH2); 7.55 (1H, t, H-7); 7.45 (1H, d, H-8); 7.23 (1H, t, H-6);
4.25 (1H, t, OCH2); 3.76 (3H, s, COOCH3); 1.64 (2H, q, OCH2CH2); 1.35 (2H, q, OCH2CH2CH2); 1.13 [8H, m,
(CH2)4CH3]; 0.76 (3H, s, CH3). Found, %: C 69.10; H 7.78; N 8.64. C19H26N2O3. Calculated, %: C 69.06;
H 7.93; N 8.48.
4-Amino-1-methyl-2-oxoquinoline-3-carboxylic Acid Ethyl Ester (1a). C. A solution of 4-hydroxy-1-
methyl-2-oxoquinoline-3-carboxylic acid ethyl ester (7) (2.47 g, 0.01 mol) in POCl3 (15 ml) was boiled for 2 h.
The excess of POCl3 was distilled off, finally at reduced pressure. The residue was treated with a mixture of ice
and water. After decomposing the POCl3, Na2CO3 was added to the reaction mixture to pH 8 in the aqueous
1155

layer. The separated 4-chloro substituted ester 8 may be filtered off and characterized. However it is more
expedient to extract it with CH2Cl2 (3 × 30 ml). The pH of the aqueous layer was checked and Na2CO3 was
added if necessary. The solvent was removed, and to the residue were added ethanol (30 ml), benzylamine
(1.31 ml, 0.012 mol), and triethylamine (1.4 ml, 0.01 mol), and the mixture boiled for 5 h. The reflux condenser
was changed to a downward condenser and the alcohol was distilled off. The obtained 4-benzylaminoquinolone
11 may also be separated in the pure state [13]. If there is no need the reaction mixture is treated with water, and
the resulting 4-benzylaminoquinolone 11 extracted with CH2Cl2 (3 × 30 ml). The organic extracts were
combined, washed with water, and the solvent distilled. Conc. HCl (15 ml) was added to the residue, rapidly
heated to boiling, boiled for 2 min, after which the mixture was poured directly into cold water. The reaction
mixture was neutralized with Na2CO3. After several hours the precipitated solid 4-amino ester 1a was filtered
off, washed with water, and dried. Yield 2.04 g (83%).
The esters of 1-substituted 4-amino-2-oxoquinoline-3-carboxylic acids 1c,d,f,g were obtained
analogously (Tables 1 and 2).
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