4-hydroxy-2-quinolones. 169. Synthesis and bromination of 1-allyl-3-(arylamino- methylene)quinoline-2, 4-(1H, 3H)-diones

Article abstract of DOI:10.1007/s10593-010-0412-6

Bromination of 1-allyl-substituted 3-(arylaminomethylene)quinoline-2, 4-(1H, 3H)-diones with one equivalent of molecular bromine in glacial acetic acid and subsequent dilution of the reaction mixture with water is accompanied by halocyclization and hydrol

Full text of DOI:10.1007/s10593-010-0412-6

Chemistry of Heterocyclic Compounds, Vol. 45, No. 10, 2009
4-HYDROXY-2-QUINOLONES. 169*. SYNTHESIS
AND BROMINATION OF 1-ALLYL-3-(ARYLAMINO-
METHYLENE)QUINOLINE-2,4-(1H,3H)-DIONES
I. V. Ukrainets1**, Liu Yangyang1, N. L. Bereznyakova1, and A. V. Turov2
Bromination of 1-allyl-substituted 3-(arylaminomethylene)quinoline-2,4-(1H,3H)-diones with one
equivalent of molecular bromine in glacial acetic acid and subsequent dilution of the reaction mixture
with water is accompanied by halocyclization and hydrolysis to form 2-bromomethyl-5-oxo-1,2 dihydro-
5H-oxazolo[3,2-a]quinoline-4-carbaldehyde.
Keywords: 1-allyl-3-(arylaminomethylene)quinoline-2,4-(1H,3H)-diones, 1-allyl-4-hydroxy-2-oxo-
1,2-dihydroquinoline-3-carbaldehyde, enamines, oxazolo[3,2-a]quinolines, Schiff bases, bromination,
halocyclization.
As we have shown previously Schiff bases obtained by reaction of 1R-4-hydroxy-2-oxo-
1,2 dihydroquinoline-3-carbaldehydes with anilines exist exclusively in the enamine tautomer form. The
3-(arylaminomethylene)quinoline-2,4-(1H,3H)-diones synthesized in this way do not react with thioglycolic
acid and its esters. It was concluded that they were unable to form azomethines, i.e. 4-hydroxy-2-oxo- or
2-hydroxy-4-oxo forms [2]. In fact, this structural feature served as the reason for its involvement in the scope of
our work on the bromination of ortho-allyl-substituted oxoheterocycles [3-7] and 1-allyl-3-(aryl-
aminomethylene)quinoline-2,4-(1H,3H)-diones 1a,b. Their preparation used the tested [8] synthetic scheme of
ester 2 → hydrazide 3 → β-N-tosylhydrazide 4 → aldehyde 5 → enamines 1. It should be noted that an
alternative method including fusion of equimolar amounts of ester 2 and p-toluenesulfonylhydrazide at 140ºC
proved unacceptable. In this case the tendency for decomposition of the p-toluenesulfonylhydrazide affected not
only the yield of the final product but also its composition. Along with the target 1-allyl derivative 4 there was
formed the 1-propyl analog 6, the ratio of the β-N-tosylhydrazides 4 and 6 in the reaction mixture being 1:1
1
from H NMR spectroscopy. Under the indicted conditions it was clear that a significant part of the
p-tolylsulfonylhydrazide decomposed with evolution of diimide [9, 10] which, correspondingly, was actually
responsible for partial reduction of the allyl double bond.
_______
* For Communication 168 see [1].
** To whom correspondence should be addressed, e-mail: uiv@kharkov.ua.
1National University of Pharmacy, Kharkiv 61002, Ukraine.
2Taras Shevchenko National University, Kiev 01033, Ukraine, e-mail: nmrlab@univ.kiev.ua.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.10, pp. 1539-1545, October, 2009.
Original article submitted December 18, 2008.
0009-3122/09/4510-1235©2009 Springer Science+Business Media, Inc.
1235

The same process also occurs under milder conditions, e.g. in refluxing ethanol, the only difference
being that the carbethoxy group of ester 2 is not affected overall but the N-allyl fragment is reduced to propyl by
78% with the same equimolar ratio of reagents. Most of all, introduction of a small amount of
p-toluenesulfonylhydrazide as source of diimide can achieve a 100% conversion of ester 2 to 3-ethoxycarbonyl-
4-hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline [7]. Reactions of this type were, however, outside the terms of
our investigation and were not investigated further.
OH
O
OH
O
H
N
OEt
N
Ts
H
N
O
N
O
C3H7
7
C3H7
6
+
H2NNH–Ts, EtOH
OH
O
OH
O
OH
N
O
O
H2NNH–Ts,
140°C
HOCH2CH2OH,
Na2CO3, 160°C
H
N
N
OEt
Ts
H
H
N
O
N
O
4
2
5
Ts–Cl
Ar–NH2
H NNH H2O
.
2
2
O
N
O
N
HN
O
OH
O
O
R
NH2
N
H
N
H
R
O
N
E-isomer
Z-isomer
3
1a,b
1. Br2, AcOH
2. H2O
O
O
H
N
O
Br
8
1 a R = 2-MeO-5-Cl, b R = 4-Br
1236

The 1-allyl-substituted 3-(arylaminomethylene)quinoline-2,4-(1H,3H)-diones 1a,b are formed in good
yields and are light yellow materials existing (at least in DMSO-d6) as the two geometric E- and Z- isomers with
a marked predominance of the former (see Experimental section). As in the case of 4-hydroxy-2-quinolones,
their bromination by molecular bromine in glacial acetic acid occurs very readily, the brown color of the
bromine disappearing almost instantly. It was interesting that dilution of both reaction mixtures gives the same
1
product in which the aniline fragment was absent (according to the H NMR spectrum). The mass spectrum
supported this conclusion, pointing to the presence in the compound formed of only one bromine atom which
can be the result of a later halocyclization.
For a convincing confirmation of the structure of the compound formed we have carried out
1
heteronuclear H–13C correlation experiments and also a NOESY experiment. Although the proton spectrum of
the sample analyzed shows the presence of a signal at 10.11 pm, the chemical shift of which is typical of an
13
aldehyde proton, the C NMR spectrum signal for the carbon atom bound to this atom appears at 186.1 ppm
which is somewhat less than might be anticipated for the carbonyl group of an aldehyde fragment. Hence a
reliable decision regarding the structure of the molecule could only be made on the basis of heteronuclear
correlation through one (HMQC method) or through 2-3 (HMBC method) chemical bonds. Table 1 shows the
cross peak coordinates seen in the corresponding 2D spectra.
Revealing the cross peaks allowed the identification of all of the carbon signals. The assignments made
in this way are given in the Scheme below. The presence of an oxazolidine fragment annelated to the quinoline
ring in the molecule is confirmed by the presence of cross peaks between the bridging C-3a atom with chemical
8.17
H
O
O
126.8
7.40
7.74
H
101.6
125.6
10.11
4.05
186.1
177.8
H
124.8
133.6
136.2
162.0
H
N
O
116.6
48.7
H
H
81.2
7.48
H
3.97
H
4.60
H
4.24
34.7
H
5.65
Br
NOE
1
TABLE 1. Full Listing of Heteronuclear H–13C Correlations Found for
the Oxazoloquinoline 8
Position of cross peaks in the 13C measurement 13
HMBC
С
1Н signal, δ, ppm
НМQC
10.11
8.17
7.74
7.48
7.40
5.65
4.60
4.24
4.05
3.97
186.1
126.8
133.6
116.6
124.8
81.2
162.0; 101.6; 177.8
177.8; 136.2; 133.6
136.2; 126.8
177.8; 133.6; 125.6; 124.8
177.8; 133.6; 125.6; 116.6
162.0; 34.7
162.0; 81.2; 34.7
162.0; 81.2; 34.7
48.7; 81.2
48.7
48.7
34.7
34.7
48.7; 81.2
1237

shift of 162.0 ppm and the proton signals for the N–CH2 methylene group and also the signal for the H-2 proton
positioned next to the heterocyclic oxygen atom. The localization of the aldehyde group was confirmed by cross
peaks found for the aldehyde proton and the neighboring C-3a, C-4, and C-5 atoms. Extremely suggestive in
terms of the molecular structure is the chemical shift of the C-4 atom at 101.6 ppm, being close to the position of
the signal for this atom in compounds with a related chemical structure [3-6].
The NOESY experiment showed that the signals for 1-CH methylene group located at 4.60 and 4.24 ppm
show a strong NOE with the aromatic protons signal at 7.48 pm. This infers that the given protons are close
together in space and hence the oxazolidine ring is annelated to the quinolone ring along the a edge such that the
studied compound is 2-bromomethyl-5-oxo-1,2-dihydro-5H-oxazolo[3,2-a]quinoline-4-carbaldehyde (8).
Dilution of the reaction mixture with water was carried out after the starting enamines 1a,b had reacted
with bromine. It therefore follows that heterocyclization clearly preceded hydrolysis. Other questions connected
with the processes appearing in our investigation remain open for now. None the less, the experimental data
obtained currently allows us to establish unambiguously that bromination of the 1-allyl-3-(arylamino-
methylene)quinoline-2,4-(1H,3H)-diones occurs via halocyclization to give oxazolo[3,2-a]quinolines.
EXPERIMENTAL
1
1H and 13C NMR Spectra for the oxazoloquinoline 8, H COSY NMR 2D spectroscopic experiments,
homonuclear Overhauser NOESY-2D, and also heteronuclear HMQC and HMBC experiments were recorded on a
Varian Mercury-400 spectrometer (400 and 100 MHz respectively). All 2D experiments were carried out with
1
2-3
gradient selection of useful signals. Mixing times in the pulse sequences were JCH = 140 and
J
CH
= 8 Hz. The
number of increments in the COSY and HMQC spectra was 128 and 400 in the HMBC spectra. The mixing time in
1
the NOESY-2D experiment was 500 ms. The H NMR spectra of the remaining compounds were recorded on a
Varian Mercury-VX-200 instrument (200 MHz). In all cases the solvent was DMSO-d6 with TMS as internal
standard. The mass spectrum of the oxazoloquinoline 8 was recorded on a Varian 1200L instrument in full scanning
mode in the range 35-700 m/z, 70 eV electron impact ionization, and direct sample introduction. The synthesis and
properties of 1-allyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid hydrazide (3) are given in [11].
1-Allyl-3-(5-chloro-2-methoxyphenylaminomethylene)quinoline-2,4-(1H,3H)-dione (1a). 5-Chloro-
2-methoxyaniline (1.57 g, 0.01 mol) was added to a solution of 1-allyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-
3-carbaldehyde (2.29 g, 0.01 mmol) in dry xylene (25 ml) and refluxed for 5 h distilling off the water formed as
an azeotrope with the xylene. The reaction mixture was cooled, diluted with hexane, and left in a freezer for
several hours. The light-yellow precipitate of enamine 1a formed was filtered off, washed with hexane, and
1
dried. Yield 3.12 g (85%); mp 163-165ºC (ethanol). H NMR spectrum, δ, ppm (J, Hz): 13.95 (0.61H, d,
J = 13.4, NH E-isomer); 12.92 (0.31H, d, J = 13.8, NH Z-isomer); 8.99 (0.66H, d, J = 13.4, =CH E-isomer);
8.95 (0.34H, d, J = 13.8, =CH Z-isomer); 8.08 (1H, dd, J = 7.8 and 1.2, H-5); 7.91 (0.66H, d, J = 2.1, H-6'
E-isomer); 7.86 (0.34H, d, J = 2.1, H-6' Z-isomer); 7.60 (1H, td, J = 7.7 and 1.5, H-7); 7.33-7.12 (4H, m,
H-6,8,3',4'); 5.91 (1H, m, CH=CH2); 5.11 (1H, d, J = 10.7, NCH2CH=CH cis); 5.04 (1H, d, J = 18.0,
NCH2CH=CH trans); 4.78 (2H, s, NCH2); 3.95 (1.98H, s, OCH3 E-isomer); 3.91 (1.02H, s, OCH3 Z-isomer).
Found, %: C 65.22; H 4.78; N 7.71. C20H17ClN2O3. Calculated, %: C 65.13; H 4.65; N 7.60.
1-Allyl-3-(4-bromophenylaminomethylene)quinoline-2,4-(1H,3H)-dione (1b) was prepared using the
method reported above. Yield 3.56 g (93%); mp 168-170ºC (ethanol). 1H NMR spectrum, δ, ppm (J, Hz): 13.73
(0.53H, d, J = 12.8, NH E-isomer); 12.65 (0.28H, d, J = 13.4, NH Z-isomer); 8.91 (0.61H, d, J = 12.8, =CH
E-isomer); 8.86 (0.39H, d, J = 13.4, =CH Z-isomer); 8.08 (1H, dd, J = 7.9 and 1.5, H-5); 7.68-7.52 (5H, m,
N-7,2',3',5',6'); 7.28 (1H, d, J = 8.2, H-8); 7.19 (1H, t, J = 7.5, H-6); 5.92 (1H, m, CH=CH2); 5.14 (1H, d,
J = 10.9, NCH2CH=CH cis); 5.06 (1H, d, J = 18.1, NCH2CH=CH trans); 4.79 (2H, s, NCH2). Found, %:
C 59.69; H 4.06; N 7.23. C19H15BrN2O2. Calculated, %; C 59.55; H 3.95; N 7.31.
1238

1-Allyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic
Acid
β-N-Tosylhydrazide
(4).
Triethylamine (1.54 ml, 0.011 mol) was added to a solution of hydrazide 3 (2.59 g, 0.01 mol) in dry DMF
(20 ml) followed, with stirring, by p-toluenesulfonyl chloride (2.1 g, 0.011 mol). The product was left for
10-12 h at room temperature and the reaction mixture was then diluted with cold water and acidified with dilute
HCl to pH 5. The precipitated β-N-tosylhydrazide 4 was filtered off, washed with water, and dried. Yield 4.00 g
1
(97%); mp 177-179ºC (DMF-ethanol). H NMR spectrum, δ, ppm (J, Hz): 15.75 (1H, br. s, OH); 11.54 (H, s,
CONH); 10.30 (1H, br. s, SO2NH); 8.06 (1H, dd, J = 7.8 and 1.5, H-5); 7.79 (1H, td, J = 7.9 and 1.5, H-7); 7.73
(2H, d, J = 8.3, H-2',6'); 7.52 (1H, d, J = 8.5, H-8); 7.40 (2H, d, J = 8.3, H-3',5'); 7.36 (1H, t, J = 7.8, H-6); 5.91
(1H, m, CH=CH2); 5.13 (1H, dd, J = 10.6 and 1.1, NCH2CH=CH cis); 4.97 (1H, dd, J = 17.2 and 1.1,
NCH2CH=CH trans); 4.86 (2H, m, NCH2); 2.38 (3H, s, Ar–CH3). Found, %: C 58.25; H 4.76; N 10.05.
C20H19N3O5S. Calculated, %: C 58.10; H 4.63; N 10.16.
1-Allyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (5). Anhydrous Na2CO3 (3.18 g,
0.03 mol) was added in one portion to a solution of β-N-tosylhydrazide 4 (4.13 g, 0.01 mol) in ethylene glycol
(20 ml) heated to 160ºC. (Caution, frothing!) Evolution of gas ceased after several minutes. The reaction
mixture was cooled, diluted with water, and acidified with HCl (1:1) to pH ~ 4. The precipitated aldehyde 5 was
filtered off, washed with cold water, and dried. Yield 2.15 g (94%); mp 84-86ºC (ethanol). 1H NMR spectrum, δ,
ppm (J, Hz): 10.08 (1H, s, CHO); 8.09 (1H, dd, J = 8.0 and 1.3, H-5); 7.78 (1H, td, J = 7.9 and 1.5, H-7); 7.46
(1H, d, J = 8.5, H-8); 7.33 (1H, t, J = 7.6 and 1.1, H-6); 5.92 (1H, m, CH=CH2); 5.13 (1H, dd, J = 10.4 and 1.3,
NCH2CH=CH cis); 5.02 (1H, dd, J = 17.4 and 1.3, NCH2CH=CH trans); 4.85 (2H, m, NCH2). Found, %:
C 68.23; H 4.95; N 5.98. C13H11NO3. Calculated, %: C 68.11; H 4.84; N 6.11.
2-Bromomethyl-5-oxo-1,2-dihydro-5H-oxazolo[3,2-a]quinoline-4-carbaldehyde (8). A solution of
bromine (0.52 ml, 0.01 mol) in glacial acetic acid (5 ml) was added with vigorous stirring to a solution of the
quinoline-2,4-dione 1a (3.68 g, 0.01 mol) in the same solvent (30 ml). The decolorization of the bromine was
virtually instantaneous. The reaction mixture was diluted with cold water and left for 12-14 h at room
temperature. The precipitated oxazoloquinoline 8 was filtered off, washed with water, and dried. Yield 1.87 g
(61%). When using the quinoline-2.4-dione 1b as starting material the yield was 57%. Mp 231-233ºC (ethanol).
1H NMR spectrum,δ, ppm (J, Hz): 10.11 (1H, s, CHO); 8.17 (1H, dd, J = 8.0 and 1.4, H-6); 7.74 (1H, td, J = 7.8
and 1.6, H-8); 7.48 (1H, d, J = 8.1, H-9); 7.40 (1H, td, J = 7.4 and 1.2, H-7); 5.65 (1H, m, NCH2CHO); 4.60
(1H, dd, J = 9.8 and 9.8, NCH); 4.24 (1H, dd, J = 9.8 and 6.6, NCH); 4.05 (1H, dd, J = 11.0 and 4.4, CHBr);
3.97 (1H, dd, J = 11.0 and 4.0, CHBr). 13C NMR spectrum, δ, ppm: 186.1 (CHO); 177.8 (5-C=O); 162.0 (C-3a);
136.2 (C-9a); 133.6 (C-8); 126.8 (C-6); 124.8 (C-7); 125.6 (C-5a); 116.6 (C-9); 101.6 (C-4); 81.2 (NCH2CH);
48.7 (NCH2); 34.7 (CH2Br). Mass spectrum, m/z (Irel, %): 309/307 [M]+ (7.6/8.2), 281/279 [M-CHO]+
(100.0/79.4), 199 [M-CHO-HBr]+ (5.8). Found, %: C 50.33; H 3.39; N 4.66. C13H10BrNO3. Calculated, %:
C 50.67; H 3.27; N 4.55.
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