Reaction of 3-benzoyl-2,3-dibromo-propionic acid with substituted ortho-phenylenediamines

Article abstract of DOI:10.1023/A:1022697628823

3-Benzoyl-2,3-dibromopropionic acid reacts with 4-substituted o-phenylenediamines to give 3-aryl-2-carboxymethylene-1,2-dihydroquinoxalines.

Full text of DOI:10.1023/A:1022697628823

Chemistry of Heterocyclic Compounds, Vol. 38, No. 12, 2002
REACTION OF 3-BENZOYL-2,3-DIBROMO-
PROPIONIC ACID WITH SUBSTITUTED
ortho
-PHENYLENEDIAMINES
N. N. Kolos, T. V. Berezkina, V. D. Orlov, Yu. N. Surov, and I. V. Ivanova
3-Benzoyl-2,3-dibromopropionic acid reacts with 4-substituted o-phenylenediamines to give 3-aryl-2-
carboxymethylene-1,2-dihydroquinoxalines.
Keywords: 3-aryl-2-carboxymethylene-1,2-dihydroquinoxalines, 3-benzoyl-2,3-dibromopropionic acid,
4-R-o-phenylenediamines.
In continuation of our work on the reaction of polyelectrophilic systems with bidentate nucleophiles [1],
we have studied the reaction of 3-benzoyl-2,3-dibromopropionic acid (1) with 4-substituted
o-phenylenediamines 2a-g. By refluxing the starting reagents in alcohol in the presence of triethylamine as
dehydrobrominating agent acid 1 gives the geminally activated olefins 3 and 4 and these can act as
polyfunctional building units in reaction with diamines 2a-g. This can result in the possible formation of a series
of reaction products, the most likely of which are dihydroquinoxalines 5, benzodiazepines 6, and quinoxalines 7.
A negative test for the diazotropylium cation in the reaction products (absence of a violet coloration
upon treatment with concentrated sulfuric acid) allows one to exclude the diazepine structure 6.
Phenacylidenequinoxaline 7 (R1 = R2 = H) has been prepared before [2] from benzoylpyruvic acid and
1
o-phenylenediamine but its parameters (mp, H NMR data) do not agree with the parameters for compound 5a
(Tables 1 and 2).
The combined spectroscopic data for the obtained products (Table 2) allows us to assign them the
structure of dihydroquinoxalines 5.
1
In their H NMR spectra (measured in DMSO-d6 solutions) a singlet for the C=CH group proton, two
singlets at 12.0 and 13.0 ppm which disappear in conditions of deuterium exchange and which we assign to the
NH and OH group signals respectively, and also multiplets for the aromatic protons at 7.0-8.1 ppm are observed.
The presence of substituents in the molecules of diamines 2b-g suggests the formation of isomeric
1
6- and 7- substituted dihydroquinoxalines 5b-k. In fact, the H NMR spectra of the products obtained from
diamines 2b-d,f show a doubling of the signal for the =CH group proton and for the signals of the OH and NH
group protons.
The isomeric ratio was calculated by a comparison of the integrated intensities of these signals and also
integration of the signals for the aromatic protons in positions 5 and 8 of the indicated products. It did not prove
possible to separate the isomeric dihydroquinoxalines 5b and 5h, 5c and 5i, 5d and 5j, or 5f and 5k using the
TLC method. The reaction of acid 1 with diamine 2e led to only the 5-nitro isomer 5e.
__________________________________________________________________________________________
V. N. Karazin National University, Kharkov 61077, Ukraine; e-mail: orlov@univer.kharkov.ua.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1690-1695, December, 2002. Original
article submitted September 20, 2000; revision submitted June 28, 2001.
0009-3122/02/3812-1491$27.00©2002 Plenum Publishing Corporation
1491

H
H H
Et3N
Ph–C–C=C–COOH
Ph–C–C–C–COOH
2a–g
O
4
O
Br
Br
Br
1
Ph
R1
R2
H
R1
N
Ph–C–C=C–COOH
N
R
O
Br
3
N
H
6
N
H
COOH
1
R
NH2
COOH
7
2
2a
R
NH2
H
2b–g
N
O
O
R1
R2
5a
+
N
Ph
N
H
8
C
O
N
H
CH
OH
5b–k
H
H
Ph–C–C–C–COOH
2a
5a
+
O
Cl
Br
9
2 a R1 = H, b R1 = 4-Cl, c R1 = 4-Br, d R1 = 4-CN, e R1 = 3-NO2, f R1 = 4-Me, g R1 = 4-Me, a-f R2 = H, g R2 = 5-Me;
5 a R1 = H, b R1 = 6-Cl, c R1 = 6-Br, d R1 = 6-CN, e R1 = 5-NO2, f R1 = 6-Me, g R1 = 6-Me, h R1 = 7-Cl,
i R1 = 7-Br, j R1 = 7-CN, k R1 = 7-Me, a-f, h-k R2 = H, g R2 = 7-Me
The UV spectra of compounds 5a,e,g and the mixtures of isomers 5b,h, 5c,i, and 5f,k were measured in
2-propanol and showed intense absorption bands at 270-440 nm (Table 2). Dihydroquinoxalines 5 obtained
luminesce in methanol solutions and in the solid phase but, in contrast to 3-aryl-1,2-dihydroquinoxalines [3],
they are stable on storage in air.
The IR spectra of compounds 5 (KBr tablets) show bands for a C=CH group near 1620, carbonyl group
in the region of 1680-1695, and a broad band at 3000-3100 cm-1 which we assign to an associated hydroxyl
group. In CCl4 solutions they show bands for the secondary amino group (see Table 2) as well as three bands in
the region for carbonyl absorption. The high-frequency band in the latter is assigned to the free carboxyl group
while that at low frequency is very likely related to the formation of dimeric associates in the products 5a-k.
It should be noted that the IR spectrum of acid 1 in CCl4 shows bands for the free and bound hydroxyl
groups (νOHfree 3538, νOHbound (br.) 3066 cm-1) as well as three bands for the carbonyl absorption at 1679 (benzoyl
fragment absorption), 1709, and 1743 cm-1 (carboxyl group cyclic dimer and monomer respectively). These data
point to the retention of the carboxyl group in the molecules 5a-k. The presence of a certain amount of the
monomer form in the solution is confirmed by the appearance of absorption band due to stretching vibrations for
a free hydroxyl group in compounds 5a, 5b,h, 5c,i, and 5e. Thus, from the IR spectroscopic data for compounds
5a-k follows that they are characterized by the formation of dimers at the carboxyl group (structure A) and not
intramolecular associates (B). This shows that the compounds obtained are in the E-isomer form.
N
Ph
N
Ph
Ph
N
HO
O
O
CH
C
N
H
C
H
C
H
C
N
H
C
N
H
OH
O
OH
A
B
1492

TABLE 1. Characteristics for the Compounds Synthesized
Empirical
formula
Found, %
Compound
——————
mp, °С
Yield, %
Calculated, %
С16Н12N2O2
C16H11ClN2O2
C16H11BrN2O2
C17H11N3O2
С16H11N3O4
C17H14N2O2
C18H16N2O2
10.57
10.59
222-224
283-285
228-230
288-290
259-260
282-284
270-272
45*
62
64
60
56
40
48
5а
9.39
5b+5h
5c+5i
5d+5j
5е
9.38
8.18
8.16
14.52
14.53
13.59
13.59
10.09
5f+5k
5g
10.07
9.58
9.58
_______
* Yield using method A.
According to the data in Table 2, electron acceptor substituents in position 6 cause a related shift to low
field for the vinyl bond C=CH protons whereas the opposite effect is observed for the hydroxyl group proton
signals. Donor substituents raise the acidity of the carboxyl group and acceptors lower it, while for the
7-isomers the acidity is lower (Table 2). This can be explained by a competitive interaction of the imino
nitrogen atom with two π-electronic fragments: the substituted phenyl ring and the C=CH–COOH group. Hence
the introduction of acceptor substituents into the aromatic ring leads to a weakening of the interaction of the
nitrogen atom unshared electron pair with the multiple bond and this is accompanied by a lowering of the
acidity.
The yields of the products 5a-k are low and, in the case of diamine 2a, 3-phenacylquinoxal-2-one (8)
was obtained along with compound 5a. The compound 8 was identified by comparison with characteristics of a
previously reported product [1]. We associate its formation with the reduction of the intermediate bromoolefin
to benzoylacrylic acid in the presence of triethylamine which takes part as a reductant (as is known for activated
olefins [4]).
The formation of olefin 3 in the reaction of acid 1 with diamines 2a-g points above all to the high
regioselectivity of the dehydrobromination process. A conjugative addition at the β-position of the olefin 3 is
subsequently observed with cyclization and dehydrobromination leading to dihydroquinoxalines 5a-k. Such a
route for the dehydrobromination process is confirmed by the formation of compound 5a also in the reaction of
3-bromobenzoyl-2-chloropropionic acid with diamine 2a where the intermediate compound is 3-benzoyl-2-
chloroacrylic acid.
The possibility of ipso-substitution in the intermediate bromoolefin 3 is, to us, less likely on the basis of
the values of the charges on the carbon atoms of the ethylene fragment and the LUMO energy values as
obtained by the AM1 method (Table 3).
Product 5a is also formed under conditions of direct nucleophilic substitution (the reaction being carried
out at 20-25°C without triethylamine). Evidently, in this case, substitution of the bromine atom in the β-position
of acid 1 occurs with subsequent cyclization.
Hence, in the reaction discussed, a change in the direction of the nucleophilic addition of aromatic
amine is observed when compared with the direction in the reaction previously studied by us for amines and
benzoylacrylic acid [1] and this is due to the increased electrophilicity of the β-carbon atom in the intermediate
olefin 3.
1493

TABLE 2. Spectroscopic Characteristics for the Compounds Synthesized
Isomer content,
%
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm
UV spectrum,
Com-
propan-2-ol,
pound
C=O
(in CCl4)
N–H
OH
H arom.,
m
C=C
λmax, nm (ε·10-4)
ОН, s
NH, s
=CH, s
6.83
6
7
(KBr)
(in KBr)
1687
(in CCl4) (in KBr) (in CCl4)
1615
1610
1610
1620
1618
1610
1615
1682, 1702, 1742
1684, 1702, 1743
1687, 1701, 1747
1682, 1702, 1742
1687, 1712, 1742
1682, 1702, 1742
1677, 1700, 1742
3403
3399
3402
3393
3343
3402
3403
3086
3099
3112
3085
3118
3113
3098
3566
3528
3533
439 (14.9); 416 (17.1);
254 (9.2)
13.67
12.08 br.
12.10 br.
12.12 br.
7.16-8.00
7.10-8.00
7.26-8.00
7.19-8.10
7.28-8.00
6.97-8.00
6.91-7.90
—
45
30
20
*
—
55
70
80
—
75
—
5а
1691
1692
1692
1695
1692
1683
438 (19.1); 415 (22.5);
13.53,
13.38
6.85,
6.83
6.85,
5b+5h
5с+5i
5d+5j
5е
270 (7.8)
439 (14.0); 416 (16.4);
270 (5.9)
13.51,
13.37
6.83
6.91,
6.86
428 (17.1); 407 (20.1);
13.33,
13.26
13.43
12.30,
12.16
264 (7.9)
3523
440 (19.2); 385 (12.9);
283 (17.1)
11.10
12.02
11.94
6.88
448 (15.4); 423 (17.9);
13.71,
13.80
13.83
6.82,
6.78
6.77
25
—
5f+5k
5g
272 (6.4)
454 (22.9); 428 (26.7);
253 (12.9)
_______
* 100% 5-Nitro isomer.

TABLE 3. Effective Charges on the Ethylene Carbon Atoms and LUMO
Energies
Br
Br
H
H
Ph–C–C=C–COOH
Ph–C–C=C–COOH
β α
β α
O
O
3
4
LUMO Energy,
Compound
Atom
Charge
a.u.
-0.139
-0.106
-0.110
0.183
-0.0506
-0.3678
3
4
α
β
α
β
EXPERIMENTAL
1H NMR spectra were recorded on a Varian VXR-300 (300 MHz) instrument using DMSO-d6 and TMS
as internal standard. IR spectra were obtained on a Specord IR-75 spectrometer for KBr tablets and solutions in
CCl4. UV spectra were taken on a Hitachi U-3210 apparatus for solutions in propan-2-ol. Monitoring of the
course of the reaction and the purity of the products was carried out using TLC on Silufol UV-254 plates in the
system methanol–chloroform (1:3).
3-Benzoyl-2,3-dibromopropionic Acid (1). Solution of bromine (6.1 g, 38 mmol) in glacial acetic acid
(10 ml) was added dropwise with stirring and at room temperature to solution of β-benzoylacrylic acid (6.8 g,
38 mmol) in glacial acetic acid (50 ml). Stirring was continued to full disappearance of the color. The reaction
mixture was poured onto ice. The precipitate formed was filtered off and crystallized from toluene to give acid 1
(10.4 g, 80%); mp 143°C. IR spectrum (KBr tablet), ν, cm-1: 3550 (OH), 1685 (C=O), 1670 (C=O).
3-Benzoyl-3-bromo-2-chloropropionic Acid (9). N-Bromosuccinimide (2.8 g, 17 mmol) and
concentrated hydrochloric acid (3.4 ml) were added to solution of β-benzoylacrylic acid (3.0 g, 17 mmol) in
acetic acid (40 ml). The mixture was stirred for 24 h, poured onto ice, and the precipitated product obtained was
1
filtered off to give acid 9 (3.23 g, 66%); mp 137°C. H NMR spectrum, δ, ppm, J (Hz): 8.17 (2H, d, J = 8.3,
o-HPh); 7.75 (1H, p-HPh); 7.60 (2H, m, J = 8.3, m-HPh); 5.92 (1H, d, J = 10.5, CH); 4.86 (1H, d, J = 10.5, CH);
4.70 (1H, s, OH).
2-Carboxymethylene-3-phenyl-1,2-dihydroquinoxaline (5a). A. Solution of acid 1 (1.30 g, 3.8 mmol)
and triethylamine (0.5 ml) in ethanol (12 ml) was refluxed for 20 min, diamine 2a (0.42 g, 3.8 mmol) was then
added, and the reaction mixture was held for 40 min on a water bath at 70-80°C. The precipitate formed was
crystallized from ethanol–dimethylformamide to give the product 5a (0.40 g). Evaporation of the mother liquor
to one third gave 3-phenacylquinoxal-2-one (8) (0.33 g, 33%); mp 171°C (mp 171°C [1]). Compound 8 does not
give a depression of melting point when mixed with a previously known sample.
Compounds 5b-k were prepared similarly.
B. Solution of acid 9 (0.61 g, 2.10 mmol) and diamine 2a (0.23 g, 2.10 mmol) in ethanol (7-10 ml) was
refluxed for 20 min. The precipitate formed was crystallized from ethanol to give the product 5a (0.13 g, 26%).
C. Solution of acid 9 (1.0 g) and diamine 2a (0.3 g) in ethanol (10 ml) was stirred for 2 h at room
temperature using a magnetic stirrer and the reaction mixture was further held at the same temperature for
12-15 h to give compound 5a (0.26 g, 34%).
1495

REFERENCES
1.
2.
N. N. Kolos, A. A. Tishchenko, V. D. Orlov, T. V. Berezkina, S. V. Shishkina, and O. V. Shishkin,
Khim. Geterotsikl. Soedin., 1407 (2001).
Yu. S. Andreichikov, S. G. Pitirimova, R. F. Saraeva, V. L. Gein, G. D. Plakhina, and L. A. Voronova,
Khim. Geterotsikl. Soedin., 407 (1978).
N. N. Kolos, B. Insuasti, Kh. Kiroga, and V. D. Orlov, Khim. Geterotsikl. Soedin., 1127 (1986).
G. S. Kaitmazova, N. P. Gambaryan, and E. M. Rokhlin, Usp. Khim., 58, 2011 (1989).
3.
4.
1496