The reaction of benzoylacrylic acid with ortho-phenylenediamines

Article abstract of DOI:10.1023/A:1013866030936

The reaction of β-benzoylacrylic acid with substituted o-phenylenediamines gives substituted quinoxal-2-ones. The structure of one of the products has been proved using X-ray analysis.

Full text of DOI:10.1023/A:1013866030936

Chemistry of Heterocyclic Compounds, Vol. 37, No. 10, 2001
THE REACTION OF BENZOYLACRYLIC
ortho
ACID WITH
-PHENYLENEDIAMINES
N. N. Kolos, A. A. Tishchenko, V. D. Orlov, T. V. Berezkina,
S. V. Shishkina, and O. V. Shishkin
The reaction of -benzoylacrylic acid with substituted o-phenylenediamines gives substituted quinoxal-
β
2-ones. The structure of one of the products has been proved using X-ray analysis.
Keywords: benzoylacrylic acid, 3-phenacylquinoxal-2-ones, o-phenylenediamines, cyclocondensation.
In a continuation of our investigation of the reactivity of enone systems towards nitrogen-containing
binucleophiles [1, 2] we have studied the reaction of -benzoylacrylic acid (1) with substituted
β
o-phenylenediamines 2a-g. The presence of different kinds of electrophilic centers in the molecule 1 leads us to
suggest that six- or seven-membered annelated, nitrogen-containing heterocycles of types 5 or 6 can be formed
via the intermediate products of addition 3 and/or amidation 4 respectively. Substituents in the starting diamine
set up the ground for the formation of the isomeric products.
Refluxing acid 1 with diamines 2a-g in alcohol gives satisfactory yields (57-75%) of quinoxalones 5a-j
(Table 1). As a rule, similar reactions of other unsaturated carbonyl compounds need the participation of an
acid- (HOAc) or base-type (triethylamine) catalyst [3]. We have found that neither the direction of the reaction
nor the yield of the product in this reaction depend on the presence of catalyst. The activity of the carboxyl
group of acid 1 is not decreased on conversion to the salt form. The reaction of the sodium (or triethylamine)
salt of acid 1 with diamine 2a gives exclusively the product 5a (Scheme 1).
The structure of the products 5 agrees with their spectroscopic parameters. Hence the IR spectra, taken
for KBr tablets, show two bands in the region of 1660-1690 cm-1 which are assigned to the vibrations of the
carbonyl groups and also a band for the stretching vibrations of the secondary amino group at 3336-3383 cm-1.
A new absorption band at 3398-3415 cm-1 appears in the spectra taken in CCl4 along with the regular shift of the
considered bands to the higher frequencies. The mass spectrum of the compound 5e shows a molecular ion peak
with m/z 311.
1
The H NMR spectra (see Table 2) show aromatic proton multiplets together with double doublets for
the methylene group protons, double doublets for the methine proton (JAB = 17.1-17.4, JAX = 6.9, JBX = 4.3 Hz),
a broadened signal for the amino group ( = 5.9-6.65 ppm), and also a lowfield singlet (
10 ppm) which is
δ ≥
δ
assigned to the amido NH proton.
1
We should mention that the H NMR spectra of the products obtained from diamines 2b,d,e show
doubling of the signals for the methine proton and the proton of the secondary amino group and this confirms
the formation of a mixture of the 6- (5b,d,e) and 7-substituted (5h,i,j) 3-phenacylquinoxal-2-ones.
__________________________________________________________________________________________
V. N. Karazin National University, Kharkov 61077, Ukraine; e-mail: desenko@univer.kharkov.ua.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1407-1414, October, 2001. Original
article submitted July 14, 1999; revision submitted March 23, 2000.
0009-3122/01/3710-1289$25.00©2001 Plenum Publishing Corporation
1289

Scheme 1
R1
O
NH2
NH2
EtOH, ∆
OH
+
Ph
1. HOAc
2. Et3N
O
R2
1
2a–g
R1
OH
O
O
NH2
O
H
N
R2
and/or
Ph
Ph
R2
N
H
O
4
R1
NH2
O
3
R1
R2
R1
O
O
H
N
H
N
∆
O
Ph
N
H
R2
N
H
Ph
5a–j
6
EtOH, 20 oC
2a
3a
2a
1
+
EtOH, ∆
5a
+
Ph COCH
=CHCOONa(Et3N H)
+
Ph
Me
COCH2CHNH
COOH
EtOH, 20 oC
+2a
EtOH, ∆
1
NH2
Me
+
5a
7
EtOH, ∆
Ph
Me
COCH=CHCONH
EtOH, ∆
8
H
N
NH2
SH
O
EtOH, ∆
O
1
+
S
Ph
9
2-4 a-f R2 = H, a R1 = H, b R1 = 4-CN, c R1 = 4-Br, d R1 = 4-Me, e R1=4-NO2,
f R1 = 3-NO2, g R1 = 4-Me, R2 = 5-Me; 5 a-f R2 = H, a R1 = H, b R1 = 6-CN,
c R1 = 6-Br, d R1 = 6-Me, e R1 = 6-NO2, f R1 = 8-NO2, g R1 = 6-Me, R2 = 7-Me,
h-j R2 = H, h R1 = 7-CN, i R1 = 7-Me, j R1 = 7-NO2
The ratio of isomers can be evaluated from the integrated intensity of the signals for the mentioned
groups. Identification of the isomers takes into account the electronic effect of the substituent on the protons of
both NH groups and also the fact that the signal for amide group proton is observed to low field in comparison
with an imino group proton. The contribution of the 6-isomer increases with an increase in the electron-acceptor
properties of the substituent R (see Table 2). Hence the isomers 5d and 5i are formed in approximately equal
1290

TABLE 1. Characteristics of the Compounds Synthesized
Com-
pound
Empirical
formula
Found N, %
IR spectrum, cm-1*
——————
Yield, %
mp, °C
Calculated N, %
νC=O
νN–H
С16Н16N2O3
9.9
9.8
160
171
1660, 1700а)
3280, 3380а)
69
3a
C16H14N2O2
10.3
1678, 1685a)
1680, 1702b)
3383a)3413,
3373b)
61*2
5а
10.5
14.3
14.4
C17H13N3O2
225-226 1662, 1674a)
3368a)
3353b)
64
5b+5h
1667, 1677b)
C16H13BrN2O2
C17H16N2O2
C18H18N2O2
C16H13N3O4
C16H13N3O4
8.0
194
1672, 1682a)
1680, 1700b)
3362a)
72
61*2
63
5c
3407, 3371b)
8.1
10.0
9.9
222-224 1667, 1682a)
1681, 1697b)
3376a)
5d+5i
5g
3413, 3378b)
9.5
218-220 1667, 1680a)
3369a)
1682, 1697b)
3415, 3388b)
9.5
13.3
13.5
225
175
1662, 1672a)
1679, 1712b)
3383a)
71
5e+5j
5f
3403, 3378b)
13.4
1677, 1692a)
1687, 1717b)
3336a)
75
3398, 3350b)
13.5
C17H17NO3
C17H15NO2
С16Н13NO2S
4.6
4.9
138
153
171
1680, 1730а)
1660а)
3360а)
3220а)
3376b)
80
53*3
76
7
8
9
5.1
5.3
4.7
4.9
1677,1695b)
_______
* a) for KBr tablets; b) for solution in CCl4.
*2 Yield using method A. The yields for methods B-E are 59, 57, 58, and
53% respectively.
*3 Yield using method A. The yield for method B is 52%.
amounts (45:55, see Table 2) but the ratio of the isomers 5e and 5j is 85:15. Separation of the isomeric
quinoxalones 5b,d,e and 5h,i,j using thin layer chromatography did not prove possible. For the same reason,
compound 5c should probably be assigned as the 6-Br isomer. In the reaction of diamine 2f with acid 1 8-nitro
isomer 5f is isolated, in the molecule of which an intramolecular hydrogen bond is realized, and this explains
the marked diamagnetic shift of the amido group proton.
However, the given spectroscopic evidence could correspond, equally, to 4-benzoyltetrahydrodiazepin-
2-ones (6). Hence, in order to obtain an unambiguous answer to the structure of the products, an X-ray structural
analysis was carried out for compound 5a (Tables 2-5) and this confirmed it to be 3-phenacylquinoxal-2-one.
The pyrazine ring in the product 5a is found to exist in distorted chair-type conformation (Figure 1).
Atoms C(6) and C(7) deviate from the plane of the remaining ring atoms by 0.23 and 0.59 Å respectively. The
substituent at atom C(7) is planar (the mean deviation from the plane not exceeding 0.01 Å) and is axially
orientated (torsion angle N(1)–C(6)–C(7)–C(9) 95.7 (2)°). In the crystalline state, molecule 5a forms infinite chains
due to the intermolecular hydrogen bonds N(1)–H(1N)···O(1) (-x, -y, 1-z) (H···O distance 2.02 Å, N–H···N angle
179°) and N(1)–H(2N)···O(1) (1-x, -y, -z) (H···O 2.34 Å, N–H···O 145°).
Formation of the isomeric quinoxal-2-one derivatives can be explained in the following way. The more
basic amino group takes part in both -addition reactions (formation of compound type 3) and amidation
α
reactions (formation of compound type 4) such that, in the molecules of certain diamines 2, the difference in the
basicity of the amino groups is not large and, even in the first stage, the isomeric intermediates of type 3 or 4 are
formed. The first route is confirmed by an experiment with diamine 2a in which the -adduct 3a is formed in its
α
reaction with acid 1 in ethanol at 20°C.
1291

TABLE 2. 1H NMR Spectral Characteristics of the Synthesized Compounds
(DMSO-d6), , ppm
δ
Isomer content, %
Com-
pound
CH2, dd
CH, dd
Х
NH
NHСО, s
Нarom
br. s
А
B
6-
7-
3.60
3.60
3.30
3.53
4.36
5.90
6.45 br.
10.30
8.10-6.60
8.00-6.40
—
60
—
40
5а
5b+5h
4.58
10.78
4.44
10.61
3.56
5d+5i* 3.58
3.35
3.28
4.40
6.28
10.48
8.00-6.69
8.10-6.40
100
45
—
55
5c
4.32
5.92
10.32
4.28
5.81
10.28
3.60
3.40
4.50
4.62
6.52
6.75
10.85
10.63
8.10-6.80
85
15
5e+5j
3.58
3.80
3.53
—
3.43
3.27
3.48
—
4.55
4.30
4.45
6.65
5.74
3.39
—
9.99
10.28
—
8.10-6.88
8.10-6.50
8.00-6.70
7.80-7.00
—
—
—
—
—
—
—
—
5f
5g*
7*
8*
6.40
10.00
6.10
4.10
3.70
4.45
—
10.65
8.00-7.00
—
—
9
_______
* Signals for the CH3 group protons: 2.16 (5d + 5j), 2.10 (5g), 2.10 (7),
2.30 (8).
The possibility of realizing the second route is indicated by the following data. In the reaction of acid 1
with p-toluidine (for which the basicity is close to that of o-phenylenediamine (pKa for o-phenylenediamine = 4.47,
pKa of p-toluidine = 4.39 [4]) but cyclization reaction is excluded) the product 2-(p-methylanilino)-3-
benzoylpropionic acid (7) is formed at room temperature.
Refluxing the mentioned compounds in alcohol gives amide 8. The latter is also obtained in 53% yield
by heating acid 7 in alcohol. Hence acid 7 is kinetically controlled and compound 8 is thermodynamically
controlled reaction product. When the products 7 and 8 are refluxed with diamine 2a they undergo
transamination and subsequent cyclization to the thermodynamically stable quinoxalone ring. In our opinion,
these results allow us to propose that the formation of the 6-isomer occurs via addition stage while the formation
of the 7-isomer may also include initial amidation step.
Fig. 1. General view of the molecule of compound 5a.
1292

TABLE 3. Bond lengths (d) in the Structure of Compound 5a
Bond
d, Å
Bond
d, Å
N(1)–C(6)
N(2)–C(8)
O(1)–С(6)
С(1)–С(8)
С(2)–С(3)
С(4)–С(5)
С(6)–С(7)
С(9)–С(10)
С(11)–С(12)
С(12)–С(13)
С(14)–С(15)
1.343(3)
1.389(3)
1.239(3)
1.384(3)
1.385(4)
1.386(3)
1.524(3)
1.515(3)
1.386(3)
1.384(4)
1.361(5)
N(1)–С(5)
N(2)–С(7)
1.411(3)
1.465(3)
1.218(3)
1.385(3)
1.386(3)
1.402(3)
1.534(3)
1.507(3)
1.390(3)
1.394(4)
1.376(4)
O(2)–С(10)
С(1)–С(2)
С(3)–С(4)
С(5)–С(8)
С(7)–С(9)
С(10)–С(11)
С(11)–С(16)
С(13)–С(14)
С(15)–С(16)
Our data is in good agreement with the results of studying the reaction of arylamides and
benzoylpyruvic acid esters with o-phenylenediamine [5, 6], in which derivatives of 3-phenacylidenequinoxal-2-
one and not those of benzodiazepine are formed. In this case reactions occur via an initial stage of amination of
the -keto group and this is in agreement with the sequence of stages proposed by us for kinetically controlled
α
conditions.
We have also studied the reaction of acid 1 with o-aminothiophenol under the same conditions as for the
synthesis of compound 5. According to the spectroscopic parameters (see Table 1) the product 9 is
2-phenylacylbenzo-1,4-thiazin-3-one and not benzothiazepine derivative as claimed in the report [7]. The first
stage of nucleophilic α-addition of the mercapto group is clear in this case [8] and it serves as an indirect
confirmation of the proposed reaction scheme.
TABLE 4. Bond Angles ( ) in the Structure of Compound 5a
ω
Angle
С(6)–N(1)–С(5)
ω, deg.
Angle
С(8)–N(2)–С(7)
ω, deg.
124.3(2)
120.7(2)
119.6(3)
120.6(2)
118.5(2)
120.3(2)
110.8(2)
107.6(2)
118.6(2)
113.4(2)
120.7(2)
118.8(2)
118.9(2)
118.9(3)
120.3(3)
118.9(2)
120.5(2)
120.0 (2)
120.9(2)
122.7(2)
116.9(2)
113.3(2)
123.1(2)
118.2(2)
120.6(2)
118.6(2)
122.3(2)
120.8(3)
120.6(3)
120.5(3)
С(8)–С(1)–С(2)
С(2)–С(3)–С(4)
С(4)–С(5)–С(8)
C(8)–C(5)–N(1)
O(1)–С(6)–С(7)
N(2)–C(7)–C(6)
С(6)–С(7)–С(9)
С(1)–С(8)–С(5)
С(10)–С(9)–С(7)
O(2)–С(10)–С(9)
С(12)–С(11)–С(16)
С(16)–С(11)–С(10)
С(12)–С(13)–С(14)
С(14)–С(15)–С(16)
С(3)–С(2)–С(1)
С(3)–С(4)–С(5)
C(4)–C(5)–N(1)
O(1)–C(6)–N(1)
N(1)–C(6)–C(7)
N(2)–C(7)–C(9)
C(1)–C(8)–N(2)
N(2)–C(8)–C(5)
O(2)–C(10)–C(11)
C(11)–C(10)–C(9)
C(12)–C(11)–C(10)
C(13)–C(12)–C(11)
C(15)–C(14)–C(13)
C(15)–C(16)–C(11)
1293

TABLE 5. Coordinates (×104) and Equivalent Isotropic Thermal Parameters
for the Non-hydrogen Atoms in Structure of Compound 5a
Atom
х
y
z
U(eq)
N(1)
N(2)
O(1)
O(2)
С(1)
С(2)
С(3)
С(4)
С(5)
С(6)
С(7)
С(8)
С(9)
С(10)
С(11)
С(12)
С(13)
С(14)
С(15)
С(16)
2257(3)
3430(4)
-329(3)
4830(4)
6608(5)
7769(5)
7119(5)
5288(5)
4123(4)
1299(4)
2470(4)
4756(4)
4577(4)
5713(5)
7990(5)
9008(5)
11103(6)
12215(6)
11237(6)
9130(5)
620(2)
717(2)
3922(1)
1742(2)
3927(1)
692(1)
45(1)
50(1)
53(1)
65(1)
55(1)
61(1)
62(1)
54(1)
41(1)
44(1)
45(1)
44(1)
45(1)
45(1)
51(1)
67(1)
82(1)
87(1)
88(1)
70(1)
-862(2)
-1411(2)
2121(2)
2829(2)
2811(2)
2080(2)
1371(2)
-211(2)
-405(2)
1395(2)
-1511(2)
-1901(2)
-2892(2)
-3489(2)
-4394(3)
-4682(3)
-4094(3)
-3207(2)
1821(2)
2411(2)
3506(2)
4011(2)
3422(2)
3462(2)
2366(2)
2310(2)
2637(2)
1615(2)
1762(2)
2801(2)
2907(3)
1949(4)
926(3)
824(3)
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker AM-300 (300 MHz) instrument for solutions in DMSO-d6
with TMS as internal standard. IR spectra were taken on a Specord IR-75 spectrometer for KBr tablets and
solutions in CCl4. Mass spectra were recorded on a Finnigan MAT INCOS 50 instrument (70 eV). Monitoring
of the reaction course and the degree of purity of the products was carried out using TLC on Silufol UV-254
plates in the system ethyl acetate-chloroform (1:4).
o
2-( -Aminophenylamino)-3-benzoylpropionic Acid (3a).
1
Solution of acid (0.44 g, 2.5 mmol) and
diamine 2a (0.3 g, 2.5 mmol) in ethanol (10 ml) was stirred at room temperature for 30-40 min to give acid 3a
(0.49 g).
3-Phenacylquinoxal-2-one (5a). A. Solution of acid 1 (1 g, 5.6 mmol) and diamine 2a (0.61 g,
5.6 mmol) in ethanol (20 ml) was refluxed for 1 h. The precipitated solid was crystallized from ethyl acetate to
give the product 5a (0.92 g).
Compounds 5b-j were obtained similarly from the corresponding amines 2b-j.
B. Solution of acid 1 (1 g, 5.6 mmol), diamine 2a (0.61 g, 5.6 mmol), and acetic acid (0.5 ml) in ethanol
(20 ml) was refluxed for 1 h. The precipitated solid was crystallized from ethyl acetate to give the product 5a
(0.88 g).
C. Solution of acid 1 (1 g, 5.6 mmol) in ethanol (10 ml) was added to solution of sodium hydroxide
(0.2 g) in ethanol (2 ml) and diamine 2a (0.61 g, 5.6 mmol) in ethanol (2 ml). The mixture was refluxed for 1 h.
The precipitate formed was filtered off and the filtrate was diluted with water, acidified with acetic acid, and an
additional amount of product separated. The overall yield of the product 5a was 0.85 g,
D. Solution of acid 3a (1 g) in ethanol (10 ml) was refluxed for 1 h. The precipitate was filtered off and
crystallized from ethyl acetate to give quinoxalone 5a (0.55 g).
1294

E. Solution of acid 7 (1.2 g, 4.6 mmol) (see below) and diamine 2a (0.5 g, 4.6 mmol) in ethanol (10 ml)
was refluxed for 1 h. The precipitate was filtered off and crystallized from ethyl acetate to give quinoxalone 5a
(0.6 g).
The product 5a was synthesized similarly from amide 8. Mixed samples of compound 5a prepared using
the different methods did not give a depression of melting point.
p
2-( -Methylphenylamino)-3-benzoylpropionic Acid (7).
1
Mixture of acid (1.5 g, 8.4 mmol) and
p-toluidine (0.9 g, 8.4 mmol) in ethanol (15 ml) was stirred for 30-40 min at room temperature. The precipitate
was filtered off and crystallized from chloroform. Yield 1.9 g.
Benzoylacrylic acid N-(4-methylphenyl)amide (8). A. Mixture of acid 1 (1.5 g, 8.4 mmol), p-toluidine
(0.9 g, 8.4 mmol), and triethylamine (1.2 ml) in ethanol (11 ml) was refluxed for 30 min. The amide formed was
filtered off and recrystallized from ethanol to give the product 8 (1.18 g).
B. Refluxing the product 7 (1 g, 3.5 mmol) in ethanol (10 ml) for 1-1.5 h gave amide 8 (0.49 g, from
ethanol) which did not give the melting point depression with a sample obtained by method A.
2-Phenacylbenzo-1,4-thiazin-3-one (9). Solution of acid 1 (1.5 g, 8.5 mmol), o-aminothiophenol
(1.06 g, 8.5 mmol), and acetic acid (0.5 ml) in ethanol (10 ml) was stirred at room temperature for 15-20 min.
The precipitate was filtered off and crystallized from ethanol to give the product 9 (1.8 g).
X-Ray Structural Investigation of Compound 5a. Crystals of the compound 5a (C16H14N2O2) are
= 82.98 (2)°;
triclinic. At 20°C a = 5.201 (1), b = 11.255 (4), c = 12.337 (4) Å; = 77.11 (3), = 89.26 (2),
γ
α
β
V = 698.6 (4) Å3; dcalc = 1.266 g/cm3; space group P1; Z = 2. The unit cell parameters and intensities of
2451 independent reflection (Rind = 0.004) were measured using a Siemens P3/PS automatic four-circle
diffractometer ( MoK , graphite monochromator, /2 scanning, 2θ max = 50°).
λ
α
θ θ
The structure was solved by a direct method using the SHELXTL PLUS [9] computer package. The
positions of the hydrogen atoms were calculated geometrically and refined using the "rider" model with fixed
Uiso = 1.2Ueq of the non-hydrogen atom bonded to the given hydrogen atom. Refinement of F2 by full-matrix,
least-squares analysis in the anisotropic approximation for non-hydrogen atoms gave R2 = 0.1486 (R1 = 0.051
ω
for 1242 reflections with F 4 (F), S = 0.908). The coordinates for the non-hydrogen atoms are given in
> σ
Table 5.
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1295