Interaction of esters of β-aroylacrylic acids with o-phenylenediamines and 1,2-diamino-4-phenylimidazole

Article abstract of DOI:10.1007/s10593-007-0216-5

3-Phenacylquinoxalin-2-ones were synthesized by the reaction of the ethyl esters of β-aroylacrylic acids with o-phenylenediamines, while interaction with 1,2-diamino-4-phenylimidazole gave ethyl 7-amino-2-aryl-5-phenyl-3,4- dihydroimidazolo[1,5-b]pyridazine-4-carboxylates. Their chemical properties have been investigated.

Full text of DOI:10.1007/s10593-007-0216-5

Chemistry of Heterocyclic Compounds, Vol. 43, No. 11, 2007
INTERACTION OF ESTERS
OF β-AROYLACRYLIC ACIDS
WITH o-PHENYLENEDIAMINES
AND 1,2-DIAMINO-4-PHENYL-
IMIDAZOLE
N. N. Kolos1, L. Yu. Kovalenko1, S. V. Shishkina2,
O. V. Shishkin2, and I. S. Konovalova2
3-Phenacylquinoxalin-2-ones were synthesized by the reaction of the ethyl esters of β-aroylacrylic acids with
o-phenylenediamines, while interaction with 1,2-diamino-4-phenylimidazole gave ethyl 7-amino-2-aryl-5-
phenyl-3,4-dihydroimidazolo[1,5-b]pyridazine-4-carboxylates. Their chemical properties have been
investigated.
Keywords: dihydroimidazolo[1,5-b]pyridazine-4-carboxylates, o-phenylenediamines, 1,2-diamino-
4-phenylimidazole, β-aroylacrylic acid ethyl esters, chemical properties, cyclocondensation.
β-Aroylacrylic acids are convenient polyelectrophilic reagents in the synthesis of heterocycles, for which
the addition reaction of N-, S-, P-, or C-nucleophiles occurs exclusively at the α-carbonyl-electrophilic center of
the molecule [1-3]. The products of C-nucleophilic addition were successfully isolated on interaction of the acids
with 1,2-diamino-4-phenylimidazole, however cyclization of the intermediates is accompanied by
decarboxylation and aromatization, which enabled the preparation only of heteroaromatic derivatives of
imidazopyridazine [4]. This limitation was taken off when using N-arylamides of aroylacrylic acids in reaction
with the amine indicated [5].
With the aim of broadening the synthetic potential of β-aroylacrylic acids, the behavior of their ethyl
esters 1a-f was studied in reaction with o-phenylenediamines 2a,b and 1,2-diamino-4-phenylimidazole (3).
Several electrophilic centers are present in the molecules of α,β-unsaturated γ-keto esters 1, viz. atoms C(2) and
C(4) and the carbon atom of the ester group, which is hopeful for many reaction routes with nucleophilic
reagents.
The initial γ-keto esters 1a-f were synthesized by known literature methods [6-8]. Their interaction (in
the example of compounds 1a,b) with diamine 2a in methanol leads to 3-phenacylquinoxalin-2-ones 4a,b,
isolated in high yield. The latter were obtained previously by the reaction of the appropriate β-aroylacrylic acids
with o-PDA (o-phenylenediamine) [9].
__________________________________________________________________________________________
1Chemical Faculty, Kharkiv V. N. Karazin National University, Ukraine; e-mail:
2
kolos@univer.kharkov.ua. STC, Institute for Single Crystals, National Academy of Sciences of Ukraine,
Kharkiv 61001; e-mail: s.v.shishkina@isc.kharkov.com. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 11, pp. 1646-1654, November, 2007. Original article submitted April 24, 2007.
0009-3122/07/4311-1397©2007 Springer Science+Business Media, Inc.
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TABLE 1. Characteristics of the Synthesized Compounds 7-9
Found, %
Calculated, %
N
IR spectrum,
——————
Com-
pound
Empirical
formula
ν, cm-1
mp, °C
Yield, %
(in KBr)
7а
7b
7c
7d
7e
7f
13.80
14.12
224-225
213-214
218-219
228-229
196-197
222-223
164-165
236-237
226-227
231-232
207-208
255-256
1682, 1720,
3200, 3300
58
61
70
62
66
60
63
65
60
55
88
69
С21H20N4O2 ⋅HCl
С22H22N4O2
14.90
14.96
1652, 1725,
3292, 3396
1646, 1720,
3295, 3390
С21H19ClN4O2
С21H19BrN4O2
С22H22N4O3
14.10
14.19
12.65
12.75
1648, 1719,
3303, 3400
14.55
14.35
1650, 1720,
3303, 3400
1682, 1722,
3245, 3353
С22H22N4O3 ⋅ HCl
С23H24N4O2 ⋅HCl
С21H19ClN4O2 ⋅HBr
С23H21ClN4O5
С23H21BrN4O5
С21H22N6O
13.50
13.12
7g
7i
13.40
13.19
1682, 1722,
3210, 3303
12.00
11.78
1686, 1723,
3273, 3375
1645, 1665,
1722, 3390
8a
8b
9a
9b
13.00
12.82
11.82
11.64
1650, 1670,
1726, 3425
22.10
22.44
1660, 3396,
3260, 3198
1658, 3486,
3376, 3316
С19H17BrN6O
19.90
19.76
With the aim of synthesizing 3-(2-benzimidazolyl)propenones 6 we investigated the interaction of ester
1a and diamine 2a on boiling in 2-propanol in the presence of catalytic amounts of HCl, on carrying out the
reaction in toluene, and also on fusing the starting materials [10]. However exclusively quinoxalone 4a was
isolated in these experiments. The α-carbon atom of the molecule acts as the center for initial nucleophilic attack
in all cases. This is indicated, particularly, by the formation of a mixture of 6/7-nitroquinoxalin-2-ones (4c + 5c)
in the reaction of ester 1c with diamine 2b (ratio of isomers was 4 : 1). The same ratio of isomers was also
obtained in the reaction of diamine 2a with p-chlorobenzoylacrylic acid, where nucleophilic addition by the
more basic amino group occurs at the α-position [9].
Compounds 7b-e and 7a,f,g were obtained in satisfactory yield (see EXPERIMENTAL) on boiling
diaminoazole 3 with esters 1a-f briefly in methanol, without a catalyst, or in the presence of catalytic amounts of
HCl respectively. Their structures were confirmed by IR and 1H NMR spectra. In the IR spectra (KBr disks) of
compounds 7b-e bands were observed for the stretching vibrations of the ester carbonyl group at 1720-1725, and
intense bands at 1645-1650 cm-1 attributed to the stretching vibrations of the hydrazone group. Two medium
intensity bands were seen at 3200-3400 cm-1 which indicates preservation of the primary amino group. The same
set of absorption bands was characteristic of the IR spectra of products 7a,f,g, but the bands of the stretching
vibrations of the C=N bond were displaced by 30 cm-1 towards higher frequency, which indicates the presence of
a less conjugated system.
Signals were displayed in the 1H NMR spectra of compounds 7a-g for the protons of the ABX system of
the dihydropyridazine ring, a doublet of doublets, and a doublet for the protons of the methylene group, a
doublet for the methine proton, a triplet and a quartet for the ethoxycarbonyl group, a two-proton singlet for the
amino group on the imidazole ring (signal disappears on deuterium exchange) at 6.1-6.2 (compounds 7b-e) and
8.1-8.3 ppm (compounds 7a,f,g), and multiplets for the protons of the two aromatic nuclei. The geminal
1399

1400

constant of the ABX system of protons of the dihydropyridazine ring was equal to 17.7 Hz. One of the vicinal
constants reached 6.5 Hz, while the second constant approached zero, i.e. the vicinal protons of the
dihydropyridazine ring are disposed at an angle close to 90°.
The spectral data and also the results of elemental analysis indicate the formation of ethyl 7-amino-
2-aryl-5-phenyl-3,4-dihydroimidazo[1,5-b]pyridazine-4-carboxylates 7b-e or their hydrochlorides 7a,f,g. The
hydrazone group of the pyridazine fragment acts as the center of protonation, as indicated by the increase of its
frequency in IR spectra to 1680 cm-1. Protonation of the C=N bond of the pyridazine, and not the imidazole, ring
is also confirmed by the 1H NMR spectra. It follows from Table 2 that the o-protons of the 2-aryl substituent in
salts 7a,f,g undergo a low field displacement, while the positions of the o-protons of the phenyl group in position
5 are unchanged on going from base to salt.
Ph
Ph
N
O
N
O
NH2
NHCOMe
N
H2NNH
EtO
N
N
N
Ac2O
N
H2NNH2
Ar
9a,b
Ar
8a,b
Ph
O
NH2
EtO
N
N
Ar
Me
NH2
HOAc
7
Ph
Br2
N
O
Ph
N
O
NH2
EtO
N
N
NH2
MeC6H4HN
.
N
N
HBr
Ar
Ar
7i
10a
7i, 8a Ar = 4-ClC6H4; 8b, 9b Ar = 4-BrC6H4; 9a Ar = 2,4-Me2C6H3; 10a Ar = Ph
The structures of dihydropyridazines 7 were also confirmed by X-ray structural analysis using
compound 7c as example (Fig. 1). The dihydropyridazine ring is in a distorted sofa conformation (folding
parameters [11]: S = 0.51°, θ = 44.4°, Ψ = 17.2°). The deviations of the C(1) and C(6) atoms from the mean
square plane of the remaining atoms were 0.14 and 0.58 Å respectively. Bond lengths and the conformation of
the heterocycle in the 7c molecule were analogous to those of the 7-amino-2-(p-methoxyphenyl)-
5-(p-methylphenyl)-4-phenyl-3,4-dihydroimidazo[1,5-b]pyridazine studied previously [12].
The chlorophenyl substituent is folded relative to the endocyclic N(3)-C(4) double bond of the bicyclic
fragment ([torsion angle N(3)–C(4)–C(10)–C(11) 23.4(3)°), probably as a result of repulsion between the atoms
of the aromatic and the dihydropyridazine rings [intramolecular shortened contacts H(15A)···H(5B) 2.07 Å (sum
of van der Waals radii [13] 2.34 Å), H(15A)···C(5) 2.70 (2.87), H(5B)···C(15) 2.63 Å (2.87 Å)]. The ester
substituent is in a pseudoaxial position (torsion angle C(4)–C(5)–C(6)–C(7) 78.7(2)°).
1401

Fig. 1. Molecular structure of compound 7c.
The phenyl substituent is unfolded relative to the plane of the imidazole fragment (torsion angle C(1)–
C(2)–C(16)–C(21) 25.9(3)°), which is probably the result of two opposing factors: on the one hand, repulsion
between the H(21) and H(6) atoms (intramolecular shortened contact H(21)···H(6) 2.20 (2.34)), and on the other
hand, the attractive interaction of H(17)···N(1) 2.61 Å (2.67 Å).
Dimers are formed in the crystal of the 7c molecule as a result of an intermolecular hydrogen bond
N(4)–H(4NB)···N(1)′ (-x + ½, -y - ½, -z + 2) H···N 2.15 Å, N–H···N 160°.
The C(2) atom of the molecule therefore acts as the center of nucleophilic attack in reactions of esters of
β-aroylacrylic acids with both 1,4- and 1,3-azabinucleophiles. The further course of the reaction is determined
by the formation of the thermodynamically more stable six-membered rings, quinoxaline or pyridazine
respectively. In the latter case the α-effect of the hydrazine amino group of diaminoazole 3 favors its formation.
We have also studied some chemical properties of imidazopyridazines 7. On boiling imidazopyridazines
7c,d in acetic anhydride, the acetyl derivatives 8a,b are formed in satisfactory yield. Bromination of
imidazopyridazine 7c with bromine in acetic acid did not lead to the expected 3-bromo derivative, only the
hydrobromide of imidazopyridazine 7i was isolated from the reaction mixture. Base 7c and also the salt forms of
imidazopyridazines 7a,i were not successfully reduced by NaBH4 in acetic acid.
TABLE 3. Bond Lengths (l) in the Structure of Compound 7c
Bond
N(1)–C(3)
l, Å
Bond
N(1)–C(2)
l, Å
1.322(2)
1.195(2)
1.743(2)
1.497(3)
1.387(2)
1.450(3)
1.281(2)
1.478(3)
1.527(2)
1.514(3)
1.338(3)
1.321(3)
1.385(3)
1.393(3)
1.362(4)
1.383(3)
1.405(3)
1.362(2)
1.387(2)
1.371(2)
1.320(2)
1.471(3)
1.346(3)
1.495(3)
1.512(3)
1.323(3)
1.387(3)
1.290(3)
1.377(3)
1.384(3)
1.371(3)
O(1)–C(7)
C(1)–C(2)
Cl(1)–C(13)
C(1)–C(6)
C(1)–N(2)
N(2)–C(3)
N(2)–N(3)
O(2)–C(8)
О(2)–C(7)
C(2)–C(16)
C(3)–N(4)
N(3)–C(4)
C(4)–C(10)
C(5)–C(6)
C(4)–C(5)
C(6)–C(7)
C(8)–C(9)
C(10)–C(11)
C(11)–C(12)
C(13)–C(14)
C(16)–C(21)
C(17)–C(18)
C(19)–C(20)
C(10)–C(15)
C(12)–C(13)
C(14)–C(15)
C(16)–C(17)
C(18)–C(19)
C(20)–C(21)
1402

TABLE 4. Valence Angles (ω) in the Structure of Compound 7c
Angle
ω, deg.
Angle
ω, deg
C(3)–N(1)–C(2)
C(2)–C(1)–N(2)
N(2)–C(1)–C(6)
C(3)–N(2)–N(3)
C(7)–O(2)–C(8)
C(1)–C(2)–C(16)
C(4)–N(3)–N(2)
N(1)–C(3)–N(2)
N(3)–C(4)–C(10)
C(10)–C(4)–C(5)
C(1)–C(6)–C(7)
C(7)–C(6)–C(5)
O(1)–C(7)–C(6)
O(2)–C(8)–C(9)
C(11)–C(10)–C(4)
C(10)–C(11)–C(12)
C(14)–C(13)–C(12)
C(12)–C(13)–Cl(1)
C(10)–C(15)–C(14)
C(21)–C(16)–C(2)
C(18)–C(17)–C(16)
C(18)–C(19)–C(20)
C(16)–C(21)–C(20)
105.77(17)
104.87(19)
115.51(17)
122.43(19)
118.93(18)
129.3(2)
115.03(18)
110.2(2)
115.9(2)
119.7(2)
106.83(17)
112.27(17)
125.7(2)
105.2(2)
C(3)–N(1)–C(2)
C(2)–C(1)–C(6)
N(2)–C(1)–C(6)
C(1)–N(2)–N(3)
C(1)–C(2)–N(1)
N(1)–C(2)–C(16)
N(1)–C(3)–N(4)
N(4)–C(3)–N(2)
N(3)–C(4)–C(5)
C(4)–C(5)–C(6)
C(1)–C(6)–C(5)
O(1)–C(7)–O(2)
O(2)–C(7)–C(6)
C(11)–C(10)–C(15)
C(15)–C(10)–C(4)
C(13)–C(12)–C(11)
C(14)–C(13)–Cl(1)
C(13)–C(14)–C(15)
C(21)–C(16)–C(17)
C(17)–C(16)–C(2)
C(19)–C(18)–C(17)
C(19)–C(20)–C(21)
105.77(17)
138.5(2)
115.51(17)
128.89(17)
110.46(18)
120.15(19)
127.3(2)
122.42(19)
124.29(18)
114.84(18)
109.07(18)
123.6(2)
110.64(19)
115.5(2)
121.3(2)
123.2(2)
122.4(2)
120.5(3)
118.0(2)
121.8(2)
120.0(3)
121.9(3)
121.6(3)
117.7(2)
122.1(2)
120.2(2)
121.0(3)
119.6(3)
120.3(3)
120.4(3)
121.0(2)
Hydrazides 9a,b were obtained by reacting esters 7d,g with hydrazine hydrate. Amide 10a was
synthesized by fusing ester 7a with p-toluidine.
Convenient routes for th functionalization of 7-amino-4-ethoxycarbonyl-3,4-dihydroimidazo-
[1,5-b]pyridazine derivatives are proposed, which do not lead to aromatization of the dihydropyridazine
fragment of the molecule.
EXPERIMENTAL
The 1H NMR spectra were measured on a Varian Mercury VX-200 instrument (200 MHz) in solution in
DMSO-d6, internal standard was TMS. The IR spectra were recorded on an IR-75 instrument in KBr disks. A
check on the course of reactions, and also on the homogeneity of the compounds obtained, was effected by TLC
on Silufol UV-254 plates in the system toluene–ethyl acetate.
X-ray Structural Investigation. Crystals of 7c were monoclinic, grown in ethanol, C21H19ClN4O2, at
20°C: a = 28.806(8), b = 8.835(3), c = 17.105(9) Å, β = 102.06(3)°, V = 3928(2) Å3, Mr = 394.85, Z = 8, space
group C2/c, dcalc = 1.335 g/cm3, µ(MoKα) = 0.219 mm-1, F(000) = 1648. The parameters of the unit cell and the
intensities of 10301 reflections (3418 independent, Rint = 0.038) were measured on a Xcalibur-3 diffractometer
(MoKα radiation, CCD detector, graphite monochromator, ω-scanning, 2θmax = 50).
The structure was solved by the direct method with the SHELXTL set of programs [14]. The positions of
the hydrogen atoms were made apparent from an electron density difference synthesis and were refined by the
"rider" model with Uiso = nUeq for the non-hydrogen atom linked to the given hydrogen (n = 1.5 for a methyl
group and n = 1.2 for the remaining hydrogen atoms). The structure was refined on F2 with the full matrix least
squares method in an anisotropic approximation for non-hydrogen atoms to wR2 = 0.074 for 3374 reflections
1403

(R1 = 0.035 for 1320 reflections with F >4σ(F), S = 0.709). The coordinates of atoms and the complete table of
bond lengths and valence angles have been deposited in the Cambridge structural data bank (CCDC 664799).
Quinoxalones 4a,b, and also the mixture of quinoxalones 4c + 5c were obtained by the procedure
reported in [9]. Yields were 62, 80, and 75% respectively.
Compound 4a was isolated in 68% yield on carrying out the reaction in 2-propanol in the presence of
catalytic amounts of HCl. On carrying out the reaction in toluene the yield was 72%, and on fusing the reactants
65%.
1
6-Nitroquinoxalone 4c. H NMR spectrum, δ, ppm (J, Hz): 3.42 (1H, dd, JAB = 17.2, JAX = 6.4, HA
CH2); 3.58 (1H, dd, JAX = 6.4, HB CH2); 4.49 (1H, t, JBX = 4.0, HX CH); 6.65 (1H, br. s, NH); 6.94-7.89 (7H, m,
Ar); 10.95 (1H, s, NH).
1
7-Nitroquinoxalone 5c. H NMR spectrum, δ, ppm (J, Hz): 3.42 (1H, dd, JAB = 17.2, JAX = 6.4, HA
CH2); 3.58 (1H, dd, JAX = 6.4, HB CH2); 4.54 (1H, t, JBX = 4.0, HX CH), 6.65 (1H, br. s, NH); 6.94-7.89 (7H, m,
Ar), 10.71 (1H, s, NH).
Ethyl 7-Amino-2-(4-methylphenyl)-5-phenyl-3,4-dihydroimidazo[1,5-b]pyridazine-4-carboxylate
(7b). A mixture of diamine 3 (0.174 g, 1 mmol) and ester 1b (0.218 g, 1 mmol) in EtOH (10 ml) was boiled
under reflux for 1 h. The mixture was cooled, the solid was crystallized from ethanol, and compound 7b
(0.23 g) was obtained.
Bases 7c-e were obtained analogously. Base 7c was also obtained in 56% yield on boiling salt 7i in
methanol in the presence of an excess of Et3N.
Ethyl 7-Amino-2,5-diphenyl-3,4-dihydroimidazo[1,5-b]pyridazine-4-carboxylate Hydrochloride
(7a). Conc. HCl (5 drops) was added to a mixture of diamine 3 (0.174 g, 1 mmol) and ester 1a (0.204 g, 1 mmol)
in EtOH (10 ml), and the mixture boiled under reflux for 1 h. The solid, which precipitated on cooling, was
washed with ethanol.
Salts 7f,g were obtained analogously.
Ethyl
7-Amino-2-(4-chlorophenyl)-5-phenyl-3,4-dihydroimidazo[1,5-b]pyridazine-4-carboxylate
Hydrobromide (7i). Bromine (0.1 ml, 1 mmol) in AcOH (5 ml) was added dropwise with stirring to a solution
of compound 7c (0.394 g, 1 mmol) in AcOH (10 ml). After the end of bromination the solution was stirred for
0.5 h, and poured onto ice. The solid was filtered off, and crystallized from ethanol.
Ethyl
7-(N-Acetylamino)-2-(4-chlorophenyl)-5-phenyl-3,4-dihydroimidazo[1,5-b]pyridazine-
4-carboxylate (8a). A mixture of imidazopyridazine 7c (0.394 g, 1 mmol) and Ac2O (1 ml) was boiled under
reflux for 10 min. The reaction mixture was poured into ice-water, the solid was filtered off, and crystallized
from ethanol.
Compound 8b was obtained analogously.
7-Amino-2-(4-bromophenyl)-5-phenyl-3,4-dihydroimidazo[1.5-b]pyridazine-4-carbohydrazide (9b).
A solution of pyridazine 7d (0.475 g, 1 mmol) in 95% hydrazine hydrate (2.5 ml, 50 mmol) was heated on a
water bath for 5 h. The yellow solid precipitated on cooling was washed with water, and crystallized from
ethanol. Yield was 0.32 g.
Hydrazide 9a was obtained analogously.
4-[N-(4-Methylphenyl)carboxamido-7-amino-2,5-diphenyl-3,4-dihydroimidazo[1,5-b]pyridazine
(10a). A mixture of salt 7a (0.397 g, 1 mmol) and p-toluidine (0.160 g, 1.5 mmol) was maintained at 170°C for 1
h, then at 200oC for 0.5 h. The mixture was cooled, and benzene (10 ml) was added. The precipitated solid was
recrystallized from ethanol. Yield was 0.25 g (65%) of mp 219-220°C (lit. 219°C [5]).
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