Reaction of 2-(phenylamino)benzoic and 2-(phenylamino)- and 2-methyl-6-phenylpyridine-3-carboxylic acid hydrazides with succininc anhydride

Article abstract of DOI:10.1134/S1070428012040136

Reactions of 2-(phenylamino)benzoic and 2-(phenylamino)- and 2-methyl-6-phenylpyridine-3- carboxylic acid hydrazides with succinic anhydride in organic solvents at room temperature gave the corresponding 4-(2-aroylhydrazinyl)-4-oxobutanoic acids. The reactions in boiling acetic acid afforded N-(2,5-dioxopyrrolidin-1-yl)benzamide or N-(2,5-dioxopyrrolidin-1-yl) pyridine-3-carboxamide. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070428012040136

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 4, pp. 544–546. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © M.E. Kon’shin, A.L. Efremov, M.I. Vakhrin, A.A. Gorbunov, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48,
No. 4, pp. 546–548.
Reaction of 2-(Phenylamino)benzoic and 2-(Phenylamino)-
and 2-Methyl-6-phenylpyridine-3-carboxylic Acid Hydrazides
with Succininc Anhydride
M. E. Kon’shina, A. L. Efremova, M. I. Vakhrina, and A. A. Gorbunovb
a Perm Pharmaceutical Academy, Ministry of Health Protection of the Russian Federation,
ul. Polevaya 2, Perm, 614000 Russia
e-mail: pfa@mail.ru
b Institute of Technical Chemistry, Ural Division, Russian Academy of Sciences, Perm, Russia
Received April 7, 2011
Abstract—Reactions of 2-(phenylamino)benzoic and 2-(phenylamino)- and 2-methyl-6-phenylpyridine-3-
carboxylic acid hydrazides with succinic anhydride in organic solvents at room temperature gave the
corresponding 4-(2-aroylhydrazinyl)-4-oxobutanoic acids. The reactions in boiling acetic acid afforded
N-(2,5-dioxopyrrolidin-1-yl)benzamide or N-(2,5-dioxopyrrolidin-1-yl)pyridine-3-carboxamide.
DOI: 10.1134/S1070428012040136
melting compounds IIIa–IIIc which were insoluble in
aqueous sodium hydrogen carbonate. Compounds
IIIa–IIIc were also formed when hydrazides IIa–IIc
were heated in glacial acetic acid. Analogous results
were obtained at 140°C.
Derivatives of 2-(phenylamino)benzoic [1] and
2-(phenylamino)pyridine-3-carboxylic acid hydrazides
[2] exhibit a broad spectrum of biological activity
(anticonvulsant, anti-inflammatory, and bactericidal).
They are also used in the synthesis of biologically
active substituted 3-aminoquinazolin-4-ones [3, 4].
Presumably, heating of hydrazides Ia–Ic with
succinic anhydride in acetic acid initially gives acyl-
hydrazides IIa–IIc whose cyclization can take two
paths with closure of pyrrolidine (IIIa–IIIc) or pyrida-
zine ring (B). According to [6, 7], cyclodehydration of
N′-acyl succinic acid hydrazides yields succinimide
derivatives. We believe that the cyclization of hydra-
zides IIa–IIc also leads to the formation of succin-
imides IIIa–IIIc. To confirm this assumption we
calculated the total energies of compound IIIa and
its pyridazine analog B, which turned out to be
–2733553.92 and –2733496.89 kJ/mol, respectively. It
is seen that structure IIIa is more stable; therefore, its
formation should be preferred.
No products like A were detected, presumably
because of lower nucleophilicity of the arylamino
group in IIa and IIb as compared to amino group in
anthranilic acid derivatives; in addition, steric factor
cannot be ruled out.
The structure of the newly synthesized compounds
was confirmed by their 1H NMR and mass spectra. All
compounds characteristically underwent McLafferty
rearrangement [8] under electron impact, which is
A conventional procedure for the preparation of
acylhydrazides is based on the reaction of hydrazides
with carboxylic acid anhydrides. As shown in [5, 6],
2-(phenylamino)benzohydrazide reacts with succinic
anhydride to give either 4-oxo-4-{2-[2-(phenylamino)-
benzoyl]hydrazinyl}butanoic acid or 2,3,4,10-tetra-
hydro-1H-pyridazino[3,2-b]quinazoline-2,10-dione,
depending on the conditions.
We examined the reactions of succinic anhydride
with 2-(phenylamino)benzohydrazide (Ia), 2-(phenyl-
amino)pyridine-3-carbohydrazide (Ib), and (for com-
parison) 2-methyl-6-phenylpyridine-3-carbohydrazide
(Ic) at different temperature conditions. We expected
to obtain compounds like A under severe conditions,
i.e., by heating hydrazides Ia and Ib with succinic
anhydride in boiling glacial acetic acid.
The reactions performed at room temperature in
different solvents (glacial acetic acid, chloroform, ben-
zene) gave the corresponding 4-(2-aroylhydrazinyl)-4-
oxobutanoic acids IIa–IIc (Scheme 1). By heating the
reactants in acetic acid at 100°C we obtained high-
544

REACTION OF 2-(PHENYLAMINO)BENZOIC AND 2-(PHENYLAMINO)- ...
545
Scheme 1.
O
O
H
N
20°C
N
OH
H
O
R2
X
R1
O
O
O
H
IIa–IIc
O
O
NH2
O
N
N
AcOH
N
H
AcOH, 100°C
O
R2
X
R1
R2
O
NH
Ia–Ic
O
Ph
N
100°C
B
N
O
O
H
O
O
R2
X
R1
IIIa–IIIc
AcOH, 100–150°C
O
H
N
O
N
X
N
Ph
A
R1 = PhNH, R2 = H, X = CH (a); R1 = PhNH, R2 = H, X = N (b); R1 = Me, R2 = Ph, X = N (c).
typical of anthranilic and 2-methylbenzoic acid deriva-
tives. The mass spectrum of IIa contained no molec-
ular ion peak, but that belonging to IIIa was observed.
Presumably, in the course of mass spectrometric anal-
ysis compound IIa is readily converted into IIIa via
elimination of water.
trum, δ, ppm: 2.44 m (4H, CH2CH2), 7.16 m (9H,
Harom), 9.21 s (1H, C6H5NH), 9.81 s, 10.19 s (2H,
NHNH), 11.80 br.s (1H, OH). Mass spectrum, m/z
(Irel, %): 309.10 (37.9) [M – H2O]+, 195 (100), 167
(38.5), 139 (5.0), 115 (2.4), 77.0 (4.4), 51 (2.3). Found,
%: C 59.32; H 5.57; N 12.10. C17H17N3O4. Calculated,
%: C 59.18; H 5.54; N 12.07. M 327.32.
EXPERIMENTAL
Compounds IIb and IIc were synthesized in a sim-
The 1H NMR spectra were recorded on a Tesla BS-
567A spectrometer at 100 MHz from 5% solutions in
DMSO-d6 using hexamethyldisiloxane as internal
reference. Quantum-chemical calculations were per-
formed at the RHF/6-31-G(d) level of theory with full
geometry optimization using Gaussian 03W [9]. The
mass spectra were obtained on an Agilent Technologies
6890N/5975B GC–MS system (HP-5ms column,
30 m×0.25 mm, film thickness 0.25 μm; carrier gas
helium; electron impact, 70 eV). The elemental com-
positions were determined on a LECO CHNS-932
analyzer (USA).
ilar way.
4-Oxo-4-{2-[2-(phenylamino)pyridin-3-ylcarbon-
yl]hydrazinyl}butanoic acid (IIb) was obtained from
1.14 g (5 mmol) of 2-(phenylamino)pyridine-3-carbo-
hydrazide (Ib) and 0.5 g (5 mmol) of succinic anhy-
dride in anhydrous benzene. Yield 0.95 g (61%),
1
mp 145–147°C. H NMR spectrum, δ, ppm: 2.44 m
(4H, CH2CH2), 7.49 m (8H, Harom), 9.92 s and 10.30 s
(2H, NHNH), 10.50 br.s (1H, NHPh). Found, %:
C 58.75; H 4.95; N 16.93. C16H17N4O4. Calculated, %:
C 58.53; H 4.88; N 17.07.
4-[2-(2-Methyl-6-phenylpyridin-3-ylcarbonyl)-
hydrazinyl]-4-oxobutanoic acid (IIc) was obtained
from 1.15 g (5 mmol) of 2-methyl-6-phenylpyridine-3-
carbohydrazide (Ic) and 0.5 g (5 mmol) of succinic
anhydride. Yield 1.15 g (71%), mp 207–208°C.
1H NMR spectrum, δ, ppm: 2.39 m (4H, CH2CH2),
2.63 s (3H, CH3), 7.80 m (7H, Harom), 9.88 s and 10.1 s
(2H, NHNH). Found, %: C 62.41; H 5.23; N 12.70.
C17H17N3O4. Calculated, %: C 62.50; H 5.17; N 12.72.
4-Oxo-4-{2-[2-(phenylamino)benzoyl]hydrazinyl}-
butanoic acid (IIa). A solution of 0.5 g (5 mmol) of
succininc anhydride in 10 ml of chloroform was added
to a solution of 1.14 g (5 mmol) of 2-(phenylamino)-
benzohydrazide (Ia) in 10 ml of chloroform, and the
mixture was kept for 2 h at 20°C. The precipitate was
filtered off and recrystallized from aqueous ethanol.
1
Yield 1.05 g (68%), mp 154–155°C. H NMR spec-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 4 2012

KON’SHIN et al.
546
N-(2,5-Dioxopyrrolidin-1-yl)-2-(phenylamino)-
REFERENCES
benzamide (IIIa). a. A mixture of 0.4 g (4 mmol) of
succinic anhydride and 1.0 g (4.4 mmol) of hydrazide
Ia in 10 ml of glacial acetic acid was heated for 4–6 h
at 100°C. The mixture was cooled and diluted with
water, and the precipitate was filtered off and recrystal-
lized from dioxane. Yield 1.0 g (80%), mp 178–180°C.
1H NMR spectrum, δ, ppm: 2.82 m (4H, CH2CH2),
7.24 m (9H, Harom), 9.22 s (1H, C6H5NH), 10.94 s (1H,
CONH). Mass spectrum, m/z (Irel, %): 309.20 (36.88)
[M]+, 195 (100), 167 (38.5), 139 (5.0), 115 (2.4), 77
(4.4), 51 (2.3). Found, %: C 66.15; H 4.93; N 13.73.
C17H15N3O3. Calculated, %: C 66.02; H 4.85; N 13.59.
M 309.31.
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of glacial acetic acid was heated for 4–6 h at 100°C.
The mixture was cooled and diluted with water, and
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dioxane. Yield 0.25 g (53%), mp 178–180°C. The
product showed no depression of the melting point on
mixing with a sample prepared as described in a.
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Compounds IIIb and IIIc were synthesized in
a similar way (method a).
N-(2,5-Dioxopyrrolidin-1-yl)-2-(phenylamino)-
pyridine-3-carboxamide (IIIb) was obtained from
1.14 g (5 mmol) of Ib and 0.5 g (5 mmol) of succinic
anhydride. Yield 0.4 g (37%), mp 210–211°C. 1H NMR
spectrum, δ, ppm: 2.86 m (4H, CH2CH2), 7.56 m (8H,
soedinenii fizicheskimi
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H
arom), 10.15 s (1H, C6H5NH), 11.18 s (1H, CONH).
Mass spectrum, m/z (Irel, %): 310.10 (55.3) [M]+, 197
(100), 168 (71.7), 140 (7.8), 99 (8.2), 77 (17.9), 51
(6.6). Found, %: C 61.31; H 4.57; N 17.62.
C16H14N4O3. Calculated, %: C 61.65; H 4.49; N 17.73.
M 310.29.
N-(2,5-Dioxopyrrolidin-1-yl)-2-methyl-6-phenyl-
pyridine-3-carboxamide (IIIc) was obtained from
0.5 g (2.17 mmol) of Ic and 0.2 g (2 mmol) of succinic
1
anhydride. Yield 0.20 g (29%), mp 192°C. H NMR
spectrum, δ, ppm: 2.65 s (3H, CH3), 2.83 m (4H,
CH2CH2), 7.7 m (7H, Harom), 10.90 s (1H, CONH).
Mass spectrum, m/z (Irel, %): 309.10 (4.0) [M]+, 196
(100), 168 (15.9), 141 (12.5), 115 (5.9), 77 (3.0), 51
(1.3). Found, %: C 62.33; H 5.22; N 12.75.
C17H15N3O3. Calculated, %: C 62.27; H 5.01; N 12.73.
M 309.31.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 4 2012