o-Acetylaminophenylglyoxylic acid anil and its derivatives

Article abstract of DOI:10.1023/A:1015477719361

1-Acetyl- and 1-benzoyl-2- and -3-phenyliminooxoindolines were synthesized. o-(Acetylamino)-phenylglyoxylic acid anil was prepared from 1-acetyl-3-phenylimino-2-oxoindoline. More stable o-(acetylamino)phenylglyoxylanilide anil can be prepared not only from o-(acetylamino)phenylglyoxylanilide but also from an ester or chloride of o-(acetylamino)phenylglyoxylic acid anil. o-(Acetylamino)phenylglyoxylothiosemicarbazide was prepared from o-(acetylamino)phenylglyoxylic acid anil and from the corresponding anilide.

Full text of DOI:10.1023/A:1015477719361

Russian Journal of General Chemistry, Vol. 72, No. 2, 2002, pp. 244 250. Translated from Zhurnal Obshchei Khimii, Vol. 72, No. 2, 2002,
pp. 264 271.
Original Russian Text Copyright
2002 by Shirokii, Zelenin.
o-Acetylaminophenylglyoxylic Acid Anil and Its Derivatives
G. A. Shirokii and K. N. Zelenin
Academy of Military Medicine, St. Petersburg, Russia
Received January 18, 2000
Abstract 1-Acetyl- and 1-benzoyl-2- and -3-phenyliminooxoindolines were synthesized. o-(Acetylamino)-
phenylglyoxylic acid anil was prepared from 1-acetyl-3-phenylimino-2-oxoindoline. More stable o-(acetyl-
amino)phenylglyoxylanilide anil can be prepared not only from o-(acetylamino)phenylglyoxylanilide but also
from an ester or chloride of o-(acetylamino)phenylglyoxylic acid anil. o-(Acetylamino)phenylglyoxylothio-
semicarbazide was prepared from o-(acetylamino)phenylglyoxylic acid anil and from the corresponding anilide.
The stability of the ring in isatin-3-thiosemicarba-
zones determines their physicochemical properties and
biological activity [1, 2]. 1-Acetylisatin 2- and 3-anils
Ia, Ib, IIa, and IIb are stable. Data on preparation
procedures and physicochemical properties of 1-alkyl-
and 1-alkoxycarbonylisatins are systematized in [3],
whereas data on synthesis and properties of 1-acetyl-
and 1-benzoylisatins and their derivatives (in partic-
ular, anils) are scarce [4 9]; their preparation proce-
dures were not compared, and physicochemical prop-
erties were not reported. Acetylisatin 2- (IIa) and
3-anils (Ia) and 1-benzoylisatin 3-anil (Ib) were not
prepared previously. Parisi [10] reported on synthesis
of 1-acetylisatin 3-anil (Ia) without taking into ac-
count the possibility of the isatin ring opening, and
this result seems to be erroneous. Actually the com-
pound prepared in [10] is o-(acetylamino)phenylgly-
oxylanilide [11].
firmed by the presence of strong absorption bands at
1570 cm in the IR spectra of anils VIa and VIb,
originating from antisymmetric vibrations of the car-
boxylate ion [14]. o-(Acetylamino)phenylglyoxylic
acid anils VIa and VIb are very unstable in aqueous
solutions.
1
By careful evaporation of solutions of o-(acetyl-
amino)phenylglyoxylic acid anils VIa and VIb or of
solutions of the initial isatin 3-anils Ia and Ib in
ethanolic sodium ethylate, we obtained sodium salts
of o-(acetylamino)phenylglyoxylic acid anils VIIa and
VIIb, which were alkylated with methyl iodide or eth-
yl bromide to give unstable esters VIIIa and VIIIb.
Stefanovic et al. [15] reported on synthesis of methyl
ester of o-(amino)phenylglyoxylic acid hydrazone by
methylation of the corresponding hydrazone with di-
azomethane.
In Table 1 we give the preparation conditions for
Ia, Ib, IIIb, and IIIc and compare their physicochem-
ical properties with published data. In contrast to
anils Ia and Ib, 1-benzoyl-2-phenylimino-3-oxoindo-
line IIb has already been studied in [17].
The goals of this study were to prepare 1-acetyl-
isatin 2- and 3-anils and to study their structure, hy-
drolysis products, and derivatives.
We found that the reaction of 1-acetylisatins IIIa
and IIIb with aniline yields the corresponding o-(ace-
tylamino)phenylglyoxylanilides IVa and IVb, which
is consistent with the published data on reaction of
IIIa with primary amines [11]. We were able to pre-
pare 1-acetylisatin 3-anils Ia and Ib by reaction of
acetyl chloride with sodium salt of 3-phenylimino-2-
oxoindoline V. This salt undergoes slow ring cleavage
at the HN CO bond [12], which can be accompanied
by hydrolysis of the anilide group. We took advantage
of the fact that the isatin ring is unstable in basic
solutions and prepared from Ia and Ib o-(acetylami-
no)phenylglyoxylic acid anils VIa and VIb, which is
consistent with data of [12, 13]. This result is con-
For preparing the above-mentioned acylated anils,
we developed a general procedure involving acylation
of the corresponding salt IX; this procedure allows
preparation of compounds IIa and IIb of higher purity.
To prepare stable derivatives of o-(acetylamino)-
phenylglyoxylic acid anils, we attempted to perform
the reaction of esters VIIIa and VIIIb with thiosemi-
carbazide; however, we found that virtually no reac-
tion occurs in aqueous alcohol at room temperature,
and in acidic buffer solutions an intractable mixture is
formed. Therefore, we prepared o-(acetylamino)phen-
ylglyoxylothiosemicarbazide anil Xa (the chemical
1070-3632/02/7202-0244$27.00 2002 MAIK Nauka/Interperiodica

o-ACETYLAMINOPHENYLGLYOXYLIC ACID ANIL AND ITS DERIVATIVES
245
I III, VI, VII, XI, XIII, R = Me (a), Ph (b); IV, R = Me, R = Ph (a), R = R = Ph (b); R = Me, R = Et (c); VIII,
Alk = Me (a), Et (b); X, R = H (a), R = CH2Ph (b); XIV, R = Me (a), Ph (b); XV, R = R = H (a), R = H, R = Me (b),
R = R = Me (c).
form convenient for identification) from o-(acetylami-
no)phenylglyoxylanilide anil XIa. The synthesis of
o-(acetylamino)phenylglyoxylic acid alkylamides from
1-acetylisatin was reported in [11], and their structure
was proved.
The IR spectrum of the product formed by reaction
of XIa with thiosemicarbazide contains, along with
a broadened carbonyl absorption band shifted toward
longer waves, also a strong amide II band originat-
ing from interaction of the bending vibrations of the
NH group of the thiosemicarbazide fragment bonded
to the carboxy group with the NH stretching vibra-
tions of the thioamide moiety.
Reaction of equimolar amount of aniline with IIIa
and IIIb yields anilides IVa and IVb, and from
the reaction of IIIa with a tenfold excess of aniline
we obtained o-(acetylamino)phenylglyoxylanilide anil
XIa. When treated with thiosemicarbazide in a meth-
anolic solution of anhydrous HCl, compound XIa
transforms into thiosemicarbazide Xa identified by
1H NMR and IR spectra.
1
The H NMR spectrum of the presumed thiosemi-
carbazide Xa contains, along with two proton signals
of the thioamide group, also signals from protons at
the N1 and N2 atoms of the thiosemicarbazide chain
at 7.92 and 12.72 ppm. Splitting of the acetylamide
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 2 2002

246
SHIROKII, ZELENIN
Table 1. Yields, melting points, UV and IR spectra, and elemental analyses of 1-acyl-3-phenylimino-2-oxoindolines Ia
and Ib and of 1-acyl-2-phenylimino-3-oxoindolines IIa and IIb
mp,
(solvent for
crystal-
C
UV spectrum
(CHCl3),
max
nm (log )
IR spectrum
(CCl4), , cm
Found, %
H
Calculated, %
1
Formula
,
lization)
C=O C=N N C(=O)R
C
N
C
H
N
Ia 20 138 144
(benzene
cyclohexane, 455 (1.64)
3 : 1)
Ib 26 137
259 (4.01),
308 (3.61),
1755 1650
1755 1640
1702
1704
70.29, 4.72, 10.22, C16H14N2O2 68.12 5.03 10.16
70.21 4.82 10.03
237 (2.97),
263 (3.04),
591 (3.92)
47.01, 4.34, 8.55, C21H14N2O3 46.64 4.32 8.68
46.92 4.45 8.60
(m-xylene
methylene
chloride,
2 : 1)
IIa 22 133.5 [16]
282 (3.22),
352 (3.81),
461 (3.77)
1760 1655
1760 1652
1702
1704
70.33, 4.74, 10.21, C16H14N2O2 68.12 5.03 10.16
69.97 4.77 10.13
IIb 14 134.5 135
(benzene) [6]
Table 2. IR and 1H NMR spectra of thiosemicarbazides Xa, XIIa, and XIIb
IR spectrum
(CCl4), , cm
1H NMR spectrum (DMSO-d6), , ppm
1
phenyl
o-acylaminophenyl
NH
substituent
ring
COMe
C(=O)NH C N C(=O)R
Ho Hm Hp
3
4, 5
6
C(S)NH2 C(=O)NH NHC(S) NHCOR
Xa
1545, 1625 1670 2.10 s 6.98 t 7.26 8.88 8.52 6.62 t, 7.48 d,
9.74 s,
7.98 s
7.66 d
12.72 s 10.68 s,
12.56 s
12.11 s 10.10 s,
9.67 s
1505
1545,
1500
1545,
1500
t
q
t
7.22 t 7.55 s 10.14 s
XIIa
XIIb
1645 1.83 s
1670
9.02 7.11 s, 7.33 d
7.37 q
7.72 d, 7.93 7.99 8.76 7.20 t, 7.40 t
7.74 d 7.60 t
8.60 s
8.31 s
q
8.00 m 12.75 s 11.19 s
t
d
d
1
proton signal in the H NMR spectrum of Xa ( 10.68
and 12.56 ppm) suggests the presence of the Z and E
isomers of Xa with respect to the N C=O bond in the
acetylamino group.
of the carbonyl groups in the acylamide moieties at
1660 1665 cm .
1
1
The H NMR spectra of thiosemicarbazides XIIa
and XIIb, along with the signals of two protons of the
thioamide group at 8.83 and 9.11 ppm (for XIIb),
contain the signals originating from the protons at the
amide nitrogen atom of the acylamide group ( 8.47
and 8.34 ppm, respectively, for XIIa and XIIb). In
To confirm the structure of the product formed by
the reaction of XIa with thiosemicarbazide, we exam-
ined the possibility of preparing o-(acetylamino)phen-
ylglyoxylic acid derivatives VIIIa and VIIIb from
anilides IVa and IVb under conditions of synthesis
of Xa. Anilides IVa and IVb were prepared according
to [11]; compound IVb was unknown previously.
Reactions of IVa and IVb with thiosemicarbazide
yield individual compounds whose IR spectra contain
absorption bands of carbonyl groups at 1690 cm 1 and
of the C=O bond in the amide group of the thiosemi-
1
the H NMR spectrum of XIIb, the proton signal of
the acetylamino group is also split owing to the Z E
isomerism (Table 2).
The 13C NMR spectrum of XIIa, along with six
signals of the aromatic carbon atoms, contains signals
originating from the carbon atoms of the acetylamino
1
carbazide chain at 1625 cm , and also the bands
group ( 161.17 and 161.47 ppm, Z and E isomers),
C
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o-ACETYLAMINOPHENYLGLYOXYLIC ACID ANIL AND ITS DERIVATIVES
247
carbonyl group of the carbonylamide fragment (
158.89 ppm), and carbonyl and thiocarbonyl groupCs
(see Experimental).
anol. The resulting suspension was shaken for 15 min
with cooling on a water bath. The suspension was
filtered, and the precipitate was dried in a vacuum at
70 C over granulated KOH; yield of dark violet crys-
talline salt V 7.7 g (70%).
o-(Acetylamino)phenylglyoxylanilide anil XIa,
which is an intermediate in synthesis of Xa, is formed
in a higher yield from chlorides of o-(acetylamino)-
phenylglyoxylic acid anils XIIIa and XIIIb, which
are prepared by reaction of oxalyl chloride with VIIa
and VIIb (see Experimental).
A 6.5-g portion of V was suspended in 80 ml of
anhydrous benzene, with protection from atmospheric
moisture. To this suspension, 2.5 ml of freshly dis-
tilled acetyl chloride was added dropwise with cooling
on an ice bath. The mixture was warmed up to 55 C
over a period of 40 min and stirred at this temperature
for 2.5 h. To the resulting solution, 32 ml of anhy-
drous benzene was added, and the mixture was quick-
ly filtered while hot. The precipitate was treated with
dry ethyl acetate (2 15 ml), and the crystalline prod-
uct was separated and vacuum-dried at 70 C; Rf 0.23
(cyclohexane methyl acetate, 3 : 1).
Reaction of o-(acetylamino)phenylglyoxylothio-
semicarbazide XIIa with an equimolar amount of
aniline does not yield Xa.
We have also examined the possibility of preparing
the structural isomer of o-(acetylamino)phenylglyox-
ylic acid, o-(acetylamino)phenylglyoxylanilide XIVa,
which can be prepared by hydrolysis of 1-acetyl-2-
phenylimino-3-oxoindoline IIa. In contrast to 1-acyl-
3-phenylimino-2-oxoindolines Ia and Ib, anil IIa,
when heated in aqueous acetone, does not undergo
cleavage of the isatin ring. The absorption band at
1-Benzoyl-3-phenylimino-2-oxoindoline Ib. Salt
V was prepared as described above for Ia from 1 g
of 3-phenylimino-2-oxoindoline. The product (0.7 g,
63%) was suspended in 10 ml of dry benzene, with
protection from atmospheric moisture. To this suspen-
sion, 0.84 ml of purified and distilled benzoyl chloride
was added with cooling on a water bath. The mixture
was warmed up to room temperature over a period of
10 min. To the resulting precipitate, 3 ml of toluene
was added, and the precipitate was filtered off and
vacuum-dried over granulated NaOH at 70 C; Rf 0.98
(butanol acetic acid water, 4 : 5 : 1).
1
3060 3430 cm , assignable to the acetylamino group
[16] in XIVa, appears only on treatment of IIa with
weakly alkaline aqueous solutions. The compound ob-
tained from hydrolysis of IIa is similar in the phys-
icochemical properties to the structural isomer, o-(ace-
tylamino)phenylglyoxylanilide IVa.
From the reaction of anil II with thiosemicarbazide
and its alkyl derivatives under standard conditions of
synthesis of thiosemicarbazones [18], we prepared
thiosemicarbazides XVa XVc, stable without heating
in neutral solutions. The 13C NMR spectrum of XIIa,
along with six signals of aromatic carbon atoms,
contains two signals belonging to the carbon atoms
in acetylamino group of the Z and E isomers (see
Experimental).
1-Acetyl-2-phenylimino-3-oxoindoline IIa. Sodi-
um salt IX was prepared as described above from
1.31 g of 2-phenylimino-3-oxoindoline. The product
(0.9 g, 72%) was suspended in 10 ml of dry ben-
zene. The suspension was cooled on an ice bath, and
0.36 ml of acetyl chloride was added. The mixture was
stirred at 0 C for 20 min, gradually warmed up to
55 C, and kept at this temperature for 80 min. To the
hot solution, 10 ml of dry boiling benzene was added.
The solution was filtered, allowed to cool to room tem-
perature, and then carefully evaporated at a bath tem-
perature of 35 C. The resulting dark brown oily mass
crystallized on treatment with pentane (3 6 ml). The
dark brown crystalline product was filtered off and
vacuum-dried at 50 C; yield of IIa 0.08 g (15%). The
pentane extract was evaporated to dryness and treated
with CCl4 (2 2.5 ml); the crystalline precipitate was
filtered off and dried. An additional crop of IIa (0.02 g,
EXPERIMENTAL
The IR spectra were taken on Specord-75, UR-10,
and SF-22 spectrophotometers (KBr pellets or solu-
1
tions in CCl4 or CF3Cl). The H NMR spectra were
recorded on a Tesla-497 spectrometer (100.1 MHz)
in DMSO-d6 and CDCl3, and also on a Bruker CXP-
300 spectrometer (300 MHz); internal reference
HMDS. The 13C NMR spectra were taken on a Bruker
CXP-300 spectrometer (75 MHz), internal reference
DMSO-d6. The product purity was checked by TLC
on Silufol UV-254 plates (UV development).
1
4%) was obtained. IR spectrum (CCl4), , cm : 1655
(C=N), 1702 (C=O in COCH3), 1760 (C=O).
1-Acetyl-3-phenylimino-2-oxoindoline Ia. A solu-
tion of 10 g of 3-phenylimino-2-oxoindoline [19],
dried over P2O5, in 90 ml of absolute methanol was
added to a solution of sodium methylate, prepared
from 1.17 g of sodium metal and 70 ml of dry meth-
1-Benzoyl-2-phenylimino-3-oxoindoline IIb was
prepared similarly according to [6].
1-Acetylisatin IIIa and 1-benzoylisatin IIIb were
prepared according to [5, 7] from sodium isatin [20].
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 2 2002

248
SHIROKII, ZELENIN
o-(Acetylamino)phenylglyoxylanilide IVa was
prepared according to [11]; mp 177 C [11]. Rf 0.34
o-(Benzoylamino)phenylglyoxylanilide IVb.
A 0.26-g portion of 1-benzoyl-3-phenylimino-2-oxo-
indoline Ib was dissolved in 1 ml of 1 M aqueous
K2CO3 with heating on a water bath for 15 min. The
resulting suspension was cooled to room temperature
and then with ice-cold water, after which it was neu-
tralized with 0.8 ml of 2 N HCl. The yellow-green
precipitate was filtered off and dried in a vacuum de-
siccator. Yield of IVb 0.04 g (24%); mp 166 167 C.
(cyclohexane ethyl acetate, 5 : 2). IR spectrum (KBr),
1
, cm : 1675 (C=O of carbonylanilide moiety), 1685
(C=O of the phenylglyoxyl moiety), 3240 (NH of the
anilide group).
o-(Benzoylamino)phenylglyoxylanilide IVb.
a. To a solution of 0.1 g of 1-benzoylisatin IIIb in
4 ml of dry methanol was added 0.36 ml of aniline;
the mixture was refluxed with stirring for 2 h, the
solution was cooled, and the precipitate was collected;
yield of IVb 0.04 g (53%), mp 177.5 C.
o-(Acetylamino)phenylglyoxylic acid anil, methyl
ester VIIIa. A solution of 0.27 g of 1-acetyl-3-phenyl-
imino-2-oxoindoline Ia, dried in a vacuum desiccator
over P2O5, in 6 ml of absolute methanol was gradually
added to a sodium methylate solution prepared from
0.057 g of sodium metal and 3 ml of methanol. The
mixture was evaporated to dryness, 2 ml of DMF and
0.15 ml of methyl iodide were added, and the mixture
was kept at 0 C for 12 h. The resulting precipitate was
filtered off; yield of VIIIa 0.05 g (16%). Crystalliza-
tion from ethyl acetate gave a sample with mp 86
b. A 0.34-g portion of sodium salt of o-(benzoyl-
amino)phenylglyoxylic acid [21] dried in a vacuum
desiccator over granulated NaOH was suspended in
7 ml of benzene dried over sodium metal. To the fine
suspension of the salt, 0.41 ml of freshly distilled
oxalyl chloride was added dropwise with cooling on
a bath with ice-cold water over a period of 5 min, and
then a mixture of 0.4 ml of freshly distilled aniline and
4 ml of diethyl ether was added dropwise at 10 C. The
suspension was stirred for 15 min. The resulting thick
precipitate was filtered off and dried for 2 h at 70 C.
Yield of o-(benzoylamino)phenylglyoxylanilide hydro-
chloride 0.31 g (53%); mp 177.5 179 C. Found, %:
C 39.96; H 4.24; N 7.23. M 330.86.1 C21H17Cl2N2O2.
Calculated, %: C 39.96; H 4.23; N 7.35. M 380.88.
1
87 C. IR spectrum (CHCl3), , cm : 1400 1410
[C(=O)Me], 1660 [C=O in C(=O)Me]. The compound
is insufficiently stable for recording the UV spectrum.
o-(Acetylamino)phenylglyoxylic acid anil, ethyl
ester VIIIb. A solution of sodium methylate prepared
from 0.057 g of sodium metal and 3 ml of methanol
was added to a solution of 0.65 g of 1-acetyl-2-phenyl-
imino-2-oxoindoline Ia, dried over P2O5, in 10 ml of
anhydrous ethanol. The mixture was quickly filtered
with protection from atmospheric moisture. The filtrate
was allowed to stand at room temperature for 4 min
and then evaporated to dryness; 2 ml of DMF and
0.65 ml of ethyl bromide were added. The mixture was
kept at 0 C, and the precipitate was filtered off. Yield
of VIIIb 0.18 g (21%). After crystallization from
toluene hexane cyclohexane (3 : 4 : 1), mp 163 C. IR
Neutralization of this hydrochloride with 0.5 M
aqueous Na2CO3 gave IVb; yield 0.14 g (41%).
o-(Acetylamino)phenylglyoxylethylamide IVc
was described in [11].
o-(Acetylamino)phenylglyoxylic acid anil VIa.
a. A solution of 0.13 g of 1-acetyl-3-phenylimino-
2-oxoindoline Ia in 5 ml of 30% aqueous ethanol was
refluxed for 1.5 h. The precipitate was filtered off and
dried in a vacuum desiccator over granulated KOH;
1
spectrum (CF3Cl CHCl3, 3 : 1), , cm : 1450 (C=O
1
yield of VIa 0.1 g (65%); mp 164 165 C. H NMR
in COOEt), 1670 (C=O in COMe). The compound is
insufficiently stable for recording the UV spectrum.
spectrum (CD3OD), , ppm: 2.10 s (3H, COMe),
6.40, 6.50 m (1H, Ar H), 6.92 s (1H, Ar H), 7.10
7.30 m (3H, Ar H), 7.53 7.66 m (4H, Ar H), 8.07 d
(1H, NH).
o-(Acetylamino)phenylglyoxylothiosemicarbazide
anil Xa. a. A solution of 0.36 g of thiosemicarbazide
in 3 ml of methanol was added to a solution of 0.55 g
of o-(acetylamino)phenylglyoxylanilide anil IXa in
6 ml of absolute methanol containing 0.5% HCl. The
mixture was heated for 3 h with protection from at-
mospheric moisture on a water bath at a temperature
no higher than 50 C. A part of the solvent was vacu-
um-evaporated, and the mixture was cooled on an ice
bath. The precipitate was filtered off and dried in a
vacuum desiccator over CaCl2. o-(Acetylamino)phen-
ylglyoxylothiosemicarbazide anil hydrochloride was
obtained; yield 0.43 g (68%), mp 180 183 C. Neutra-
lization with aqueous Na2CO3 and drying gave XIa;
b. A 0.42-g portion of 1-acetyl-3-phenylimino-2-
oxoindoline Ia was dissolved in 2.5 ml of 1.6 N aque-
ous K2CO3, and the solution was heated on a boiling
water bath for 10 min. Then the solution was cooled
with ice-cold water and neutralized with 2 ml of 2 N
HCl to pH 6. The precipitate was filtered off and
vacuum-dried at 70 C over granulated KOH; yield of
VIa 0.2 g (54%). The product is identical to that pre-
pared by method a.
1
The molecular weight was determined by comparing the heats
of vaporization of dioxane solutions.
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o-ACETYLAMINOPHENYLGLYOXYLIC ACID ANIL AND ITS DERIVATIVES
249
mp 160 164 C, Rf 0.53 (ethyl acetate chloroform,
7 : 1). H NMR spectrum (CD3CN), , ppm: 1.82 s
c. A 0.42-g portion of IVa was dissolved in 35 ml
of absolute methanol with heating and stirring, and
a mixture of 1.8 ml of aniline and 2 ml of absolute
methanol was added. The mixture was refluxed for
2.5 h with protection from atmospheric moisture.
After cooling to room temperature, the precipitate was
filtered off and dried in a vacuum desiccator over
granulated KOH. Yield of XIa 0.14 g (43%), mp 157
1
(6H, Me in COMe, Z and E isomers), 6.56 d, 6.62 d
(1H, Ar H), 7.05 7.48 m (7H, Ar H), 7.84 s [1H,
NHC(=O) in thiosemicarbazide moiety], 8.20 s (1H,
Ar H), 8.50 s [1H, NH2C(S)], 9.00 9.12 m [1H,
NH2C(S) in thiosemicarbazide moiety], 12.58 s [1H
at N2H in NHC(S)]. Found, %: C 57.22; H 4.86; N
20.22. C17H17N5O2. Calculated, %: C 57.40; H 4.76;
N 19.96.
1
158 C (from 1-butanol). IR spectrum (CCl4), , cm :
1640 (C=N), 1680 [C=O in C(=O)NHPh], 1693 [C=O
in C(=O)Me], 3190 (N1H). 13C NMR spectrum
(DMSO-d6), C, ppm (the signal of the carbon atom
of the solvent is not given): 29.10 (1C, Me), 116.03
(1C, Ar C), 116.96 (1C, Ar C), 128.33 (2C, Ar C),
129.44 (2C, Ar C), 129.65 (1C, Ar C), 131.88 (1C,
Ar C), 134.53 (1C, Ar C), 135.07 (1C, Ar C),
136.71 (1C, Ar C), 136.82 (1C, C=N), 161.03 [1C,
C=O in C(=O)Me]. Found, %: C 92.84; H 4.57; N
11.08. C27H21N3O2. Calculated, %: C 92.99; H 4.87;
N 11.28.
b. A 1.2-g portion of ethyl ester of o-(acetylamino)-
phenylglyoxylic acid anil VIIIb was mixed with
1.76 g of finely divided thiosemicarbazide, and 16 ml
of ethanol was added. After a day, the resulting
suspension was filtered. The filtrate was vacuum-
evaporated at a temperature not exceeding 45 C. The
1
residue, according to TLC and H NMR spectra, was
a mixture of three compounds. The precipitate was
washed with hot chloroform and treated with hot
acetone; the extract was vacuum-evaporated, and
0.21 g (14%) of Xa was obtained.
o-(Benzoylamino)phenylglyoxylanilide anil XIb.
First, anil VIb was prepared: 0.42 g of Ib was heated
with a solution of 0.2 g of Na2CO3 in 2 ml of water
on a boiling water bath for 10 min, and the
mixture was cooled on an ice bath and neutralized
with 1.6 ml of 2 M HCl. The precipitate was filtered
off, and compound VIb was obtained. The product
(0.08 g, 18%) was dissolved in a sodium methylate
solution prepared as described for V. The resulting
solution was evaporated, and the residue containing
sodium o-(benzoylamino)phenylglyoxylate VIIb was
dried in a vacuum desiccator over NaOH and treated
with dry benzene (6 1 ml). The resulting product
[VIIb, yield 0.03 g (36%)] was dissolved in 1.5 ml of
benzene, and 0.15 ml of freshly distilled oxalyl chlo-
ride was added, which resulted in precipitation of
chloride XIIIb. The precipitate was filtered off and
vacuum-dried at 60 C. Transformation into XIb was
performed as described above for XIa (procedure a);
XIb, mp 148 149.5 C.
o-(Acetylamino)phenylglyoxylo(4-benzyl)thio-
semicarbazide anil Xb was prepared similarly to Xa
by procedure b from VIIIb. Benzylthiosemicarbazide
was prepared according to [22]. Along with ethanol,
the reaction of VIIIb with benzylthiosemicarbazide can
also be performed in ethyl acetate. The reaction occurs
within 1.5 h on heating; yield of Xb 2.6 g (40%), mp
1
198 204 C. H NMR spectrum (acetone-d6), , ppm:
2.10 s (3H, Me in NHCOMe), 4.97 d (2H, CH2Ph),
6.90 7.10 m (2H, Ar H), 7.15 7.37 t (10H, Ar H),
7.91 s [1H, NH(C=O) in thiosemicarbazide moiety],
9.13 d (1H, Ar H), 9.98 10.00 m (1H, Ar H), 10.12 d
(1H, NHCH2Ph), 12.72 s (1H, NHCOCH3, Z isomer),
12.79 s (1H, N2H of thiosemicarbazide moiety).
o-(Acetylamino)phenylglyoxylanilide anil XIa.
a. Oxalyl chloride (0.3 ml) was added dropwise with
shaking and cooling on an ice bath to a solution of
0.09 g of VIIa in 2 ml of dry methylene chloride.
The solution was shaken while cooling in ice. Chlo-
ride of o-(acetylamino)phenylglyoxylic acid anil VIIIa
was obtained, to which a mixture of 0.07 ml of aniline
in 0.05 ml of diethyl ether was immediately added
dropwise. The resulting precipitate was filtered off
and dried in a vacuum desiccator over granulated
alumina. Yield of XIa 0.05 g (48%); mp 157 158 C.
o-(Acetylamino)phenylglyoxylothiosemicarbazide
XIIa. A 0.42-g portion of o-(acetylamino)phenylgly-
oxylanilide was dissolved in 15 ml of a 3% solution
of HCl in absolute methanol. The solution was heated
with protection from atmospheric moisture for 3 h at
a bath temperature not exceeding 50 C. The solution
was vacuum-evaporated to a volume of 3 ml and
cooled. The precipitate was filtered off and dried in
a vacuum desiccator over CaCl2. The thiosemicarba-
zide was obtained in the form of hydrochloride; yield
0.36 g (58%), mp 187 188 C; melting point after
neutralization with 1.5 ml of 1 M of aqueous Na2CO3
and vacuum drying 182 184 C (Table 2). UV spec-
b. A 0.29-g portion of IIIa was dissolved in 3.5 ml
of absolute methanol with heating and stirring, and
1.4 ml of aniline was added. The mixture was refluxed
for 2.5 h with protection from atmospheric moisture;
after cooling, the thick precipitate was filtered off and
dried in a vacuum desiccator over granulated KOH;
yield of XIa 0.14 g (43%), mp 157 158 C.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 2 2002

250
SHIROKII, ZELENIN
trum (CHCl3), max, nm (log ): 242 (4.70), 306
(3.81). 13C NMR spectrum (DMSO-d6), C, ppm (the
signal of the solvent carbon atom is not given): 23.17
(1C, Me, Z isomer), 26.58 (1C, E isomer), 121.0
(1C, Ar C), 124.7 (1C, Ar C), 129.9 (1C, Ar C),
139.35 (1C, Ar C), 161.17 (1C, NHCO), 161.43 (1C,
NHCO), 169.89 (1C, C=O), 178.69 (1C, CONH),
181.41 (1C, CSNH2). Found, %: C 43.11; H 4.25;
N 18.34. C11H13ClN4O3. Calculated, %: C 43.06;
H 4.26; N 18.26.
3. Tacconi, G., Righetti, N., and Desimone, G., J. Pr.
Chem., 1973, vol. 315, no. 2, p. 339.
4. Suida, W., Chem. Ber., 1878, vol. 1, no. 2, p. 584.
5. Gamps, R., Arkiv Pharm., 1899, vol. 237, no. 2,
p. 687.
6. Hantzch, A. and Krober, W., J. Pr. Chem., 1927,
vol. 115, no. 1, p. 126.
7. Callow, R.K. and Hope, E., J. Chem. Soc., 1929,
no. 2, p. 1131.
8. Gulland, J.M. and Haworth, R.D., J. Chem. Soc.,
1929, no. 3, p. 1666.
9. Stenkopf, W. and Wilhelm, H., Lieb. Ann., 1940,
o-(Benzoylamino)phenylglyoxylothiosemicarba-
zide XIIb was prepared similarly to XIIa. Neutraliza-
tion of the hydrochloride with 1 M aqueous Na2CO3
gave XIIb; mp 180 181 C. UV spectrum (ethanol),
max, mn (log ): 244 (4.10), 306 (3.77).
vol. 546, no. 1, p. 211.
10. Parisi, F., J. Am. Chem. Soc., 1952, vol. 75, no. 12,
p. 3848.
11. Popp, F.D. and Picirilli, R.M., J. Heterocyclic Chem.,
1972, vol. 8, no. 3, p. 473.
12. Restariale, A. and Domansky, R., Chem. Zvesti, 1973,
vol. 27, no. 1, p. 227.
13. Johnston, H. and Price, R., Aust. J. Chem., 1954,
o-(Acetylamino)phenylglyoxylanilides XIVa and
XIVb. A 0.15 g portion of IIa or 0.11-g portion of
IIb was dissolved in 2 or 1 ml, respectively, of 1 M
aqueous Na2CO3. The mixture was heated on a boil-
ing water bath for 30 min and, after cooling, neutra-
lized with 2 M HCl to pH 7.0. The precipitated crys-
tals were dried in a vacuum desiccator over granulated
CaCl2. XIVa: yield 0.03 g (31%), mp 197 C; IR spec-
vol. 74, no. 1, p. 204.
14. Silverstein, R.M., Bassler, G.C., and Morrill, T.C.,
Spectrometric Identification of Organic Compounds,
New York: Wiley, 1974, 3rd ed.
1
15. Stefanovic, Gj., Pavicic-Woss, M., Lorenc, Li., and
trum (CCl4), , cm : 1545 (C=O), 1665 (C=O in
COMe), 3080 (Me in C(=O)NHMe]. XIVb: yield
Mihailovik, K., Tetrahedron, 1959, vol. 6, no. 1, p. 97.
16. Ioffe, B.V., Kostikov, R.R., and Razin, V.V., Fizi-
cheskie metody opredeleniya stroeniya organicheskikh
soedinenii (Physical Methods for Determination of the
Structure of Organic Compounds), Moscow: Vysshaya
Shkola, 1984, p. 13.
0.04 g (43%), mp 214 C; IR spectrum (CCl4),
cm : 1545 (C=O), 1660 (C=O in COPh), 3100 (NH).
,
1
1-(3-Oxoindol-2-yl)thiosemicarbazide XVa was
prepared according to [23].
17. Mostoslavskii, M.A. and Shevchuk, I.N., Khim.
Geterotsikl. Soedin., 1970, no. 1, p. 21.
18. Shriner, R.L., Fuson, R.C., Curtin, D.Y., and Mor-
rill, T.C., The Systematic Identification of Organic
Compounds. A Laboratory Manual, New York: Wiley,
1980, 6th ed. Translated under the title Identifikatsiya
organicheskikh soedinenii, Moscow: Mir, 1983, p. 20.
1-(3-Oxoindol-2-yl)(4 -methyl)thiosemicarbazide
XVb and 1-(3-oxoindol-2-yl)(4 ,4 -dimethyl)thio-
semicarbazide XVc, along with the synthesis from
isatin methyl ether [24], can also be prepared from
2-phenylimino-3-oxoindoline II; the UV and IR data
for these compounds are given in [24]. 4-Methylthio-
semicarbazide was prepared according to [25].
19. Pummerer, R. and Gottler, M., Chem. Ber., 1910,
vol. 43, no. 8, p. 1376.
20. Deussen, E., Heller, G., and Notzel, O., Chem. Ber.,
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22. Hoggart, E. and Young, E.H.P., J. Chem. Soc., 1950,
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23. Ioffe, I.S., Tomchin, A.B., and Shirokii, G.A., Zh.
Org. Khim., 1971, vol. 7, no. 1, p. 179.
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25. Jensen, K.A., Antoni, U., Kagi, B., Larsen, Ch., and
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p. 1.
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