Synthesis of isatin and 5-bromoisatin derivatives

Article abstract of DOI:10.1023/A:1013412330472

New N-derivatives of isatin were synthesized by treating ethyl chloroacetate, N-(2-chloroethyl)-morpholine, and 1,4-di(chloromethyl)benzene with isatin sodium salt. N-Derivatives of isatin and 5-bromoisatin were also prepared by Mannich reaction.

Full text of DOI:10.1023/A:1013412330472

Russian Journal of Organic Chemistry, Vol. 37, No. 10, 2001, pp. 1476 1477. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 10, 2001,
pp. 1545 1546.
Original Russian Text Copyright
2001 by Mesropyan, Ambartsumyan, Avetisyan, Sarkisyan, Amazaspyan.
Synthesis of Isatin and 5-Bromoisatin Derivatives
E. G. Mesropyan, G. B. Ambartsumyan, A. A. Avetisyan,
M. G. Sarkisyan, and G. S. Amazaspyan
Yerevan State University, 375049 Armenia
Received August 11, 2000
Abstract New N-derivatives of isatin were synthesized by treating ethyl chloroacetate, N-(2-chloroethyl)-
morpholine, and 1,4-di(chloromethyl)benzene with isatin sodium salt. N-Derivatives of isatin and 5-bromo-
isatin were also prepared by Mannich reaction.
In extension of our studies in the field of isatin
chemistry [1 4] we carried out syntheses of new
N-substituted derivatives of isatin and 5-bromoisatin.
EXPERIMENTAL
IR spectra were recorded on UR-20 instrument,
1H NMR spectra were registered on spectrometer
Mercury-300 Varian at operating frequency
300 MHz from solutions in DMSO (compounds V
VII) and acetone-d6 (compounds IX XIV), internal
reference HMDS.
We established that reaction of isatin (I) in the
form of its sodium salt with various haloderivatives
II IV at molar ratio of reagents 1: 1 or 2: 1 in di-
methylformamide gave rise to compounds V VII. In
Mannich reaction isatin (I) and 5-bromoisatin (VIII)
form with formaldehyde, glycine, alanine, and
sarcosine compounds IX XIV. A crucial importance
for reaction has a choice of solvent: in ethanol the
reaction fails whereas in acetic acid compounds XI
XIV are obtained in up to 45% yield (see table).
The homogeneity and purity of compounds
obtained was checked by TLC on Silufol UV-254
plates, eluent dioxane heptane (1 1.8 : 1), develop-
ment in iodine vapor (compounds V VII), and a
system benzene ethyl acetate diethylamine (30: 8: 2),
development under UV irradiation (compounds
IX XIV).
1-Ethoxycarbonylmethyl)isatin (V). To a solu-
tion of 25 mmol of isatin (I) sodium salt in 30 ml of
anhydrous DMF was added 25 mmol of ethyl chloro-
acetate. The mixture was heated for 3 h, then the
solvent was distilled off, and the residue was dis-
solved in cold water. The part of the product that did
not dissolve was recrystallized from water. The target
product is a yellow crystalline solid (mp 125 C), well
soluble in ethyl ether, ethanol, DMSO, insoluble in
hexane and carbon tetrachloride. IR spectrum,
,
1
cm : 1600 (Ar), 1720 1740 (C=O). 1H NMR
spectrum (DMSO), , ppm: 7.0 7.8 m (4H, Ar H),
4.6 s (2H, NCH2), 4.2 q (2H, CH2 CH3), 1.3 t (3H,
CH2CH3 ).
We prepared yellow-brown thiosemicarbazone of
compound V, mp 230 235 C, and phenylhydrazone
of compound V, mp 165 C [2, 4].
Compound VI was obtained in a similar way.
X = H (I, IX XI), Br (VIII, XII XIV); X = CO2Et
(II, V), morpholinomethyl (III, VI), p-phenylene
(IV, VII), NHCH2CO2H (IX, XII), NHCH(Me)CO2H
(X, XIII), N(Me)CH2CO2H (XI, XIV); n = 1 (II,
III), 2 (IV).
Compound VII was prepared along a modified
procedure. To a solution of salt (I) in 50 ml of an-
hydrous DMF was added 30 mmol of 1,4-di(chloro-
methyl) benzene. The reaction mixture was stirred at
1070-4280/01/3710-1476$25.00 2001 MAIK Nauka/Interperiodica

SYNTHESIS OF ISATIN AND 5-BROMOISATIN DERIVATIVES
1477
room temperature till the color completely changed
from violet to orange-brown. Then the reaction mix-
ture was poured into ice water. The undissolved part
was recrystallized from water. Compound VII
obtained, mp 320 C, is soluble in chloroform,
DMSO, insoluble in ethanol and ethyl ether. IR
added 30 ml of ethanol, and the residue was recrystal-
lized from ethyl acetate.
REFERENCES
1. Mesropyan, E.G., Martirosyan, E.V., Ambartsu-
myan, G.B., Galoyan, L.A., and Avetisyan A.A.,
Arm. Khim. Zh., 1989, vol. 42, no. 4, pp. 264 266.
2. Zhungietu, G.I. and Rekhter, M.A., Izatin i ego pro-
izvodnye (Isatin and Derivatives), Kishinev: Shtiintsa,
1977.
3. Movrin, M., Marok, E., et al., Acta Pharm. Jugosl.,
1982, vol. 32, no. 3, pp. 169 175.
4. Tomchin, A.B. and Krylova, N.M., Zh. Org. Khim.,
1986, vol. 22, no. 11, pp. 2420 2434.
1
spectrum, , cm : 1600 (Ar), 1725 1740 (C=O),
1
3520 (NH). H NMR spectrum (DMSO), , ppm:
8.0 6.6 m (12H, Ar H), 4.4 q (4H, CH2).
Aminoacids IX XIV. A mixture of 25 mmol of
isatin (bromoisatin), 25 mmol of aminoacid, and
37.5 mmol of paraformaldehyde in 25 ml of glacial
acetic acid was heated on a boiling water bath for 2 h.
The solvent was distilled off, to the residue was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 10 2001