Synthesis of 1-alkyl-3-arylamino-pyrrole-2,5-diones

Article abstract of DOI:10.1007/s10593-007-0134-6

Reaction of 1-alkyl-3-alkylaminopyrrole-2,5-diones with primary arylamine hydrochlorides in methanol or DMSO gives 1-alkyl-3-arylaminopyrrole-2,5-diones which could also be obtained from the reaction of arylaminofumarates with primary aliphatic amines.

Full text of DOI:10.1007/s10593-007-0134-6

Chemistry of Heterocyclic Compounds, Vol. 43, No. 7, 2007
SYNTHESIS OF 1-ALKYL-3-ARYLAMINO-
PYRROLE-2,5-DIONES
S. V. Chepyshev, Yu. N. Mazurkevich,
O. S. Lebed', and A. V. Prosyanik
Reaction of 1-alkyl-3-alkylaminopyrrole-2,5-diones with primary arylamine hydrochlorides in methanol
or DMSO gives 1-alkyl-3-arylaminopyrrole-2,5-diones which could also be obtained from the reaction
of arylaminofumarates with primary aliphatic amines.
Keywords: arylaminofumarates, maleimide, pyrrole-2,5-dione, transamination.
3-Arylaminopyrrole-2,5-dione derivatives show fungistatic [1], herbicidal, insecticidal [2], and antitumor
activity [3] and are used for the treatment and/or prophylaxis of cancer as well as conditions needing inhibition
of the enzyme GSK-3 (diabetes, Alzheimer disease, and acute stroke) [4].
The synthesis of 3-arylaminopyrrole-2,5-diones and their 1-alkyl derivatives is based on the cyclization
of arylaminofumarates with ammonia [5], treatment of maleimides with arylhydroxylamines [6], or on the
reaction of 3-halo- [4, 5, 7, 8] or 3-hydroxy- [4, 8] pyrrole-2,5-diones with arylamines. It is also known that
enamines are transaminated by amines under conditions of acid or base catalysis: 1,4-bis(dimethylamino)-1,3-
butadiene by aryl and alkylamines in the presence of catalytic amounts of acetic and/or hydrochloric acid [9] and
1-nitro-2-dimethylaminopropylene by ammonia and alkylamines (without acid) or arylamines in the presence of
an equimolar amount of p-toluenesulfonic acid [10].
We have studied the reaction of 1-alkyl-3-alkylaminopyrrole-2,5-diones with arylamines with the aim of
preparing 1-alkyl-3-arylaminopyrrole-2,5-diones.
It was found that 1-methyl-3-methylaminopyrrole-2,5-dione 1 does not react with aniline at a reagent
ratio from 1: 1 to 1: 3 under various conditions (refluxing in methanol, heating at 100-120ºC in DMSO, or at
100ºC without solvent over 5-40 h in the absence or presence of a catalytic or an equimolar amount of acetic
acid. By contrast maleimide 1 reacts rapidly with an equimolar amount of the arylamine hydrochlorides 2a-m by
heating for 1 h in methanol or DMSO to give good yields of the corresponding 3-arylamino-1-methylpyrrole-
2,5-diones 3a-m (Tables 1, 2). In a similar reaction 1-(2-hydroxyethyl)-3-(2-hydroxyethylamino)pyrrole-
2,5-dione reacts with p-anisidine hydrochloride to give 1-(2-hydroxyethyl)-3-(p-methoxyphenylamino)pyrrole-
2,5-dione (3n) (Tables 1, 2). The reaction of maleimide 1 with an equimolar amount of aniline in the presence of
15 mole % of aniline hydrochloride (refluxing in methanol for 1 h) gave a low yield (5%) of the 1-methyl-
3-phenylaminopyrrole-2,5-dione 3a.
__________________________________________________________________________________________
Ukrainian
State
Chemical
Engineering
University,
Dnepropetrovsk
49005;
e-mail:
schepyshev@gmail.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1001-1007, July,
2007. Original article submitted February 28, 2007.
844
0009-3122/07/4307-0844©2007 Springer Science+Business Media, Inc.

1
According to the H NMR spectra of the reaction products the maleimide 1 does not react with
benzylamine (molar ratio of reagents 1: 1 or 1: 2, 90% aqueous methanol, 18 days at 20ºC or 1: 2, 90% aqueous
methanol, 10 h at 20ºC with subsequent refluxing for 8 h) and the 1-benzyl-3-benzylaminopyrrole-2,5-dione is
inert towards methylamine (molar ratio of reagents 1: 3, 90% aqueous methanol, 10 h at 20ºC and 8 h at 95ºC in
a sealed ampul). At the same time, refluxing maleimide 1 in a 5 fold excess of morpholine gave a 1: 1 mixture of
maleimide 1 and 1-methyl-3-morpholinopyrrole-2,5-dione (3o) (Tables 1, 2) (from the corresponding CH signals
at 4.73 and 5.13 ppm in the 300 MHz 1H NMR spectrum). Treatment of maleimide 1 with an equimolar amount
of benzylamine hydrochloride gave a satisfactory yield of 3-benzylamino-1-methylpyrrole-2,5-dione 3p
(Tables 1, 2). By contrast 1-methyl-3-phenylaminopyrrole-2,5-dione does not react with an equimolar amount of
benzylamine or its hydrochloride (refluxing in methanol for 1 h).
NHMe
O
NHAr
O
.
ArNH2 HCl
+
O
N
O
N
2a-m
Me
1
Me
3a-m
2,3 a Ar = Ph, b Ar = p-BrC6H4, c Ar = p-MeC6H4, d Ar = m-MeC6H4, e Ar = o-MeOC6H4,
f Ar = p-HOC6H4, g Ar = p-O2NC6H4, h Ar = m-O2NC6H4, i Ar = m-HOCH2CH2OC6H4,
j Ar = p-Me2NC6H4, k Ar = p-Me2NC6H4 ⋅HCl, l Ar = p-H2NSO2C6H4,
MeO
N
NHSO C H -
p
2 6 4
m
Ar =
N
MeO
NHAr
O
MeO2C
NHAr
CO2Me
RNH2
+
O
N
R
4a, c
3a, 5a–c
5 a Ar = Ph, R = PhCH2; b Ar = p-MeC6H4, R = PhCH2,
c Ar = p-MeC6H4, R = CH2CH2OH
It is known that the reaction of anilinofumarate 4a with ammonia gives 2-anilinomaneimide [5] whereas
treatment of aminofumarate with primary aliphatic amines gives principally the 1-alkyl-3-alkylaminopyrrole-
2,5-dione [11] and not the likely 1-alkyl-3-amino derivative. We found that reaction of arylaminofumarates with
primary aliphatic amines gives exclusively the 1-alkyl-3-arylaminopyrrole-2,5-diones 3a, 5a-c (Tables 1, 2), i.e.
in this reaction an exchange of arylamino group for alkylamine does not occur.
The 1H NMR spectra of compounds 3a-n, 5a-c show singlet signals for the vinyl proton (5.35-6.06) and
NH group (8.24-10.21 ppm). The IR spectra show stretching bands for the N–H bond (3365-3310) and C=C
845

TABLE 1. Characteristics of Compounds 3a-p, 5a-c
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
70
C
H
N
3a
C11H10N2O2
199-200
65.28
65.34
4.95
4.98
13.84
13.85
3b
3c
3d
3e
3f
C11H9BrN2O2
C12H12N2O2
C12H12N2O2
C12H12N2O3
C11H10N2O3
C11H9N3O4
C11H9N3O4
C13H14N2O4
C13H15N3O2
C13H16ClN3O2
C11H11N3O4S
C17H17N5O6S
C13H14N2O4
С9H12N2O3
C12H12N2O2
C17H14N2O2
C18H16N2O2
C13H14N2O3
47.11
47.00
66.60
66.65
66.54
66.65
62.12
62.06
60.57
60.55
53.39
53.44
53.52
53.44
59.55
59.54
63.80
63.66
55.54
55.42
46.95
46.97
48.72
48.68
59.62
59.54
55.15
55.09
66.65
66.65
73.32
73.37
3.25
3.23
5.58
5.59
5.52
5.59
5.25
5.21
4.63
4.62
3.69
3.67
3.70
3.67
5.43
5.38
6.22
6.16
5.75
5.72
3.90
3.94
4.13
4.09
5.40
5.38
6.18
6.16
5.58
5.59
5.10
5.07
10.02
9.97
12.89
12.96
12.90
12.96
12.06
12.06
12.91
12.84
17.12
17.00
17.05
17.00
10.74
10.68
17.00
17.13
14.87
14.91
14.85
14.94
16.75
16.70
10.65
10.68
14.37
14.28
12.97
12.96
10.18
10.07
237-238 (dec.)
208-210
70
67
56
50
57
51
45
45
82
75
64
72
78
12
56
56
60
75
206-208
162-164
251-254 (dec.)
289-291 (dec.)
286-287 (dec.)
165-167
3g
3h
3i
3j
207-209
3k
3l
195-198
282-285 (dec.)
215-217
3m
3n
3o
3p
5a
5b
5c
169-171
128-129
144-146
165-166
73.84
73.95
63.52
63.40
5.55
5.52
5.70
5.73
9.63
9.58
11.44
11.38
195-196.5
162-162.5
bonds (1660-1625) and also the asymmetric (1770-1750) and symmetric (1720-1695 cm-1) carbonyl group
stretching vibrations of the pyrrole-2,5-dione ring in agreement with data in [2, 4, 5] (Table 2).
In our opinion, the experimental data indicates that the driving force for the transamination of the
1-alkyl-3-alkylaminopyrrole-2,5-diones by the amine hydrochlorides is likely to be formation of the less basic
maleimide and the salt of the weaker conjugated acid i.e. alkylammonium. Hence the pKa values of the amines
increase in the series aniline (4.60), benzylamine (9.35), and methylamine (10.64) [12] and the values of the pKa
calculated by us using the ACD/pKaDB:Chem.Sketch program [13] show that the basicity decreases in the series
aniline (4.61±0.20), maleimide 1 (3.38±0.20) and maleimide 3a (-2.69±0.20).
The transamination reaction evidently occurs as the result of a preliminary protonation of the 1-alkyl-
3-alkylaminopyrrole-2,5-diones by the amine hydrochlorides leading to an increase in the electrophilicity of the
carbon atom bound to the alkylamino group with subsequent attack of the formed cation by the free base and
separation of the alkylamine.
846

847

EMPERIMENTAL
1H NMR Spectra were taken on Bruker DRX-500 (500 MHz), Varian VXR-300 (300 MHz), and Varian
VX-200 (200 MHz) spectrometers with TMS as internal standard. IR Spectra were recorded on a UR-20
spectrometer for KBr tablets. CHN-analysis was performed on a Perkin Elmer 2400 instrument. 2-(3-Amino-
phenoxy)ethanol was prepared by method [14] and 1-methyl-3-methylaminopyrrole-2,5-dione 1, 1-benzyl-
3-benzylaminopyrrole-2,5-dione, and 1-(2-hydroxyethyl-3-(2-hydroxyethylamino)pyrrole-2,5-dione by [11].
p-Aminobenzenesulfamide and 4-amino-N-(2,6-dimethoxypyrimidin-4-yl)benzenesulfamide were prepared from
the medicines streptocid and sulfadimethoxine. Monitoring of the reaction course and purity of the materials was
carried out by TLC on Silufol UV-254 plates in the system chloroform-methanol (10: 1) and revealed using UV
light and/or iodine vapor.
1-Methyl-3-phenylaminopyrrole-2,5-dione (3a). A solution of compound 2a (prepared from aniline
(0.73 g, 7.8 mmol), hydrochloric acid (8.371 N, 0.85 ml), and methanol (10 ml)) was added to a solution of
maleimide 1 (1.0 g, 7.1 mmol) in methanol (10 ml), refluxed for 1 h, and then left overnight. The precipitate was
filtered off, washed with methanol, and recrystallized from 2-propanol to give compound 3a (1.0 g). Using the
hydrochloride of 2a the yield of maleimide 3a was 1.08 g (75%).
Compounds 3b-k,n,p were prepared similarly. Compounds 3g,h were crystallized from acetic acid,
compound 3p from methanol, and compounds 3f,k were purified by refluxing in methanol.
1-Methyl-3-(p-sulfamidophenylamino)pyrrole-2,5-dione (3l). A solution of compound 2l (prepared
from p-aminobenzenesulfamide (1.34 g, 7.8 mmol), hydrochloric acid (8.371 N, 0.85 ml), and DMSO (15 ml))
was added to a solution of maleimide 1 (1.0 g, 7.1 mmol) in DMSO (5 ml), heated for 1 h at 50ºC, left overnight,
and poured into methanol (100 ml). The precipitate was filtered off, washed with methanol, and refluxed in
methanol to give compound 3l (1.28 g).
Compound 3m was prepared similarly.
1-Methyl-3-morpholinopyrrole-2,5-dione (3o). Maleimide (3.5 g, 25 mmol) was added to morpholine
(11 ml, 11 g, 126 mmol), refluxed for 11.5 h, allowed to stand overnight, and morpholine (7.8 ml) was removed
by distillation in vacuo. The residue was dissolved in benzene (5 ml), cooled to 0ºC and the precipitate formed
was filtered off and washed with cold benzene to give a 1: 1 mixture of maleimides 1 and 3o (1.5 g) with
mp 99-101ºC. The latter was recrystallized from ethanol with the addition of active charcoal to give the product
(0.71 g) with mp 125-128ºC which was recrystallized from a mixture of benzene and petroleum ether. Yield of
maleimide 3o 0.58 g.
Dimethyl Phenylaminofumarate (4a). A solution of aniline (12.8 g, 137 mmol) in benzene (50 ml) was
added dropwise over 1 h with stirring at 5-10ºC to a solution of dimethyl acetylenedicarboxylate (19.4 g, 137
mmol) in benzene (50 ml). Solvent was evaporated at reduced pressure and the residue was distilled in vacuo to
20
give compound 4a (25.7 g, 80%) with bp 140.5-141.5 (0.5 mm Hg) and nD 1.5883 (bp 105-107ºC at 0.05 to
0.07 mm Hg [5]). 1H NMR spectrum (300 MHz, CDCl3), δ, ppm: 3.64 (3H, s, OCH3); 3.70 (3H, s, OCH3); 5.38
(1H, s, CH); 6.83-7.28 (5H, m, C6H5); 9.67 (1H, br. s, NH).
Dimethyl p-tolylaminofumarate (4b) was prepared similarly, yield 70%, mp 89-91ºC, bp 175-177ºC
(2 mm Hg) (mp 89ºC, bp 140ºC (0.5 mm Hg) [15]). 1H NMR spectrum, (300 MHz, CDCl3), δ, ppm (J, Hz): 2.30
(3H, s, CH3); 3.69 (3H, s, OCH3); 3.73 (3H, s, OCH3); 5.33 (1H, s, CH); 6.82 (2H, d, 3J = 8.4, Ar); 7.06 (2H, d,
3J = 8.4, Ar); 9.62 (1H, br. s, NH).
1-Methyl-3-phenylaminopyrrole-2,5-dione (3a). An aqueous solution of methylamine (12.7 N, 1.5 ml,
19.1 mmol) was added to a solution of phenylaminofumarate 4a (1.5 g, 6.4 mmol) in methanol (15 ml) and held
for 7 days at 20ºC. The precipitate was filtered off, washed with methanol, and recrystallized from 2-propanol to
give the maleimide 3a (0.90 g, 70%).
848

1-Benzyl-3-phenylaminopyrrole-2,5-dione (5a). Benzylamine (3.5 ml, 3.4 g, 31.7 mmol) was added to
a solution of phenylaminofumarate (5.0 g, 21.3 mmol) in methanol (20 ml) and held for 10 days at 20ºC. The
precipitate was filtered off, washed with methanol, and recrystallized from 2-propanol to give the maleimide 5a
(3.3 g).
Compound 5b was prepared similarly.
1-(2-Hydroxyethyl)-3-(p-tolylamino)pyrrole-2,5-dione (5c). Ethanolamine (2.0 ml, 2.0 g, 33.4 mmol)
was added to a solution of p-tolylaminofumarate 4b (5.0 g, 20 mmole) in methanol (30 ml), held for 0.5 h at
60ºC, and then left for 10 days at 20ºC. The precipitate was filtered off, washed with methanol, and
recrystallized from methanol to give compound 5c (28 g, 57%). The filtrate was evaporated in vacuo and the
residue was extracted with chloroform (60 ml), washed with water (3 x 10 ml), dried over CaCl2, and the
chloroform was evaporated. The residue was crystallized from methanol to give an additional yield of compound
5c (1.1 g, 18%).
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