2-Aminopyrrole-2,5-diones 2.* vinyl nucleophilic substitution of the alkylamino group in 1-alkyl-3-alkylaminopyrrole-2,5-diones by arylamines

Article abstract of DOI:10.1007/s10593-008-0071-z

In vinyl nucleophilic substitution (S_Nvin) with the hydrochlorides or 4-toluenesulfonates of primary arylamines 1-alkyl-3- alkylaminopyrrole-2,5-diones form the corresponding 1-alkyl-3-arylamino-pyrrole- 2,5-diones, which are also produced in s

Full text of DOI:10.1007/s10593-008-0071-z

Chemistry of Heterocyclic Compounds, Vol. 44, No. 5, 2008
2-AMINOPYRROLE-2,5-DIONES
2.* VINYL NUCLEOPHILIC SUBSTITUTION
OF THE ALKYLAMINO GROUP IN 1-ALKYL-
3-ALKYLAMINOPYRROLE-2,5-DIONES
BY ARYLAMINES
S. V. Chepyshev1, Yu. N. Chepysheva1, A. B. Ryabitskii2, and A. V. Prosyanik1
In vinyl nucleophilic substitution (SNvin) with the hydrochlorides or 4-toluenesulfonates of primary
arylamines 1-alkyl-3-alkylaminopyrrole-2,5-diones form the corresponding 1-alkyl-3-arylamino-
pyrrole-2,5-diones, which are also produced in situ from the corresponding arylaminofumarates and
primary alkylamines.
Keywords: arylaminofumarates, pyrrole-2,5-dione, vinyl nucleophilic substitution.
Derivatives of 3-aminopyrrole-2,5-dione are used as kinase inhibitors [2-4], antiallergic and
immunotherapeutic agents [5], and local anesthetics [3].
The reaction of 1-methyl-3-methylaminopyrrole-2,5-dione with arylamine hydrochlorides and of
1-(2-hydroxyethyl)-3-(2-hydroxyethylamino)pyrrole-2,5-dione with 4-methoxyaniline hydrochloride leads to
SNvin substitution of the alkylamino group by an arylamino group with the formation of the corresponding
1-alkyl-3-arylaminopyrrole-2,5-diones [1]. In a continuation of our investigations it seemed of interest to study
this reaction for other 1-alkyl-3-alkylaminopyrrole-2,5-diones. It was established that the corresponding 1-alkyl-
3-arylaminopyrrole-2,5-diones 3a-j (Tables 1 and 2) are formed during the reaction of 1-alkyl-3-alkyl-
aminopyrrole-2,5-diones 1a-e with the hydrochlorides or 4-toluenesulfonates of arylamines 2a-j.
1-Alkyl-3-arylaminopyrrole-2,5-diones can also be obtained by the reaction of the individual
arylaminofumarates with primary aliphatic amines [1]. Since it is difficult in a number of cases to isolate the
arylaminofumarates in the individual state we developed a modification of this method, involving the production
of the arylaminofumarates 5a,b,d in situ from dimethyl acetylenedicarboxylate 4 and arylamines.
The motivating force of the SNvin substitution of the alkylamino group in the reaction of 1-alkyl-
3-alkylaminopyrrole-2,5-diones with the arylamine hydrochlorides or 4-toluenesulfonates is probably the
formation of a weaker conjugate acid (the alkylammonium cation) and a weaker base (the corresponding
1-alkyl-3-arylaminopyrrole-2,5-dione). In actual fact the experimental values of pKa for all the investigated
_______
* For Communication 1 see [1].
__________________________________________________________________________________________
1Ukrainian State Chemical Engineering University, Dnepropetrovsk 49005; e-mail:
2
schepyshev@gmail.com. Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev
03660; e-mail: ryabitskiy@lifechemicals.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5,
pp. 668-675, May, 2008. Original article submitted October 11, 2007.
0009-3122/08/4405-0523©2008 Springer Science+Business Media, Inc.
523

NHR
O
NHAr
O
.
.
RNH2 HX
ArNH2 HX
+
+
O
O
N
N
2a–j
R
R
1a–e
3a–j
1 a R = PhCH2, b R = MeOCH2CH2, c R = PhCH2CH2, d R = 3,4-(MeO)2C6H3CH2CH2, e R = 2-furfuryl;
2, 3, 5 a Ar = Ph, X = Cl, R = PhCH2, b Ar = 3-HOCH2CH2OC6H4, X = Cl, R = PhCH2, c Ar = 3-O2NC6H4,
X = TsO, R = MeOCH2CH2, Ar = 2-MeOC6H4, X = Cl, R = MeOCH2CH2, e Ar = 4-Me2NC6H4, X = Cl,
R = PhCH2CH2, f Ar = 4-HO2CC6H4, X = TsO, R = 3,4-(MeO)2C6H3CH2CH2, g Ar = 4-MeO2CC6H4,
X = TsO, R = 3,4-(MeO)2C6H3CH2CH2, h Ar = 2-HO2CC6H4, X = TsO, R = 3,4-(MeO)2C6H3CH2CH2,
i Ar = 3-MeOC6H4, X = Cl, R = 2-furfuryl, j Ar =1-naphthyl, X = Cl, R = 2-furfuryl
NHAr
MeO2C
NHAr
RNH2
ArNH2
O
MeO2C
CO2Me
O
N
R
CO2Me
4
5a,b,d
3a,b,d
nucleophiles are significantly lower than for the corresponding nucleofuges (Table 3). The pKa values of aryl-
and alkylamines calculated by means of the ACD/pKa DB program [6] agree well with the experimental data
(Table 3). On this basis we calculated the pKa values of all the possible protonated forms 6a-d for one of the
initial compounds 1-benzyl-3-benzylaminopyrrole-2,5-dione 1a [6a (-3.16 ± 0.40) < 6b (2.83 ± 0.20) < 6c (3.49
± 0.20) < 6d (3.63 ± 0.20)] and for the corresponding reaction product 1-benzyl-3-phenylaminopyrrole-2,5-
dione 3a [6a (−3.50 ± 0.40) < 6b (−2.73 ± 0.20) < 6c (1.39 ± 0.20) < 6d (3.31 ± 0.40)]; the smallest pKa values
for each of the tautomers are given. According to the Kabachnik rule [7] the protonated forms 6c,d, as having
the lowest acidity, should predominate in the equilibrium mixture. From comparison of the calculated
TABLE 1. The Characteristics of Compounds 3a-j
Com-
pound
Empirical
formula
Found N, %
Calculated N, %
——————
mp, °C
164-166
Yield, %
73
3a
C17H14N2O2
9.93
10.07
165-166 [1]
3b
3c
3d
3e
3f
C19H18N2O4
C13H13N3O5
C14H16N2O4
C20H21N3O2
C21H20N2O6
C22H22N2O6
C21H20N2O6
C16H14N2O4
C19H14N2O3
8.45
8.28
14.30
14.43
10.02
10.14
12.37
12.53
7.12
7.07
6.95
6.83
7.16
7.07
9.20
9.39
147.5-149.5
51
69
194-195
121-122
199-200.5
223-226
206-209
220-222
144-145
135-136
73
41
74
3g
3h
3i
93
78
55.5
40.5
3j
8.92
8.80
524

525

pKa values of the protonated forms 6c,d of the initial 1-alkyl-3-alkylaminopyrrole-2,5-diones 1a-e and final
3-arylamino derivatives 3a-j (Tables 3 and 4) it then follows that the weaker bases 1-alkyl-3-arylaminopyrrole-
2,5-diones are always formed in the SNvin reaction.
Both the imine and the enamine forms of 3-aminopyrrole-2,5-dione derivatives were examined in [8, 9],
but later investigations showed that they exist exclusively in the enamine form [1-5, 10-16]. It's pronation in
accodance with the conducted analysis of the tautomers results in predominance of imine forms 6c,d.
Accordingly, protonation on account of increase in the effective electronegativity of the nitrogen atom stabilizes
the imine form in the derivatives of 3-aminopyrrole-5-dione compared with the enamine form, and this gives
rise to the possibility of nucleophilic addition of the arylamine at the imine carbon atom followed by removal of
the alkylamine, securing the realization of the SNvin reaction.
+
+
+
NHR1
O
NH2R1
NHR1
NHR1
H
H
+
O
O
O
O
O
O
HO
NH
N
R2
N
R2
N
R2
R 2
6a
6d
6c
6b
R1 = Alk or Ar; R2 = Alk
EXPERIMENTAL
1
The H NMR spectra were obtained on Varian VXR-300 (3006 MHz) (compound 3i and 2-(3-amino-
phenoxy)ethanol) and Varian GEMINI-2000 (400 MHz) (compounds 1b and 3a-h,j) with TMS as internal
standard, and the signals were assigned by means of ACD/HNMR DB software [6]. The IR spectra were
recorded on a UR-20 spectrometer in tablets with potassium bromide. The 1-alkyl-3-alkylaminopyrrole-
2,5-diones (1a,c-e) were obtained by the method in [16], dimethyl aminofumarate by the method in [18], and
2-(3-nitrophenoxy)ethanol by the method in [19]. The reactions and the individuality of the substances were
monitored by chromatography on Silufol UV-254 plates in the 10:1 chloroform–methanol system with
development in UV light and/or in iodine vapor.
1-(2-Methoxyethyl)-3-(2-methoxyethylamino)pyrrole-2,5-dione (1b). 2-Methoxyethylamine (4.1 g,
(Merck) 4.75 ml, 54 mmol) to a solution was added of dimethyl aminofumarate (4.0 g, 25 mmol) in of 90%
aqueous methanol (10 ml). The mixture was heated at 75°C for 9 h and left overnight. The solvent was removed
at reduced pressure, and the residue was extracted with benzene (2×25 ml). The extract was filtered, and the
filtrate was evaporated under vacuum. The residue was cooled to 0°C, triturated with of methanol (5 ml), and
left overnight at 0°C. The precipitate was filtered off, washed with cold methanol, and dried under vacuum at
35°C. Yield of compound 1b 3.3 g (58%); mp 62-64°C. Found, %: N 12.45. C10H16N2O4. Calculated, %:
1
N 12.27. H NMR spectrum, δ, ppm: 3.21 (3Н, s, ОСН3); 3.25 (3Н, s, ОСН3); 3.38-3.54 (8Н, m, 4СН2); 4.90
(1Н, s, СН); 7.65 (1Н, br. s, NH).
2-(3-Aminophenoxy)ethanol. Preparation of Catalyst. Sodium hydroxide (6×2 g, 0.3 mol) was added
to a suspension of a reduction alloy of nickel with aluminum (10.0 g) in water (70 ml). The mixture was allowed
to stand for 15 min and kept at 75°C for 35 min. The liquid above the catalyst was decanted, and the catalyst
was washed successively with water (2×25 ml) and with methanol (2×20 ml). Reduction. The catalyst was
added with stirring to a solution of 2-(3-nitrophenoxy)ethanol (50.0 g, 0.273 mol) and 80% aqueous N2H4·H2O
(d420 1.034) (43.4 g, 42 ml, 0.685 mol) in methanol (400 ml) over 1 h at 50°C. The mixture was kept at 65°C for
25 min and boiled for 1 h. The reaction mixture was cooled, the catalyst was filtered off, and the
526

TABLE 3. The pKa Values at 25°C and Ionic Strength I = 0
pKa
Experiment [6]
Compound
Conjugate acid
Calculation
Benzylamine
9.35
9.40±0.10
8.80±0.10
9.90±0.10
2-Methoxyethylamine
2-Phenylethylamine
9.43
+
9.92±0.04 (0.1)
RNH3
2-(3,4-Dimethoxyphenyl)ethylamine
2-Furfurylamine
9.88±0.01 (0.1)
8.89 (1.0/30)
4.60
9.74±0.10
9.12±0.29
4.61±0.10
4.09±0.10
2.46±0.10
4.54±0.10
2.51±0.10
Aniline
2-(3-Aminophenoxy)ethanol
3-Nitroaniline
—
2.46
2-Methoxyaniline
4.53
+
4-Aminobenzoic acid (4-ABA)
2.41±0.04
ArNH3
Methyl ester of 4-ABA
2-Aminobenzoic acid
3-Methoxyaniline
2.47
2.47±0.10
2.10±0.10
4.17±0.10
3.94±0.10
6.64±0.12
2.11
4.20
3.94±0.02
6.59
1-Naphthylamine
+
N,N-Dimethyl-1,4-diaminobenzene
Me2NHC6H4NH2
+
+
Me2NHC6H4NH3
—
2.68±0.10
TABLE 4. The Calculated pKa Values
pKa
Compound
6с*
6d*2
1a
1b
1c
1d
1e
3a
3b
3c
3d
3e
3f
3.49±0.20
2.45±0.20
3.28±0.20
3.02±0.20
2.02±0.20
1.39±0.20
0.80±0.20
-1.17±0.20
-0.10±0.20
2.51±0.20
-0.39±0.20
-0.46±0.20
0.07±0.20
0.47±0.20
0.95±0.20
3.63±0.20
3.37±0.20
3.57±0.20
3.51±0.20
3.34±0.20
3.31±0.40
2.72±0.40
0.94±0.40
2.01±0.40
3.34±0.20
1.68±0.40
1.62±0.40
2.15±0.40
2.56±0.40
3.04±0.40
3g
3h
3i
3j
_______
* pKaNH+
.
*2 The smallest of the two possible pKa values is given (pKaOH for
compounds 1a-e and 3e; pKaNH+ for compounds 3a-d, f-j); most of the
enaminones have pKa values in the range of 2.8-3.1 [17].
filtrate was boiled for 3 min with 1.5 g of active carbon. The carbon was then filtered off, and the filtrate was
evaporated under vacuum. The residue was triturated with ether and cooled to 5°C, and the precipitate was
filtered off, washed with cold ether, and dried. The product (37.5 g) was distilled under vacuum. Yield of 2-(3-
aminophenoxy)ethanol 32.6 g, (80%); bp 155.5-157°C (1 mm Hg), mp 52-53°C (mp 52°C [19])
527

1
(hydrochloride 2b, mp 134.5-139.5°C). H NMR spectrum (CDCl3), δ, ppm): 2.88 (1Н, br. s, ОН); 3.72 (2Н,
br. s, NH2); 3.84-3.93 (2Н, m, СH2ОН); 3.93-4.02 (2H, m, ОСН2); 6.20-6.24 (1Н, m, НAr-2); 6.26-6.34 (2Н, m,
НAr-4,6); 6.97-7.10 (1H, m, НAr-5).
1-Benzyl-3-phenylaminopyrrole-2,5-dione (3a). A solution of the hydrochloride 2a (0.45 g, 3.5 mmol)
in methanol (5 ml) was added to a solution of compound 1a (1.0 g, 3.4 mmol) in methanol (25 ml). The mixture
was boiled for 1 h and left overnight at 5°C. The precipitate was filtered off, washed with methanol, and
recrystallized from 2-propanol. We obtained compound 3a (0.69 g).
Compounds 3e,i,j were obtained similarly. Compounds 3i,j were crystallized from methanol.
1-Benzyl-3-[3-(2-hydroxyethoxy)phenylamino]pyrrole-2,5-dione (3b). Methanol (34 ml) was added
to a mixture of compound 1a (1.50 g, 5 mmol) and hydrochloride 2b (1.07 g, 5.6 mmol) The mixture was boiled
for 1 h and left overnight. The solution was evaporated under vacuum, and the residue was triturated with cold
water. The precipitate was filtered off, washed with cold water, and dried. The product (1.72 g) was
recrystallized twice from 2-propanol and compound 3b (0.88 g) was obtained.
1-(2-Methoxyethyl)-3-(3-nitrophenylamino)pyrrole-2,5-dione (3c). A solution of 3-nitroaniline
(0.64 g, 4.6 mmol) and of 4-toluenesulfonic acid monohydrate (0.84 g, 4.4 mmol) in methanol (10 ml) was
added to a solution of compound 1b (1.01 g, 4.4 mmol) in methanol (5 ml). The mixture was boiled for 1 h and
left overnight at 5°C. The precipitate was filtered off, washed with methanol, and recrystallized from
2-propanol. Compound 3c (0.89 g) was obtained.
Compounds 3f-h were obtained similarly. Compound 3f was crystallized from methanol. Compounds
3g,h were purified by boiling in methanol.
1-(2-Methoxyethyl)-3-(2-methoxyphenylamino)pyrrole-2,5-dione 3d. Absolute ethanol (10 ml) was
added to a mixture of compound 1b (1.0 g, 4.4 mmol) and the hydrochloride 2d (0.74 g, 4.6 mmol). The mixture
was boiled for 1 h and left overnight at 5°C. The precipitate was filtered off, washed with cold absolute ethanol,
and recrystallized from absolute ethanol. Compound 3d (0.89 g) was obtained.
Dimethyl Phenylaminofumarate (5a). A solution of aniline (2.51 g, 2.45 ml, 27 mmol) in absolute
benzene (10 ml) was added dropwise with stirring at 20°C over 10 min to a solution of compound 4 (3.81 g,
3.30 ml, 27 mmol) in absolute benzene (40 ml). The mixture was left overnight, boiled for 4 h, and cooled, and
the solvent was removed under vacuum. Compound 5a (6.32 g, 100%) was obtained.
Compound 5d was obtained similarly.
Dimethyl 3-(2-Hydroxyethoxy)phenylaminofumarate (5b). A solution of compound 4 (1.85 g,
1.60 ml, 13 mmol) in absolute methanol was added dropwise with stirring at 20°C (10 ml) to a solution of 2-(3-
aminophenoxy)ethanol (2.0 g, 13 mmol) in absolute methanol (11 ml) over 15 min. The mixture was boiled for
30 min and left overnight, and the solvent was evaporated under vacuum. of compound 5b (3.85 g, 100%) was
obtained.
The obtained arylaminofumarates 5a,b,d were used in the following syntheses without additional
purification.
1-Benzyl-3-phenylaminopyrrole-2,5-dione (3a). Benzylamine (4.34 g, 4.42 ml, 40.5 mmol) was added
to a solution of the phenylaminofumarate 5a (6.32 g, 27 mmol) in methanol (15 ml). The mixture was kept at
20°C for 10 days. The precipitate was filtered off, washed with methanol, and recrystallized from 2-propanol.
Compound 3a (3.08 g, 41%) was obtained.
Compound 3b was obtained similarly with a yield of 1.09 g (25%).
1-(2-Methoxyphenylamino)pyrrole-2,5-dione (3d). 2-Methoxyethylamine (Merck) (3.0 g, 3.5 ml,
40 mmol) was added to a solution of compound 5d (7.06 g, 27 mmol) in methanol (10 ml). The mixture was
kept at 20°C for 28 days. The solvent was evaporated under vacuum, and the residue was cooled to 5°C,
triturated with 5 ml of cold methanol, and left overnight at 5°C. The precipitate was filtered off, washed with
cold methanol, and crystallized from methanol. Compound 3d (2.7 g, 37%) was obtained.
528

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