Substituent effects on the regioselectivity of maleamic acid formation and hydrogen chloride addition to N-aryl maleimides

Article abstract of DOI:10.3906/kim-1203-34

Itaconic anhydride reacts with aryl amines to give a substituent controlled equilibrium mixture of regioisomeric (Z)-2-methyl- and (Z)-3-methyl-4-oxo-4- (arylamino)but-2-enoic acids. Electron-donating groups favor nucleophilic attack on C-5 carbonyl, while the presence of electron-withdrawing groups enhances the bias for attack on C-2 carbonyl. The treatment of (Z)-2-methyl- and (Z)-3-methyl-4-oxo-4-(arylamino)but-2-enoic acids with SOCl₂-Et ₃N in THF provided the corresponding maleimides in high yields while under the same conditions the maleic anhydride aryl amine addition products gave predominately the corresponding 3-chloro-1-arylpyrrolidine-2,5-diones and maleimides in substituent dependent ratio. TUeBITAK, 2012.

Full text of DOI:10.3906/kim-1203-34

Turk J Chem
36 (2012) , 749 – 758.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1203-34
Substituent effects on the regioselectivity of maleamic
acid formation and hydrogen chloride addition to N-aryl
maleimides
Yeliz FATURACI, Necdet COS¸KUN∗
Department of Chemistry, Uluda˘g University, 16059 G¨oru¨kle, Bursa-TURKEY
Received: 17.03.2012
Itaconic anhydride reacts with aryl amines to give a substituent controlled equilibrium mixture of re-
gioisomeric (Z)-2-methyl- and (Z)-3-methyl-4-oxo-4-(arylamino)but-2-enoic acids. Electron-donating groups
favor nucleophilic attack on C-5 carbonyl, while the presence of electron-withdrawing groups enhances the
bias for attack on C-2 carbonyl. The treatment of (Z)-2-methyl- and (Z)-3-methyl-4-oxo-4-(arylamino)but-2-
enoic acids with SOCl2 -Et3 N in THF provided the corresponding maleimides in high yields while under the
same conditions the maleic anhydride aryl amine addition products gave predominately the corresponding
3-chloro-1-arylpyrrolidine-2,5-diones and maleimides in substituent dependent ratio.
Key Words: Cyclic anhydrides, maleimides, chlorosuccinimides, LFERs, substituent effect
Introduction
A number of methods for the preparation of imides have been developed and the main strategy used is the
dehydration of the intermediate amidocarboxylic acid with acetic anhydride.1,2 N -Arylmaleimides have been
prepared in 2 steps via a reaction of aniline with maleic anhydride in ethyl ether to produce an intermediate
amide, which is then cyclized to the imide by refluxing its solution in toluene and dimethyl sulfoxide in
the presence of a catalytic amount of concentrated sulfuric acid.3,4 However, attempts to exploit the known
procedures in maleimide synthesis2 in some cases were reported to be disappointing in terms of both yield and
reproducibility.5 N-Arylmaleamic acids were reported to convert to N-aryl 3-chlorosuccinimides in moderate
to good yields when dissolved in SOCl2 at room temperature.6 An intramolecular chloride ion migration
is considered for the formation of the corresponding 3-chlorosuccinimides.6c The dehydrohalogenation of 3-
chlorosuccinimides in the presence of Et3 N to give the corresponding maleimides was also reported.6b
∗Corresponding author
749

Substituent effects on the regioselectivity of maleamic acid..., Y. FATURACI, N. COS¸KUN
The reaction of tert-butyl 2-aminobenzylcarbamate with methylmaleic anhydride was reported to give 2
regioisomers, namely (Z)-2-methyl- as major and (Z)-3-methyl-4-oxo-4-(arylamino)but-2-enoic acids as minor
in 85/15 ratio respectively.7a The anilic acids prepared have been converted to the corresponding esters by
using diazomethane. The base catalyzed cyclizations of the latter furnish the corresponding N-aryl imides,
which are converted to tricyclic and tetracyclic 1,3-diaza-heterocycles with potential anti-cancer activity upon
treatment with TFA.7a The synthesis of ( )-piliformic7b and ( )-erythro-roccellic acids7c are examples of
N-arylmaleimide use in the synthesis of natural products.
X
X
X
NH
NH
3
NH
CO2H
O
O
O
O
O
OH
OH
B'
R
A'
3'
Me group enhances
Me group has no effect on
the π−π interaction
the π−π interactions
X
X
X
X
1
NH2
O
C-2 attack
C-5 attack
H2N
NH
CO2H
H2N
R
O
O
O
O
O
3'
O
O
O
O
R
B
A
3
2a; R=Me 2b; R=H
Me group has no effect on
Me group lowers
the π−π interactions
the π−π interactions
Scheme 1. Probable mechanism for the substituent controlled regioisomers 3/3’ ratio.
As a continuation of our interest in the substituent effect on the diastereoselectivity of cycloaddition
reactions we needed a series of substituted N-aryl maleimides. During the search for an optimal method for
the synthesis of the latter we found that substituents control the transamidation equilibrium of regioisomeric
(Z)-2-methyl- 3 and (Z)-3-methyl-4-oxo-4-(arylamino)but-2-enoic acids 3’, which are products from the ring-
opening reaction of itaconic anhydride with aryl amines (Scheme 1). A plausible mechanism for the substituent
dependent regiochemistry of the above reaction is discussed (Scheme 1).
Results and discussion
Substituted anilines 1 were reacted with maleic anhydrides 2 in THF heating at reflux temperature to give the
corresponding maleamic acids 3 and 3’ (Scheme 1). In the case of 2a the reaction mixtures were investigated
with 1 H-NMR and the ratio of 3 to 3’ was determined (Table 1).
750

Substituent effects on the regioselectivity of maleamic acid..., Y. FATURACI, N. COS¸KUN
Table 1. Effect of substituents on the formation of (Z)-4-oxo-4-(arylamino)but-2-enoic acids and their cyclizations in
the presence of SOCl2 -Et3 N.
a
ꢀ
1-5
a
b
c
X
H
R
3
3’
logK3/3
0.67
1.01
1.29
0.00
0.61
0.69
0
4a
5
0
0
0
0
0
0
log(K4/5)
Me 82.4b 17.6
100
100
100
100
100
100
Me
Me 91.1
MeOc Me 95.1
8.9
4.9
d
e
NO2
Cl
Me 50.2 49.8
Me 80.2 19.8
Me 83.4 16.6
f
Br
g
h
i
H
H
H
H
H
H
H
50
50
50
50
50
50
50
50
50
50
50
50
21.9 78.1
18 82
–0.55
–0.66
–0.59
–0.21
–0.47
–0.46
Me
MeO
NO2
Cl
0
0
20.6 79.4
38.3 61.7
25.4 74.6
25.9 74.1
j
0
k
l
0
Br
0
a The values are averages of 3 experiments and were determined by 1 H-NMR; standard deviations for the 3/3’ and 4/5
ratios are within the range 0.01-0.07. b The isolated 3 were heated in THF at reflux temperature for 24 h to give the
corresponding equilibrium mixtures of 3 and 3’. In the case of 3d the corresponding amine (22%) and 3-methylfuran-
2,5-dione (9%) were also detected in the reaction mixture. c The reaction of 3-methoxyaniline and 2a gave 3 and 3’ in
70/30 ratio. Antranilic acid reacted to give 52/48 ratio for 3/3’ as expected for an electron-withdrawing group. Electron-
donating SH group in the case of 2-aminobenzenethiol led to 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)propanoic
acids, which implies that SH favors C-5 attack to give the corresponding maleamic acid, which cyclizes to give the latter.
(Z)-2-Methyl-4-oxo-4-(arylamino)but-2-enoic acids 3 were isolated and purified by recrystallization from
THF. The regio- and stereochemistry of compounds 3 and 3’ were confirmed by NOESY1D experiments (Figure
1). The irradiation of the methyl’s singlet at 1.96 ppm enhances the singlet of C3-H by 1.5%, while the irradiation
of the C3-H at 6.08 ppm leads to enhancements of the methyl and amide protons’ singlets. The irradiation of
the amide proton’s singlet leads also to enhancement of the C3-H proton signal. The irradiation of the singlet
at 5.87 ppm of compound 3’d enhances the methyl’s singlet at 2.05 ppm. These experiments clearly prove the
assigned regio- and stereochemistry of compounds 3 and 3’.
−
ꢀ
The plot of the regioisomers ratio (logK3/3 ) versus the substituent constants σ and σ revealed that
the regioselectivity of the reaction in THF at reflux temperature is controlled by the substituents on the aniline
derivatives. The correlations with σ and σ− constants have ρ = –1.08 and r2 = 0.93, and ρ = –0.74 and
r2 = 0.88 respectively. It was surprising that σ+ constants derived for electron-deficient intermediates like
= -0.82σ+ + log(K3/3
)
(Figure 2).
ꢀ
ꢀ
X=H
carbocations provided the correlation log(K3/3
)
X
Electron-donating groups favor the attack on C-5 carbonyl while the presence of electron-withdrawing
groups enhances the bias for attack on the carbonyl that is closer to the C-3 methyl group (C-2 carbonyl).
751

Substituent effects on the regioselectivity of maleamic acid..., Y. FATURACI, N. COS¸KUN
O2N
O
N
O
N
H
CO2H
10.14 ppm
5.4%
H
CO2H
H
3.4%
1.96 ppm
2.05 ppm
5.87 ppm
H
8.8%
2.0%
1.5%
6.08 ppm
3a
3'd
Figure 1. Selected NOESY1D experiments for compounds 3a and 3’d.
1.60
1.40
y =-0.82x + 0.71
MeO
R² = 0.98
1.20
1.00
0.80
0.60
0.40
0.20
0.00
Me
Br
Cl
NO
2 1
-1
-0.5
0
0.5
σ+
Figure 2. Effect of substituents on the regioselectivity of ring opening of 3-methylmaleic anhydride.
ꢀ
The above discussed correlation of log(K3/3 ) implies that the substituents in the rate limiting steps
leading to 3 and 3’ are interacting with both positively or uncharged centers, intermediates A, B and A’, B’ in
Scheme 1. The nucleophilic attack on C-5 and C-2 will produce A and B, respectively. The correlation implies
that electron-donating groups stabilize intermediates A and B, pushing electrons to the carbon bearing the
ammonium nitrogen. We assume that π − π stacking between the N-aromatic ring and the lactone carbonyl
may play an important role. In the cases of electron-donating substituents, intermediates A are better stabilized
than B due to the unfavorable effect of the electron-donating methyl at C-3. Thus, in the cases of electron-
donating substituents, compounds 3 probably form through ring-opening and proton migration of A. Electron-
withdrawing substituents destabilize A and B and shift the equilibria to A’ and B’. The π − π interactions
in this case we assume to be between the same groups discussed above but the direction of charge transfer is
reversed. Thus the C-3 methyl in B’ now is favoring stacking, thus leading to 3’, while it has no effect on the
stability of A’.
Compounds 3 and 3’ were heated in THF at reflux temperature with equimolar amounts of Et3 N and
SOCl2 until the maleamic acid was fully consumed. In the cases of maleamic acids 3-3’/a-f the only product
752

Substituent effects on the regioselectivity of maleamic acid..., Y. FATURACI, N. COS¸KUN
from the cyclization was the corresponding maleimide 4, while under the same conditions compounds 3g-l (R
= H) converted mainly to succinimides 5 and maleimides 4 in substituent dependent ratios (Scheme 2, Table
1).
O
O
H
SOCl2-Et3N,
THF, reflux.
SOCl2-Et3N,
THF, reflux.
Cl
Me
R
X
N
HO2C
NH
+
X
N
4
X
R = Me
R = H
O
O
O
3
4
5
Scheme 2. SOCl2 -Et3 N induced cyclization of N-arylmaleamic acids to 4 and 5.
A probable mechanism for the formation of compounds 4 and 5 (when R = H) through initially formed
acid chloride C is depicted below. The intramolecular cyclization of the latter can lead to intermediate A
(Scheme 3), which probably is in equilibrium with B.
H
O
Cl
O
O
Cl
R
R
R
Cl
H
X
N
X
N
N
X
H
O
O
O
A
B
C
-Cl
O
O
O
O
R
-H
HCl
-HCl
N
X
N
X
N
X
X
N
Cl
R
+
R
R
O
O
O
O
H
H
5
4
D
Favored when
X = MeO; Me and R = H
Scheme 3. Probable mechanism for the formation of compounds 4 and 5.
The elimination of HCl in the cases of less basic aniline derivatives (e.g., 4-nitroaniline) is favored to
give the corresponding maleimides 4. However, in the cases of aniline derivatives 3 with electron-donating
substituents the formation of 3-chlorosuccinimides 5 is predominating (e.g., 4-methoxyaniline). If we assume
that compounds 5 arise from the electrophilic addition of HCl to 4 then 4a-f can be expected to give 5a-f more
easily due to formation of a more stable tertiary carbocation. However, it was not the case that the only products
formed were the corresponding maleimides 4a-f. HCl(g) was passed through the THF solutions of 4f and 4l
and the mixtures left overnight at room temperature. It was surprising that the methyl substituted 4f remained
unchanged while 4l was converted to 5l in quantitative yield. It seems that the formation of compounds 5g-
l under the conditions discussed somewhat deviates from the mechanism of electrophilic addition to alkene.
The presence of an electron-donating alkyl group probably stabilizes the intermediates of type D (Scheme 3),
which are less prone to undergo addition of chloride ion to the olefinic carbon than their hydrogen substituted
analogs. However, the effect of the substituents on the aniline ring in the case of C-3 unsubstituted 4g-l is
just the reverse. The presence of electron-donating groups favor the HCl addition and thus 5 predominates in
753

Substituent effects on the regioselectivity of maleamic acid..., Y. FATURACI, N. COS¸KUN
the mixture, while electron-withdrawing groups (e.g. -NO2) enhance relatively the amount of corresponding 4.
The plot of log(K4/5) versus the σ− constants10 (Table 1 and Figure 3) provided the equation log(K4/5
)
X
=
0.28σ− + log(K4/5
situ formed maleimides 4g-l.11
)X=H , which describes the effect of substituents on the electrophilic addition reactions of in
Figure 3. Effect of substituents on the hydrogen chloride addition to N-aryl maleimides.
The correlation with σ provided ρ constant 0.39 (r2 = 0.93). No satisfactory correlation with σ+
constants was observed.
Conclusion
For the first time we report on substituent control on the interconversion of (Z)-2-methyl- and (Z)-3-methyl-4-
oxo-4-(arylamino)but-2-enoic acids 3 and 3’. (Z)-2- or 3-methyl-4-oxo-4-(arylamino)but-2-enoic acids convert
quantitatively to N-arylmaleimides upon treatment with SOCl2 -Et3 N in THF upon heating at reflux tem-
perature, while their C-3(2) unsubstituted analogs convert mainly to 3-chlorosuccinimides 5 under the same
conditions. Plausible mechanisms for the regioselectivity of maleamic acid formations as well as their cyclizations
under the discussed reaction conditions were proposed.
Experimental
The solvents and reagents were Aldrich or Merck quality and were used without additional purification. Melting
points were taken on an Electrothermal Digital melting point apparatus. Infrared spectra were recorded on a
Thermo-Nicolet 6700 FTIR. 1D and 2D NMR experiments were performed on a Varian Mercury Plus 400 MHz
spectrometer. Elemental analyses were performed on a EuroEA 3000 CHNS analyzer. Attempts to record
the MS spectra of compounds 5g-l with a GC-MS spectrometer revealed their thermal instability at 250 ◦ C
754

Substituent effects on the regioselectivity of maleamic acid..., Y. FATURACI, N. COS¸KUN
injection temperature. The retention times of the peaks in the chromatograms and the corresponding mass
spectra were identical with those of the corresponding 4g-l.
Synthesis of (Z)-2-methyl-4-oxo-4-(arylamino)but-2-enoic acid 3a-f. General procedure: To
a solution of 3-methylmaleic anhydride (20 mmol, 2.2872 g) in THF (60 mL) was added aniline derivative (20
mmol) and the mixture heated at reflux for 2 h. The solvent was partly evaporated and the mixture left to
crystallize at room temperature. The formed crystals were collected by filtration and dried under vacuum.
(Z)-2-methyl-4-oxo-4-(phenylamino)but-2-enoic acid 3a. Yield, 3.283 g, 80%. White crystals, mp
;
175-176 ◦ C. Lit2 mp 172 ◦ C. IR (KBr) νOH 3449, νNH 3287, νC=O 1709, νC=C 1631 cm−1 1 H-NMR (400
MHz, DMSO-d6): δ 1.96 (3H, s), 6.08 (1H, s), 7.03 (1H, t, J = 7.0 Hz), 7.28 (2H, t, J = 7.6 Hz), 7.59 (2H,
d, J = 8.8 Hz), 10.14 (1H, s), 12.9 (1H, brs). 13 C-NMR (100 MHz, DMSO-d6): δ 21.0; 119.6; 123.6; 123.9;
129.2; 139.4; 143.1; 163.1; 170.7. Anal calcd for C11 H11 NO3 (205.21) C, 64.38; H, 5.40; N, 6.83; Found C,
64.50; H, 5.25; N, 6.90.
(Z)-4-(p-toluidino)-2-methyl-4-oxobut-2-enoic acid 3b. Yield, 3.771 g, 86%. Yellowish crystals,
;
mp 179-180 ◦ C. IR (KBr) νOH 3477, νNH 3289, νC=O 1700, νC=C 1632 cm−1 1 H-NMR (400 MHz, DMSO-
d6): δ 1.96 (3H, s), 2.23 (3H, s), 6.06 (1H, s), 7.09 (2H, d, J = 8.0 Hz) 7.47 (2H, d, J = 8.0 Hz), 10.07 (1H,
s), 12.9 (1H, s). 13 C-NMR (100 MHz, DMSO-d6): δ 20.9, 21.0; 119.6; 123.6; 129.6; 132.9, 136.8, 143.0; 162.9;
170.6. Anal calcd for C12 H13 NO3 (219.24) C, 65.74; H, 5.98; N, 6.39; Found C, 66.00; H, 6.04; N, 6.59.
(Z)-4-(4-methoxyphenylamino)-2-methyl-4-oxobut-2-enoic acid 3c. Yield, 4.328 g, 92%. Green
;
powder, mp 181-182 ◦ C. IR (KBr) νOH 3500, νNH 3279, νC=O 1690, νC=C 1627 cm−1 1 H-NMR (400 MHz,
DMSO-d6): δ 1.96 (3H, s), 3.70 (3H, s), 6.06 (1H, s), 6.87 (2H, d, J = 7.6 Hz) 7.51 (2H, d, J = 7.6 Hz), 10.06
(1H, s), 13.0 (1H, s). 13C-NMR (100 MHz, DMSO-d6): δ 21.1; 55.6; 114.3; 121.2; 123.7; 132.4; 142.8; 155.8;
162.7; 170.5. Anal calcd for C12 H13 NO4 (235.24) C, 61.27; H, 5.57; N, 5.95; Found C, 61.13; H, 5.60; N, 6.00.
(Z)-2-methyl-4-(4-nitrophenylamino)-4-oxobut-2-enoic acid 3d.12 Yield, 1.5 g, 30%. Yellow
needles, mp 166-167 ◦ C. IR (KBr) νOH 3473 cm−1 , νNH 3279, νC=O 1702, νC=C 1633 cm−1
;
1 H-NMR
(400 MHz, DMSO-d6): δ 1.98 (3H, s), 6.11 (1H, s), 7.83 (2H, d, J = 9.2 Hz) 8.2 (2H, d, J = 9.2 Hz), 10.71
(1H, s), 12.9 (1H, s). 13C-NMR (100 MHz, DMSO-d6): δ 20.8; 119.3; 123.2; 125.5; 142.7; 144.2; 145.7; 163.9;
170.5. Anal calcd for C11 H10 N2 O5 (250.21) C, 52.80; H, 4.03; N, 11.20; Found C, 53.00; H, 3.91; N, 11.30.
(Z)-4-(4-chlorophenylamino)-2-methyl-4-oxobut-2-enoic acid 3e. Yield 3.834 g, 80%. Cream
;
powder, mp 188-189 ◦ C. IR(KBr) νOH 3464, νNH 3280, νC=O 1707, νC=C 1631 cm−1 1 H-NMR(400 MHz,
DMSO) : δ 1.96 (3 H, s), 6.06 (1H, s), 7.34 (2H, d, J = 8.8 Hz), 7.62 (2H, d, J = 8.8 Hz), 10.26 (1H, s), 12.86
(1H, s). 13 C-NMR (100 MHz, DMSO-d6): δ 20.9; 121.2; 123.4; 127.4; 129.1; 138.4; 143.3; 163.2; 170.6. Anal
calcd for C11 H10 ClNO3 (239.65) C, 55.13; H, 4.21; N, 5.84; Found C, 55.30; H, 3.97; N, 6.01.
(Z)-4-(4-bromophenylamino)-2-methyl-4-oxobut-2-enoic acid 3f. Yield 4.546 g, 80%. Yellow
;
powder, mp 185-186 ◦ C. IR (KBr) νOH 3456, νNH 3282, νC=O 1710, νC=C 1634 cm−1 1 H-NMR (400 MHz,
DMSO): δ 1.96 (3 H, s), 6.06 (1H, s), 7.47 (2H, d, J = 9.2 Hz), 7.57 (2H, d, J = 9.2 Hz), 10.26 (1H, s), 12.86
(1H, s). 13 C-NMR (100 MHz, DMSO-d6): δ 20.9; 115.4; 121.5; 123.4; 132.0; 138.8; 143.3; 163.2; 170.6. Anal
calcd for C11 H10 BrNO3 (284.11) C, 46.50; H, 3.55; N, 4.93; Found C, 46.55; H, 3.38; N, 5.10.
Synthesis of N-aryl maleimides 4a-f. General procedure: To a solution of maleic anhydride 2a
(20 mmol, 2.2872 g) in THF (60 mL) was added aniline derivative (20 mmol) and the reaction mixture stirred
755

Substituent effects on the regioselectivity of maleamic acid..., Y. FATURACI, N. COS¸KUN
for 2 h. Triethylamine (20 mmol, 2.8 mL) and SOCl2 (24 mmol, 1.76 mL) were added successively and the
reaction mixture stirred at reflux for 6 h. The solvent was evaporated and the mixture poured into water (80
mL) and extracted with chloroform (3 × 15 mL). The combined extracts were dried over anhydrous Na2 SO4 .
The organic solvent was evaporated and the residue dissolved in ethanol-ether (1:2) and left to crystallize in a
refrigerator.
3-Methyl-1-phenyl-1H-pyrrole-2,5-dione 4a. Yield 2.471 g, 66%. Brown powder, mp 93-94 ◦ C. IR
(KBr) νC=O 1709 cm−1 ; νC=C 1653 cm−1 1 H-NMR (400 MHz, CDCl3): δ 2.17 (3H, d, J = 2.0 Hz), 6.48
;
(1H, q, J = 2.0 Hz), 7.35 (3H, t, J = 7.2 Hz), 7.46 (2H, t, J = 7.2 Hz). 13 C-NMR (100 MHz, CDCl3): δ
11.2; 125.9; 127.5; 127.7; 129.1; 131.6; 145.8; 169.6; 170.6. Anal calcd for C11 H9 NO2 (187.19) C, 70.58; H,
4.85; N, 7.48; Found C, 70.75; H, 4.73; N, 7.70.
3-Methyl-1-p-tolyl-1H-pyrrole-2,5-dione 4b. Yield 2.696 g, 67%. Brown powder, mp 112-113 ◦ C.
;
IR (KBr) νC=O 1701 cm−1 ; νC=C 1638 cm−1 1 H-NMR (400 MHz, CDCl3): δ 2.16 (3H, d, J = 2.0 Hz),
2.38 (3H, s), 6.46 (1H, q, J = 2.0 Hz), 7.2 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.4 Hz). 13 C-NMR (100
MHz, CDCl3): δ 11.2; 21.2; 125.9; 127.4; 128.9; 129.7; 137.8; 145.7; 169.8; 170.8. Anal calcd for C12 H11 NO2
(201.22) C, 71.63; H, 5.51; N, 6.96; Found C, 71.70; H, 5.65; N, 7.17.
1-(4-Methoxyphenyl)-3-methyl-1H-pyrrole-2,5-dione 4c. Yield 3.345 g, 77%. Brown powder, mp
;
115-116 ◦ C. IR (KBr) νC=O 1708 cm−1 ; νC=C 1641 cm−1 1 H-NMR (400 MHz, CDCl3): δ 2.16 (3H, d,
J = 2.0 Hz), 3.82 (3H, s), 6.46 (1H, q, J = 2.0 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.8 Hz).
13 C-NMR (100 MHz, CDCl3): δ 11.2; 55.5; 114.4; 124.2; 127.4; 127.5; 145.7; 159.0; 169.9; 170.9. Anal calcd
for C12 H11 NO3 (217.22) C, 66.35; H, 5.10; N, 6.45; Found C, 66.50; H, 5.14; N, 6.55.
3-Methyl-1-(4-nitrophenyl)-1H-pyrrole-2,5-dione 4d. Yield 3.111 g, 67%. Brownish plates, mp
;
154-155 ◦ C. IR (KBr) νC=O 1721 cm−1 ; νC=C 1642 cm−1 1 H-NMR (400 MHz, CDCl3): δ 2.22 (3H, d, J
= 2.0 Hz), 6.57 (1H, q, J = 2.0 Hz), 7.69 (2H, d, J = 9.6 Hz), 8.32 (2H, d, J = 9.6 Hz). 13 C-NMR (100 MHz,
CDCl3): δ 11.3; 124.4; 125.2; 127.9; 137.5; 145.9; 146.4; 168.5; 169.7. Anal calcd for C11 H8 N2 O4 (232.19) C,
56.90; H, 3.47; N, 12.06; Found C, 56.88; H, 3.48; N, 12.20.
1-(4-Chlorophenyl)-3-methyl-1H-pyrrole-2,5-dione 4e. Yield 3.236 g, 73%. Brownish plates, mp
;
114-115 ◦ C. IR (KBr) νC=O 1710 cm−1 ; νC=C 1638 cm−1 1 H-NMR (400 MHz, CDCl3): δ 2.17 (3H, d, J
= 1.6 Hz), 6.49 (1H, q, J = 1.6 Hz), 7.32 (2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.8 Hz). 13 C-NMR (100 MHz,
CDCl3): δ 11.2; 126.9; 127.6; 129.2; 130.2; 133.3; 146.0; 169.2; 170.3. Anal calcd for C11 H8 ClNO2 (221.64)
C, 59.61; H, 3.64; N, 6.32; Found C, 59.70; H, 3.75; N, 6.50.
1-(4-Bromophenyl)-3-methyl-1H-pyrrole-2,5-dione 4f. Yield 3.725 g, 70%. Brownish plates, mp
;
113-114 ◦ C. IR (KBr) νC=O 1711 cm−1 ; νC=C 1642 cm−1 1 H-NMR (400 MHz, CDCl3): δ 2.18 (3H, d, J
= 2.0 Hz), 6.49 (1H, q, J = 2.0 Hz), 7.26 (2H, d, J = 9.2 Hz), 7.58 (2H, d, J = 9.2 Hz). 13 C-NMR (100 MHz,
CDCl3): δ 11.2; 121.3; 127.2; 127.6; 130.7; 132.2; 146.0; 169.1; 170.2. Anal calcd for C11 H8 BrNO2 (266.09)
C, 49.65; H 3.03; N, 5.26; Found C, 49.80; H, 3.35; N, 5.37.
Synthesis of 3-chloro-1-arylsuccinimides 5. General procedure: To a solution of maleic anhydride
2b (5 mmol, 0.49 g) in THF (15 mL) was added aniline derivative (5 mmol) and the reaction mixture stirred
for 2 h. Triethylamine (5 mmol, 0.7 mL) and SOCl2 (6 mmol, 0.44 mL) were added successively and the
reaction mixture stirred at reflux for 6 h. The solvent was evaporated and the mixture poured into crushed ice
756

Substituent effects on the regioselectivity of maleamic acid..., Y. FATURACI, N. COS¸KUN
(20 g). The formed amorphous solid was filtered and dried in a vacuum oven. Pure samples were obtained by
crystallization from THF-ether (1:2).
3-Chloro-1-phenylsuccinimide 5g. Yield 0.755 g, 72%. Brownish plates, mp 114-116, lit6a mp 115
◦ C. IR (KBr) νC=O 1722 cm−1 1 H-NMR (400 MHz, CDCl3): δ 3.09 (1H, dd, J = 18.8; 4 Hz), 3.48 (1H, dd,
;
J = 18.8; 9.2 Hz), 4.79 (1H, dd, J = 9.2; 4.4 Hz), 7.31 (2H, d, J = 7.2 Hz), 7.41-7.51 (3H, m). 13 C-NMR (100
MHz, CDCl3): δ 39.4; 48.9; 125.32; 126.2; 129.2; 129.4; 171.9; 172.0. Anal calcd for C10 H8 ClNO2 (209.63)
C, 57.30; H, 3.85; N, 6.68; Found C, 57.45; H, 3.95; N, 6.80.
3-Chloro-1-p-tolylsuccinimide 5h. Yield 0.850 g, 76%. Yellow powder, mp 157-158, lit6b mp 157-158
;
◦ C. IR (KBr) νC=O 1720 cm−1 1 H-NMR (400 MHz, CDCl3): δ 2.39 (3H, s), 3.07 (1H, dd, J = 18.8; 4.4
Hz), 3.46 (1H, dd, J = 18.8; 8.8 Hz), 4.77 (1H, dd, J = 8.8; 4.4 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.29 (2H, d,
J = 8.4 Hz). 13 C-NMR (100 MHz, CDCl3): δ 21.3; 39.4; 48.9; 126.0; 128.5; 130.0; 139.4; 172.1; 172.2. Anal
calcd for C11 H10 ClNO2 (223.66) C, 59.07; H, 4.51; N, 6.26; Found C, 59.17; H, 4.50; N, 6.46.
3-Chloro-1-(4-methoxyphenyl)succinimide 5i. Yield 0.911 g, 76%. Brown powder, mp 145-146,
;
lit8 mp 144-145.5 ◦ C. IR (KBr) νC=O 1712 cm−1 1 H-NMR (400 MHz, CDCl3): δ 3.07 (1H, dd, J = 18.8;
4.0 Hz), 3.46 (1H, dd, J = 18.8; 8.4 Hz), 3.83 (3H, s), 4.77 (1H, dd, J = 8.4; 4.0 Hz), 6.99 (2H, d, J = 8.8 Hz),
7.22 (2H, d, J = 8.8 Hz). 13 C-NMR (100 MHz, CDCl3): δ 39.3; 48.9; 55.5; 114.6; 123.7; 127.5; 159.9; 172.2;
172.3. Anal calcd for C11 H10 ClNO3 (239.66) C, 55.13; H, 4.21; N, 5.84; Found C, 54.95; H, 4.19; N, 6.01.
3-Chloro-1-(4-nitrophenyl)succinimide 5j. Yield 0.611 g, 48%. Brownish powder, mp 167-170, lit6b
mp 173-174 ◦ C. IR (KBr) νC=O 1722 cm−1 1 H-NMR (400 MHz, CDCl3): δ 3.16 (1H, dd, J = 19.2; 4.4
;
Hz), 3.50 (1H, dd, J = 19.2; 8.4 Hz), 4.84 (1H, dd, J = 8.4; 4.4 Hz), 7.63 (2H, d, J = 9.2 Hz), 8.37 (2H, d, J
= 9.2 Hz). 13 C-NMR (100 MHz, CDCl3): δ 39.4; 48.7; 124.6; 126.8; 134.6; 136.5; 171.1; 171.2. Anal calcd for
C10 H7 ClN2 O4 (254.63) C, 47.17; H, 2.77; N, 11.00; Found C, 47.30; H, 2.78; N, 11.15.
3-Chloro-1-(4-chlorophenyl)succinimide 5k. Yield 0.659 g, 54%. Cream powder, mp 151-152, Lit6b
mp 153-154 ◦ C. IR (KBr) νC=O 1722 cm−1 1 H-NMR (400 MHz, CDCl3): δ 3.10 (1H, dd, J = 19.2; 4.4
;
Hz), 3.49 (1H, dd, J = 19.2; 8.8 Hz), 4.78 (1H, dd, J = 8.8; 4.4 Hz) 7.29 (2H, d, J = 9.2 Hz), 7.47 (2H,
d, J = 9.2 Hz). 13C-NMR (100 MHz, CDCl3): δ 39.3; 48.8; 127.5; 129.6; 135.0; 171.1 (2 C). Anal calcd for
C10 H7 Cl2 NO2 (244.07) C, 49.21; H, 2.89; N, 5.74; Found C, 49.10; H, 2.90; N, 6.00.
1-(4-Bromophenyl)-3-chlorosuccinimide 5l. Yield 0.779 g, 54%. Cream powder, mp 162-163 ◦ C.
IR (KBr) νC=O 1720 cm−1 1 H-NMR (400 MHz, CDCl3): δ 3.09 (1H, dd, J = 18.8; 4.4 Hz), 3.48 (1H, dd, J
;
= 18.8; 8.8 Hz), 4.78 (1H, dd, J = 8.8; 4.4 Hz) 7.23 (2H, d, J = 8.4 Hz), 7.63 (2H, d, J = 8.4 Hz). 13C-NMR
(100 MHz, CDCl3): δ 39.4; 48.8; 123.1; 127.7; 130.1; 132.5; 171.6 (2 C). Anal calcd for C10 H7 BrClNO2
(288.53) C, 41.63; H, 2.45; N, 4.85; Found C, 41.42; H, 2.50; N, 5.05.
Acknowledgment
Uludag˘ University Scientific Research Project Commission is gratefully acknowledged for its financial support.
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Substituent effects on the regioselectivity of maleamic acid..., Y. FATURACI, N. COS¸KUN
References
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3. Miller, C. W.; Jonsson, E. S.; Hoyle, C. E.; Viswanathan, K.; Valente, E. J. J. Phys. Chem. B. 2001, 105, 2707-2717.
4. Miller, C. W.; Hoyle, C. E.; Valente, E. J.; Magers, D. H.; Jonsson, E. S. J. Phys. Chem. A. 1999, 103, 6406-6412.
5. Garner, P.; Ho, W. B.; Grandhee, S. K.; Youngs, W. J.; Kennedy, V. O. J. Org. Chem. 1991, 56, 5893-5903.
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Chim. 2005, 50, 655-661. (c) Verma, R. K.; Kumar, B.; Ind. J. Chem. 1991, 30B, 822-824.
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N. J. Chem. Soc. Perkin 1, 2000, 3290-3291. (c) Mangaleswaran, S.; Argade, N. J. Chem. Soc. Perkin 1, 2001,
1764-1766.
8. Roderick, W. R. J. Am. Chem. Soc. 1956, 79, 1710-1712.
9. Olson, K. G; George B. Butler, G. B. Macromolecules 1984; 17, 2486-2501.
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11. Maleimides 4g-l. The crude mixtures from the cyclization of maleamic acids in the presence of triethylamine (5
mmol, 0.7 mL) and SOCl2 (6 mmol, 0.44 mL) were treated with additional amounts of triethylamine (4.1 mmol,
0.57 mL) for 0.5 h at room temperature. The mixture was poured into crushed ice (20 g) and the formed solid
was filtered and dissolved in ethanol or ethanol-ether (1:2) and left to crystallize in a refrigerator. The crystalline
product was filtered and dried under vacuum. The identity of the products was proved by spectral means and
comparison with authentic samples. 4g; Yield 71%, mp 87-88, lit6b mp 89-90 ◦ C. 4h; Yield 73%, mp 147-148,
lit6b mp 145-146 ◦ C. 4i; Yield 90%, mp 150-151, lit8 mp 148-148.5 ◦ C. 4j; Yield 91%, mp 167-168, lit6b mp
168-170 ◦ C. 4k; Yield 63%, mp 116-117, lit6b mp 114-115 ◦ C. 4l; Yield 90%, mp 126-127, lit9 mp 123-124 ◦ C.
12. (Z)-2-methyl-4-(4-nitrophenylamino)-4-oxobut-2-enoic acid 3ꢀ d. 1 H-NMR (400 MHz, DMSO-d6): δ 2.05
(3H, s), 5.87 (1H, s), 7.83 (2H, d, J = 9.2 Hz) 8.2 (2H, d, J = 9.2 Hz), 10.74 (1H, s), 12.69 (1H, s). The spectrum
is elicited from a mixture of 3d and 3’d containing 41% 3’d.
758

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