Esters of 4-(3-dialkylamino-2,5-dioxo-2,3,4,5-tetrahydro-1H-pyrrolyl) phenylacetic acids

Article abstract of DOI:10.1007/s11178-006-0014-z

Reaction of equivalent amounts of alkyl 4-aminophenylacetates with maleic anhydride gave rise to the corresponding alkyl 4-N-maleimidophenylacetates which with diethylamine, piperidine, and morpholine afforded esters of 4-(3-dialkylamino-2,5-dioxo-2,3,4,5

Full text of DOI:10.1007/s11178-006-0014-z

Russian Journal of Organic Chemistry, Vol. 41, No. 11, 2005, pp. 1657-1660. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 11, 2005,
pp. 1691-1694.
Original Russian Text Copyright Ó 2005 by Kolyamshin, Danilov, Dashkova, Kol’tsov.
.
Esters of 4-(3-Dialkylamino-2,5-dioxo-2,3,4,5-tetrahydro-1H-
pyrrolyl)phenylacetic acids
O.A. Kolyamshin, V.A. Danilov, G.Yu. Dashkova, and N.I. Kol'tsov
Ul’yanov Chuvash State University, Cheboksary, 428015 Russia
Received October 9, 2004
Abstract— Reaction of equivalent amounts of alkyl 4-aminophenylacetates with maleic anhydride gave rise to the
corresponding alkyl 4-N-maleimidophenylacetates which with diethylamine, piperidine, and morpholine afforded
esters of 4-(3-dialkylamino-2,5-dioxo-2,3,4,5-tetrahydro-1H-pyrrolyl)phenylacetic acids as stereoisomer mixtures.
A number of N-aryl-2-(4-alkylpiperazino)- and
2-(benzimidazol-2-yl)succinimides are known to possess
soporific, anticonvulsive, antiarrhythmic, and other types
of activity [1–3]. At the same time a series of substituted
derivatives of phenylacetic acid and its esters, in particular,
with pyrrole and pyrazole rings as para-substituents show
antiphlogistic, analgesic, antirheumatic, and anticonvulsive
activity [4–6]. Therefore it looks promising to prepare
phenylacetic acids esters having a 2-dialkylamino-
succinimide ring as a substituent and to study their
properties.
elemental analysis and TLC, and the structure was proved
by IR and H NMR spectra. In the IR spectra of male-
imides IIIa–IIId the stretching vibrations of the CH=CH
1
bond give rise to a weak but characteristic absorption
–1
band in the region 3095–3070 cm , and the stretching
vibrations of the C=O group appear as several strong
–1
bands in the region 1700–1645 cm and a weak overtone
–1
at 3455–3445 cm . In the 1H NMR spectra of maleimides
IIIa–IIId the protons of the maleimide ring give a singlet
at 7.15 ppm.
The treatment of maleimides IIIa–IIId with equivalent
amounts of diethylamine (IVa), piperidine (IVb), and
morpholine (IVc) in dioxane at 45–90°C afforded the
corresponding esters of 4-(3-dialkylamino-2,3,4,5-tetra-
hydro-1H-pyrrolyl)phenylacetic acids Va–Vj.
The reaction of alkyl p-aminophenylacetates Ia–Id
with maleic anhydride afforded the corresponding
maleamic acids IIa–IId whose cyclization effected by
acetanhydride in DMF resulted in alkyl 4-N-maleimido-
phenylacetates IIIa–IIId.
Compounds Va–Vj are crystalline or amorphous
powders of color varying from colorless to light-brown.
In their IR spectra the bands of the stretching vibrations
of the C=O groups appear in the same region as in the
spectra of maleimides IIIa–IIId, and additional medium
Maleamides IIa–IId are yellow powders, and male-
imides are crystals of light-yellow (IIIb and IIIc) or light-
brown (IIIa and IIId) color. The composition and the
homogeneity of the substances were confirmed by
Scheme.
2
2
2
&
&
+ 1
&+ &225
&+ &225
,jꢀꢀꢀ,G
2
1
2
&
&
+22&&+ &+&21+
&+ &225
B
B
,,,jꢀꢀꢀ,,,G
,,jꢀꢀꢀ,,G
R = Me (a), Et (b), CH2CH2Cl (c), C4H9 (d).
1070-4280/05/4111-1657Ó2005 Pleiades Publishing, Inc.

KOLYAMSHIN et al.
1658
B
3260, 3185 (NHCO), 1700, 1660 (C=O), 1090 (COC).
,,,jꢀꢀꢀ,,,G 5ꢁ 1+
ꢀ
Found, %: C 59.21; H 4.91; N 5.38. C13H13NO5.
Calculated, %: C 59.32; H 4.98; N 5.32.
B
,9jꢀꢀꢀ,9F
2
&
1
&
Compounds IIb–IId were prepared in the same way.
5ꢁ 1
3-[(4-Ethoxycarbonylmethyl)phenylcarbamoyl]-
&+ &225
2-propenoic acid (IIb). Yield 92.4%, mp 153–154°C,
–1
Rf 0.62. IR spectrum, n, cm : 3280, 3200 (NHCO), 1700,
2
B
9jꢀꢀꢀ9M
1670 (C=O), 1100 (COC). Found, %: C 60.48; H 5.51;
N 5.01. C14H15NO5. Calculated, %: C 60.65; H 5.45;
N 5.05.
IV, R' = Et (a), R2' = (CH2)5 (b), (CH2)2O(CH2)2 (c); V, R =
Me, R' = Et (a); R = Et, R' = Et (b), R2' = (CH2)5 (c),
(CH2)2O(CH2)2 (d); R = CH2CH2Cl, R' = Et (e), R2' = (CH2)5
(f), (CH2)2O(CH2)2 (g); R = C4H9, R' = Et (h), R2' = (CH2)5
(i), (CH2)2O(CH2)2 (j).
3-{[4-(2-Chloroethoxy)carbonylmethyl]phenyl-
carbamoyl}-2-propenoic acid (IIc). Yield 81.2%, mp
–1
134–136°C. Rf 0.55. IR spectrum, n, cm : 3260, 3185
(NHCO), 1690, 1670 (C=O), 1115 (COC). Found, %:
C 53.66; H 4.52; N 4.52. C14H14ClNO5. Calculated, %:
C 53.95; H 4.53; N 4.49.
–1
1
absorption band is seen at 1745–1735 cm . In the H
NMR spectra of compounds Va–Vd and Vh–Vj the
protons of the CH2 group of the succinimide ring give
rise to two characteristic signals: a doublet of doublets in
the region 2.72–2.83 ppm (3JHH 4 and 12 Hz), and
a quartet at 2.95–2.98 ppm (3JHH 8 Hz). The signal from
the proton belonging to the CH group of the succinimide
ring appears as a quartet at 3.98–4.25 ppm (3JHH 8 Hz).
The chemical shift of this proton grows in the series of
substituents: piperidino > morpholino > diethylamino. The
multiplet character of the protons from the succinimide
ring indicates that the compounds obtained are mixtures
of stereoisomers. It is also revealed by the nonequivalence
of the CH2 groups attached to nitrogen in the piperidine
(Vc and Vi) and morpholine (Vd and Vj) rings; these
signals appear as two multiplets in the 2.47–2.50 and
2.52–2.85 ppm.
3-[(4-Butoxycarbonylmethyl)phenylcarbamoyl]-
2-propenoic acid (IIc). Yield 48.0%, mp 118.5–121°C.
–1
Rf 0.58. IR spectrum, n, cm : 3280, 3200 (NHCO), 1705,
1675 (C=O), 1090 (COC). Found, %: C 63.07; H 6.63;
N 4.63. C16H19NO5. Calculated, %: C 62.95; H 6.27;
N 4.59.
Methyl [4-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)-
phenyl]acetate (IIIa). Amixture of 7.89 g of maleamide
IIa, 0.45 g of anhydrous sodium acetate, 4.5 g of acet-
anhydride, and 25 ml of DMF was stirred for 4 h at 45–
50°C. The reaction mixture was cooled to room tempera-
ture and mixed with 150 ml of water. The precipitate
was filtered off, washed with water (10´5 ml), and dried
in air. Yield 5.6 g (76.1%), light-brown crystals, mp 91–
–1
92°C (2´MeOH), Rf 0.66. IR spectrum, n, cm : 3455,
1700, 1670 (C=O), 3085 (CH=CH), 1110 (COC).
1H NMR spectrum, d, ppm: 3.63 s (3H, CH3), 3.73 s (2H,
CH2Ar), 7.15 s (2H, CH=CH), 7.28 d and 7.38 d (4H,
Harom, 3JHH 8 Hz). Found, %: C 63.97; H 4.50; N 5.68.
C13H11NO4. Calculated, %: C 63.68; H 4.52; N 5.71.
EXPERIMENTAL
IR spectra were recorded on a spectrometer IR-75
1
from thin films. The H NMR spectra were registered
on a spectrometer Bruker DRX500 (500.13 MHz) in
DMSO-d6, internal reference TMS. TLC was carried
out on Sorbfil PTLC-P-V, eluent ethanol–hexane, 3:1,
development in iodine vapor. Elemental analyses were
carried out on an analyzer Perkin Elmer 2400 CHN.
Compounds IIIb–IIId were prepared similarly.
Ethyl [4-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)-
phenyl]acetate (IIIb). Yield 81%, mp 83–85°C
–1
(2´EtOH). Rf 0.68. IR spectrum, n, cm : 3450, 1690,
1
1670 (C=O), 3095 (CH=CH), 1110 (COC). H NMR
3-[(4-Methoxycarbonylmethyl)phenyl-
carbamoyl]-2-propenoic acid (IIa). To a solution of
5.78 g of methyl 4-aminophenylacetate in 25 ml of ether
was gradually added within 10–15 min a solution of
3.43 g of maleic anhydride in 25 ml of ether. In 2 h the
separated precipitate was filtered off, washed with ether
(3 ´ 3 ml), and dried in air. Yield 8.9 g (96.7%), yellow
3
spectrum, d, ppm: 1.20 t (3H, CH3, JHH 8 Hz), 3.72 s
(2H, CH2Ar), 4.10 q (2H, CH2, 3JHH 8 Hz), 7.15 s (2H,
3
CH=CH), 7.28 d and 7.38 d (4H, Harom, JHH 8 Hz).
Found, %: C 65.02; H 5.08; N 5.43. C14H13NO4.
Calculated, %: C 64.86; H 5.05; N 5.40.
2-Chloroethyl [4-(2,5-dioxo-2,5-dihydro-1H-
pyrrolyl)phenyl]acetate (IIIc). Yield 99.0%, mp 114–
–1
powder, mp 161–163°C, Rf 0.48. IR spectrum, n, cm :
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 11 2005

ESTERS OF 4-(3-DIALKYLAMINO-2,5-DIOXOO-2,3,4,5-TETRAHYDRO-1H-
1659
–1
3
116
°
C (2 ´ EtOH). Rf 0.63. IR spectrum, n, cm : 3450,
3JHH 8 Hz), 1.20 t (3H, CH3, JHH 8 Hz), 2.63 m (4H,
1700, 1670, 1650 (C=O), 3070 (CH=CH), 1250 (CH2–
Cl), 1105 (COC). 1H NMR spectrum, d, ppm: 3.77 s
(2H, CH2Ar), 3.83 t (2H, CH2Cl, 3JHH 8 Hz), 4.35 t (2H,
2CH2N), 2.72 d.d. and 2.95 q (2H, CH2 of ring), 3.72 s
(2H, CH2Ar), 4.10 q (2H, CH2O, 3JHH 8 Hz), 4.25 q (1H,
3
CH of ring, JHH 8 Hz), 7.20 d and 7.37 d (4H, Harom
,
3
CH2O, JHH 8 Hz), 7.15 s (2H, CH=CH), 7.28 d and
3JHH 8). Found, %: C 65.01; H 7.33; N 8.48. C18H24N2O4.
3
7.38 d (4H, Harom, JHH 8 Hz). Found, %: C 57.41;
Calculated, %: C 65.05; H 7.28; N 8.43.
H 4.15; N 4.81. C14H12ClNO4. Calculated, %: C 57.26;
H 4.12; N 4.77.
Ethyl [4-(3-piperidino-2,5-dioxo-2,3,4,5-tetra-
hydro-1H-pyrrolyl)phenyl]acetate (Vc). Yield 85.8%,
Butyl [4-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)-
mp 102.5–104
°
C (2 ´ EtOH). Rf 0.62. IR spectrum,
–1
phenyl]acetate (IIId). Yield 65.9%, mp 59–61
°
C (2 ´
n, cm : 3445, 1735, 1680, 1665 (C=O), 1110 (COC).
1H NMR spectrum, d, ppm: 1.20 t (3H, CH3, 3JHH 8 Hz),
1.40 m (2H, CH2 of piperidine), 1.57 s (4H, 2CH2 of
piperidine), 2.47 m and 2.78 m (4H, 2CH2 of piperidine),
2.75 d.d and 2.97 q (2H, CH2 of ring), 3.70 s (2H, CH2Ar),
3.98 q (1H, CH of ring), 4.12 q (2H, CH2O, 3JHH 8 Hz),
7.18 d and 7.37 d (4H, Harom, JHH 8 Hz). Found, %:
C 66.37; H 7.10; N 8.08. C19H24N2O4. Calculated, %:
C 66.26; H 7.02; N 8.13.
–1
BuOH), Rf 0.73. IR spectrum, n, cm : 3445, 1690, 1660,
1
1645 (C=O), 3085 (CH=CH), 1095 (COC). H NMR
spectrum, d, ppm: 0.87 t (3H, CH3, 3JHH 8 Hz), 1.32 m
and 1.56 m (4H, 2CH2), 3.72 s (2H, CH2Ar), 4.05 t (2H,
CH2O, 3JHH 8 Hz), 7.15 s (2H, CH=CH), 7.28 d and 7.38
d (4H, Harom, 3JHH 8 Hz). Found, %: C 67.01; H 6.00;
N 4.92. C16H17NO4. Calculated, %: C 66.89; H 5.96;
N 4.88.
3
Alkyl [4-(3-diethylamino-2,5-dioxo-2,3,4,5-tetra-
hydro-1H-pyrrolyl)phenyl]acetates Va–Vj. To a solu-
tion of 0.01 mol of an appropriate maleimide IIIa–IIId
in 4 ml of dioxane was gradually added a solution of
0.01 mol of secondary amine IVa–IVc in 4 ml of dioxane,
the mixture was stirred for 2–4 h at room temperature
Ethyl [4-(3-morpholino-2,5-dioxo-2,3,4,5-tetra-
hydro-1H-pyrrolyl)phenyl]acetate (Vd). Yield 60.7%,
mp 142–143
°
C (dioxane and MeOH), Rf 0.53. IR
–1
spectrum, n, cm : 3450, 1740, 1680, 1670 (C=O), 1105
(COC). 1H NMR spectrum, d, ppm: 1.20 t (3H, CH3,
3JHH 8 Hz), 2.50 m and 2.85 m (4H, 2CH2 of morpholine),
2.82 d.d and 2.98 q (2H, CH2 of ring), 3.60 s (4H, 2CH2
of morpholine), 3.72 s (2H, CH2Ar), 4.00 q (1H, CH of
and then heated for 1 h at 45–50°C (with diethylamine)
or 1 h at 60–90 C (with piperidine and morpholine). The
°
ring), 4.12 q (2H, CH2O, 3JHH 8 Hz), 7.20 d and 7.38 d
reaction mixture was cooled to room temperature and
mixed with 150–200 ml of water. The separated
precipitate was filtered off, washed with water (10´5 ml),
and dried in air. Compounds Va, Vb, and Vb precipitated
(Vb partially) directly from the reaction mixture. The
compounds obtained were additionally purified by
crystallization.
3
(4H,
H
arom, JHH 8 Hz). Found, %: C 62.49; H 6.35;
N 8.14. C18H22N2O5. Calculated, %: C 62.42; H 6.40;
N 8.09.
2-Chloroethyl [4-(3-diethylamino-2,5-dioxo-
2,3,4,5-tetrahydro-1H-pyrrolyl)phenyl]acetate (Ve).
Yield 59.9%, mp 62–65
°
C (50% EtOH), Rf 0.53. IR
Methyl [4-(3-diethylamino-2,5-dioxo-2,3,4,5-
tetrahydro-1H-pyrrolyl)phenyl]acetate (Va). Yield
–1
spectrum, n, cm : 3425, 1665 (C=O), 1260 (CH2Cl),1105
(COC). Found, %: C 59.01; H 6.23; N 7.69.
C18H23ClN2O4. Calculated, %: C 58.94; H 6.32; N 7.64.
58.2%, mp 124–124.5
°
C (dioxane and MeOH), Rf 0.58.
–1
IR spectrum, n, cm : 3445, 1740, 1690, 1670 (C=O),
2-Chloroethyl [4-(3-piperidino-2,5-dioxo-2,3,4,5-
1
1110 (COC). H NMR spectrum, d, ppm: 1.02 t (6H,
tetrahydro-1H-pyrrolyl)phenyl]acetate (Vf). Yield
3
2CH3, JHH 8 Hz), 2.65 m (4H, 2CH2N), 2.72 d.d and
–1
51.6%, mp 67–71
°
C. Rf 0.59. IR spectrum, n, cm : 1640
2.95 q (2H, CH2 of ring), 3.63 s (3H, CH3O), 3.73 C
(2H, CH2Ar), 4.25 q (1H, CH of ring, 3JHH 8 Hz), 7.18 d
and 7.37 d (4H, Harom, 3JHH 8 Hz). Found, %: C 64.28;
H 7.04; N 8.85. C17H22N2O4. Calculated, %: C 64.14;
H 6.97; N 8.80.
(C=O), 1250 (CH2Cl), 1110 (COC). Found, %: C 60.33;
H 6.15; N 7.73. C19H23ClN2O4. Calculated, %: C 60.24;
H 6.12; N 7.39.
2-Chloroethyl [4-(3-morpholino-2,5-dioxo-
2,3,4,5-tetrahydro-1H-pyrrolyl)phenyl]acetate (Vg).
Ethyl[4-(3-diethylamino-2,5-dioxo-2,3,4,5-tetra-
Yield 59.1%, mp 79–81
°
C, Rf 0.46. IR spectrum, n,
hydro-1H-pyrrolyl)phenyl]acetate (Vb). Yield 81.2%,
–1
cm : 1740, 1680, 1640 (C=O), 1245 (CH2Cl), 1100
(COC). Found, %: C 56.89; H 5.63; N 7.41.
C18H21ClN2O5. Calculated, %: C 56.77; H 5.56; N 7.36.
mp 111.5–112.5°C (dioxane and EtOH), Rf 0.68. IR
–1
spectrum, n, cm : 3450, 1745, 1690, 1670 (C=O), 1110
1
(COC). H NMR spectrum, d, ppm: 1.03 t (6H, 2CH3,
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 11 2005

KOLYAMSHIN et al.
1660
Butyl [4-(3-morpholino-2,5-dioxo-2,3,4,5-tetra-
hydro-1H-pyrrolyl)phenyl]acetate (Vj). Yield 81.6%,
Butyl [4-(3-diethylamino-2,5-dioxo-2,3,4,5-
tetrahydro-1H-pyrrolyl)phenyl]acetate (Vh). Yield
–1
mp 97–98.5
°
C (BuOH), Rf 0.54. IR spectrum, n, cm :
79.2%, mp 67–68
°
C (ether), Rf 0.67. IR spectrum, n,
–1
3455, 1740, 1685, 1670 (C=O), 1105 (COC). 1H NMR
spectrum, d, ppm: 0.88 t (3H, CH3 of butyl, 3JHH 8 Hz),
1.32 m and 1.56 m (4H, 2CH2 of butyla), 2.52 m and
2.85 m (4H, 2CH2 of morpholine), 2.83 d.d and 2.98 q
(2H, CH2 of ring), 3.60 c (4H, 2CH2 of morpholine),
cm : 3445, 1740, 1685, 1670, 1640 (C=O), 1100 (COC).
1H NMR spectrum, d, ppm: 0.88 t (3H, CH3 of butyl,
3JHH 8 Hz), 1.03 s (6H, 2CH3, JHH 8 Hz), 1.33 m and
3
1.57 m (4H, 2CH2 of butyl), 2.63 m (4H, 2CH2, N),
2.72 d.d and 2.95 q (2H, CH2 of ring), 4.72 s (2H, CH2Ar),
3.72 c (2H, CH2Ar), 4.00 q (1H, CH of ring), 4.07 t (2H,
4.05 t (2H, CH2O, 3JHH 8 Hz), 4.25 q (1H, CH of ring),
3
CH2O, JHH 8 Hz), 7.20 d and 7.37 d (4H, Harom
,
3
7.18 d and 7.37 d (4H,
H
arom, JHH 8 Hz). Found, %:
3JHH 8 Hz) Found, %: C 64.27; H 7.08; N 7.43.
C 66.78; H 7.90; N 7.72. C20H28N2O4. Calculated, %:
C 66.65; H 7.83; N 7.77.
C20H26N2O5. Calculated, %: C 64.16; H 7.00; N 7.48.
REFERNECES
Butyl [4-(3-piperidine-2,5-dioxo-2,3,4,5-tetra-
hydro-1H-pyrrolyl)phenyl]acetate (VI). Yield 79.3%,
1. Umio, Suminori, Japan Patent 30313, 1968; Ref. Zh. Khim.,
1970, 7N375P.
2. Umio, Suminori, Kariene, Kadzuo, and Nakamura, Nindzi,
Japan Patent 21433, 1968; Ref. Zh. Khim., 1969, 23N310P.
3. Ahmed, Quazi and Wagner-Jauregg, Theodor, Swiss Patent
583226, 1976; Ref. Zh. Khim., 1977, 14O131P.
4. Denss, Rolf, Glauson-Kaas, Niels, and Ostermayer, Franz,
Swiss Patent 480333, 1969; Ref. Zh. Khim., 1970, 16N407P.
5. Denss, Rolf, Glauson-Kaas, Niels, and Ostermayer, Franz,
CPP Patent 55632, 1973; Ref. Zh. Khim., 1975, 8097P.
6. Kodamu, Tsutomu, Nakabayasi, Masao, Vatanabe, Isao,
Saadaki, Khirosi, et al., Japan 52-122367, 1977; Ref. Zh. Khim.,
1979, 10143P.
–1
mp 82–84
°
C (ether), Rf 0.65. IR spectrum, n, cm : 3455,
1
1745, 1690, 1670 (C=O), 1110 (COC). H NMR
spectrum, d, ppm: 0.83 t (3H, CH3 of butyl, 3JHH 8 Hz),
1.40 m (2H, CH2 of piperidine), 1.32 m and 1.57 m (4H,
2CH2 of butyl), 1.52 s (4H, 2CH2 of piperidine), 2.48 m
and 2.78 m (4H, 2CH2), 2.75 d.d and 2.97 q (2H, CH2 of
ring), 3.70 s (2H, CH2Ar), 3.98 q (1H, CH of ring),
3
4.07 t (2H, CH2O, JHH 8 Hz), 7.18 d and 7.37 d (4H,
H
arom, 3JHH 8 Hz). Found, %: C 67.69; H 7.48; N 7.48.
C21H28N2O4. Calculated, %: C 67.72; H 7.58; N 7.52.
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 11 2005