Products from condensation of 1-(3(4)-acetylphenyl)-4-carboxy-2- pyrrolidinones with o-phenylenediamine and their properties

Article abstract of DOI:10.1007/s10593-007-0213-8

2-Substituted benzimidazoles were synthesized by the reaction of 1-(3(4)-acetylphenyl)-4-carboxy-2-pyrrolidinones with o-phenylenediamine. Their reactions with sodium hydroxide and hydrazine and some of their chemical characteristics were investigated.

Full text of DOI:10.1007/s10593-007-0213-8

Chemistry of Heterocyclic Compounds, Vol. 43, No. 11, 2007
PRODUCTS FROM CONDENSATION
OF 1-(3(4)-ACETYLPHENYL)-4-CARBOXY-
2-PYRROLIDINONES WITH o-PHENYLENE-
DIAMINE AND THEIR PROPERTIES
A. Voskiene and V. Mickevicius
2-Substituted benzimidazoles were synthesized by the reaction of 1-(3(4)-acetylphenyl)-4-carboxy-
2-pyrrolidinones with o-phenylenediamine. Their reactions with sodium hydroxide and hydrazine and
some of their chemical characteristics were investigated.
Keywords: 4-(arylamino)-3-(1H-benzimidazol-2-yl)butyric acids, 1-aryl-4-(1H-benzimidazol-2-yl)-
2-pyrrolidinones, 1-aryl-4-carboxy-2-pyrrolidinones, hydrazones, o-phenylenediamine, condensation.
Derivatives of benzimidazole have a broad spectrum of biological activity [1-5]. The synthesis and
investigation of compounds containing this fragment therefore represent a vital task. One of the most widely
used methods for the synthesis of 2-substituted benzimidazoles is the Phillips method [6] – heating carboxylic
acids or their derivatives with o-phenylenediamines in a 4 M solution of hydrochloric acid.
While continuing investigations into the reactivity of 1-aryl-substituted 4-carboxy-2-pyrrolidinones we
realized the condensation of 1-(3(4)-acetylphenyl)-4-carboxy-2-pyrrolidinones 1a,b, synthesized by the method
in [7], with o-phenylenediamine under the conditions of the Phillips method. The reaction mixture was boiled,
and the products in the form of 2-substituted benzimidazoles 2a,b were isolated by making the reaction mixture
alkaline to pH 10 with a concentrated solution of ammonia.
It is known that the 2-pyrrolidinone ring is stable to the action of acids but can undergo decyclization in
an alkaline medium. We established that when compounds 2a,b were boiled in a 20% solution of sodium
hydroxide the 2-pyrrolidinone ring broke down into the corresponding sodium salts of N-substituted γ-amino
acids 3a,b). The free γ-amino acids 4a,b were isolated by acidifying the aqueous solutions of the sodium salts to
pH 6 with acetic acid.
During comparison of the data from the 1H NMR spectra of compounds 2a,b and 4a,b it is seen that the
signals for the protons of the 2-pyrrolidinone ring and for the compounds with an open chain are similar and
only differ in their shifts. In the compounds with an open chain 4a,b the signals of the substituted amino group
are also observed at 6.14 and 6.82 respectively. In the 13C NMR spectra the line at 173 ppm indicates that
compounds 4a,b contain noncyclic bonds, while the chemical shifts of the CH2CHCH2 and CH2CO carbon
atoms are fairly close – the difference is only ~0.4 ppm, while the difference in the cyclic compounds 2a,b
amounts to ~7 ppm.
__________________________________________________________________________________________
Kaunas University of Technology, Kaunas LT-50254, Lithuania; e-mail: Vytautas.Mickevicius@ktu.lt.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp.1625-1630, November, 2007. Original
article submitted July 4, 2007.
0009-3122/07/4311-1379©2007 Springer Science+Business Media, Inc.
1379

Sheme 1
Me
Me
O
O
H2N
H2N
4M, HCl, ∆
+
N
O
N
O
N
O
NH
2a,b
20 % NaOH
OH
1a,b
Me
Me
O
O
MeCOOH
HN
HN
O
O
N
N
OH
ONa
NH
NH
3a,b
4a,b
a 3-MeCO; b 4-MeCO
During study of the reaction of compound 2b with hydrazine hydrate it was established that compound 5
is formed when the reaction is carried out in methanol at the boiling point of the mixture. Increase of the
temperature and also increase of the reaction time lead to the formation of a dimeric structure. Thus, by
conducting the reaction in boiling dioxane for 22 h, we synthesized a compound of the azine type 6. In order to
increase the solubility and to confirm the structure the compound was alkylated with iodoethane. In addition to
1
the signals of protons characteristic of compound 6, the H NMR spectrum of the alkyl derivative 7 contains
signals for the protons of the N–CH2CH3 groups at 1.37 and of the N–CH2CH3 groups in the range of 4.15-4.40
ppm, which overlap with the signals for the protons of the 2-pyrrolidinone ring.
During the condensation of compound 5 with 9-ethyl-3-formyl-carbazole and para-diethyl-
aminobenzaldehyde the corresponding hydrazones 8 and 9 were obtained. Their structure was confirmed by
elemental analysis, 1H and 13C NMR spectra, mass spectrometry, and IR spectra.
EXPERIMENTAL
1
The H and 13C NMR spectra were obtained on a Varian Unity Inova spectrometer (300 and 75 MHz
respectively) in DMSO-d6 with TMS as internal standard. The IR spectra were recorded on a Perkin–Elmer
Spectrum Bx FT IR instrument in tablets with potassium bromide. The mass spectra were obtained on a Waters
1380

Scheme 2
Me
N
O
Me
Me
N
NH2
N
R
O
R
.
N2H4 H2O, 2 h
H
N
O
N
N
O
O
N
N
N
NH
NH
NH
2b
8, 9
5
.
N2H4 H2O, 22 h
H
N
O
Me
N
N
N
N
N
N
Me
O
N
6
H
Me
MeCH2I
O
N
N
Me
N
N
N
N
N
N
Me
7
O
Me
Me
Me
8 R =
N
9 R =
,
N
Me
ZQ 2000 spectrometer with electrospray ionization (ESI, 20 V, compounds 2a,b and 4a,b) and chemical
ionization at atmospheric pressure (APCI, compounds 5, 6, 8, and 9). The reaction and the purity of the products
were monitored by TLC (on Alugram Sil G/UV-254 plates) with development in UV light (λ = 254 and
366 nm).
1381

1-(3(4)-Acetylphenyl)-4-(1H-benzimidazol-2-yl)-2-pyrrolidinones 2a,b (General Method).
A
mixture of the respective 2-pyrrolidinone 1a, b (2.47 g, 10 mmol) and o-phenylenediamine (2.16 g, 20 mmol)
was boiled for 5-6 h in a 4 M solution of hydrochloric acid (20 ml), cooled, and diluted to pH ca 10 with a
24-26% aqueous solution of ammonia. The aqueous layer was decanted, and the obtained resinous mass was
inundated with 5% sodium hydroxide solution (20 ml) and heated to boiling. The crystals that separated after the
mixture had cooled were filtered off, washed with water, and dried.
1-(3-Acetylphenyl)-4-(1H-benzimidazol-2-yl)-2-pyrrolidinone (2a). Yield 38%; mp 103-104°C
(1,4-dioxane). IR spectrum, ν, cm−1: 1707, 1678 (СО); 3089, 3051 (NH). 1H NMR spectrum, δ, ppm: 2.59 (3Н,
s, СН3СО); 2.98-3.13 (2Н, m, СН2СО); 3.98-4.08 (1Н, m, СН2СНСН2); 4.26-4.39 (2Н, m, CH2N); 7.15-8.22
(8Н, m, Н arom.); 12.52 (1Н, s, NH). 13C NMR spectrum, δ, ppm: 26.79 (СН3); 30.61 (СН2СНСН2); 37.44
(СН2СО); 52.04 (CH2N); 111.06, 118.47, 123.87, 123.94, 129.14, 134.46, 137.18, 139.51 (С6Н5); 154.84
[C(N)NH]; 172.34 (NCO); 197.65 (СО). Mass spectrum, m/z (I, %): 320 [М + Н]+ (100). Found, %: С 71.62;
Н 5.72; N 12.95. C19H17N302. Calculated, %: С 71.46; Н 5.37; N 13.16.
1-(Acetylphenyl)-4-(1H-benzimidazol-2-yl)-2-pyrrolidinone (2b). Yield 40%; mp 222-223°C
1
(1,4-dioxane). IR spectrum, ν, cm−1: 1699, 1682 (СО); 3053, 3007 (NH). H NMR spectrum, δ, ppm (J, Hz):
2.55 (3Н, s, СН3СО); 2.98-3.15 (2Н, m, СН2СО); 3.98-4.09 (1Н, m, СН2СНСН2); 4.25-4.38 (2Н, m, CH2N);
7.13-8.01 (8Н, m, Н arom.); 12.51 (1Н, s, NH). 13C NMR spectrum, δ, ppm: 26.49 (СН3); 30.48 (СН2НСН2);
37.65 (CН2СО); 51.95 (CH2N); 111.05, 118.39, 121.16, 121.99, 129.18, 132.01, 134.45, 142.73, 143.19 (С6Н5);
154.77 [C(N)NH]; 172.77 (NCO); 196.63 (СО). Mass spectrum, m/z (I, %): 320 [М + Н]+ (100). Found, %:
С 71.37; Н 5.30; N 13.02. C19H17N302. Calculated, %: С 71.46; Н 5.37; N 13.16.
4-[3(4)-Acetylphenylamino]-3-(1H-benzimidazol-2-yl)butyric Acids 4a,b (General Method). A
mixture of the respective compound 2a,b (0.32 g, 1 mmol) and 20% sodium hydroxide solution (8 ml) was
boiled for 3 h, diluted with water (15 ml), cooled, and filtered. The filtrate was acidified to pH 6 with acetic acid.
The crystals of compounds 4a,b that formed were purified by dissolving them in a 5% solution of sodium
hydroxide, filtration, and acidification to pH 6 with acetic acid. The crystals that separated were filtered off,
washed with water, and dried.
4-(3-Acetylphenylamino)-3-(1H-benzimidazol-2-yl)butyric Acid (4a). Yield 81%; mp 172-173°C.
IR spectrum, ν, cm−1: 1681, 1603 (СО); 3372, 3262, 3057 (ОН + NH). 1H NMR spectrum, δ, ppm (J, Hz): 2.40
(3H, s, СН3СО); 2.79-2.96 (2Н, m, СН2СО); 3.34-3.68 (3H, m, СН2СНСН2 + CH2N); 6.14 (1H, t, J = 5.5, NH);
6.78-7.60 (8Н, m, Н arom.); 12.28 (1Н, bs, СООН). 13C NMR spectrum, δ, ppm: 26.73 (СН3); 35.43
(СН2СНСН2); 35.80 (СН2СО); 46.53 (CH2NH); 111.13, 115.86, 116.48, 121.18, 129.17, 137.67, 148.56 (С6Н5);
155.81 (C=N); 173.10 (СООН); 198.29 (СО). Mass spectrum, m/z (I, %): 338 [М + Н]+ (100). Found, %: С
67.29; Н 5.34; N 12.23. C19H19N303. Calculated, %: С 67.64; Н 5.68; N 12.46-212°C. IR spectrum, ν, cm−1:
1
1656, 1601 (СО); 3265, 3152, 3057 (ОН + NH). H NMR spectrum, δ, ppm (J, Hz): 2.40 (3H, s, СН3СО);
2.76-2.95 (2Н, m, СН2СО); 3.36-3.45 (1Н, m, СН2СНСН2); 3.51-3.67 (2Н, m, CH2N); 6.82 (1H, t, J = 5.8,
NH); 6.67-7.73 (8Н, m, Н arom.); 12.37 (1Н, bs, СООН). 13C NMR spectrum, δ, ppm: 25.89 (СН3); 35.36
(CH2CHCH2; 35.70 (СН2СО); 46.04 (CH2NH); 110.88, 121.22, 125.03, 130.42, 152.47, 155.54 (C=N); 172.99
(СООН); 195.01 (СО). Mass spectrum, m/z (I, %): 338 [М + Н]+ (100). Found, %:С 67.29; Н 5.80; N 12.19.
C19H19N303. Calculated, %: С 67.64; Н 5.68; N 12.46.
4-(4-Acetylphenylamino)-3-(1H-benzimidazol-2-yl)butyric Acid (4b). Yield 88%; mp 211-212°C. IR
1
spectrum, ν, cm−1: 1656, 1601 (СО); 3265, 3152, 3057 (ОН + NH). H NMR spectrum, δ, ppm (J, Hz): 2.40
(ЗН, s, СН3СО); 2.76-2.95 (2Н, m, СН2СО); 3.36-3.45 (1Н, m, СН2СНСН2); 3.51-3.67 (2Н, m, CH2N); 6.82
(1H, t, J = 5.8, NH); 6.67-7.73 (8Н, m, H arom.); 12.37 (1Н, bs, СООН). 13C NMR spectrum, δ, ppm: 25.89
(СН3); 35.36 (CH2CHCH2; 35.70 (СН2СО); 46.04 (CH2NH); 110.88, 121.22, 125.03, 130.42, 152.47, 155.54
(C=N); 172.99 (СООН); 195.01 (СО). Mass spectrum, m/z (I, %): 338 [М + Н]+ (100). Found, %: С 67.29;
Н 5.80; N 12.19. C19H19N303. Calculated, %: С 67.64; Н 5.68; N 12.46.
1382

4-(1H-Benzimidazol-2-yl)-1-[4-(1-hydrazonoethyl)phenyl]-2-pyrrolidinone (5).
A
mixture of
compound 2b (2.24 g, 7 mmol), hydrazine monohydrate (1.05 g, 21 mmol), and methanol (10 ml) was boiled for
2 h. The crystals that separated on cooling were filtered off and washed with 2-propanol and ether. Yield 41%;
mp >350°C (decomp.) (1,4-dioxane). IR spectrum, ν, cm−1: 1703 (СО); 3387, 3212, 3086, 3052 (NH + NH2). 1H
NMR spectrum, δ, ppm (J, Hz): 2.01 (3Н, s, (CH3)C=NNH2); 2.94-3.10 (2Н, m, СН2СО); 3.93-4.06 (1H, m,
СН2СНСН2); 4.20-4.32 (2Н, m, CH2N); 6.35 (2Н, s, NH2); 7.11-7.68 (8Н, m, Н arom.); 12.49 (1Н, s, NH). 13C
NMR spectrum, δ, ppm: 11.24 (СН3); 30.61 (CH2CHCH2); 37.55 (СН2СО); 52.04 (CH2N); 111.03, 118.46,
118.86, 121.14, 121.97, 124.93, 135.45, 138.12, 141.61; 142.74 (C=N); 154.96 (N=CNH); 171.90 (NCO). Mass
spectrum, m/z (I, %): 334 [M + H]+ (100). Found, %: С 68.07; H 5.59; N 20.78. C19H19NsO. Calculated, %:
С 68.45; Н 5.74; N 21.01.
4-(1H-benzimidazol-2-yl)-1-(4-{1-[(1-{4-[4-(1H-benzimidazol-2-yl)-2-oxopyrrolidin-1-yl]phenyl}-
ethylidene)hydrazono]ethyl}phenyl)-2-pyrrolidinone (6). A mixture of compound 2b (21.8 g, 66 mmol),
hexane monohydrate (6.51 g, 130 mmol), and 1,4-dioxane (100 ml) was boiled for 22 h. The crystals that
separated on cooling were filtered off and washed with 2-propanol and with ether. Yield 51%; mp >360°C
(decomp.) (1:1 mixture of 1,4-dioxane and DMF). IR spectrum, ν, cm−1: 1697 (СО); 3370, 3054 (NH). 1H NMR
spectrum, δ, ppm (J, Hz): 2.30 (6Н, s, 2СН3); 2.99-3.15 (4Н, m, 2СН2СО); 3.01-4.12 (2Н, m, 2СН2СНСН2);
4.24-4.39 (4Н, m, 2CH2N); 7.17-7.97 (18Н, m, 2NH + Н arom.). 13C NMR spectrum, δ, ppm: 14.48 (СН3);
30.46 (CH2CHCH2); 37.52 (СН2СО); 51.93 (CH2N); 114.69, 118.79, 121.76, 125.01, 126.96, 133.29, 140.41
(С6Н5); 154.76 (N=CNH); 157.26 (C=N); 172.17 (СН2СО). Mass spectrum, m/z (I, %): 635 [М + Н]+ (100).
Found, %: С 71.47; Н 5.59; N 17.78. C38H34O2. Calculated, %: С 71.91; Н 5.40; N 17.65.
4-(1-Ethyl-1H-benzimidazol-2-yl)-1-(4-{1-[(1-{4-[4-(1-ethyl-1H-benzimidazol-2-yl)-2-oxopyrrolidin-
1-yl]phenyl}ethylidene)hydrazono]ethyl}phenyl)-2-pyrrolidinone (7). A mixture of compound 6 (1.9 g,
3 mmol), iodoethane (50 ml), potassium hydroxide (2.36 g, 42 mmol), potassium carbonate (0.97 g, 7 mmol),
and tetrabutylammonium iodide (ca 1 g) was boiled for 10 h. The liquid fractions were distilled under vacuum
on a rotary evaporator, and the residue was inundated with water (10 ml) and stirred. The crystals were filtered
off, washed with water, and dried. Yield 83%; mp 242-244°C (1,4-dioxane). 1H NMR spectrum, δ, ppm (J, Hz):
1.37 (6Н, t, J = 7.2, 2СН2СH3; 2.30 (6Н, s, 2СН3С); 2.94-3.17 (4Н, m, 2СН2СО); 4.15-4.40 (10Н, m,
2СН2СНСН2 + 2CH2N + 2CH2СН3); 7.16-7.98 (16Н, m, Н arom.). Found, %: С 72.87; Н 5.86; N 16.15.
C42H42N802. Calculated, %: С 73.02; Н 6.13; N 16.22.
4-(1H-Benzimidazol-2-yl)-1-(4-{1-[(9-ethyl-9H-carbazol-3-ylmethylene)hydrazono]ethyl}phenyl)-2-
pyrrolidinone (8). A mixture of compound 6 (3.0 g, 9 mmol), 9-ethyl-3-formyl-carbazole (4.0 g, 18 mmol), and
1,4-dioxane (100 ml) was boiled for 4 h. The crystals that formed on cooling were filtered off, washed with 2-
propanol, and dried. Yield 52%; mp 195-197°C (1:1 mixture of 1,4-dioxane and 2-propanol). IR spectrum,
1
ν, cm−1: 1697 (СО); 3051 (N=CH); 3386 (NH). H NMR spectrum, δ, ppm (J, Hz): 1.33 (3Н, t, J = 7.2,
СН2СН3); 2.56 (3Н, s, СН3С); 2.99-3.15 (2Н, m, СН2СО); 4.00-4.10 (1H, m, СН2СНСН2); 4.26-4.39 (2Н, m,
CH2N); 4.45-4.52 (2Н, m, СH2СНз); 7.14-8.73 (16Н, m, N=CH + Н arom.); 12.53 (1H, s, NH). 13C NMR
spectrum, δ, ppm: 13.70 (СН3); 14.48 (СН3); 30.54 (СН2СНСН2); 37.12 (СН2); 37.61 (СН2CО); 51.97 (CH2N);
109.51, 118.66, 119.46, 120.57, 121.49, 121.60, 125.39, 125.64, 126.24, 127.16, 133.12, 139.94, 139.99,
140.69; 141.11, 154.86 (С6Н5 + N=CH); 159.27 (C=N); 162.63 (N=CNH); 172.32 (NCO). Mass spectrum, m/z
(I, %): 561 [M + Na]+ (100). Found, %: С 75.27; H 5.69; N 15.84. C34H30N6O. Calculated, %: С 75.81; Н 5.61;
N 15.60.
4-(1H-Benzimidazol-2-yl)-1-(4-{1-[(4-diethylaminobenzylidene)hydrazono]ethyl}phenyl)-2-pyrrolini-
none (9). A mixture of compound 6 (1.0 g, 3 mmol), of para-diethylaminobenzaldehyde (0.64 g, 3.6 mmol), and
1,4-dioxane (10 ml) was boiled for 5 h. The crystals that formed on cooling were filtered off, washed with
2-propanol and with ether, and dried. Yield 66%; mp 244-245°C (1,4-dioxane). IR spectrum, ν, cm−1: 1672
1
(СО); 3055, 3012 (N=CH); 3391, 3182, 3146 (NH). H NMR spectrum, δ, ppm (J, Hz): 1.12 (6Н, t, J = 7.2,
2СН2СН3); 2.48 (3Н, s, СН3С); 2.97-3.13 (2Н, m, СН2СО); 3.32-3.43 (4Н, m, 2СН2СН3); 3.98-4.09 (1Н, m,
1383

СН2СНСН2); 4.25-4.37 (2Н, m, CH2N); 6.71-8.40 (13Н, m, N=CH + Н arom.); 12.49 (1Н, s, NH). 13C NMR
spectrum, δ, ppm: 12.38 (2СН3); 14.33 (СН3); 30.54 (СН2СНСН2); 37.61 (СН2СО); 43.74 (2СН2); 51.99
(CH2N); 110.92, 111.02, 118.46, 118.65, 120.75, 121.13, 121.97, 126.98, 130.07, 133.35, 134.50, 140.47,
142.73, 149.43, 152.36, 154.87 (С6Н5 + N=CH); 159.02 (C=N); 161.66 (N=CNH); 172.27 (NCO). Mass
spectrum, m/z (I, %): 515 [M + Na]+ (100). Found, %: С 72.73; H 6.48; N 16.72. C30H32N6O. Calculated, %:
С 73.14; Н 6.55; N 17.06.
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1384