Polycyclic systems containing 1,2,4-oxadiazole ring 2*. 4-(1,2,4-Oxadiazol-5-YL)pyrrolidin-2-ones: Synthesis and prediction of biological activity

Article abstract of DOI:10.1007/s10593-008-0080-y

A one-pot condensation of 5-oxopyrrolidine-3-carboxylic acids, carbonyldiimidazole, and benzamidoximes leads to the formation of the novel 4-(1,2,4-oxadiazol-5-yl)pyrrolidin-2-one bicyclic systems, the structures of which have been confirmed by IR and

Full text of DOI:10.1007/s10593-008-0080-y

Chemistry of Heterocyclic Compounds, Vol. 44, No. 5, 2008
POLYCYCLIC SYSTEMS
CONTAINING 1,2,4-OXADIAZOLE RING
2*. 4-(1,2,4-OXADIAZOL-5-YL)PYRROLIDIN-
2-ONES: SYNTHESIS AND PREDICTION
OF BIOLOGICAL ACTIVITY
Yu. V. Kharchenko, O. S. Detistov, and V. D. Orlov
A
one-pot condensation of 5-oxopyrrolidine-3-carboxylic acids, carbonyldiimidazole, and
benzamidoximes leads to the formation of the novel 4-(1,2,4-oxadiazol-5-yl)pyrrolidin-2-one bicyclic
1
systems, the structures of which have been confirmed by IR and H NMR methods and by liquid
chromato-mass spectrometry. The results of a PASS prediction of the biological activity of the
synthesized compounds are presented.
Keywords: 1,2,4-oxadiazole, pyrrolidin-2-one, biological activity, one-pot synthesis.
The intensive use of the 1,2,4-oxadiazole (isoxadiazole) system in medicinal chemistry [2-4] as
bioisosteres of carboxylic acid esters and amides [5, 6] makes the question of the development and optimization
of methods for their synthesis timely. There is particular interest in compounds whose molecules have an
isoxadiazole ring combined with another heterocyclic pharmacophore as this may lead to compounds having a
broader spectrum of biological activity.
As subjects for this investigation we chose compounds whose molecules would contain a pyrrolidin-
2-one ring along with the 1,2,4-oxadiazole. It is known that the isoxadiazole system is a component of antiviral
(Picovir) [7], antiglaucomal, cardiovascular (Proxodolol) [8] and other medicinal compounds [9-11].
Neurological (Etiracetam, Memolog) [12, 13], respiratory (Rolipram) [14], immunostimulatory (Pidotimod) [15]
and other medicinal preparations [16-20] are found amongst pyrrolidin-2-one derivatives.
In [21] routes were reported for the synthesis of 3-(1,2,4-oxadiazol-5-yl)pyrrolidin-2-ones based on the
preparatively inconvenient reaction of substituted 3-cyanopyrrolidin-2-ones with N-hydroxybenzimidoyl
chlorides or on the acid catalyzed reaction of the difficult to obtain 5-amino-4-(1,2,4-oxadiazol-5-yl)-
2,3-dihydropyrroles. Information concerning the target 4-(1,2,4-oxadiazol-5-yl)pyrrolidin-2-ones has not
appeared in the literature. For their preparation we have taken advantage of the method of parallel liquid phase
synthesis based on a one-pot condensation of 5-oxopyrrolidine-3-carboxylic acids, carbodiimidazole (CDI),
_______
* For Communication 1 see [1]
__________________________________________________________________________________________
V. N. Karazin National University, Kharkiv 61077, Ukraine; e-mail: orlov@univer.kharkov.ua.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 758-764, May, 2008. Original article
submitted February 1, 2008.
600
0009-3122/08/4405-0600©2008 Springer Science+Business Media, Inc.

and benzamidoximes. The starting 1-aryl-5-oxopyrrolidine-3-carboxylic acids 4, 5 were prepared by the reaction
of amines 1 and 2 with itaconic acid 3 as reported in [22]. The benzamidoximes 7a-e were synthesized from the
corresponding benzonitriles 6a-e and hydroxylamine using the method [23]. Reaction of the heteryl carboxylic
acids 4, 5, CDI 8, and benzamidoximes 7a-e was carried out by a one-pot procedure with consecutive
addition of reagents into DMF medium with variation of the temperature in the range 50-110ºC to give the 4-
(1,2,4-oxadiazol-5-yl)pyrrolidin-2-ones 9a-e, 10a-e in 63-87% yields (Table 1). It should be noted that this
method is the most universal and efficient amongst existing variations of 1,2,4-oxadiazole syntheses [24].
O
O
O
HO
Ar1
1, 2
NH2
+
OH
OH
N
O
CH2
Ar1
N
3
4, 5
OH
Ar2
Ar2
C
N
N
NH2OH
+
NH2
7a–e
6a–e
O
N
O
O
Ar2
.
4, 5
7a–e
N
+
+
N
N
N
N
Ar1
8
9a–e, 10a–e
1, 4, 9 Ar1 = Ph; 2, 5, 10 Ar1 = 4-MeC6H4; 6, 7, 9, 10 a Ar2 = Ph, b Ar2 = 2-MeC6H4,
c Ar2 = 3-ClC6H4, d Ar2 = 2-FC6H4, e Ar2 = 4-MeOC6H4
TABLE 1. Characteristics of 1-Ar1-4-(3-Ar2-1,2,4-Oxadiazol-5-yl)-
pyrrolidin-2-ones 9a-e, 10a-e
Com-
pound
Empirical
formula
Found N, %
Calculated N, %
——————
mp, °С
Yield, %
9a
C18H15N3O2
13.81
13.76
13.12
13.16
12.38
12.37
13.08
13.00
12.59
12.53
13.17
13.16
12.67
12.60
11.80
11.88
118-119
124-125
130-131
105-106
143-144
103-104
116-117
145-146
95-96
65
73
60
59
63
87
77
73
65
63
9b
C19H17N3O2
C18H14ClN3O2
C18H14FN3O
C19H17N3O3
C19H17N3O2
C20H19N3O2
C19H16ClN3O2
C19H16FN3O
C20H19N3O3
9c
9d
9e
10a
10b
10c
10d
10e
12.53
12.46
12.01
12.03
142-143
601

Thanks to the possibility of introducing a series of different benzamidoximes into the condensation with
the one activated 5-oxopyrrolidine-3-carboxylic acid with the same reaction conditions for the majority of
reactants and variation of substituents in the starting reagents the method is readily adapted to parallel liquid
phase synthesis. This allowed the preparation of a larger group of 4-(1,2,4-oxadiazol-5-yl)pyrrolidin-2-ones in
high yield, in a short time, and generally without further purification.
The mechanism of the three-component one-pot condensation with consecutive addition of reagents
comprises three stages, the progress of which is controlled by the temperature factor. In the first step at 50ºC in
dry DMF activation of the carboxylic acids 4, 5 by the CDI 8 occurs to give the acid imidazolides 11, 12.
The heterocyclic carboxylic acid imidazolides are generally stable in inert solvents (in the absence of
moisture). In the following step the introduction of the benzamidoximes 7a-e into the reaction medium at 80ºC
gives the O-(heterylcarbonyl)benzamidoximes 13a-e, 14a-e, the formation of which is not in doubt as shown by
the authors of previous studies and also their separation in individual cases (when the cyclization to the 1,2,4-
oxadiazole ring does not occur spontaneously) [25, 26]. In the final step the increase in temperature to 110ºC
causes cyclization to give the 1,2,4-oxadiazole ring.
O
O
DMF, 50°C
N
4, 5
8
+
N
N
– CO , –
HN
N
2
Ar1
11, 12
O
H2N
2
.
Ar
O
DMF, 80°C
– HN
+
7a–e
11, 12
O
N
N
N
Ar1
13a–e, 14a–e
DMF, 110°C
– H2O
9a–e, 10a–e
13a–e, 14a–e
The structure of the compounds obtained was confirmed by IR and 1H NMR spectroscopic methods and
also by liquid chromato-mass spectrometry. The IR spectra of the samples show characteristic C=O stretching
absorption bands for the pyrrolidin-2-one ring at 1689-1702 cm-1. The synthesized 4-(1,2,4-oxadiazol-5-yl)-
pyrrolidin-2-ones 9, 10 have a chiral C-4 atom as a result of which the methylene protons on the C-3 and C-5
1
atoms are diastereotopic. This causes a complex H NMR spectroscopic picture for the pyrrolidin-2-one
fragment protons, especially for the H-4 proton which is obscured by the H-3 proton signals to form a three-
proton multiplet at 4.20-4.75 ppm. The signals for the H-5 protons are seen at 2.85-3.25 ppm (2H), also as a
multiplet. The spectroscopic characteristics of compounds 9, 10 are given in Table 2.
Compound 10e was studied by liquid chromato-mass spectrometry. Upon chromatography of the sample
ultraviolet (UV, 254 nm) and evaporative light scattering light (ELSD) detectors showed a clear region of
maximum absorption. The mass spectrum of the compound corresponding to this retention time showed a high
intensity peak for the molecular ion of 10e and low intensity fragments indicating a stable molecule.
The biological activity of the synthesized 4-(1,2,4-oxadiazol-5-yl)pyrrolidin-2-ones was predicted using
the PASS C&T computer system (Prediction Activity Spectra for Substances: Complex and Training) [27, 28].
The results of the PASS prediction showed that compounds in this series are potential antagonists of
GABA A receptors, histamine N-methyltransferase inhibitors, and antagonists of benzodiazepine receptors.
They can show arrhythmic, antiepileptic, anxiolytic, antispasmodic, neuroprotecting, psychotropic, and
nootropic activity and affect cognitive dysfunction.
602

TABLE 2. Spectroscopic Characteristics of Compounds 9a-e, 10a-e
IR spectrum,
ν
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)
С=О, cm-1
9a
1702
2.85-3.25 (2H, m, H-5); 4.15-4.45 (3H, m, H-4,3);
7.14 (1H, t, J4,3 = 7.6, p-H Ar1); 7.39 (2H,t, J3,2 = 8.2, m-H Ar1);
7.50-7.60 (3H, m, p-, m-H Ar2); 7.65 (2H, d, J2,3 = 8.2, o-H Ar1);
8.00 (2H, dd, J2,3 = 7.9, J2,6 = 1.9, o-H Ar2)
9b
1702
2.52 (3H, s, CH3); 2.85–3.20 (2H, m, H-5);
4.15-4.45 (3H, m, H-4,3); 7.14 (1H, t, J4,3 = 7.6, p-H Ar1);
7.30-7.50 (5H, m, m-H Ar1, p-, m-H Ar2);
7.65 (2H, d, J2,3 = 8.2, o-H Ar1); 7.92 (1H, d, J2,3 = 7.4, o-H Ar2)
9c
1700
1699
2.85-3.20 (2H, m, H-5); 4.15-4.45 (3H, m, H-4,3);
7.15 (1H, t, J4,3 = 7.6, p-H Ar1); 7.47 (2H, t, J3,2 = 8.2, m-H Ar1);
7.55-.75 (4H, m, o-H Ar1, p-, m-H Ar2); 7.95 (2H, m, o-H Ar2)
9d
2.95-3.10 (2H, m, H-5); 4.15-4.40 (3H, m, H-4,3);
7.15 (1H, t, J4,3 = 7.6, p-H Ar1); 7.32-7.49 (4H, m, m-H Ar1, m-H Ar2);
7.59-7.70 (3H, m, p-H Ar2, o-H Ar1);
8.05 (1H, dt, J2,3 = 7.8, J2,6<F> = 2.6, o-H Ar2)
9e
1694
1689
1693
2.85-3.20 (2H, m, H-5); 3.80 (3H, s, ОCH3); 4.15-4.35 (3H, m, H-4,3);
7.05-7.20 (3H, m, p-H Ar1, m-H Ar2); 7.38 (2H, t, J3,2 = 8.2, m-H Ar1);
7.65 (2H, d, J2,3 = 8.2, o-H Ar1); 7.93 (2H, d, J2,3 = 9.0, o-H Ar2)
10a
10b
2.26 (3H, s, CH3); 2.95-3.20 (2H, m, H-5); 4.15-4.35 (3H, m, H-4,3);
7.19 (2H, d, J3,2 = 8.1, m-H Ar1); 7.50-7.61 (5H, m, o-H Ar1, m-, p-H Ar2);
8.08 (2H, dd, J2,3 = 7.9, J2,6 = 1.9, o-H Ar2)
2.26 (3H, s, CH3); 2.52 (3H, s, CH3); 2.85-3.20 (2H, m, H-5);
4.12-4.40 (3H, m, H-4,3); 7.19 (2H, d, J3,2 = 8.1, m-H Ar1);
7.35-7.48 (3H, m, m-, p-H Ar2); 7.54 (2H, d, J2,3 = 8.1, o-H Ar1);
7.91 (1H, d, J2,3 = 7.4, o-H Ar2)
10c
10d
1695
1698
2.27 (3H, s, CH3); 2.90-3.15 (2H, m, H-5); 4.10-4.35 (3H, m, H-4,3);
7.19 (2H, d, J3,2 = 8.1, m-H Ar1);
7.50-7.71 (4H, m, o-H Ar1, m-, p-H Ar2); 7.94-8.02 (2H, m, o-H Ar2)
2.27 (3H, s, CH3); 2.85-3.20 (2H, m, H-5); 4.10-4.40 (3H, m, H-4,3);
7.19 (2H, d, J3,2 = 8.1, m-H Ar1);
7.35-7.73 (5H, m, o-H Ar1, m-, p-H Ar2);
8.05 (2H, dt, J2,3 = 7.8, J2,6<F> = 2.5, o-H Ar2)
10e
1702
2.25 (3H, s, CH3); 2.85-3.15 (2H, m, H-5); 3.80 (3H, s, ОCH3);
4.10-4.40 (3H, m, H-4,3); 7.09 (2H, d, J3,2 = 9.0, m-H Ar2);
7.18 (2H, d, J3,2 = 8.1, m-H Ar1); 7.52 (2H, d, J2,3 = 8.1, o-H Ar1);
7.93 (2H, d, J2,3 = 9.1, o-H Ar2)
Hence we have developed a preparative method for novel biheterocyclic compounds containing 1,2,4-
oxadiazole and pyrrolidin-2-one rings (4-(1,2,4-oxadiazol-5-yl)pyrrolidin-2-ones) which is based on a one-pot
condensation of 5-oxopyrrolidine-3-carboxylic acids, carbodiimidazole, and benzamidoximes. We have also
presented the results of computer modelling of their biological activity.
EXPERIMENTAL
IR spectra were taken for KBr tablets on an IR-75 spectrophotomer. 1H NMR spectra were recorded on a
Varian VXR-400 instrument (400 MHz) using DMSO-d6 solvent and TMS as internal standard. Melting points
for compounds 9a-e, 10a-e were measured on a Buchi (Switzerland) model B-520 apparatus. TLC monitoring of
the course of the reaction and the purity of the products was carried out on Sorbfil AFV-UV plates using CHCl3
as eluent. Elemental analysis for nitrogen was performed using the Dumas method.
Liquid chromato-mass spectrometer for compound 10e was performed on a PE SCIEX API 150 EX
instrument using UV (254 nm) and ELSD detectors.
603

1-Phenyl-5-oxopyrrolidine-3-carboxylic Acid (4). Aniline 1 (13.95 g, 150 mmol) and itaconic acid 3
(19.5 g, 150 mmol) were placed in a 100 ml volume flask and heated for 2 h at 115-120ºC. The crystalline mass
melted with effervescence. At the end of the reaction the effervescence had ceased and droplets of water ran
down the walls of the flask. The hot solution was poured into iced water (20 ml) and the organic layer formed
was triturated with a glass rod to crystallization. The product was filtered and washed on the filter with cold
water (100 ml). For further purification the obtained 5-oxopyrrolidine-3-carboxylic acid was dissolved with
heating in 10% NaOH solution (100 ml) and refluxed for 10 min with activated carbon (2-3 g). The carbon was
filtered off and washed with hot water (15-20 ml) and the mother liquor was cooled and acidified with HCl to
acid Congo reaction. The separated product 4 was filtered off and washed with cold water to neutral reaction.
Mp 168-169ºC, yield 54%.
1-(4-Methylphenyl)-5-oxopyrrolidine-3-carboxylic Acid (5). From p-toluidine 2 and acid 3 similarly
to give compound 5 with mp 182-183ºC, yield 67%.
2-Methylbenzamidoxime (7b). Ethanol (100 ml) was placed in a 150 ml volume flask and NH2OH·HCl
(13.90 g, 200 mmol) and KOH (11.20 g, 200 mmol) were added. The 2-methylbenzonitrile 6b (17.55 g, 150
mmol) was then added and the reaction mixture was refluxed for 4-5 h. At the end of the reaction (TLC
monitoring) the mixture was poured into a beaker containing iced water (200 ml). The target compound was
formed as a crystalline precipitate which was filtered, washed on the filter with cold water and then dried to give
the benzamidoxime 7b with mp 142-143ºC, yield 68%.
Benzamidoximes 7c-e were prepared similarly from the corresponding benzonitriles (mp, yield given):
7c (116-117ºC, 70%); 7d (89-90ºC, 53%), 7e (105ºC, 89%).
Benzamidoxime 7a. The reaction mixture was additionally diluted with water (100 ml), extracted with
ethyl acetate (3×50 ml), and the organic layer was dried over MgSO4, solvent distilled off in vacuo, and the
residue treated with hexane with glass rod trituration. The benzamidoxime 7a did not form a crystalline
precipitate and had mp 79-80ºC, yield 48%.
1-Phenyl-4-(3-phenyl-1,2,4-oxadiazol-5-yl)pyrrolidin-2-one (9a). CDI 8 (0.195 g, 1.2 mmol) was
added to a solution of compound 4 (0.205 g, 1 mmol) in dry DMF (3 ml) and held for 20 min at 50ºC. The acid
imidazolide formed was treated with the benzamidoxime 7a (0.164 g, 1.2 mmol) and the mixture was held for
30 min at 80ºC. The reaction temperature was then raised to 110ºC and held for a further 3 h. At the end of the
reaction the mixture was diluted with water (10 ml) and the solid product 9a was filtered off, washed on the
filter with water, and dried.
The target products 9b-e, 10a-e were prepared similarly using the corresponding combination of
starting 1-aryl-5-oxopyrrolidine-3-carboxylic acids 4,5 and benzamidoximes 7a-e.
The indicated method allows the synthesis of analytically pure 4-(1,2,4-oxadiazol-5-yl)pyrrolidin-2-ones
9a-e, 10a-e.
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