Condensation products of 1-Aryl-4-carboxy2- Pyrrolidinones with o-diaminoarenes, o-aminophenol, and their structural studies

Article abstract of DOI:10.1002/hc.20171

A series of 2-substituted benzimidazoles, benzoxazoles were synthesized by the condensation reactions of 1-aryl-4-carboxy-2-pyrrolidinones and aromatic ortho-diamines or ortho-aminophenol. Alkylation of benzimidazoles with iodoalkanes led to 1-aryl-4-(1-a

Full text of DOI:10.1002/hc.20171

Heteroatom Chemistry
Volume 17, Number 1, 2006
Condensation Products of 1-Aryl-4-carboxy-
2- pyrrolidinones with o-Diaminoarenes,
o-Aminophenol, and Their Structural Studies
Marius Mickevicius,1 Zigmuntas Jonas Beresnevicius,1
Vytautas Mickevicius,1 and Gema Mikulskiene2
1Department of Organic Chemistry, Kaunas University of Technology, Radvilenu pl. 19, LT-50254,
Kaunas, Lithuania
2Department of Bioorganic Compounds Chemistry, Institute of Biochemistry, Mokslininku str.12,
LT-08662, Vilnius, Lithuania
Received 18 November 2004; revised 19 October 2005
quite wide—from merely heating the diamines with
ABSTRACT: A series of 2-substituted benzimida-
carboxylic acid to heating in the presence of acids
zoles, benzoxazoles were synthesized by the conden-
such as hydrochloric acid [1–3], PPA [4–7], and oth-
sation reactions of 1-aryl-4-carboxy-2-pyrrolidinones
ers. Careful choice of reaction conditions is essential
and aromatic ortho-diamines or ortho-aminophenol.
if good yields are to be obtained in all instances [8,9].
Alkylation of benzimidazoles with iodoalkanes led to
The heating of reagents together in the presence of
1-aryl-4-(1-alkyl-1H-benzimidazol-2-yl)-2-pyrrolidin-
hydrochloric acid, usually around 4 M, are the most
ones or 1,3-dialkylbenzimidazolium iodides. N-Subs-
widely used conditions (Philips method) [10]. Fused
tituted γ-amino acids were prepared by the hydrolysis
heterocycles such as benzimidazoles, benzoxazoles
of 1-aryl-4-(1H-benzimidazol-2-yl)-2-pyrrolidinones
are very useful intermediates for the development of
in sodium hydroxide solution, followed by treatment
pharmaceutical compounds.
with acetic acid. The structure of the synthesized pro-
The synthesis of 2-substituted benzimidazoles
1
ducts was investigated using IR and H, 13C NMR
and benzoxazoles with 1-aryl-2-pyrrolidinone frag-
spectra, MM2 molecular mechanics, and AM1 semi-
ment and the features of the structural details of the
ꢀ
C
empirical quantum mechanical methods.
2006
obtained products are presented in this paper.
Wiley Periodicals, Inc. Heteroatom Chem 17:47–
56, 2006; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20171
RESULTS AND DISCUSSION
Most of 2-substituted benzimidazoles 2 were ob-
tained by heating a mixture of 1-aryl-4-carboxy-
2-pyrrolidinones and 1,2-diaminobenzene at 170◦C
for 2 h and then at 230◦C for 30 min. The men-
tioned derivatives were also prepared by the Philips
method, but in worse yields. Compound 2e was ob-
tained by the Philips method in 17% yield while heat-
ing without solvent gave 79% yield.
INTRODUCTION
The condensation of o-diaminobenzenes with car-
boxylic acids or their derivatives is the most impor-
tant method for synthesis of a wide range of benz-
imidazoles. The range of reaction conditions used is
It should be noted that only those of 4-carboxy-2-
pyrrolidinones possessing halogen in aromatic ring
Correspondence to: Gema Mikulskiene; e-mail: gemam@bchi.lt.
2006 Wiley Periodicals, Inc.
c
ꢀ
47

48 Mickevicius et al.
reacted under conditions of the Philips method. Oth-
erwise, reaction practically failed. In the case of the
reaction catalyzed by the hydrochloric acid, the for-
mation of benzimidazole ring and the yields depend
probably on the polarization of the carbonyl bond in
carboxyl group [11].
The structure of the study compounds was in-
1
vestigated using IR and H, 13C NMR spectra. The
assignment of the resonances in the NMR spectra
was based on the chemical shift theory and signal
intensity arguments, multiplicities, and comparison
with structurally related compounds [12,13]. 1H, 13
C
1-Aryl-4-(1,3-benzoxazol-2-yl)-2-pyrrolidinones
5a,d,f were obtained from the corresponding pyrro-
lidinones 1a,d,f by heating with o-aminophenol at
170◦C for 2 h and then at 230◦C for 30 min.
NMR spectroscopic data were unambiguous in most
cases, and their reliability was checked by 13C NMR
DEPT, 1H/13C 2D (HETCOR) NMR experiments. The
data of the 1H and 13C NMR chemical shifts are
listed in Tables 1–5. The carbon atoms in tables
are marked according to the numbering given in
Scheme 1.
The more exhaustive information about the
structural features of the study compounds was ob-
tained using NMR data together with the computer
molecular modeling results.
1-Substituted 2-pyrrolidinones are acid resis-
tant, but in basic medium they cleave forming corre-
sponding N-arylamino-3-carboxybutanoic salts. N-
aryl substituted ꢀ-amino acids 6 were synthesized
by heating suitable bisubstituted 2-pyrrolidinones 2
in sodium hydroxide solution, followed by acidifica-
tion of these solutions with acetic acid to pH 6.
Alkylation of benzimidazoles 2a,d,e,h in the
presence of potassium hydroxide and sodium car-
bonate with excess of ethyl or methyl iodide with-
out solvent at room temperature led to 1-aryl-4-(1-
methyl-1H-benzimidazol-2-yl)-2- pyrrolidinones 7
and 1-aryl-4-(1-ethyl-1H-benzimidazol-2-yl)-2-pyrr-
olidinones 8 in quantitative yields. Hardly soluble
in organic solvents 1,3-dialkylbenzimidazolium io-
dides 9 were obtained using DMF as a solvent.
The investigated compounds possess pyrrolidi-
none ring [14,15], which atoms feel sensitively
the influence of its 1,4-substituents. The structural
changes as in the benzene fragment as in the benz-
imidazole ring moieties affect the pyrrolidinone frag-
ment specifically. The nonsubstituted pyrrolidinone
has a nearly planar structure (RMS deviation from
˚
plane according to the Mopac AM1 data are 0.000 A,
˚
MM2 – 0.114 A). The studies of 2-series of the
TABLE 1 13C NMR Chemical Shifts (δ, in ppm) of Compounds 2a–e
2a
2b
2c
2d
2e
C-1
C-2
C-3
C-4
139.20
119.43
128.61
123.98
137.51
135.40
130.59
126.56 or
126.48
127.37
126.56 or
126.48
171.40
36.03
132.39
121.26
113.79
155.83
140.53
117.50
133.10
123.64
138.47
121.22
131.39
115.81
C-5
C-6
128.61
119.43
113.79
121.26
130.30
118.96
131.39
121.22
C-2ꢁ
C-3ꢁ
C-4ꢁ
C-5ꢁ
C-8
171.89
37.48
30.62
52.07
154.91
118.43 or
110.98
121.90 or
121.09
121.90 or
121.09
118.43 or
110.98
142.76 or
134.50
142.76 or
134.50
171.34
37.24
30.65
172.39
37.50
30.48
51.98
154.76
118.42 or
110.99
122.02 or
121.14
122.02 or
121.14
118.42 or
110.99
142.80 or
134.73
142.80 or
134.73
172.13
37.42
30.43
31.97
53.98
52.40
51.91
155.06
118.51 or
110.97
121.48 or
121.10
121.48 or
121.10
118.51 or
110.97
142.83 or
134.48
142.83 or
134.48
2-Me
154.93
118.34 or
111.19
121.26
154.78
118.41 or
110.95
121.91
121.07
121.91 or
121.07
118.41 or
110.95
142.71 or
134.00
142.71 or
134.00
C-10
C-11
C-12
C-13
C-14
C-15
Others
121.26
118.34 or
111.19
142.79 or
134.34
142.79 or
134.34
4-OMe
17.49
55.15

Condensation Products of 1-Aryl-4-carboxy-2-pyrrolidinones with o-Diaminoarenes, o-Aminophenol 49
TABLE 2 13C NMR Chemical Shifts (δ, in ppm) of Compounds 2g, 2h, 2k, 3d, 3e, 4f
2g
2h
2k
3d
3e
4f
C-1
C-2
139.84
115.62,
115.56
129.93
120.25,
120.19
126.19
122.69
172.64
37.48
30.50
51.96
154.73
118.39 or
110.92
121.39
134.94
135.12
142.84
118.51
140.20
117.94
138.50
121.38
138.12
120.86
C-3
C-4
131.17
136.74
133.11
121.84
133.11
124.52
131.54
115.90
128.50
127.74
C-5
127.08
126.47
171.56
36.10
32.01
54.14
128.79
111.03
172.01
35.69
32.19
53.52
154.56
116.06 or
115.79
121.93 or
121.16
121.93 or
121.16
116.06 or
115.79
137.65 or
134.51
137.65 or
134.51
131.22
119.68
171.19
36.78
29.78
51.11
131.54
121.38
172.11
37.38
30.36
51.90
128.50
120.86
172.18
37.02
30.02
52.05
154.41
115.42 or
114.37
132.50
C-6
C-2ꢁ
C-3ꢁ
C-4ꢁ
C-5ꢁ
C-8
155.23
Not obs.
155.19
114.22
156.51
114.51
C-10
C-11
C-12
C-13
C-14
C-15
Others
121.48
121.48
130.49
123.91
117.90
134.29
140.19
130.49
124.28
117.90
134.58
141.38
121.39
123.55
118.39 or
110.92
142.44 or
134.64
142.44 or
134.64
130.15
129.65
129.14
128.64
(CF3)
Not obs.
Not obs.
Not obs.
115.42 or
114.34
134.84
138.38
2-Me 17.47
4-Me 20.57
TABLE 3 13C NMR Chemical Shifts (δ, in ppm) of Compounds 5a, 7d, 9d
9d
Low Intensity
Form
High Intensity
Form
5a
7d
C-1
C-2
C-3
C-4
C-5
C-6
C-2ꢁ
C-3ꢁ
C-4ꢁ
C-5ꢁ
C-8
C-10
139.04
119.54
128.69
124.20
128.69
119.54
171.38
36.29
30.30
50.87
150.48
110.77
140.53
117.54
133.10
123.60
130.26
118.89
172.42
37.04
29.50
51.51
154.85
109.85
140.11
117.83
133.14
124.04
130.47
119.18
171.18
36.21
139.84
118.30
133.10
124.41
130.40
119.67
170.93
34.94
25.89
49.42
151.68
112.96
27.60
50.62
153.73
112.23 or
114.91
124.95 or
125.25
124.95 or
125.25
112.23 or
114.91
Not obs.
Not obs.
31.15
C-11
C-12
C-13
125.12 or
124.49
125.12 or
124.49
121.36 or
121.86
121.36 or
121.86
126.38
126.38
112.96
119.54
118.61
C-14
C-15
Others
150.48
140.46
136.20
141.66
28.37
131.72
131.72
32.55
7-NMe
7,9-NMe
7,9-NMe

50 Mickevicius et al.
TABLE 4 13C NMR Chemical Shifts (δ, in ppm) of Compounds 6a, 6c, 6d, 6e, 6f, 6i and Extended Hu¨ckel Partial Charges*
for C-3ꢁ and C-4ꢁ Atoms (∗∗First Line in Cells is Obtained by MM2, While Second Line is Obtained by AM1)
6a
6c
6d
6e
6f
6i
C-1
C-2
C-3
C-4
C-5
C-6
C-2ꢁ
C-3ꢁ
∗
148.32
112.05
128.92
115.83
128.92
112.05
173.17
35.52
−0.108/
−0.526
35.85
0.005/
0.078
142.57
113.19
114.69
150.82
114.69
113.19
173.39
35.65
−0.108/
−0.526
36.07
0.003/
0.077
149.88
111.14
133.76
115.17
130.39
110.76
173.09
35.38
−0.113/
−0.538
35.78
0.014/
0.082
147.63
114.01
131.42
106.40
131.42
114.01
173.13
35.36
−0.102/
−0.538
35.84
0.015/
0.082
147.27
113.40
128.59
119.02
128.59
113.40
173.10
35.37
−0.102/
−0.529
35.78
0.015/
0.076
142.97
112.98
116.44
145.61
116.44
112.98
173.34
35.60
−0.109/
C-3ꢁ
C-4ꢁ
∗
−0.533
36.12
0.003/
0.071
47.20
C-4ꢁ
C-5ꢁ
C-8
C-10
C-11
C-12
46.76
47.66
46.46
155.78
46.67
46.73
154.56
Not obs.
Not obs.
121.18
156.25
Not obs.
Not obs.
121.37 or
121.21
121.37 or
121.21
Not obs.
Not obs.
55.34
155.84
Not obs.
Not obs.
121.23
155.82
Not obs.
Not obs.
121.22
Not obs.
Not obs.
Not obs.
121.76 or
121.16
121.76 or
121.16
Not obs.
Not obs.
4-OPh
121.25
121.25
C-13
121.18
121.23
121.22
C-14
C-15
Others:
Not obs.
Not obs.
Not obs.
Not obs.
Not obs.
Not obs.
Not obs.
Not obs.
OCH3
C-1ꢁꢁ − 158.89
C-2ꢁꢁ, C-6ꢁꢁ − 116.44
C-3ꢁꢁ, C-5ꢁꢁ − 129.75
C-4ꢁꢁ − 121.01
molecular models of the synthesized products have
suggested that there are some changes in the geom-
etry of the pyrrolidinone ring (Table 6). Changes in
the geometry affect the values of the chemical shift
pounds have shown the formation of partially double
bond between N(1ꢁ)–C(2)O fragment.
The molecules of the synthesized compounds in-
clude the benzimidazole fragment. The exploration
of the structural features by 13C NMR spectra of such
type of compounds excites some problems [16]. Ow-
ing to the versatility of the heterocyclic part, two
tautomer forms of the benzimidazole fragment are
presumed [12,13]. The characteristics of the solu-
tion and of the rest of the molecule determine the
rate of transitions between the tautomer forms. Ob-
viously, dimethylsulfoxide affects specific solvation
of the compounds examined [16]. Although six sig-
nals of benzimidazole fragment of benzene moiety in
13C NMR spectra of compounds 2a, 2b, 2d, 2e, 2g,
2k are broadened, they are well resolved. The suit-
able signals in compound 2c are poorly resolved and
broadened. All signals in compound 2h with the ex-
ception of signal at 121.48 ppm are only within the
noise level.
1
in 13C NMR and H NMR spectra. The suitable val-
ues of the chemical shift differences of the pyrro-
lidinone atoms arising due to variant substitution
in benzene ring are also summarized in Table 6.
It has been noticed that C-3ꢁ, C-4ꢁ, and C-5ꢁ atoms
of pyrrolidinone ring are affected more significantly
by o-substituents in benzene ring (2b, 2h, and 2k).
The influence on C-3ꢁ atom and both of its hydro-
gens had a shielding effect, on C-4ꢁ atom and the
hydrogen attached to it—deshielding effect, but C-5ꢁ
atoms were deshielded though both of its hydrogens
were shielded. Molecular modeling data were in ac-
cordance with this interpretation. It was impossible
to evaluate the electronic effects of 1N-substitution
on the pyrrolidinone ring of the study compounds
by molecular modeling data. It may be considered
that the shielding or deshielding direction could be
jumbled due to the arising of the extended ꢁ-system
between benzene ring and N(1ꢁ)-CO fragment. The
molecular-modeling experiments of all study com-
NMR spectra of compounds 3d, 3e, 4f, and 7d
showed that the introduction of the substituent (Cl
or CH3) at C-11 or N-1 position of benzimidazole
fragment stabilized its form [17–19]. The carbon

Condensation Products of 1-Aryl-4-carboxy-2-pyrrolidinones with o-Diaminoarenes, o-Aminophenol 51
TABLE 5 IR and 1H NMR Spectroscopic Data of the Study Compounds
IR, v (cm−1
)
1 H NMR (δ, in ppm), J (Hz)
2a
2b
2c
1694 (C O), 2779,
2911, 3059, 3185,
3372 (NH) + (ArH)
1669 (C O), 2921,
3048, 3101, 3170,
3419 (NH) + (ArH)
1694 (C O), 2835
(OCH3), 2909,
2.91–3.12 (m, 2H, CH2CO), 3.95–4.07 (m, 1H, CH), 4.18–4.33 (m, 2H, CH2N),
7.08–7.73 (m, 9H, ArH), 12.45 (br. s, 1H, NH)
2.15 (s, 3H, o-CH3), 2.91–3.09 (m, 2H, CH2CO), 4.01–4.20 (m, 3H, CH + CH2N),
7.10–7.68 (m, 8H, ArH), 12.42 (br. s, 1H, NH)
2.94–3.04 (m, 2H, CH2CO), 3.75 (s, 3H, OCH3), 3.91–4.08 (m, 1H, CH), 4.15–4.27
(m, 2H, CH2N), 6.90–7.65 (m, 8H, ArH), 12.43 (br. s, 1H, NH)
3054, 3180, 3378
(NH) + Ar(H)
2d
2e
1694 (CO), 2683,
2844, 3058 (NH) +
(ArH)
2.92–3.14 (m, 2H, CH2CO), 3.92–4.08 (m, 1H, CH), 4.18–4.36 (m, 2H, CH2N),
7.08–7.93 (m, 8H, ArH), 12.44 (br. s, 1H, NH)
1713 (C O), 2637,
2767, 2852, 2909,
2962, 3057, 3180
(NH) + (ArH)
2.96–3.08 (m, 2H, CH2CO), 3.93–4.08 (m, 1H, CH), 4.15–4.32 (m, 2H, CH2N),
7.06–7.73 (m, 8H, ArH), 12.44 (br. s, 1H, NH)
2f
3.04–3.12 (m, 2H, CH2CO), 3.90–4.53 (m, 3H, CH + CH2N), 7.16–7.83 (m, 8H, ArH),
12.91 (br. s, 1H, NH)
2g
1693 (C O), 2704,
2751, 2790, 2852,
2913, 2956, 3066
(NH) + (ArH)
2.95–3.16 (m, 2H, CH2CO), 4.96–4.11 (m, 1H, CH), 4.22–4.46 (m, 2H, CH2N),
7.10–8.24 (m, 8H, ArH), 12.46 (br. s, 1H, NH)
2h
2i
1674 (C O), 2920,
2965, 3049, 3099
(NH) + (ArH)
2.12 (s, 3H, p−CH3), 2.29 (s, 3H, o-CH3), 2.94–2.97 (m, 2H, CH2CO), 4.03–4.11 (m,
3H, CH2N + CH), 7.09–7.57 (m, 7H, ArH), 12.47 (br. s, 1H, NH)
1683 (C O), 2785,
3053, 3180 (NH) +
(ArH)
2.93–3.25 (d, 2H, CH2CO), 3.83–4.37 (m, 3H, CH2N + CH), 6.90–7.82 (m, 13H, ArH),
12.44 (br. s, 1H, NH)
2k
1707 (C O), 2614,
2730, 2809, 2908,
2967, 3027, 3085,
3139, 3397 (NH) +
(ArH)
2.95–3.01 (m, 2H, CH2CO), 4.00–4.27 (m, 3H, CH2N + CH), 7.16–7.75 (m, 8H, ArH),
12.48 (br. s, 1H, NH)
3d
1710 (C O), 2579,
2608, 2676, 2775,
2857, 2900, 3107,
3406 (NH) + (ArH)
1708 (C O), 2599,
2733, 2889, 3059,
3369 (NH) + (ArH)
1711 (C O), 2631,
2825, 2883, 3028,
3066, 3397 (NH) +
(ArH)
3.17–3.21 (m, 2H, CH2CO), 4.30–4.55 (m, 3H, CH2N + CH), 7.24–7.88 (m, 7H, ArH),
12.60 (br. s, 1H, NH)
3e
4f
2.99–3.06 (m, 2H, CH2CO), 4.03–4.21 (m, 1H, CH), 4.21–4.30 (m, 2H, CH2N),
7.19–7.70 (m, 7H, ArH), 12.69 (br. s, 1H, NH)
2.41 (s, 3H, 11-CH3), 2.95–3.11 (m, 2H, CH2CO), 3.94–4.05 (m, 1H, CH), 4.19–4.32
(m, 2H, CH2N), 6.97–7.76 (m, 7H, ArH), 12.39 (br. s, 1H, NH)
5a
5d
5f
1697 (C O)
1701 (C O)
1692 (C O)
3.03–3.11 (m, 2H, CH2CO), 4.23–4.36 (m, 3H, CH + CH2N), 7.16–7.73 (m, 7H, ArH)
3.00–3.20 (m, 2H, CH2CO), 4.00–4.58 (m, 3H, CH + CH2N), 7.13–7.98 (m, 7H, ArH)
3.00–3.20 (m, 2H, CH2CO), 4.00–4.4 (m, 3H, CH + CH2N), 7.2–8.0 (m, 7H, ArH)
2.80–2.97 (m, 2H, CH2CO), 3.27–3.52 (m, 2H, CH2N), 3.61–3.70 (m, 1H, CH), 5.83 (br.
s, 1H, NH), 6.54–7.53 (m, 9H, ArH), 12.30 (br. S, 1H, NH of benzimidazole)
6a
1603 (C O), 2842,
2925, 3054, 3286,
(NH) + (NH) + (OH)
+ (ArH)
6c
6d
1576 (C O), 2632,
2933, 3057, 3257
(NH) + (NH) + (OH)
+ (ArH)
2.79–2.96 (m, 2H, CH2CO), 3.23–3.47 (m, 2H, CH2N), 3.62–3.68 (m, 1H, CH), 3.65 (s,
3H, OCH3), 6.59–7.53 (m, 9H, ArH + NH), 12,21 (br. s, 1H, NH of benzimidazole)
1600 (C O), 2855,
2920, 3068, 3283,
(NH) + (NH) + (OH)
+ (ArH)
2.79–2.96 (m, 2H, CH2CO), 3.30–3.68 (m, 3H, CH + CH2N), 6.20 (br. t, 1H, NH),
6.54–7.53 (m, 8H, ArH), 12.28 (br. s, 1H, NH of benzimidazole)
Continued

52 Mickevicius et al.
TABLE 5 Continued
IR, v (cm−1
)
1 H NMR (δ, in ppm), J (Hz)
6e
6f
1593 (C O), 2734,
2.78–2.96 (m, 2H, CH2CO), 3.28–3.50 (m, 2H, CH2N), 3.58–3.67 (m, 1H, CH), 6.09 (br.
s, 1H, NH), 6.60–7.53 (m, 8H, ArH), 12.15 (br. s, 1H, NH of benzimidazole)
2844, 2916, 3069,
3283, (NH) + (NH)
+ (OH) + (ArH)
1598 (C O), 2743,
2844, 2920, 3073,
3165, 3283, (NH) +
(NH) + (OH) +
(ArH)
2.78–2.97 (m, 2H, CH2CO), 3.27–3.51 (m, 2H, CH2N), 3.58–3.67 (m, 1H, CH), 6.07 (br.
s, 1H, NH), 6.64–7.54 (m, 8H, ArH), 12.45 (br. s, 1H, NH of benzimidazole)
6i
1590 (C O), 2744,
2843, 2923, 3072,
3284, 3407 (NH) +
(NH) + (OH) +
(ArH)
2.79–2.96 (m, 2H, CH2CO), 3.28–3.67 (m, 3H, CH + CH2N), 5.80 (br. s, 1H, NH),
6.67–7.53 (m, 8H, ArH), 12.55 (br. s, 1H, NH of benzimidazole)
7a
7d
7e
7h
8d
8e
9d
1702 (C O)
2.98–3.06 (m, 2H, CH2CO), 3.82 (s, 3H, CH3), 4.00–4.39 (m, 3H, CH2N + CH),
7.13–7.80 (m, 9H, ArH)
1697 (C O)
1696 (C O)
1694 (C O)
1710 (C O)
1709 (C O)
1702 (C O)
2.95–3.20 (m, 2H, CH2CO), 3.82 (s, 3H, NCH3), 4.08–4.40 (m, 3H, CH2N + CH),
7.11–7.90 (m, 8H, ArH)
2.99–3.07 (m, 2H, CH2CO), 3.82 (s, 3H, CH3), 4.03–4.45 (m, 3H, CH2N + CH),
7.10–7.80 (m, 8H, ArH)
2.13 (s, 3H, p-CH3), 2.27 (s, 3H, o-CH3), 2.91–3.05 (m, 2H, CH2CO), 3.80
(s, 3H, NCH3), 4.05–4.36 (m, 3H, CH2N + CH), 7.07–7.75 (m, 8H, ArH)
1.36 (t, 3H, J = 7.5 Hz, N–CH2CH3), 2.99–3.07 (m, 2H, CH2CO), 4.03–4.50
(m, 5H, N–CH2CH3 + CH2N + CH), 7.06–8.06 (m, 8H, ArH)
1.41 (t, 3H, J = 7.5 Hz, N–CH2CH3), 3.01–3.20 (m, 2H, CH2CO), 4.08–4.60
(m, 5H, N–CH2CH3 + CH2N + CH), 7.11–7.87 (8H, m, ArH)
3.12–3.36 (m, 2H, CH2CO), 4.05 (s of low intensity form, 3H, NCH3), 4.15 (s of high
intensity form, 3H, NCH3), 4.34–4.60 (m, 2H, CH2N), 4.75–4.92 (m, 1H, CH),
7.20–8.14 (m, 8H, ArH)
9e
1704 (C O)
resonances of benzimidazole of benzene moiety be-
came sharp. The molecular modeling data of these
compounds showed that, as expected, the benzimi-
dazole fragment system is essentially planar. It was
determined that the substituents of Cl and Br and
CH3 are quite coplanar with respect to benzimida-
zole plane.
The NMR spectra of compound 5a were as-
signed by comparison with the model compounds
[12,13]. The disappearance of proton signal of the
NH group in 1H NMR spectrum confirmed existence
of the above-mentioned 5a compound. The study
compounds 9d,e were synthesized as a salt deriva-
tives. The formation of such salts is widely described
in the literature [20–23]. The structure of compound
9d in our case was analyzed in more detail. Molecu-
lar modeling studies demonstrated the most negative
of the nitrogen atoms in the parent (2d) molecule
of 9d. This investigation revealed that the benzimi-
dazole protonated at N-3 (Extended Hu¨ckel partial
charge is −0.523 a.u.) to form the cationic species.
Taking into account the possibility of formation of
the tautomeric forms in the protonated compounds,
two forms of compounds were suggested. NMR spec-
tra of compound 9d gave two sets of resonances with
the intensity rate 1:9.
A series of compounds 6 with the cleaved pyrro-
lidinone ring were synthesized. The comparison of
study compounds 6a, 6c, 6d, 6e with their parent cy-
clization products permits to examine the structure
of these compounds as well as that of 6f and 6i by
the NMR spectroscopy. Carboxylic groups produce
13C NMR resonances at 173 ppm that are typical to
the saturated, open chain products. The difference of
the chemical shifts of the pairs of C-3ꢁ and C-4ꢁ car-
bons in 6-series compounds is quite close—nearly
0.4 ppm—meanwhile that of the suitable cyclic pair
carbons is 7.0 ppm.
The tendencies of the changes of extended
Hu¨ckel partial charges calculated for the atoms C-
3ꢁ and C-4ꢁ of the open chain molecules of 6-series
(Table 4) are in the satisfactory agreement with
the variation of the suitable NMR chemical shifts.
The proton resonance of N(1ꢁ)H group recorded at
1
∼6.0 ppm in H NMR spectra confirmed the exis-
tence of open chain compounds. These signals have
a low intensity and are broad. In the case of com-
pound 6d, a broad triplet indicated the interaction

Condensation Products of 1-Aryl-4-carboxy-2-pyrrolidinones with o-Diaminoarenes, o-Aminophenol 53
SCHEME 1 Synthesis of benzimidazole and benzoxazole derivatives. R = (a) C6H5; (b) 2-CH3-C H ; (c) 4-CH O-C6H4;
(d) 3-Cl-C H ; (e) 4-Br-C H ; (f) 4-Cl-C H ; (g) 3-CF -C H ; (h) 2,4-(CH ) -C H ; (i) 4-C H5-O-C H6; (4j) 2-Br-C H3.
6
4
6
4
6
4
3
6
4
3 2
6
3
6
6
4
6 4
between 1-NH and 5ꢁ-CH2 fragment due to slow ex-
change. The proton of NH of benzimidazole moi-
ety is observed as particularly broadened singlet at
∼12.3 ppm. Only one or two resonances of C-11 and
C-12 atoms at 121 ppm are visible in the 13C NMR
spectra. Other carbon atoms of the benzimidazole
fragment are more sensitive to the charge distribu-
tion changes and are not observed in all open chain
compounds.
IR spectra were measured in a Perkin-Elmer FT-IR
system Spectrum GX ( KBr tablets). Silica gel plates
(Silufol UV-254) were used for analytical TLC. All
melting points were taken in one tail-end open cap-
illary tubes. The physical properties, analytical data,
and yields are presented in Table 7.
Method A: General Procedure for the Preparation
of 1-Phenylsubstituted 4-(1H-benzimidazol-2-yl)-
2-pyrrolidinones (2a–n)
EXPERIMENTAL
A mixture of 2-pyrrolidinone 1a–k (0.1 mol) and 1,2-
diaminobenzene (14.04 g, 0.13 mol) was heated at
170◦C for 2 h and then at 230◦C for 30 min. The re-
action mixture was cooled to the room temperature
and 150 mL of 5% solution of sodium carbonate was
1
The H and 13C NMR spectra were recorded on a
AC 250-P Bruker 250 MHz and Varian Unity Inova
300 MHz spectrometer operating in Fourier trans-
form mode with TMS as an internal standard. The

54 Mickevicius et al.
TABLE 6 The Length of the Bond between Benzene and Pyrrolidinone Ring, N(1ꢁ) Atom’s RMS Deviation from the Benzene
Ring Plane (ND), RMS Deviation from the Plane of the Pyrrolidinone Ring (PD). The Differences of the Chemical Shifts Arising
due to Variant Substituents in Benzene Ring in Compounds 2a–e, 2g, 2h, 2k
∗∗ꢀδ (ppm)
∗Lengthꢁof C(1) N
∗
∗
PD (A)
C-5ꢁ/CH2
˚
˚
˚
(1 ) (A)
ND (A)
C-2 ꢁ
–
C-3 ꢁ/CH2
C-4ꢁ/CH
2a
2b
2c
2d
2e
2g
2h
2k
1.433/
1.406
1.455/
1.416
1.433/
1.407
1.434
1.404
1.435
1.403
1.403
1.403
1.451
1.415
1.440
1.411
0.004/
0.006
0.022/
0.003
0.010/
0.003
0.003/
0.006
0.003/
0.008
0.014/
0.004
0.026/
0.006
0.014/
0.002
0.153/
0.045
0.136/
0.072
0.122/
0.046
0.146/
0.044
0.144/
0.041
0.142/
0.039
0.128/
0.065
0.163/
0.061
–
–
–
−0.49
−0.55
0.50
0.24
0.72
0.33
0.12
−1.45/
−0.04, −0.06
−0.24/
1.35/
0.09
0.03/
−0.01
−0.14/
0.10
1.91/
−0.13, −0.19
0.33/
−0.02, 0.08
−0.02, –0.05
0.02/
0.00, 0.02
−0.06/
−0.09/
−0.01, −0.01
−0.16/
−0.19/
−0.02
−0.12/
0.02
−0.02, 0.00
−0.01, 0.00
−0.11/
0.00/
0.04, 0.10
−1.38/
0.08, 0.05
2.07/
1.39/
0.08
1.57/
0.10
−0.04, −0.06
−1.78/
−0.14, −0.20
1.45/
−0.05, −0.02
−0.12, −0.18
∗First line in cells is obtained by MM2, second line is obtained by AM1.
∗∗First line in cells—of the carbon atoms of pyrrolidinone ring, second—of each hydrogen.
TABLE 7 Characterization of the Study Compounds and Elemental Analysis Data
Found (Calcd)
H
Molecular Formula
(Molecular Weight)
Yield (%)
mp ( ◦C)
C
N
2aA
2bA
2cA
2dA
2eA
2eB
2fA
2fB
2gA
2hA
2iA
2kA
3d
76
73
63
80
79
17
70
15
65
62
70
80
15
18
16
60
50
53
87
86
93
91
95
87
88
93
94
83
91
90
40
48
215–216
220–221
224–225
226–227
220–221
C17H15N3O (27733)
7342 (7363)
7444 (7421)
7024 (7034)
6534 (6549)
5744 (5732)
564 (545)
601 (588)
563 (558)
466 (453)
409 (396)
1529 (1515)
1425 (1442)
1376 (1367)
1365 (1348)
1158 (1180)
C
C
C
C
18H17N3O (29136)
18H17N3O2 (30736)
17H14ClN3O (31177)
17H14BrN3O (35622)
212–213
C
17H14ClN3O (31177)
6530 (6549)
441 (453)
1356 (1348)
221–222
179–180
212–213
291–292
167–168
142–143
179–180
148–149
136–137
174–175
>170 dec
>149 dec
>180 dec
>179 dec
>192 dec
>198 dec
162–163
166–167
194–195
138–139
132–133
167–168
273–274
248–249
C
C
C
C
C
C
C
C
C
C
18H14F3N3O (34533)
19H19N3O (30538)
6255 (6261)
7492 (7473)
7461 (7478)
5748 (5732)
5907 (5898)
5233 (5227)
6630 (6636)
7347 (7337)
6505 (6529)
6520 (6529)
6930 (6914)
6633 (6645)
6175 (6192)
5437 (5456)
6175 (6192)
7155 (7130)
7407 (7421)
6618 (6636)
5855 (5839)
7502 (7521)
6710 (6716)
5957 (5939)
4860 (4858)
4445 (4438)
415 (409)
617 (627)
501 (518)
400 (396)
377 (378)
342 (335)
499 (495)
501 (507)
433 (419)
430 (419)
601 (580)
573 (589)
474 (489)
442 (431)
474 (489)
531 (546)
594 (588)
504 (495)
426 (436)
680 (663)
520 (534)
491 (472)
457 (451)
415 (412)
1216 (1217)
1371 (1376)
1151 (1137)
1199 (1180)
1206 (1214)
1062 (1076)
1287 (1290)
1020 (1007)
902 (896)
23H19N3O2 (36943)
17H14BrN3O (35622)
17H13Cl2N3O (34622)
17H13BrClN3O (39067)
18H16ClN3O (32580)
17H14N2O2 (27831)
17H13ClN2O2 (31276)
17H13ClN2O2 (31276)
3e
4f
5a
5d
5f
905 (896)
6a
C17 17
C18 19
C17 16
H
N3O2 (29534)
N3O3 (32537)
H ClN3O2 (32979)
1402 (1423)
1301 (1291)
1291 (1274)
1105 (1123)
1291 (1274)
1057 (1085)
1455 (1442)
1277 (1290)
1150 (1135)
1300 (1316)
1254 (1237)
1074 (1093)
885 (895)
6c
H
6d
6e
6f
6i
C
C
17H16BrN3O2 (37424)
17H16ClN3O2 (32979)
H N3O2 (38744)
C23 21
7a
C
18H17N3O (29136)
7d
C18 16
H
ClN3O (32580)
7e
C18 16
H BrN3O (37025)
7h
C
20H21N3O (31941)
C19 18ClN3O (33983)
19H18BrN3O (38428)
8d
H
8e
C
C
C
9d
19H21ClIN3O (46976)
19H21BrIN3O (51421)
9e
808 (817)

Condensation Products of 1-Aryl-4-carboxy-2-pyrrolidinones with o-Diaminoarenes, o-Aminophenol 55
added and refluxed for 10 min and left to cool. The
residue was filtered, washed with water, and crystal-
lized from appropriate solvent.
out with water (50 mL), stirred for a few minutes,
and crystals were filtered and washed with water.
The product was crystallized from the appropriate
solvent.
Method B: General Procedure for the Preparation
of 1-Phenylsubstituted 4-(1H-benzimidazol-2-yl)-
2-pyrrolidinones (2e, f, 3d, e, 4f)
(Philips Method)
Synthesis of 2-(1-Aryl-5-oxopyrrolidin-3-yl)-1,3-
dimethyl-1H-3,1-benzimidazol-3-ium Iodides
(9d,e)
2-Pyrrolidinone 1d,e,f (0.05 mol) and 1,2-diam-
inobenzene in 150 mL of 10% hydrochloric acid
were heated at reflux for 24 h. The reaction mix-
ture was cooled, the residue was filtered, and washed
with water. Produced crystals were poured over with
75 mL of 5% solution of sodium carbonate; the
mixture was heated at reflux for 10 min and left
to cool. The residue was filtered and washed with
water, dried, and crystallized from the appropriate
solvent.
Benzimidazole 2d,e (0.02 mol) was dissolved in
dimethylformamide (30 mL). Potassium hydroxide
powder (4.48 g, 0.08 mol) was added to a stirred mix-
ture. After 5 min, methyl iodide (9.7 ml, 0.16 mol)
was dropwise added during 15 min. The mixture
was stirred for 30 min and left for 12 h at room
temperature. The solvent was evaporated under re-
duced pressure; residue was poured out with water
(100 mL). The precipitate was filtered, washed with
water, and heated at reflux in 50 mL acetone for
10 min. After cooling, the residue was filtered and
crystallized from the appropriate solvent.
General Procedure for the Preparation of 1-Phen-
ylsubstituted 4-(1H-benzoxozol-2-yl)-2-pyrrolid-
inones (5a,d,f)
REFERENCES
Mixture of 2-pyrrolidinone 1a,d,f (0.1 mol) and
2-aminophenole (14.17 g, 0.13 mol) was heated at
170◦C for 2 h and then at 230◦C for 30 min. The
reaction mixture was cooled to room temperature,
and 150 mL of 5% solution of sodium carbonate was
added and heated at reflux for 10 min and left to
cool. The residue was filtered, washed with water,
and crystallized from appropriate solvent.
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56 Mickevicius et al.
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