Synthesis, characterization and X-ray structure of heterocyclic systems prepared via 1,3-dipolar cycloaddition of nitrile oxides with benzimidazolone

Article abstract of DOI:10.1016/j.molstruc.2018.03.128

We report here a one-step synthesis of the new isoxazolyl-benzimidazolones and isoxazolinyl-benzimidazolones by 1,3-dipolar cycloaddition of the p-substituted benzonitrile oxides and mesitonitrile oxide with 1-cyclohex-1-en-1-yl-3-propargyl-benzimidazolone or 1-cyclohex-1-en-1-yl-3-allyl-benzimidazolone. In all cases these cycloadditions are completely regio- and chemoselective. The structures of new cycloadducts obtained are elucidated by their analytical and spectral data. The relative stereochemistry of the cycloadduct 8 was confirmed by single crystal X-ray analysis.

Full text of DOI:10.1016/j.molstruc.2018.03.128

Accepted Manuscript
Synthesis, characterization and X-ray structure of heterocyclic systems prepared via
1,3-dipolar cycloaddition of nitrile oxides with benzimidazolone
Adardour Mohamed, Elena Zaballos-García, Loughzail Mohamed, Slimane Dahaoui,
Abdesselam Baouid
PII:
S0022-2860(18)30425-3
10.1016/j.molstruc.2018.03.128
MOLSTR 25067
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 31 January 2018
Revised Date: 27 March 2018
Accepted Date: 28 March 2018
Please cite this article as: A. Mohamed, E. Zaballos-García, L. Mohamed, S. Dahaoui, A. Baouid,
Synthesis, characterization and X-ray structure of heterocyclic systems prepared via 1,3-dipolar
cycloaddition of nitrile oxides with benzimidazolone, Journal of Molecular Structure (2018), doi: 10.1016/
j.molstruc.2018.03.128.
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ACCEPTED MANUSCRIPT
GRAPHICAL ABSTRACT
N
N
N
O
O
N
2
3
N
N
N
N
O
O
Ar
C
N
O
Ar
Ar
O
O
N
N
6a - 6d, 9
5a - 5d, 8

ACCEPTED MANUSCRIPT
Synthesis, characterization and X-ray structure of heterocyclic systems prepared
via 1,3-dipolar cycloaddition of nitrile oxides with benzimidazolone
Adardour Mohamed,a Elena Zaballos-García,b Loughzail Mohamed,a Slimane Dahaouic and
Abdesselam Baouida,*
aLaboratory of Molecular Chemistry, Department of Chemistry, Faculty of Sciences Semlalia,
University of Cadi Ayyad, BP. 2390, 40001 Marrakech, Morocco.
bDepartamento de Quimica Organica, Facultad de Farmacia, Universidad de Valencia, Ave. Vte.
Andres Estelles s/n46100 Valencia, España.
cCristallographie, Résonance Magnétique et Modélisation (CRM2), Université Henri Poincaré, Nancy
1, Faculté des Sciences, BP 70239, 54506 Vandoeuvre lès Nancy Cedex, France
Corresponding authors: Tel.: +212 676440039; fax: +212 524437408.
E-mail addresses: baouid@uca.ac.ma
Abstract
We report here a one-step synthesis of the new isoxazolyl-benzimidazolones and isoxazolinyl-
benzimidazolones by 1,3-dipolar cycloaddition of the p-substituted benzonitrile oxides and
mesitonitrile oxide with 1-cyclohex-1-en-1-yl-3-propargyl-benzimidazolone or 1-cyclohex-1-en-1-yl-3-
allyl-benzimidazolone. In all cases these cycloadditions are completely regio- and chemoselective. The
structures of new cycloadducts obtained are elucidated by their analytical and spectral data. The
relative stereochemistry of the cycloadduct 8 was confirmed by single crystal X-ray analysis.
Keywords: Benzimidazolone, 1,3-dipolar cycloaddition, arylonitrile oxides, mesitonitrile oxide, isoxazoles,
isoxazolines, chemoselective, regioselective.
Introduction
Benzimidazole derivatives started to be envisaged as compounds with biological and medical
relevance since the discovery of 5,6-dimethyl-1-(α-D-ribofuranosyl) benzimidazole as part of
the structure of vitamin B12 in 1950 [1]. The benzimidazole scaffold is a very useful
structural motif in developing molecules of pharmaceutical or biological interest. We find
structures benzimidazole-based on several drugs that serve in the diverse areas of medicine
and they are applied for his antimicrobial [2-7], antibacterial [8-11], analgesic [12-16], anti-
inflammatory [17-18], antioxidant [19-20], anti-cancer [21], antitumor [22], and
therapeutically activity [23].
Isoxazoles show pronounced pharmacological applications as anti-inflammatory [24],
antimicrobial [25] and anti-cancer agents [26]. Amongst different methods for the preparation
of isoxazoles and isoxazolines the 1,3-dipolar cycloaddition is the most important and
versatile one. In addition to their potential applications, they can be conveniently modified,
allowing thus the transformation of molecules with simple structures into functional complex
systems [27-28]. We report here a one-step synthesis of a series of new isoxazoles and
isoxazolines heterocycles containing benzimidazolone rings by 1,3-dipolar cycloaddition.
This cycloaddition of arylonitrile oxide with benzimidazole derivatives gave a new
isoxazolyl-benzimidazolones and isoxazolinyl-benzimidazolones. Our attention has been
attracted to synthesizing benzimidazolone ring and its N-alkylation derivatives. Thus, we have
used these new dipolarophiles in 1,3-dipolar cycloaddition reaction with some dipoles, that
could lead to new benzimidazolone derivatives containing various five-membered
heterocycles.
1

ACCEPTED MANUSCRIPT
Results and discussion
Synthesis of the target compounds 5a-d, 6a-d, 8 and 9 were successfully achieved as
illustrated in schemes 1, 2, 3 and 4. The 1-cyclohex-1-en-1-yl-1H-benzimidazol-2(3H)-one
(1) is obtained with a yield 92% by condensation of o-phenylenediamine with ethyl 2-
oxocyclohexanecarboxylate in xylene according to the method described by Rossi et al. [29].
The alkylated compounds 1-cyclohex-1-en-1-yl-3-propargyl-1H-benzimidazol-2(3H)-one (2)
and 1-allyl-3-cyclohex-1-en-1-yl-1H-benzimidazol-2(3H)-one (3) were obtained on reaction
of benzimidazolone 1 with propargyl bromide and allyl bromide, respectively, in the presence
of sodium hydroxide and benzyltriethylammonium chloride in benzene (scheme 1), yielding
80-85%. The arylonitrile oxides were prepared in situ during the cycloaddition reaction, from
corresponding p-substituted benzaldehyde oximes 4a-d using sodium hypochlorite by a
conventional method [30]. The reaction of the dipolarophiles 2 or 3 with the arylonitrile
oxides afforded the new isoxazolyl-benzimidazolones 5a-d (scheme 2) and isoxazolinyl-
benzimidazolones 6a-d (scheme 3). Further, the 2,4,6-trimethylbenzonitrile N-oxide (7) was
synthesized by treating the mesitaldehyde with hydroxylamine hydrochloride in a basic
medium according the chemical literature [31].
NH2
O
N
N
1
Xylene
R
Br / NaOH
ClBzEt3N
O
O
+
3
N
∆ (4h)
O
N
H
NH2
R
OC2H5
1
2 : R = HC
C
CH2
3 : R = CH2 CH CH2
Scheme 1
The structures of all the compounds were determined analytical and spectroscopic analyses.
The known compound (1) was identified by comparison of their spectroscopic data with those
reported in the literature [29].
1
The H NMR spectrum of compound 1 is mainly characterized by the presence of four
methylene groups at 1.77-2.44 ppm and a multiplet at 6.02 ppm assigned to the ethylene
13
proton of the cyclohexenyl group. The C NMR reveals in particular five signals at 21.65,
22.60, 24.76, 26.87 and 127.76 ppm assigned to the four methylene groups and to the ethylene
carbon (CH=) of the cyclohexenyl and one signal at 154.06 ppm attributed to the carbonyl
group.
1
13
The H and C NMR spectra of compounds 2 and 3 reveal besides the signals typical of the
skeleton of the compound 1 those of the propargyl and the allyl groups respectively.
The 1,3-dipolar cycloaddition reaction between a propargylbenzimidazolone 2 or
allylbenzimidazolone 3 with p-substituted benzaldehyde oximes 4a-d in the presence of
sodium hypochlorite were carried out in chloroform at 0°C afforded new isoxazolyl-
benzimidazolones 5a-d (scheme 2) and isoxazolinyl-benzimidazolones 6a-d (scheme 3). They
were purified by column chromatography and isolated with moderate to quantitative yields
(66-85%) (Table 1). No trace of the corresponding stereoisomers has been isolated. This study
shows that these reactions are completely chemoselective and regioselective.
2

ACCEPTED MANUSCRIPT
N
H
OH
N
N
N
1
NaOCl
CHCl3 / 5h / 0°C
O
+
O
3
N
R
4'
5'
2
Ar
2'
N
O1'
4a : R = H
4b : R = CH
4c : R = Cl
3
5a : Ar = C H
5b : Ar = 4-CH -C H
5c : Ar = 4-Cl-C H
6
5
3
6 4
4d : R = NO
2
6
4
5d : Ar = 4-NO -C H
2
6
4
Scheme 2
N
H
OH
N
N
NaOCl
CHCl3 /5h / 0°C
1
O
+
O
3
N
N
R
4'
5'
3'
3
Ar
1'
O
4a : R = H
4b : R = CH
4c : R = Cl
N
3
6a : Ar = C H
6b : Ar = 4-CH -C H
6
5
4d : R = NO
2
3
6 4
6c : Ar = 4-Cl-C H
6
4
6d : Ar = 4-NO -C H
2
6 4
Scheme 3
Structures of all these new compounds were established on the basis of their analytical and
spectral data.
1
The H NMR spectra of the compounds 5a-d exhibited a singlet at 6.57, 6.40, 6.40 and 6.51
ppm respectively, due to isoxazolyl protons in position 4’. The opposite regioselectivity of the
dipolar addition would correspond at 8 ppm to an isoxazolyl proton in position 5’ [32]. The
13C NMR spectra of 5a-d exhibited a signal at 101.26, 101.19, 101.15 and 101.42 ppm
respectively, corresponding to C-4', thus confirming the regioselectivity of reaction.
1
The H NMR spectra of 6a-d revealed a multiplet at 5.01, 4.96, 5.15 and 5.13 ppm
consecutively, due to the isoxazolinyl protons in position 5' and a multiplet at 3.33, 3,29, 3.45
and 3.43 ppm respectively, corresponding to two isoxazolinyl non equivalents protons in
position 4'. The regioselectivity of the addition is confirmed by the presence of signals at
79.57, 79.42, 79.81 and 80.59 ppm consecutively of the C-5' isoxazoline ring in the 13C NMR
spectrum [32].
Table 1: Characterization of compounds 1-9
Mass found
[M+H]+
Melting
point (°C)
Yield
(%)
Structure of the
compounds
Molecular
formula
Compound
Mass calculated
[M+H]+
3

ACCEPTED MANUSCRIPT
215.1179
215.1140
181-183
118-120
92
C13H14N2O
1
2
N
O
N
H
253.1335
253.1296
255.1492
255.1453
85
C16H16N2O
Oily
80
68
C16H18N2O
3
372.1707
140-142
C23H21N3O2
5a
372.1667
386.1863
386.1824
406.1317
406.1278
156-158
138-140
80
70
C24H23N3O2
5b
5c
N
O
N
C23H20ClN3O2
O
N
Cl
417.1557
417.1518
374.1863
N
N
O
180-182
66
C23H20N4O4
5d
O
N
O2N
N
O
N
158-160
176-178
174-176
83
85
80
C23H23N3O2
C24H25N3O2
C23H22ClN3O2
6a
6b
6c
O
374.1824
388.2020
388.1980
N
N
N
O
O
N
408.1473
408.1434
N
O
N
O
N
Cl
4

ACCEPTED MANUSCRIPT
419.1714
419.1675
N
O
N
222-224
76
C23H22N4O4
6d
O
N
O2N
414.2176
414.2137
416.2333
416.2293
N
O
N
112-114
186-188
93
90
C26H27N3O2
8
9
O
N
N
N
O
C26H29N3O2
O
N
Analogs regioselectivity results have been reported by engaging the dipolarophiles 2 and 3 via
1,3-dipolar cycloaddition reactions with the mesitonitrile oxide 7 prepared outside the
reaction medium [31]. This reaction was carried out at room temperature in ether,
monocycloadducts 8 and 9 (scheme 4) were obtained with excellent yields (93 and 90%,
respectively); this reaction was highly regio- and chemoselective.
1 N
N
N
O
3
N
O
4'
5'
2
3'
1'
O
N
8
Ether
C
N O
ambient T
7
1N
N
N
O
3
N
O
4'
5'
3'
3
O
1'
N
9
Scheme 4
The molecular structures of the new heterocyclic systems 1-cyclohex-1-en-1-yl-3-((3-
mesitylisoxazol-5-yl)methyl)-1H-benzimidazol-2(3H)-one (8) and 1-cyclohex-1-en-1-yl-3-
((3-mesityl-4,5-dihydroisoxazol-5-yl)methyl)-1H-benzimidazol-2(3H)-one
established on the basis of H and C NMR spectroscopic data and High-Resolution Mass
Spectrometry (HRMS).
(9)
were
1
13
The polyheterocyclic 8 results from the cycloaddition of mesitonitrile oxide 7 to the alkyne
group (C≡C) of product 2. In fact, the 1H NMR spectrum of the compound 8 show a singlet at
5

ACCEPTED MANUSCRIPT
6.16 ppm, which corresponds to the proton of the isoxazolyl ring, and two singlets at 2.12,
2.32 ppm assigned to the proton of three methyl groups of the mesityl group. In the 13C NMR
spectrum, the regioselectivity is proved by chemical shift of the isoxazolyl C-4’ at 104.60
ppm that excluded the opposite dipolar addition [33]. At 20.23 and 21.06 ppm appear the
signals of the methyl groups of the mesityl group.
The regioselectivity of the 1,3-dipolar cycloaddition of propargylbenzimidazolone with
arylonitrile oxides was confirmed by the X-ray analysis on single crystals of compound 8
(Figure 1); this product crystallizes with ethyl acetate/ethanol (4:1 v/v). This molecule
crystallizes in a monoclinic space group I2/a. A summary of the crystallographic data,
selected lengths and binding angles is given in tables 2, 3 and 4, respectively. In the molecular
structure of product 8, the benzimidazole system and the isoxazole fragment are planar. The
isoxazole ring wich is normal to the benzimidazole system [dihedral angle is being 65.01(7)°]
makes a dihedral angle of 59.31(8)° with his attached mesityl. The carbon–carbon and
carbon–nitrogen bond lengths in the isoxazole ring [C(15)-C(16) = 1.348(2) Å, C(16)-C(17) =
1.422(2) Å and C(17)-N(3) = 1.3139(19) Å] agree with their expected double bond character.
The endocyclic and exocyclic torsion angles are reported in Table 4. In the crystal, molecules
are linked by C(22)---H(22)...O(1) hydrogens bonds.
Figure 1
:
Crystal structure of 1-cyclohex-1-en-1-yl-3-((3-mesitylisoxazol-5-yl) methyl)-
1H-benzimidazol-2(3H)-one (8)
Table 2: Crystallographic data and structure refinement for compound 8
Empirical formula
Formula weight
Temperature K
Wavelength
C26H27N3O2
413.50
100
1.54184
Crystal system
Space group
Monoclinic
I2/a
Unit cell dimensions
a = 10.5711 (2) Å α = 90
b = 23.5384 (3) Å β = 104.197 (2)
c = 19.2413 (4)Å χ = 90
4641.52 (24)
8
Volume (Å3)
Z
Density (g.cm-1)
1.183
6

ACCEPTED MANUSCRIPT
Absorption coefficient (mm-1) 0.600
F(000) 1760
Theta range for data collection 3.00–74.5°
Index ranges
-
13 ≤ h ≤ 13, -29 ≤ k ≤ 29, -23 ≤ l ≤ 17
Independent reflections
Data/restraints/parameters
Goodness-of-fit on
4721 [R(int) = 0.0799]
4721/0/284
1.042
R indices (all data)
Largest diff. peak and hole
R1 = 0.0657, wR2 = 0.1334
0.329 and -0.299 eÅ-3
Table 3: Selected bond lengths (Å) for compound 8
C1-C2
C1-N2
C1-C6
C2-C3
C2-H2
C3-C4
C3-H3
C4-C5
1.381(2)
1.3915(18)
1.4035(19)
1.400(2)
0.9500
1.393(2)
0.9500
1.400(2)
0.9500
1.3835(19)
1.527(2)
0.9900
0.9900
1.532(2)
0.9900
C5-H5
C6-N1
C7-O1
C7-N2
C7-N1
C8-C9
C8-N1
C8-C13
0.9500
1.3963(19)
1.2222(19)
1.383(2)
1.3905(18)
1.335(2)
1.4314(19)
1.501(2)
1.500(2)
0.9500
1.4079(18)
1.4084(18)
1.394(2)
1.5113(19)
1.390(2)
0.9500
1.400(2)
1.510(2)
1.395(2)
0.9500
1.5161(18)
0.9800
0.9800
0.9800
0.9800
0.9800
C4-H4
C5-C6
C9-C10
C9-H9
C10-C11
C10-H10A
C10-H10B
C11-C12
C11-H11A
C11-H11B
C12-C13
C12-H12A
C12-H12B
C13-H13A
C13-H13B
C14-N2
C14-C15
C14-H14A
C14-H14B
C15-C16
C15-O2
C18-C23
C18-C19
C19-C20
C19-C24
C20-C21
C20-H20
C21-C22
C21-C25
C22-C23
C22-H22
C23-C26
C24-H24A
C24-H24B
C24-H24C
C25-H25A
C25-H25B
C25-H25C
C26-H26A
C26-H26B
C26-H26C
N3-O2
0.9900
1.526(2)
0.9900
0.9900
0.9900
0.9900
1.4546(17)
1.4947(19)
0.9900
0.9900
1.348(2)
1.3502(19)
1.422(2)
0.9500
1.3139(19)
1.4851(18)
0.9800
0.9800
0.9800
0.9800
C16-C17
C16-H16
C17-N3
C17-C18
1.4104(17)
Table 4: Selected angles (°) for compound
8
C2-C1-N2
C2-C1-C6
131.80(13)
121.67(13)
C8-C9-C10
C8-C9-H9
122.73(14)
118.6
N2-C1-C6
C1-C2-C3
C1-C2-H2
106.53(12)
117.10(14)
121.5
C10-C9-H9
C9-C10-C11
C9-C10-H10A
118.6
112.13(12)
109.2
7

ACCEPTED MANUSCRIPT
C3-C2-H2
121.5
C11-C10-H10A
109.2
C4-C3-C2
121.36(14)
119.3
C9-C10-H10B
C11-C10-H10B
H10A-C10-H10B
C10-C11-C12
C10-C11-H11A
C12-C11-H11A
C10-C11-H11B
C12-C11-H11B
H11A-C11-H11B
C13-C12-C11
109.2
C4-C3-H3
109.2
C2-C3-H3
119.3
107.9
C3-C4-C5
C3-C4-H4
121.26(13)
119.4
110.45(14)
109.6
C5-C4-H4
119.4
109.6
C6-C5-C4
117.23(13)
121.4
109.6
C6-C5-H5
109.6
C4-C5-H5
121.4
108.1
C5-C6-N1
131.28(13)
121.37(13)
107.33(12)
126.92(13)
127.04(14)
106.03(12)
119.63(14)
124.16(14)
116.17(12)
109.4
110.31(14)
109.6
C5-C6-C1
C13-C12-H12A
C11-C12-H12A
C13-C12-H12B
C11-C12-H12B
H12A-C12-H12B
C8-C13-C12
N1-C6-C1
O1-C7-N2
109.6
109.6
O1-C7-N1
109.6
N2-C7-N1
108.1
C9-C8-N1
111.28(13)
109.4
C9-C8-C13
N1-C8-C13
C8-C13-H13B
C12-C13-H13B
H13A-C13-H13B
N2-C14-C15
N2-C14-H14A
C15-C14-H14A
N2-C14-H14B
C15-C14-H14B
H14A-C14-H14B
C16-C15-O2
C16-C15-C14
O2-C15-C14
C15-C16-C17
C8-C13-H13A
C12-C13-H13A
C23-C22-H22
109.4
119.4
119.4
109.4
C21-C22-H22
108.0
C22-C23-C18
119.27(12)
119.56(12)
121.16(12)
109.5
112.98(11)
109.0
C22-C23-C26
C18-C23-C26
109.0
C19-C24-H24A
C19-C24-H24B
H24A-C24-H24B
C19-C24-H24C
H24A-C24-H24C
H24B-C24-H24C
C21-C25-H25A
C21-C25-H25B
109.0
109.5
109.0
109.5
107.8
109.5
109.5
110.08(12)
133.52(14)
116.41(12)
104.53(12)
109.5
109.5
109.5
C15-C16-H16
C17-C16-H16
N3-C17-C16
N3-C17-C18
C16-C17-C18
C23-C18-C19
C23-C18-C17
C19-C18-C17
C20-C19-C18
C20-C19-C24
C18-C19-C24
C21-C20-C19
C21-C20-H20
C19-C20-H20
127.7
H25A-C25-H25B
C21-C25-H25C
H25A-C25-H25C
H25B-C25-H25C
C23-C26-H26A
C23-C26-H26B
H26A-C26-H26B
C23-C26-H26C
H26A-C26-H26C
H26B-C26-H26C
C7-N1-C6
109.5
127.7
109.5
111.34(12)
119.91(12)
128.75(12)
120.22(12)
119.02(11)
120.75(12)
118.67(12)
118.61(12)
122.72(12)
122.14(13)
118.9
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.57(12)
123.12(12)
127.27(12)
110.55(11)
C7-N1-C8
C6-N1-C8
118.9
C7-N2-C1
8

ACCEPTED MANUSCRIPT
C20-C21-C22
C20-C21-C25
C22-C21-C25
C23-C22-C21
118.43(13)
C7-N2-C14
C1-N2-C14
C17-N3-O2
C15-O2-N3
122.31(12)
127.08(13)
105.62(12)
108.43(11)
120.49(14)
121.07(14)
121.26(13)
1
The H NMR spectrum of the compound 9 is mainly characterized a multiplet at 5.05 ppm,
which corresponds to the proton on position 5’ of the isoxazolinyl ring and a multiplet at 3.17
ppm attributable to methylene group on position 4’. In the 13C NMR spectrum, the
regioselectivity is proved by chemical shifts of the isoxazolinyl carbons C-4’ at 41.98 ppm
and C-5’ at 78.53 ppm that excluded the opposite dipolar addition.
Conclusion
We have synthesized the new classes of isoxazolyl-benzimidazolones and isoxazolinyl-
benzimidazolones by 1,3-dipolar cycloaddition of the p-substituted benzonitrile oxides and
mesitonitrile oxide with 1-cyclohex-1-en-1-yl-3-propargyl(allyl)benzimidazolone. In all cases
these cycloaddition reactions resulted in a single regioisomer. These reactions are completely
chemoselective and regioselective since a single site dipolarophile carbon-carbon of the
propargyl (allyl) benzimidazolone group is affected and the sense of addition is unique.
Experimental section
General methods
Melting points were taken in an open capillary tube on a Buchi 510 apparatus and are
1
uncorrected. Spectra were recorded with the following instruments: H NMR (300 MHz) and
13C NMR (75 MHz) spectra were recorded on Bruker spectrometer with chemical shift values
given in part per million (ppm) relative to TMS (0.00 ppm). High-Resolution Mass Spectral
(HRMS) data were obtained on a Triple TOF™ 5600 LC/MS/MS System, (AB SCIEX). The
ionization mode used in mass spectra was Ion Spray Voltage (ISVF): 5500. Column
chromatography was carried out using E-Merck silica gel 60F254. The reaction progress was
monitored by Thin Layer Chromatography (TLC) using, silica gel 60-F254, and the spots were
detected with UV light (254 or 365 nm). IR spectra were recorded on Bruker Vertex 70
spectrometer as potassium bromide discs. The structure of all the compounds was determined
by analytical and spectroscopic methods and by comparison with data of the structural related
compounds reported in literature. Reagents and solvents were purified in the usual way.
I/ Preparation of 1-cyclohex-1-en-1-yl-1H-benzimidazol-2(3H)-one (1)
A mixture of o-phenylenediamine (2.5 g, 23 mmol) and ethyl 2-oxo-cyclohexanecarboxylate
(4.4 g, 26 mmol) in xylene (100 mL) was refluxed for 4h. The title compound was isolated by
column chromatography using hexane/ethyl acetate (8:2 v/v) as eluent. The 1-cyclohex-1-en-
1-yl-1H-benzimidazol-2(3H)-one (1) was obtained as white solid.
Yield: 92%. Mp: 181-183°C (ethanol), (Lit. [29]: 180-181°C). IR (KBr, ν (cm-1), 3413
(imidazole-NH), 1602 (C=O). 1H NMR (300 MHz, CDCl3): δppm: 1.69, 1.78, 2.22, 2.33 (4m,
8H, 4CH2-cyclohexenyl), 5.90 (m, 1H, =CH-cyclohexenyl), 6.89 - 7.17 (m, 4H, H-Ar), 10.77
(s, 1H, NH). 13C NMR (75 MHz, CDCl3): δppm: 21.65, 22.60, 24.76, 26.87 (4CH2-
9

ACCEPTED MANUSCRIPT
cyclohexenyl), 127.76 (1C, =CH-cyclohexenyl), 108.71, 110.09, 121.38, 121.69 (CH-Ar),
128.44, 130.54, 132.07 (=C-), 154.06 (C=O). HRMS of [M+H]+ m/z 215.1179, calcd for
C13H15N2O, 215.1140.
II/ Procedure for alkylation
A mixture of benzimidazolone 1 (1g, 4.7 mmol), benzyltriethylammonium chloride
(C6H5CH2N(Cl)(C2H5)3) (2.3 mmol) and sodium hydroxide aqueous solution (5 mL, 50%) in
benzene (25 mL) was stirred at ambient temperature. After 15 min, alkyl (propargyl or allyl)
bromide (4.8 mmol) was added slowly. After 6 h of stirring at 25°C, the reaction mixture was
diluted with water (30 mL). The organic layer was extracted with dichloromethane (3 × 10
mL), dried over anhydrous sodium sulfate and evaporated under vacuum. The 1-cyclohex-1-
en-1-yl-3-propargyl-1H-benzimidazol-2(3H)-one (2) and 1-allyl-3-cyclohex-1-en-1-yl-1H-
benzimidazol-2(3H)-one (3) was isolated by column chromatography using hexane/ethyl
acetate mixture (9:1 v/v) as eluent.
1-Cyclohex-1-en-1-yl-3-propargyl-1H-benzimidazol-2(3H)-one (2)
White solid. Yield: 85%. Mp: 118-120°C (ethyl acetate). 1H NMR (300 MHz, CDCl3): δppm:
1.63, 1.73, 2.16, 2.40 (4m, 8H, 4CH2-cyclohexenyl), 2.15 (t, J= 3 Hz, 1H, HC≡C), 4.56 (d, J=
3 Hz, 2H, N-CH2-C), 5.82 (m, 1H, HC=C-cyclohexenyl), 6.89-7.14 (m, 4H, H-Ar). 13C NMR
(75 MHz, CDCl3): δppm: 21.63, 22.56, 24.71, 26.75 (4CH2- cyclohexenyl), 30.37 (1C, N-
CH2-C), 72.67 (1C, HC≡C), 127.41 (1C, =CH-cyclohexenyl), 108.40, 108.74, 121.42, 121.66
(CH-Ar), 128.56, 129.67, 132.15 (=C-), 154.60 (C=O). HRMS of [M+H]+ m/z 253.1335,
calcd for C16H17N2O, 253.1296.
1-Allyl-3-cyclohex-1-en-1-yl-1H-benzimidazol-2(3H)-one (3)
Oily product. Yield: 80%. 1H NMR (300 MHz, CDCl3): δppm: 1.71, 1.79, 2.22, 2.33 (4m, 8H,
4CH2-cyclohexenyl), 4.38 (d, J = 3Hz, 2H, N-CH2-C), 5.15 (m, 2H, CH2=CH), 5.92 (m, 2H,
13
CH2=CH and =CH-cyclohexenyl), 6.89-7.14 (m, 4H, H-Ar). C NMR (75 MHz, CDCl3):
δppm: 20.62, 21.54, 23.67, 25.73 (4CH2-cyclohexenyl), 42.41 (1C, N-CH2-C), 116.59
(C=CH2), 126.08 (1C, =CH-cyclohexenyl), 108.40, 108.74, 121.42, 121.66 (-CH=CH2, CH-
Ar), 128.38, 131.05, 131.06, 131.25 (=C-), 160.81 (C=O). HRMS of [M+H]+ m/z 255.1492,
calcd for C16H19N2O, 255.1453.
III/ General procedure for the 1,3-dipolar cycloaddition reactions
III-1- Synthesis of cycloadducts 5a-d and 6a-d
To a solution of dipolarophile 2 or 3 (3.97 mmol) and the appropriate p-substituted
benzaldoximes 4a-d (9.93 mmol) in chloroform (30 mL), then we added, drop by drop, at 0°C
and with vigorous stirring, of bleach at 24° (20 mL). Stirring was continued for 5 hours. The
organic layer was dried over anhydrous sodium sulfate (Na2SO4) and the solvent evaporated
under reduced pressure. The residue was then purified by column chromatography eluting
with hexane/ethyl acetate mixture (7:3 v/v) to isolate cycloadducts 5a-d or 6a-d.
1-Cyclohex-1-en-1-yl-3-((3-phenylisoxazol-5-yl)methyl)-1H-benzimidazol-2(3H)-one (5a)
10

ACCEPTED MANUSCRIPT
White solid. Yield: 68%. Mp: 140-142°C (ethanol). IR (KBr, ν (cm-1): 1706 (C=O), 1612
1
(C=N). H NMR (300 MHz, CDCl3): δppm: 1.78, 1.88, 2.32, 2.43 (4m, 8H, 4CH2-
cyclohexenyl), 5.24 (s, 2H, N-CH2-C), 5.99 (m, 1H, =CH-cyclohexenyl), 6.57 (s, 1H, CH-
isoxazolyl), 7.14-7.79 (m, 9H, H-Ar). 13C NMR (75 MHz, CDCl3): δppm: 21.59, 22.38,
24.43, 26.75 (4CH2-cyclohexenyl), 36.35 (1C, N-CH2-C), 101.26 (1C, CH-isoxazolyl),
127.54 (1C, =CH-cyclohexenyl), 108.12, 108.90, 121.42, 121.70, 126.81, 128.87, (CH-Ar),
129.61, 130.10, 132.05 (=C-), 152.59, 162.73, 167.55 (C=N, =C-O, C=O). HRMS of [M+H]+
m/z 372.1707, calcd for C23H22N3O2, 372.1667.
1-Cyclohex-1-en-1-yl-3-((3-p-tolylisoxazol-5-yl)methyl)-1H-benzimidazol-
2(3H)-one (5b)
White solid. Yield: 80%. Mp: 156-158°C (ethanol). IR (KBr, ν (cm-1):1708 (C=O), 1611
1
(C=N). H NMR (300 MHz, CDCl3): δppm: 1.63, 1.75, 2.13, 2.28 (4m, 8H, 4CH2-
cyclohexenyl), 2.28 (s, 3H, CH3), 5.09 (s, 2H, N-CH2-C), 5.85 (m, 1H, =CH-cyclohexenyl),
13
6.40 (s, 1H, CH-isoxazolyl), 6.98-7.53 (m, 8H, H-Ar). C NMR (75 MHz, CDCl3): δppm:
21.63, 22.57, 24.73, 26.78 (4CH2-cyclohexenyl), 21.42 (1C, CH3-Ar), 36.52 (1C, N-CH2-C),
101.19 (1C, CH-isoxazolyl), 127.52 (1C,=CH-cyclohexenyl), 108.16, 108.89, 121.70, 121.88,
109.97, 125.79, 126.71, 128.70 (CH-Ar), 129.52, 129.62, 132.07, 140.27, (=C-), 152.61,
162.68, 167.36 (C=N, =C-O, C=O). HRMS of [M+H]+ m/z 386.1863, calcd for C24H24N3O2,
386.1824
1-((3-(4-Chlorophenyl)isoxazol-5-yl)methyl)-3-cyclohex-1-en-1-yl-1H-benzimidazol-2(3H)-
one (5c)
White solid. Yield: 70%. Mp: 138-140°C (ethanol). IR (KBr, ν (cm-1): 1705 (C=O), 1608
1
(C=N). H NMR (300 MHz, CDCl3): δppm: 1.63, 1.75, 2.17, 2.28 (4m, 8H, 4CH2-
cyclohexenyl), 5.09 (s, 2H, N-CH2-C), 6.40 (s, 1H, CH-isoxazolyl), 5.85 (m, 1H, =CH-
13
cyclohexenyl), 6.93-7.58 (m, 8H, H-Ar). C NMR (75 MHz, CDCl3): δppm: 21.61, 22.56,
24.72, 26.78 (4CH2-cyclohexenyl), 36.49 (1C, N-CH2-C), 101.15 (1C, CH-isoxazolyl),
127.59 (1C, =CH-cyclohexenyl), 108.06, 108.97, 121.74, 121.97, 127.13, 128.09, 128.62
(CH-Ar), 128.18, 129.63, 132.02, 136.17 (=C-), 152.90, 161.78, 167.92 (C=N, =C-O, C=O).
HRMS of [M+H]+ m/z 406.1317, calcd for C23H21ClN3O2, 406.1278.
1-Cyclohex-1-en-1-yl-3-((3-(4-nitrophenyl) isoxazol-5-yl) methyl)-1H-benzimidazol-2(3H)-
one (5d)
White solid. Yield: 66%. Mp: 180-182°C (ethanol). IR (KBr, ν (cm-1): 1705 (C=O), 1608
1
(C=N). H NMR (300 MHz, CDCl3): δppm: 1.63, 1.74, 2.11, 2.24 (4m, 8H, 4CH2-
cyclohexenyl), 5.14 (s, 2H, N-CH2-C), 5.85 (m, 1H, =CH-cyclohexenyl), 6.51 (s, 1H, CH-
isoxazolyl), 6.93-8.19 (m, 8H, H-Ar). 13C NMR (75 MHz, CDCl3): δppm: 21.60, 22.55,
24.72, 26.78 (4CH2-cyclohexenyl), 36.47 (1C, N-CH2-C), 101.42 (1C, CH-isoxazolyl),
127.71 (1C, =CH-cyclohexenyl), 107.94, 109.07, 121.79, 122.08, 124.20, 127.67, 128.54
(CH-Ar), 129.65, 131.98, 134.71, 148.75 (=C-), 152.58, 160.95, 168.76 (C=N, =C-O, C=O).
HRMS of [M+H]+ m/z 417.1557, calcd for C23H21N4O4, 417.1518.
11

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1-Cyclohex-1-en-1-yl-3-((3-phenyl-4,5-dihydroisoxazol-5-yl)methyl)-1H-benzimidazol-
2(3H)-one (6a)
White solid. Yield: 83%. Mp: 158-160°C (ethanol). IR (KBr, ν (cm-1): 1699 (C=O), 1612
1
(C=N). H NMR (300 MHz, CDCl3): δppm: 1.63, 1.72, 2.18 (3m, 8H, 4CH2-cyclohexenyl),
3.33 (m, 2H, =C-CH2-CH-O), 4.03(m, 2H, N-CH2-CH-O), 5.01 (m, 1H, CH-isoxazolinyl),
13
5.78 (m, 1H, =CH-cyclohexenyl), 6.83-7.34 (m, 9H, H-Ar). C NMR (75 MHz, CDCl3):
δppm: 21.64, 22.57, 24.69, 26.68 (4CH2-cyclohexenyl), 38.07 (1C, =C-CH2-CH-O), 44.51
(1C, 1C, N-CH2-CH-O), 79.57 (1C, CH-isoxazolinyl), 127.24 (1C, =CH-cyclohexenyl),
108.52, 108.89, 121.49, 121.64, 126.82, 128.65, 129.94, (CH-Ar), 129.27, 129.58, 130.14,
132.24 (=C-), 153.51, 156.80 (C=N, C=O). HRMS of [M+H]+ m/z 374.1863, calcd for
C23H24N3O2, 374.1824.
1-Cyclohex-1-en-1-yl-3-((3-p-tolyl-4,5-dihydroisoxazol-5-yl)methyl)-1H-benzimidazol-
2(3H)-one (6b)
White solid. Yield: 85%. Mp: 176-178°C (ethanol). IR (KBr, ν (cm-1): 1705 (C=O), 1614
1
(C=N). H NMR (300 MHz, CDCl3): δppm: 1.66, 1.72, 2.18 (3m, 8H, 4CH2-cyclohexenyl),
2.24 (s, 3H, CH3-Ar), 3.29 (m, 2H, =C-CH2-CH-O), 3.99 (m, 2H, N-CH2-CH-O), 4.96 (m,
13
1H, CH-isoxazolinyl), 5.76 (m, 1H, =CH-cyclohexenyl), 6.85-7.38 (m, 8H, H-Ar). C NMR
(75 MHz, CDCl3): δppm: 21.43 (1C, CH3-Ar), 21.65, 22.57, 24.70, 26.68 (4CH2-
cyclohexenyl), 38.16 (1C, =C-CH2-CH-O), 44.49 (1C, 1C, N-CH2-CH-O), 79.42 (1C, CH-
isoxazolinyl), 127.39 (1C, =CH-cyclohexenyl), 108.53, 108.95, 121.48, 121.66, 127.28,
129.37, (CH-Ar), 126.78, 129.52, 129.93, 132.18, 140.42 (=C-), 153.48, 156.80 (C=N, C=O).
HRMS of [M+H]+ m/z 388.2020, calcd for C24H26N3O2, 388.1980.
1-((3-(4-Chlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl)-3-cyclohex-1-en-1-yl-1H-
benzimidazol-2(3H)-one (6c)
White solid. Yield: 80%. Mp: 174-176°C (ethanol). IR (KBr, ν (cm-1): 1703 (C=O), 1609
1
(C=N). H NMR (300 MHz, CDCl3): δppm: 1.73, 1.82, 2.29 (3m, 8H, 4CH2-cyclohexenyl),
3.45 (m, 2H, =C-CH2-CH-O), 4.16 (m, 2H, N-CH2-CH-O), 5.15 (m, 1H, CH-isoxazolinyl),
13
5.90 (m, 1H, =CH-cyclohexenyl), 6.99-7.59 (m, 8H, H-Ar). C NMR (75 MHz, CDCl3):
δppm: 21.56, 22.50, 24.65, 26.63 (4CH2-cyclohexenyl), 37.84 (1C, =C-CH2-CH-O), 44.35
(1C, N-CH2-CH-O), 79.81 (1C, CH-isoxazolinyl), 127.63 (1C, =CH-cyclohexenyl), 108.56,
108.81, 121.55, 121.66, 127.43, 128.03 (CH-Ar), 128.92, 129.50, 129.78, 136.17, 132.05
(=C-), 153.50, 155.97 (C=N, C=O). HRMS of [M+H]+ m/z 408.1473, calcd for
C23H23ClN3O2, 408.1434.
1-Cyclohex-1-en-1-yl-3-((3-(4-nitrophenyl)-4,5-dihydroisoxazol-5-yl)methyl)-1H-
benzimidazol-2(3H)-one (6d)
White solid. Yield: 76%. Mp: 222-224°C (ethanol). IR (KBr, ν (cm-1): 1706 (C=O), 1612
1
(C=N). H NMR (500 MHz, CDCl3): δppm: 1.66, 1.76, 2.21 (3m, 8H, 4CH2-cyclohexenyl),
3.43 (m, 2H, =C-CH2-CH-O), 4.11 (m, 2H, N-CH2-CH-O), 5.13 (m, 1H, CH-isoxazolinyl),
13
5.80 (m, 1H, =CH-cyclohexenyl), 6.62–8.16 (m, 8H, H-Ar). C NMR (75 MHz, CDCl3):
δppm: 21.64, 22.32, 24.49, 26.62 (4CH2-cyclohexenyl), 80.59 (1C, CH isoxazolinyl), 37.39
12

ACCEPTED MANUSCRIPT
(1C, =C-CH2-CH-O), 44.22 (1C, N-CH2-CH-O), 127.71 (1C, =CH-cyclohexenyl), 108.66,
108.70, 121.55, 121.69, 127.52, 123.90 (CH-Ar), 129.50, 129.66, 131.97, 135.17, 148.50
(=C-), 153.53, 155.41 (C=N, C=O). HRMS of [M+H]+ m/z 419.1714, calcd for C23H23N4O4,
419.1675.
III-2- Synthesis of cycloadducts 8 and 9
A solution of N-propargylbenzimidazolone 2 (3.97 mmol) or N-allylbenzimidazolone 3 (3.97
mmol) and mesitonitrile oxide 7 [31] (4.7 mmol) in anhydrous diethyl ether (30 mL) was
stirred at room temperature to ten days. After evaporating the solvent, the residue obtained is
chromatographed by column chromatography eluting with hexane/ethyl acetate mixture (6:4
v/v) to isolate cycloadducts 8 or 9.
1-Cyclohex-1-en-1-yl-3-((3-mesitylisoxazol-5-yl)methyl)-1H-benzimidazol-2(3H)-one (8)
White solid. Yield: 93%. Mp: 112-114°C (ethyl acetate). IR (KBr, ν (cm-1): 1713 (C=O),
1
1610 (C=N). H NMR (300 MHz, CDCl3): δppm: 1.78, 1.88, 2.31, 2.42 (4m, 8H, 4CH2-
cyclohexenyl), 2.12, 2.32 (s, 9H, 3CH3-Ar), 5.27 (s, 2H, N-CH2-C), 6.00 (m, 1H, =CH-
13
cyclohexenyl), 6.16 (s, 1H, CH-isoxazolyl), 6.92-7.29 (m, 6H, H-Ar). C NMR (75 MHz,
CDCl3): δppm: 21.58, 22.53, 24.68, 26.59 (4CH2-cyclohexenyl), 20.23, 21.06 (3C, 3CH3-Ar),
36.63 (1C, N-CH2-C), 104.60 (1C, CH-isoxazolyl), 127.53 (1C, =CH-cyclohexenyl), 108.14,
108.88, 121.61, 121.84, 128.31 (CH-Ar), 125.61, 128.76, 129.65, 132.05, 137.08, 138.84
(=C-), 152.63, 162.38, 166.77 (C=N, =C-O, C=O). HRMS of [M+H]+ m/z 414.2176, calcd for
C26H28N3O2, 414.2137. Crystal data for 8: monoclinic, space group I2/a, a = 10.5711 (2), b =
23.5384 (3), c = 19.2413 (4)Å, β = 104.197 (2)°, V = 4641.52 (24)Å3, Z = 8, 4721
independent reflections, R1 = 0.0657, wR2 = 0.1334.
1-Cyclohex-1-en-1-yl-3-((3-mesityl-4,5-dihydroisoxazol-5-yl)methyl)-1H-benzimidazol-
2(3H)-one (9)
White solid. Yield: 90%. Mp: 186-188°C (ethanol). IR (KBr, ν (cm-1): 1704 (C=O), 1611
1
(C=N). H NMR (300 MHz, CDCl3): δppm: 1.69, 1.76, 2.19, 2.28 (4m, 8H, 4CH2-
cyclohexenyl), 2.02, 2.15 (s, 9H, 3CH3-Aryl), 3.17 (m, 2H, =C-CH2-CH-O), 4.08 (m, 2H, N-
CH2-CH-O), 5.05 (m, 1H, CH-isoxazolinyl), 5.83 (m, 1H, =CH-cyclohexenyl), 6.74-7.24 (m,
13
6H, H-Ar). C NMR (75 MHz, CDCl3): δppm: 19.55, 21.07 (3C, 3CH3-Ary), 21.66, 22.60,
24.74, 26.78 (4CH2-cyclohexenyl), 41.68 (1C, =C-CH2-CH-O), 44.58 (1C, N-CH2-CH-O),
78.53 (1C, CH-isoxazolinyl), 127.34 (1C, =CH-cyclohexenyl), 108.53, 109,15 121.63,
121.78, 128.44 (CH-Ar), 125.89, 129.55, 129.91, 132.23, 136.45, 138.73 (=C-), 153.68,
157.43 (C=N,C=O). HRMS of [M+H]+ m/z 416.2333, calcd for C26H30N3O2, 416.2293.
X-ray crystallography
The analysis and recording of our structure 8 was performed on an Oxford Supernova
automatic diffractometer, equipped with a two-dimensional CrysAlis CCD detector, and
equipped with an X-ray source using Kα radiation of molybdenum. The reflection intensities
were collected on a Kappa-CCD diffractometer at 100 K. The structure was solved by direct
method and subsequent Fourier analysis. All the hydrogen atoms were located in the Fourier
difference map. The programs SHELX-S [34], SHELX-L [35] and WINGX [36] were used
13

ACCEPTED MANUSCRIPT
for computations. Crystal data and pertinent details of data collection and refinement are
reported in Table 2 for the compound 8. Table 3 and Table 4 lists selected geometric
parameters.
Appendix A. Supplementary material
Crystallographic data for 8 have been deposited with the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB22 1eZ, UK (fax: +44 1223 336 033; e-mail:
deposit@ccdc.cam.uk or http://www.ccdc.cam.uk) and it is available on request quoting the
deposition number CCDC 1820200. Supplementary data associated with this article can be
found, in the online version, at http://www.ccdc.cam.ac.uk/Community/blog/2016-12-01.
References
[1] L.B. Townsend, G.R. Revankar, Benzimidazole nucleosides, nucleotides, and related
derivatives, Chem. Rev. 70 (1970) 389-438.
[2] P.S. Rathee, R. Dhankar, S. Bhardwaj, M. Gupta, R. Kumar, Synthesis and Antimicrobial
studies of novel Benzimidazole derivatives, J. App. Pharm. Sci. 01 (2011) 127-130.
[3] A.H. El-masry, H.H. Fahmy, S.H. Ali Abdelwahed, Synthesis and Antimicrobial Activity
of Some New Benzimidazole Derivatives, Molecules 5 (2000) 1429-1438.
[4] K.F. Ansari, C. Lal, Synthesis, physicochemical properties and antimicrobial activity of
some new benzimidazole derivatives, Eur. J. Med. Chem. 44 (2009) 4028-4033.
[5] S. Özden, D. Atabey, S. Yıldız, H. Göker, Synthesis and potent antimicrobial activity of
some novel methyl or ethyl 1H-benzimidazole-5-carboxylates derivatives carrying amide or
amidine groups, Bioorg. Med. Chem. 13 (2005) 1587-1597.
[6] M. Tunçbilek, T. Kiper, N. Altanlar, Synthesis and in vitro antimicrobial activity of some
novel substituted benzimidazole derivatives having potent activity against MRSA, Eur. J.
Med. Chem. 44 (2009) 1024-1033.
[7] M. Noolvi, S. Agrawal, H. Patel, A. Badiger, M. Gaba, A. Zambre, Synthesis,
antimicrobial and cytotoxic activity of novel azetidine-2-one derivatives of 1H-
benzimidazole, Arabian J. Chem. 7 (2014) 219-226.
[8] A. Khalafi-Nezhad, M.N. Soltani Rad, H. Mohabatkar, Z. Asraria, B. Hemmateenejad,
Design, synthesis, antibacterial and QSAR studies of benzimidazole and imidazole
chloroaryloxyalkyl derivatives, Bioorg. Med. Chem. 13 (2005) 1931-1938.
[9] C. Hubschwerlen, P. Pflieger, J.L. Specklin, K. Gubernator, H. Gmûnder, P. Angehrn, I.
Kompis, Pyrimido[1,6-a ]benzimidazoles: A New Class of DNA Gyrase Inhibitors, J. Med.
Chem. 35 (1992) 1385-1392.
[10] P.T.M. Nguyen, J.D. Baldeck, J. Olsson, R.E. Marquis, Antimicrobial actions of
benzimidazoles against oral streptococci, Oral Microbiol. Immunol. 20 (2005) 93-100.
[11] H. Göker, S. Özden, S. Yıldız, D.W. Boykin, Synthesis and potent antibacterial activity
against MRSA of some novel 1,2-disubstituted-1H-benzimidazole-N-alkylated-5-
carboxamidines, Eur. J. Med. Chem. 40 (2005) 1062-1069.
[12] K.C.S. Achar, K.M. Hosamani, H.R. Seetharamareddy, In-vivo analgesic and anti-
inflammatory activities of newly synthesized benzimidazole derivatives, Eur. J. Med. Chem.
45 (2010) 2048-2054.
14

ACCEPTED MANUSCRIPT
[13] M. Gaba, D. Singh, S. Singh, V. Sharma, P. Gaba, Synthesis and pharmacological
evaluation of novel 5-substituted-1-(phenylsulfonyl)-2-methylbenzimidazole derivatives as
anti-inflammatory and analgesic agents, Eur. J. Med. Chem. 45 (2010) 2245-2249.
[14] K. Taniguchi, S. Shigenaga, T. Ogahara, T. Fujitsu, M. Matsuo, Synthesis and anti-
inflammatory and analgesic properties of 2-Amino-1H-benzimidazole and 1,2-Dihydro-2-
iminocycloheptimidazole Derivatives, Chem. Pharm. Bull. 41 (1993) 301-309.
[15] S.M. Sondhi, N. Singh, A. Kumar, O. Lozach, L. Meijer, Synthesis, anti-inflammatory,
analgesic and kinase (CDK-1,CDK-5 and GSK-3) inhibition activity evaluation of
benzimidazole/benzoxazole derivatives and some Schiff’s bases, Bioorg. Med. Chem. 14
(2006) 3758-3765.
[16] S.M. Sondhi, N. Singh, M. Johara, A. Kumarb, Synthesis, anti-inflammatory and
analgesic activities evaluation of some mono, bi and tricyclic pyrimidine derivatives, Bioorg.
Med. Chem. 13 (2005) 6158-6166.
[17] S.M. Sondhi, R. Rani, J. Singh, P. Roy, S.K. Agrawal, A.K. Saxena, Solvent free
synthesis, anti-inflammatory and anticancer activity evaluation of tricyclic and tetracyclic
benzimidazole derivatives, Bioorg. Med. Chem. Lett. 20 (2010) 2306-2310.
[18] P.A. Thakurdesai, S.G. Wadodkar, C.T. Chopade, Synthesis and anti-inflammatory
activity of some benzimidazole-2-carboxylic acids, Pharmacologyonline 1 (2007) 314-329.
[19] A.Ts. Mavrova, D. Yancheva, N. Anastassova, K. Anichina, J. Zvezdanovic, A.
Djordjevic, D. Markovic, A. Smelcerovic, Synthesis, electronic properties, antioxidant and
antibacterial activity of some new benzimidazoles, Bioorg. Med. Chem. 23 (2015) 6317-6326.
[20] C. Kus¸ G. Ayhan-Kilcigil, S. Özbey, F. BetȕlKaynak, M. Kaya, T. Çoban, B. Can-Eke,
Synthesis and antioxidant properties of novel N-methyl-1,3,4-thiadiazol-2-amine and 4-
methyl-2H-1,2,4-triazole-3(4H)-thione derivatives of benzimidazole class, Bioorg. Med.
Chem. 16 (2008) 4294-4303.
[21] N.R. Thimmegowda, S.N. Swami, C.S.A. Kumar, Y.C.S. Kumar, S. Chandrappa, W.Y.
George, K.S. Rangappa, Synthesis, characterization and evaluation of benzimidazole
derivative and its precursors as inhibitors of MDA-MB-231 human breast cancer cell
proliferation, Bioorg. Med. Chem. Lett. 18 (2008) 432-435.
[22] K. Paul, A. Sharma, V. Luxami, Synthesis and in vitro antitumor evaluation of primary
amine substituted quinazoline linked benzimidazole, Bioorg. Med. Chem. Lett. 24 (2014) 624-
629.
[23] T.D. Penning, G.D. Zhu, V.B. Gandhi, J.C. Gong, S. Thomas, W. Lubisch, R. Grandel,
W. Wernet, C.H. Park, E.H. Fry, X.S. Liu, Y. Shi, V. Klinghofer, E.F. Johnson, C.K.
Donawho, D.J. Frost, V. Bontcheva-Diaz, J.J. Bouska, A.M. Olson, K.C. Marsh, Y. Luo, S.H.
Rosenberg, V.L. Giranda, Discovery and SAR of 2-(1-propylpiperidin-4-yl)-1H-
benzimidazole-4-carboxamide: A potent inhibitor of poly(ADP-ribose) polymerase (PARP)
for the treatment of cancer, Bioorg. Med. Chem. 16 (2008) 6965.
[24] M. Maçzyński, J. Artym, M. Kocięba, I. Kochanowska, S. Ryng, M. Zimecki, Anti-
inflammatory properties of an isoxazole derivative - MZO-2, Pharmacol. Rep. 68 (2016) 894-
902.
[25] R. Beniwal, A. Kapoor, Design, synthesis, characterization and antimicrobial evaluation
of isoxazole derivatives, Der Pharmacia Lett. 8 (2016) 47-54.
15

ACCEPTED MANUSCRIPT
[26] A. Kamal, J.S. Reddy, M. Janaki Ramaiah, D. Dastagiri, E. Vijaya Bharathi, M.
Ameruddin Azhar, F. Sultana, S.N.C.V.L. Pushpavalli, M. Pal-Bhadra, A. Juvekar, S. Sen, S.
Zingde, Design, synthesis and biological evaluation of 3,5-diaryl-isoxazoline/isoxazole-
pyrrolobenzodiazepine conjugates as potential anticancer agents, Eur. J. Med. Chem. 45
(2010) 3924-3937.
[27] G. Stork, S. Danishefsky, M. Ohashi, The Isoxazole Annelation Reaction. A Method for
the Construction of Cyclohexenone Rings in Polycyclic Systems, J. Am. Chem. Soc. 89
(1967) 5459-5460.
[28] P.G. Braldi, A. Barco, S. Benetti, S. Manfredini, D. Simoni, Ring Cleavage of 3,5-
Disubstituted 2-Isoxazolines by Molybdenum Hexacarbonyl and Water to β-Hydroxy
Ketones, Synthesis (1987) 276-278.
[29] A. Rossi, A. Hunger, J. Kebrle, K. Hoffmann, Benzimidazol-Derivate und verwandte
Heterocyclen VI Die Kondensation von o-Phenylendiamin mit aliphatischen und alicyclischen
P-Ketoestern, Helv. Chim. Acta 43 (1960) 1298-1313.
[30] G.A. Lee, A Simplified Synthesis of Unsaturated Nirtogen Heterocycles using Nitrile
Betaines, Synthesis (1982) 508-509.
[31] K.C. Liu, B.R. Shelton, R.K. Howe, A Particularly Convenient Preparation of
Benzohydroximinoyl Chlorides (Nitrile Oxide Precursors), J. Org. Chem. 45 (1980) 3916-
3918.
[32] D. Chiarino, M. Napoletano, A. Sala, 1,3-Dipolar Cycloaddition Synthesis of 3-Bromo-
5-Substituted Isoxazoles, Useful Intermediates for the Preparation of Pharmacologically
Active Compounds, J. Heterocyclic Chem. 24 (1987) 43-46.
[33] H.D. Camara, K. Attar, M. Benchidmi, E.M. Essassi, B. Garriques, Synthesis of new 1-
hydroxyindole derivatives, Indian, J. Chem. 43B (2004) 660-666.
[34] G.M. Sheldrick, Shelxs-97, Program for the solution of crystal structures, University of
Gӧttingen, Germany, 1990.
[35] G.M. Sheldrick, Shelxl-97, Program for crystal structure determination, University of
Göttingen, Germany, 1997.
[36] L.J. Farrugia, WINGX-version 1.70.01, single crystal X-ray diffraction data (1997-2005).
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HIGHLIGHTS
• A simple strategy to prepare efficiently isoxazolyl (isoxazolinyl)benzimidazolones
• The nitrile oxides with propargylbenzimidazolone affords isoxazolylbenzimidazolones
• The nitrile oxides with allylbenzimidazolone affords isoxazolinylbenzimidazolones
• These 1,3-dipolar cycloaddition reactions are completely regio- and chemoselective