Synthesis of Novel Structurally Diverse N-Mono- and N,N′-Disubstituted Benzimidazol-2-one Derivatives by the Alkylations of 1,3-Dihydro-2H-benzimidazol-2-one with Some Alkyl Halides under Transfer Catalysis Conditions

Article abstract of DOI:10.1002/jhet.3289

A series of N-mono- and N,N′-disubstituted benzimidazol-2-one derivatives optionally substituted on both secondary amine functionalities were prepared with excellent yields by reacting 1,3-dihydro-2H-benzimidazol-2-one in one and two steps respectively with various alkyl halides under phase transfer catalytic conditions. One of the synthesized N,N-disubstituted benzimidazol-2-one derivatives underwent a regiospecific 1,3-dipolar cycloaddition reaction at its side allyl substituent with the in situ generated 4-chloro benzonitrile N-oxide from 4-chlorobenzaldoxime to afford in good yield the corresponding N,N′-disubstituted derivative incorporating the 2,5-dihydro-isoxazole nucleus in one of the side chain. All the new compounds were fully characterized by their physical and spectroscopic data.

Full text of DOI:10.1002/jhet.3289

Month 2018
Synthesis of Novel Structurally Diverse N-Mono- and N,N0-Disubstituted
Benzimidazol-2-one Derivatives by the Alkylations of 1,3-Dihydro-2H-
benzimidazol-2-one with Some Alkyl Halides under Transfer Catalysis
Conditions
a
b
*
*
and Emmanuel Sopbué Fondjo
Taoufik Rohand
aLaboratory of Analytical and Molecular Chemistry, Faculty Polydisciplinaire of Safi, University Cadi ayyad Marrakech,
Route Sidi Bouzid BP 4162, Safi 46000, Morocco
bLaboratory of Applied Synthetic Organic Chemistry, Faculty of Sciences, University of Dschang, P.O. Box 067,
Dschang, Cameroon
*E-mail: trohand@hotmail.com; sopbue@yahoo.fr
Received July 12, 2017
DOI 10.1002/jhet.3289
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of N-mono- and N,N0-disubstituted benzimidazol-2-one derivatives optionally substituted on both
secondary amine functionalities were prepared with excellent yields by reacting 1,3-dihydro-2H-
benzimidazol-2-one in one and two steps respectively with various alkyl halides under phase transfer
catalytic conditions. One of the synthesized N,N-disubstituted benzimidazol-2-one derivatives
underwent a regiospecific 1,3-dipolar cycloaddition reaction at its side allyl substituent with the in situ
generated 4-chloro benzonitrile N-oxide from 4-chlorobenzaldoxime to afford in good yield the correspond-
ing N,N0-disubstituted derivative incorporating the 2,5-dihydro-isoxazole nucleus in one of the side chain.
All the new compounds were fully characterized by their physical and spectroscopic data.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
The development of new synthetic methods of
heterocyclic compounds in solution and in solid phase
[12] is a fast-growing field of combinatory chemistry.
The benzimidazole nucleus is a substrucrture [13] that
can be found in many pharmaceutical agents possessing
a large spectrum of biological properties [14]. These
include antiviral, anti-ulcerous, antihypertensive, and
anticancer agents [12,15–17].
Despite the existence of many methods for the
preparation of benzimidazoles [18], there is a real need to
designing new synthetic procedures that are simple,
reliable, cost effective, and eco-friendly.
In this work, the reactivity of the two nitrogen atoms of
benimidazol-2-one toward alkylation with various alkyl
halides including benzyle chloride, allyl bromide, n-octyl
bromide, n-nonyl bromide, n-dodecyl bromide, and
propargyle bromide was investigated under phase transfer
catalytic (PTC) conditions. The 1,3-dipolar cycloaddition
The chemistry of macrocyclic compounds have attracted
much attention during the past few decades, and because of
the search for new complexing agents, molecular receptors
are able to bind efficiently and selectively charged (ionic)
species. Moreover, the high rate at which resistant strains of
parasites are developing makes it urgent to search for newer
drugs with better therapeutic profile. Among the broad
range of templates, benzimidazoles scaffolds represent a
class of promising molecules as leading structures for the
discovery of novel synthetic drugs. Investigations on the
benzimidazole derivatives have led to the findings of new
commercial drugs such as Omeprazole [1] and Pimobendan
[2]. In particular, drugs incorporating the Benzimidazol-2-
one moiety including Domperidone [3–5], Milenperone
[6–8], Declenperone [8], Benperidol [8], Neflumozide
[9,10], and Benzitramide [11] are widely used.
© 2018 Wiley Periodicals, Inc.

T. Rohand and E. Sopbué Fondjo
Vol 000
reaction of the side allyl substituent of one of the N,N0-
disubstituted benzamidazol-2-one derivatives with 4-
chlorobenzaldehyde oxime was equally studied.
there are two types of phase transfer catalytic conditions:
the liquid/liquid and the solid/liquid. In the first case, the
base is sodium hydroxide in solution in an aprotic solvent
such as dichloromethane, benzene, or toluene. In the
second case, a less stronger base such as potassium
carbonate is used in solution in DMF, in the presence of
a catalyst such as tetra n-butylammonium bromide
(TBAB). The salt is insoluble in the organic solvent in
which the phase transfer catalyst (TBAB) is dissolved.
Alkylations with alkyl halides have been extensively
investigated in the literature [19,20]. Diversely N-
alkylated benzimidazol derivatives have been the focus
of intensive investigations aiming at generating
combinatorial libraries and contributing to the worldwide
drug discovery efforts [21–24].
In the light of the previous findings, we reacted
compound 4 with benzyle chloride in the heterogeneous
liquid–solid phase transfer catalytic conditions, whereby
DMF was used as solvent and K2CO3 as the base. The
crude reaction product obtained consisted of a mixture
of the N-monobenzylated (5a) and N,N0-dibenzylated
(6a) derivatives, which were readily separated by
silica gel column chromatography. When subjected to
the same alkylating conditions, compound 5a was
successfully converted in to 6a. All the other diversely
alkylated derivatives 5b–e and 6b–d (Scheme 2) were
respectively prepared by N-alkylating compound 4 or
the corresponding primarily synthesized precursors 5
with the appropriate alkyl bromide in similar reaction
conditions.
RESULTS AND DISCUSSION
Benzimidazolon-2-one substrate used in the
alkylating reactions was synthesized by condensing
orthophenylenediamine with ethyl chloroformate in
refluxing pyridine for 24 h (Scheme 1).
1,3-Dihydro-2H-benzimidazolon-2-one possesses two
secondary amine functionalities likely to be alkylated.
The classical alkylation techniques require the use of
strong bases such as sodium or potassium alcoholates,
sodium amide in liquid ammonia or in N,N-dimethyl
formamide. Alternatively, weak bases such as potassium
carbonate in acetone can be used [12]. However, these
techniques have some drawbacks: They are costly, the
reactions are slow, and the reaction products are difficult
to purify. To overcome these disadvantages, the
alkylation technique under heterogeneous phase transfer
catalytic conditions [13] has hitherto been reported to be
a
more efficient, cost-effective, and environmental
friendly alternative.
From a synthetic point of view, this technique has many
advantages, namely, the requirement of less energy
(reactions proceed at room temperature), the
improvement of the yields, and the simpleness of the
reactions’ logistic. According to the nature of the base,
Scheme 1. Reactions sequences to 1,3-dihydro-2H-benzimidazolon-2-one (4).
Scheme 2. Reactions sequences to the mono-N-alkylated benzimidazolone derivatives (5a–e) and N,N0-dialkylated benzimidazolone derivatives (6a–e).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis of Novel Structurally Diverse N-Mono- and N,N0-Disubstituted
Benzimidazol-2-one Derivatives by the Alkylations of 1,3-Dihydro-2H-
benzimidazol-2-one with Some Alkyl Halides under Transfer Catalysis Conditions
Month 2018
The treatment of compound 6b with 4-chlorobenzaldoxime
in the presence of sodium hypochlorite (NaOCl) gave after the
appropriate work-up and purification, a compound to which
structure 6e (Scheme 3) was assigned on the basis of the
available spectroscopic data.
EXPERIMENTAL
Uncorrected melting points were measured with a Buchi
apparatus. The NMR spectra where recorded on a Brucker
AC300- instrument. The chemical shifts are given in parts
per million (ppm) with reference to tetramethylsilane
(TMS) used as internal reference, with a precision of 0.1
The transformation of 4-chlorobenzaldoxime to 4-chloro-
benzonitrile N-oxide is essentially a dehydrogenation
process. Different procedures of this dehydrogenation are
thoroughly discussed in the literature [25–29]. It is only
necessary to note here that the process is carried out
mainly as halogenation dehydrohalogenation. The
intermediate hydroximoyl chloride is frequently not isolated
(Scheme 3). Two mechanistic alternatives consecutive to the
“head-to-head” and the “head-to-tail” interactions between
compound 6b and 4-chloro-benzonitrile N-oxide are
envisageable. The 1,3-dipolar cycloaddition leading to
compound 6e in which the imine form of the isoxazole
nucleus is predominant in comparison with the enamine
form is however the most plausible.
1
for the 13C-NMR and 0.05 for the H-NMR. The mass
spectra were recorded on a Nermag R10-10C instrument.
1,3-Dihydro-2H-benzimidazol-2-one (4). In a two-necked
round-bottom flask fitted with
a dropping cylinder
(containing ethyl chloroformate) was dissolved 4 g
(0.037 mol) of o-phenylenediamine (1) in pyridine (30 mL).
To the vigorously stirred and ice-cooled (0°C) solution was
added dropwise 1.2 g (4.123 mL) of ethyl chloroformate
over a 20-min period, and the reaction mixture was refluxed
for 24 h. The solvent was then evaporated to dryness under
reduced pressure, and the resulted residue was purified by
silica gel column chromatography using ethyl acetate/
petroleum ether (1:2) as eluent to afford a product that was
crystallized from dichloromethane to give 3.32 g (83%) of
compound 4 as white crystals; mp: 300–302°C; Rf: 0.46
from Petroleum ether/ethyl acetate (2:1); 1H NMR (DMSO-
d6, 400 MHz): δ 6.92 (m, 4H), 10.2 (s, 2H); IR (KBr): νmax
The alternative structure 6e’, which would result from
the “head-to-tail” attack, was readily ruled out of
1
consideration on the basis of H- and 13C-NMR spectral
evidences. In fact, besides the 13 aromatic protons
observed around δH ppm 7.56 (dd, J = 8.6, J’ = 1.2 Hz,
2H), 7.56 (dd, J = 8.6, J’ = 1.2 Hz, 2H), 7.30 (m, 5H,
aromatic), and 7.07–6.97 (m, 4H, aromatic) because of
the three aromatic rings, three groups of multiplets could
be found around 5.17–5.13, 4.19–4.15, and 3.44 ppm.
They were respectively assigned to the two methylene
groups attached to the nitrogen atoms, the methylene of
the isoxazole ring, and the hydrogen atom carried by the
tertiary carbon atom of the isoxazole ring. The
corresponding signals of the previous carbons were found
in the 13C-NMR spectrum and readily assigned. These
spectral evidences clearly confirmed the regioselectivity
of the previous 1,3-dipolar cycloaddition mechanism
(Scheme 3). The structures of all the new compounds
were assigned on the basis of the available physical and
spectroscopic data.
;
3016, 1755, 1629, 1483 cmꢀ1 13C NMR (CDCl3,
100 MHz): δ121, 124.6, 129.9, 155.2; ESI-MS: m/z (rel.
abund.%) 135.2 (M+, 100).
Preparation of compounds 5a and 6a. In a two-necked
round-bottom flask fitted with a dropping cylinder
(containing benzyl bromide) was dissolved 1.2
g
(0.34 mol) of benzimidazolone 4, 1.47 g (0.01 mol) of
K2CO3 in DMF (30 mL). The mixture was stirred over
5 min after what, 0.01 g of TBAB was added and 1.36 g
of benzyl bromide was subsequently added dropwise to
the vigorously magnetic stirred mixture. The mixture was
then further stirred at room temperature for 24 h. The
precipitating salts were filtered, and the DMF was
evaporated under reduced pressure to afford a residue that
was dissolved in dichloromethane, washed three times
Scheme 3. In situ generation of 4-chloro-benzonitrile N-oxide and the two mechanistic alternatives of its 1,3-dipolar cycloaddition with compound 6b.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

T. Rohand and E. Sopbué Fondjo
Vol 000
with distilled water to remove all traces of salts. The
combined organic fractions were dried with Na2SO4.
After filtration, dichloromethane was evaporated and the
resulted crude material consisting of two different
substances (analytical TLC) was purified by silica gel
column chromatography using ethyl acetate/hexane (1:2)
as eluent to afford two different crude products that were
crystallized from dichloromethane to give respectively
0.8 g (67%) of compound 6a as white crystals and
0.372 g (31%) of compound 5a as white crystals.
Compound 5a could be subsequently alkylated to
compound 6a by applying the same protocol.
7.28–7.00 (4H, m, Ar-H); 3.91(2H, t, J = 7.5 Hz, CH2);
1.84–1.75 (2H, m, CH2); 1.43–1.28 (10H, m, CH2); 0.88
(3H, t, J = 6.3 Hz, CH3). 13C-NMR (CDCl3, 100 MHz): δC
ppm 155.93 (C=O); 130.36, 128.18 (quaternary C-atoms);
121.34, 121.10, 109.79, 107.85 (arom. CH); 40.92, 31.78,
29.27, 29.18, 28.44, 26.88, 22.61 (CH2); 14.06(CH3).
ESI-MS: m/z (rel. abund.%) 434 (100).
1-Nonyl-1,3-dihydro-2H-benzimidazol-2-one (5c).
In a
two-necked round-bottom flask fitted with a dropping
cylinder (containing nonan-1-yl bromide) was dissolved
1.2 g (0.09 mol) of benzimidazolone 4, 2.47 g of K2CO3
in DMF (20 mL). The mixture was stirred over 5 min
after what, 0.001 g of TBAB was added and 2 g (3
equivalents) of nonan-1-yl bromide was subsequently
added dropwise to the vigorously magnetic stirred
mixture. The mixture was then further stirred at ambient
temperature for 12 h. The precipitating salts were filtered,
and the DMF was evaporated under reduced pressure to
afford a residue that was dissolved in dichloromethane,
washed three times with distilled water to remove all
traces of salts. The combined organic fractions were dried
with Na2SO4. After filtration, dichloromethane was
evaporated and the resulted crude material was purified
by silica gel column chromatography using ethyl
acetate/petroleum ether (1:2) as eluent to afford a crude
product that was crystallized from dichloromethane to
give (0.852 g, 71%) of compound 5c as white crystals.
mp: 180–182°C; Rf: 0.31 from petroleum ether/ethyl
acetate (2:1); 1H-NMR (CDCl3, 400 MHz): δH ppm
10.54 (1H, s, NH), 7.28–7.00 (4H, m, Ar-H); 3.91 (2H, t,
J = 7.2 Hz, CH2); 1.82–1.71 (2H, m, CH2); 1.50–1.00
(12H, m, CH2); 0.90 (t, 3H, J = 4.5 Hz, CH3). 13C-NMR
(CDCl3, 100 MHz): δC ppm 155.89 (C=O); 130.36,
128.16 (quaternary C-atoms); 130.90, 128.84, 109.77,
107.85 (Arom. CH); 65.57 (CH2); 40.92, 31.83, 30.58,
29.47, 29.31, 29.23, 28.44, 26.88, 22.64, 19.19 (CH2);
1-Benzyl-1,3-dihydro-2H-benzimidazol-2-one (5a).
mp:
197–200°C; Rf: 0.442 from hexane/ethyl acetate (2:1);
IR: νmax cmꢀ1 (KBr) 3043, 2946, 1705, 1494, 1435,
1398, 1246, 1121, 1003, 731; 1H-NMR (CDCl3,
500 MHz): δH ppm = 7.34–7.29 (m, 4H), 7.27–7.25 (m,
1H), 7.09–7.06 (m, 1H), 7.02–6.97 (m, 2H), 6.87 (d,
J = 7.5 Hz, 1H), 5.08 (s, 2H). 13C-NMR (CDCl3,
125 MHz): δC ppm = 154.7, 136.5, 130.2, 129.3, 128.8,
127.8, 127.6, 121.4, 121.3, 108.3, 107.5, 45.0. ESI-MS:
m/z (rel. abund.%) 225 (100).
1,3-Dibenzyl-1,3-dihydro-2H-benzimidazol-2-one (6a).
mp: 166–168°C; Rf: 0.785 from hexane/ethyl acetate
(2:1); IR (KBr): νmax cmꢀ1 3025, 2926, 1691, 1489,
1436, 1407, 1356, 1164, 750, 696, 659; 1H-NMR
(CDCl3, 400 MHz): δH ppm 7.41–7.26 (m, 10H, Ar-H);
7.01–6.97 (m, 2H, Ar-H); 6.95–6.90 (m, 2H, Ar-H);
5.15–5.4 (s, 4H, CH2). 13C-NMR (CDCl3, 100 MHz): δC
ppm 154.68 (C=O); 136.39, 129.27 (quaternary
C-atoms); 128.85, 127.54, 121.57, 108.53 (arom. CH).
45.01 (CH2). ESI-MS: m/z (rel. abund.%) 315 (100).
1-Octyl-1,3-dihydro-2H-benzimidazol-2-one (5b).
In a
two-necked round-bottom flask fitted with a dropping
cylinder (containing octan-1-yl bromide) was dissolved
0.2 g (0.0015 mol) of benzimidazolone 4, 0.25 g (1.2
equivalent) of K2CO3 in DMF (20 mL). The mixture was
stirred over 5 min after what, 0.001 g of TBAB was added
and 0.53 g (0.9 equivalent) of octan-1-yl bromide was
subsequently added dropwise to the vigorously magnetic
stirred mixture. The mixture was then further stirred at
ambient temperature for 12 h. The precipitating salts were
filtered, and the DMF was evaporated under reduced
pressure to afford a residue that was dissolved in
dichloromethane, washed three times with distilled water to
remove all traces of salts. The combined organic fractions
were dried with Na2SO4. After filtration, dichloromethane
was evaporated and the resulted crude material was purified
by silica gel column chromatography using ethyl
acetate/petroleum ether (1:2) as eluent to afford a crude
product that was crystallized from dichloromethane to give
(0.134 g, 67%) of compound 5b as white crystals. mp:
280°C; Rf: 0.57 from petroleum ether/ethyl acetate (2:1);
1H-NMR (CDCl3, 400 MHz): δH ppm 10.61 (1H, s, NH);
14.08 (CH3). ESI-MS: m/z (rel. abund.%) 260 (100).
1-Dodecyl-1,3-dihydro-2H-benzimidazol-2-one (5d). In a
two-necked round-bottom flask fitted with a dropping
cylinder (containing dodecan-1-yl bromide) was
dissolved 0.2 g (0.0015 mol) of benzimidazolone 4,
0.27 g (1.2 equivalent) of K2CO3 in DMF (20 mL). The
mixture was stirred over 5 min after what, 0.01 g of
TBAB was added and 0.31 mL (0.46 g, 0.9 equivalent)
of dodecan-1-yl bromide was subsequently added
dropwise to the vigorously magnetic stirred mixture. The
mixture was then further stirred at ambient temperature
for 12 h. The precipitating salts were filtered, and the
DMF was evaporated under reduced pressure to afford a
residue that was dissolved in dichloromethane, washed
three times with distilled water to remove all traces of
salts. The combined organic fractions were dried with
Na2SO4. After filtration, dichloromethane was evaporated
and the resulted crude material was purified by silica gel
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis of Novel Structurally Diverse N-Mono- and N,N0-Disubstituted
Benzimidazol-2-one Derivatives by the Alkylations of 1,3-Dihydro-2H-
benzimidazol-2-one with Some Alkyl Halides under Transfer Catalysis Conditions
Month 2018
column chromatography using ethyl acetate/petroleum
ether (1:2) as eluent to afford a crude product that was
crystallized from dichloromethane to give 0.118 g (59%)
of compound 5d as white crystals. mp: 280°C; Rf: 0.67
from petroleum ether/ethyl acetate (2:1); 1H-NMR
(CDCl3, 400 MHz): δH ppm 10.39 (1H, s, NH);
7.28–7.00 (4H, m, Ar-H); 3.90 (2H, t, J = 7.5 Hz, CH2);
1.84–1.74 (2H, m, CH2); 1.37–1.26 (18H, m, CH2); 0.89
(3H, t, J = 6.3 Hz, CH3). 13C-NMR (CDCl3, 100 MHz):
δC ppm 155.82 (C=O); 130.36, 128.11 (quaternary
C-atoms), 121.35, 121.14, 109.75, 107.87 (Arom. CH);
40.94, 31.91, 29.62, 29.61, 29.58, 29.51, 29.33, 29.31,
28.44, 26.88, 22.68 (CH2); 14.11 (CH3). ESI-MS: m/z
precipitating salts were filtered, and the DMF was
evaporated under reduced pressure to afford a residue that
was dissolved in dichloromethane, washed three times
with distilled water to remove all traces of salts. The
combined organic fractions were dried with Na2SO4.
After filtration, dichloromethane was evaporated and the
resulted crude material was purified by silica gel column
chromatography using ethyl acetate/hexane (1:2) as
eluent to afford a crude product that was crystallized
from dichloromethane to give (0.176 g, (84%) of
compound 6c as white crystals. mp: 205–207°C; Rf: 0.67
petroleum ether/ethyl acetate (2:1); 1H-NMR (CDCl3,
400 MHz): δH ppm 7.20–6.99 (m,4H, Ar-H); 4.69 (2H,
d, J = 2.7 Hz, CH2); 3.88 (2H, m, CH2); 2.30 (1H, t,
(rel. abund.%) 434 (100).
1-Benzyl-3-(prop-2-en-1-yl)-1,3-dihydro-2H-benzimidazol-2-
one (6b). In a two-necked round-bottom flask fitted with
J = 2.4 Hz, ≡CH); 1.80–1.70 (2H, m, CH ); 1.34–1.26
2
(12H, m, CH ); 0.88 (3H, t, J = 6.3 Hz, CH3). 13C-NMR
2
a dropping cylinder (containing allyl bromide) was
dissolved (0.487 g, 0.0021 mol) of 1-benzyl-1H-benzo
[d]imidazol-2(3H)-one (5a), 0.58 g (1.2 equivalent) of
K2CO3 in DMF (20 mL). The mixture was stirred over
5 min after what, 0.07 g of TBAB was added and
0.22 mL (two equivalents) of allyl bromide was
subsequently added dropwise to the vigorously magnetic
stirred mixture. The mixture was then heated to reflux for
48 h. The precipitating salts were filtered, and the DMF
was evaporated under reduced pressure to afford a
residue that was dissolved in dichloromethane, washed
three times with distilled water to remove all traces of
salts. The combined organic fractions were and dried
with Na2SO4. After filtration, dichloromethane was
evaporated and the resulted crude material was purified
by silica gel column chromatography using ethyl
acetate/hexane (1:2) as eluent to afford a crude product
that was crystallized from dichloromethane to give
compound 6b as white crystals. mp: 150–151°C; Rf:
0.42; 1H-NMR (CDCl3, 400 MHz): δH ppm 7.33–7.25
(m, 5H, Ar-H); 7.07–6.87 (m, Ar-H); 5.95 (m, 1H,
CH=C), 5.27 (m, CH2 = C); 5.1 (S, -CH2-N); 4.65–4.58
(dt, N-CH2-CH). 13C-NMR (CDCl3, 100 MHz): δC ppm
171.098 (C=O); 136.29, (Cq Ar-C-CH2-), 132.01
(C=CH-N), 129.35–129.21 (C-N), 129.2–127.45 (Ar-
CH); 117.59 (=CH2), 65.228 (N-CH2-); 29.62, 29.61,
29.58, 29.51, 29.33, 29.31, 28.44, 26.88, 22.68 (-CH2-);
(CDCl3, 100 MHz): δC ppm 155–169 (C = 0); 130.39,
129.55, 128.45, 128.22 (quaternary C-atoms); 130.88,
128.83, 121.61, 121.26, 121.17, 121.04, 109.69, 108.41,
107.79 (Arom.CH) 72.65, 65.53, 41.37, 40.87, 31.82,
30.42, 29.46, 29.42, 29.30, 29.27, 29.22, 28.43, 28.39,
26.86 (-CH2-); 26.84 (CH3). ESI-MS: m/z (rel. abund.%)
298(100).
1,3-Di(prop-2-yn-1-yl)-1,3-dihydro-2H-benzimidazol-2-one
(6d). In a two-necked round-bottom flask fitted with a
dropping cylinder (containing propargyl bromide) was
dissolved 0.4 g (0.003 mol) of benzimidazolone 4, 0.37 g
(2.4 equivalent) of K2CO3 in DMF (20 mL). The mixture
was stirred over 5 min after what, 0.072 g (0.2
equivalent) of TBAB was added and 0.2 mL (2
equivalents) of propargyl bromide was subsequently
added dropwise to the vigorously magnetic stirred
mixture. The mixture was then further stirred and heated
to reflux for 48 h. The precipitating salts were filtered,
and the DMF was evaporated under reduced pressure to
afford a residue that was dissolved in dichloromethane,
washed three times with distilled water to remove all
traces of salts. The combined organic fractions were dried
with Na2SO4. After filtration, dichloromethane was
evaporated and the resulted crude material was purified
by silica gel column chromatography using ethyl
acetate/hexane (1:2) as eluent to afford a crude product
that was crystallized from dichloromethane to give
(0.244 g and 61% of compound 6d as white crystals; mp:
121–123°C; Rf: 0.41from petroleum ether/ethyl acetate
14.11 (CH3). ESI-MS: m/z (rel. abund.%) 264(100).
1-Nonyl-3-(prop-2-yn-1-yl)-1,3-dihydro-2H-benzimidazol-2-
one (6c). In a two-necked round-bottom flask fitted with a
1
(2:1); H-NMR (CDCl3, 400 MHz): δH ppm 7.28–7.16
dropping cylinder (containing propargyl bromide) was
dissolved (0.21 g, 0.0015 mol) of compound 5c, 0.28 g
(1.2 equivalent) of K2CO3 in DMF (20 mL). The mixture
was stirred over 5 min after what, 0.072 g of TBAB was
added and 0.15 mL (two equivalent) of propargyl
bromide was subsequently added dropwise to the
vigorously magnetic stirred mixture. The mixture was
then further stirred at ambient temperature for 6 h. The
(4H, m, Ar-H); 4.7 (S, CH2-N); 2.31 (S, ≡CH). ESI-MS:
m/z (rel. abund.%) 210 (100).
1-Benzyl-3-[3-(4-chlorophenyl)-4,5-dihydro-1,2-oxazol-5-yl]-
1,3-dihydro-2H-benzimidazol-2-one (6e). In a two-necked
round-bottom flask fitted with a dropping cylinder
(containing 7.5 mL NaOCl) were dissolved (0.48 g,
00018 mol) of compound 6b and 0.35 g (1.2 equivalent)
of 4-chlorobenzaldoxime in 160 mL of chloroform. The
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

T. Rohand and E. Sopbué Fondjo
Vol 000
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mixture was cooled to ꢀ5 to 0°C in an ice-NaCl bath. To
the mixture was added dropwise under vigorous magnetic
stirring 7.5 mL of NaOCl. The reaction was carried out
for 5 h. The resulted mixture was extracted with
dichloromethane, and the organic layer was dried with
Na2SO4. After removing the solvent by evaporation
under reduced pressure, the crude product was purified
by silica gel column chromatography using hexane/ethyl
acetate (2:1) as eluent to afford a white powder that was
crystallized from dichloromethane to give (0.259 g, 54%)
of compound 6e as white crystals. mp: 144–146°C; Rf:
0.72 (ethyl acetate/hexane 1:2); 1H NMR (CDCl3,
400 MHz): δH ppm 7.57–7.55 (dd, J = 8.6, J’ = 1.2, 2H),
7.54–7.52 (dd, J = 8.6, J’ = 1.2, 2H), 7.35–7.25 (m, 5H,
aromatic), 7.07–6.87 (m, 4H, aromatic), 5.17 (broad
singlet, 1H, NH,), 5.13 (s, 1H), 4.19 (S, 2H, -CH2-N),
4.15 (S, 2H, -CH2-N), 3.44 (s, 2H, -CH2-). 13C-NMR
(CDCl3, 100 MHz): δC ppm 171.098 (C=O); 155 (C-Cl);
136.29 (Cq Ar-C-CH2), 132.01(C=CH-N), 129.35–
129.21 (C-N), 129.2–127.45 (arom-CH); 117.59 (arom-
CH), 65.228 (N-CH2-), 62.228 (N-CH2-), 61.228, 29.62,
29.58, 29.51, 29.33, 29.31, 28.44, 26.88, 22.68 (-CH2-).
ESI-MS: m/z (rel. abund.%) 417(100).
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CONCLUSIONS
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In summary, a simple, efficient, selective, and eco-friendly
method for the preparation of diversely substituted mono-N-
and N,N0-dialkylated benzimidazolone derivatives from 1,3-
dihydro-2H-benzimidazolon-2-one and various alkyl halides
under phase transfer catalysis was reported. Further studies
are on-going with the aim to establish a more rational and
generalizable protocol for the alkylation of the secondary
amine functionalities of 1,3-dihydro-2H-benzimidazolon-2-
one under PTC. Investigations toward the construction of
hybrid polycyclic molecular architectures incorporating
isoxazole or other potential heteroaromatic pharmacophores
from substrate 4 are on the way.
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Acknowledgments. Prof. Dr. Taoufik Rohand thanks the
University Cadi Ayyad and specially the Faculty
Polydisciplinaire of Safi for the profesoralship. Prof. Dr.
Emmanuel Sopbué Fondjo thanks the research grants committee
of both the Ministry of Higher Education of the Republic of
Cameroon and the University of Dschang for financial supports.
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
REFERENCES AND NOTES
[1] Melnichouk, S.; Friendship, R. M.; Dewey, C. E.; Bildfell, R.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet