Efficient microwave-assisted synthesis of new sulfonylbenzimidazole-4,7- diones: Heterocyclic quinones with potential antitumor activity

Article abstract of DOI:10.1016/j.tet.2004.07.070

New benzimidazoloquinones substituted at 2-position by a sulfonyl group have been synthesized via a final microwave assisted step using 2-chloromethyl-1,5,6-trimethylbenzimidazole-4,7-dione 7 as starting material.

Full text of DOI:10.1016/j.tet.2004.07.070

Tetrahedron 60 (2004) 9131–9137
Efficient microwave-assisted synthesis of new
sulfonylbenzimidazole-4,7-diones: heterocyclic quinones with
potential antitumor activity
*
` ´
Narimene Boufatah, Armand Gellis, Jose Maldonado and Patrice Vanelle
´ ´ ´ ´
Laboratoire de Chimie Organique Pharmaceutique, LCOP-UMR CNRS 6517, Faculte de Pharmacie, Universite de la Mediterranee,
27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France
Received 24 May 2004; revised 19 July 2004; accepted 27 July 2004
Available online 28 August 2004
Abstract—New benzimidazoloquinones substituted at 2-position by a sulfonyl group have been synthesized via a final microwave assisted
step using 2-chloromethyl-1,5,6-trimethylbenzimidazole-4,7-dione 7 as starting material.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
A great number of heterocyclic quinones have been
extensively investigated for their biological activity and
especially for their noticeable antitumor activity. Mito-
mycins1–4 and the corresponding mitosenes (such as EO95
and many indole analogues6) are well-known examples of
reductive alkylating quinones (Scheme 1). The reductive
alkylation process involves the formation of an alkylating
quinone methide species upon reduction of the quinone and
elimination of the leaving group.7 Pyrrolo[1,2-a]benz-
imidazoles (PBI) represent a new class of antitumor agent
exhibiting cytotoxic activity against a variety of cancer cell
lines. Significant biological properties also appear in some
benzimidazolediones.8,9 5-Amino-6-bromobenzimidazole-
4,7-dione shows good antitumor activity in vivo on P388
leukemia.10 Furthermore, arylsulfone derivatives are well
Scheme 1.
known for their biological properties such as antiviral11 and
antitumor12–15 effects.
involve sensitive reagents or when products may decompose
under prolonged reaction conditions. The possibilities
On the other hand, microwave irradiation is extensively
offered by this technology are particularly attractive for
used for the rapid synthesis of a variety of heterocyclic
multi-step synthesis26–28 and drug discovery process where
high yielding protocols and avoidance or ease of purification
are highly desirable.
compounds.16–21 The beneficial effects of microwave
irradiation are finding an increased role in process
chemistry, especially when conventional methods require
forcing conditions or prolonged reaction times.22–25
In the light of the above reports and our continued interest in
the preparation of new biologically active compounds,29–32
we decided to synthesize a series of variously substituted
benzimidazole-4,7-diones in order to evaluate their anti-
proliferative activity. The aim is to develop original and
environmentally friendly procedures partially under micro-
wave irradiation, and to investigate the influence of the
Microwaves have also shown an advantage where processes
Keywords: Benzimidazole-4,7-diones; Microwave irradiation; S-Alky-
lation; Sulfones.
* Corresponding author. Tel.: C33-4-91-83-55-80; fax: C33-4-91-79-46-
77; e-mail: patrice.vanelle@pharmacie.univ-mrs.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.070

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N. Boufatah et al. / Tetrahedron 60 (2004) 9131–9137
The hydroxyl functions of the commercially available 2,3-
dimethyl-1,4-hydroquinone were protected by methylation
using dimethylsulfate in alkaline medium to give compound
1 (98% yield).37 The 1,4-dimethoxy-2,3-dimethyl-5,6-
dinitrobenzene 2 was carried out by nitration of 1,4-
dimethoxy-2,3-dimethylbenzene 1 with fuming nitric acid
in acetic anhydride, with a 90% yield compared to 18.5% by
using acetic acid (Scheme 2).38
The reduction of 2 has been described in the literature with
catalytic hydrogenation (83%),38 using Pd/C, CH3OH/HCl.
In order to simplify the procedure, several trials were
attempted to reduce the nitro groups of the 1,4-dimethoxy-
2,3-dimethyl-5,6-dinitrobenzene 2 using Zn in acetic acid
(34%), FeCl3 in hydrazine (monoreduction), NaBH4 or
TiCl3 in water-acetone (43%), but the yields obtained were
rather poor and the reduction was sometimes incomplete.
However, when the reduction was carried out using tin in
concentrated hydrochloric acid the yield of the resulting
diamine 3 was as high as 95%, and the process simplified.
Scheme 2.
Table 1. Synthesis of (4,7-dimethoxy-5,6-dimethyl-1H-benzimidazol-2-
yl)-methanol 4
Entry
Conditions
Reflux toluene, 120 h
Reflux PPA, 120 h
Reflux 4N HCl, 24 h
Reflux 4N HCl, 48 h
Reflux 4N HCl, 120 h
800 W, 100 8C, 4N HCl, 30 min
800 W, 100 8C, 4N HCl, 1 h
800 W, 100 8C, 4N HCl, 1 h 30
Yielda (%)
1
2
3
4
5
6
7
8
49
55
14
32
71
34
70
92
The hydroxymethylbenzimidazole 4 could be obtained via
the reaction of the o-diamine 3 with glycolic acid. In order
to optimize the reaction yield, several experiments were
attempted in refluxing toluene or in refluxing PPA (Table 1).
After 120 h of reaction, a portion of starting material
remained unchanged. When the cyclocondensation of 3 with
glycolic acid was performed in refluxing 4N HCl solution,
during 120 h, 4 was obtained in 71% yield (Scheme 3).
Microwave irradiation is another potential strategy to
realize this cycloaddition. The hydroxymethyl compound
4 was prepared in 92% yield from the condensation of the
o-diamine 3 with glycolic acid in typical procedure (800 W,
100 8C, 4N HCl, 1 h 30). The reaction rate was accelerated
from 120 to 1 h 30, which represents a rate increase of up to
80 times, with a simplified procedure and a higher yield
(Table 1).
a
Yield of isolated and purified product.
Scheme 3.
Two methods were tested to carry out a selective
methylation of the NH group of 4. Comparison of reaction
times for N-methylation clearly shows the advantage of the
protocol using lithium bis(trimethylsilyl)amide.39,40 Indeed,
we discovered that a more efficient conversion (85%) can be
achieved in a shorter time at a lower temperature when
method B is used (Scheme 4).
sulfonyl group at the 2-position of the benzimidazole-4,7-
dione nucleus.
2. Results and discussion
The (4,7-dimethoxy-1,5,6-trimethyl-1H-benzimidazol-2-
yl)-methanol 5 was treated with thionyl chloride to give
the corresponding chloromethyl derivative 6 in good yield
(Scheme 5).
Some benzimidazole-4,7-dione derivatives have been
previously reported in the literature.33–35 Their synthesis
was based on Day’s method.36 The (4,7-dimethoxy-5,6-
dimethyl-1H-benzimidazol-2-yl)-methanol 4 was syn-
thesized according to this procedure with significant
modifications.
In the last step, an oxidative demethylation of 6 by treatment
Scheme 4.

N. Boufatah et al. / Tetrahedron 60 (2004) 9131–9137
9133
Treating with the sodium salts of sulfinic acid derivatives
8a–j in aqueous solution gave the corresponding
S-alkylation products 9a–j in 65–78% yields. Under
conventional heating, a temperature of 80 8C was selected
for 2 h. To evaluate the purely non-thermal microwave
effects, the same temperature was applied under microwave
irradiation, in water, during 4 min (Scheme 7). The results
are summarized in Table 2. The use of microwave
irradiation led to the same products, with higher yields
(80–92%) in a shorter time (2 h to 4 min). It is evident that
the effect lies in the enhancement by microwave radiation of
nucleophilic attack by the sulfur atom on the chloromethyl
group. This effect can be easily understood by considering
the possible microwave activation affects by dipole–dipole
interactions and by an increase in the polarity of the system
during the reaction.
Scheme 5.
Scheme 6.
with cerium ammonium nitrate (CAN) gave the target
quinone 7 in good yield (Scheme 6).10
The 2-chloromethyl-1,5,6-trimethylbenzimidazole-4,7-
dione 7 served as a point of departure for the synthesis of
several new sulfonyl derivatives in benzimidazole-4,7-
dione series.
Scheme 7.
All the products obtained are to be screened for their
antitumor activity and results will subsequently be
published.
Table 2. Benzimidazole-4,7-diones derivatives 9a–j produced via Scheme
7a
Entry
1
R
Product
Yieldb (%)
87 (70)
9a
9b
9c
9d
9e
9f
3. Conclusion
2
3
4
5
6
7
82 (68)
85 (70)
81 (65)
89 (73)
90 (75)
80 (65)
We describe here an efficient route to new benzimidazole-
4,7-diones, from the intermediate 2-chloromethyl-1,5,6-
trimethylbenzimidazole-4,7-dione 7 prepared in high yield
(50%) in 7 steps. The microwave-assisted process, in
contrast to conventional heating, gives the desired com-
pounds in higher overall yield with shorter reaction times
and products that are more easily purified. The specific non-
thermal microwave effects are attributed to enhancements in
microwave-materials interaction due to polarity increase
during the reaction. This work confirms that reaction
mixtures exposed to microwaves allow an easy and rapid
access to original heterocyclic quinones with potential
antitumor activities.
9g
4. Experimental
4.1. General experimental
8
9
9h
92 (78)
Melting points were determined on Bu¨chi B-540 and are
uncorrected. Elemental analyses were performed by the
Microanalyses center of the University of Aix-Marseille 3
9i
9j
80 (65)
88 (71)
and of the INP-ENSCT (Toulouse, France). Both 1H and 13
C
NMR spectra were determined on a Bruker ARX 200
1
10
spectrometer. The H chemical shifts are reported as ppm
downfield from tetramethylsilane (Me4Si), and the 13C
chemical shifts were referenced to the solvent peak: CDCl3
(76.9 ppm). Solvents were dried by conventional methods.
The following adsorbent was used for column
a
All the reactions are performed using 3 equiv. of 8.
b
Yield of isolated and purified product, under microwave irradiation
(800 W, 4 min, 80 8C). Parentheses show yield obtained using oil-bath
heating (80 8C, 2 h).

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N. Boufatah et al. / Tetrahedron 60 (2004) 9131–9137
chromatography: silica gel 60 (Merck, particle size 0.063–
0.200 mm, 70–230 mesh ASTM). TLC were performed on
5 cm!10 cm aluminium plates coated with silica gel 60F-
254 (Merck) in an appropriate solvent.
ether–chloroform (5/5) gave 3 (95%) as a white solid; mp
112 8C (Lit., 107–110 8C);38 dH (200 MHz; CDCl3) 2.11
(6H, s, CH3), 3.43 (4H, s, NH2), 3.68 (6H, s, OCH3); dC
NMR (50 MHz; CDCl3) 11.91 (2 CH3), 59.80 (2 OCH3),
119.94 (2 C), 126.20 (2 C), 143.17 (2 C).
4.2. Microwave instrumentation
4.3.4. (4,7-Dimethoxy-5,6-dimethyl-1H-benzimidazol-2-
yl)methanol (4). Conventional conditions. To a solution of
3,6-dimethoxy-4,5-dimethylbenzene-1,2-diamine 3 (10 g,
51 mmol) in 4N HCl (100 mL) was added glycolic acid
(5.8 g, 76.3 mmol) in 4N HCl (50 mL). The reaction
mixture was refluxed for 120 h. After cooling, the mixture
was basified with 20% ammonia. The precipitate was
filtered, washed with water and dried in air. Recrystalliza-
tion from chloroform–ethanol (9/1) gave 4 (71%) as a white
solid.
Multimode reactor: ETHOS Synth Lab station (Ethos start,
Milestone Inc). The multimode microwave has a twin
magnetron (2!800 W, 2.45 GHz) with a maximum
delivered power of 1000 W in 10 W increments (pulsed
irradiation). Built-in magnetic stirring (Teflon-coated stir-
ring bar) was used in all operations. During experiments,
time, temperature and power were measured with the ‘easy
WAVE’ software package. The temperature was measured
throughout the reaction and evaluated by an infrared
detector, which indicated the surface temperature.
Microwave irradiation conditions. To a solution of 3,6-
dimethoxy-4,5-dimethylbenzene-1,2-diamine 3 (10 g,
51 mmol) in 4N HCl (100 mL) was added glycolic acid
(5.8 g, 76.3 mmol) in 4N HCl (50 mL). The reaction
mixture was irradiated in a microwave oven (Ethos start)
for 1 h 30 at a power of 800 W. After cooling, the mixture
was basified with 20% ammonia. The precipitate was
filtered, washed with water and dried in air. Recrystalliza-
tion from chloroform–ethanol (9/1) gave 4 (92%) as a white
solid; mp 163–164 8C; dH (200 MHz; CDCl3) 2.23 (6H, s,
CH3), 3.88 (6H, s, OCH3), 4.92 (2H, s, CH2); dC (50 MHz;
CDCl3) 12.33 (2 CH3), 58.00 (CH2), 61.12 (2 OCH3),
123.45 (2 C), 130.68 (2 C), 141.83 (2 C), 153.62 (C); Anal.
Calcd for C12H16N2O3: C, 61.00; H, 6.83; N, 11.86; found:
C, 60.52; H, 6.79; N, 11.71.
In order to compare microwave irradiation with conven-
tional heating, the reactions were performed under similar
experimental conditions (weight of reactants and tempera-
ture) using a thermostated oil bath. The temperature was
measured by the insertion of a Quick digital thermometer
into the reaction mixture and the rate of the temperature rise
was adjusted to be the same as measured under microwave
irradiation.
4.3. Experimental procedure
4.3.1. 1,4-Dimethoxy-2,3-dimethylbenzene (1). 2,3-
Dimethyl-1,4-hydroquinone (9.5 g, 70 mmol) was dissolved
in methanol (75 mL) containing dimethyl sulfate (75 mL).
The solution was heated and stirred vigorously, then a
solution of potassium methoxide (95 g of KOH in 475 mL
of methanol) was added quickly. The mixture was refluxed
for 1 h. The precipitate was filtered, washed with water and
dried in air. Recrystallization from methanol gave 1 (98%)
as a white solid; mp 78 8C (Lit., 76–77 8C);37 dH (200 MHz;
CDCl3) 2.16 (6H, s, 2 CH3), 3.78 (6H, s, 2 OCH3), 6.66 (2H,
s, H Ar).
4.3.5. (4,7-Dimethoxy-1,5,6-trimethyl-1H-benzimida-
zol-2-yl)methanol (5). Method A. To a solution of (4,7-
dimethoxy-5,6-dimethyl-1H-benzimidazol-2-yl)methanol 4
(10 g, 42.3 mmol) in dimethyl carbonate (100 mL) was
added dropwise DBU (1,8-diazabicyclo[5,4,0]undec-7-ene)
(6.4 g, 42.03 mmol). The reaction mixture was heated to
90 8C and stirred during 16 h. After evaporation, the residue
was dissolved in chloroform and washed with water (3!
30 mL). The organic layer was dried over magnesium
sulfate and the solvent was removed under vacuum. The
residue was dissolved in chloroform and washed with water.
Purification on silica gel eluting with ethyl acetate and
recrystallization from chloroform–ethanol (9/1) gave 5
(40%) as a white solid.
4.3.2. 1,4-Dimethoxy-2,3-dimethyl-5,6-dinitrobenzene
(2). To a solution of 1,4-dimethoxy-2,3-dimethylbenzene
1 (10 g, 60.2 mmol) in acetic anhydride (80 mL) was added
dropwise at 0 8C fuming nitric acid (15 mL). The reaction
mixture was then heated at 90 8C for 1 h, poured into
crushed ice (100 mL). The precipitate was filtered, washed
with water and dried in air. Recrystallization from ethanol
gave 2 (90%) as a yellow solid; mp 155 8C (Lit., 147–
150 8C);38 dH (200 MHz; CDCl3) 2.30 (6H, s, 2 CH3), 3.87
(6H, s, 2 OCH3); dC NMR (CDCl3) 13.53 (2 CH3), 63.10
(2 OCH3), 137.90 (2 C), 146.60 (2 C).
Method B. To a solution of (4,7-dimethoxy-5,6-dimethyl-
1H-benzimidazol-2-yl)methanol 4 (10 g, 42.3 mmol) in
THF (150 mL) was added dropwise at 0 8C under nitrogen
lithium bis(trimethyl)silyl amide (14 g, 83.66 mmol). The
reaction mixture was warmed to room temperature and
stirred for 20 min. A solution of methyl iodide (6.63 g,
46.72 mmol) in THF (10 mL) was added dropwise via a
syringe. The solution was stirred for 7 h. Water (200 mL)
was added and the mixture was extracted with ethyl acetate
(3!50 mL). The combined organic layers were dried over
magnesium sulfate and the solvent was removed under
vacuum. Purification on silica gel eluting with ethyl acetate
and recrystallization from chloroform–ethanol (9/1) gave 5
(85%) as a white solid; mp 192–193 8C; dH (200 MHz;
CDCl3) 2.16 (6H, s, CH3), 3.12 (3H, s, NCH3), 3.98 (6H, s,
4.3.3. 3,6-Dimethoxy-4,5-dimethylbenzene-1,2-diamine
(3). To a solution of tin (37 g, 312 mmol) in concentrated
HCl (100 mL), was added 1,4-dimethoxy-2,3-dimethyl-5,6-
dinitrobenzene 2 (10 g, 39 mmol). The reaction mixture was
stirred vigorously until the excess of tin disappeared. The
solution was then filtered, the precipitate was dissolved in
water (100 mL), basified with 20% ammonia and extracted
three times with chloroform (50 mL). The organic layers
were dried over magnesium sulfate and concentrated under
vacuum. Recrystallization of the residue from petroleum

N. Boufatah et al. / Tetrahedron 60 (2004) 9131–9137
9135
OCH3), 4.85 (2H, s, CH2); dC (50 MHz; CDCl3) 12.12
(CH3), 12.35 (CH3), 31.29 (NCH3), 56.92 (CH2), 61.04
(OCH3), 62.12 (OCH3), 122.13 (C), 124.80 (C), 127.92 (C),
134.08 (C), 139.83 (C), 145.05 (C), 152.51 (C). Anal. Calcd
for C13H18N2O3: C, 62.38; H, 7.25; N, 11.19; found: C,
62.31; H, 7.26; N, 11.22.
mixture was irradiated in a microwave oven (Ethos start) for
4 min at a power of 800 W. The aqueous solution was
extracted with toluene (3!20 mL). The organic extracts
were dried over anhydrous magnesium sulfate, and
evaporated under reduced pressure. The product required
was recrystallized from 2-propanol/chloroform (8:2).
4.4.1. 2-Benzenesulfonylmethyl-1,5,6-trimethyl-1H-
benzimidazole-4,7-dione (9a). Yellow solid; 87% yield;
mp 256–258 8C; dH (200 MHz; CDCl3) 2.07 (6H, s, CH3),
4.12 (3H, s, NCH3), 4.65 (2H, s, CH2); 7.51–7.73 (5H, m, H
Ar); dC (50 MHz; CDCl3) 12.17 (CH3), 12.45 (CH3), 33.30
(NCH3), 54.68 (CH2), 128.46 (2 CH), 129.40 (2 CH),
131.90 (C), 134.66 (CH), 137.65 (C), 140.31 (C), 141.04
(C), 141.90 (C), 143.19 (C), 178.66 (C), 180.47 (C). Anal.
Calcd for C17H16N2O4S: C, 59.29; H, 4.68; N, 8.13; found:
C, 59.29; H, 4.70; N, 8.13.
4.3.6. 2-Chloromethyl-4,7-dimethoxy-1,5,6-trimethyl-
1H-benzimidazole (6). To a solution of (4,7-dimethoxy-
1,5,6-trimethyl-1H-benzimidazol-2-yl)methanol 5 (10 g,
40 mmol) in chloroform (125 mL) was added dropwise
thionyl chloride (10.5 mL). The mixture was refluxed for
4 h. The excess of thionyl chloride was then evaporated
under vacuum. The residue was dissolved in chloroform and
washed with water (3!50 mL). The organic layer was dried
over magnesium sulfate. Purification of the crude product
on silica gel eluting with chloroform and recrystallization
from petroleum ether–chloroform (5/5) gave 6 (80%) as a
white solid; mp 98–99 8C; dH (200 MHz; CDCl3) 2.24 (3H,
s, CH3), 2.27 (3H, s, CH3), 3.78 (3H, s, NCH3), 4.03 (3H, s,
OCH3), 4.08 (3H, s, OCH3), 4.80 (2H, s, CH2); dC (50 MHz;
CDCl3) 12.22 (CH3), 12.44 (CH3), 31.54 (NCH3), 36.96
(CH2), 61.12 (OCH3), 62.21 (OCH3), 122.24 (C), 125.74
(C), 128.22 (C), 134.72 (C), 139.64 (C), 145.51 (C), 147.43
(C); Anal. Calcd for C13H17ClN2O2: C, 58.10; H, 6.38; N,
10.42; found: C, 58.13; H, 6.50; N, 10.40.
4.4.2. 1,5,6-Trimethyl-2-(toluene-4-sulfonylmethyl)-1H-
benzimidazole-4,7-dione (9b). Yellow solid; 82% yield;
mp 274–276 8C; dH (200 MHz; CDCl3) 2.00 (6H, s, CH3),
2.43 (3H, s, CH3), 4.13 (3H, s, NCH3), 4.62 (2H, s, CH2),
7.29–7.32 (2H, d, JZ7.9 Hz, H Ar), 7.56–7.60 (2H, d, JZ
7.9 Hz, H Ar); dC (50 MHz; CDCl3) 12.05 (CH3), 12.24
(CH3), 21.27 (CH3), 32.82 (NCH3), 53.33 (CH2), 128.32 (2
CH), 129.98 (2 CH), 131.65 (C), 135.73 (C), 139.85 (C),
140.01 (C), 140.55 (C), 143.76 (C), 145.19 (C), 178.25 (C),
180.44 (C). Anal. Calcd for C18H18N2O4S: C, 60.32; H,
5.06; N, 7.82; found: C, 60.34; H, 5.08; N, 7.80.
4.3.7. 2-Chloromethyl-1,5,6-trimethyl-1H-benzimida-
zole-4,7-dione (7). To a solution of 2-chloromethyl-4,7-
dimethoxy-1,5,6-trimethyl-1H-benzimidazole
6 (5 g,
18.6 mmol) in acetonitrile (100 mL) was added dropwise
a mixture of CAN (25.5 g, 46.5 mmol) in water (30 mL).
The reaction mixture was stirred for 3 h and the solvent was
evaporated under vacuum. The residue was dissolved in
chloroform and washed with water (3!30 mL). The
organic layer was dried over magnesium sulfate and the
solvent was removed under vacuum. Recrystallization from
2-propanol gave 7 (85%) as a yellow solid; mp 168–169 8C;
dH (200 MHz; CDCl3) 2.06 (3H, s, CH3), 2.09 (3H, s, CH3),
4.03 (3H, s, NCH3), 4.72 (2H, s, CH2); dC (50 MHz; CDCl3)
12.53 (CH3), 12.89 (CH3), 32.97 (NCH3), 35.98 (CH2),
131.92 (C), 140.63 (C), 141.02 (C), 141.54 (C), 149.55 (C),
179.30 (C), 181.12 (C); Anal. Calcd for C11H11ClN2O2: C,
55.36; H, 4.65; N, 11.74; found: C, 55.30; H, 4.61; N, 11.75.
4.4.3. 2-(4-Methoxybenzenesulfonylmethyl)-1,5,6-tri-
methyl-1H-benzimidazole-4,7-dione (9c). Yellow solid,
85% yield; mp 264–265 8C; dH (200 MHz; CDCl3) 2.00
(6H, s, CH3), 3.87 (6H, s, NCH3 and OCH3), 5.08 (2H, s,
CH2), 7.12–7.16 (2H, d, JZ8.9 Hz, H Ar), 7.69–7.73 (2H,
d, JZ8.9 Hz, H Ar); dC (50 MHz; CDCl3) 12.39 (CH3),
12.57 (CH3), 33.14 (NCH3), 53.82 (CH2), 56.36 (OCH3),
115.05 (2 CH), 130.38 (C), 130.98 (2 CH), 131.95 (C),
140.18 (C), 140.65 (C), 142.40 (C), 144.27 (C), 164.18 (C),
178.58 (C), 180.78 (C). Anal. Calcd for C18H18N2O5S: C,
57.74; H, 4.85; N, 7.48; found: C, 57.90; H, 4.80; N, 7.45.
4.4.4. 2-(4-Chlorobenzenesulfonylmethyl)-1,5,6-tri-
methyl-1H-benzimidazole-4,7-dione (9d). Yellow solid,
81% yield; mp 294–295 8C; dH (200 MHz; CDCl3) 1.98
(6H, s, CH3), 3.91 (3H, s, NCH3), 5.23 (2H, s, CH2), 7.71
(2H, d, JZ8.9 Hz, H Ar), 7.80 (2H, d, JZ8.9 Hz, H Ar); dC
(50 MHz; CDCl3) 12.25 (2 CH3), 33.93 (NCH3), 55.05
(CH2), 129.04 (2 CH), 130.42 (2 CH), 137.23 (C), 139.65
(C), 140.05 (C), 143.47 (C), 150.20 (C),153.40 (C), 154.35
(C), 178.60 (C), 180.30 (C). Anal. Calcd for C17H15ClN2-
O4S: C, 53.90; H, 3.99; N, 7.39; found: C, 53.76; H, 4.02; N,
7.35.
4.4. General procedure for the synthesis of the sulfone
derivatives (9a–j)
The sodium salts were commercially available or prepared
as previously described.41
Conventional conditions. To a solution of sodium salt of
substituted sulfinic acid (2.52 mmol) in water (50 mL) at
80 8C, was added 2-chloromethyl-1,5,6-trimethyl-1H-ben-
zimidazole-4,7-dione 7 (0.2 g, 0.84 mmol). The reaction
mixture was heated at 80 8C for 2 h and filtered. The
precipitate was dried in air, recrystallized from 2-propanol/
chloroform (8:2).
4.4.5. 2-(4-Fluorobenzenesulfonylmethyl)-1,5,6-tri-
methyl-1H-benzimidazole-4,7-dione (9e). Yellow solid,
89% yield; mp 288–290 8C; dH (200 MHz; CDCl3) 1.97
(6H, s, CH3), 3.90 (3H, s, NCH3), 5.21 (2H, s, CH2), 7.43–
7.50 (2H, m, H Ar), 7.82–7.89 (2H, m, H Ar); dC (50 MHz;
CDCl3) 12.03 (CH3), 12.21 (CH3), 33.23 (NCH3), 53.50
(CH2), 116.85 (CH), 117.31 (CH), 131.98 (CH), 132.19
(CH), 134.71 (C), 140.20 (C), 140.42 (C), 140.95 (C),
143.97 (C), 144.10 (C), 156.05 (C), 178.40 (C), 181.90 (C).
Microwave irradiation conditions. To a solution of sodium
salt of substituted sulfinic acid (2.52 mmol) in water
(50 mL) was added 2-chloromethyl-1,5,6-trimethyl-1H-
benzimidazole-4,7-dione 7 (0.2 g, 0.84 mmol). The reaction

9136
N. Boufatah et al. / Tetrahedron 60 (2004) 9131–9137
Anal. Calcd for C17H15FN2O4S: C, 56.35; H, 4.17; N, 5.24;
found: C, 56.20; H, 4.13; N, 5.30.
Acknowledgements
This work was supported by the Centre National de la
Recherche Scientifique and the Universities of Aix-
Marseille. We express our thanks to Professor H. El-Kashef
for stimulating discussions, and G. Lanzada for technical
collaboration.
4.4.6. 2-(4-Bromobenzenesulfonylmethyl)-1,5,6-tri-
methyl-1H-benzimidazole-4,7-dione (9f). Yellow solid,
90% yield; mp 295–296 8C; dH (200 MHz; CDCl3) 1.99
(6H, s, CH3), 3.91 (3H, s, NCH3), 5.22 (2H, s, CH2), 7.71
(2H, d, JZ8.9 Hz, H Ar), 7.86 (2H, d, JZ8.9 Hz, H Ar); dC
(50 MHz; CDCl3) 12.39 (CH3), 12.57 (CH3), 33.23 (NCH3),
53.50 (CH2), 130.10 (2 CH), 131.20 (2 CH), 136.50 (C),
138.90 (C), 139.95 (C), 144.20 (C), 151.10 (C),153.80 (C),
154.68 (C), 178.50 (C), 180.75 (C). Anal. Calcd for
C17H15BrN2O4S: C, 48.24; H, 3.57; N, 6.62; found: C,
48.39; H, 3.63; N, 6.56.
References and notes
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solid, 80% yield; mp 260–261 8C; dH (200 MHz; CDCl3)
2.08 (6H, s, CH3), 2.29 (3H, s, CH3), 2.43 (6H, s, CH3), 4.14
(3H, s, NCH3), 4.61 (2H, s, CH2), 6.93 (2H, s, H Ar); dC
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22.84 (2 CH3), 33.35 (NCH3), 53.67 (CH2), 131.93 (C),
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