Asymmetric epoxidation of aldehydes catalyzed by new C2-symmetrical chiral sulfide

Article abstract of DOI:10.3987/COM-02-9520

Asymmetric synthesis of chiral epoxides from various aldehydes with benzyl bromide was investigated using new C₂-symmetrical chiral sulfides, which were readily prepared from (R,R)-tartaric acid.

Full text of DOI:10.3987/COM-02-9520

HETEROCYCLES, Vol. 57, No. 8, 2002, pp. 1423 - 1432, Received, 19th April, 2002
MICROWAVE ASSISTED SYNTHESIS OF NEW BENZIMIDAZOLES
Yves Njoya,a,b Narimène Boufatah,a,b Armand Gellis,a,b Pascal Rathelot,a
Michel P. Crozet,b and Patrice Vanelle a,b*
aDepartment of Organic Chemistry, University of Mediterranée, Faculty of
Pharmacy, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France
Fax: (33) 04 91 79 46 77; E-mail: patrice.vanelle@pharmacie.univ-mrs.fr
bLCMO, UMR 6517, CNRS-Universities of Aix-Marseille 1 and 3, BP 562,
13397 Marseille Cedex 20, France
Abstract – New potentially bioactive and highly functionalized benzimidazoles
were synthesized by using microwave irradiation methodology in multi-steps:
construction of benzimidazole ring, N-methylation and electron transfer C-
alkylation (followed by base-promoted nitrous acid elimination) or S-alkylation.
Microwave irradiation and its applications for organic reactions is currently under extensive examination
and has been recently reviewed.1-6 Heterogeneous reactions facilitated by supported reagents on various
solid inorganic surfaces such as SiO2 have received attention in recent years because of the greater
selectivity and simple reaction work-up.7,8 Microwave heating has been used for the rapid synthesis of a
variety of heterocyclic compounds both in solution phase as well as under solvent-free conditions.9-14 The
use of such microwave approach has several advantages such as short reaction times compared to
conventional procedure, ease of work-up, reduction in the usual thermal degradation and formation of
pure products in high yields. Further, the solventless microwave-assisted reactions are now gaining
popularity as they provide an opportunity to work with open vessels, thus avoiding the risk of high
pressure development and with a possibility of scaling up the reactions on preparative scale.15-18
Compounds containing benzimidazole group have been shown to exhibit a broad spectrum of
pharmacological activities.19 Clinical examples include mebendazole, albendazole (anthelmintics),20,21
astemizole (antihistamine),22 and omeprazole (antiulcerative).23 In addition, benzimidazole based
compounds have shown such diverse biological activities as inhibition of phosphodiesterase IV24 and
antagonism of angiotensin 125,26 and neuropeptide Y27 binding.

On the other hand, the single electron transfer reactions,28-31 recently under microwave irradiation,32-34 are
one of the main research topics in our laboratories. As a part of our program to develop the synthesis of
heterocyclic compounds under these conditions and to adapt heterocyclic methodologies to a high speed
synthesis, we report here a microwave assisted preparation of new potentially bioactive benzimidazole
derivatives.
2-Alkylbenzimidazoles were prepared by classical cyclocondensation of 1,2-arylenediamines with the
corresponding aldehydes35 or carboxylic acids.11,36,37 Generally, the reaction time was 4 to 48 h and yield
30 to 65%.
2-Chloromethyl-1H-benzimidazole (1) was obtained in 92% yield following the classical method
(chloroacetic acid, 5 N HCl, refluxed for 8 h). Microwave irradiation is another potential strategy to
realize this cycloaddition. In typical procedure (SiO2, 500 W, 4 min), the chloride (1) was prepared in
90% yield from the condensation of chloroacetyl chloride with 1,2-phenylenediamine. The reaction rate
was accelerated from 8 h to 4 min, which represents a rate increase of up to 120-fold (Scheme 1).
Scheme 1
O
HO
CH2Cl
92%
Classical conditions:
5 N HCl, reflux, 8 h
N
Cl
NH2
NH2
O
N
H
1
Cl
CH2Cl
90%
Microwave irradiation:
SiO2, 4 min, 900 W
2-Chloromethyl-1H-benzimidazole (1) can be methylated by using dimethyl sulfate in toluene at 80 °C,
during 2 h. These classical operating conditions led us to 2-chloromethyl-1-methyl-1H-benzimidazole (2)
in 49% yield. An attractive alternative to accelerate the methylation reaction was accomplished by
applying microwave irradiation.38 Therefore, the methylation of 1 performed under microwave conditions
can be accelerated to 2 min with a higher yield (91%), which represents a 60-fold rate increase (Scheme
2).
Scheme 2
Classical conditions:
DMS, 2 h, 80 °C
49%
91%
N
N
Cl
Cl
Microwave irradiation:
DMS, NaOH, 2 min, 500 W
N
N
H
CH3
2
1

The intermediate compound (2) was nitrated using HNO3-H2SO4 mixture, leading to 2-chloromethyl-1-
methyl-6-nitro-1H-benzimidazole (3) in 62% yield (Scheme 3).
Scheme 3
HNO3
N
N
Cl
Cl
N
N
O2N
H2SO4
CH3
CH3
2
3
62%
Derivative (3) was treated under nitrogen and photostimulation with 2-nitropropane anion (4) during 5 h
to give the ethylenic compound (5) in 81% yield as shown in Scheme 4. This alkene was classically
formed by electron transfer reaction and base-promoted nitrous acid elimination from the C-alkylation
product. The electron transfer mechanism was confirmed by inhibition studies.39 Moreover, the
importance of the nitro group has been demonstrated by the reaction of 2 with 4 under classical
conditions (DMSO, 5 h, hν, N2) leading to unidentifiable tarry matters.
Scheme 4
81%
N
Cl
H3C
Classical conditions:
N
CH3
N
O2N
DMSO, 5 h, hν, N2
CH3
N
O2N
3
CH3
92%
Microwave irradiation:
DMSO, 1 min, 900 W
+
5
Li + -C(CH3)2NO2
4
The same reaction performed during 1 min under microwave irradiation led to 92% yield of 5. This
reaction with 2-nitropropane anion showed that microwave irradiation procedure can induce a fast
electron transfer reaction to give in best yield the expected alkene derivative. Therefore, we became
interested in preparation of benzimidazole derivatives from different anions according to the microwave
irradiation procedure.
The chloride (3) reacted with 3 equivalents of different cyclic and heterocyclic nitronate anions (6-10) to
give the corresponding ethylenic derivatives (14-18) as indicated in Table. By using 3 equivalents of the
sodium salt of 1,3,6-trimethyl-5-nitro-1H-pyrimidine-2,4-dione (11), following the same procedure, the
reaction with 3 gave the C-alkylated product (19) in 83% yield. On the other hand, the reaction between
S-centered anions, the sodium salts of benzenethiol (12) and benzenesulfinic acid (13) and derivative (3)
gave the required products (20) and (21) in respectively 85 and 72% yields. The reactions were fast (1
min), the procedure was simple, and gave the expected products (14-21) in good yields (59% to 91%).

Table
Anions
Final products a
Yield b(%)
64
NO2
N
-
Li +
N
O2N
O2N
6
CH3
14
15
NO2
-
N
Li +
71
74
N
CH3
7
NO2
N
-
Li +
N
O2N
CH3
16
8
N
N
NO2
59
O2N
-
Li +
CH3
17
18
9
N
O
O
NO2
CH3
91
83
N
Li+
O2N
O
CH3
CH3
CH3
O
10
CH3
O
O
N
CH3
O2N
NO2
CH2- +Na
N
N
CH3
N
N
O2N
O
N
O
CH3
19
CH3
CH3
11
S- Na+
N
N
85
72
S
O2N
12
CH3
20
-
SO2 Na+
N
SO2
N
O2N
CH3
13
21
a
All reactions were performed by using open Erlenmeyer Pyrex flask. Irradiations were carried out in
a domestic microwave oven (Whirlpool MO 111).
b Yield of pure isolated products.

In conclusion, we have demonstrated that microwave irradiation can be effectively employed to
synthesize new potentially active benzimidazole derivatives in multi-steps: construction of benzimidazole
ring, N-methylation and electron transfer C-alkylation (followed by base-promoted nitrous acid
elimination) or S-alkylation. These results demonstrate that the versatility of the process as considerable
reaction rate enhancement has been observed by bringing down the reaction time from hours to minutes
with improved yields as compared to conventional procedure. Study of biological properties of related
compounds is under active investigation.
ACKNOWLEDGEMENTS
This work has been 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 M.
Noailly for 1H and 13C NMR spectra recording.
EXPERIMENTAL
Melting points were determined on Büchi B-540 and are uncorrected. Elemental analyses were performed
by the Centre de Microanalyses of the University of Aix-Marseille 3 and of the INP-ENSCT (Toulouse,
1
13
1
France). Both H and C NMR spectra were determined on a Bruker ARX 200 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 chromatography: silica gel 60 (Merck, particule
size 0.063-0.200 mm, 70-230 mesh ASTM). TLC were performed on 5 cm x 10 cm aluminum plates
coated with silica gel 60F-254 (Merck) in an appropriate solvent. Reactions under microwave irradiation
were performed in a domestic microwave oven, Whirlpool MO 111.
2-Chloromethyl-1H-benzimidazole (1)
Classical conditions: To a solution of 1,2-phenylenediamine (30 g, 280 mmol) in 5 N hydrochloric acid
(130 mL), chloroacetic acid (31.8 g, 336 mmol) in solution of 5 N hydrochloric acid (110 mL) was added.
The reaction mixture was stirred at reflux for 8 h. After basification with 20% ammonia, the residue
obtained was washed with water and dried in air. Recrystallization from benzene-hexane (6/4) gave 42.92
1
g (92%) of yellow solid. 1, mp 154-155 °C (lit.,40 153-155 °C), H NMR (CDCl3) δ 4.81 (s, 2H); 7.27-
7.36 (m, 2H); 7.56 (m, 2H); 9.14 (br s, 1H).
Microwave irradiation conditions: 1,2-Phenylenediamine (1 g, 9.25 mmol), chloroacetyl chloride (1.13
mL, 13.9 mmol) and 5 g of silica gel (Merck, Geduran SI 60, 70-230 microns, pH = 7, surface area 550
m2 g-1) was intimately mixed and introduced in a glass vessel (open Erlenmeyer Pyrex flask). The mixture
was irradiated in a domestic microwave oven (Whirlpool MO 111) for 4 min at a power of 900 W. After

cooling down, water (20 mL) was added. The reaction mixture was basified with 20% ammonia and the
expected product was filtered and recrystallized from benzene-hexane (6/4) giving 1.39 g (90%) of 1.
2-Chloromethyl-1-methyl-1H-benzimidazole (2)
Classical conditions: To a solution of 2-chloromethyl-1H-benzimidazole (3 g, 18 mmol) in toluene (10
mL), dimethyl sulfate (2.73 g, 21 mmol), was added dropwise at rt. The reaction mixture was stirred at
80 °C for 2 h. After cooling, water (30 mL) was added and the mixture was basified with 20% ammonia.
After filtration, the solution was extracted with chloroform (3 x 50 mL). The organic layer was dried over
magnesium sulfate and removed under vacuum. Purification by chromatography on silica gel eluting with
chloroform and recrystallization from methanol gave 1.6 g (49%) of yellow solid. 2, mp 92 °C (lit.,41 93-
95 °C), 1H NMR (CDCl3) δ 3.85 (s, 3H); 4.83 (s, 2H); 7.20 (m, 2H); 7.56 (m, 1H); 7.75-7.78 (m, 1H). 13C
NMR ( CDCl3) δ 30.11; 36.75; 109.38; 120.11; 122.51; 123.47; 136.06; 141.98; 148.93.
Microwave irradiation conditions: 2-Chloromethyl-1H-benzimidazole (0.3 g, 1.8 mmol), dimethyl sulfate
(0.45 g, 3.6 mmol) and 1 N sodium hydroxide (3 mL) were intimately mixed and introduced in a glass
vessel (open Erlenmeyer Pyrex flask). The mixture was irradiated in a domestic microwave oven
(Whirlpool MO 111) for 2 min at a power of 500 W. After cooling down, 1 N sodium hydroxide (10 mL)
was added. The mixture was extracted with chloroform (3 x 10 mL). The solvent was dried over
magnesium sulfate and removed under vacuum. Purification by chromatography on silica gel eluting with
chloroform and recrystallization from methanol gave 0.30 g (91%) of 2.
2-Chloromethyl-1-methyl-6-nitro-1H-benzimidazole (3)
To a solution of 2-chloromethyl-1-methyl-1H-benzimidazole (5 g, 27.7 mmol) in concentrated sulfuric
acid (20 mL), fuming nitric acid (3 mL) was added dropwise at 0 °C. The reaction mixture was stirred at
the same temperature for 2 h, poured into crushed ice (100 mL), neutralized with sodium carbonate and
extracted with dichloromethane (3 x 30 mL). The solvent was dried over magnesium sulfate and removed
under vacuum. Purification by chromatography on silica gel eluting with chloroform and recrystallization
1
from ethanol gave 3.87 g (62%) of yellow solid. 3, mp 190-192 °C, H NMR (CDCl3) δ 3.94 (s, 3H);
4.85 (s, 2H); 7.56 (d, J = 9.0 Hz, 1H); 8.23 (dd, J = 9.0 Hz and 2.2 Hz, 1H); 8.60 (d, J = 2.2 Hz, 1H). 13C
NMR (CDCl3) δ 30.84; 36.33; 109.57; 117.01; 119.31; 140.06; 141.28; 143.95; 152.79. Anal. Calcd for
C9H8N3O2Cl: C, 47.91; H, 3.57; N, 18.62. Found: C, 48.00; H, 3.53; N, 18.60.
The lithium salt of 2-nitropropane (4),42 nitroalkanes (6-9),43,44 5,5-dimethyl-2-nitro-[1,3]-dioxane45,46
(10) and the sodium salt of 1,3,6-trimethyl-5-nitro-1H-pyrimidine-2,4-dione47,48 (11) were prepared as
previously described.
The sodium salts of benzenethiol (12) and benzenesulfinic acid (13) were commercially available.
Preparation of benzimidazoles (5, 14-21)

Classical conditions: To a solution of 2-nitropropane lithium salt (0.25 g, 2.64 mmol) in dry DMSO (10
mL), was added 2-chloromethyl-1-methyl-6-nitro-1H-benzimidazole (0.2 g, 0.88 mmol) under nitrogen
and anhydrous conditions. The reaction mixture was irradiated with two 60 W tungsten lamps and stirred
at rt during 5 h. Then it was poured into water (100 mL). The aqueous solution was extracted with toluene
(3 x 20 mL). The organic extracts were washed with water, dried over anhydrous magnesium sulfate, and
evaporated under reduced pressure. Purification by chromatography on silica gel eluting with
dichloromethane and recrystallization from ethanol gave 0.165 g (81%) of 5.
Microwave irradiation conditions: The appropriate salt of nitro or sulfur derivatives (4, 6-13) (2.64 mmol),
2-chloromethyl-1-methyl-6-nitro-1H-benzimidazole (0.88 mmol) and silica gel (Merck, Geduran SI 60,
70-230 microns, pH = 7, surface area 550 m2 g-1, 1 g) in DMSO (4 mL) were intimately mixed and placed
in an open Erlenmeyer Pyrex flask. The reaction mixture was irradiated in a domestic microwave oven
(Whirlpool MO 111) for 1 min at a power of 900 W. After cooling, methanol (10 mL) was added. After
filtration over anhydrous magnesium sulfate, the reaction mixture was evaporated. The crude product was
dissolved in water (100 mL). After extraction with toluene (3 x 20 mL), the organic extracts were then
dried over anhydrous magnesium sulfate, evaporated under reduced pressure. Purification by
chromatography on silica gel eluting with dichloromethane and recrystallization from ethanol gave the
expected products (5, 14-21).
1-Methyl-2-(2-methylpropenyl)-6-nitro-1H-benzimidazole (5)
1
Yellow solid, 92% yield, mp 145-146 °C, H NMR (CDCl3) δ 2.05 (s, 3H); 2.26 (s, 3H); 3.75 (s, 3H);
6.17 (s, 1H); 7.30 (d, J = 9.0 Hz, 1H); 8.14 (dd, J = 9.0 Hz and 2.2 Hz, 1H); 8.77 (d, J = 2.2 Hz, 1H).13C
NMR (CDCl3) δ 20.97; 27.67; 30.27; 105.87; 110.53; 118.06; 118.96; 134.42; 142.35; 147.51; 151.15;
157.26. Anal. Calcd for C12H13N3O2: C, 62.33; H, 5.67; N, 18.17. Found: C, 62.03; H, 5.61; N, 18.08.
2-Cyclopentylidenemethyl-1-methyl-6-nitro-1H-benzimidazole (14)
Yellow solid, 64% yield, mp 147-149 °C, 1H NMR (CDCl3) δ 1.76-1.87 (m, 4H); 2.62 (t, J = 6.2 Hz, 2H);
3.00 (t, J = 6.2 Hz, 2H); 3.80 (s, 3H); 6.43 (s, 1H); 7.76 (d, J = 9.0 Hz, 1H); 8.14 (dd, J = 9.0 Hz and 2.2
Hz, 1H); 8.24 (d, J = 2.2 Hz, 1H).13C NMR (CDCl3) δ 25.81; 27.53; 30.52; 30.73; 38.25; 108.13; 118.38;
118.89. Anal. Calcd for C14H15N3O2: C, 65.35; H, 5.88; N, 16.33. Found: C, 65.28; H, 5.83; N, 16.31.
2-Cyclohexylidenemethyl-1-methyl-6-nitro-1H-benzimidazole (15)
Yellow solid, 71% yield, mp 168-169 °C, 1H NMR (CDCl3) δ 1.58-1.68 (m, 6H); 2.40 (t, J = 6.0 Hz, 2H);
2.94 (t, J = 6.0 Hz, 2H); 3.82 (s, 3H); 6.18 (s, 1H); 7.75 (d, J = 9.0 Hz, 1H); 8.18 (dd, J = 9.0 Hz and 2.2
Hz, 1H); 8.26 (d, J = 2.2 Hz, 1H).13C NMR (CDCl3) δ 26.20; 27.75; 28.68; 30.30; 30.67; 38.32; 107.56;
118.08; 118.94. Anal. Calcd for C15H17N3O2: C, 66.40; H, 6.32; N, 15.49. Found: C, 66.34; H, 6.27; N,
15.47.
2-Cycloheptylidenemethyl-1-methyl-6-nitro-1H-benzimidazole (16)

Yellow solid, 74% yield, mp 127-128 °C, 1H NMR (CDCl3) δ 1.58-1.61 (m, 6H); 1.74 (m, 2H); 2.57 (t, J
= 5.8 Hz, 2H); 3.06 (t, J = 5.8 Hz, 2H); 3.81 (s, 3H); 6.24 (s, 1H); 7.77 (d, J = 9.0 Hz, 1H); 8.12 (dd, J =
9.0 Hz and 2.2 Hz, 1H); 8.24 (d, J = 2.2 Hz, 1H).13C NMR (CDCl3) δ 26.43; 28.74; 29.68; 29.80; 30.25;
33.07; 39.60; 105.76; 109.74; 117.94; 118.88; 134.27; 142.79; 147.87; 156.04; 161.43. Anal. Calcd for
C16H19N3O2: C, 67.35; H, 6.71; N, 14.73. Found: C, 67.41; H, 6.75; N, 14.75.
2-Cyclododecylidenemethyl-1-methyl-6-nitro-1H-benzimidazole (17)
1
Yellow solid, 59% yield, mp 162-163 °C, H NMR (CDCl3) δ 1.25-1.38 (m, 14H); 1.61-1.77 (m, 4H);
2.26 (t, J = 6.3 Hz, 2H); 2.45 (t, J = 6.3 Hz, 2H); 3.80 (s, 3H); 6.28 (s, 1H); 7.74 (d, J = 9.0 Hz, 1H); 8.16
(dd, J = 9.0 Hz and 2.2 Hz, 1H); 8.24 (d, J = 2.2 Hz, 1H).13C NMR (CDCl3) δ 25.87; 25.91; 26.09; 26.27;
26.40; 27.35; 28.71; 29.69; 29.85; 30.20; 33.17; 39.68; 105.71; 108.64; 115.98; 119.72; 134.46; 143.29;
147.75; 156.15; 161.49. Anal. Calcd for C21H29N3O2: C, 70.95; H, 8.22; N, 11.82. Found: C, 70.85; H,
8.12; N, 11.80.
2-(2,2-Dimethyl-[1,3]-dioxan-5-ylidenemethyl)-1-methyl-6-nitro-1H-benzimidazole (18)
1
Yellow solid, 91% yield, mp 165-167 °C, H NMR (CDCl3) δ 1.45 (s, 6H); 3.80 (s, 3H); 4.45 (s, 2H);
5.06 (s, 2H); 6.21 (s, 1H); 7.33 (d, J = 9.0 Hz, 1H); 8.17 (dd, J = 9.0 Hz and 2.2 Hz, 1H); 8.57 (d, J = 2.2
Hz, 1H).13C NMR (CDCl3) δ 23.95; 30.30; 62.24; 63.79; 99.95; 106.19; 108.95; 115.94; 118.40; 139.11;
151.19; 152.63. Anal. Calcd for C15H17N3O4: C, 59.40; H, 5.65; N, 13.85. Found: C, 59.33; H, 5.61; N,
13.82.
1,3-Dimethyl-6-[2-(1-methyl-6-nitro-1H-benzimidazol-2-yl)ethyl]-5-nitro-1H-pyrimidine-2,4-dione
(19)
Yellow solid, 83% yield, mp 297-299 °C, 1H NMR (CDCl3) δ 3.33-3.36 (m, 2H); 3.41 (s, 3H); 3.59-3.61
(m, 2H); 3.69 (s, 3H); 3.84 (s, 3H); 7.49 (d, J = 9.0 Hz, 1H); 8.25 (dd, J = 9.0 Hz and 2.0 Hz , 1H); 8.61
(d, J = 2.0 Hz, 1H).13C NMR (CDCl3) δ 25.69; 27.16; 29.75; 31.37; 33.71; 111.79; 115.82; 118.90;
130.20; 141.74; 142.28; 143.77; 151.43; 153.72; 156.28; 158.51. Anal. Calcd for C16H16N6O6: C, 49.49;
H, 4.15; N, 21.64. Found: C, 49.39; H, 4.09; N, 21.60.
1-Methyl-6-nitro-2-phenylsulfanylmethyl-1H-benzimidazole (20)
1
Yellow solid, 85% yield, mp 142-144 °C, H NMR (CDCl3) δ 3.96 (s, 3H) ; 5.64 (s, 2H); 7.43-7.54 (m,
5H); 7.60 (d, J = 9.0 Hz, 1H); 8.07 (dd, J = 9.0 Hz and 2.2 Hz, 1H); 8.25 (d, J = 2.2 Hz, 1H).13C NMR
(CDCl3) δ 30.82; 58.50; 109.61; 116.93; 128.58; 128.73; 129.84; 133.73; 141.53; 143.79; 152.49; 165.72.
Anal. Calcd for C15H13N3O2S: C, 60.18; H, 4.38; N, 14.04. Found: C, 60.05; H, 4.33; N, 14.02.
2-Benzenesulfonylmethyl-1-methyl-6-nitro-1H-benzimidazole (21)
Yellow solid, 72% yield, mp 255-256 °C (lit.,49 255.5-256.5 °C), 1H NMR (CDCl3) δ 3.94 (s, 3H); 4.70 (s,
2H); 7.36-7.58 (m, 2H); 7.60-7.66 (m, 3H); 8.14 (d, J = 9.0 Hz, 1H); 8.21 (dd, J = 9.0 Hz and 2.2 Hz,

1H); 8.45 (d, J = 2.2 Hz, 1H).13C NMR (CDCl3) δ 31.52; 55.43; 106.91; 109.92; 116.79; 118.42; 119.28;
120.24; 128.45; 129.40; 134.74; 137.36. Anal. Calcd for C15H13N3O4S: C, 54.37; H, 3.95; N, 12.68.
Found: C, 54.37; H, 3.99; N, 12.70.
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