A facile synthesis of 5(6)-(chloromethyl)benzimidazoles: Replacement of a sulfonic acid functionality by chlorine

Article abstract of DOI:10.1002/jhet.5570450208

(Chemical Equation Presented) Valuable new synthetic intermediates, 5(6)-(chloromethyl)benzimidazoles, were prepared by the facile elimination of sulfur dioxide under the influence of thionyl chloride from benzimidazole-5(6)- methanesulfonic acids easily

Full text of DOI:10.1002/jhet.5570450208

Mar-Apr 2008
343
A Facile Synthesis of 5(6)-(Chloromethyl)benzimidazoles:
Replacement of a Sulfonic Acid Functionality by Chlorine
Béla Pete,* Bálint Szokol and László Tőke
Organic Chemical Technology Research Group of the Hungarian Academy of Sciences, Budapest University of
Technology and Economics, H-1521 Budapest, PO Box 91, Hungary
E-Mail:bpete@chemres.hu
Received March 9, 2007
SO3H
RCO2H
NH2
SO3H
SO3H
Cl
N
SOCl2
N
R
R
N
H
N
H
NH2
NH2
Valuable new synthetic intermediates, 5(6)-(chloromethyl)benzimidazoles, were prepared by the facile
elimination of sulfur dioxide under the influence of thionyl chloride from benzimidazole-5(6)-methane-
sulfonic acids easily obtained from (3,4-diaminophenyl)methanesulfonic acid with formic-, or trifluoroacetic
acid. Both reaction steps involved only acidic conditions, thus the synthesis of polysubstituted 5(6)-
(chloromethyl)benzimidazoles incorporating base-sensitive substituents became possible.
J. Heterocyclic Chem., 45, 343 (2008).
INTRODUCTION
circumstances (lithiation of 5(6)-bromo-benzimidazoles
[11] or lithium aluminum hydride reduction of 5(6)-
carboxybenzimidazoles [12]) are preceded by strongly
acidic conditions applied in generating the imidazole
portion from o-diamino-benzenes. As a result, neither
acid-, nor base-sensitive substituents other than the ones
introduced for further elaboration, can be incorporated in
the targeted benzimidazoles. Although the strongly basic
conditions can be avoided in case of halogen substituents
by transition-metal-based couplings [13 there is still a
need for a benzimidazole substituent which, like halogens
or carboxy group, can easily be introduced regio-
selectively but its transformation toward the desired
functionalities requires acidic or neutral conditions.
The steadily increasing frequency of bacterial resistance
to antibiotics has become a severe health problem and has
revitalized the search for bactericidal molecules acting via
a novel mechanism. Benzimidazole derivatives, as a new
class of antibiotics, clearly demonstrated the potential for
a broad spectrum of therapeutic application [1].
In cancer chemotherapy there is a move away from the
traditional drugs, which change DNA in a non-selective
fashion, to new agents that interact non-covalently and
modify the process of DNA replication. Bis-benzimi-
dazoles are promising pharmacophores among this type of
compounds [2].
Moreover, substituted 2-trifluoromethylbenzimidazoles
inhibit photosynthesis and therefore exhibit appreciable
herbicidal activity [3]. Antifungal, antibacterial [4,5],
antiprotozoal [6] and anticancer [2] activities of benzimi-
dazoles have also been observed.
RESULTS AND DISCUSSION
Earlier we reported that 2-ethoxycarbonyl-1H-indole-4,
5-, 6- and 7-methanesulfonic acids were easily transformed
into 4-, 5-, 6- and 7-chloromethyl-1H-indole-2-
carboxylates, respectively, using typical conditions for the
formation of sulfonylchlorides [14]. As a continuation of
our work aimed at assessing the scope and limits of the
transformation of hetarylmethanesulfonic acids to (chloro-
methyl)hetarenes we now report the synthesis of benzimi-
dazole-5(6)-methanesulfonic acids 6, 7 and their transfor-
mation to 5(6)-(chloromethyl)benzimidazoles 11, 12.
We used a conventional strategy to prepare sulfonic
acids 6, 7 (Scheme 1): (4-aminophenyl)methanesulfonic
acid [15] 1 was N-acylated using acetic anhydride and
sodium acetate in acetic acid to yield the N-protected
derivative 2. Nitration of 2 was effected by mixed acid
(concentrated nitric acid-concentrated sulfuric acid 1:1) at
0° to give exclusively (4-acetylamino-3-nitrophenyl)-
The widespread interest in benzimidazole-containing
structures has promted extensive studies of their synthesis
[7]. Nevertheless, there are few methods available to
prepare benzimidazole derivatives bearing substituents
attached to the homocycle, since most of the known
routes are directed to functionalize C-2 and nitrogens (N-
1, N-3) [8]. Although direct bromination [9] or nitration
[10] is accomplished at C-5(6) of the benzimidazole ring,
the usual approach toward C-5(6)-substituted benzim-
idazoles is the construction of a suitably funtionalized
benzenoid ring followed by annulation of the imidazole
portion to generate benzimidazole system. Bromine [11]
or carboxy [12] group is applied in these cases to
elaborate to the more reactive functionalities actually
found in the targeted benzimidazoles. The strongly basic

344
B. Pete, B. Szokol and L. Tőke
Vol 45
Scheme 1
SO3H
NH2
SO3H
SO3Na
SO3Na
1. mixed acid
SO3H
H2/Pd/C
71%
Ac2O
aq HCl
O
O
N
O
60 oC
75%
N
O
NaOAc
72%
2. NaOH
76%
NH2
NH2
O
NH
O
NH
NH2
4
1
2
3
5
methanesulfonic acid 3. Isolation of 3 was accomplished
after neutralization of the reaction mixture with 50%
aqueous sodium hydroxide, and evaporation of most of
the solvent as the sodium salt of 3 separates from the
concentrated aqueous solution as yellow crystals in good
yield. As the N-acetyl-group can be removed easily at
both acidic and basic pH, care must be taken when
neutralizing the reaction mixture to avoid formation of
nitroamine 4. This compound has a good solubility even
in concentrated sodium sulfate-sodium nitrate solution
and its isolation requires evaporation of the neutralized
solution to dryness and tedious extraction with
methanol. Accordingly, hydrolysis of 3 was carried out
in 3% hydrochlorid acid at 60° to yield 4 in good yield.
Catalytic reduction of the nitro-group furnished the o-
phenylendiamine 5, which was used in the next step as
obtained after filtering off the catalyst and neutralization
of the filtrate. The condensation of diamine 5 with
formic acid provided the benzimidazole-5(6)-methane-
sulfonic acid 6 at rt (3 days) while trifluoroacetic acid
required reflux temperature (6 hours) to produce 2-
triflurormethyl-5(6)- benzimidazolemethanesulfonic acid
7 (Scheme 2). Diazotization of diamine 5 yielded
benztriazole-5(6)-methanesulfonic acid 8 in a clean
process (Scheme 2). Since benzimidazole-5(6)-methane-
sulfonic acid 6 is completely insoluble in organic
solvents, its sodium salt 6a, still having very low
solubility in common organic solvents, was used in the
subsequent steps.
The sodium sulfonate 6a, and the sulfonic acid 7, when
subjected to the usual conditions of formation of
sulfonylchlorides showed the same peculiar behavior as 4,
5-, 6- and 7-indolemethanesulfonic acids: not sulfonyl-
chlorides 9, 10, but 5(6)-(chloromethyl)benzimidazoles
11, 12 were formed (Scheme 3). The reaction conditions,
however, were more forcing than in case of indoles: [14]
dry acetonitrile at 80° was necessary instead of
dichloromethane at rt. This might be caused by the poor
solubility of sodium sulfonate 6a and sulfonic acid 7 in
acetonitrile compared to that of indolemethanesulfonic
acids in dichloromethane. Pyridinium-, or ammonium
salts did not improve the solubility of benzimidazoles 6 or
7. Benztriazolemethanesulfonic acid 8 gave a complex
mixture when refluxed in dry acetonitrile-thionyl chloride
with catalytic amount of dimethylformamide and seemed
not attractive for further investigation. (Chloromethyl)-
benzimidazoles 11, 12 were simply isolated by
evaporation of solvent and were reacted further without
characterization as they appeared sensitive to atmospheric
moisture. Analysis of crude 11, 12 by mass- and NMR
spectroscopy was not informative because acetonitrile
proved not to be a completely inert solvent contaminating
the
(chloromethyl)benzimidazoles.
(Chloromethyl)-
benzimidazoles 11, 12 underwent aminolysis with
dimethylamine and piperidine at 0° to give 5(6)-(di-
alkylaminomethyl)benzimidazoles 13, 14, 15 and 16
(Scheme 3). The amines needed flash-chromatography on
neutral alumina for purification and were obtained in 51-
68% yields. Crude 13 and 14 contained several
byproducts according to thin-layer chromatography.
Screening for sulfonamides among byproducts, we were
not able to find the respective sulfonamides 17 and 18
during chromatography of crude 13, or 14. In order to get
a clear-cut proof that all of the sulfonylchloride 9 suffered
sulfur dioxide elimination when refluxing in acetonitrile-
thionyl chloride we subjected the crude reaction mixture
to hydrolysis. The product was the known (hydroxy-
methyl)benzimidazole [12b] 19 not containing the starting
benzimidazole-5(6)-methanesulfonic acid 6, that is,
elimination of sulfur dioxide from 9 was complete.
Trifluoromethylbenzimidazole-5(6)-methanesulfonic acid
7 provided (chloromethyl)benzimidazole 12 in a much
cleaner reaction as the only product. Neither the
Scheme 2
SO3H
SO3H
HCO2H
N
N
H
NH2
55%
NH2
NaNO2
5
6
aq HCl
50%
TFAA
SO3H
75%
SO3H
N
N
CF3
N
N
H
N
H
8
7

Mar-Apr 2008
Replacement of a Sulfonic Acid Functionality by Chlorine
345
Sodium (4-acetylaminophenyl)methanesulfonate (2).
A
suspension of (4-aminophenyl)methanesulfonic acid 1 (5.6 g, 30
mmol) and sodium acetate (1.23 g, 15 mmol) was refluxed in acetic
anhydride-acetic acid mixture (1:1, 25 ml) for 36 hours. The
reaction mixture was filtered, the filtrate was evaporated to dryness,
and the solid residue was crystallized from methanol to give 5.4 g
of 2 (72%) as beige solid, mp > 270°; ir: 1544, 1193, 1060; 1H nmr
(D2O): δ 2.01 (s, 3H), 4.01 (s, 2H), 7.34 (s, 4H); 13C nmr (D2O): δ
23.10, 56.48, 121.27, 128.45, 131.01, 136.86, 172.57; Anal. Calcd
for C9H10NNaO4S: C, 43.03; H, 4.01; N, 5.58. Found: C, 42.66; H,
3.92; N, 5.50.
appropriate sulfonamide nor the starting benzimidazole-
sulfonic acid 7 could be found in the product of
aminolysis or hydrolysis (not isolated) of 12, respectively.
The reason for this may be the better solubility of 7
compared to 6a, but the role of the electron-deficient
trifluoromethylimidazole ring of 7, in an analogy with the
2-ethoxycarbonylindolemethanesulfonic acids, cannot be
ruled out facilitating sulfur dioxide elimination from
sulfonylchloride 10.
Scheme 3
NR1R2
SO3X
Cl
SO2Cl
R1R2NH
N
N
N
-SO2
N
MeCN
R
R
R
R
CH2Cl2
0 °C
SOCl2
N
H
N
N
H
N
H
H
DMF cat.
11 R=H
12 R=CF3
6a R=H X=Na
R=CF3 X=H
9 R=H
10 R=CF3
13 R=H R1=R2=Me
56%
51%
64%
68%
7
14 R=H R1+R2=(CH2)5
15 R=CF3 R1=R2=Me
16 R=CF3 R1+R2=(CH2)5
SO2NR1R2
OH
N
N
N
H
N
H
17 R1=R2=Me
18 R1=R2=(CH2)5
19
Sodium (4-acetylamino-3-nitrophenyl)methanesulfonate
(Chloromethyl)benzimidazoles are little known in the
literature. Although unprotected 5(6)-(chloromethyl)-
benzimidazole 11 is described in the patent-literature [16],
(3). Finely powdered sodium (4-acetylaminophenyl)methane-
sulfonate 2 (10 g, 40 mmol) was added to 65% nitric acid – 98%
sulfuric acid mixture (1:1, 20 ml) at -4° while thoroughly stirred
to keep the reaction mixture as a clear solution over a period of 4
hours. It was stirred at the same temperature for an additional 6
hours. The colourless solution was poured onto ice (300 g) and
carefully neutralized with 50% aqueous sodium hydroxide
solution while stirring vigorously. The temperature of the
reaction mixture was kept below 5° by adding ice if necessary.
The volume of the reaction mixture was reduced to one-fourth
by rotary evaporation and the precipitated yellow crystals were
filtered off to give 9 g of 3 (76%), mp > 270° (methanol); ir:
other known (chloromethyl)benzimidazoles carry
protecting group on N1 [17].
a
In summary, the above results clearly demonstrate that
benzimidazole-5(6)-methanesulfonic acids are useful
intermediates for the facile preparation of 5(6)-(chloro-
methyl)benzimidazoles without using any protecting
group. The overall procedure applies only acidic
circumstances to produce (chloromethyl)benzimidazoles
thus avoiding the usual metallation or hydride-reduction
techniques and allowing the presence of base-sensitive
functionalities. The sulfo group, as one of the chemically
most stable ones, survives the synthesis of benzimidazole
core, and it can then easily be replaced by chlorine with
thionyl chloride.
1
3363, 1384, 1213; H nmr (D2O): δ 2.22 (s, 3H), 4.24 (s, 2H),
7.73 (s, 2H), 8.10 (s, 1H); 13C nmr (D2O): δ 23.54, 55.52,
125.46, 127.02, 130.17, 130.66, 136.86, 140.58, 173.07; Anal.
Calcd for C9H9N2NaO6S: C, 36.49; H, 3.06; N, 9.46. Found: C,
36.00; H, 2.98; N, 9.35.
(4-Amino-3-nitrophenyl)methanesulfonic acid (4). Sodium
(4-acetylamino-3-nitrophenyl)methanesulfonate
3 (12 g, 40
mmol) was dissolved in 5% hydrochloric acid (100 ml) and kept
at 60° for 4 hours. The orange solution was evaporated to
dryness and the solid residue was crystallized from methanol to
give 7 g of 4 (75 %) as orange crystals, mp > 270°; ir: 2895,
EXPERIMENTAL
1H nmr and 13C nmr spectra were recorded at 300.13 MHz or
75.46 MHz, respectively, on a Bruker DRX 300 spectrometer.
1
1523, 1182, 1044; H nmr (D2O): δ 3.80 (s, 2H), 6.68 (d, J=8.2
Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 7.70 (s, 1H); 13C nmr (D2O): δ
55.32, 120.53, 122.66, 127.01, 132.16, 137.82, 141.59; Anal.
Calcd for C7H8N2O5S: C, 36.21; H, 3.47; N, 12.06. Found: C,
36.12; H, 3.42; N, 11.98.
(3, 4-Diaminophenyl)methanesulfonic acid (5). (4-Amino-
3-nitrophenyl)methanesulfonic acid 4 (10 g, 43 mmol) and
sodium hydroxide (1.6 g) were dissolved in water (100 ml).
Palladium on carbon (1 g, 10%) was added and the reaction
All
δ values are given in ppm, TMS or sodium 3-
(trimethylsilyl)-1-propanesulfonate was used as an internal
standard. MS spectra were measured on a MAT 312 instrument
equipped with a MASPEC II32 data system (FAB, V/E scan). IR
spectra were measured on Perkin-Elmer 1600 series FTIR
spectrophotometer and the values are given in cm-1. All
chemicals were reagent grade and used without further
purification.

346
B. Pete, B. Szokol and L. Tőke
Vol 45
mixture was hydrogenated at ambient pressure for 24 hours.
After removal of the catalyst the pH of the solution was rendered
to 6-7 with 35% hydrochloric acid and the precipitated solid was
filtered off to give 6.2 g of 5 (71%) as a yellowish solid. This
purified on a short column of alumina with ethyl acetate-hexane
1:1.
5(6)-(Dimethylaminomethyl)benzimidazole (13). This
compound was obtained as a pale yellow oil (0.98 g, 56%); ir:
3094, 1472, 1299; 1H nmr (CDCl3): δ 2.31 (s, 6H), 3.59 (s, 2H),
7.22 (d, J=8.5 Hz, 1H), 7.57 (s, 1H), 7.58 (d, J=8.5 Hz, 1H),
8.00 (s, 1H); 13C nmr (CDCl3): δ 45.14, 64.63, 115.69, 115.98,
124.41, 132.78, 137.86, 137.97, 141.77; ms: m/z 176 [M+H]+;
Anal. Calcd for C10H13N3: C, 68.54; H, 7.48; N, 23.98. Found: C,
68.19; H, 7.38; N, 23.80.
1
material was sufficiently pure for H and 13C nmr and was used
without further purification; ir: 3361, 1384, 1197;1H nmr (D2O):
δ 3.96 (s, 2H), 6.72 (d, J=7.5 Hz, 1H), 6.77 (d, J=7.5 Hz, 1H),
6.79 (s, 1H); 13C nmr (D2O): δ 56.46, 117.59, 119.45, 122.75,
123.80, 134.06, 134.10.
Benzimidazole-5(6)-methanesulfonic acid (6). (3,4-Di-
aminophenyl)methanesulfonic acid 5 (6 g, 30 mmol) was
dissolved in 100% formic acid (10 ml) and was kept at rt for
three days. The pale brown solution was evaporated to
dryness and the solid residue was triturated with acetone and
was crystallized from water to give 3.5 g of 6 (55 %) as beige
crystals, mp > 300°; ir: 3137, 1183, 1035; 1H nmr (D2O): 4.23
(s, 2H), 7.48 (d, J=8.7 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.68
(s, 1H), 8.94 (s, 1H); 13C nmr (D2O): 56.52, 114.06, 115.73,
128.96, 129.51, 129.95, 130.72, 139.27; Anal. Calcd for
C8H8N2O3S: C, 45.28; H, 3.80; N, 13.20. Found: C, 45.00; H,
3.73; N, 13.12.
5(6)-(Piperidinomethyl)benzimidazole (14). This compound
was obtained as a pale yellow oil (1.1 g, 51 %); ir: 3012, 1453,
1
1180; H nmr (CDCl3): δ 1.46 (m, 2H), 1.61 (m, 4H), 2.48 (m,
4H), 3.66 (s, 2H), 7.26 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.5 Hz,
1H), 7.61 (s, 1H), 8.02 (s, 1H); 13C nmr (CDCl3): δ 23.90, 25.17,
54.10, 63.62, 115.69, 116.26, 124.68, 130.76, 137.42, 138.01,
141.37; ms: m/z 216 [M+H]+; Anal. Calcd for C13H17N3: C,
72.52; H, 7.96; N, 19.52. Found: C, 72.06; H, 7.88; N, 19.35.
5(6)-(Dimethylaminomethyl)-2-trifluoromethylbenzimid-
azole (15). This compound was obtained as a pale yellow oil
(1.55 g, 64%); ir: 3061, 1486, 1258; 1H nmr (CDCl3): δ 2.32 (s,
6H), 3.60 (s, 2H), 7.24 (d, J=8.5 Hz, 1H), 7.39 (s, 1H), 7.54 (d,
J=8.5 Hz, 1H); 13C nmr (CDCl3): δ 44.64 , 64.09, 117.28, 118.70
(q, J=270 Hz), 125.84, 133.41, 137.57, 138.41, 141.93 (q, J=39
Hz); ms: m/z 244 [M+H]+; Anal. Calcd for C11H12F3N3: C, 54.32;
H, 4.97; N, 17.28. Found: C, 54.16; H, 4.90; N, 17.10.
2-Trifluoromethylbenzimidazole-5(6)-methanesulfonic
acid (7). (3,4-Diaminophenyl)methanesulfonic acid 5 (4 g, 20
mmol) was dissolved in trifluoroacetic acid (20 ml) and was
refluxed for six hours. The pale brown solution was evaporated
to dryness and the solid residue was triturated with acetone and
was crystallized from water to give 4.2 g of 7 (75 %) as beige
5(6)-(Piperidinomethyl)-2-trifluoromethylbenzimidazole
(16). This compound was obtained as a pale yellow oil (1.92 g,
1
crystals, mp > 300°; ir: 3431, 1195, 1173; H nmr (D2O): 4.18
1
(s, 2H), 7.32 (d, J=5.1 Hz, 1H), 7.47 (d, J=5.1 Hz, 1H), 7.67 (s,
1H); 13C nmr (D2O): 56.59, 115.30, 116.86, 117.26 (q, J=271
Hz), 128.31, 129.82, 133.45, 133.65, 138.97 (q, J=43 Hz); Anal.
Calcd for C9H7F3N2O3S: C, 38.58; H, 2.52; N, 10.00. Found: C,
38.36; H, 2.48; N, 9.91.
Benztriazole-5(6)-methanesulfonic acid (8). A solution of
(3,4-diaminophenyl)methanesulfonic acid 5 (4 g, 20 mmol) in
water (30 ml) and concentrated hydrochloric acid (6 ml) was
diazotized by adding sodium nitrite (0.69 g, 10 mmol) at –4°.
The reaction mixture was stirred for 3 hours at 0°-5° and the
separated solid was collected by filtration to give 2.1 g of 9
(50%) as a beige solid, mp > 300°; ir: 3256, 1212, 1042; 1H nmr
(D2O): 4.20 (s, 2H), 7.41 (d, J=8.7 Hz, 1H), 7.65 (d, J=8.7 Hz,
1H), 7.69 (s, 1H); 13C nmr (D2O): 56.54, 114.05, 115.50, 129.31,
130.87, 136.48, 136.80; Anal. Calcd for C7H7N3O3S: C, 39.43;
H, 3.31; N, 19.71. Found: C, 39.26; H, 3.27; N, 19.54.
68%); ir: 2937, 1657, 1167; H nmr (CDCl3): δ 1.44 (s, 2H),
1.57 (m, 4H), 2.48 (s, 4H), 3.60 (s, 2H), 7.23 (d, J=8.5 Hz, 1H),
7.46 (s, 1H), 7.49 (d, J=8.3 Hz, 1H). 13C nmr (CDCl3): δ 23.92 ,
25.20, 54.12, 63.53, 116.68, 116.97, 119.18 (q, J=270 Hz),
126.00, 132.75, 137.94, 138.26, 142.19 (q, J=39 Hz); ms: m/z
284 [M+H]+; Anal. Calcd for C14H16F3N3: C, 59.36; H, 5.69; N,
14.83. Found: C, 58.95; H, 5.60; N, 14.70.
5(6)-(Hydroxymethyl)benzimidazole (19). Crude 5(6)-
(chloromethyl)benzimidazole 11, prepared from sodium
benzimidazole-5(6)-methanesulfonate 6a (2.34 g, 10 mmol) as
described in the general procedure for the preparation of 5(6)-
aminobenzimidazoles, was added as
a solid to sodium
hydrocarbonate (2.5 g, 30 mmol) and ice (10 g). The mixture
was stirred for 10 minutes then extracted with chloroform to
give 0.8 g of 19 (56%), which proved to be identical with the
compound already described [12b].
General Prodedure for the Preparation of (Aminomethyl)-
benzimidazoles (13, 14, 15, 16). Sodium benzimidazole-5(6)-
methanesulfonate 6a (2.34 g, 10 mmol, prepared by neutral-
ization of 6 with aqueous sodium carbonate and evaporation of
the solution to dryness) or 2-trifluoromethylbenzimidazole-5(6)-
methanesulfonic acid 7 (2.8 g, 10 mmol) was suspended in dry
acetonitrile (60 ml) containing thionyl chloride (4 ml, 56 mmol)
and dimethylformamide (0.06 ml) and was refluxed for 5 hours
(in case of 7 for 3 hours). The brown solution was evaporated to
dryness. The solid residue was suspended in dry dichloro-
methane (20 ml) and the suspension was added to either aqueous
dimethylamine solution (5 ml, 38%, 38 mmol) or piperidine (4
ml, 40 mmol) in dichloromethane (30 ml) at 0° over a period of
10 minutes. The reaction mixture was stirred for an additional 10
minutes then the aqueous layer was separated, potassium
carbonate (1 g) was added and the aqueous layer was extracted
with dichloromethane (20 ml). The combined dichloromethane
solutions were evaporated to give an oily residue, which was
Acknowledgement The authors would like to thank the
National Fund for Science and Research (OTKA Project No.
T038329) for financial support.
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