A general method for the synthesis of benzimidazole-4-sulfonamides

Article abstract of DOI:10.1016/j.tetlet.2009.01.015

A general method for the synthesis of benzimidazole-4-sulfonamides is described. This methodology employs commercially available benzothiadiazole-4-sulfonyl chloride as a benzimidazole equivalent. Reaction with a variety of amines followed by highly chemo

Full text of DOI:10.1016/j.tetlet.2009.01.015

Tetrahedron Letters 50 (2009) 1219–1221
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Tetrahedron Letters
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A general method for the synthesis of benzimidazole-4-sulfonamides
*
Mark D. Rosen , Zahna M. Simon, Kyle T. Tarantino, Lucy X. Zhao, Michael H. Rabinowitz
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method for the synthesis of benzimidazole-4-sulfonamides is described. This methodology
employs commercially available benzothiadiazole-4-sulfonyl chloride as a benzimidazole equivalent.
Reaction with a variety of amines followed by highly chemoselective reductive desulfurization gives
intermediate 1,2-phenylenediamines, which may then react with aryl, heteroaryl, and alkyl aldehydes
to provide substituted benzimidazole sulfonamides.
Received 26 November 2008
Revised 22 December 2008
Accepted 7 January 2009
Available online 11 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The sulfonamide functional group has a long and rich history in
organic chemistry and drug discovery. Beginning with the discov-
ery of the ‘sulfa’ antibiotics in the 1930s that revolutionized the
treatment of bacterial infections (Prontosil Rubrum, 1), and contin-
uing into the present day with the development of potent anti-ret-
rovirals used to treat patients infected with HIV (Prezista, 2),
sulfonamides remain a particularly important class of compounds
for the treatment of infectious diseases (Fig. 1).1–3
heterocyclic compounds. Herein, we report the development of a
general method for the conversion of commercially available
2,1,3-benzothiadiazole 8 into a wide variety of benzimidazole
sulfonamides.
Our investigation began with the preparation of known 2,1,3-
benzothiadiazoles 9, 10, and 11, which represent aryl, benzyl,
and alkyl-substituted sulfonamides (Scheme 2).10 We were aware
from the outset that extrusion of sulfur from 2,1,3-benzothiadiaz-
oles typically requires the use of strong reducing agents such as
LiAlH4, and therefore a key challenge would be achieving chemose-
lectivity for the benzothiadiazole ring in the presence of the reduc-
tively labile sulfonamide group.11
However, the use of sulfonamides as medicinal agents is not
limited to the realm of infectious diseases; for example, as early
as the 1950s certain sulfonamides were discovered to be effective
treatments for hypertension and congestive heart failure (e.g., diu-
ril, 3).1 Similarly, the benzimidazole ring system is also of long-
standing medicinal importance. Examples of widely used classes
of drugs containing the benzimidazole ring system include anthel-
mintics (albendazole, 4) and proton pump inhibitors (omeprazole,
5).4,5 Additional examples of the utility of benzimidazole com-
pounds include, among others, H4 receptor antagonists,6
O
O
Cl
N
S
S
NH2
NH2
H2N
NH
N
S
O O
N-methyl-D
-aspartate receptor antagonists,7 and hepatitis C RNA
N
O O
polymerase inhibitors.8
3: Diuril
(diuretic)
H2N
1: Prontosil Rubrum
During the course of our investigation of cholecystokinin-2
receptor (CCK2-R) antagonists, we required benzimidazole sulfon-
amide 6 (Scheme 1).9 Despite the voluminous body of literature
devoted to the benzimidazole ring system, we were unable to find
a straightforward method for the preparation of benzimidazole-4-
sulfonamides. It is immediately apparent that the key problem is
that the hypothetical reagent benzimidazole-4-sulfonyl chloride
7 does not exist due to the incompatibility of the benzimidazole
nitrogen atom with sulfonyl chlorides, and to the best of our
knowledge a suitable substitute has not been developed. We
reasoned that commercially available 2,1,3-benzothiadiazole-4-
sulfonyl chloride 8 could serve as an effective benzimidazole-2-
sulfonamide synthon, and thus enable a synthesis of this class of
(antibiotic)
Ph
O
H
O
O O
S
2: Prezista
(HIV)
O
O
N
H
N
H
OH
i-Pr
NH2
MeO
OMe
O
N
O
S
N
n-PrS
N
N
H
Me
OMe
NH
N
H
Me
4: albendazole
(anthelmetic)
5: omeprazole
(gastric reflux)
* Corresponding author. Tel.: +1 858 320 3395; fax: +1 858 784 3267.
E-mail address: mrosen1@its.jnj.com (M.D. Rosen).
Figure 1. Drugs containing the sulfonamide or benzimidazole functional groups.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.015

1220
M. D. Rosen et al. / Tetrahedron Letters 50 (2009) 1219–1221
benzimidazole-4-sulfonamides in yields ranging from 57% to 88%
(Table 2).15
We next examined the cognate transformation of 2,1,3-benzo-
Br
N
O
thiadiazole-4-sulfonamides 10 and 11 to their corresponding benz-
imidazole-4-sulfonamides (Table 3). It should be noted that while
10 has three reductively labile functional groups (N-benzyl, sulfon-
amide N–S, and benzothiadiazole ring), conversion to the phenyl-
enediamine proceeds with high chemoselectivity. Thus, reduction
of 10 and 11 with zinc metal and acetic acid provided diamines
14 and 15 in yields of 76% and 80%, respectively. Oxidative conden-
sation with aldehydes in the presence of Na2S2O5 gave the desired
benzimidazole-2-sulfonamides 16a–g and 17a–g in generally good
yield (37–94%).
O
O
NH
O
Cl
Cl
S
S
S
O
O
O
N
N
N
N
S
N
H
N
H
6: CCK2R
antagonist
7
8
Scheme 1. Benzimidazole-4-sulfonamide CCK2-R antagonist.
In summary, an efficient and general method for the synthesis of
benzimidazole-4-sulfonamides was developed.16,17 This methodol-
ogy utilizes commercially available 2,1,3-benzothiadiazole-4-sulfo-
nyl chloride as a benzimidazole-4-sulfonyl chloride synthon. Mild
and chemoselective conditions for reduction of the benzothiadiazole
ring in the presence of sulfonamide and benzyl functional groups
were developed, and subsequent conversion of the intermediate
O
O
O
O
O
O
NHPh
N
NHBn
N
N
S
amine,
pyridine
S
S
N
N
8
S
S
S
CH2Cl2
N
N
9
10
11
Table 2
Scheme 2. 2,1,3-Benzothiadiazole sulfonamide substrates.
Conversion of phenylenediamine 12 to benzimidazoles 13a–i
O
O
NHPh
N
S
Using sulfonamide 9 as a test substrate, we surveyed various
reducing agents in order to effect excision of the ring sulfur atom
while leaving the sulfonamide moiety intact (Table 1). The use of
LiAlH4 led to both reduction of the benzothiadiazole ring and scis-
sion of the S–N bond of the sulfonamide (entry 1).11 Treatment of 9
with magnesium turnings and refluxing methanol returned un-
changed starting material (entry 2), possibly due to competitive
deprotonation of the acidic sulfonamide NH proton that may ren-
der the substrate inert to reduction under these conditions.12 The
reagent combination NaBH4/CoCl2 provided the desired phenyl-
enediamine 12 in modest yield (entry 3), although reduction of
the sulfonamide N-S bond was also observed.13 While Sn/HCl also
produced 12 in modest yield, isolation of the product proved prob-
lematic due to persistent tin emulsions (entry 4). Fortunately,
exposure of 9 to zinc and acetic acid at 50 °C for 1 h provided high
yields of 12 (entry 5), which could be conveniently isolated as the
stable hydrochloride salt in 84% yield after subsequent treatment
with 4 M HCl in dioxane.14
RCHO (1.05 eq)
Na2S2O5, DMA
R
12
N
H
13a-i
80 °C, 16 h
Compound
R
Yield (%)
13a
13b
13c
13d
13e
13f
13g
13h
13i
Ha
Ph
73
88
52
82
72
83
81
66
57
3-Methoxyphenyl
4-Methoxyphenyl
2-Chlorophenyl
4-Chlorophenyl
4-Pyridyl
tert-Butyl
n-Pentyl
a
Prepared using neat CH(OMe)3, reflux, 1 h.
Having found a reliable method for the chemoselective reduc-
tion of the 2,1,3-benzothiadiazole ring, we turned our attention
to the conversion of phenylenediamine sulfonamide 12 to substi-
tuted benzimidazoles. We found that the reaction of 12 with a vari-
ety of aryl, heteroaryl, and alkyl aldehydes proceeded smoothly in
the presence of Na2S2O5 as an oxidant, providing 2-substituted
Table 3
Conversion of 2,1,3-benzothiadiazoles 10 and 11 to benzimidazoles 16a–g and 17a–g
R1
R1
O
O
O
S
S
O
R2CHO, Na2S2O5
NH2
NH2
N
Zn, AcOH
R2
10 or 11
N
H
14: R1 = NHBn (76%)
16a-g
17a-g
15: R1 = N-piperidinyl (80%)
Table 1
Compound
R1
R2
Yield (%)
Reduction of 2,1,3-benzothiadiazole 9 to phenylenediamine 12
16a
16b
16c
16d
16e
16f
Ph
79
77
49
76
74
67
70
O
O
NHPh
NH2
4-Methoxyphenyl
S
N
H
3-Methoxyphenyl
4-Chlorophenyl
2-Chlorophenyl
tert-Butyl
conditions
9
NH2
16g
n-Pentyl
12
17a
17b
17c
17d
17e
17f
Ph
94
79
76
87
70
82
37
Entry
Reagents and conditions
Yield (%)
4-Methoxyphenyl
3-Methoxyphenyl
4-Chlorophenyl
2-Chlorophenyl
tert-Butyl
N
1
2
3
4
5
LiAlH4, Et2O, 23 °C
Mg, MeOH, reflux, 16 h
<5
<5
27
38
84
NaBH4/CoCl2, EtOH, reflux, 1 h
Sn/HCl, 50 °C, 2 h
Zn/AcOH, 50 °C, 1 h
17g
n-Pentyl

M. D. Rosen et al. / Tetrahedron Letters 50 (2009) 1219–1221
1221
13. DaSilveira Neto, B. A.; Lopes, A. S.; Wust, M.; Cost, V. E. U.; Ebeling, G.; Dupont,
J. Tetrahedron Lett. 2005, 46, 6843–6846.
14. Pesin, V. G.; Sergeev, V. A.; Khaletskii, A. M. Zh. Obsch. Khim. 1964, 34, 1263–
1266.
15. Fray, J. M.; Cooper, K.; Parry, M. J.; Richardson, K.; Steele, J. J. Med. Chem. 1995,
38, 3514–3523.
phenylenediamines into fully functionalized benzimidazole-4-sul-
fonamides was demonstrated. This methodology is tolerant of a wide
variety of aryl, heteroaryl, and alkyl substitution, and is suitable for
the preparation of diverse sets of benzimidazole sulfonamides.
16. Representative Procedure for Reduction of 2,1,3-Benzothiadiazoles-4-sulfonamides
to Phenylenediamines: 2,3-Diamino-N-phenyl-benzenesulfonamide hydro-
Acknowledgments
chloride (12).
A mixture of 9 (1.5 g, 5.2 mmol) and AcOH (20 mL) was
warmed to 50 °C with stirring, then zinc dust (1.7 g, 26 mmol) was added in
portions over 10 min. The reaction mixture was stirred for 1 h, and then was
allowed to cool to room temperature. The mixture was diluted with MeOH and
filtered through Celite, rinsing well with MeOH, and filtrate was concentrated.
The residue was partitioned between saturated aqueous NaHCO3 (150 mL) and
EtOAc (100 mL), and the organic phase was collected. The aqueous phase was
extracted with two additional volumes of EtOAc (100 mL). The combined
organic phases were dried with Na2SO4 and concentrated to give 1.5 g of a
crude yellow solid. This material was suspended in MeOH (15 mL) and cooled
to 0 °C, then HCl (4.0 M in dioxane, 6.5 mL, 26 mmol) was added, and a green
solution was obtained. This solution was concentrated, and the residue was
triturated well with Et2O to provide the hydrochloride salt 12 as a solid (1.3 g,
84%). This material was sufficiently pure to be used in the subsequent step (92-
94%, HPLC). 1H NMR (600 MHz, DMSO-d6) d 10.55 (s, 1H), 7.51 (d, J = 8.0 Hz,
1H), 7.31 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.9 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.99
(t, J = 7.4 Hz, 1H), 6.67 (t, J = 7.9 Hz, 1H).; 13C NMR (150 MHz, DMSO-d6) d
139.7, 137.2, 129.2, 129.1, 128.4, 123.8, 121.7, 120.3, 119.2, 115.4; MS (ESI/CI)
m/z 264.1 [MH]+. Anal. Calcd for C12H14ClN3O2S: C, 48.08; H, 4.71; N, 14.02.
Found: C, 47.98; H, 5.17; N, 14.04.
We are grateful for a CORD Fellowship for Z.M.S. from Johnson &
Johnson Corporate Office of Science and Technology. We also thank
Dr. Jiejun Wu for helpful discussions regarding 1H and 13C NMR
spectra of tautomeric benzimidazoles.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.015.
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assignable are noted)
d 154.3 (major tautomer), 154.1 (minor tautomer),
146.6, 140.7, 139.2, 137.0, 131.6 (major tautomer), 131.5 (minor tautomer),
130.4 (major tautomer), 130.3 (minor tautomer), 130.1 (minor tautomer),
129.9 (major tautomer), 129.8 (minor tautomer), 129.6 (major tautomer),
128.1 (minor tautomer), 128.1 (major tautomer), 125.8 (minor tautomer),
125.3 (minor tautomer), 125.0 (major tautomer), 123.8 (minor tautomer),
123.1(major tautomer), 122.8 (major tautomer), 122.5 (minor tautomer), 122.0
(minor tautomer), 121.5 (major tautomer), 117.1 (major tautomer). MS (ESI)
m/z 350.1 [MH]+. Anal. Calcd for C19H15N3O2S: C, 65.31; H, 4.33; N, 12.03.
Found: C, 64.99; H, 4.68; N, 12.06.
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