P. Lan et al. / Tetrahedron Letters 49 (2008) 1910–1914
1911
Table 1
Recently, efforts have been made to apply a palladium
catalyst to 2-chlorobenzimidazole to synthesize 2-alkyl-
amino and -alkoxy benzimidazoles.11
Substitution of 2-methylsulfonylbenzimidazole 1 with m-cresol (3) under
various conditions
Besides 2-chlorobenzimidazoles, 2-methylsulfonylbenz-
imidazoles have also served as intermediates to synthesize
2-substituted benzimidazoles. Methylsulfonylbenzimidaz-
ole was shown to react with alcohols formed in situ from
epoxides in an intramolecular fashion with the methylsulf-
one acting as a leaving group.12 Also, there are examples
showing that the nucleophilic displacement of 2-methylsulf-
one moiety in compound 1 proceeded smoothly with
thiophenol.6 Alkylamines react with 2-methylsulfonylbenz-
imidazoles when the benzimidazole nitrogen was pro-
tected13 or when harsh conditions were applied (>150 °C,
high pressure).14 Thus, the development of a more efficient
and unified method for assembling 2-substituted benzimi-
dazoles with more diverse functional groups could become
a valuable addition to the synthetic arsenal toward the syn-
theses of these pharmaceutically important scaffolds.
In connection with a drug discovery program, we
recently required an efficient entry into the substitution of
a benzimidazole at the 2-position with a diverse set of
nucleophiles. We chose 2-methylsulfonylbenzimidazole (1)
as the key intermediate to explore. Compound 1 can be
readily synthesized under mild conditions via methylation
of benzimidazole-2-thione followed by oxidation with
3-chloroperoxybenzoic acid.15 By applying the same syn-
thetic route, other substituted 2-methylsulfonyl benzimida-
zoles (e.g., 5-methoxy-2-(methylsulfonyl) benzimidazole)
could also be accessed in good yield and on multigram
scale.
With the desired intermediate 1 in hand, we initially set
out to test the reactivity between 1 and thiophenols using
ethanol as the solvent. Thiophenols substituted with both
electron-withdrawing and electron-donating groups
reacted smoothly with 1 (Scheme 1). It should also be noted
that under these reaction conditions there is selectivity
between a thiophenol and phenol (i.e., 2e).
With the result of 2e in hand, it was not surprising to
observe that when similar conditions were applied to 1
and phenol 3, no conversion to the desired product was
observed with only starting material being recovered
(Table 1). Raising the temperature of the reaction to
Me
N
N
SO2Me
+
O
N
H
N
H
HO
Me
1
3
4
Entry
Solvent
Base
Temperaturea
Result
1
2
3
4
5
6
a
EtOH
DMF
DMF
EtOH
None
None
None
None
NaHb
Et3Nb
None
Et3Nb
rt to 180 °C
rt to 180 °C
rt to 180 °C
rt to 180 °C
120 °C
No reaction
No reaction
No reaction
Partial conversion
Completion, 28%c
Completion, 49%c
120 °C
Oil bath was used for heating at temperature lower than 160 °C;
microwave was used for heating at 180 °C.
b
Five equivalents of base was used.
Isolated yields.
c
180 °C also resulted in no product formation (Table 1,
entry 1). Replacing EtOH with DMF also had no effect
on conversion (Table 1, entry 2). Generating the phenoxide
with NaH (Table 1, entry 3) also resulted in no reaction.
This is consistent with previous observations that 2-chloro-
benzimidazole will not react with phenoxides and alkoxides
unless the benzimidazole nitrogen is protected.8,9 Adding
Et3N to the solvent appeared to have some beneficial effect
with extremely low conversion to product being observed
at higher temperatures (Table 1, entry 4). The use of micro-
wave heating resulted in no obvious benefit over traditional
heating.
On the other hand, it was gratifying to find that simply
mixing the two reactants together neat at 120 °C resulted in
the formation of the desired product 4 (Table 1, entry 5)
with an isolated yield of 28%. Finally, when 5 equiv of
Et3N were added to the same reaction conditions reported
in entry 5 the yield increased to 49% (Table 1, entry 6).16
Encouraged by this result, we set out to explore the
scope of this reaction condition with other nucleophiles
which include substituted phenols, anilines, alkylamines,
and alkylthiols.17 The results are summarized in Tables 2
and 3. We first explored the reaction of several substituted
phenols with benzimidazole 1 and its 5-methoxy analog
(Table 2). We were pleased to observe that both electron-
withdrawing and electron-donating groups in the ortho,
meta, and para positions of the phenol worked equally well
(30–66% yield) under the solvent-free conditions. Most
reactions required warming to 120 °C, but some needed
140 °C for complete conversion. Interestingly, 2-hydroxy
pyridine worked well under these conditions providing
the product in 62% yield. After the discovery of these reac-
tion conditions with 1 we enlisted 2-chloro benzimidazole
as the electrophilic partner with two different phenols
(Table 2, entries 6 and 7; data in parentheses) and subjected
them to the reaction conditions reported here. We observed
similar yields to that obtained with 1, albeit higher
R
N
N
SO2Me
EtOH
+
S
R
N
H
N
H
HS
rt, 16 hrs
1
2a-2e
R
Yield (%)
2a
H
62
80
78
75
68
2b 4-OMe
2c 3-F
2d 4-NHAc
2e 3-OH
Scheme 1.