A one-pot method for the synthesis of 2-aminobenzimidazoles and related heterocycles

Article abstract of DOI:10.1016/j.tetlet.2006.03.112

A rapid and efficient one-pot method for the synthesis of 2-aminobenzimidazoles and related heterocycles is described. The reaction is mediated by a polymer-supported carbodiimide, which simplifies product isolation. The scope and limitations of this method are described.

Full text of DOI:10.1016/j.tetlet.2006.03.112

Tetrahedron Letters 47 (2006) 3747–3750
A one-pot method for the synthesis of 2-aminobenzimidazoles
and related heterocycles
*
Victor J. Cee and Nicholas S. Downing
Amgen Inc., Chemistry Research and Discovery, One Kendall Square Building 1000, Cambridge, MA 02139, USA
Received 27 February 2006; revised 16 March 2006; accepted 17 March 2006
Available online 12 April 2006
Abstract—A rapid and efficient one-pot method for the synthesis of 2-aminobenzimidazoles and related heterocycles is described.
The reaction is mediated by a polymer-supported carbodiimide, which simplifies product isolation. The scope and limitations of this
method are described.
ꢀ
2006 Elsevier Ltd. All rights reserved.
The aminobenzimidazole is an important structural mo-
tif in medicinal chemistry and can be found in a number
of biologically active molecules. A popular approach to
Table 1. Application of reported cyclodesulfurization conditions in a
one-pot process
1
Br
H
this heterocycle involves the cyclodesulfurization of a
pre-formed thiourea (Eq. 1). Reported desulfurization
N
NH2
NH
NCS
2
N
ð2Þ
agents include mercury (II) oxide, mercury (II) chlo-
NH2
conditions
3
4
5
ride, copper (I) chloride, methyl iodide, tosyl chlo-
6
7
ride, and dicyclohexylcarbodiimide.
Br
H
N
Entry
Reagent
Conditions
Yield (%)
S
desulfurizing
H N HN
2
R1
NH
1
2
3
4
HgO, S (cat.)
CuCl
DCC
EtOH, reflux
4:1 PhMe/ACN, reflux
THF, 70 ꢁC
53
35
68
63
agent
HN
N
ð1Þ
R2
EDC
THF, 70 ꢁC
R1
R2
We recognized that this process could be considerably
simplified by the development of a one-pot procedure
involving the combination of a diamine, isothiocyanate,
and desulfurizing agent, thereby avoiding the isolation
of the intermediate thiourea (Eq. 2). To this end, meth-
ods reported for the cyclodesulfurization of thioureas
were studied in a one-pot process (Table 1). Metal-med-
While the carbodiimide conditions were acceptable, we
wished to avoid the time-consuming removal of carbo-
diimide byproducts from the reaction. A number of
reports have highlighted the procedural improvements
1
0
offered by polymer-supported (PS) carbodiimide, and
we found this reagent to be quite effective in promoting
the desired transformation (Table 2, Eq. 2). THF proved
to be the optimal solvent (entry 4), with toluene, DMF,
and DCE requiring longer reaction times. The amount
of PS-carbodiimide necessary to effect cyclodesulfuriza-
tion was also studied (entries 4–7) and 2 equiv of PS-car-
bodiimide (entry 5) proved to be optimal. The reaction
proceeded at ambient temperature (entry 8), but re-
quired an extended reaction time. Under optimized con-
ditions (entry 5), the desired benzimidazole was isolated
8
iated reactions proved to be significantly less effective in
a one-pot approach (entries 1 and 2), while carbodiimide
reagents, DCC and EDC (entries 3 and 4), provided bet-
9
ter yields.
Keywords: Aminobenzimidazole; Cyclodesulfurization; Polymer-sup-
ported carbodiimide.
*
Corresponding author. Tel.: +1 617 444 5197; fax: +1 617 621
908; e-mail: victor.cee@amgen.com
1
1
3
in 86% yield.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.112

3748
V. J. Cee, N. S. Downing / Tetrahedron Letters 47 (2006) 3747–3750
Table 2. Optimization of conditions for PS-carbodiimide-mediated
cyclodesulfurization Eq. 2
(entry 17). We subsequently found that aminobenzthiaz-
ole could be produced in good yield in the absence of
PS-carbodiimide. This result appears to be unique to
a
b
12
Entry Solvent Temp. (ꢁC) Equiv Time (h)
Yield (%)
2
-aminothiophenol; 2-aminophenol and o-phenylenedi-
1
2
3
4
5
6
7
8
PhMe
DMF
DCE
THF
THF
THF
THF
THF
70
70
70
70
70
70
70
20
3
3
3
3
2
1
0
2
2.5
4
6
2
2
48
—
24
79
98
72
97
amine do not produce cyclized products under the reac-
tion conditions in the absence of PS-carbodiimide.
1
3
c
d
99 (86)
The procedure could also be extended beyond phenylene
diamines (Table 4) to other diamine motifs, providing
94
—
98
a
Table 4. Cyclization of other diamines
a
b
c
Time until thiourea was consumed (monitored by TLC).
Measured by HPLC with naphthalene as internal standard.
b
Entry
Reactant
Product
Time
(h)
Yield
(%)
1,2-Dicholoroethane.
d
Isolated yield.
NH2
N
1
24
44
Ar
NH2
N
N
H
H
A variety of functionalized 2-aminobenzimidazoles can
be prepared from structurally diverse diamines (Table
H
O
H
N
O
N
Bn
c
2
3
4
Ar
24
18
6
62
NH2
3
). The reaction tolerated both electron withdrawing
N
NH2
groups (entries 3–6) and electron donating groups (en-
tries 7 and 8), although in the case of nitro-substituted
diamines (entries 3 and 4) extended reaction times were
necessary. The reaction was also successful with hetero-
Bn
NH2
H
N
49
63
NH
Ar
NH2
NH2
N
1
cyclic diamines (entries 12 and 13). N -Substituted benz-
H
N
imidazoles could also be obtained (entries 14 and 15),
but N-methyl phenylenediamine proved to be a difficult
substrate, requiring high temperature and extended
reaction time to achieve full conversion of the intermedi-
ate thiourea. Aminobenzoxazole was obtained from 2-
aminophenol in reasonable yield (entry 16). In contrast,
NH
Ar
NH2
N
a
b
c
Reaction conditions: 2 equiv PS-carbodiimide, THF, 70 ꢁC.
Ar = 4-bromophenyl.
Product is 99.8% ee as determined by chiral HPLC: ChiralPak AD-H,
2
-aminothiophenol provided the aminobenzthiazole
R R
5–40% isopropanol/heptane, 1 mL/min, T (major) = 12.0 min, T
(minor) = 9.7 min.
product in low yield under the standard conditions
Table 3. Diamine scope
Br
Br
R3
NH2
R3
N
ð3Þ
SCN
NH
2
equiv. PS-carbodiimide
X
R2
XH
R2
o
70 C, THF
R1
R1
Entry
R
1
R
2
R
3
X
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
H
H
Me
H
NO
CF
3
CN
OMe
4-Me-Piperazine
Br
F
H
H
H
H
H
H
H
H
H
F
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NMe
NPh
O
2
2
48
48
3
3
2
3
2
7
3
4
4
36
3
3
86
62
62
63
72
57
71
61
80
67
66
83
82
75
66
63
Me
NO
H
H
H
H
H
H
H
2
2
10
11
12
13
14
15
16
17
H
Cl
Cl
2,3-Diaminopyridine
3,4-Diaminopyridine
a
H
H
H
H
H
H
H
H
H
H
H
H
b
c
S
4
38 (75)
a
b
c
1
4
0
00 ꢁC, sealed tube.
equiv PS-carbodiimide.
equiv PS-carbodiimide.

V. J. Cee, N. S. Downing / Tetrahedron Letters 47 (2006) 3747–3750
3749
Table 5. Isothiocyanate scope
Br
S
PS-carbodiimide
70 ºC, THF, 40%
NH2
R2
N C N
ð5Þ
N
N
H
H
NH2
R1
N
Br
R1
R2
ð4Þ
2
eqiuv PS-carbodiimide
NH R3
SCN
70 ºC, THF
N
H
R3
A rapid and efficient one-pot method for the synthesis of
-aminobenzimidazoles and related heterocycles has
Entry
R
1
R
2
R
3
Time (h)
Yield (%)
2
1
2
3
4
5
6
7
8
9
1
1
1
1
H
H
H
H
H
H
Me
Me
Cl
Br
H
OMe
CN
NO
H
H
H
H
H
H
H
Me
Cl
2
4
4
3
2
3
5
24
2
4
86
85
64
75
66
71
86
54
88
75
68
63
73
been developed. The reaction is mediated by a poly-
mer-supported carbodiimide reagent, which simplifies
product isolation. This procedure is successful with a
wide range of structurally diverse diamine and isothiocy-
anate substrates, and does not require the isolation of
the intermediate thiourea. The related benzoxazole and
benzthiazole heterocycles can be produced under these
conditions, but it was found that the cyclization of 2-
aminothiophenol proceeds best in the absence of the
desulfurizing agent. It was also shown that PS-carbodii-
mide is capable of transforming a diaryl thiourea to the
corresponding carbodiimide under the reaction condi-
tions, suggesting that carbodiimides may be intermedi-
ates in the reaction.
2
COMe
H
H
H
0
1
2
3
1-Naphthylisothiocyanate
Benzyl isothiocyanate
22
16
3
Ethyl 2-isothiocyanatoacetate
Benzoyl isothiocyanate
quinazoline, imidazolinone, and hexahydrobenzimidaz-
ole products in modest yields. It is notable that the cycli-
zation of phenylalanine amide to aminoimidazolinone
Acknowledgements
(
entry 2) proceeds with no detectable racemization.
We thank Karina Romero for conducting preliminary
experiments, and Larry Miller and Matt Potter for chi-
ral HPLC analysis.
a
A variety of N -substituted aminobenzimidazoles could
be synthesized from diverse isothiocyanates (Table 5).
Electron donating (entry 3) and electron withdrawing
groups (entries 4–6) were well tolerated in the para posi-
tion. A single ortho-methyl substituent was well toler-
ated (entry 7), but 2,6-dimethylisothiocyanate required
an extended reaction time and provided only a modest
yield of the desired product (entry 8). In contrast, 2,6-
dichloroisothiocyanate (entry 9) was rapidly converted
to the aminobenzimidazole in excellent yield. It is nota-
ble that alkyl as well as acyl isothiocyanates were also
successful (entries 11–13).
References and notes
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. (a) Beaulieu, C.; Wang, Z.; Denis, D.; Greig, G.;
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7
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2
002, 45, 3394–3405; (d) Janssens, F.; Torremans, J.;
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(
Eq. 5) suggests that pathway A is possible, but does not
1
4
rule out pathway B.
4
5
6
Path A
N
C N
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H
N
NH2
R
R
7
. Omar, A.-M. M. E.; Habib, N. S.; Aboulwafa, O. M.
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N
N
NH
R
H
H
N
NH2
H
N
SH
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NH
R
N
H
Scheme 1. Possible mechanisms for benzimidazole formation.

3750
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9
. The use of dicyclohexylcarbodiimide for such a one-pot
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1
(0.124 g, 86% yield) as a white solid: H NMR (400 MHz,
6
DMSO-d ) d 11.16 (s, 1H) 9.70 (s, 1H) 7.77 (d, J = 8.8 Hz,
1
790.
2H) 7.47 (d, J = 8.8 Hz, 2H) 7.27–7.36 (m, 2H) 7.00 (dd,
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