A practical synthesis of 2-(N-substituted)-aminobenzimidazoles utilizing CuCl-promoted intramolecular cyclization of N-(2-aminoaryl)thioureas

Article abstract of DOI:10.1016/j.tetlet.2004.07.042

A practical protocol for synthesis of 2-(N-substituted)-aminobenzimidazoles was developed. N-(2-Aminoaryl)thioureas undergo a CuCl-promoted intramolecular cyclization to give the corresponding 2-(N-substituted amino)benzimidazoles in good to excellent isolated yields.

Full text of DOI:10.1016/j.tetlet.2004.07.042

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7167–7170
A practical synthesis of 2-(N-substituted)-amino-
benzimidazoles utilizing CuCl-promoted intramolecular
cyclization of N-(2-aminoaryl)thioureas
*
Xiao-jun Wang, Li Zhang, Yibo Xu, Dhileepkumar Krishnamurthy and
Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield CT 06877, USA
Received 16 June 2004; revised 24 June 2004; accepted 8 July 2004
Abstract—A practical protocol for synthesis of 2-(N-substituted)-aminobenzimidazoles was developed. N-(2-Aminoaryl)thioureas
undergo a CuCl-promoted intramolecular cyclization to give the corresponding 2-(N-substituted amino)benzimidazoles in good
to excellent isolated yields.
Ó 2004 Elsevier Ltd. All rights reserved.
2
-(N-substituted)-aminobenzimidazoles are widely used
stituted)-aminobenzimidazole moieties from their
corresponding N-(2-aminoaryl)thioureas since the cur-
rently available methods using HgO and dehydration
conditions, such as DCC, are impractical for a large
scale preparation. Furthermore, cyclocondensation of
diamines with 2,6-dichlorophenylcarbonimidoyl dichlo-
ride was found to be inefficient to 1 and 2 due to the
structural motifs in drug discovery and represent the
core structure for a variety of biologically significant
molecules. A considerable number of synthetic method-
1
ologies have been reported for the synthesis of unsubsti-
tuted 2-aminobenzimidazoles. However, there are a very
limited number of methods for the preparation of 2-(N-
substituted)-amino derivatives. The most widely used
approach is oxidation–cyclization of N-(2-amino-
aryl)thioureas with highly toxic mercury(II) oxide in
absolute ethanol. In connection with a drug discovery
program, we recently required an efficient entry into a
new class of potent inhibitors of the tyrosine kinase
5
reduced reactivity of the corresponding diamines. To
circumvent these limitations, we have searched for a
thiophilic metal reagent that is less toxic and efficient
to promote an intramolecular cyclization of N-(2-amino-
aryl)thioureas.
2
,3
4
p56lck, exemplified by 1 and 2 (Fig. 1). We were parti-
cularly interested in the practical synthesis of 2-(N-sub-
Herein we disclose that copper(I) salts are highly effi-
cient in promoting an intramolecular cyclization of
thioureas to the corresponding 2-(N-substituted)-amino-
6
benzimidazoles in good to excellent isolated yields. The
initial experiments were performed with thiourea 3 using
CuI in the presence of diisopropylethylamine in a 5:1
mixture of toluene and acetonitrile. A portion of Celite
was added to the reaction mixture to facilitate filtration
after complete conversion. Thus, after heating at 80°C
for 30min, 2-aminobenzimidazole 4 was isolated in
71% yield without any difficulty. Encouraged by this
result we set out to explore the scope of this cyclization
with respect to different copper(I) and copper(II) salts.
The results of this investigation are summarized in Table
Cl
N
Cl
N
NH Cl
NH Cl
N
H
N
H
O
N
H
O
N
H
O
5
a
1
2
Figure 1.
1
. Thiourea 3 was prepared by condensation of 1,2-
Keywords: Aminobenzimidazole; CuCl; N-(2-Aminoaryl)thiourea.
*
Corresponding author. Tel.: +1 203 791 6168; fax: +1 203 791
199; e-mail: xwang@rdg/boehringer-ingelheim.com
phenylenediamine with 3,5-dichlorophenyl isothiocya-
nate and isolated in 90% yield after recrystallization. It
6
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.042

7168
X. Wang et al. / Tetrahedron Letters 45 (2004) 7167–7170
Table 1. Copper(I) and (II) salt-promoted cyclization of 3 to 4
Cl
H
H
N
Cl
N
N
S
NH
NH2
N
H
3
4
a
Yield (yield) (%)
b
Entry
Copper reagents
Equivalents
Equivalent of iPr
2
NEt
Reaction time (h)
1
2
3
CuI
CuBr
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.1
2.1
2.1
2.1
2.1
2.1
2.1
0.5
0.5
0.5
1.0
1.0
1.0
1.0
71 (79)
71 (80)
80 (86)
87 (93)
80 (83)
(47)
CuBrÆSMe
CuCl
2
7
4
5
6
7
CuOAc
CuBr
CuCl
2
2
40 (65)
a
Isolated yield by crystallization from toluene or ethyl acetate.
Weight % assay by HPLC.
b
6
is important to note that CuCl-promoted cyclization of
provided the best result to produce 4 (entry 4). Inter-
estingly, copper(II) salts such as CuCl2 and CuBr2
entries 6 and 7) were much less effective in promoting
this cyclization with a moderate yield of 4. While a firm
explanation for this behavior cannot be given, one can
conclude that copper(II) salts may be less thiophilic than
copper(I) salts. It is obvious that more air-sensitive cop-
per(I) salts such as CuI, CuBr, and CuOAc (entries 1, 2,
and 5) are less effective than more air-stable CuCl (entry
4). This observation may be attributable to the fact that
more air-sensitive CuI, CuBr, and CuOAc are readily
oxidized to copper(II) salts under the stated reaction
condition making them less effective. Subsequently, it
3
(
Table 2. Cyclization of N-(2-aminoaryl)thioureas to 2-(N-substituted)-aminobenzimidazoles with CuCl
a
a
b
Entry
Thiourea
Product
Time (h)
0.5
Yield (%)
S
NH
NH
N
NH
NH
1
78
NH
NH
N
H
2
S
N
2
NH
NH
1.5
86
N
H
2
Cl
S
NH
NH
NH
8
,c
NH
3
1.0
1.5
78
79
N
NH
NH2
N
H
Cl
S
c
4
N
NH
NH
N
H
NH
2
S
MeO C
N
2
c
5
NH
NH
2.0
1.5
82
74
NH
CO Me
N
2
H
2
H
N
S
N
6
2
MeO C
NH
NH2
NH
N
H
MeO C
2

X. Wang et al. / Tetrahedron Letters 45 (2004) 7167–7170
7169
Table 2 (continued)
a
a
b
Entry
Thiourea
Product
Time (h)
3.0
Yield (%)
S
Cl
N
NH Cl
MeO C
7
2
NH
Cl
NH
86
90
NH Cl
MeO C
N
H
2
2
S
MeO C
N
2
NH
8
NH
NH2
1
0.5
NH
CO Me
2
N
MeO C
2
MeO C
H
2
a
13
All new compounds had satisfactory H and C NMR, MS and elemental analyses.
Isolated yield by recrystallization from ethyl acetate (not optimized).
Thiourea as a 3:1 to 5:1 mixture of two regioisomers.
b
c
was also found that cyclization of 3 with fresh CuI and
arylenediamine 5 with 2,6-dichlorophenyl isothiocyanate
in a 2:1 mixture of toluene and acetonitrile led to thio-
urea 6. Without work-up or isolation, this reaction mix-
ture was directly subjected to CuCl in the presence of
CuBr was faster and generally higher yielding. Clearly,
CuCl is a more amenable reagent for this transforma-
tion on a large scale considering that CuCl is easier to
handle and more economical. The cyclization proceeds
fairly efficiently in many organic solvents; however, tolu-
ene was found to be more desirable because copper by-
products precipitated from the reaction mixture, which
can be efficiently removed by filtration. Addition of
acetonitrile was necessary to facilitate dissolution of
both copper reagents and thiourea 3 for cyclization
process. Interestingly, triethylamine and N-methyl-
morpholine provided sluggish cyclization, which may
be due to the precipitation of their copper complexes.
iPr NEt and Celite. After 1h at 80°C, the cyclization
2
was completed. Crystallization of the crude product from
ethyl acetate afforded 7 in an 82% overall yield (two
steps). Compound 7 was then converted to 2 using a
4
known literature procedure without any difficulty.
In conclusion, we have developed a very simple and
practical procedure for preparation of a wide variety
of 2-(N-substituted)-aminobenzimidazoles via CuCl/
iPr NEt mediated thiourea cyclization. This procedure
2
is amenable to scale-up for many aminobenzimidazoles,
and it is general and can be applied to many biological
targets.
The scope of this newly-discovered methodology was
extended to a variety of N-(2-aminoaryl)thioureas using
CuCl as the promoter. The results summarized in Table
2
illustrate that CuCl-promoted cyclization of N-(2-amino
aryl)thioureas provides 2-(N-substituted)-aminobenz-
imidazoles bearing a wide range of substituents in good
to excellent isolated yields. Thioureas were prepared by
condensation of appropriate 1,2-arylenediamines with
either commercially available or in situ prepared isothio-
cyanates in excellent yields by simple recrystallization.
We next applied this methodology to the synthesis of
lck inhibitor 2 (Scheme 1). Thus, condensation of 1,2-
References and notes
1. (a) Rastogi, R.; Sharma, S. Synthesis 1983, 861–882; (b)
Senanayake, C. H.; Hong, Y.; Xiang, T.; Vilkinson, H. S.;
Bakale, R. P.; Jurgens, A. R.; Pippert, M. F.; Butler, H. T.;
Wald, S. A. Tetrahedron Lett. 1999, 40, 6875–6879.
. Perkins, J. J.; Zartman, A. E.; Meissner, R. S. Tetrahedron
Lett. 1999, 40, 1103–1106, and references cited therein.
. Seth, P. P.; Robinson, D. E.; Jefferson, E. A.; Swayze, E. E.
Tetrahedron Lett. 2002, 43, 7303–7306.
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Morwick, T. M.; Prokopowicz, A. S.; Takahashi, H.;
Tan, J. D.; Tschantz, M. A.; Wang, X.-J. Tetrahedron Lett.
2002, 43, 7553–7556.
5. (a) Murphy, D. B. J. Org. Chem. 1964, 29, 1613–1615; (b)
Ayyangar, N. R.; Brahme, K. C.; Srinivasan, K. V.
Synthesis 1987, 64–65.
3
2
3
4
Cl
H
NH2
H
N
N
MeO C
ArNCS
toluene
3
2
MeO C
S
Cl
NH2
2
NH
2
CN
CH CN
O
CN
O
6. For complexes between copper(I) and (II) salts with
thioureas, see: (a) Taylor, I. F., Jr.; Weininger, M. S.;
Amma, E. Inorg. Chem. 1974, 13, 2835–2842; (b) Weinin-
ger, M. S.; Hunt, G. W.; Amma, E. Chem. Commun. 1972,
5
6
Cl
N
2
0, 1140–1141, and references cited therein.
CuCl/iPr
2
NEt
7. A typical experimental procedure: To a suspension of
thiourea 3 (12.1g, 43.56mmol) and Celite (4.0g) in a 4:1
mixture of toluene and acetonitrile (135mL) was added
diisopropylethylamine (16.7mL, 95.83mmol), followed by
CuCl (9.0g, 90.92mmol). The resulting mixture was heated
to 80°C and kept at this temperature for 30min. The
reaction mixture was then cooled to 40°C and filtered. The
NH Cl
MeO C
2
2
toluene
CH CN
2%
N
H
3
CN
O
8
7
Scheme 1.

7170
X. Wang et al. / Tetrahedron Letters 45 (2004) 7167–7170
filtrate was washed with a 4:1 mixture of toluene and
acetonitrile (40mL). The combined filtrates were washed
with 7% ammonium hydroxide (120mL) and concentrated
to about 100mL. The solution was cooled to room
temperature and kept at room temperature for 5h. The
slurry was filtered to give 4 as a light brown solid (9.2g,
(400MHz, DMSO-d
(ABq, J = 8.8Hz, 2H), 7.37 (ABq, J = 8.8, 2H), 7.37 (m,
2H), 7.02 (m, 2H); C NMR (400MHz, DMSO-d ) d
6
) d 11.01 (br s, 1H), 9.62 (s, 1H), 7.85
1
3
6
150.2, 139.9, 128.5, 123.9, 120.2, 118.5; LRMS m/z 244
+
(M + 1); HRMS (APCI) calcd for C13
+
(M + 1)
H11ClN
3
244.0636, found 244.0636.
8. El-Sharief, A. M.; Ammar, Y. A.; Mohamed, Y. A.;
El-Gaby, M. S. A. Heteroat. Chem. 2002, 13, 291–298.
8
7%). An analytical sample of 4 was obtained by recrys-
5
a 1
tallization from ethyl acetate: mp 195–197°C;
H NMR