Phosphonium-mediated cyclization of N-(2-aminophenyl)thioureas: Efficient synthesis of 2-aminobenzimidazoles

Article abstract of DOI:10.1016/j.tetlet.2011.05.146

BOP efficiently promoted the phosphonium-mediated cyclization of thioureas, leading to a convenient synthesis of 2-aminobenzimidazoles. Compared to conventional methods, the reactions were complete at room temperature with times ranging from a few minutes

Full text of DOI:10.1016/j.tetlet.2011.05.146

Tetrahedron Letters 52 (2011) 4149–4152
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Phosphonium-mediated cyclization of N-(2-aminophenyl)thioureas:
efficient synthesis of 2-aminobenzimidazoles
⇑
Zhao-Kui Wan , Erena Farah Ousman, Nikolaos Papaioannou, Eddine Saiah
Pfizer Worldwide Research and Development, Pfizer Inc., 200 Cambridge Park Drive, Cambridge, MA 02140, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
BOP efficiently promoted the phosphonium-mediated cyclization of thioureas, leading to a convenient
synthesis of 2-aminobenzimidazoles. Compared to conventional methods, the reactions were complete
at room temperature with times ranging from a few minutes to 1 h in near quantitative yields. This
method is also applicable to the synthesis of more challenging structures such as 2-akylaminobenzimi-
dazoles and 2-(N-acyl)-aminobenzimidazoles. The methodology described herein represents a mild
and efficient route to a variety of 2-aminobenzimidazoles.
Received 10 May 2011
Revised 26 May 2011
Accepted 29 May 2011
Available online 23 June 2011
Keywords:
Phosphonium-mediated cyclization
Thioureas
Ó 2011 Elsevier Ltd. All rights reserved.
2-Aminobenzimidazoles
Introduction
its N-1 isomer), when 2-amino-5-phenylacylbenzimidazole was
treated with methyl chloroformate.12
2-Aminobenzimidazoles are interesting heterocycles that are
found both in natural products as well as in drugs and drug candi-
dates.1 Despite the prevalence of the 2-aminobenzimidazole motif
in drugs and natural products, the synthesis of 2-aminobenzimi-
dazoles remains challenging. The conventional syntheses typically
involve the mediation of a metal salt, alkylating agent or acylating
agent.2 While these methods are valuable, they also suffer from
various limitations. A typical method for the cyclization of thio-
ureas involves using stoichiometric amounts of metal salts of mer-
cury2–4 and copper,5,6 as well as oxidants such as PhI(OAc)2.7
Another method relies on nonselective alkylating and acylating
agents such as methyl iodide8 and sulfonyl chloride.9 Recent ad-
vances in this area using carbodiimide based reagents, such as
DCC and EDC,10 represent a milder method, but frequently require
heating and long reaction times. Furthermore, formation of urea
side-products can pose significant challenges during purification.
The direct synthesis of 2-(N-acyl)aminobenzimidazoles,
through thiourea intermediates, is also challenging and has been
sporadically reported with limited success.11 This subclass of benz-
imidazoles possesses unique properties and has been exploited in
the development of compounds such as Mebendazole 2 (Scheme
1, R = PhC(@O), R0 = OMe). Conventional acylation of 2-aminobenz-
imidazoles often lacks regio-selectivity and thus, leads to the
formation of complex mixtures (Scheme 1).2 For instance,
Mebendazole was obtained as a minor product (a 1: 5 mixture with
We previously disclosed an efficient phosphonium-mediated
bond formation13 and applied this method to the synthesis of het-
erocycles such as 2-amino-3,4-oxadiazoles in an intermolecular
fashion.13d While this methodology works well in various hetero-
cyclic systems, formation of 2-aminobenzimidazoles from the
corresponding benzimidazol-2-ones or benzimidazol-2-thiones
was not successful. To circumvent this problem, we envisioned
that an intramolecular amination would facilitate the formation
of the desired products.
To our satisfaction, treatment of thiourea 6a with BOP
(1.5 equiv) in the presence of DBU (2.0 equiv) in MeCN provided
the desired product 7a at room temperature in near quantitative
conversion, without the formation of side products, in just
10 min (Scheme 2). A solvent screen using the cyclization of thio-
urea 6a as a model reaction (Scheme 2, Table 1) revealed that
O
R'
NH2
O
NH
N
R'COX
R'
R'
N
N
N
NH2
+
+
N
H
R
N
H
R
R
1
2
3
O
O
R'
NH
N
N
+
NH
R'
N
R
N
R'
R
4
O
5
O
⇑
Corresponding author.
E-mail address: zhao-kui.wan@pfizer.com (Z.-K. Wan).
Scheme 1. Nonselective synthesis of 2-(N-acyl)amino-benzimidazoles in literature.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.146

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Z.-K. Wan et al. / Tetrahedron Letters 52 (2011) 4149–4152
H
N
H
N
BOP, DBU
N
BOP (1.5 eq), DBU (2.0 eq)
H
N
H
N
R
N
MeCN, rt
NH
R
30 min
S
MeCN, rt
NH
N
H
X
X
NH2
10 - 70 min
S
N
H
NH2
99% conv
NMe2
6a - n: R = aryl, akyl
7a - n: R = aryl, akyl
6a
7a
8a - f: R = C(=O)-aryl, CO2R'
9a - f: R = C(=O)-aryl, CO2R'
N
N
Me2N P+
Me2N
O N
Scheme 3. Synthesis of 2-aryl- and 2-alkyl-amino-benzimidazoles and 2-N-
(acyl)amino-benzimidazoles.
-
PF6
BOP
Scheme 2. BOP-mediated synthesis of 7a.
Table 3
Phosphonium mediated synthesis of 2-aryl- and 2-alkyl-amino-benzimidazoles16
Entry
Substrate
X
R
Product
7a
Yielda (%)
Table 1
Base effect on the formation of 7a from 6aa
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
H
H
H
H
H
H
94
97
96
76
98
91
Entry
Base
Conv (%)
1
2
3
4
5
6
7
58
—
DBU
DBN
DIPEA
TEA
DMAP
Pyridine
Cs2CO3
Trace
99
95
86
25
9
7b
O
7c
CN
Cl
7d
5
23
7e
a
Reaction was run at rt (BOP: 1.5 equiv; base: 2.0 equiv); reaction was moni-
CF3
7f
tored by LC–MS at 30 min.
F3C
7
8
6g
6h
H
H
7g
7h
73b,c
91
solvents, such as acetonitrile and dimethylformamide (DMF) were
optimal amongst the solvents screened (DCM, THF, EtOAc, acetone,
MeCN, DMF and DMSO). Furthermore, a base screen showed that
stronger organic bases, such as DBU, DBN and diisopropylethyl-
amine (DIPEA) are preferred (entries 2–4, respectively) and that
the reaction does not proceed in the absence of a base. Reaction
with inorganic bases such as Cs2CO3 was observed albeit with
low conversion (23%).14
After completing the solvent and base studies, we turned our
attention to evaluating a variety of commercially available phos-
phonium reagents. We chose to include EDC in this evaluation as
we were eager to compare our method with the literature meth-
ods. We began as before with 6a and employed our previously
optimized conditions (DBU, acetonitrile and activating agent).
The reactions were monitored at 10 and 30 min, respectively, by
LC–MS (Table 2). The reaction with BOP proceeded to near comple-
tion in just 10 min (entry 1) and was found to be the optimal
reagent of the ones evaluated (PyBOP, PyAOP, BroP, PyBroP, Ph3PI2
and EDC). Interestingly, in a head-to-head comparison, the BOP
mediated reaction was complete in 10 min. while the EDC
promoted reaction was at 16% conversion after 10 min (entry 7).
With the reaction conditions tuned, we set out to evaluate the
substrate scope of our method (Scheme 3, Tables 3 and 4). As
disclosed in Table 3, most reactions were complete within 1 h at
room temperature. The desired products were isolated in good to
9
6i
H
7i
99
94
97
99
95
10
11
12
13
6j
F
7j
6k
6l
CN
NO2
7k
7l
6m
CO2Et
7m
O
CO2Et
14
6n
7n
95
Ph
a
b
c
Isolated yield by SiO2 column chromatography.
Precipitation observed during column purification.
Quantitative conversion observed by LC–MS.
excellent yields with no obvious electronic effect observed. Neither
electron rich (entries 2 and 3) nor electron deficient substituents
(entries 4–7; 10–14) affected the reaction efficiencies or the
reaction times. A steric effect was also briefly explored. Compared
with cyclization of 6f, which was complete in 10 min at room
temperature, the cyclization of ortho-substituted thiourea 6g was
complete within 1 h. Furthermore, this method is useful for the
construction of 2-alkylaminobenzimidazoles, which tends to be
more challenging. The treatment of alkyl thioureas 6h and 6i with
BOP under the standard conditions provided the desired 2-alkyla-
minobenzimidazoles 6h and 6i within 30 min in excellent yields
(91% and 99%, respectively, entries 8 and 9). Overall, the assembly
of compounds found in Table 3 is efficient under the BOP-mediated
cyclization conditions and is complementary to other methods.
With our substrate scope studies complete, we were curious to
see if our method could be applied to the direct synthesis of 2-(N-
acyl)-aminobenzimidazoles. Direct and selective synthesis of these
compounds has been rarely reported in the literature.12 We found
that treatment of a variety of acylthioureas 8a–f with BOP under
Table 2
Activation agent effect on the formation of 7a from 6aa
Entry
Base
Conv (10, 30 min)
1
2
3
4
5
6
7
BOP
98, 99+
26, 58
50, 60
PyBOP
PyAOP
Ph3Pl2
BroP
PyBroP
EDC
ꢀ50, ꢀ50b
<5, ꢀ5
<5, ꢀ5
16, 28c
a
b
c
Reaction (BOP: 1.5 equiv; base: 2.0 equiv) was monitored by LC–MS.
Reaction was messier than others.
No DBU used.

Z.-K. Wan et al. / Tetrahedron Letters 52 (2011) 4149–4152
4151
Table 4
BOP, DBU
O
O
N
NH2
S
Synthesis of 2-(N-acyl)aminobenzimidazoles
MeCN, rt
30 min
NH
Entry
1
Substrate
X
R
Product
Yielda (%)
77
95%
N
H
N
H
eq. 1
eq. 2
N
H
O
O
O
12
13
8a
H
9a
BOP, DBU
MeCN, rt
30 min
N
N
S
H
N
N
H
O
N
H
N
H
81%
2
3
8b
8c
H
H
9b
9c
95
O
14
15
87 (94b)
Scheme 5. Synthesis of 2-(phenylamino)quinazolin-4(3H)-one 13 and 2-Phenyla-
mino-5-phenyl-1,3,4-oxadiazole 15.
O
O
4
8d
H
H
9d
76
-
H
N
H
N
H
N
PF6
R
P+
H
N
DBU
BOP
- HOBt
N
N
+ HOBt
R
Cl
R
S
NMe2
NMe2
S
OBt
O
O
- (Me2N)3P=S
NH2
NH2
NH2
5
6
8e
8f
9e
9f
94
98
NMe2
O
O
6
A
B
- (Me2N)3P=S
O
- HOBt
- HOBt
Ph
DBU
- (Me2N)3P=S
a
Product collected by direct filtration of the crude reaction mixture.
Isolated yield by SiO2 column chromatography.
b
H
N
DBU
N
SH
N
BOP
5-exo
N
R
R
NH
R
N
H
N
H
- HOBt
NH2
N
H
- (Me2N)3P=S
Method A:
D
C
ArNCS, BOP, DBU
7
NH2
NH2
N
MeCN, rt
NH
N
H
Scheme 6. Proposed mechanism.
X
X
Method B:
i) ArNCS, MeCN, rt
11a: X = Me, 83%
11b: X = Br, 82%
ii) BOP, DBU, MeCN, rt
10a - b
hexamethylthio-phosphonamide [(Me2N)3P@S)]. Intermediate A
could also be subject to nucleophilic attack by HOBt and lead to
the formation of the second intermediate B. In addition, intramo-
lecular cyclization of B could lead to product 9 upon expulsion of
HOBt. Alternatively, both intermediates A and B could be trans-
formed into intermediate C upon loss of 1 equiv (Me2N)3P@S or
HOBt, respectively. Intramolecular cyclization of C would provide
the same product 7. Compound 6 may be in equilibrium with
intermediate D10b, which could also lead to the desired product
7, upon activation by BOP.
Scheme 4. Synthesis of 11a and 11b in one-pot fashion.
the optimized conditions afforded the desired products 9a–f in
excellent yields and as single regioisomers (Scheme 3, Table 4).
As an illustration of this method, a close analogue of Mebendazole
was synthesized (Table 4, entry 6, 9f, 98%) in near quantitative
yield. Furthermore, we found that a number of products directly
precipitated out of the reaction mixtures and could be collected
by filtration. As in our previous studies, no electronic effect was ob-
served. In order to increase the utility of our method, we decided to
explore whether the two step sequence (thiourea formation and
cyclization) could be executed in a one-pot synthesis. We were
surprised to find that while the method A (without pre-formation
of thioureas) provided the desired product, a two-step, one-pot
protocol in method B offered a cleaner reaction. As an example,
treatment of diamine 10a and 10b with phenylthioisocyanate in
MeCN followed by the reaction with BOP reagent in the presence
of DBU provided the desired products 11a and 11b in 83% and
82% isolated yields, respectively (Scheme 4).
This BOP-mediated methodology was also briefly tested in other
heterocyclic systems. When thiourea 12 was treated with BOP
reagent, the desired 2-(phenylamino)quinazolin-4(3H)-one 13 was
isolated in 95% yield (Scheme 5, eq. 1). Similarly, acyl-thiosemicar-
bazide 14 was converted to the desired 2-phenylamino-5-phenyl-1,
3,4-oxadiazole 15 in 81% yield (Scheme 5, eq. 2).15
Although the detailed reaction pathway is not known, involve-
ment of one or more of intermediates A, B, C and D might be
possible. We propose that the intermediate A is formed upon
Conclusion
A facile and efficient, phosphonium-mediated synthesis of 2-
aryl and 2-alkyl-amino-benzimidazoles has been discovered, thus
providing a highly efficient and complementary route to these
biologically interesting heterocycles. Selective formation of
2-(N-acyl)aminobenzimidazoles was also possible under similar
conditions.
Acknowledgements
We thank the Pfizer Summer Intern Program for a summer
intership (EFO), Ms. Eva Chenail, Dr. Sumrit Wacharasindu and
Dr. Christopher Levins for technical support, Dr. Walter Massefski
for NMR studies on tautomerization of thiourea 6a to intermediate
D, Dr. Tarek Mansour for useful discussions and Dr. Neelu Kaila for
reviewing this manuscript.
nucleophlic attack of
6
to BOP after elimination of 1 equiv
Supplementary data
1-hydroxybenzotriazole (HOBt). Once formed, a number of possible
pathways become viable (Scheme 6). Intramolecular cyclization of
A would lead to the desired product 7 upon the loss of 1 equiv of
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.146.

4152
Z.-K. Wan et al. / Tetrahedron Letters 52 (2011) 4149–4152
10. Selected recent examples: (a) Omar, A.-M. M. E.; Habib, N. S.; Aboulwafa, O. M.
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