Novel synthesis of 2-aminobenzimidazoles from isoselenocyanates

Article abstract of DOI:10.1055/s-0029-1219395

An efficient one-pot procedure for the synthesis of 2-aminobenzimidazoles from isoselenocyanates and various substituted diamines is described. Precipitation of elemental selenium from the reaction mixture greatly simplifies the purification procedure and also allows it to be re-used for preparation of isoseleno?cyanates. A possible mechanism for the formation of 2-aminobenzimidazoles is proposed. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219395

LETTER
901
Novel Synthesis of 2-Aminobenzimidazoles from Isoselenocyanates
S
ynthesis of 2-A
m
u
inobenzimid
a
azole
s
nyuan Xie,* Fan Zhang, Jianjun Li, Xiangjun Shi
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, P. R. of China
Fax +86(571)88320752; E-mail: pharmlab@zjut.edu.cn
Received 10 December 2009
preferred method to 2-aminobenzimidazole, as it can give
relatively high overall yield of products. The most fre-
quently used desulfurizing agents4 are HgO, HgCl2, CuCl,
MeI, tosyl chloride, dicyclohexylcarbodiimide, diisopro-
Abstract: An efficient one-pot procedure for the synthesis of 2-
aminobenzimidazoles from isoselenocyanates and various substi-
tuted diamines is described. Precipitation of elemental selenium
from the reaction mixture greatly simplifies the purification proce-
dure and also allows it to be re-used for preparation of isoseleno- pylcarbodiimide, N-(3-dimethyl-aminopropyl)-N′-ethyl-
cyanates.
aminobenzimidazoles is proposed.
A possible mechanism for the formation of 2-
carbodiimide hydrochloride. To simplify this process,
one-pot synthesis from diamines and isothiocyanates has
been developed [method (iv)]. Carbodiimide reagents, es-
pecially polymer-supported carbodiimides serve as ideal
desulfurizing agents.5
Key words: 2-aminobenzimidazoles, isoselenocyanates, cycliza-
tion, selenium recycling
As our interests in selenium chemistry and consistent ef-
forts in developing parallel reaction with isoselenocyan-
ates, we herein report our latest result: an one-pot
procedure to prepare 2-aminobenzimidazoles using iso-
selenocyanates and various substituted diamines. We
found that solid selenium precipitated in the reaction with-
out any deselenizing agent.
Benzimidazole is an important structural unit in medicinal
chemistry, which comprises nearly one-quarter of the top-
100-selling drugs.1 Specifically, 2-aminobenzimidazoles
can be found in a number of biologically active molecules
used as antiviral, antihistamine, and anticancer agents.2
Therefore, the synthesis of 2-aminobenzimidazoles has
attracted considerable interest.
Isoselenocyanates were generally introduced as key mate-
rials for the preparation of selenium-containing heterocy-
cles.6 Fernández-Bolaños’s group developed a procedure
for the preparation of unprotected glycopyranosyl sele-
noureas from isoselenocyanates. The selenoureas were
further converted into bicyclic isoureas with precipitation
of elemental selenium.7
1) H2, Pd/C
2) HgO, cat S8
EtOH, reflux
H
H
N
N
Ar
S
NO2
N
140–150 °C
Cl
H2N Ar
N
H
N
Table 1 Optimization of the Reaction Conditionsa
NH
Ar
H
N
H
N
desulfurizing
agent
N
H
Entry
Solvents
DMF
Temp (°C) Time (h)b
Yields (%)c
Ar
S
NH2
1
2
50
4
4
86
91
90
82
80
65
–
NH2
desulfurizing
agent
DMF
70
S
C
Ar
N
3
DMF
120
4
NH2
4
THF
reflux
70
16
6
Scheme 1 Conventional routes to 2-aminobenzimidazole
5
pyridine
MeCN
toluene
CH2Cl2
CHCl3
EtOAc
Conventional routes for the preparation of 2-aminobenz-
imidazoles include: i) cyclization of nitrothioureas; ii)
SNAr reaction of chlorobenzimidazole; iii) cyclization of
aminothioureas; iv) one-pot cyclization of diamines and
isothiocyanates (Scheme 1). Method (i) often gives poor
yield during the reduction of nitro group, while method
(ii) requires elevated temperature and usually yields self-
arylation products.3 Since 1999, method (iii) has been the
6
reflux
70
12
24
24
24
24
7
8
reflux
reflux
70
–
9
–
10
–
a 1-Isoselenocyanato-4-methoxybenzene (1 mmol) and benzene-1,2-
diamine (1 mmol).
SYNLETT 2010, No. 6, pp 0901–0904
x
x.
x
x.
2
0
1
0
b Monitored by TLC, until selenourea is fully consumed.
c Isolated yield by column chromatography.
Advanced online publication: 17.02.2010
DOI: 10.1055/s-0029-1219395; Art ID: W19609ST
© Georg Thieme Verlag Stuttgart · New York

902
Y. Xie et al.
LETTER
Similar phenomenon was observed in our experiment that cyanates with electron-withdrawing groups gave the
the element selenium precipitated when we treated isose- products in better yields and the reaction completed in
lenocyanate with diamine in DMF. TLC analysis detected shorter time. The ortho-substituted isoselenocyanate
the formation of 2-aminobenzimidazole, which was iden- (Table 2, entries 3 and 4) gave relatively lower yields due
tified by both NMR and MS analyses (Scheme 2).
to the steric hindrance effect. Alkyl-substituted isoseleno-
cyanate also gave good product yields.
NH2
R
N
R
The procedure could also be applied to structurally di-
verse 1,2-phenylenediamine. Both electron-donating and
electron-withdrawing groups on 1,2-phenylenediamine
provided the corresponding 2-aminobenzimidazoles in
good yields (Table 2, entry 10–15). Unfortunately, the de-
sired products were not obtained by treating cyclohexane-
1,2-diamine or propane-1,2-diamine with isoselenocyan-
ates. Compared with the previous reported methodolo-
gies,4 this method has several advantages such as higher
product yields, shorter reaction time, and milder reaction
conditions. Since the solid selenium could precipitate
from the reaction medium in nearly quantitative amount
(typical recovery was 95–97%), it could be used for the
preparation of isoselenocyanates following Koketsu’s
procedure.8
NH
+
N
C
Se
N
NH2
H
1
3
Scheme 2 A new route to 2-aminobenzimidazole
Encouraged by this result, we proceeded to find out the
most favorable reaction conditions. As shown in Table 1,
DMF was the best reaction solvent. After the optimization
of reaction conditions, we explored the scope of this reac-
tion by changing the substrates. A variety of functional-
ized 2-aminobenzimidazoles were then obtained by this
method (Table 2). Both electron-donating and electron-
withdrawing groups on phenyl isoselenocyanates were
well tolerated in this reaction. However, phenyl isoseleno-
Table 2 Preparation of 2-Aminobenzimidazolea
R1
NH2
N
DMF
Se
R1
C
NH
+
R2
R2
N
N
NH2
H
1
3
Entry
1
R1
R2
Product
3a
Time(h)
Yield (%)b
Ph
H
6
4
83
91
85
83
90, 89c
95
94
81
85
75
77
81
82
72
79
–
2
3-MeC6H4
2-MeC6H4
2-EtC6H4
H
3b
3c
3
H
6
4
H
3d
3e
6
5
4-MeOC6H4
4-ClC6H4
4-BrC6H4
1-naphthyl
cyclohexyl
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
Ph
H
4
6
H
3f
2
7
H
3g
3h
3i
2
8
H
8
9
H
6
10
11
12
13
14
15
16
17
4-O2N
4-O2N
4-Me
4-Me
4-Cl
4-Cl
3j
12
12
6
3k
3l
3m
3n
3o
–
6
10
10
24
24
propane-1,2-diamine
Ph
cyclohexane-1,2-diamine
–
–
a Monitored by TLC, until selenourea is fully consumed.
b Isolated yield by column chromatography.
c Using reproduced 1-isoselenocyanato-4-methoxybenzene.
Synlett 2010, No. 6, 901–904 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Aminobenzimidazoles
903
Two possible reaction pathways are proposed in selenium largely simplifies the purification procedures.
Scheme 3. Path A includes an oxygen-participated cy- Meanwhile, the starting material isoselenocyanates can be
clization of selenourea, thereafter elemental selenium is prepared by using the recovered element selenium to
generated to give 2-aminobenzimidazole. Path B starts avoid pollution problems.
with the decomposition of selenourea to give H2Se and
corresponding carbodiimide, which then cyclized to 2-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
amino-benzimidazole. H2Se then underwent photolysis9
or oxidation10 to yield element selenium.
In order to determine the reaction pathway of the whole
process, a control experiment was performed. First, a sus-
pension of 1-(2-aminophenyl)-3-(4-methoxyphenyl) sele-
nourea (2e) prepared previously11 in DMF was heated up
Acknowledgment
We are grateful to the National Natural Science Foundation of Chi-
na (No. 20906083 and No. 20806073) and Natural Science Found-
to 70 °C in an opened vessel. Two other experiments were ation of Zhejiang Province (No. Y40900488) for financial support.
carried out simultaneously.12 The first reaction was per-
formed in a nitrogen-protected vessel while the second
References and Notes
reaction was carried out in a light-avoiding but non-nitro-
(1) (a) Janssens, F.; Torremans, J.; Janssen, M.; Stokbroekx,
gen-protected vessel.
R. A.; Luyckx, M.; Janssen, P. A. J. Med. Chem. 1985, 28,
1925. (b) Bovet, D.; Bovet-Nitti, F. Médicaments du
R
H
H
N
Système Nerveux Végétatif, 5th ed.; Karger: Basel, 1948,
741. (c) The Extra Pharmacopeia, 27th ed.; Wade, A., Ed.;
The Pharmaceutical Press: London, 1978, 1287. (d) Martin,
E. J.; Critchlow, R. E. J. Comb. Chem. 1999, 1, 32.
(2) (a) Beaulieu, C.; Wang, Z.; Denis, D.; Greig, G.;
Lamontagne, S.; O’Neill, G.; Slipetz, D.; Wang, J. Bioorg.
Med. Chem. Lett. 2004, 14, 3195. (b) Kling, A.; Backfisch,
G.; Delzer, J.; Geneste, H.; Graef, C.; Hornberger, W.;
Lange, U. E. W.; Lauterbach, A.; Seitz, W.; Subkowski, T.
Bioorg. Med. Chem. 2003, 11, 1319. (c) Snow, R. J.;
Cardozo, M. G.; Morwick, T. M.; Busacca, C. A.; Dong, Y.;
Eckner, R. J.; Jacober, S.; Jakes, S.; Kapadia, S.; Lukas, S.;
Panzenbeck, M.; Peet, G. W.; Peterson, J. D.; Prokopowicz,
A. S. III.; Sellati, R.; Tolbert, R. M.; Tschantz, M. A.; Moss,
N. J. Med. Chem. 2002, 45, 3394.
N
N
NH
R
1/2 O2
SeH
NH2
N
H
SeH
H2O
Se
path A
H
H
N
N
N
R
NH
N
H
3e
R
Se
NH2
path B
2e
N
C
R
N
H2Se
NH2
hν
1/2 O2
H2O
4e
R = 4-MeOC6H4
(3) Carpenter, R. D.; DeBerdt, P. B.; Lam, K. S.; Kurth, M. J.
J. Comb. Chem. 2006, 8, 907.
H2
Se
+
Se
Scheme 3 Possible pathways of the reaction
(4) (a) Perkins, J. J.; Zartman, A. E.; Meissner, R. S.
Tetrahedron Lett. 1999, 40, 1103. (b) Omar, A.-M. M. E.;
Ragab, M. S.; Farghaly, A. M.; Barghash, A. M. Pharmazie
1976, 31, 348. (c) Wang, X.-J.; Zhang, L.; Xu, Y.;
Krishnamurthy, D.; Senanayake, C. H. Tetrahedron Lett.
2004, 45, 7167. (d) Omar, A.-M. M. E. Synthesis 1974, 41.
(e) Heinelt, U.; Schultheis, D.; Jager, S.; Lindenmaier, M.;
Pollex, A.; Beckmann, H. S. G. Tetrahedron 2004, 60,
9883. (f) Omar, A.-M. M. E.; Habib, N. S.; Aboulwafa,
O. M. Synthesis 1977, 864.
(5) Cee, V. J.; Downing, N. S. Tetrahedron Lett. 2006, 47, 3747.
(6) Heimgartner, H.; Zhou, Y.; Atanassov, P. K.; Sommen, G. L.
Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 840.
(7) Fernández-Bolaños, J. G.; López, O.; Ulgar, V.; Maya, I.;
Fuentes, J. Tetrahedron Lett. 2004, 45, 4081.
(8) Koketsu, M.; Sakai, T.; Kiyokuni, T.; Garud, D. R.; Ando,
H.; Ishikara, H. Heterocycles 2006, 68, 1607.
(9) Dobson, D. C.; James, F. C.; Safarik, I.; Gunning, H. E.;
Strausz, O. P. J. Phys. Chem. 1975, 75, 771.
(10) Pittman, R. W. J. Chem. Soc. 1949, 1811.
(11) Typical Procedure for Compound 2e
In the case of normal reaction conditions13 and light-
avoiding control, the reaction completed in 4 hours, 2-
aminophenylselenourea 2e was totally completely reacted
and 2-aminobenzimidazole 3e and element selenium were
formed. However, no selenium was observed in nitrogen
atmosphere control (only a trace of 3e detected by TLC)
even with longer reaction time of 36 hours. The signifi-
cant difference of conversion ratios obtained in the normal
conditions, light-avoiding control and nitrogen-atmo-
sphere control suggested oxygen was crucial to this reac-
tion. If path B was the main pathway of this reaction, 2-
aminophenylselenourea 2e should have decomposed and
converted into compound 4e and hydrogen selenide in ni-
trogen. Moreover, compound 4e is not stable and would
transform to 3e immediately. However, only trace amount
of 3e was detected, which meant that path B was not the
main pathway. In contrast, path A seems to be more rea-
sonable as the main pathway.
A mixture of 1-isoselenocyanato-4-methoxybenzene (1e;
0.212 g, 1 mmol) and phenylene-1,2-diamine (0.108 g, 1
mmol) were suspended in CHCl3 (20 mL). The reaction was
carried out at r.t. After 10 min the reaction was ceased, and
the reaction mixture was concentrated under vacuum. The
residue was washed with a mixture of hexane and EtOAc
(hexane–EtOAc = 20:1) to obtain 1-(2-aminophenyl)-3-(4-
methoxyphenyl) selenourea (2e) as a yellow solid (0.313 g,
In summary, we have successfully developed a one-pot
procedure for 2-aminobenzimidazoles and avoided the
isolation of intermediate selenourea. In contrast to con-
ventional methods, isoselenocyanates were firstly used in
this route as the key reagents. The precipitation of element
Synlett 2010, No. 6, 901–904 © Thieme Stuttgart · New York

904
Y. Xie et al.
LETTER
98% yield). 1H NMR (400 MHz, DMSO-d6): d = 9.63 (s, 1
H), 9.34 (s, 1 H), 7.26–7.29 (m, 2 H), 6.96–7.02 (m, 2 H),
6.87–6.90 (m, 2 H), 6.74 (dd, 1 H, J = 1.2, 8.0 Hz), 6.56 (dt,
1 H, J = 1.6, 7.6 Hz), 4.89 (s, 2 H), 3.74 (s, 3 H). 13C NMR
(100 MHz, DMSO-d6): d = 178.8, 157.0, 143.9, 132.5,
128.2, 127.4, 127.0, 124.4, 116.4, 115.9, 113.5, 55.2. HRMS
(EI): m/z calcd for C14H15N3OSe: 320.0302; found:
320.0317.
(13) Typical Procedure for Compound 3e
A mixture of 1-isoselenocyanato-4-methoxybenzene (1e;
0.212 g, 1 mmol) and phenylene-1,2-diamine (0.108 g, 1
mmol) was suspended in DMF (20 mL). The reaction vessel
was heat to 70 °C with magnetic stirring. Tracing by TLC,
the reaction completed when selenourea 2e disappeared. The
reaction mixture was then cooled to r.t. and filtered to
separate solid selenium. The solid selenium was washed by
EtOAc (10 mL). The combined filtrate was concentrated
under vacuum, and the residue was purified by column
chromatography on silica gel (hexane–EtOAc = 1:1). A
white solid N-(4-methoxyphenyl)-1H-benzo[d]imidazol-2-
amine (3e, 0.215 g, 90% yield), was then obtained. 1H NMR
(400 MHz, DMSO-d6): d = 10.79 (s, 1 H), 9.15 (s, 1 H), 7.65
(d, 2 H, J = 8.8 Hz), 7.26 (s, 2 H), 6.95–6.96 (m, 2 H), 6.91
(d, 2 H, J = 9.2 Hz), 3.73 (s, 3 H). 13C NMR (100 MHz,
DMSO-d6 + CDCl3): d = 154.1, 151.7, 138.0, 133.9, 119.8,
119.5, 114.0, 112.2, 55.1. ESI-MS: m/z = 240 [M + H]+.
(12) Procedure for Controlled Experiment
1-(2-aminophenyl)-3-(4-methoxyphenyl) selenourea (2e,
1 mmol) was suspended in DMF (20 mL) with magnetic
stirring. The reaction was carried out at 70 °C. A light-
avoiding control and a nitrogen-atmosphere control reaction
were set up at the same time. The reaction was monitored by
TLC. 2-Aminophenylselenourea was totally converted into
3e after 4 h in normal and light-avoiding control. The
reaction in nitrogen atmosphere was prolonged to 36 h, but
only trace of 3e was found.
Synlett 2010, No. 6, 901–904 © Thieme Stuttgart · New York