Cobalt-Catalyzed Aerobic Oxidative Cyclization of 2-Aminoanilines with Isonitriles: Facile Access to 2-Aminobenzimidazoles

Article abstract of DOI:10.1002/cctc.201902011

A ligand- and additive-free aerobic cobalt-catalyzed synthesis of 2-aminobenzimidazoles from 2-aminoanilines was developed. A variety of aminoanilines and isonitriles undergo efficient coupling to furnish substituted 2-aminobenzimidazoles in moderate to excellent yields. This protocol enables efficient access to the unsubstituted 2-aminobenzimidazoles.

Full text of DOI:10.1002/cctc.201902011

Accepted Article
Title: Cobalt-Catalyzed Aerobic Oxidative Cyclization of 2-
Aminoanilines with Isonitriles: Facile Access to 2-
Aminobenzimidazoles
Authors: Jiaqi Liu, Sarah Morgan, and Jessica Hoover
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10.1002/cctc.201902011
ChemCatChem
COMMUNICATION
Cobalt-Catalyzed Aerobic Oxidative Cyclization of 2-
Aminoanilines with Isonitriles: Facile Access to 2-
Aminobenzimidazoles
Jiaqi Liu, Sarah Morgan, and Jessica M. Hoover*
Abstract:
A
ligand- and additive-free aerobic cobalt-catalyzed
The most common traditional route to access these
heterocyclic structures relies on the cyclodesulfurization of a pre-
formed thiourea that can be accessed from either the coupling of
ortho-phenylenediamine with the corresponding isothiocyanate10
or the reduction of the appropriate ortho-nitroaryl thiourea11
(Scheme 1a). Unfortunately, these reactions often require toxic
and/or hazardous desulfurization agents such as HgO, HgCl2, and
MeI among others.12,10c Alternatively, TsCl has been employed
under basic conditions13 and coupling agents such as 1,3-
diisopropylcarbodiimide (DIC) or N-(3-dimethylaminopropyl)-N’-
synthesis of 2-aminobenzimidazoles from 2-aminoanilines was
developed. A variety of aminoanilines and isonitriles undergo efficient
coupling to furnish substituted 2-aminobenzimidazoles in moderate to
excellent yields. This protocol enables efficient access to the
unsubstituted 2-aminobenzimidazoles.
Benzimidazoles are important heterocyclic structures that are
key targets and intermediates in the synthesis of pharmaceutical
compounds and other biologically active molecules.1 More
specifically, the 2-aminobenzimidazole scaffold is a common
substructure in a variety of antihistimines,2 antihelmintics,3 kinase
inhibitors,4,5 and integrin avb3 antagonists.6 These structures
have also been shown to have antimalarial7 and anticancer8
activities (Chart 1).9
ethylcarbodiimide
hydrochloride
(EDC)
(or
dicyclohexylcarbodiimine (DCC)) have also been shown to be
effective.11c,14 Yet all of these routes suffer from poor atom and
step economies.
This Work
NH2
R
N
+
CNR
norastemizole
antihistimine
Cl
R = H
R =
NH2
O
CF3
N
N
Co catalyst, air
(e)
O
O
N
NH
N
NH
H
N
N
H
astemizole
antihistimine
antimalarial activity
anticancer
O
H
N
H
H
R
NH
N
N
N
(a)
(d)
Ar
Cl + H2NR
O
F
N
H
S
N
O
N
NH2
NH
Cl
N
H
N
(b)
(c)
NH Cl
mebendazole
anthelmintic
N
H
N
X
X
HN
H
N
H
lck kinase inhibitor
Ar
+
N
O
O
O
N
H
O
NH2
O
H2N
N
NH
N
HN
N
Scheme 1. Selected current methods for the synthesis of 2-
aminobenzimidazoles. Conditions: (a) desulfurization agent such as HgO,
carbodiimide or Cu catalyst and base (b) Cu catalyst and O2 (c) Cu catalyst and
base, (d) Reflux at high temperature or Pd catalyst, (e) Co catalyst and air.
F3C
N
S
N
O
NH
NH
N
N
H
OH
H
integrin αvβ3 antagonist
aurora kinase inhibitor
Chart 1. Selected biologically active molecules containing the
2-aminobenzimidazole substructure.
More recently, transition metal-catalyzed cyclization reactions
have provided attractive alternative routes to access 2-(N-
substituted)-aminobenzimidazoles.
The
copper-catalyzed
intramolecular cyclization reactions of thioureas15 or guanidines
(Scheme 1b)16 and the amination of aryl halides with guanidines
(Scheme 1c)17 eliminate the need for stoichiometric
desulfurization agents. Other approaches enable the
arylamination of 2-chlorobenzimidazoles either by Pd catalysis18
or by high temperature10,19 or high pressure20 SNAr protocols
[a]
J. Liu, S. E. Morgan, Prof. J. M. Hoover
C. Eugene Bennett Department of Chemistry
West Virginia University
Morgantown, WV 26506
E-mail: Jessica.Hoover@mail.wvu.edu
(Scheme 1d). Finally, transition-metal-free cyclization reactions
21a,b
using I2
or hypervalent iodine21c based oxidants have also
Supporting information for this article is given via a link at the end of
the document.
been developed. The ability to utilize readily available coupling
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10.1002/cctc.201902011
ChemCatChem
COMMUNICATION
1H NMR spectroscopy with a dimethyl sulfone internal standard (0.03 mmol).
[c]80 °C
partners in combination with environmentally benign oxidants,
such as O2 or air, and abundant first-row transition metal catalysts
would represent a significant advance toward the facile synthesis
of substituted benzimidazoles.22 A variety of cobalt-catalyzed
cyclization reactions of isonitriles have been developed.22c In
particular, Wang and coworkers have reported cyclization
reactions with bisnucleophiles employing persulfate-based
oxidants22b and we recently reported the aerobic cobalt-catalyzed
oxidation of aminophenols with isonitriles to generate
2-aminobenzoxazoles.23 Thus, we wondered if our aerobic cobalt
catalyst system might enable the synthesis of other classes of
heterocycles. Here, we report the cobalt-catalyzed aerobic
oxidative cyclization of ortho-phenylenediamines with isonitriles to
generate substituted 2-aminobenzimidazoles.
A variety of substituted ortho-phenylenediamine coupling
partners were investigated (1, Table 2). This methodology is
broadly tolerant of a range of functional groups including both
electron-rich and electron-deficient substituents. Of the ortho-
phenylenediamines explored, the reaction does not favour
electron withdrawing or donating substituents. Electronically
neutral (1a, 1b), electron withdrawing (1e-1j) and electron
donating (1c and 1d) groups all lead to high yields of the
benzimidazole products. Similarly, steric influences on the
reaction yield are minimal. For example, high yields are obtained
in the presence of methyl-substitution in both the 3- and
4-positions of the ortho-phenylenediamine (96% and 75%
respectively). Furthermore, functional groups such as a 4-tert-
butyl (1c) or naphthalene (1m) are also tolerated.
We began our studies with the model coupling reaction of
ortho-phenylenediamine (1a) and tert-butylisonitrile (2a) under
aerobic cobalt-catalyzed conditions (Table 1). Of the cobalt salts
explored, Co(OAc)2 was found to provide the highest yields of 3a
(entries 1-3). Reactions run in CH3CN provided higher yields of
3a than those run in other common solvents such as THF and
DMF (Table S2). The inclusion of basic additives (entries 4-9)
improved the reaction yield, with 2 equivalents of K2CO3 providing
the greatest improvement to provide 3a in 85% (entry 4). Finally,
the yield of 3a increased to 95% when the reaction temperature
was raised to 80 °C (entry 10). The strong dependence of this
reaction on the base loading as well as the reaction temperature
and O2 concentration was confirmed using the method reported
by Glorius and coworkers (Tables S5 and S6, Figure S3).24 Thus,
the optimized reaction conditions employ 10 mol % of Co(OAc)2
with 2 equivalents of K2CO3 and an air balloon in CH3CN at 80 °C
for 24 h.
Table 2. Scope of ortho-phenylenediamine and isonitrile coupling
partners.[a]
Co(OAc)2 (10 mol%)
K2CO3 (2.0 equiv)
N
NH2
NH2
R1
NHR2
CNR2
R1
N
H
MeCN, 80 °C, 24 h
air balloon
1
2
3
N
N
N
NHtBu
NHtBu
NHtBu
NHtBu
NHtBu
N
N
H
N
H
H3C
Br
tBu
Cl
H
3a, 95%
3b, 96%
3c, 93%
N
N
N
NHtBu
NHtBu
NHtBu
N
H
N
H
H3CO
N
H
3e, 75%
3d, 63%
3f, 81%
N
N
N
NHtBu
Table 1. Optimization of the reaction conditions.[a]
N
H
F3C
N
H
N
H
O2N
F
[Co] (10 mol%)
base (2.0 equiv)
NH2
N
3h, 52%
3g, 80%
3i, 67%
CNtBu
NHtBu
CH3CN, 65 °C, 24 h
air balloon
N
H
Br
CH3
NH2
N
N
N
NHtBu
1a
Entry
2a
3a
NHtBu
NHtBu
N
H
NC
N
H
N
H
[Co]
Base
Yield (%)[b]
3j, 34%
3l, 87%
3k, 75%
1
CoCO3•H2O
Co(acac)2•H2O
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
-
3
N
N
NHtBu
NH
N
H
N
H
2
-
35
68
85
74
67
82
62
65
95
3n, 84%
3m, 63%
3
-
N
N
NH
NH
4
K2CO3
Na2CO3
Li2CO3
KOAc
NaOAc
LiOAc
K2CO3
N
H
N
H
5
3p, 62%
3o, 78%
6
[a] Isolated Yields. Reaction conditions: 1 (0.3 mmol), 2a (0.3 mmol), K2CO3 (0.6
mmol), Co(OAc)2 (10 mol%) in MeCN (3 mL), at 80 °C with an air balloon for 24
h. [b] Yield in parentheses determined by 1H NMR spectroscopy.
7
8
In addition to substituted ortho-phenylenediamine coupling
partners, various isonitrile coupling partners (2) were also
investigated. Bulky aliphatic substituents, such as tert-butyl,
neopentyl, and adamantly groups (2a, 2n and 2o), were required
to obtain efficient product formation. In contrast, less bulky
n-pentyl isonitrile undergoes multiple isonitrile insertion steps to
generate the corresponding diamino quinoxazoline product (4) in
9
10[c]
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), cobalt catalyst (10 mol%),
MeCN (3 mL), at 65 °C with an air balloon. [b] The yield of 3a was determined by
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10.1002/cctc.201902011
ChemCatChem
COMMUNICATION
25% yield (Scheme 3). Finally, a small series of aromatic and
aliphatic isonitriles were found to be inefficient coupling partners
under these reaction conditions (Chart S1).
benzimidazoles for use as synthetic intermediates or final targets.
For example, the treatment with triphenylphosphine dibromide
generates iminophosphoranes (Scheme 6a),26 while treatment
with aryl sulfonyl chlorides (Scheme 6b)27 or oximes (Scheme
6c)28 allow access to unique fused heterocyclic structures. Finally,
others have shown this compound to be an intermediate in the
synthesis of biologically active structures such as mebendazole
(Scheme 7d) and enviroxime (Scheme 7e).29
H
N
Co(OAc)2 (10 mol%)
K2CO3 (2.0 equiv)
NH2
NH2
N
N
CN(C5H11
)
CH3CN, 80 °C, 24 h
air balloon
N
H
4, 25%
OH
N
O
O
Scheme 3. Synthesis of N-substituted diamino quinoxazoline.
N
O
S
N
Ph
Ph
NH2
NH
N
S
N
H
We also explored the reactivity of N-substituted ortho-
phenylenediamine coupling partners. The reactions of N-methyl-
and N-phenyl-substituted ortho-phenylenediamines (1q and 1r)
enviroxime
O
mebendazole
O
(d)
(e)
allow
access
to
the
corresponding
N-substituted
N
O
H
N
2-aminobenzimidazoles in moderate yields (Scheme 4).
N
(a)
(c)
NH2
R
N PPh3
N
N
H
N
N
N
NH
Co(OAc)2 (10 mol%)
K2CO3 (2.0 equiv)
(b)
N
N
NH2
HO2C
NHtBu
CNtBu
O
R
N
O
MeCN, 80 °C, 24 h
air balloon
S
R
H
N
R = Me 3q, 44%
Ph 3r, 27%
N
N
R1
Scheme 4. Synthesis of N-substituted 2-aminobenzimidazoles.
Scheme 6. Utility of unsubstituted 2-aminobenzimidazoles in synthesis.
Conditions: (a) Ph3PBr2 and base [ref 26] (b) Sulfonyl chloride/Cu catalyst then
Pd catalyst [ref 27] (c) hydroximoyl chloride and reflux [ref 28] (d) methyl
chloroformate and base [ref 29] (e) Isopropylsulfonyl chloride, base and reflux
[ref 26].
In our prior studies on the oxidative cyclization of
aminophenols with isonitriles,23 we found the reaction to proceed
through a pathway involving initial oxidation of an aminophenol-
coordinated cobalt(II) species by O2 to generate semiquinonato-
type species.25 These stabilized ligand radical intermediates were
not trappable with common radical trapping agents. Similarly, no
trappable free-radicals are formed under the current conditions.
When the standard catalytic reaction is conducted in the presence
of TEMPO, no radical trapped products are obtained and no
decrease in the yield is observed (Scheme 5). Similarly, inclusion
of 1,1-diphenylethylene results in no radical trapped products and
no significant decrease in the reaction yield.
Thus, we sought to enable efficient access to the
unsubstituted 2-aminobenzimidazole 3s. Other researchers have
shown the N-tert-butyl benzimidazole to undergo deprotection
upon treatment with strong acid.22a Based on this precedent, we
devised
a convenient sequence for facile access to 2-
aminobenzimidazole from ortho-phenylenediamine and the
readily available tert-butylisonitrile. After following the standard
reaction conditions, the resulting product 3a, is treated with strong
acid
under
reflux
to
generate
the
unsubstituted
2-aminobenzimidazole 3s in 82% yield (Scheme 7).
Co(OAc)2 (10 mol %)
K2CO3 (2.0 equiv)
radical trap (2.0 equiv)
NH2
N
NH2
NH2
1. Co(OAc)2 (10 mol%)
K2CO3 (2.0 equiv)
CH3CN, 80 °C
24 h, air balloon
2. conc. HCl, reflux 12 h
3. 3M NaOH
+
NHtBu
N
H
3a
NH2 CNtBu (1.0 equiv)
CH3CN, 80 °C
R
N
R
NH2
NH2
NH2
N
CHNtBu
air balloon, 24 h
H
TEMPO
1,1-diphenylethylene
86%
68%
ND
24%
3s, R = H, 82%
3t, R = Bz, 70%
Scheme 5. Control experiments with TEMPO and 1,1-diphenylethylene as
radical trapping agents.
Scheme 7. Synthesis of the unsubstituted 2-aminobenzimidazoles 3p and 3q.
Finally, we applied this new methodology to the synthesis of 3t, a
precursor to mebendazole and enviroxime. This method allows
access to 3t in a convenient two-step sequence from the
ortho-diaminobenzophenone and tert-butylisonitrile in 70% yield
(Scheme 7). This intermediate can then be converted to
Next, we sought to explore the utilization of the cobalt-
catalyzed
2-aminobenzimidazoles. These compounds are convenient
precursors to access variety of differently substituted
method
to
access
the
unsubstituted
a
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ChemCatChem
COMMUNICATION
[3]
[4]
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Castillo, Bioorg. Med. Chem. Lett. 2002, 12, 2221-2224.
mebendazole or enviroxime by selective acylation or sulfonylation,
respectively.29 We anticipate that this protocol will provide access
to a variety of other 2-aminobenzimidazole substructures of
biological importance.
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In summary, we have described here a new cobalt-catalyzed
oxidative cyclization of ortho-phenylenediamines with isonitriles to
generate substituted 2-aminobenzimidazoles. The convenient
and mild aerobic conditions also provide access to the
unsubstituted 2-aminobenzimidazoles from an acid-promoted
dealkylation of the 2-(tert-butylamino)-benzimidazoles. This route
affords structures that can serve as important intermediates in the
synthesis of pharmaceutically valuable small molecules.
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Experimental Section
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Representative
Procedure
for
the
Synthesis
of
2-
Aminobenzimidazoles.
(a) J.-F. Bonfanti, F. Doublet, J. Fortin, J. Lacrampe, J. Guillemont, P.
Muller, L. Queguiner, E. Arnoult, T. Gevers, P. Janssens, H. Szel, R.
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2-(tert-butylamino)-benzimidazole (3a). Ortho-phenylenediamine (32.4
mg, 0.300 mmol), Co(OAc)2 (5.31 mg, 0.0300 mmol, 10 mol %), and
K2CO3 (82.9 mg, 0.600 mmol) were combined in a 6-inch test tube in an
N2 filled glovebox. CH3CN (3 mL) and tert-butylisonitrile (35.2 µL, 0.300
mmol) were added and the test tube was sealed with a septum before
being removed from the glovebox. Upon removal, an air balloon attached
to a needle was inserted through the septum and the reaction mixture was
then stirred for 24 hours at 80 °C in an oil bath. Upon completion, the
reaction mixture was cooled to room temperature and passed through a
pad of Celite via vacuum filtration. The resulting Celite cake was washed
with ethyl acetate (50 mL), the filtrate was collected and the solvent was
removed by rotary evaporation. The resulting concentrate was then
passed through a silica gel plug Pasteur pipette and rinsed with ~10 mL
ethyl acetate. The solvent was removed by rotary evaporation again. The
residue was purified by silica column chromatography (98:2 EtOAc:
MeOH). All 2-aminobenzimidazole compounds (3) were prepared
following the standard procedure unless otherwise noted.
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We are grateful to West Virginia University and ACS PRF
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spectroscopy facilities were partially supported by the NSF (CHE-
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Keywords: homogeneous catalysis • cyclization • oxidation •
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10.1002/cctc.201902011
ChemCatChem
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Jiaqi Liu, Sarah E. Morgan, Jessica M.
Hoover*
- 20 examples
NHR2 - up to 96% yield
- ligand free
N
NH2
R1
CoII, air
CNR2
R1
N
H
Page No. – Page No.
NH2
- air as oxidant
Cobalt-Catalyzed Aerobic Oxidative
Cyclization of 2-Aminoanilines with
Isonitriles: Facile Access to 2-
Aminobenzimidazoles
Simple, Clean, and Mild: 2-Aminobenzimidazoles are accessed from cobalt-
catalyzed conditions using air as the oxidant. The catalytic reaction is efficient
under simple and mild ligand-free conditions.
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