Nickel-catalyzed Chan-Lam cross-coupling: Chemoselective: N -arylation of 2-aminobenzimidazoles

Article abstract of DOI:10.1039/c6ob01307d

A complementary set of Ni- and Cu-based catalyst systems for the selective N-arylation of 2-aminobenzimidazoles have been developed. Selective N-arylation of the primary amine (C-NH₂) group was achieved by Ni-catalyzed, boronic acid promoted cr

Full text of DOI:10.1039/c6ob01307d

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Organic & Biomolecular Chemistry
PAPER
Nickel-catalyzed Chan-Lam cross-coupling: Chemoselective N-
arylation of 2-aminobenzimidazoles
a,b
a,b
a,b
a,b,*
K. Anil Kumar, Prakash Kannaboina, D. Nageswar Rao, and Parthasarathi Das
Received 00th January 20xx,
Accepted 00th January 20xx
A
complementary set of Niꢀ and Cuꢀbased catalyst system for the selective Nꢀarylation of 2ꢀ
DOI: 10.1039/x0xx00000x
aminobenzimidazoles have been developed. Selective Nꢀarylation of primary amine (CꢀNH ) group was
2
www.rsc.org/
achieved by the Niꢀcatalyzed, boronic acid promoted crossꢀcoupling reactions in air, whereas, selective Nꢀ
arylation of the azole nitrogen was achieved with Cuꢀcatalysis and aryl halides. These protocols are general
and give rapid access to an array of both the Nꢀarylated isomers of 2ꢀaminobenzimidazoles.
1
0
1
Introduction
CꢀNH
imidazoles
antiplasmodial activity, aurora kinase inhibitors, integrin α
2
ꢀarylaminobenzimidazoles
and
N ꢀarylꢀ2ꢀaminobenz
11
exhibits versatile biological activities such as
1
2
13
Transitionꢀmetalꢀcatalyzed C(aryl)ꢀN bond crossꢀcoupling reactions
have emerged as powerful tools in organic synthesis. Numerous
protocols for the Nꢀarylation have been developed over the years.
Besides the Cuꢀcatalyzed traditional Ullmann procedures,
4
β
1
1
14
15
16
antagonists, Tieꢀ2 kinase inhibitors and Ca channel blockers.
N ꢀarylꢀsubstituted benzimidazoles as ligands for the hepatitis C
virus (HCV) internal ribosome entry site (IRES) RNA. (Fig 1).
1
2
17
3
Buchwald and Hartwig discovered the useful Pdꢀcatalyzed Nꢀ
N
arylation reaction, which have significantly contributed in this area
of research. In 1998, Chan and Lam independently reported a
H
H
CF
3
N
N
N
N
general conditions for the Nꢀarylation of amines in the presence of
N
O
HN
N
N
N
N
N
Me
4
H
H
Cu(OAc)
2
and boronic acids as aryl source at room temperature.
N
N
NH
2
HN
Me
S
N
N
O
Due to the simplicity of the reaction conditions and functional
group tolerance this Cuꢀsalt promoted Chan–Lam coupling became
Ligand for HCV IRES RNA
Tie-2 kinase inhibitor
Aurora kinase inhibitor
5
a valuable tool for medicinal chemist. Like other crossꢀcoupling
1
Fig 1. Biologically important CꢀNH ꢀaryl and N ꢀarylꢀ2ꢀaminobenzꢀ
2
reactions the Chan–Lam process has been the subject of intensive
investigations with similar goals of optimizing the reaction with
imidazoles
6
various substrates as demonstrated by various groups including
The selective Nꢀarylation of substrate possessing multiple
nucleophilic sites, without protection/deprotection while challenꢀ
ging, but would be valuable as it delivers rapid access to designed
molecules with minimum synthetic manipulations. The tautomeric
nature of 2ꢀaminobenzimidazoles make them a unique structural
class where such an approach includes the formation of
regioisomers and/or polyarylated products due to the presence of
7
ours. Many of these studies have focused on the pairing of
effective copper ion sources with various ligands, whereas relatively
less attention has been paid in the use of alternative metalꢀsource.
The nickelꢀbased catalyst today are well recognized in aromatic C–
N coupling reactions and constitutes an essential part of modern
8
amination methodologies. Despite the progress on the development
of methodologies for aromatic CꢀN bond formation reactions, few
studies have been published on nickelꢀcatalyzed ChanꢀLam type of
1
3
three adjacent nucleophilic nitrogens (N , N and C2ꢀamino group).
18
19
Although Pd ꢀ and Cu ꢀcatalyzed conditions for Nꢀarylations of
some benzimidazole derivatives with aryl halides have been
achieved successfully, the chemoselective Nꢀarylation of 2ꢀ
aminobezimidazoles are rare. In 2012 Buchwald made an elegant
approach with catalystꢀcontrolled chemoselective Nꢀarylation of 2ꢀ
9
coupling.
2ꢀAminobenzimidazole is an important heterocyclic scaffold and is
considered to be a privileged structure in medicinal chemistry. Both
2
0
aminobenzimidazoles.
Recently,
we
have
successfully
a
1
Medicinal Chemistry Division, CSIR-Indian Institute of Integrative
demonstrated the Cuꢀcatalyzed ChanꢀLam coupling for selective N
and CꢀNH2 arylation of 2ꢀaminobenzimidazoles, and other Cꢀ
aminoꢀNHꢀazoles. Seeking to expand upon this work, we
envisioned an alternative approach to contribute to the existing
methods of chemoselective Nꢀarylation of 2ꢀaminobenzimidazole.
Herein, we report nickel as alternative catalyst for selective CꢀNH2ꢀ
Medicine, Jammu 180001, India; Tel: 91-191-2560000; Fax:91-191-
2
569019; E-mail: partha@iiim.ac.in
21
b
Academy of Scientific and Innovative Research (AcSIR), New Delhi-
1
10025, India
†
Electronic Supplementary Information (ESI) available: [spectroscopic
data for all compounds]. See DOI: 10.1039/c000000x/
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Journal Name
arylation of 2ꢀaminobenzimidazoles under ligand free conditions.
We further report the Cuꢀcatalyzed conditions for selective N ꢀ
arylation of 2ꢀaminobenzimidazoles (Scheme 1). To the best of our
knowledge the Niꢀcatalyzed ChanꢀLam coupling reaction of
aminoazoles and boronic acids has not yet been reported.
for the cross coupling reacton. We observed significant
1
improvement in the yield (85%), when the reaction was carried
o
out at 50 C (entry 7, Table 1). Under these conditions the
N
ꢀ
ꢀ
arylation is completely chemoselective as only CꢀNH
2
arylbenzimidazole was isolated. The solvent (DMSO) played
an important role in this reaction as other solvents like DMF,
DCE, MeCN and MeOH (entries 8ꢀ11, Table 1) were less
effective. Further screening of different Niꢀsalts such as
I
Ar
O, KOH
(HO)
2
B
Ar
N
N
N
N
Cu
2
Ni(OAc)
2
NH
2
NH
NH
Ar
2
DMSO, 120 o
DBU, DMSO,
NiCl
NiF
attempt to further reduce the amount of Ni(OAc)
remained unsuccessful (entry 15, Table 1). Reaction under 1
atm O did not show any further improvement in the yield of
the reaction (entry 16, Table 1), while incomplete conversion
and poor yield was observed under a N atmosphere (entry 17,
Table 1) and the reaction did not work without the catalyst
entry 18, Table 1).
.6H
(entry 14, Table 1) were proved inferior to Ni(OAc)
(10 mol%)
O (entry 12, Table 1), NiBr
(entry 13, Table 1) and
C
N
H
N
H
2
2
2
o
50 C, 10-15 h
2
N , 14-18 h
2
2
. An
air
Ar
2 examples
Cu-Catalyzed
15 examples
yield up to 85%
Ni-Catalyzed
2
1
yield up to 90%
'ligand-free condition'
'open-flask chemistry'
2
Scheme
1.
Chemoselective Nꢀarylation of 2ꢀaminobenz
imidazoles
2
Results and discussion
(
To find an optimized protocol for the selective CꢀNH2ꢀ
arylation of 2ꢀaminobenzimidazoles, we commenced our
investigation between 2ꢀaminobenzimidazole (1a) and phenyl
boronic acid (1.0 equiv) in the presence of Ni(OAc)2 (0.2
With the establishment of the optimized conditions, the scope and
generality of the reactions were evaluated between 2ꢀ
aminobenzimidazoles and electronically diverse phenylboronic
acids (Table 2).
Table 2 Niꢀcatalyzed CꢀNH
equiv), Et N (2.0 equiv) as base in DMSO at room
3
a
2
ꢀarylation of 2ꢀaminobenzimidazoles
temperature, but failed to isolate the desired product (2a
entry 1, Table 1). When we changed the base to CsF, the
desired product (2a) was isolated in 15% yield (entry 2, Table
).
)
(
(HO)2B
Ar
N
N
Ni(OAc)
2
(20 mol%)
NH
Ar
1
NH2
N
H
DBU (2 equiv), DMSO, 50 o
C
N
H
1
a
air, 10-15 h
N
a
2a-o
Table 1 Optimization of reaction conditions
N
N
NH
NH
NH
(
HO)
2
B
N
H
N
H
N
H
N
N
Ni-catalyst
NH
NH
2
base, solvent, temp
air, 10 h
N
H
2
a, 85%, 10 h
2b
, 84%, 10 h Me
2c, 82%, 10 h
N
H
a
2
a
1
N
N
N
NH
NH
NH
N
N
H
Entry
Catalyst
Base
Solvent Temp Yield
N
H
H
o
b
(
C)
(%)
Br
1
2
3
4
5
6
7
8
9
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
2
2
2
2
2
2
Et
CsF
PO
tꢀBuOK
Cs CO
3
N
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
rt
rt
n.r.
15
35
45
52
65
85
70
50
55
40
58
42
30
71
85
22
n.r.
2
d, 81%, 12 h CF
3
2
CO Me
Br
2e, 78%, 13 h
2
f, 77%, 11 h
K
3
4
80
80
80
80
50
50
50
50
50
50
50
50
50
50
50
50
N
N
NH
N
NH
N
H
NH
2
3
N
H
N
H
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
MeO
N
Ni(OAc)
2
2
g, 80%, 10 h
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
2
2
2
2
2h, 68%, 15 h
2i, 83%, 10 h
DCE
N
N
10
11
12
13
14
MeCN
MeOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Cl
Cl
N
NH
NH
NH
N
H
N
H
Br
Br
N
H
NiCl
NiBr
NiF
2
.6H
2
2
O
NO
2
2j, 85%, 10 h
F
2l, 78%, 10 h
2
2k
,
82%, 14 h
HN
c
1
5
6
7
8
Ni(OAc)
Ni(OAc)
Ni(OAc)
ꢀꢀ
2
2
2
d
e
Cl
Cl
N
1
1
1
Me
H
N
NH
OMe
N
H
N
N
N
Br
N
H
H
a
2m
, 80%, 10 h
Br
2n, 75%, 10 h
2o, 70%, 10 h
Reaction conditions: 1a (1.0 equiv), phenylboronic acid (1.0 equiv),
Ni(OAc)
isolated yields; 10 mol% Niꢀcatalyst was used; reaction under O
atmosphere; reaction under N
o
a
2
(20 mol%), DBU (2.0 equiv), DMSO (1 mL), 50 C;
Reaction conditions: 1a (0.40 mmol), phenylboronic acid (0.40 mmol),
b
c
d
o
2
2
Ni(OAc) (0.08 mmol), DBU (0.80 mmol), DMSO (1 mL), 50 C, air.
e
2
atmosphere; n. r.= no reaction.
Interestingly, all the examined boronic acids underwent clean
conversion to give the desired CꢀNH ꢀarylated products (2aꢀm) in
good yields (68ꢀ85%). Electronic nature or the substitution pattern
did not have much effect on the crossꢀcoupling reaction. As an
Subsequently, Ni(OAc) was used as catalyst in DMSO at 80
C, by varying different bases like K PO , tꢀBuOK, Cs CO ,
2 3
DBU (entries 3ꢀ6, Table 1) revealed that DBU was best suited
2
2
o
3
4
2
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o
example, when the reaction was carried out with simple 2ꢀ
aminobenzimidazole with phenylboronic acids bearing electronꢀ
donating (2bꢀc) or electronꢀ withdrawing groups (2dꢀe), the desired
product isolated in excellent yields (78ꢀ85%). Di substituted 3, 5ꢀ
dibromophenylboronic acid undergo smooth coupling to give
desired product in 77% yield (2f). Bicyclicboronic acid was also
investigated successfully as an example, 2ꢀnapthylboronic acid gave
have also attempted different temperatures, but 120 C was found
optimal for smooth coupling (entries 12ꢀ13, Table 3). When we
changed the coupling partner from iodobenzene to bromobenzene,
the desired product isolated in 82% yield (entry 14, Table 3), while
low loading of catalyst (5 mol%) decreased the yield (71%; entry
15, Table 3).
Having the optimal conditions in hand, the substrate scope of the
Cuꢀcatalyzed N ꢀselective arylation was also investigated by
1
80% (2g) yield, while heterocyclic 3ꢀpyridylboronic acid afforded
the coupling product (2h) in 68% yield. Then the effect of the
substituent attached on the benzimidazole ring was examined.
Pleasingly, all the substituted 2ꢀaminobenzimidazoles underwent
clean conversion with these optimized conditions and furnished the
coupling of different 2ꢀaminobenzimidazoles with variety of
functionalized aryliodides and arylbromides (Table 4). Both
electronꢀrich (3b) and electronꢀdeficient (3c) aryl halides reacted
1
smoothly to give N ꢀarylated products in high yields (83% and 81%
CꢀNH
2
ꢀarylated products (2iꢀm) in excellent yields (78ꢀ85%). Both
respectively). Further different hetero aryl halides were also tested.
To our delight the optimized conditions worked well for monocyclic
heteroaryl halides and resulted heteroaryl coupling products (3dꢀ3e)
were isolated in excellent yields (78–81%). In this context
bicyclichetero aryl halides have also been investigated for crossꢀ
coupling and the desired products (3fꢀ3g) were isolated in good
yields (74ꢀ79%). To enhance the generality of the reaction
conditions substituted 2ꢀaminobenzimidazoles were investigated.
Bromo, dichloro and nitro substituted 2ꢀaminobezimidazoles have
bromo (2jꢀk) and chloro (2lꢀm) groups were well tolerated under
these conditions and amenable to further functional group
transformation. Furthermore two important aminoꢀpyrazoles were
subjected to the crossꢀcoupling reaction. To our delight the
optimized conditions proceeded well in case of 3ꢀaminopyrazole
(75%) (2n) and 3ꢀmethylꢀ1Hꢀpyrazolꢀ4ꢀamine (70%) (2o).
1
Next we focused our attention for N ꢀarylation of 2ꢀamino
benzimidazole, we initially tested with 2ꢀaminobenzimidazole and
1
afforded the desired N ꢀarylated products (3hꢀj) in excellent yields
iodobenzene by using Cu
2
O as catalyst, K
3
PO
4
as base in DMSO at
(78ꢀ85%).
o
120 C the desired product (3a) was isolated in 35% yield (entry 1,
1
a
Table 3).
Table 4 Cuꢀcatalyzed N ꢀarylation of 2ꢀaminobenzimidazoles
X
N
N
a
2
Cu O (10 mol%)
Table 3 Optimization of reaction conditions
NH2
NH
2
Ar
N
H
1a
KOH (2 equiv),
N
X
DMSO, N , 120 oC
2
N
(X = I or Br)
3a-l
N
Cu-catalyst
14-18 h
Ar
NH
2
NH
2
N
base, solvent,
N
H
temp, N
2
, 14 h
N
N
N
N
1
a
(X = I or Br)
3a
N
N
N
NH
2
NH
2
NH2
NH2
N
Entry
Catalyst
X
Base
Solvent
Temp
Yield
(%)
o
b
(
C)
N
1
2
3
4
5
6
7
8
9
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
CuBr
CuI
Cu
Cu
Cu
Cu
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
I
I
I
I
I
I
I
I
I
I
K
3
PO
4
DMSO
120
120
120
120
120
120
120
120
120
120
120
100
80
35
40
50
65
85
72
48
53
trace
75
73
70
63
82
71
Me
NO
3c, 81%, 14 h
X = I)
Cl
2
tꢀBuOK DMSO
Cs
3
a, 85%, 14 h
(X = I)
3
b, 83%, 14 h
3d, 78%, 18 h
(X = Br)
2
CO
3
DMSO
DMSO
DMSO
DMF
DMA
EtOH
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
(
X = I)
(
NaOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
N
N
N
N
N
N
NH2
NH2
NH2
NH
2
N
N
Br
S
N
Cl
1
1
1
1
1
0
1
2
3
4
N
Bn
N
I
I
I
Br
3e, 81%, 14 h
3h, 85%, 14 h
Bn
g, 74%, 18 h
X = Br)
NH
2
O
2
O
2
O
2
O
(X = Br)
(X = I)
3
f, 79%, 18 h
(X = Br)
3
(
120
120
NH
2
c
2
1
5
I
Cl
Cl
N
N
N
NH
2
NH2
N
N
a
N
N
2
O N
N
Reaction conditions: 1a (1.0 equiv), aryl halide (1.5 equiv), Cu
mol%.), KOH (2.0 equiv), DMSO (1mL), 120 C, isolated yields; 5 mol%
Cuꢀcatalyst was used.
2
O (10
o
b
c
Cl
Me
i, 80%, 14 h
X = I)
F
Me
3l, 86%, 14 h
3
3j, 78%, 16 h
3k, 90%, 14 h
Further systematic screening of various bases (entries 2ꢀ5, Table 3)
revealed that in presence of KOH the N ꢀarylated product (3a) was
isolated in best yield (85%; entry 5, Table 3). While testing of other
solvents such as DMF (enrty 6, Table 3), DMA (enrty 7, Table 3),
EtOH (enrty 8, Table 3) and toluene (entry 9, Table 3) proved
inferior to DMSO (entry 5, Table 3). Next catalyst screening
(X = I)
(
(X = I)
1
(X = I)
a
2
Reaction conditions: 1a (0.45 mmol), aryl halide (0.67 mmol), Cu O (0.045
o
mmol), KOH (0.90 mmol), DMSO (1mL), N
2
, 120 C.
In case of 3ꢀamino pyrazole, aryl halides bearing both electronꢀrich
3k) and electronꢀdeficient (3l) afforded the N ꢀarylated products in
high yields (86ꢀ90%). The reaction is highly selective only afforded
1
(
2
showed Cu O gave the best yield, while other copperꢀsource such as
CuBr or CuI produced moderate yields (entries 10ꢀ11, Table 3). We
1
the N ꢀarylated products.
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Conclusion
50 C for 10 h. The progress of the reaction was monitored by TLC
and after completion of the reaction. The crude reaction mixture
was diluted with 15 mL of ice cooled water and extracted with ethyl
acetate (3x10 mL). The combined organic layers were dried over
In conclusion, we have developed an efficient Niꢀcatalysed protocol
for selective CꢀNH ꢀarylation of 2ꢀaminobenzimidazoles and amino
2
pyrazoles with various arylboronic acids under open air atmosphere.
This “openꢀflask” chemistry can be carried out under ligandꢀfree
conditions, and it is first method for the Niꢀcatalyzed selective Cꢀ
2 4
Na SO and concentrated under vacuum. The crude product was
purified by column chromatography (hexane/EtOAc) to provide the
desired product 2a. By following the above general procedure A,
NH ꢀarylation in the presence of other reactive nucleophilic sites.
2
C2ꢀNH ꢀarylated
2ꢀaminobenzimidazoles
(2b-m)
and
2
This method is general and the reaction conditions are mild
compared to Pdꢀcatalyzed Buchwald–Hartwig crossꢀcoupling,
making it a vital tool in the fast thriving CꢀN bond crossꢀcoupling
chemistry. The use of Niꢀcatalyst as an alternative expand the scope
of ChanꢀLam coupling in de novo designing of catalyst employing
different metalꢀsource. We further reported the Cuꢀcatalyzed
aminopyrazoles (2nꢀo) were synthesized.
21b
N-Phenyl-1H-benzo[d]imidazol-2-amine (2a):
Purification:
Hexane/EtOAc (3: 2), light brown solid (85% yield, 71 mg), mp.
o
1
6
188ꢀ190 C; H NMR (400 MHz, DMSOꢀd ) δ 10.91 (br s, 1H),
9.42 (br s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 7.5 Hz, 4H),
6.99 (dd, J = 5.3, 3.0 Hz, 2H), 6.93 (t, J = 7.2 Hz, 1H); C NMR
1
13
optimized conditions for selective N ꢀarylation of 2ꢀ
aminobenzimidazoles with different halo benzenes, under ligand
free conditions. Finally, we believe the catalyst controlled
chemoselective strategy will open an avenue in establishing further
reaction conditions for selective Nꢀarylation of heterocycles bearing
multiple nucleophilic sites.
(100 MHz, DMSOꢀd ) δ 162.3, 150.5, 143.9, 140.8, 128.7, 120.5,
6
119.9, 117.0 (signals for C2 and bridgehead carbons of the
benzimidazole ring were too weak to observe); HRMS (ESI): Calcd
+
for C13
H
12
N
[M+H] : 210.1026, found: 210.1033.
3
21b
N-(p-Tolyl)-1H-benzo[d]imidazol-2-amine (2b):
Purification:
Experimental
Hexane/EtOAc (3: 2), light brown solid (84% yield, 75 mg), mp.
o
1
1
21ꢀ123 C; H NMR (400 MHz, DMSOꢀd
9.32 (br s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.30 (dd, J = 5.3, 3.3 Hz,
H), 7.13 (d, J = 8.1 Hz, 2H), 6.98 (dd, J = 5.5, 3.1 Hz, 2H), 2.27 (s,
6
) δ 10.94 (br s, 1H),
General Information
2
13
All purchased chemicals were used without further purification. All
reactions were performed under open air. Analytical thin layer
chromatography was performed using TLC preꢀcoated silica gel 60
F254 MERCK (20x20 cm). TLC plates were visualized by exposing
UV light or by iodine vapors. Organic solutions were concentrated
by rotatory evaporation on BUCHIꢀSwitzerland; Rꢀ120 rotatory
evaporator and vacuum pump Vꢀ710. Flash column
chromatography was performed on Merck flash silica gel 100ꢀ200
mesh size. Melting points of solid compounds were determined on
6
3H); C NMR (125 MHz, DMSOꢀd ) δ 162.3, 150.7, 148.9, 138.2,
133.9, 129.3, 129.1, 119.9, 117.2, 20.3 (signals for bridgehead
carbons were too weak to observe); HRMS (ESI): Calcd for
+
C
H
14
N
3
[M+H] : 224.1182, found: 224.1190.
14
N-(4-Isopropylphenyl)-1H-benzo[d]imidazol-2-amine
(2c):
Purification: Hexane/EtOAc (3: 2), colourless semi solid (82%
1
yield, 82 mg); H NMR (400 MHz, DMSOꢀd ) δ 7.67 (d, J = 8.4
6
Hz, 2H), 7.33 (dd, J = 5.5, 3.1 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H),
7.00 (dd, J = 5.7, 3.1 Hz, 2H), 2.86 (dq, J = 20.6, 7.0 Hz, 1H), 1.21
1
13
BUCHIꢀBꢀ545ꢀSwitzerland melting point apparatus. H and
C
13
NMR spectra were recorded with BRUKER 500 and 400 MHz
NMR instruments. Proton and carbon magnetic resonance spectra
6
(d, J = 6.9 Hz, 6H); C NMR (125 MHz, DMSOꢀd ) δ 155.2, 150.8,
140.7, 138.5, 134.2, 126.9, 126.5, 125.3, 119.9, 117.4, 114.9, 32.7,
1
13
ꢀ1
(
(
H NMR and C NMR) were recorded using tetramethylsilane
24.0; IR (NaCl) ν (cm ) 3428, 2956, 2925, 2869, 2853, 2096, 1650,
1
TMS) in the solvent of CDCl
3
as the internal standard ( H NMR:
at 7.24 ppm; C NMR: CDCl
1565, 1514, 1463, 1377, 1246, 1214, 1190, 1159, 1082, 1018, 846,
13
+
TMS at 0.00 ppm, CDCl
3
3
at 77.0
741; HRMS (ESI): Calcd for C16
H
18
N
3
[M+H] : 252.1495, found:
ppm) or were recorded using tetramethylsilane (TMS) in the solvent
252.1498.
1
of DMSOꢀd
DMSOꢀd at 2.50 ppm; C NMR: DMSOꢀd
recorded using tetramethylsilane (TMS) in the solvent of Acetoneꢀ
6
as the internal standard ( H NMR: TMS at 0.00 ppm,
1
3
6
6
at 40.0 ppm) or were
N-(4-(Trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine
(2d): Purification: Hexane/EtOAc (3: 2), pale yellow liquid (81%
Yield, 90 mg); H NMR (400 MHz, DMSOꢀd ) δ 11.16 (br s, 1H),
9.95 (br s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H),
7.40 (br, 2H), 7.09 – 7.04 (m, 2H); C NMR (100 MHz, DMSOꢀd6)
δ 149.6, 144.4, 128.8, 126.0 (dd, J = 7.4, 3.7 Hz), 123.4, 120.5,
120.4, 120.2, 119.8, 116.6 (signals for bridgehead carbons were too
1
1
d
6
as the internal standard ( H NMR: TMS at 0.00 ppm, Acetoneꢀd
6
6
13
at 2.09 ppm; C NMR: Acetoneꢀd
6
at 29.9 ppm, 206.7 ppm). All
1
3
the NMR spectra were processed in MestReNova. HRMS spectra
were recorded with LCMSꢀQTOF Module No. G6540 A (UHD)
instrument.
ꢀ
1
weak to observe); IR (NaCl) ν (cm ) 3355, 2923, 2853, 1653, 1612,
571, 1456, 1324, 1255, 1164, 1115, 1068, 1017, 837, 740, 655;
General procedure for the synthesis of Nickel-catalyzed
1
Selective C2-NH
2
-arylation of 2-aminobenzimidazoles with
+
HRMS (ESI): Calcd for C14
78.0898.
11 3 3
H F N [M+H] : 278.0900, found:
boronic acids: (Procedure A)
2
To a stirred solution of 2ꢀaminobenzimidazole (53.5 mg, 0.40
mmol) in DMSO (1 mL) was added phenylboronic acid (49 mg,
Methyl 4-((1H-benzo[d]imidazol-2-yl)amino)benzoate (2e):
0
.40 mmol), Ni(OAc) (14.2 mg, 0.08 mmol) and DBU (122.4 mg,
2
Purification: Hexane/EtOAc (1: 1), white solid (78% yield, 83 mg),
0.8 mmol) at room temperature. The reaction mixture was stirred at
o
1
mp. 258ꢀ260 C; H NMR (400 MHz, DMSOꢀd ) δ 11.20 (br s, 1H),
6
4
| J. Name., 2016, 00, 1-8
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DOI: 10.1039/C6OB01307D
Journal Name
0.05 (br s, 1H), 7.96 (dd, J = 19.5, 8.9 Hz, 4H), 7.43 (d, J = 23.3
Paper
ꢀ
1
1
IR (NaCl) ν (cm ) 3321, 3052, 2922, 2852, 1658, 1599, 1508, 1403,
1349, 1218, 1156, 1016, 919, 832, 678; HRMS (ESI): Calcd for
1
3
Hz, 2H), 7.10 (dd, J = 5.4, 2.2 Hz, 2H), 3.87 (s, 3H); C NMR (100
MHz, DMSOꢀd ) δ 166.5, 149.8, 145.7, 143.1, 134.7, 131.9, 131.8,
+
6
C
13
H10BrFN
3
[M+H] : 306.0037, found: 306.0036.
ꢀ
1
1
2
7
30.9, 128.4, 121.5, 116.5, 110.2, 52.1; IR (NaCl) ν (cm ) 3381,
925, 2853, 1713, 1654, 1607, 1513, 1436, 1377, 1280, 1165, 1021,
72, 618; HRMS (ESI): Calcd for C15H N O [M+H] : 268.1081,
14 3 2
6
-Bromo-N-(3-nitrophenyl)-1H-benzo[d]imidazol-2-amine (2k):
Purification: Hexane/EtOAc (1: 1), yellow solid (82% yield, 64
mg), mp. 269ꢀ271 C; H NMR (400 MHz, DMSOꢀd ) δ 11.45 (br s,
+
found: 268.1083.
o
1
6
1
H), 10.25 (br s, 1H), 8.89 (s, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.84 (d,
N-(3, 5-Dibromophenyl)-1H-benzo[d]imidazol-2-amine (2f):
Purification: Hexane/EtOAc (7: 3), colour less liquid (77% yield,
J = 9.7 Hz, 1H), 7.65 (t, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.38 (d, J =
1
3
21.5 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H); C NMR (125 MHz,
DMSOꢀd ) δ 177.5, 148.7, 142.2, 132.3, 130.5, 123.7, 119.1, 118.3,
1
1
2
12 mg); H NMR (500 MHz, DMSOꢀd
6
) δ 8.07 (d, J = 1.4 Hz,
6
1
3
ꢀ1
H), 7.38 (s, 2H), 7.31 (s, 1H), 7.05 (dd, J = 5.8, 3.2 Hz, 2H);
) δ 171.9, 149.2, 143.6, 124.6, 122.4,
20.5, 118.2 (signals for C2 and bridgehead carbons of the
C
115.7, 112.9, 111.8, 111.5; IR (NaCl) ν (cm ) 3385, 2922, 2852,
NMR (100 MHz, DMSOꢀd
6
1653, 1532, 1457, 1350, 1260, 1017, 769, 666; HRMS (ESI): Calcd
+
1
for C13
H10BrN
4
O
2
[M+H] : 332.9982, found: 332.9977.
ꢀ
1
benzimidazole ring were too weak to observe); IR (NaCl) ν (cm )
3
384, 2923, 2852, 1652, 1577, 1457, 1354, 1217, 1020, 833, 760,
5, 6-Dichloro-N-phenyl-1H-benzo[d]imidazol-2-amine
(2l):
+
666; HRMS (ESI): Calcd for C13
H10Br
2
N
3
[M+H] : 365.9236,
Purification: Hexane/EtOAc (3: 2), white semi solid (78% yield, 53
1
found: 365.9229.
mg); H NMR (400 MHz, DMSOꢀd ) δ 11.12 (br s, 1H), 9.70 (br s,
6
1
H), 8.06 (s, 2H), 7.80 (d, J = 6.6 Hz, 2H), 7.33 (t, J = 7.1 Hz, 3H);
21b
13
N-(Naphthalen-2-yl)-1H-benzo[d]imidazol-2-amine
(2g):
C NMR (125 MHz, DMSOꢀd ) δ 152.9, 140.6, 134.5, 130.5,
6
ꢀ
1
Purification: Hexane/EtOAc (3: 2), brown solid (80% yield, 83 mg),
129.8, 129.4, 127.8, 121.7, 119.3, 117.9, 115.6; IR (NaCl) ν (cm )
3224, 3053, 2923, 2852, 1660, 1601, 1508, 1440, 1349, 1220, 1021,
864, 758, 692; HRMS (ESI): Calcd for C H Cl N [M+H] :
o
1
mp. 193ꢀ195 C; H NMR (400 MHz, Acetoneꢀd
6
) δ 8.41 (s, 1H),
.69 (dd, J = 11.7, 9.0 Hz, 3H), 7.59 (dd, J = 8.8, 2.1 Hz, 1H), 7.34
7.29 (m, 1H), 7.26 – 7.21 (m, 2H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H),
+
7
–
6
1
1
13
10
2
3
278.0247, found: 278.0244.
1
3
.92 (dd, J = 5.8, 3.2 Hz, 2H); C NMR (125 MHz, CDCl ) δ
77.7, 148.8, 133.9, 132.4, 132.1, 128.7, 127.8, 125.8, 125.2, 124.9,
23.2, 120.4, 118.9, 114.5, 110.5; HRMS (ESI): Calcd for C H N
3
N-(4-Bromophenyl)-5, 6-dichloro-1H-benzo[d]imidazol-2-amine
(2m): Purification: Hexane/EtOAc (3: 2), light brown solid (80%
1
7
14
3
+
o
1
[
M+H] : 260.1182, found: 260.1182.
6
yield, 70 mg), mp. 256ꢀ258 C; H NMR (400 MHz, DMSOꢀd ) δ
1
1.28 (br s, 1H), 9.93 (br s, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.60 (s,
21b
13
N-(Pyridin-3-yl)-1H-benzo[d]imidazol-2-amine
(2h):
1H), 7.58 (s, 1H), 7.55 (d, J = 8.9 Hz, 2H); C NMR (100 MHz,
Purification: Hexane/EtOAc (2: 3), brown solid (68% yield, 57 mg),
DMSOꢀd ) δ 152.5, 140.0, 136.6, 133.1, 132.0, 130.8, 124.6, 119.8,
118.0, 112.9, 111.2; IR (NaCl) ν (cm ) 3203, 2921, 1715, 1659,
6
o
1
ꢀ1
mp. 178ꢀ180 C; H NMR (400 MHz, DMSOꢀd ) δ 11.12 (br s, 1H),
6
9
.67 (br s, 1H), 8.85 (s, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.14 (d, J =
1587, 1467, 1340, 1218, 1010, 817; HRMS (ESI): Calcd for
1
3
+
3
.9 Hz, 1H), 7.35 (dd, J = 8.2, 4.6 Hz, 3H), 7.11 – 6.93 (m, 2H);
) δ 150.0, 142.7, 141.4, 139.0, 137.6,
32.7, 123.5, 123.4, 120.5, 120.0, 116.0, 109.5; HRMS (ESI): Calcd
C
C H BrCl N [M+H] : 355.9352, found: 355.9344.
1
3
9
2
3
NMR (125 MHz, DMSOꢀd
1
6
N-(4-Methoxyphenyl)-1H-pyrazol-3-amine (2n): Purification:
+
for C12
H
11
N
4
[M+H] : 211.0978, found: 211.0985.
Hexane/EtOAc (7: 3), brown solid (75% yield, 85 mg), mp. 175ꢀ
o
1
1
77 C; H NMR (400 MHz, DMSOꢀd ) δ 7.99 (d, J = 2.5 Hz, 1H),
6
6
-Methoxy-N-phenyl-1H-benzo[d]imidazol-2-amine
(2i):
7.56 (d, J = 9.1 Hz, 2H), 6.96 (d, J = 9.1 Hz, 2H), 5.70 (d, J = 2.4
13
Purification: Hexane/EtOAc (3: 2), brown liquid (83% yield, 60
Hz, 1H), 4.95 (br s, 1H), 3.43 (s, 3H); C NMR (125 MHz, DMSOꢀ
) δ 156.1, 155.4, 133.3, 126.8, 117.3, 113.8, 94.7, 54.7; IR (NaCl)
1
mg); H NMR (400 MHz, DMSOꢀd
6
) δ 10.74 (br s, 1H), 9.32 (br s,
H), 7.73 (d, J = 7.8 Hz, 2H), 7.30 (t, J = 7.9 Hz, 2H), 7.19 (d, J =
.4 Hz, 1H), 6.92 (d, J = 7.0 Hz, 2H), 6.62 (dd, J = 8.5, 2.3 Hz, 1H),
.75 (s, 3H); C NMR (100 MHz, DMSOꢀd ) δ 172.4, 154.9, 151.0,
41.4, 129.3, 129.2, 120.8, 117.3, 115.7, 112.5, 108.1, 55.9; IR
d
6
ꢀ
1
1
8
3
1
ν (cm ) 3315, 2919, 2838, 2607, 1651, 1588, 1514, 1483, 1302,
1251, 1180, 1029, 951, 830, 761, 696; HRMS (ESI): Calcd for
1
3
+
C
10
H
12
N
3
O [M+H] : 190.0975, found: 190.0979.
6
2
1b
ꢀ
1
N-(4-Bromophenyl)-3-methyl-1H-pyrazol-4-amine
(2o):
(
1
NaCl) ν (cm ) 3356, 2924, 2853, 2255, 1736, 1651, 1592, 1502,
463, 1323, 1220, 1158, 1113, 1023, 829, 761, 691; HRMS (ESI):
Purification: Hexane/EtOAc (7: 3), light brown semi solid (70%
1
+
yield, 90 mg); H NMR (400 MHz, DMSOꢀd ) δ 8.32 (br s, 1H),
Calcd for C14
H
14
N
3
O [M+H] : 240.1132, found: 240.1135.
6
7
.78 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 8.8 Hz, 2H), 2.12
13
(
s, 3H); C NMR (125 MHz, DMSOꢀd
6
) δ 147.1, 138.5, 132.0,
6-Bromo-N-(4-fluorophenyl)-1H-benzo[d]imidazol-2-amine
1
30.1, 121.6, 115.2, 108.1, 9.8; HRMS (ESI): Calcd for C10
H11BrN
3
(2j): Purification: Hexane/EtOAc (3: 2), light brown solid (85%
+
o
1
[M+H] : 252.0131, found: 252.0149.
yield, 61 mg), mp. 228ꢀ230 C; H NMR (400 MHz, DMSOꢀd
1.09 (br s, 1H), 9.60 (br s, 1H), 8.12 (s, 1H), 7.85 (dd, J = 8.6, 6.5
Hz, 1H), 7.77 (dd, J = 9.1, 4.9 Hz, 2H), 7.25 (d, J = 8.3 Hz, 1H),
6
) δ
1
1
General Procedure for the synthesis of Cu-catalyzed N -
arylation of 2-aminobenzimidazoles: (Procedure B)
1
3
7
1
1
6
.20 – 7.12 (m, 2H); C NMR (125 MHz, DMSOꢀd ) δ 170.8,
65.2, 163.2, 158.3, 156.4, 152.0, 137.4, 136.9 (d, J = 7.9 Hz),
19.3 (d, J = 7.6 Hz), 115.7 (d, J = 22.2 Hz), 114.7 (d, J = 19.7 Hz);
An ovenꢀdried sealed tube equipped with a magnetic stirring bar
was charged with 2ꢀaminobenzimidazole (1a) (60 mg, 0.45 mmol),
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Paper
Cu O (6.45 mg, 0.045 mmol) and KOH (50.6 mg, 0.90 mmol). The
Journal Name
2
1107, 1021, 830, 738, 668; HRMS (ESI): Calcd for C12H10ClN
4
+
reaction tube was sealed with a rubber septum, evacuated and backꢀ
filled with nitrogen three times. Dry DMSO (1 mL) and
iodobenzene (75.4 µL, 0.67 mmol) was added by syringe. The
rubber septum was exchanged with Teflon cap and the reaction
[M+H] : 245.0589, found: 245.0587.
1
-(Thiophen-3-yl)-1H-benzo[d]imidazol-2-amine
(3e):
Purification: Hexane/EtOAc (1: 4), white solid (81% yield, 78 mg),
o
mixture was stirred at 120 C for 14 h. The progress of the reaction
o
1
mp. 152ꢀ154 C; H NMR (400 MHz, DMSOꢀd
6
) δ 7.85 (dd, J =
.9, 2.9 Hz, 2H), 7.33 (dd, J = 4.9, 1.6 Hz, 1H), 7.26 (d, J = 7.7 Hz,
H), 7.06 (t, J = 8.1 Hz, 1H), 7.00 – 6.91 (m, 2H), 6.39 (br s, 2H);
was monitored by TLC and after completion, the mixture was
allowed to cool down to room temperature. The crude reaction
mixture was diluted with 15 mL of ice cooled water and extracted
with ethyl acetate (3x15 mL). The combined organic layer was
dried over Na SO and concentrated under vacuum. The crude
2 4
product was purified by column chromatography (hexane/EtOAc) to
7
1
13
6
C NMR (125 MHz, DMSOꢀd ) δ 154.7, 143.1, 135.1, 133.2,
ꢀ1
1
3
1
27.9, 125.3, 121.7, 121.5, 119.3, 115.5, 108.4; IR (NaCl) ν (cm )
448, 3313, 3104, 2922, 2849, 1636, 1550, 1464, 1449, 1410, 1303,
289, 1251, 1171, 1079, 1023, 854, 786, 741, 693, 656; HRMS
afford the desired product 3a. By following the above general
+
(
ESI): Calcd for C11
H
10
N
3
S [M+H] : 216.0590, found: 216.0590.
1
procedure B, N ꢀarylated 2ꢀaminobenzimidazoles (3b-j) and 3ꢀ
aminopyrazoles (3kꢀl) were synthesized.
1-(1-Benzyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-amine (3f):
Purification: Hexane/EtOAc (1: 4), brown solid (79% yield, 120
2
0
1
-Phenyl-1H-benzo[d]imidazol-2-amine (3a):
Purification:
o
1
mg), mp. 212ꢀ214 C; H NMR (400 MHz, DMSOꢀd
m, 2H), 7.68 (d, J = 1.8 Hz, 1H), 7.41 – 7.37 (m, 4H), 7.35 – 7.30
(m, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.18 (dd, J = 8.6, 1.9 Hz, 1H),
.03 (t, J = 7.2 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 7.7
6
) δ 7.77 – 7.72
Hexane/EtOAc (2: 3), brown solid (85% yield, 80 mg), mp. 148ꢀ
50 C; H NMR (400 MHz, CDCl ) δ 7.55 (t, J = 7.6 Hz, 2H), 7.48
7.39 (m, 4H), 7.10 (d, J = 7.3 Hz, 1H), 6.97 (d, J = 5.2 Hz, 2H),
) δ 143.3, 136.3, 131.8,
30.2, 128.1, 123.5, 121.5, 117.5, 109.8 (Signals for bridgehead
carbons were too weak to observe); HRMS (ESI): Calcd for
(
o
1
1
–
5
1
3
7
13
.31 (br s, 2H); C NMR (125 MHz, CDCl
3
13
Hz, 1H), 6.66 (d, J = 2.9 Hz, 1H), 6.21 (br s, 2H), 5.55 (s, 2H);
C
NMR (125 MHz, DMSOꢀd ) δ 155.3, 143.0, 138.5, 136.3, 135.6,
6
1
1
2
1
3
31.1, 129.3, 129.0, 128.0, 127.8, 127.0, 121.2, 120.5, 119.5, 118.9,
15.2, 111.9, 108.1, 102.1, 49.8; IR (NaCl) ν (cm ) 3446, 3318,
+
C
13
H
12
N
3
[M+H] : 210.1026, found: 210.1022.
ꢀ1
922, 2851, 1631, 1589, 1488, 1453, 1355, 1250, 1212, 1181, 1092,
1
-(p-Tolyl)-1H-benzo[d]imidazol-2-amine (3b): Purification:
+
022, 829, 738, 644; HRMS (ESI): Calcd for C H N [M+H] :
2
2
19
4
1
Hexane/EtOAc (2: 3), brown liquid (83% yield, 83 mg); H NMR
400 MHz, CDCl ) δ 7.38 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.2 Hz,
H), 7.26 (d, J = 8.3 Hz, 2H), 7.08 (t, J = 7.4 Hz, 1H), 6.96 (t, J =
.5 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 5.07 (br s, 2H), 2.40 (s, 3H);
) δ 138.1, 130.8, 130.0, 129.2, 125.5,
21.2, 120.2, 119.6, 119.3, 115.1, 107.5, 20.2; IR (NaCl) ν (cm )
442, 3298, 2922, 2852, 1632, 1543, 1515, 1463, 1330, 1256, 1108,
019, 818, 740, 668; HRMS (ESI): Calcd for C14
24.1182, found: 224.1190.
39.1604, found: 339.1601.
(
3
2
7
1-(1-Benzyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-
benzo[d]imidazol-2-amine (3g): Purification: Hexane/EtOAc (1:
13
C NMR (100 MHz, CDCl
3
1
4
), brown liquid (74% yield, 113 mg); H NMR (400 MHz, DMSOꢀ
ꢀ
1
1
3
1
2
d
6
) δ 8.35 (s, 1H), 8.15 (s, 1H), 7.83 (d, J = 3.5 Hz, 1H), 7.45 – 7.34
(
6
m, 4H), 7.31 (dd, J = 9.0, 3.8 Hz, 2H), 7.05 (t, J = 7.2 Hz, 1H),
.88 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 3.5
+
H
14
N
3
[M+H] :
13
Hz, 1H), 6.40 (br s, 2H), 5.59 (s, 2H); C NMR (125 MHz, DMSOꢀ
d
1
6
) δ 148.5, 145.8, 143.2, 140.8, 137.5, 130.3, 129.4, 128.0, 127.3,
27.0, 126.9, 123.9, 120.5, 119.8, 118.2, 114.3, 106.9, 99.7, 46.8;
1
-(4-Nitrophenyl)-1H-benzo[d]imidazol-2-amine
(3c):
Purification: Hexane/EtOAc (3: 7), yellow solid (81% yield, 92
mg), mp. 293ꢀ295 C; H NMR (400 MHz, DMSOꢀd ) δ 8.45 (d, J =
ꢀ1
IR (NaCl) ν (cm ) 3451, 3310, 2926, 2854, 1644, 1546, 1497, 1463,
1357, 1331, 1257, 1160, 1080, 1027, 897, 739, 633; HRMS (ESI):
Calcd for C21
0
1
6
8.9 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H), 7.28 (br, 1H), 7.06 (d, J = 5.2
+
H
18
N
5
[M+H] : 340.1557, found: 340.1570.
1
3
Hz, 2H), 6.93 (t, J = 7.5 Hz, 1H), 6.58 (br s, 2H); C NMR (100
MHz, DMSOꢀd ) δ 146.2, 141.0, 127.4, 125.4, 121.9, 119.2, 115.4,
07.9 (Signals for C2 and bridgehead carbons of the benzimidazole
6
6
-Bromo-1-(3-chlorophenyl)-1H-benzo[d]imidazol-2-amine (3h):
1
21a
Purification: Hexane/EtOAc (2: 3), brown liquid (85% yield, 64
ꢀ1
ring were too weak to observe); IR (NaCl) ν (cm ) 3333, 2922,
1
mg); H NMR (400 MHz, CDCl
=
3
) δ 7.55 – 7.44 (m, 3H), 7.39 (d, J
2
8
2
851, 1643, 1596, 1511, 1463, 1350, 1241, 1216, 1095, 1020, 854,
30, 759, 696; HRMS (ESI): Calcd for C13
55.0877, found: 255.0880.
10.1 Hz, 1H), 7.15 (t, J = 7.1 Hz, 1H), 7.06 – 6.95 (m, 2H), 6.09
+
H
11
N
4
O
2
[M+H] :
13
(
br, 2H); C NMR (125 MHz, CDCl ) δ 153.0, 141.2, 135.9, 135.9,
3
1
34.2, 131.4, 129.1, 126.9, 124.8, 122.5, 120.4, 116.0, 108.3;
+
HRMS (ESI): Calcd for C H BrClN [M+H] : 321.9741, found:
3
1
3
10
3
1-(6-Chloropyridin-3-yl)-1H-benzo[d]imidazol-2-amine
(3d):
21.9751.
Purification: Hexane/EtOAc (1: 4), brown liquid (78% yield, 85
mg); H NMR (400 MHz, DMSOꢀd
1
6
) δ 8.59 (s, 1H), 8.05 (dd, J =
5
, 6-Dichloro-1-(p-tolyl)-1H-benzo[d]imidazol-2-amine (3i):
8
7
.5, 2.7 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H),
.07 – 6.99 (m, 1H), 6.89 (d, J = 4.9 Hz, 2H), 6.51 (br s, 2H);
Purification: Hexane/EtOAc (2: 3), brown liquid (80% yield, 57
mg); H NMR (400 MHz, CDCl
Hz, 2H), 7.24 (d, J = 7.6 Hz, 2H), 7.00 (s, 1H), 5.28 (br s, 2H), 2.41
1
3
C
1
3
) δ 7.45 (s, 1H), 7.36 (d, J = 7.7
NMR (125 MHz, DMSOꢀd
6
) δ 154.7, 149.8, 148.8, 143.5, 140.3,
ꢀ
1
139.1, 131.9, 126.0, 122.1, 119.5, 115.6, 108.0; IR (NaCl) ν (cm )
13
(
s, 3H); C NMR (125 MHz, CDCl
3
) δ 140.3, 131.4, 126.5, 126.2,
3320, 3173, 2922, 2850, 1643, 1548, 1471, 1437, 1380, 1256, 1133,
1
24.4, 116.8, 110.3, 21.3 (signals for C2 and bridgehead carbons of
ꢀ
the benzimidazole ring were too weak to observe); IR (NaCl) ν (cm
6
| J. Name., 2016, 00, 1-8
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Paper
1
)
3344, 2924, 2853, 1742, 1673, 1511, 1463, 1379, 1248, 1181,
Saubern, J. Adams, M. P. Winters, D. M. T. Chan and A. Combs,
1
100, 1018, 828, 770, 669; HRMS (ESI): Calcd for C14
2
H12Cl N
3
Tetrahedron Lett., 1998, 39, 2941.
+
[
M+H] : 292.0403, found: 292.0408.
5. For reviews on ChanꢀLam coupling, see: (
a
) J. X. Qiao and P. Y. S.
Lam, Synthesis, 2011, 829; (
Tetrahedron, 2012, 68, 7735.
b) K. Sanjeeva Rao and T.ꢀS. Wu,
1
-(3-Chlorophenyl)-6-nitro-1H-benzo[d]imidazol-2-amine (3j):
21a
Purification: Hexane/EtOAc (3: 7), yellow solid (78% yield, 63
6. For selected articles on ChanꢀLam type coupling, see: (
Yoo, T. Tsukamoto and S. Kobayashi, Angew. Chem., Int. Ed.,
2015, 54, 6587; ( ) S.ꢀY. Moon, U. B. Kim, D.ꢀB. Sung and W.ꢀS.
Kim, J. Org. Chem., 2015, 80, 1856; ( ) M. El Khatib and G. A.
Molander, Org. Lett., 2014, 16, 4944; ( ) T. Onaka, H. Umemoto,
Y. Miki, A. Nakamura and T. Maegawa, J. Org. Chem., 2014, 79
a) W.ꢀJ.
o
1
mg), mp. 228ꢀ230 C; H NMR (400 MHz, DMSOꢀd
8.8, 1.5 Hz, 1H), 7.46 (d, J = 6.1 Hz, 1H), 7.43 (d, J = 7.7 Hz,
H), 7.32 (s, 1H), 7.07 (d, J = 8.7 Hz, 1H), 7.00 (br s, 2H), 6.71 (s,
6
) δ 7.77 (dd, J
=
b
2
1
1
c
1
3
H); C NMR (100 MHz, DMSOꢀd
32.3, 129.7, 127.8, 126.5, 119.2, 115.9, 114.4, 107.8, 103.7;
6
) δ 150.1, 139.8, 135.4, 134.8,
d
,
+
4 2
HRMS (ESI): Calcd for C13H10ClN O [M+H] : 289.0487, found:
6
073; (
e
) F. Huang, T. D. Quach and R. A. Batey, Org. Lett., 2013,
) J. Li and L. Neuville, Org. Lett., 2013, 15, 6124; ( ) E.
289.0498.
1
5, 3150; (
f
g
Racine, F. Monnier, J.ꢀP. Vors and M. Taillefer, Chem. Commun.,
013, 49, 7412; ( ) S. A. Rossi, K. W. Shimkin, Q. Xu, L. M.
Mori.ꢀQuiroz and D. A. Watson, Org. Lett., 2013, 15, 2314; ( ) J.
Li, S. Benard, L. Neuville and J. Zhu, Org. Lett., 2012, 14, 5980; (
C.ꢀY. Liu, Y. Li, J.ꢀY. Ding, D.ꢀW. Dong and F.ꢀS. Han, Chem.-
Eur. J., 2014, 20, 2373; ( ) S. Roy, M. J. Sarma, B. Kashyap and P.
Phukan, Chem. Commun., 2016, 52, 1170; ( ) J. C. Vantourout, R.
1
9d
1
-(p-Tolyl)-1H-pyrazol-3-amine
(3k):
Purification:
2
h
Hexane/EtOAc (8: 2), brown solid (90% yield, 93 mg), mp. 101ꢀ
3
) δ 7.55 (d, J = 2.5 Hz, 1H),
.35 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 5.72 (d, J = 2.5
Hz, 1H), 3.77 (br s, 2H), 2.26 (s, 3H); C NMR (125 MHz, CDCl
δ 155.6, 137.9, 134.8, 129.8, 127.7, 117.8, 95.7, 20.8; HRMS (ESI):
12 3
Calcd for C10H N [M+H] : 174.1026, found: 174.1019.
i
o
1
103 C; H NMR (400 MHz, CDCl
j)
7
13
3
)
k
l
+
P. Law, A. IsidroꢀLlobet, S. J. Atkinson and A. J. B. Watson, J.
Org. Chem., 2016, 81, 3942.
2
1a
1
-(4-Fluorophenyl)-1H-pyrazol-3-amine (3l):
Purification:
7
.
(a
)
K. Anil Kumar, P. Kannaboina, D. K. Dhaked, R. A.
Vishwakarma, P. V. Bharatam and P. Das, Org. Biomol. Chem.,
2015, 13, 1481; ( ) Sk. Rasheed, D. Nageswar Rao and P. Das, J.
Org. Chem., 2015, 80, 9321; ( ) Sk. Rasheed, D. N. Rao, K.
Ranjith Kumar, S. Aravinda, R. A. Vishwakarma and P. Das, RSC
Adv., 2014, , 4960; ( ) D. N. Rao, Sk. Rasheed, S. Aravinda, R. A.
Vishwakarma and P. Das, RSC Adv., 2013, , 11472; ( ) K. Anil
Kumar, P. Kannaboina, C K. Jaladanki, P. V. Bharatam and P. Das,
ChemistrySelect., 2016, , 601.
) S. S. Kampmann, A. N. Sobolev, G. A. Koutsantonis and S. G.
Stewart, Adv. Synth. Catal., 2014, 356, 1967; ( ) X.ꢀL. Li, W. Wu,
X.ꢀH. Fan and L.ꢀM. Yang, Org. Biomol. Chem., 2014, 12, 1232;
) L. IIies, T. Matsubara and E. Nakamura, Org. Lett., 2012, 14
570; ( ) C.ꢀY. Gao, X. Cao and L.ꢀM. Yang, Org. Biomol. Chem.,
009, , 3922; ( ) L. Hie, S. D. Ramgren, T. Mesganaw and N. K.
) N. H. Park, G. Teverovskiy
and S. L. Buchwald, Org. Lett., 2014, 16, 220; ( ) N. F. Fine
Nathel, J. Kim, L. Hie, X. Jiang and N. K. Garg, ACS Catal., 2014,
, 3289; ( ) X.ꢀQ. Zhang and Z.ꢀX. Wang, Org. Biomol. Chem.,
2014, 12, 1448; ( ) R. A. Green and J. F. Hartiwg, Angew. Chem.,
Int. Ed., 2015, 54, 3768; ( ) G. Manolikakes, A. Gavryushin and P.
Knochel, J. Org. Chem., 2008, 73, 1429.
) D. S. Raghuvanshi, A. K. Gupta and K. N. Singh, Org. Lett.,
2012, 14, 4326; ( ) G. Hu, W. Chen, T. Fu, Z. Peng, H. Qiao, Y.
Hexane/EtOAc (8: 2), brown solid (86% yield, 91 mg), mp. 101ꢀ
o
1
1
03 C; H NMR (400 MHz, CDCl ) δ 7.62 (d, J = 2.5 Hz, 1H),
3
b
7
.52 (dd, J = 9.1, 4.6 Hz, 2H), 7.15 – 7.01 (m, 2H), 5.84 (d, J = 2.5
c
13
Hz, 1H), 3.72 (br s, 2H); C NMR (100 MHz, CDCl
3
) δ 161.5,
1
9
1
59.1, 155.8, 127.8, 119.5 (d, J = 8.2 Hz), 116.0 (d, J = 22.9 Hz),
4
d
+
9 9 3
6.2; HRMS (ESI): Calcd for C H FN [M+H] : 178.0775, found:
3
e
78.0782.
1
Acknowledgements
8
.
(a
K. A. K. and D.N.R are thankful to UGC, New Delhi and P. K.
thankful to CSIRꢀNew Delhi for research fellowship. This research
work is financially supported by CSIRꢀNew Delhi (BSC0108).
IIIMꢀcommunication No IIIM/1952/2016.
b
(
c
,
5
2
d
7
e
References
Garg, Org. Lett., 2012, 14, 4182; (
f
1
.
For general review on
vander. Eycken, Chem. Soc. Rev., 2013, 42, 9283; (
Beletskaya and A. V. Cheprakov, Organometallics, 2012, 31, 7753;
) J. E. R. Sadig and M. C. Willis, Synthesis, 2011, 1; ( ) H. Kim
and S. Chang, ACS Catal., 2016, , 2341; ( ) C. Fisher and B.
Koenig, Beilstein J. Org. Chem., 2011, , 59; ( ) T. R. M. Rauws
N
ꢀarylation, see: (
a
) J. Bariwal and E.
g
b
) I. P
4
h
(c
d
i
6
e
j
7
f
and B. U. W. Maes, Chem. Soc. Rev., 2012, 41, 2463; (
C. Liu and A. Lei, Chem. Commun., 2015, 51, 1394.
g
) J. Yuan,
9.
(a
b
2
.
Reviews on Ullmannꢀtype coupling see: (
Marsden, A. J. Blacker and P. C. McGowan, Chem. Soc. Rev.,
014, 43, 3525; ( ) F. Monnier and M. Taillefer, Angew. Chem.,
Int. Ed., 2009, 48, 6954; ( ) S. V. Ley and A. W. Thomas, Angew.
a
) C. Sambiago, S. P.
Gao and Y. Zhao, Org. Lett., 2013, 15, 5362.
2
10. Selected examples for the synthesis of C ꢀNH
2
ꢀsubstituted 2ꢀamino
2
b
Benzimidazoles, see: (
D. Stevens, D. Wodka and G. M. Makara, Tetrahedron Lett., 2008,
49, 1910; ( ) X. Deng, H. McAllister and N. S. Mani, J. Org.
Chem., 2009, 74, 5742; ( ) Z.ꢀK. Wan, E. F. Ousman, N.
Papaioannou and E. Saiah, Tetrahedron Lett., 2011, 52, 4149; (
D. B. Murphy, J. Org. Chem., 1964, 29, 1613; ( ) X.ꢀJ. Wang, L.
Zhang, Y. Xu, D. Krishnamurthy and C. H. Senanayake,
Tetrahedron Lett., 2004, 45, 7167; ( ) P. Das, C. K. Kumar, K. N.
a) P. Lan, F. A. Romero, T. S. Malcolm, B.
c
Chem., Int. Ed., 2003, 42, 5400.
b
3
4
.
.
For reviews on Pdꢀcatalyzed BuchwaldꢀHartwig coupling, see: (
a
)
c
D. S. Surry and S. L. Buchwald, Angew. Chem., Int. Ed., 2008, 47,
338; ( ) J. F. Hartiwg, Acc. Chem. Res., 2008, 41, 1534; ( ) D. S.
Surry and S. L. Buchwald, Chem. Sci., 2011, , 27.
) D. M. T. Chan, K. L. Monaco, R.ꢀP. Wang and M. P. Winters,
Tetrahedron Lett., 1998, 39, 2933; ( ) P. Y. S. Lam, C. G. Clark, S.
d)
6
b
c
e
2
(
a
f
b
Kumar, M. Innus, J. Iqbal and N. Srinivas, Tehrahedron Lett.,
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DOI: 10.1039/C6OB01307D
Paper
Journal Name
2
008, 49, 992; (
Maes, R. V. A. Orru and E. Ruijter, Angew. Chem., Int. Ed., 2012,
, 13058.
1. Selected examples for the synthesis of N ꢀsubstituted 2ꢀamino
benzimidazoles, see: ( ) G. Evindar and R. A. Batey, Org. Lett.,
003, , 133; ( ) Y.ꢀQ. Wu, D. C. Limburg, D. E. Wilkinson and G.
S. Hamilton, J. Heterocycl. Chem., 2003, 40, 191; ( ) F. Wang, S.
Cai, Q. Liao and C. Xi, J. Org. Chem., 2011, 76, 3174.
g
) T. Vlaar, R. C. Cioc, P. Mampuys, B. U. W.
Kumar, A. Siva Reddy and P. Das, Adv. Synth. Catal., 2016, 358
2126.
,
5
1
1
1
1
a
2
5
b
c
2. S. Hameed P, M. Chinnapattu, G. Shanbag, P. Manjrekar, K.
Koushik, A. Raichurkar, V. Patil, S. Jatheendranath, S. S.
Rudrapatna, S. P. Barde, N. Rautela, D. Awasthy, S. Morayya, C.
Narayan, S. Kavanagh, R. Saralaya, S. Bharath, P. Viswanath, K.
Mukherjee, B. Bandodkar, A. Srivastava, V. Panduga, J. Reddy, K.
R. Prabhakar, A. Sinha, M. B. n. JiménezꢀDíaz, M. S. Martínez, I. i.
AnguloꢀBarturen, S. Ferrer, L. M. Sanz, F. J. Gamo, S. Duffy, V.
M. Avery, P. A. Magistrado, A. K. Lukens, D. F. Wirth, D.
Waterson, V. Balasubramanian, P. S. Iyer, S. Narayanan, V.
Hosagrahara, V. K. Sambandamurthy and S. Ramachandran, J.
Med. Chem., 2014, 57, 5702.
1
3. M. Zhong, M. Bui, S. Wang, S. Baskaran, D. A. Allen, R. A.
Elling, W. M. Flanagan, A. D. Fung, E. J. Hanan, S. O. Harris, S.
A. Heumann, U. Hoch, S. N. Ivy, J. W. Jacobs, S. Lam, H. Lee, R.
S. McDowell, J. D. Oslob, H. E. Purkey, M. J. Romanowski, J. A.
Silverman, B. T. Tangonan, P. Taverna, W. Yang, J. C. Yoburn, C.
H. Yu, K. M. Zimmerman, T. O Brien and W. Lew, Bioorg. Med.
Chem. Lett., 2009, 19, 5158.
1
1
4. R. D. Carpenter, M. Andrei, E. Y. Lau, F. C. Lightstone, R. Liu, K.
S. Lam and M. J. Kurth, J. Med. Chem., 2007, 50, 5863.
5. V. J. Cee, A. C. Cheng, K. Romero, S. Bellon, C. Mohr, D. A.
Whittington, A. Bak, J. Bready, S. Caenepeel, A. Coxon, H. L.
Deak, J. Fretland, Y. Gu, B. L. Hodous, X. Huang, J. L. Kim, J.
Lin, A. M. Long, H. Nguyen, P. R. Olivieri, V. F. Patel, L. Wang,
Y. Zhou, P. Hughes and S. GeunsꢀMeyer, Bioorg. Med. Chem.
Lett., 2009, 19, 424.
1
1
1
6. T. Varming, P. Christophersen, A. Møller, D. Peters, O. Axelsson
and E. Ø. Nielsen, Bioorg. Med. Chem. Lett., 1996, 6, 245.
7. K. Ding, A. Wang, M. A. Boerneke, S. M. Dibrov and T. Hermann,
Bioorg. Med. Chem. Lett., 2014, 24, 3113.
8. For Pdꢀcatalyzed
J. Yin, M. M. Zhao, M. A. Huffman and J. M. McNamara, Org.
Lett., 2002, , 3481; ( ) M. A. McGowan, J. L. Henderson and S.
L. Buchwald, Org. Lett., 2012, 14, 1432; ( ) S. Ueda, S. Ali, B. P.
Fors and S. L. Buchwald, J. Org. Chem., 2012, 77, 2543.
9. For Cuꢀcatalyzed ꢀarylation of benzimidazole derivatives, see:
) L. Zhu, G. Li, L. Luo, P. Guo, J. Lan and J. You, J. Org. Chem.,
009, 74, 2200; ( ) L. Wang, N. Liu, B. Dai and H. Hu, Eur J.
Org. Chem., 2014, 6493; ( ) A. F. Larsen and T. Ulven, Chem.
Commun., 2014, 50, 4997; ( ) A. Beyer, T. Castanheiro, P. Busca
and G. Prestat, ChemCatChem. 2015, , 2433; ( ) D. Wang, F.
Zhang, D. Kuang, J. Yu and J. Li, Green Chem., 2012, 14, 1268; (
L. Liang, Z. Li and X. Zhou, Org. Lett., 2009, 11, 3294; ( ) F.
Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2009, 121
088; Angew. Chem., Int. Ed., 2009, 48, 6954.
0. S. Ueda and S. L. Buchwald, Angew. Chem., Int. Ed., 2012, 51
0364.
) D. N. Rao, Sk. Rasheed, R. A. Vishwakarma and P. Das, Chem.
Commun., 2014, 50, 12911; ( ) D. N. Rao, Sk. Rasheed, K. Anil
Nꢀarylation of benzimidazole derivatives, see: (a)
4
b
c
1
N
(a
2
b
.
c
d
7
e
f)
g
,
7
2
2
,
1
1. (a
b
8
| J. Name., 2016, 00, 1-8
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