Copper-catalyzed cascade C-N coupling/C-H amination: one pot synthesis of imidazo[1,2-b]indazole

Article abstract of DOI:10.1039/d0nj03022h

We report an efficient synthesis of imidazo[1,2-b]indazole starting from 2-(2H-indazol-2-yl)aniline with aryl/heteroaryl/aliphatic bromide. This novel transformation involves a one-pot Cu-catalyzed cascade process combining C-N coupling between 2-(2H-indazol-2-yl)aniline and aryl/heteroaryl/aliphatic bromide followed by intramolecular C-H amination to afford the desired compounds in good yields.

Full text of DOI:10.1039/d0nj03022h

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DOI: 10.1039/D0NJ03022H
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Copper-catalyzed cascade C–N coupling/C–H amination:
One pot synthesis of imidazo[1,2-b]indazole
Received 00th January 20xx,
Accepted 00th January 20xx
Bandari Rajesham, Vemula Arunkumar, Praveen Kumar Naikawadi, K.
Shiva Kumar*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report an efficient synthesis of imidazo[1,2-b]indazole
two-fold C–N coupling route.8 Furthermore, several
approaches have been developed via Cu-catalyzed two-fold
C−N bond formation for the construction of various
heterocycles by several research groups.9-10 However, these
methods are performed by using multi-step synthesis, excess
amount of base, long reaction time and high temperature.
starting
aryl/heteroaryl/aliphatic
from
2-(2H-indazol-2-yl)aniline
bromide. This
with
novel
transformation involves a one-pot Cu-catalyzed cascade
process combining C−N coupling between 2-(2H-indazol-2-
yl)aniline and aryl/heteroaryl/aliphatic bromide followed
by intramolecular C−H amination to afford the desired
compounds in good yields.
Fused indazoles are the privileged heterocycles that are widely
found in pharmaceuticals and natural products.11 Additionally
they exhibit a broad spectrum of biological properties
including antifungal,12 anti-inflammatory,13 antimicrobial,14
cytotoxic,15 and antimalarial activities. These fascinating
biological activities have prompted researcher to devote
considerable efforts in developing more efficient synthetic
strategies. To the best of our knowledge, the synthesis of
imidazo[1,2-b]indazole from 2-(2H-indazol-2-yl)aniline and
aryl/heteroaryl/aliphatic bromide is unprecedented.
Over the past few years, the transition-metal-catalyzed direct
C−H functionalization represents one of the most powerful
strategies for the construction of pharmacophores and
biologically active molecules.
Cascade reactions are highly attractive especially in terms of
reducing the number of steps to construct complex molecules
without isolating any intermediates, from readily accessible
3
starting materials. Although cascade multiple bond formations
Previous work
a)6
using C−H functionalization are known however these
methodologies involved the use of expensive metal catalysts.4
On the other hande the use of inexpensive copper salts for
NIS
3
R-NH2
N
N
N
CH CN
L-hydroxyprolline
N
RT, 1 h
N
K PO , AgNO
3
N
3
4
DMF, 100 o
N
R
I
I
I
C
5
these cascade reactions has not been explored much. Copper
J. Org. Chem. 2018, 83, 13011-13018
36 h
is widely studied due to its low cost, easily availability and
high tolerance towards diverse functional groups. Generally,
previous reports discuss the synthesis of fused hetero cyclics
via two C−N bond formation reactions in two or multiple step
process.6-8
b)7
N
N
TsCl, Et3N
AcOEt
N
Cu(OTf) , PIDA
2
N
TFA, DCA
N
N
N
H2N
Org. Chem. Front., 2015, 2, 21–28
HN
Ts
Ts
c)8
R-NH2
Pd2(dba)3
NBS
CH3CN
N
N
N
Very recently, Banerji et al. reported synthesis of pyrido-
imidazo-indole derivatives via copper catalyzed tandem N-
arylation reaction by two step method. Gryko et al. reported a
multi step pathway to prepare pyrido-imidazo-indole
derivatives via the oxidative intramolecular C–H amination.7
N
RT, 1 h
N
Xantphos, CuI
NaOtBu, toluene
10 °C, 12 h.
N
N
R
Br
Br Br
1
6
Synlett., 2019, 30, 303-306
d) Present work
N
N
Cu
One pot operation
Two-fold C-N bond
Broad diversity
N
N
H
+ R Br
Langer et al. demonstrated four-step synthesis of pyrido-
imidazo-indole derivatives via the domino Pd/Cu-catalyzed
N
N
H
R
Ullmann type
N-arylation
N
Amidation
N
H
Department of Chemistry, Osmania University, Hyderabad-500
N
R
007, India.
I
E-mail:
Scheme 1 Methods for the synthesis of two-fold C−N bond
shivakumarkota@yahoo.co.in;shivakumarkota@osmania.ac.in
Tel: +91 40 27682337
formation.
†
Electronic supplementary information (ESI) available. see
DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry 20xx
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Motivated by the attractive bioactivity of various indazole
based heterocycles and as a result of our continuous interest on
the development of one-pot transformations for fused
indazoles 16 and indoles,17 we investigated the Cu-catalysed
one-pot two-fold C−N bond formation route to construct
imidazo[1,2-b]indazole via an Ullmann-type C−N coupling
followed by C− H amination (Scheme 1d).
13
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
.H
.H
.H
.H
.H
.H
2
2
2
2
2
2
O
O
O
O
O
O
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
DMSO
40
View Article Online
1
1
4
5
D1O,4I:-1D0i.1a0x3a9n/eD0NJ0320022H
Toluene
DMF
DMF
DMF
DMF
43
65
66
68
62
g
1
1
6
7
h
i
18
19
j
Cu(OAc) .H O
2
2
a
Reaction conditions: 1a (0.239 mmol), 2a (0.358 mmol), Cu
We investigated the proposed Cu-catalyzed one-pot two-fold C−N
bond formation by selecting 2-(2H-indazol-2-yl)aniline (1a) and
bromobenzene (2a) as model substrates. The employment of
phosphine ligands in the combination of Cu precursors has been
well established for C–N coupling.18 Therefore, first the reaction
catalyst (20 mol%), Ligand (5 mol%), solvent (2 mL), 100 °C, 8 h
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
in seal tube. Isolated yields. cK
b
PO
(1 equiv.),
d
3
4
2 3
K CO (1
e
f
g
equiv.) TBAI (1 equiv.), TBAB (1 equiv.). 15 mol% Cu catalyst
was used. 2 mol% X-Phos was used. The reaction was performed
h
i
o
j
at 120 C. The reaction was performed for 10 h.
was performed using Cu(OAc)
2
.H
2
O and X-Phos (Table 1, entries
o
Next, the scope of the Cu-catalysed one-pot two-fold C−N bond
1
) in DMF at 100 C under air and the product 3aa was obtained
formation of 2-(2H-indazol-2-yl)aniline using Cu(OAc)
2 2
.H O
in a 72% yield after 8 h (entry 1 in Table 1). Other ligands such as
Xantphos, 1,10-phen, PPh and proline could not efficiently
catalyze this reaction (Table 1, entries 2−5). Next, we checked the
role of other Cu catalysts such as Cu(OAc) , CuI, Cu(OTf) , and it
was found that product 3aa was obtained in lower yields (entries
-8). No further improvement of the yield was observed with the
catalyst, X-Phos ligand in DMF with various
3
aryl/heteroaryl/aliphatic bromides was investigated (Table 2).
Various substituted bromoanilines smoothly reacted under the
optimized conditions to give desired benzo[4,5]imidazo[1,2-
b]indazole (3aa−3ca) in moderate to good yields. For example,
bromoanilines with electron-donating substituents such as o-
methyl (2b), p-methyl (2c), m-methoxy (2d) p-methoxy (2e) o-
amine (2i), and o-hydroxy (2j) produced the corresponding
benzo[4,5]imidazo[1,2-b]indazole (3ab, 3ac, 3ad, 3ae, 3bc, 3bd,
be, 3ai, 3aj, 3bg and 3bj) in good yields (59-68%), and
bromoanilines with electron-withdrawing m-chloro (2f), p-chloro
2g) and p-nitrile (2h) groups underwent smooth conversion to
result in fused benzo[4,5]imidazo[1,2-b]indazole (3af, 3ag and
ah). To our delight, heterocyclic bromides were amenable for
one-pot two-fold C−N bond formation under standard conditions
3ak). Aliphatic iodide i.e. methyl iodide also efficiently
participated in cascade reaction to give the corresponding
benzo[4,5]imidazo[1,2-b]indazole with good yield (3al and 3bl)
comparatively with aromatic bromide. This one pot two-fold C−N
bond formation reaction was further extended to N−aryl ring of
indazole containing electron-donating substituent like Me−(2b)
which resulted in good yields of the corresponding 3-
benzo[4,5]imidazo[1,2-b]indazole (3ba, 3bc, 3bd, 3be, 3bg, 3bj,
2
2
6
addition of a base (Table 1, entry 9 and 10). Later we performed
the reaction in the presence of additives (Table 1, entry 11 and 12)
which did not affect the yield of 3aa. This indicates that there was
no role of additive for this transformation. Solvent effects were
also examined and the reaction did not proceed well in solvents
such as DMSO, 1,4-dioxane and toluene (Table 1, entries 13−15).
3
(
The reaction gave lower yield when amount of Cu(OAc)
2 2
.H O
(entry 16) or X-Phos (entry 17) was reduced. The increase in the
3
reaction temperature or time, led to decline of the reaction
efficiency (Table 3, entries 18−19).
(
Table 1 Optimization of the reaction conditions.a
N
Br
N
N
N
Cu salt
N
H N
ligand
o
solvent, 100 C
2
1a
2a
3aa
3
bm and 3ca).
PPh2
PPh2
OH
O
P
Ph
O
Ph
Ph
Table 2 Copper-catalyzed one pot cascade synthesis of
PCy2
i-Pr
N
H
i-Pr
N
N
imidazo[1,2-b]indazole (3).a,b
triphenyl
R2
i-Pr
xantphos
1,10-phen
Ligand
phosphine
L- proline
R2
Cu(OAc) .H O R
1
N
2
2
X-phos
N
N
X-Phos
N
R3 Br
o
R1
DMF, 100 C, 8 h
N
Entry
Catalyst
Solvent
Yield
b
H2N
(
%)
72
59
22
30
10
35
20
25
60
63
46
60
R3
1
2
3
1
2
3
4
5
6
7
8
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
CuI
Cu(OTf)
2
2
2
2
2
.H
.H
.H
.H
.H
2
2
2
2
2
O
O
O
O
O
X-Phos
Xantphos
1,10-phen
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
N
N
N
N
N
N
PPh
3
N
N
N
L-Proline
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
CH3
2
2
CH3
c
3ab, 68%
9
10
11
Cu(OAc)
2
2
2
2
.H
2
2
2
2
O
O
O
O
3
aa, 72%
3ac, 70%
d
Cu(OAc)
Cu(OAc)
Cu(OAc)
.H
.H
.H
e
f
1
2
2
| J. Name., 2012, 00, 1-3
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b
N
N
N
mol %) in DMF (3 mL) at 100 C for 8 h in seal tube. Isolated
View Article Online
N
N
N
c
yield. reaction performed with methyl iodDidOeI.: 10.1039/D0NJ03022H
N
N
N
As mentioned above, the formation of benzo[4,5]imidazo[1,2-
b]indazoleis assumed to take place via 2-(2H-indazol-2-yl)-N-
phenylaniline I (Scheme 1d). To confirm this, we performed a
OCH3
Cl
OCH3
reaction 2-(2H-indazol-2-yl)-N-phenylaniline intermediate (IA)
3ad, 72%
3
ae, 70%
N
3af, 70%
N
o
with Cu(OAc)
2
, X-Phos in DMF (3 mL) at 100 C for 4 h. As
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
expected, this reaction resulted in the formation of desired
benzo[4,5]imidazo[1,2-b]indazole 3al with 70% yield (Scheme 2).
In order to demonstrate the scale-up potential of our method, a
gram-scale experiment involving the copper-catalyzed one pot
cascade synthesis of imidazo[1,2-b]indazole annulation was
performed employing 1a and 2a as model substrates; the product
3aa was obtained in 70% (0.95 g) yield (Scheme 2b).
N
N
N
N
N
NH2
CN
Cl
3
ah, 70%
3ai, 65%
3ag, 68%
N
N
N
N
Cu(OAc) .H O
N
N
2a.
2
2
N
N
N
N
X-Phos
DMF, 100 oC, 4h
N
N
N
HN
CH3
N
OH
H C
CH3
3
IA
3al
N
Br Cu(OAc) .H O
N
2
2
3al, 65%c
N
X-Phos
N
2b.
3
ak, 68%
3aj, 65%
N
+
DMF, 100 oC, 8h
N
CH3
CH3
H N
2
N
N
N
N
CH3
CH3
N
N
1a
2a
(1.126 g, 7.17 mmol)
3aa
(75%, 0.95 g)
(
1.0 g, 4.78 mmol)
Scheme 2 Control experiment and large-scale reaction.
CH3
According to literature reports,18,19 the Cu(OAc)
2
2
·H O catalyst
3
ba, 71%
3bc, 70%
reacts with X-Phos to form Cu(I) (A) in the presence of mild
reducing agent DMF.20 Then the Cu(I) (A) species under goes
oxidative addition to aryl/heteroaryl/aliphatic bromide (2) to
deliver the Cu(III) (B). Then displacement of bromo group of B by
amine 1 affords the intermediate C. Later, reductive C–N coupling
takes place to give the intermediate (D). Further intermediate D is
oxidized in situ to afford intermediate E,21 which in turn
undergoes acetate-ligand-assisted, concerted C–H activation to
give intermediate F. Finally, reductive elimination gives product 3
and the regeneration of the active Cu-catalyst there by completing
the catalytic cycle.
CH3
CH3
CH3
CH3
N
N
N
N
N
N
OCH3
OCH3
3bd, 69%
3be, 70%
CH3
CH3
N
N
N
N
CH3
CH3
N
N
OH
Cl
3
bg, 70%
3bj, 66%
CH3
CH3
N
N
N
N
N
N
Br
CH3
3
bl, 65%c
3ca, 70%
a
All the reactions were carried out using compound 1 (0.47
mmol), 2 (0.71 mmol), Cu(OAc) .H O (20 mol %) and X-Phos (5
2
2
This journal is © The Royal Society of Chemistry 20xx
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X-Phos (L)
Tang and N. Jiao, Chem. Soc. Rev., 2012, 41, 3381–
View Article Online
Cu(OAc) .H O
L
Cu-OAc
A
3430.
2
2
DOI: 10.1039/D0NJ03022H
DMF
R
Br (2)
2. For selected reviews, see: (a) J. H. Gui, Q. H. Zhou, C.
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x
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+X-Phos (L)
a
i
d
d
d
i
a
t
t
i
v
i
o
e
n
Br
Cu
N
N
9
, 2931–2934; (c) D. Eom, Y. Jeong, Y. R. Kim, E. Lee,
W. Choi and P. H. Lee, Org. Lett., 2013, 15, 5210–
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AcO
R
L
B
5
0
1
2
3
4
5
6
7
8
9
0
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1
2
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8
9
0
N
Cu
1
F
R
L
n
-
o
c
i
t
n
u
F
a
s
i l
N
a
H
-
n
N
C
o
i
t
N
N
NH
3. (a) R. A. Sheldon, Pure Appl. Chem., 2000, 72, 1233–
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N
AcO Cu
R
L
Cu
H
R
O O
C
N
N
E
Cu(I)
L
Cu(II)
Cu N
D
R
OAc
dissolved
air
1
780–1824; (e) H. Wang, C. Grohmann, C. Nimphius
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Y. Zhou, Z. Zhang, Y. Jiang, X. Pan, D. Ma, Synlett.,
Scheme 3 Plausible mechanism.
5
.
In conclusion, we have developed an efficient Cu-catalyzed one-
pot, two-fold C−N bond formation protocol for the construction of
benzoimidazoindazole. Advantages of the present one-pot
1
2 2
protocol include (a) the use of inexpensive Cu(OAc) .H O as a
catalyst (b) free from the use of any base (c) use of oxygen as the
oxidant etc. The methodology was successful for various aromatic,
heteroaromatic and aliphatic bromides as substrates affording the
desired products in good yields. The present Cu catalyzed
methodis capable of generating a diverse imidazo[1,2-b]indazole
based library of small molecules that are useful for the medicinal
2
015, 26, 1586−1590.
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3011–13018.
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&
pharmaceutical chemistry research efforts. Thus we believe that
this methodology may attract considerable attention both in
organic and medicinal chemistry.
1
0. D. Chen, L. Huang, J. Yang, J. Ma, Y. Zheng, Y. Luo,
KSK thanks the University Grants Commission (UGC), New
Delhi, for faculty position under FRP. We also thank CSIR
Y. Shen, J. Wu, C. Feng and X. Lv, Tetrahedron Lett.,
2
018, 59, 2005–2009.
[
02(0036)/19/EMR-II], OU-DST-PERSE-II and UGC-UPE for
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Conflicts of interest
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The authors confirm that this article content has no conflict of
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DOI: 10.1039/D0NJ03022H
A table of contents entry
Copper-catalyzed cascade C–N coupling/C–H amination: One pot synthesis of imidazo[1,2-
b]indazole
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Bandari Rajesham, Vemula Arunkumar, Praveen Kumar Naikawadi, K. Shiva Kumar*
N
N
One pot operation
Two-fold C-N bond
Broad diversity
Cu
N
N
+ R Br
N
H N
R
H
Ullmann type
N-arylation
N
Amidation
N
H N
R
I
A one-pot, two-fold C−N bond formation protocol has been developed for the construction of
imidazo[1,2-b]indazole derivatives.