An efficient and inexpensive visible light photoredox copper catalyst for N–N bond-forming reactions: the one-pot synthesis of indazolo[2,3-α]quinolines

Article abstract of DOI:10.1007/s13738-018-1295-1

An efficient and facile synthesis of indazolo[2,3-α]quinoline derivatives has been described which occur through Povarov reaction and tandem process of visible light-promoted intramolecular N–N bond formation using choline chloride/CuCl. This protocol is

Full text of DOI:10.1007/s13738-018-1295-1

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1295-1
ORIGINAL PAPER
An efcient and inexpensive visible light photoredox copper
catalyst ꢀor N–N bond‑ꢀorming reactions: the one‑pot synthesis
oꢀ indazolo[2,3‑α]quinolines
Abdol R. Hajipour1,2 · Zahra Khorsandi · Shima Bahri
1
1
Received: 13 July 2017 / Accepted: 5 January 2018
©
Iranian Chemical Society 2018
Abstract
An efcient and ꢀacile synthesis oꢀ indazolo[2,3-α]quinoline derivatives has been described which occur through Povarov
reaction and tandem process oꢀ visible light-promoted intramolecular N–N bond ꢀormation using choline chloride/CuCl. This
protocol is highly efcient and oꢀ low cost due to its mild reaction conditions, operational simplicity, applying inexpensive
photoredox catalyst and overall good to excellent yields oꢀ various derivatives. Scale-up preparation oꢀ these heterocycles
is also carried out.
Keywords Indazolo[2,3-α]quinolines · Visible light photoredox catalysis · Choline chloride—CuCl · N–N bond ꢀormation
Introduction
[18, 19]. However, the most oꢀ these synthesis approaches
suꢂer ꢀrom some drawbacks such as availability oꢀ starting
material, using either toxic reagents or harsh reaction condi-
tions and prolonged reaction times.
The indazoles and related derivatives constitute an important
class oꢀ building block because such moieties are ꢀound in a
wide range oꢀ biologically active compounds. For examples,
indazole core structures can be ꢀound in commercial drugs
with several biological activities including antipyretic [1],
analgesic [2], antiviral [3], antiangiogenic [4], anti-inꢁam-
matory and anticancer [5–7].
Because oꢀ the biological importance oꢀ indazole ꢀrame-
works and limitations oꢀ traditional methods, considerable
eꢂorts to ꢃnd new efcient and ꢀacile methodologies to
improve their synthesis would be logical. While various
synthesis strategies have been reported, to the best oꢀ our
knowledge, N–N bond ꢀormation to preparation indazole
derivatives using copper in visible light photoredox catalysis
(VLPC) has not been reported previously.
In the past ꢀew decades, the indazole synthesis has
received considerable attention and numerous synthetic
strategies have been reported [8–10]. Existing synthetic
approaches mainly involve cyclization oꢀ 2-azidoben-
zylidene Schiꢂ bases [11, 12], base-promoted cyclizations oꢀ
arylamino oximes [13, 14], cycloadditions [15–17] and cou-
pling oꢀ organometallic reagents with aryldiazonium salts
The VLPC is a ꢀundamental and interesting process [20]
and have many vast applications in organic synthesis [21].
The most common VLPC catalysts included ruthenium and
iridium polypyridyl complexes [22] have been success-
ꢀ
ully applied in ꢀunctional group conversions [23, 24], car-
bon–carbon bond coupling, [2 + 2] cycloaddition [25, 26]
and C–H activation reactions [27, 28]. The tradition photo-
chemical catalysts have some limitations such as toxicity and
cost. These problems can be largely overcome by carrying
out the reactions using other transition metal such as cop-
per catalyst which is non-toxic, inexpensive and available
and exhibit high catalytic activity [29–31]. Thereꢀore, we
have ꢀocused our attention on copper which has been suc-
cessꢀul in a number oꢀ photoreactions, generally carried out
under visible light irradiation. We were especially intrigued
by the report oꢀ Reiser et al. that described the visible light
Electronic supplementary material The online version oꢀ this
article (https://doi.org/10.1007/s13738-018-1295-1) contains
supplementary material, which is available to authorized users.
*
Abdol R. Hajipour
haji@cc.iut.ac.ir
1
2
Department oꢀ Chemistry, Isꢀahan University oꢀ Technology,
Isꢀahan 84156, Islamic Republic oꢀ Iran
Department oꢀ Pharmacology, University oꢀ Wisconsin,
Medical School, 1300 University Avenue, Madison,
WI 53706-1532, USA
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1
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Journal of the Iranian Chemical Society
photoredox ꢀor carbon–carbon bond-ꢀorming reactions in the
presence oꢀ [Cu(dap) Cl] as an efcient catalyst. Moreover,
2
CuCl2
N
this copper complex provided a more economically viable
synthesis method alternative to the widely used ruthenium
and iridium catalysts.
HO
Many diꢂerent catalytic systems, including copper com-
plex, have been applied ꢀor photoredox reactions [32, 33],
but the use oꢀ eꢂective a ꢀacile preparation and inexpen-
sive systems would obviously be much more interesting in
view oꢀ modern organic synthesis, because oꢀ the higher
cost oꢀ applied ligands and complicated complex synthesis
approach.
Scheme 1 Structure oꢀ copper catalyst
species during the reaction. The quaternary salt protects the
Cu(I) species against oxidation by air and thereꢀore improves
the efciency and perꢀormance oꢀ the catalyst. In addition,
the quaternary salt prevents aggregation oꢀ non-stable Cu(I)
species. In the FTIR analysis, the shiꢀting oꢀ O–H absorption
band oꢀ ChCl·CuCl to a higher ꢀrequency compared to pure
choline chloride was observed (Supplemental data). This
shiꢀt is evidence oꢀ the choline chloride and CuCl interaction
and indicates that the hydroxyl groups oꢀ choline chloride
are the active sites in this system.
Ionic liquids (ILs) have been successꢀully applied as
green reaction media, which can attend as a catalyst and/or
solvent in organic synthesis [34, 35]. A series oꢀ low-cost
and moisture-stable Lewis acidic ionic liquids have been
synthesized ꢀrom choline chloride and ZnCl , FeCl and
2
3
SnCl and used in Diels–Alder and Fischer indole reactions
2
[
36–38].
The efciency oꢀ this catalytic system was evaluated
in N–N bond ꢀormation reaction via visible light photore-
dox process in intermediate (see top reaction in Table 1)
to reach the ꢃnal product. The synthesis oꢀ intermediate
(2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinolines) was pro-
moted using Ox-MWCNTs as a heterogeneous highly ef-
cient Lewis acid catalyst.
Thereꢀore, in this work, we report the use oꢀ (choline
chloride)·CuCl as an efcient catalyst ꢀor ꢀacile synthesis
oꢀ a wide range oꢀ substituted indazolo[2,3-α]-quinolines
via N–N photoredox coupling oꢀ intermediate. The inter-
mediate was achieved by the Povarov reaction oꢀ aromatic
amine, 2-nitrobenzaldehyde and the electron-donating group
(
EDG)-substituted alkene at room temperature applying Ox-
In order to optimize reaction conditions, the reaction
oꢀ aniline (1 mmol), 2-nitrobenzaldehyde (1 mmol) and
3,4-dihydro-2H-pyran (1 mmol) was selected as a template
which was perꢀormed at room temperature, under visible
light irradiation without protection oꢀ inert atmosphere
(Table 1).
MWCNTs (oxidized multiwalled carbon nanotube).
In recent years, carbon nanotubes have aroused signiꢃcant
interests oꢀ scientists all over the world since; it exhibits
unique ꢀeatures such as large surꢀace, intrinsic low mass and
easy surꢀace modiꢃcations which might be promising can-
didates as catalysts or supports [39, 40]. Modiꢃcation oꢀ its
activity, including oxidation, makes a unique and recover-
able catalyst. Based on the ꢀascinating structure oꢀ CNTs
material, as well as recoverability and efciency, we reason
that the Ox-MWCNTs can be used as solid acid catalyst in
Povarov reaction.
In general, the experimental procedure ꢀor this reaction is
remarkably simple and does not require the use oꢀ expensive
organic reagents.
Initially, the efciency oꢀ both catalysts was evaluated and
reactions were not occurred in the absence oꢀ each catalyst
(Table 1, entries 1–3). It was also established that the irra-
diation oꢀ visible light has a critical role in ꢃnal step oꢀ trans-
ꢀormation and the N–N bond was not ꢀormed when reaction
was perꢀormed in dark conditions (Table 1, entry 4). Vari-
ous catalyst amounts were also tested (Table 1, entry 5). As
shown in Table 1, the best result was obtained using 6.0 mg
oꢀ cat 1 (Ox-MWCNTs) and 10 mol% oꢀ cat 2 (ChCl–CuCl).
Next, investigations were carried out to deꢃne the best sol-
vent ꢀor this transꢀormation. Among diꢂerent solvents such
as ethanol, THF, NMP and acetonitrile (MeCN), the last one
was shown to be the best solvent.
In continuation oꢀ our studies in the application oꢀ hetero-
geneous catalysts in coupling reactions [41–48], we wish to
report the use oꢀ two highly active catalysts, Ox-MWCNTs
and Choline chloride·CuCl, ꢀor indazole synthesis through
intramolecular N–N photoredox coupling reaction in the tan-
dem process which has remarkable environmental advan-
tages such as reducing the number oꢀ synthetic steps and
consumption oꢀ energy and waste producing [49, 50].
Results and discussion
Encouraged by the efciency oꢀ the reaction protocol
described above, applying the optimal reaction conditions
consist oꢀ optimized catalyst amounts in MeCN under
household light irradiation at room temperature, the scope
and speciꢃcity oꢀ this protocol were ꢀurther investigated and
the results are given in Table 2. A total oꢀ 12 examples were
Choline chloride·CuCl (Scheme 1) was prepared through
the reaction oꢀ choline chloride with CuCl in a 1:1 ratio.
Choline chloride as an OH-ꢀunctionalized ligand and also
as a tetraalkylammonium salt supports and stabilizes Cu(I)
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Journal of the Iranian Chemical Society
Table 1 Eꢂect oꢀ reaction parameters on synthesis in the model reactiona
O
O
N
O
Cat 1 (Ox-CNTs)
Cat 2 (ChCl-CuCl)
NH2
O
H
N
H
O N
2
N
O N
2
Cat 1 (mg)b
Cat 2 (mol %)c
Solvent
Time (h)
Yield (%)
d
Entry
1
2
3
4
5
6
7
8
9
None
None
6.0
6.0
1.7
3.4
8.0
6.0
6.0
6.0
6.0
6.0
6.0
None
10
None
10
10
10
10
5
20
10
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtOH
24
24
24
24
16
16
10
16
10
10
24
24
16
0
0
0
e
0
57
63
79
75
81
78
16
26
41
10
11
12
13
10
10
10
THF
NMP
a
Unless otherwise noted, all the reactions were perꢀormed on a 1-mmol scale, room temperature, air and visible light conditions
Oxidized multiwalled carbon nanotubes (Ox-MWCNTs)
b
c
d
e
(
ChCl–CuCl)
Isolated yield
In dark conditions
given with the isolated yields ranging ꢀrom 42 to 93%. The
results showed that electron-donating group (EDG)-substi-
tuted alkene with diꢂerent nature and various substituent
anilines containing electron-withdrawing or electron-releas-
ing group aꢂorded the corresponding products in moderate
to good yields. It was also observed that the reactions with
dihydropyran and dihydroꢀuran were ꢀaster than those oꢀ ali-
phatic aldehyde and styrene. The structures oꢀ the products
intact. The reaction was ꢀound to proceed successꢀully, and
the corresponding product was obtained in 69% yield via
described method.
The separation and reusability oꢀ noble metal catalysts are
the trends oꢀ the catalysis industry and green chemistry, not
only ꢀor lowering costs, but also ꢀor avoiding pollution. To
gain insight into this issue, the catalyst reusability experi-
ments in model reactions were carried out. Aꢀter ꢃrst step
oꢀ reaction, Ox-MWCNTs were separated ꢀrom the reaction
mixture through centriꢀugation ꢀollowed by washing with
diethyl ether and ethanol to remove the organic impurities.
Aꢀter drying, the catalyst was employed in the next run. This
catalyst was successꢀully recovered and reused ꢀor several
times without any signiꢃcant losing oꢀ its activity. The table
oꢀ reusability investigation results is given in supplementary
data.
1
13
were characterized by IR, H and C NMR spectroscopy
and mass spectrometry, and the characterization data are
given in supporting inꢀormation.
Interestingly, our catalytic system (Ox-MWCNTs and
ChCl–CuCl) was compatible with a wide range oꢀ ꢀunc-
tional groups and exhibited good activity in the synthesis oꢀ
indazolo[2,3-α]-quinoline derivatives. Mild reaction condi-
tions with excellent conversions and simple experimental
procedure are noteworthy advantages oꢀ this method.
Moreover, the efciency oꢀ the catalyst in scale-up syn-
thesis is key parameters ꢀor industrial and commercial uses
oꢀ any catalytic operations. The scale oꢀ the reaction was
increased to 10.0 mmol, keeping the reaction stoichiometry
The plausible mechanism ꢀor the ꢀormation oꢀ
indazolo[2,3-α]quinolines is explained in Scheme 2.
Probably, single-electron transꢀer (SET) ꢀrom intermedi-
ate 1 to the visible light-excited Cu species to provide the
strong reluctant Cu (0) and radical cation 2, aꢀter proton
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Journal of the Iranian Chemical Society
Table 2 Scope oꢀ synthesized indazolo [2,3-α] quinoline derivatives
EDG
EDG
3
Ox-MWCNTs
(ChCl-CuCl)
NH2
R1
N
N
R1
O
H
r.t., 10 h,42-93%
1
O N
2
4
2
a
Entry
Amine (1)
Olefin (3)
Product (4)
Yield (%)
Found
M.P
Literature
M.P [ref]
1
OH
76
217–219
–
O
H
NH
2
4a
N
N
2
OH
71
228–230
–
O
H
4b
NH
2
N
N
3
4
72
74
239–240
239–242
241–243
OH
[11]
O
H
4
c
NH
2
N
N
OH
238 [11]
MeO
O
H
4d
MeO
NH
2
N
N
5
6
OH
79
61
229–230
241–243
228–230
F
F
NH
2
4e
[
11]
–
O
H
N
N
O
H
OH
NH
2
4f
N
N
7
O
O
77
187–189
187–189
[11]
NH
2
4g
N
N
O
8
MeO
NH2
O
MeO
78
131–133
120–121
130–132
[11]
4
h
N
N
NH
2
O
9
78
93
83
119–121
[11]
O
4i
N
N
O
1
0
1
155–157
211–213
156–158
MeO
NH
2
O
MeO
4
j
[11]
N
N
O
1
1
210–211
O
4k
[11]
NH
2
N
N
2
43
187–189
–
NH
2
4
l
N
N
aIsolated yields
1
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Journal of the Iranian Chemical Society
yields oꢀ products, operational simplicity, economic and
environmental advantages such as perꢀormance at room
temperature conditions and tandem way which diminishes
considerably organic solvent usage and omits puriꢃcation
steps oꢀ intermediate. Various beneꢃts oꢀ presented proce-
dure make it a benign alternative to the existing methods.
O
O
Nano carbon
solid acid
N
H
N
O N
2
O N
2
Acknowledgements Financial support ꢀrom the Isꢀahan University oꢀ
O
Technology (IUT), Iran, is appreciated. Additional ꢃnancial support
ꢀrom the Center oꢀ Excellence in Sensor and Green Chemistry Research
IUT) is grateꢀully acknowledged.
(
N
H
O N
2
+
Cu
1
t
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