Metal-free, regioselective, visible light activation of 4CzIPN for the arylation of 2H-indazole derivatives

Article abstract of DOI:10.1039/d1ra02372a

Highly regioselective organo photocatalysis of 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) for the arylation of 2H-indazole is demonstrated. The present synthetic route provides a highly safe and easily accessible aniline precursor as an arylation reagent. The photoactivated 4CzIPN organocatalyst is found to be more efficient for single electron transfer without any organic base for the radical reaction. The carbazole-based photocatalyst (4CzIPN) with wide redox potential is stable and recyclable for further reaction transformations. Many indazole and aniline derivatives were used in the reaction and provided the arylated indazole derivatives in good to excellent yield.

Full text of DOI:10.1039/d1ra02372a

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Metal-free, regioselective, visible light activation of
4CzIPN for the arylation of 2H-indazole
derivatives†
Cite this: RSC Adv., 2021, 11, 14079
*
Rajendhiran Saritha, Sesuraj Babiola Annes and Subburethinam Ramesh
Highly regioselective organo photocatalysis of 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-
dicyanobenzene) for the arylation of 2H-indazole is demonstrated. The present synthetic route provides
a highly safe and easily accessible aniline precursor as an arylation reagent. The photoactivated 4CzIPN
organocatalyst is found to be more efficient for single electron transfer without any organic base for the
radical reaction. The carbazole-based photocatalyst (4CzIPN) with wide redox potential is stable and
recyclable for further reaction transformations. Many indazole and aniline derivatives were used in the
reaction and provided the arylated indazole derivatives in good to excellent yield.
Received 25th March 2021
Accepted 31st March 2021
DOI: 10.1039/d1ra02372a
rsc.li/rsc-advances
temperature, and stability of the palladium or iridium cata-
lyst.10a–d,g,11 Two alternative methodologies10e,f have been
Introduction
recently reported for the arylation of indazole using phenyl-
diazonium salt through a photochemical reaction path.
The main drawback associated with phenyldiazonium salt is
the potential instability of the salt whatsoever the choice of
counter ion.12 The synthetic community has tended to focus on
aniline and its derivatives instead of phenyldiazonium salt to
Indazole, an important structural motif present in many drug
molecules and bioactive natural products have been attracting
the synthetic community due to the broad spectrum of its bio-
logical activities.1–8 From extensive research work, the medicinal
community looks to indazole as a bioisostere of benzimidazole,
indazole and purine.1 Among the different types of indazole,
compounds incorporated with 2H-indazole or 1H-indazole have
been receiving much attention over the last two decades owing
to their broad spectrum of biological activities.1 In particular,
2H-indazole derivatives have been widely investigated and some
notable activities are HIV protease inhibition,2 anti-inamma-
tory,3 anti-microbial,4 anti-tumor,5 etc. Moreover, drug mole-
cules like MK-4827, Niraparib, and Pazopanib are incorporated
with the 2H-indazole motif and they are used for anticancer,6
anti-inammatory7 and tyrosine kinase inhibitor8 activities
respectively (Fig. 1). A C–H activation with a transition metal
catalyst requires a pre-activated organometallic compound
which is introduced in the transmetalation step. However direct
methodology to activate the C–H bond in an aromatic com-
pound9a would not require any organometallic compounds. The
pre-activation strategy generates more bi-product in stoichi-
ometry amount which can be avoided in direct C–H bond
functionalization.9a,b To the best of our knowledge, direct ary-
lation of indazole is largely depend on metal catalyst as well as
stoichiometric base in the presence of halobenzene as an ary-
lating source. These reactions suffer from very expensive addi-
tives as well as transition metal catalysts, harsh reaction
Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed
University, Thanjavur 613401, Tamil Nadu, India. E-mail: rameshsbdu@gmail.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra02372a
Fig.
1 Representative example for 2H-indazole based drug and
pharmaceutically active molecules.
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overcome the safety issues associated with the salt. Many herein, we describe a metal-free carbazole based organo-
synthetic attempt have been proposed with the aim of gener- photocatalyzed arylation on indazole by coupling of anilines
ating the phenyldiazonium salts in situ and for subsequent with 2H-indazole as a nucleophilic partner. This approach
arylation reactions.12 Despite these interest, to the best of our involves an in situ generation of phenyldiazonium salt and
knowledge no arylation reaction on any type of indazole moiety subsequent functionalization of 2H-indazole catalysed by
using aniline as arylating precursor have been reported (Fig. 2). 4CzIPN. Our method provides a sustainable, safe, toxic less and
Our endeavour was consequently to nd a metal free less economic synthetic strategy to the indazole derivatives with
procedure and to use safer arylation precursor. In recent years, good to excellent yield.
there has been ourishing interest in the visible light mediated
photochemical organic transformation.13 In this process, the
sunlight as an energy source replaces the conventional thermal
energy for an organic reaction. Although this sustainable
Results and discussion
p-Bromoaniline (9a) and indazole (8a) were chosen for nding
the suitable reaction conditions. As expected, the indazole
derivative 10a was obtained in 52% when 5 mol% of 7a was used
in 7 W blue LED light in the presence of tBuONO in acetonitrile
process is interesting, the transition metal based redox catalyst
for the photochemical reactions suffer from high cost and
possible trace impurities in the nal product. However, organo-
catalytic photochemistry is superior in these aspects, particu-
larly the straightforward work up procedure and less toxicity of
organic photocatalyst.14 In this context, donor–acceptor uo-
rophore has been emerging as potent organo-photocatalyst.
Based upon the photophysical and the photochemical proper-
ties of organic dye molecules,14 we were interested on
compound 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene
(4CzIPN).15 The organic dye compound with carbazole unit as
donor and dicyanobenzene as acceptor displayed signicant
redox window, excellent chemical stability and vide range of
application in various organic transformations. Extending our
interest on demonstrating organocatalytic arylation reaction,16
Table 1 Optimization of the organophotocatalyzed arylation on 2H-
indazolea
S. no.
Variation of standard conditions
Solvent
Yieldb
1
2
3
4
5
6
7
8
5 mol% of 4CzIPN (7a)
15 mol% of 4CzIPN
10 mol% of 4CzIPN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
THF
Water
CH3CN
CH3CN
CH3CN
CH3CN
52
83
80
36
54
49
64
14
31
55
76
62
47
52
71
73
54
51
2 mol% of 4CzIPN
10 mol% of 4CzPN (7b)
10 mol% of 2CzPN (7c)
10 mol% of 5CzPN (7d)
10 mol% of THC (7e)
10 mol% of carbazole (7f)
10 mol% of 4CzIPN, 12 h
10 mol% of 4CzIPN
10 mol% of 4CzIPN
10 mol% of 4CzIPN
10 mol% of 4CzIPN
1 equivalent of 8a
9
10
11
12
13
14
15
16
17
18
6 W green LED instead of 7 W blue LED
24 W blue LED instead of 7 W blue LED
3 W blue LED instead of 7 W blue LED
Unless otherwise noted: aReaction conditions: 1 equiv. of 9a (0.6
mmol), 2 equiv. of 8a (1.2 mmol), 1.5 equiv. of tBuONO (0.9),
10 mol% of catalyst, room temperature, 24 h. bIsolated yield.
a
Fig. 2 Various synthetic strategies for arylation on 2H-indazole.
14080 | RSC Adv., 2021, 11, 14079–14084
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solvent (entry 1, Table 1). Surprisingly, 15 mol% of 4CzIPN
under the same condition provided 83% of the product 10a
(entry 2, Table 1). We could able to reduce the catalytic loading
up to 10 mol% without affecting the reaction conversion (entry
3, Table 1). However, the reaction with 2 mol% of 4CzIPN
showed no catalytic role as the yield of this reaction (entry 4,
Table 1) is as same as yield of reaction without any catalyst
(Scheme 3, eqn (a)). To prove the efficiency of the 4CzIPN, we
compared with other carbazole based organic-photocatalyst. All
these catalysts were prepared using the literature reports.17 The
Scheme 2 Recycling the catalyst.
catalyst 4CzPN (7b), 2CzPN (7c) and 5CzPN (7d) under the same
conditions (entry 2, Table 1) afforded the 10a in 54%, 49% and
64% yields respectively (entries 5–7, Table 1). On the other
hand, THC (7e) and carbazole (7f) provided the indazole 10a in
lower yields of 14% and 31% respectively (entries 8 & 9, Table 1).
Lowering the reaction time from 24 h to 12 h inuenced the
reaction (entry 10, Table 1), Hence, reaction time of 24 h was
considered as ideal for this transformation. Upon a brief solvent
screening (entries 11–14, Table 1), it was identied that aceto-
nitrile was suitable for synthesis of compound 10a with highest
yield of 80% (entry 3, Table 1). In acetonitrile and DMSO
solvents, the product was obtained in good yield. This is prob-
ably due to the efficiency of these solvents for the conversion of
aniline to diazonium salt with the help of tBuONO. In addition,
these polar solvents could stabilize the ionic intermediates by
solvating them (Scheme 4). Reducing the equivalent of indazole
8a decreased the yield of the arylated product 10a to 71% (entry
15, Table 1). A comparison of various light source (entries 16–
18, Table 1) for this arylation reaction showed that 7 W blue LED
is superior than other lights. The absorption and intensity of
the lights were recorded and provided in the ESI.†
Having optimized ideal reaction parameters in hand, we next
demonstrated the scope of the reaction by varying aromatic
amine derivatives (9). The aromatic aniline bearing electron
withdrawing groups such as –CF3, –CN and –CO2Me tolerated
the photochemical reaction and provided the arylated indazole
products 10d, 10e and 10w respectively, in good yields. The
carbon–halogen (C–X) bond was intact in the photochemical
reaction and corresponding products were obtained in good
yields. These halogen containing substrates (10a–c) are very
useful for further synthetic elaborations with the help of cross
coupling reactions. The aniline substrates with electron
donating groups such as –Me and –OMe provided lower yield
than that of electron withdrawing as well as halogen groups.
This is probably due to the stabilization of aryl radical formed
from in situ generated phenyldiazonium salt. The electron
donating groups on aniline lowers the reactivity by stabilizing
the electron deciency on aryl radical. Next, steric factor on
substrate was tested and ortho substituted compounds lowered
the yield (10j–l) than para substituted aniline precursor (10c,
10a & 10e). Aliphatic amine and heterocyclic amine like
Scheme 1 Scope of the organophotocatalyzed arylation on 2H-
indazole derivatives. Reaction conditions: 1 equiv. of 9a (0.6 mmol), 2
equiv. of 8a (1.2 mmol), 1.5 equiv. of tBuONO (0.9), 10 mol% of catalyst,
room temperature, 24 h. bIsolated yield.
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Scheme 4 Possible reaction mechanism.
hand, pyridyl substitution on 2N position, aliphatic amine and
heterocyclic amine did not show any product formation (10u,
10z, 10aa).
In order to check out the robustness of the photochemical
reaction, we performed a reaction with 1.0 g scale of indazole 8a
under the optimized reaction condition and the product 10a
was obtained in 78%. During this reaction, the catalyst was
recovered with help of silica gel column chromatography. The
recovered catalyst 7a was used for arylation of indazole 8a in the
presence of p-chloroaniline (9c) and the corresponding func-
tionalized product 10c was obtained in excellent yield (Scheme
2, eqn (b)). Next, we focussed on control experiments to nd out
the reaction path. As the entry shows in Scheme 3, aniline (9a)
and indazole (8a) were reacted in the presence of diazotizing
agent tBuONO and in acetonitrile solvent without light and
without any catalyst at room temperature (Scheme 3, eqn (a)).
The expected arylated product 10a was obtained, however with
low yield of 32% which is indicating the need of a catalyst. It has
been clear from eqn (b) and (c) in Scheme 3 that photoactivation
of the catalyst 4CzIPN (7a) is necessary for this transformation.
To understand the reactivity of the counter ion of phenyl-
diazonium salt, we performed a reaction with p-bromophe-
nyldiazonium salt 11 (Scheme 3, eqn (d)) in the standard
Scheme 3 Control experiments.
isopropyl amine and 4-amino pyridine respectively did not
participate in the reaction (entry 21, 26, 27, Scheme 1).
The scope of the reaction was then performed by varying
different 2N substitution on indazole. The halogen groups at
para position on this 2N phenyl ring lower the yield of the
product (10m & 10n) compared to electron donating groups
such as –Me and –OMe (10p & 10q). Methoxy substituted
indazole (8i) also participated in the ideal condition and
provided the corresponding product (10x). Ortho methyl
substitution provided the product 10y in trace quantity. This is
because of the steric hindrance that destabilize the cationic
intermediate V in Scheme 4. Similarly, benzylated compounds
(entries 19 and 20, Scheme 1) gave very poor yields of arylated
indazoles 10s (30%) and 10t (27%) respectively. On the other
ꢀ
reaction conditions. We conrmed that anions –BF4 and
–tBuOꢀ have not shown any difference in the reaction conver-
sion. To conrm the formation of Electron Donor–Acceptor
(EDA) complex between catalyst and reactant if any, a UV-Vis
spectroscopy study was performed. As expected, no shi in
UV-Vis absorbance of the mixtures (Scheme 3, eqn (e)). When we
perform a reaction using TEMPO under the standard condi-
tions, we found the formation of TEMPO trapped radical
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species 10ab/10ac (Scheme 3, eqn (f)). The aryl radical is formed (Grant No. DST/INSPIRE/04-I/2017/000002). R. S. thanks SAS-
only from diazo compound which is conrmed by a control TRA Deemed University, Thanjavur, India for the research
experiment performed in the absence of tBuONO (Scheme 3, fellowship.
eqn (g)). No product formation was formed in the absence of
tBuONO.
Notes and references
Based on the control experiments and the scope of the
reactions, we propose a possible reaction mechanism for the
formation of indazole 10a (Scheme 4). Aniline (9) reacts with
tert-butyl nitrite and converts into diazonium salt I. Upon
oxidation of the reduced carbazole catalyst 7b0, diazonium salt I
undergoes Single Electron Transfer (SET) process to produce
aryl radical II, nitrogen, tBuOꢀ and 4CzIPN (7a). The phenyl
radical reacts with indazole 8a in a homolytic aromatic substi-
tution (HAS) reaction to generate intermediate III. On the other
hand, the catalyst 4CzIPN (7a) is activated by the 7 W blue LED
light and then oxidizes the intermediate III through SET. While
completing the catalytic cycle, the reaction generates carboca-
tion species IV. Based on the yield we obtained for 2N
substituted indazole, we propose the resonance stabilization
involved in the carbocation intermediate IV and V as shown in
Scheme 4. Finally, the deprotonation of V with the help of
tBuOꢀ produces the indazole 10a.
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General procedure for the synthesis of 3-(4-bromophenyl)-2-
phenyl-2H-indazole 10a
Into a mixture of 0.6 mmol of 9a and 1.2 mmol of 8a in 1 ml of
acetonitrile was added 10 mol% of catalyst 7a and 1.2 equiva-
lent of tBuONO at room temperature. The reaction mixture was
then stirred at room temperature for 24 h. Then the reaction
mixture was then quenched with dichloromethane and water.
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Conclusions
In conclusion, 4CzIPN (7a) catalyst has been successfully
involved in the metal-free photoarylation of 2H indazole deriv-
atives with anilines. The reaction involves simple and mild
operation conditions. The strategy employs anilines as arylating
reagent which is safe and easy to handle than the diazonium
salt which is involved in the reported procedure as source of
arylation. The more sustainable energy of visible light mediated
photoarylation using 4CzIPN produces the indazole derivatives
in good to excellent yields.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
S. R. sincerely thanks DST-SERB, Government of India, New
Delhi for nancial support under DST INSPIRE Faculty Program
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