Continuous-Flow Visible Light Organophotocatalysis for Direct Arylation of 2H-Indazoles: Fast Access to Drug Molecules

Article abstract of DOI:10.1002/cssc.201900736

A continuous-flow homogeneous photocatalytic method has been devised for the direct arylation of 2H-indazoles. This visible-light-promoted approach directly accesses a wide range of structurally diverse C3-arylated scaffolds of biological interest in a fa

Full text of DOI:10.1002/cssc.201900736

Accepted Article
Title: Continuous-Flow Visible Light Organo-Photocatalysis for Direct
Arylation of 2H-Indazoles: A Fast Access to Drug molecules
Authors: Dong-Pyo Kim, Vidyacharan Shinde, Ramanjaneyulu
Bandaru T., and Seungwook Jang
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Continuous-Flow Visible Light Organo-Photocatalysis for Direct
Arylation of 2H-Indazoles: A Fast Access to Drug molecules
Shinde Vidyacharan, Bandaru T. Ramanjaneyulu, Seungwook Jang and Dong-Pyo Kim*
Abstract:
A
continuous-flow homogeneous photocatalysis is
report, a straightforward methodology for direct arylation of
2H-indazoles without the use of metal, ligand, and external
oxidant (Scheme 1) for the first time. This photocatalytic
approach utilizes a radical acceptor character of 2H-indazoles
that enables facile access to the diverse array of 3-aryl-2H-
indazoles with different substitution patterns under very mild
conditions, which is significantly different from the reported
metal catalytic paths36-39 where the anionic character of the
C3 position of 2H-indazoles was used.
devised for direct arylation of 2H-indazoles. This visible-light-
promoted approach directly accesses a wide range of structurally
diverse C3 arylated scaffolds of biological interests in a single-step
and fast synthesis (1 min) manner by using eosin Y as an organo-
photo catalyst. Furthermore, a microreactor technology is also
employed for the fast synthesis of inhibitor drugs of liver X-receptor
with very good yields under metal-free conditions, whereas the
reported methods required multi-steps and much longer reaction
time (18 -24 h).
Heteroaromatic compounds are key precursors in natural
products and pharmaceuticals.1-4 Of these, indazoles have
drawn much interest because of their wide range of potent
bioactivity in the pharma sector,5,6 such as anti-microbial,7
anti-inflammatory,8,9 HIV protease inhibition10 and promising
anticancer agents.11,12 They have also been used as a
Scheme 1. Comparative approaches for direct C3 arylation of 2H-indazoles between
the reported and this work
Batch photochemical reactions are disadvantageous with
limited penetration distance of light through absorbing
media which becomes more severe when the reactor size
increases. In contrast, photocatalysis in a continuous-flow
microreactor have showed excellent photonic proficiency by
giving sufficient irradiation to the mixed solutions of
photocatalysts and reactants that are injected into capillary
coil tube, leading to significantly decrease the reaction time
with comparable or improved yield/selectivity even under
mild conditions over batch reactors.40 The intimate contact of
the homogeneous catalyst with reactant facilitates
photoredox reactions by engaging in single-electron-transfer
(SET) events in their photoexcited states by direct absorption
of the light. Keeping this concept in mind, we have developed
an efficient strategy for a direct arylation of 2H-indazole that
directed the desired product within very short time.
bacterial gyrase
B
inhibitors13 and selective estrogen
receptors.14 Commercial important drugs such as MK-4827
(anticancer activity)15 and pazopanib (tyrosine kinase
inhibitor, votrient)16,17 incorporate the indazole as a basic
scaffold.
Functionalization of 2H-indazoles leads to formation of
privileged structural motifs that can be transformed into
diverse scaffolds in agrochemicals and pharmaceuticals.
Despite its importance, not many reports are available18-21
relative to the numerous reports on substituted 1H-
indazoles,22-26 presumably because of the low reactivity at C3
position of 2H-indazoles27-29 arising from their less aromatic
character of quinonoid form27-29 that obstructs formation of
functionalized or fused derivatives.
Of the functionalized 2H-indazoles, non-arylated scaffolds
We began our investigation of C−H arylation of 2H-
indazole (1) using phenyl diazonium tetrafluoroborate (2) as
have been synthesized via C3 alkenylation,30 annulation,31
acylation,27
phosphonylation,32
nitration33
and
a model substrate in the presence of 3 mol% Rosebengal as a
photocatalyst in DMSO solvent, and irradiated with flexible
green LED strip (70 W, 12 V, 5 meter, SMD5050 chip) at room
temperature. Delightfully, 3-phenyl-2H-indazol (3a) formed,
albeit in moderate yield (43%) after 24 h (Table 1, entry 1).
Alternative organo-photocatalysts were also checked such as
methyl red, rhodamine B, methylene blue, and eosin Y (EY)
trifluoromethylation.34 However, much less attempts have
been made for direct arylation of 2H-indazoles at C3 position
except few reports of Negishi cross-coupling,35 and arylation
by aryl halides,36-39 which required Cu or Pd metal catalysts,
expensive ligand and many additives (base, oxidant) with
long reaction time (Scheme 1). In this regard, we wish to
(Table 1, entries 2-5). Among them, eosin Y (Table 1, entry 5)
was found to be the most effective photocatlayst. Out of
several solvents screening, DMSO was found to be the best
solvent for this transformation (Table 1, entries 5-12). The
metal catalysts tested were not as efficient as eosin Y (Table
* Center of Intelligent Microprocess of Pharmaceutical Synthesis,
Department of Chemical Engineering, Pohang University of Science
and Technology (POSTECH), Pohang, 37673 Korea.
E-mail:dpkim@postech.ac.kr
Homepage: http://camc.postech.ac.kr
1
, entries 13-14). Then, the effect of various bases such as
Et3N, DBU, DBN, DIPEA, and DABCO has been studied (Table
entries 15-19). Interestingly, DIPEA enhanced the
formation of product with a significantly better yield (65%) in
Supporting information for this article is given via a link at the end
of the document. See DOI: xx.xx/x0xx00000x
1
,
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10.1002/cssc.201900736
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a shorter reaction time (from 24 h to 18 h). The positive intrinsic mixing efficiency throughout the micronscale
effect of the base could be quenching of the excited state dye
and helping in the formation of product during the
photocatalytic process. Notably, molecular oxygen/open
atmosphere instead of base was not helpful in increasing the
yield (Table 1, entries 20-21).
reaction space, leading to a highly accelerated catalysis.40, 41
Table 2. Effect of retention time on photocatalytic C3 arylation yield of 2H-
indazole in continuous-flow capillary microreactor a
Table 1. Reaction parameter study of photocatalyzed direct arylation of
2H-indazoles in a batch reactora
aReaction conditions: All reactions were carried out on 1 equiv. of
equiv. of in presence of 0.03 equiv. of eosin Y and 1 equiv. of DIPEA and 2 mL
of DMSO. All the cases apart from product 3a, we have isolated the starting
material of
bIsolated yields of chromatographically pure products. HPFA
1 and 1.2
2
1.
capillary tube (ID: 0.25 mm, L: 2 m).
Encouraged by the results, the arylation was further
probed by investigating whether it tolerates a wide variety of
substituents on both coupling partners. With respect to the
indazole, the electronic effect of the N-2 substituent of 2H-
indazoles was examined and the results are summarized in
Table 3. A strong electronic effect was found in the presence
of phenyl groups with electron donating based substituents
(
Table 3
,
3a_3c), which led to good yields, whereas bromo-
3d). The
substitution rendered very poor yields (Table 3
,
electronic effect of the arene part of 2H-indazoles was then
studied. Fluorine and bromine substituted 2H-indazole at C-6
provided the desired product 3e and 3f with good yields in
the range of 60-68% in both batch and flow processes, and
the C-7 methoxy-substituted 2H-indazole also gave very good
yields (3g 65% batch, 72% flow). N-2 substituents of 2H-
indazoles with heteroaryl, alkyl and benzyl, unfortunately
aReaction conditions: 1 (1 equiv.), 2 (1.2 equiv.) eosin Y (0.03 equiv.) base (1
equiv.) and 2 mL of solvent. Reaction time 24 h for entries 1-14, & 20-21, and
18 h for entries 15-19. bIsolated yields. cMolecular oxygen. dReaction performed
in open atmosphere.
failed to form the desired products (Table 3, 3h-3j),
presumably due to less aromatic character of 2H-indazole.27-
29
The optimal conditions established by the batch reactor
were directly applied to a continuous–flow microfluidic
reactor to take advantage such as efficient light irradiation
With respect to aryldizaonium salts, the potential of
present methodology was examined for various salts with
ortho-, meta, and para- as well as multiple-substituents. The
desired arylated products were obtained in good to very
good yields (up to 85%) in the presence of both electron
and efficient mixing. The reactor is simply
a highly
transparent perfluoroalkoxy alkane (PFA) coil capillary (ID:
0.25 mm, L: 2 m) with LED light (In SI, Figure S1). The optimal
mixture solution of photocatlyst and reactants was simply
injected into the PFA capillary through a single inlet.
Surprisingly, the desired product was obtained in very good
yield (74%). Even more surprising was the dramatic decrease
in reaction time from 18 h to 1 min (Table 2). In light of the
success, the flow rate was varied to investigate the effect of
residence time. Table 2 reveals that a residence time shorter
than 1 min leads to a decrease in the yield of product 3a
while a residence time longer than 1 min (2 and 4 min) (Table
donating (Table 4
3o-3u) substituents. The products derived from the ortho-
substituted aryldiazonium salts (Table 4 3m and 3o) were
, 3k-3n) and electron withdrawing (Table 4,
,
obtained with lower reaction yields, compared to those
obtained with meta- and para-substituted ones. However,
tri-substituted aryldiazonium salt failed to give the expected
products (Table 4, 3v), presumably owing to severe steric
hindrance, as expected from literature.42-44 Nevertheless, a
noticeable electronic effect of these substituents was not
observed. It should be pointed out here that the photo-flow
reaction approach offers a unique way to perform diverse
chemistries under simple, safe, fast, and greener way with
superior efficiency compared to batch approach.
Furthermore, we have also employed this arylation strategy
2
, entries 4-5) does not improve the yield. These results
suggest that the high surface-area-to-volume ratio of the
microfluidic reactor (0.25 mm diameter) provides high spatial
illumination homogeneity, excellent light penetration, and
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10.1002/cssc.201900736
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for different benzo-fused heterocyclic scaffolds. However, (7-methoxy-2-phenyl-2H-indazol-3-yl)benzonitrile (3w) and 3-
unfortunately, the expected products were not obtained in (4-chlorophenyl)-7-methoxy-2-phenyl-2H-indazole (3x), with
any of the cases (Scheme S1).
very good yields at room temperature in a single-step and
environmentally benign manner (Table 5). In particular, the
flow synthesis of an active pharmaceutical ingredient (API)
took only 1 min to reach superior yields (80, 78%) over the
batch synthesis (72, 65% for 18 h). This fast reaction with
good yield is well situated for large-scale production on an
industrial scale.
Table 3. Photocatalytic C3 arylation of various substituted 2H-indazoles in
batch and continuous-flow reactora,b
Table 5. Synthesis of an inhibitor of liver X receptor as a medicine of
cardiovascular disease via photocatalytic C3 arylation of 2H-indazole.
aIsolated yield in batch. bIsolated yield in flow.
aReaction conditions: 1 (1 equiv.), 1.2 equiv. of 2 in presence of 0.03 equiv. of
eosin Y, 1 equiv. of DIPEA and 2 mL of DMSO. All the cases apart from the
product 3a-3j reaming starting materials of 2H-indazoles was recovered.
bYields in the parentheses are isolated yields of chromatographically pure
products. cIsolated yield in batch. dIsolated yield in flow. HPFA capillary tube
(ID: 0.25 mm, L: 2 m) flow rate 100 µLmin-1 (1 min).
To probe the mechanistic insight into the reaction
pathway, a few control experiments were conducted under
complete absence of light, catalyst and base, and no product
was formed (Table 6, entry 2). The presence of only catalyst
showed very poor yield (Table 6
presence of base and without catalyst formed low yield of
the desiered product (Table 6 entry 4). Further, to know
, entry 3), whereas the
Table 4. Photocatalytic C3 arylation of 2H-indazoles using various substituted
aryldiazonium salts in batch and continuous-flow reactora,b
,
light effect on the reaction, we performed light switching
experiments, which revealed that the progress of the
reaction was frozen in the absence of light source during the
reaction (Table 6
agents, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and
2,6-di-tert-butyl-4-methylphenol (BHT) completely
suppressed the reaction (Table 6, entry 6).
Further, the quantum yield of the reaction was
determined to be = 0.283 (See SI, section 3), which
, entries 5). The addition of radical trapping

suggests that a photoredox pathway might be involved.
Table 6. Control reactions for photocatalyzed direct arylation of 1a
aReaction conditions: 1 (1 equiv.), 1.2 equiv. of 2 in presence of 0.03 mol% of
eosin Y, 1 equiv. of DIPEA and 2 mL of DMSO. All the cases apart from the
product 3a-3g reaming starting materials of 2H-indazoles was recovered.
bYields in the parentheses are isolated yields of chromatographically pure
products. cIsolated yield in batch. dIsolated yield in flow. HPFA capillary tube
(ID: 0.25 mm, L: 2 m) flow rate 100 µLmin-1 (1 min).
aReaction conditions: 1 (1 equiv.), 1.2 equiv. of 2, 1 equiv. of DIPEA and 2 mL
of DMSO. bYields after chromatographic purification. cReaction performed
without photo light in dark. d2 equiv of TEMPO and BHT used.
Given the successful synthesis of the regioselective direct
arylation of 2H-indazole with aryldiazonium salts, the
photochemical methodology is primed for the synthesis of
drug derivatives. An inhibitor of liver X receptor is known to
be a key medicine for preventing and treating cardiovascular
disease.45 However, the reported synthetic methods involved
tedious steps, drastic conditions and using transition metal-
catalysis.36, 46, 47 In contrast, both batch and continuous-flow
methodologies developed here synthesizes the products, 4-
A series of fluorescence quenching experiments on eosin
Y were performed to elucidate the reaction mechanism, the
excited photocatalyst was quenched by DIPEA or
aryldiazonium salt
aryldiazonium salt
2
. The increase in the concentration of
2
, there is no change in the fluorescence
intensity of eosin Y (Figure 1a), whereas, increase in the
concentration of DIPEA resulted in a significant decrease of
fluorescence intensity of eosin Y (Figure 1b). These results
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10.1002/cssc.201900736
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strongly implied that the DIPEA plays an important role in
single electron transfer with the photocatalyst and which will
be the quencher of the dye (See SI, section 4).
Acknowledgements
We gratefully acknowledge the support from the National
Research Foundation (NRF) of Korea grant funded by the
Korean government (NRF-2017R1A3B1023598). We also
acknowledge Prof. T. Park and Dr. K. S. Bejoymohandas for
their helpful suggestions in the PL analysis.
Keywords: C-H arylation; • Flow-photoredox chemistry; • Fast
reaction (1 min); • Drug synthesis; • Sustainable organic
synthesis
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Scheme 2. Plausible reaction mechanism for direct arylation of 2H-indazole
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10.1002/cssc.201900736
ChemSusChem
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Shinde
Vidyacharan,
Bandaru
T.
Ramanjaneyulu, Seungwook Jang and
Dong-Pyo Kim*
Page No. – Page No.
Continuous-Flow
Organo-Photocatalysis
Arylation of 2H-Indazoles:
Visible
for
Light
Direct
Fast
A


First metal-free approach


Synthesis of liver X-receptors
Visible-light-promoted C-H
Access to Drug molecules
Fast synthesis (1 min) arylation
A continuous-flow homogeneous photocatalysis is devised for direct arylation of 2H-
indazoles. This visible-light-promoted approach directly accesses a wide range of
structurally diverse C3 arylated scaffolds of biological interests in a single-step and fast
synthesis manner (1 min) under eosin Y as a catalyst. Furthermore, we have employed this
microreactor technology at metal-free conditions for the fast synthesis of inhibitor drugs of
liver X-receptor with very good yields.
This article is protected by copyright. All rights reserved.