Visible-light-mediated direct C3-arylation of 2: H -indazoles enabled by an electron-donor-acceptor complex

Article abstract of DOI:10.1039/c9ob02074h

A mild visible-light-mediated, photocatalyst-free arylation of 2H-indazoles was developed. The formation of an electron donor-acceptor complex by 2H-indazoles and aryl diazonium salts in the presence of pyridine allows the direct arylation of 2H-indazoles under visible-light irradiation. This process provides an efficient route for the synthesis of C3-arylated-2H-indazoles, which are important scaffolds of various bioactive compounds.

Full text of DOI:10.1039/c9ob02074h

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Visible-light-mediated direct C3-arylation
of 2H-indazoles enabled by an
electron-donor–acceptor complex†
Kim Christopher C. Aganda,a Junyoung Kimb and Anna Lee
Cite this: Org. Biomol. Chem., 2019,
17, 9698
Received 24th September 2019,
Accepted 1st November 2019
a,b
*
DOI: 10.1039/c9ob02074h
rsc.li/obc
A mild visible-light-mediated, photocatalyst-free arylation of 2H- The above-mentioned methods include concerns regarding the
indazoles was developed. The formation of an electron donor– use of toxic and expensive transition metal catalysts, reagents,
acceptor complex by 2H-indazoles and aryl diazonium salts in the or both (Scheme 1, I). Very recently, an efficient continuous-
presence of pyridine allows the direct arylation of 2H-indazoles flow organo-photocatalytic approach for the arylation of 2H-
under visible-light irradiation. This process provides an efficient indazoles was reported.5d,12 However, the substrate scope was
route for the synthesis of C3-arylated-2H-indazoles, which are limited to phenyl or aryl substituents with an electron-donat-
important scaffolds of various bioactive compounds.
ing group at N2 of the 2H-indazole.
Given this background, the development of general and
efficient approaches for the arylation of 2H-indazoles using
environmentally benign processes would still be demanded.
Herein, we report the efficient visible-light-promoted direct
arylation of 2H-indazoles using aryl diazonium salts
(Scheme 1, II). Notably, the reaction proceeds under mild reac-
tion conditions without using any catalysts or metal reagents.
With the goal of green chemistry in mind, various reaction
conditions were considered, including catalyst-free conditions.
We envisaged that the arylation of 2H-indazoles might be
Indazoles, which are bioisosteres of indoles and benzimid-
azoles, are important scaffolds in organic synthesis and medic-
inal chemistry because of their significant bioactive pro-
perties.1 The synthesis of 2H-indazoles in particular has
attracted a great deal of attention in the synthetic community
due to the prevalence of this structural motif in commercially
available pharmaceuticals and other drug candidates (Fig. 1).2
Recently, the 2H-indazole scaffold was found in compounds
which exhibit anti-inflammatory properties as well as effective
anticancer agents such as pazopanib and niraparib.2,3
accomplished via
a visible-light-induced process in the
Various approaches for the synthesis of 2H-indazoles start-
ing from acyclic precursors are known.4 However, direct
functionalization of 2H-indazoles at the C3 position is less
common because of the low reactivity at that position.5 In
spite of this, direct functionalization of 2H-indazoles would
provide efficient ways to synthesize various 2H-indazole deriva-
tives, and some examples have been reported, such as alkeny-
lation,6 acylation,5c phosphonylation,7 nitration,8 annulation,9
and trifluoromethylation.10
absence of a photocatalyst through the formation of an elec-
tron donor–acceptor (EDA) complex.13 To test this hypothesis,
we employed 2-phenyl-2H-indazole 1aa and 4-methoxybenzene-
diazonium tetrafluoroborate 2aa as model substrates. We per-
formed the reaction using various conditions, selected
examples of which are summarized in Table 1.
On the other hand, only a limited number of studies on the
direct arylation of 2H-indazoles have been reported so far,
including arylation by aryl halides, which required transition
metal catalysts, ligands, and other organometallic reagents.11
aDepartment of Energy Science and Technology, Myongji University, Yongin, 17058,
Republic of Korea
bDepartment of Chemistry, Myongji University, Yongin 17058, Republic of Korea.
E-mail: annalee@mju.ac.kr
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra. See DOI: 10.1039/
c9ob02074h
Fig. 1 Bioactive compounds containing the 2H-indazole moiety.
9698 | Org. Biomol. Chem., 2019, 17, 9698–9702
This journal is © The Royal Society of Chemistry 2019

View Article Online
Organic & Biomolecular Chemistry
Communication
It seems that the additional 1aa might be helping to accel-
erate the reaction by controlling the overall reaction profile. In
the presence of 2 equiv. of 1aa, the yield increased smoothly
over time. In contrast, in the presence of only 1 equiv. of 1aa,
the yield was around 30% after three hours, and then
increased very slowly (see the ESI† for more details).
Employing different solvents such as DMF, acetonitrile, or di-
chloromethane instead of DMSO caused the reaction yield to
diminish significantly (entries 3–5). The reaction did not take
place in toluene or 1,4-dioxane (entries 6 and 7). Intriguingly,
the desired product was obtained in 43% yield in the absence
of pyridine, which indicates that formation of the EDA
complex might be possible without pyridine (entry 8).
However, it seems that pyridine creates a synergistic effect to
improve the reaction yield (entry 1). One possible explanation
of these results could be the formation of a ternary EDA
complex by 2H-indazole, the aryl diazonium salt, and pyri-
dine.14 Varying the amount of pyridine did not improve the
reaction yield (entries 9 and 10). In addition, employing
different amines instead of pyridine generated the desired
product with diminished yield (entries 11–13). Changing the
light source did not make a significant difference; the best
reaction yield was obtained with blue LEDs (entries 1, 14–17).
The reaction yield decreased when the reaction was performed
under air (entry 18). Finally, the yield decreased dramatically
in the dark; therefore, visible light plays an important role in
this transformation (entry 19).
Scheme 1 Synthetic approaches to C3-arylated 2H-indazoles.
Table 1 Optimization of the reaction conditionsa
Entry
Variations in the reaction conditions
Yieldb (%)
1
2
3
4
5
6
7
8
None
73
47
33
12
Trace
No rxn
No rxn
43
With 1.0 equiv. of 1aa
DMF instead of DMSO
CH3CN instead of DMSO
CH2Cl2 instead of DMSO
Toluene instead of DMSO
1,4-Dioxane instead of DMSO
Without pyridine
With the optimized reaction conditions in hand, we
explored the substrate scope of the synthesis of C3-arylated
2H-indazoles. Notably, the reaction was tolerant to various aryl
diazonium salts (Table 2). Aryl diazonium salts with either
electron-donating (3aa–3ad) or electron-withdrawing (3ae–3ai)
groups provided the desired products in 44–81% yields. The
use of naphthyl diazonium salt 2ak gave the desired product
3ak in 69% yield. In addition, the reaction with heteroaryl di-
azonium salt 1al successfully provided the desired product 3al
in 60% yield.
9
With 0.5 equiv. of pyridine
With 2.0 equiv. of pyridine
TEA instead of pyridine
DIPEA instead of pyridine
TMEDA instead of pyridine
Green LEDs instead of blue LEDs
White LEDs instead of blue LEDs
20 W CFL instead of blue LEDs
Sunlight instead of blue LEDs
Under air
62
72
47
59
60
68
71
65
10
11
12
13
14
15
16
17
18
19
53
54
13
Without light
Furthermore, the products derived from the ortho-, meta-,
and para-substituted aryl diazonium salts were obtained in
44–81% yields (3aa–3ac, 3ae–3ag). A significant electronic
effect was not observed with ortho-, and meta-substituted aryl
diazonium salts (3ab–3ac vs. 3ae–3af). However, diminished
reaction yields were observed with electron-withdrawing substi-
tuents at the para-position (3aa, 3ad vs. 3ag–3ai). Next, we
a Conditions: 1aa (1.0 mmol, 2.0 equiv.), 2aa (0.5 mmol, 1.0 equiv.),
and pyridine (1.0 equiv.) in DMSO (2 mL, 0.25 M); irradiation with 4 W
blue LEDs (455 nm) at 23 °C for 15 h under Ar. b Isolated yield after
column chromatography. The yield was obtained based on the amount
of consumed 1aa (0.5 mmol).
We assumed that aryl diazonium salt 2 could act as an elec- examined various aryl substituents at N2 of the 2H-indazoles
tron-acceptor to form the key EDA complex with indazole 1. (3am–3au). Aryl substituents with either electron-donating
We found that direct arylation product 3aa was obtained in (3am–3ap) or electron-withdrawing (3aq–3as) groups afforded
73% yield in the presence of 1 equiv. of pyridine in DMSO at the desired products in 41–81% yields. The decrease in the
room temperature under blue LED light irradiation (455 nm) yields of 3am and 3aq was likely due to the steric effect of the
in an Ar environment without using a photocatalyst (Table 1, substituents at the ortho position. Similarly, the use of steri-
entry 1). Moreover, the addition of 2 equiv. of indazole 1aa cally hindered 2-(naphthalen-1-yl)-2H-indazole gave the
improved the reaction yield compared with only 1 equiv. of 1aa desired product with low yield (3au, 31% yield). The reaction
(entries 1 and 2, 47% vs. 73% yield). Interestingly, only 1 with 2-pyridyl substituted 2H-indazole 1at also successfully
equiv. of 1aa reacted with aryl diazonium salt 2aa to afford the provided the desired product 3at in 64% yield.
desired product; 1 equiv. of starting indazole 1aa was recovered
after the reaction.
The electronic effect on the arene structure of 2H-indazole
was important; 7-methoxy-2-phenyl-2H-indazole provided the
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 9698–9702 | 9699

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 2 Substrate scopea
transformation even though the reaction yields were relatively
low (3ay: 48%, 3az: 23%). However, with benzyl substituted 2H-
indazole, only a trace amount of the desired product was
obtained (3ba).
In order to gain mechanistic insight into this transform-
ation, we employed TEMPO (2,2,6,6-tetramethyl-1-piperidinyl-
oxy) as a radical inhibitor. When TEMPO was present, none of
the desired product was observed, thereby indicating that the
reaction proceeds via a radical pathway. Furthermore, the aryl
radical was trapped by TEMPO, and the TEMPO-adduct was
detected by GC-MS (Scheme 2).
To further understand this catalyst-free reaction, we investi-
gated the formation of the plausible EDA complex. First, we
analyzed the reaction components by UV-vis absorption spec-
troscopy (Fig. 2a). When a solution of 2aa in DMSO was
treated with 1aa, the color of the mixture turned yellow, and a
significant bathochromic shift was observed in the UV-vis
spectrum, which is diagnostic of an EDA complex.13 A clear
bathochromic shift was also observed with a mixture of 2aa
and pyridine in DMSO. Interestingly, a mixture of 1aa, 2aa,
Scheme 2 Radical trapping experiment.
a Conditions: 1aa (1.0 mmol, 2.0 equiv.), 2aa (0.5 mmol, 1.0 equiv.),
pyridine (1.0 equiv.) in DMSO (2 mL, 0.25 M), irradiation with 4 W
blue LEDs (455 nm) at 23 °C for 15 h under Ar. Isolated yield after
column chromatography. The yield was obtained based on the amount
of consumed 1aa (0.5 mmol).
product with a slightly increased yield compared with 5-fluoro-
2-phenyl-2H-indazole (3av: 56% vs. 3aw: 68%). Notably, alkyl
substituted 2H-indazoles were also suitable substrates in this pyridine. (c) 1H NMR spectra of 2aa. (d) Job plot of 1aa and 2aa.
Fig. 2 Mechanistic studies. (a) UV-vis absorption spectra of the reaction
components. (b) UV-vis absorption spectra with different amounts of
9700 | Org. Biomol. Chem., 2019, 17, 9698–9702
This journal is © The Royal Society of Chemistry 2019

View Article Online
Organic & Biomolecular Chemistry
Communication
without using any catalysts or metal reagents. This environ-
mentally friendly process is an efficient method for the syn-
thesis of C3-arylated 2H-indazoles, which are important
scaffolds of many bioactive compounds. In addition, the novel
reaction pathway for the arylation of 2H-indazoles through the
formation of a ternary EDA complex would provide new oppor-
tunities to expand the field of organic photochemical
reactions.
Scheme 3 Proposed reaction pathway.
Conflicts of interest
and pyridine showed a further bathochromic shift, thereby
suggesting the formation of a ternary EDA complex (Fig. 2a).14
To further clarify the role of pyridine in forming the EDA
complex, a 1 : 1 mixture of 1aa and 2aa in DMSO was treated
with different amounts of pyridine (0–10 equiv.), and the
absorption was analyzed by UV-vis spectroscopy (Fig. 2b). The
intensity of the absorption increased upon increasing the pyri-
dine concentration. These results suggest that pyridine is
involved in the formation of the EDA complex.14c This ternary
EDA complex would enhance the reactivity of the reaction;
therefore, an improved yield was observed in the presence of
pyridine in our optimization experiments (Table 1, entries 1
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MSIT)
(No. 2019R1A2C1008297). This research was also supported by
Basic Science Research Program through the National
Research Foundation of Korea (NRF) funded by the Ministry of
Education (2016R1D1A1B03931335).
1
and 8). In addition, H NMR studies showed that the aryl di-
azonium salt acts as an electron-acceptor in the EDA complex;
a noticeable chemical shift of the methoxy group of 2aa was
observed in the presence of 1aa and pyridine in DMSO-d6
(Fig. 2c). Additional NOESY studies showed possible corre-
lations between 1aa–2aa, and 2aa-pyridine in the mixture.
Furthermore, we found that the diffusion coefficient decreased
in the mixture of 1aa, 2aa, and pyridine in DOSY studies (see
the ESI† for more details).
In our previous report, we found that an aryl diazonium
salt could form an EDA complex with pyridine in a 1 : 1
ratio.15,16 We were curious about the ratio of 1aa and 2aa in
the EDA complex. A Job plot of the UV-vis spectroscopy results
indicated a 1 : 1 ratio of 1aa/2aa in the EDA complex (Fig. 2d,
see the ESI† for more details).17
A plausible reaction pathway is proposed based on the
present study and previous reports (Scheme 3).5d,7,18 The reac-
tion would start with the formation of an EDA complex of 2H-
indazole 1, aryl diazonium salt 2, and pyridine. Next, photo-
excitation of the EDA complex would trigger SET to generate
an aryl radical, which would then react with I-A (path A) or I-B
(path B), affording intermediates II-A or II-B, respectively. After
oxidation of II-A by pyridinium radical cation and subsequent
deprotonation (path A) or deprotonation of II-B (path B),
the aromaticity would be regenerated to afford the desired
product 3.
Notes and references
1 A. Schmidt, A. Beutler and B. Snovydovych, Eur. J. Org.
Chem., 2008, 4073.
2 (a) Y. Lian, R. G. Bergman, L. D. Lavis and J. A. Ellman,
J. Am. Chem. Soc., 2013, 135, 7122; (b) Y. Cheng, G. Li,
Y. Liu, Y. Shi, G. Gao, D. Wu, J. Lan and J. You, J. Am.
Chem. Soc., 2016, 138, 4730.
3 (a) M. De Angelis, F. Stossi, K. A. Carlson,
B. S. Katzenellenbogen and J. A. Katzenellenbogen, J. Med.
Chem., 2005, 48, 1132; (b) L.-J. Huang, M.-L. Shih,
H.-S. Chen, S.-L. Pan, C.-M. Teng, F.-Y. Lee and S.-C. Kuo,
Bioorg. Med. Chem., 2006, 14, 528; (c) M. Minu,
A. Thangadurai, S. R. Wakode, S. S. Agrawal and
B. Narasimhan, Bioorg. Med. Chem. Lett., 2009, 19, 2960;
(d) W. Aman, J. Lee, M. Kim, S. Yang, H. Jung and
J.-M. Hah, Bioorg. Med. Chem. Lett., 2016, 26, 1188;
(e) J. Pérez-Villanueva, L. Yépez-Mulia, I. González-Sánchez,
J. F. Palacios-Espinosa, O. Soria-Arteche, T. D. R. Sainz-
Espuñes,
M.
A.
Cerbón,
K.
Rodríguez-Villar,
A. K. Rodríguez-Vicente, M. Cortés-Gines, Z. Custodio-
Galván and D. B. Estrada-Castro, Molecules, 2017, 22, 1864;
(f) J. Liu, C. Qian, Y. Zhu, J. Cai, Y. He, J. Li, T. Wang,
H. Zhu, Z. Li, W. Li and L. Hu, Bioorg. Med. Chem., 2018,
26, 747.
4 (a) M. Akazome, T. Kondo and Y. Watanabe, J. Org. Chem.,
1994, 59, 3375; (b) D.-Q. Shi, G.-L. Dou, S.-N. Ni, J.-W. Shi,
X.-Y. Li, X.-S. Wang, H. Wu and S.-J. Ji, Synlett, 2007, 2509;
(c) B. J. Stokes, C. V. Vogel, L. K. Urnezis, M. Pan and
T. G. Driver, Org. Lett., 2010, 12, 2884; (d) Y. Fang, C. Wu,
R. C. Larock and F. Shi, J. Org. Chem., 2011, 76, 8840;
Conclusions
In summary, we have developed a photocatalyst-free, visible-
light-mediated arylation reaction of 2H-indazoles. The desired
products were obtained under mild reaction conditions
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 9698–9702 | 9701

View Article Online
Communication
Organic & Biomolecular Chemistry
(e) M. R. Kumar, A. Park, N. Park and S. Lee, Org. Lett.,
2011, 13, 3542.
(d) C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem.
Rev., 2013, 113, 5322; (e) N. A. Romero and D. A. Nicewicz,
Chem. Rev., 2016, 116, 10075; (f) D. M. Schultz and
T. P. Yoon, Science, 2014, 343, 1239176; (g) L. Shi and
W. Xia, Chem. Soc. Rev., 2012, 41, 7687; (h) K. L. Skubi,
T. R. Blum and T. P. Yoon, Chem. Rev., 2016, 116, 10035;
(i) J. W. Tucker and C. R. J. Stephenson, J. Org. Chem., 2012,
77, 1617; ( j) C.-S. Wang, P. H. Dixneuf and J.-F. Soulé,
Chem. Rev., 2018, 118, 7532.
5 (a) E. J. Brnardic, R. M. Garbaccio, M. E. Fraley,
E. S. Tasber, J. T. Steen, K. L. Arrington, V. Y. Dudkin,
G. D. Hartman, S. M. Stirdivant, B. A. Drakas, K. Rickert,
E. S. Walsh, K. Hamilton, C. A. Buser, J. Hardwick, W. Tao,
S. C. Beck, X. Mao, R. B. Lobell, L. Sepp-Lorenzino, Y. Yan,
M. Ikuta, S. K. Munshi, L. C. Kuo and C. Kreatsoulas,
Bioorg. Med. Chem. Lett., 2007, 17, 5989; (b) M. Ye,
A. J. F. Edmunds, J. A. Morris, D. Sale, Y. Zhang and 13 (a) R. S. Mulliken, J. Am. Chem. Soc., 1950, 72, 600;
J.-Q. Yu, Chem. Sci., 2013, 4, 2374; (c) G. Bogonda,
H. Y. Kim and K. Oh, Org. Lett., 2018, 20, 2711;
(d) S. Vidyacharan, B. T. Ramanjaneyulu, S. Jang and
D.-P. Kim, ChemSusChem, 2019, 12, 2581.
6 M. Naas, S. El Kazzouli, E. M. Essassi, M. Bousmina and
G. Guillaumet, Org. Lett., 2015, 17, 4320.
7 M. Singsardar, A. Dey, R. Sarkar and A. Hajra, J. Org. Chem.,
2018, 83, 12694.
8 A. Murugan, K. R. Gorantla, B. S. Mallik and D. S. Sharada,
Org. Biomol. Chem., 2018, 16, 5113.
(b) R. S. Mulliken, J. Phys. Chem., 1952, 56, 801;
(c) J. S. Miller, A. J. Epstein and W. M. Reiff, Chem. Rev.,
1988, 88, 201; (d) S. V. Rosokha and J. K. Kochi, Acc. Chem.
Res., 2008, 41, 641; (e) H. Miyasaka, Acc. Chem. Res., 2013,
46, 248; (f) U. M. Rabie, J. Mol. Struct., 2013, 1034, 393;
(g) C. G. S. Lima, T. de M. Lima, M. Duarte, I. D. Jurberg
and M. W. Paixão, ACS Catal., 2016, 6, 1389.
14 (a) J. M. Masnovi, J. K. Kochi, E. F. Hilinski and
P. M. Rentzepis, J. Phys. Chem., 1985, 89, 5387;
(b) Ł. Woźniak, J. J. Murphy and P. Melchiorre, J. Am. Chem.
Soc., 2015, 137, 5678; (c) F. Sandfort, F. Strieth-Kalthoff,
F. J. R. Klauck, M. J. James and F. Glorius, Chem. – Eur. J.,
2018, 24, 17210; (d) J. Wu, P. S. Grant, X. Li, A. Noble and
V. K. Aggarwal, Angew. Chem., Int. Ed., 2019, 58, 5697.
9 S. Vidyacharan, A. Murugan and D. S. Sharada, J. Org.
Chem., 2016, 81, 2837.
10 P. Ghosh, S. Mondal and A. Hajra, J. Org. Chem., 2018, 83,
13618.
11 (a) S. A. Ohnmacht, A. J. Culshaw and M. F. Greaney, Org. 15 J. Lee, B. Hong and A. Lee, J. Org. Chem., 2019, 84, 9297.
Lett., 2010, 12, 224; (b) K. Hattori, K. Yamaguchi, 16 Also see: A. d. A. Bartolomeu, R. C. Silva, T. J. Brocksom,
J. Yamaguchi and K. Itami, Tetrahedron, 2012, 68, 7605; T. Noël and K. T. de Oliveira, J. Org. Chem., 2019, 84, 10459.
(c) A. Unsinn and P. Knochel, Chem. Commun., 2012, 48, 17 (a) P. Job, Ann. Chim., 1928, 9, 113; (b) P. MacCarthy, Anal.
2680; (d) K. Basu, M. Poirier and R. T. Ruck, Org. Lett.,
2016, 18, 3218.
12 For selected reviews on photocatalysis, see: (a) S. Afewerki
Chem., 1978, 50, 2165; (c) J. S. Renny, L. L. Tomasevich,
E. H. Tallmadge and D. B. Collum, Angew. Chem., Int. Ed.,
2013, 52, 11998.
and A. Córdova, Chem. Rev., 2016, 116, 13512; (b) B. König, 18 (a) S. Sharma and A. Sharma, Org. Biomol. Chem., 2019, 17,
Eur. J. Org. Chem., 2017, 1979; (c) J. M. R. Narayanam and
C. R. J. Stephenson, Chem. Soc. Rev., 2011, 40, 102;
4384; (b) M. Singsardar, S. Laru, S. Mondal and A. Hajra,
J. Org. Chem., 2019, 84, 4543.
9702 | Org. Biomol. Chem., 2019, 17, 9698–9702
This journal is © The Royal Society of Chemistry 2019