Regioselective C3-H Trifluoromethylation of 2 H-Indazole under Transition-Metal-Free Photoredox Catalysis

Article abstract of DOI:10.1021/acs.joc.9b00676

Trifluoromethyl-substituted heteroarenes are biologically active compounds and useful building blocks. In this sequence, we have developed a visible-light-promoted regioselective C3-H trifluoromethylation of 2H-indazole under metal-free conditions, which

Full text of DOI:10.1021/acs.joc.9b00676

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Article
Regioselective C3-H trifluoromethylation of 2H-indazole
under transition-metal-free photoredox catalysis
Arumugavel Murugan, Venkata Nagarjuna Babu, Ashok Polu, Nagaraj
Sabarinathan, Manickam Bakthadoss, and Duddu S. Sharada
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 May 2019
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Regioselective C3-H trifluoromethylation of 2H-indazole under transition-
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metal-free photoredox catalysis
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Arumugavel Murugan,† Venkata Nagarjuna Babu,† Ashok Polu,† Nagaraj Sabarinathan,†
Manickam Bakthadoss*‡ and Duddu S. Sharada*†
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†Catalysis & Chemical Biology Laboratory, Department of Chemistry, Indian Institute of Technology
Hyderabad, Kandi – 502285, Sangareddy, Telangana, INDIA, Phone: +91 8106644794; Fax: (040) 2301 6032.
E-mail: sharada@iith.ac.in Web: http://drsharadagroup.wixsite.com/sharada
‡Department of Chemistry, Pondicherry University, Pondicherry 605 014, INDIA
Phone: (0413) 2654 830; E-mail: bhakthadoss@yahoo.com
CF3
H
Methylene blue,
PIDA, 60 W CFL bulb
R1
N
R1
N
NaSO2CF3, DCM, rt, 24 h
N
R2
R2
N
19 examples
up to 83% yield
* Regioselective radical C-H trifluoromethylation
* Chelation-free and metal-free C-H functionalization
* Inexpensive and benchtop-stable CF3 radical source
* Scale-up synthesis
Abstract: The trifluoromethylation-substituted heteroarenes are biologically active compounds and
useful building blocks. In this sequence, we have developed a visible-light-promoted regioselective C3-
H trifluoromethylation of 2H-indazole under metal-free conditions which proceed via a radical
mechanism. The combination of photocatalysis and hypervalent iodine reagent provides a practical
approach to a library of trifluoromethylated indazoles in 35-83% yields.
Introduction
Halo-organic compounds are typically considered as sites of high electron density because of
their high electronegativity. In general, the halogen atoms can form attractive interaction due to electron
donor sites (i.e. nucleophiles).1 Among them, the C-F bond finds important application in the field of
synthetic and medicinal chemistry, Which is owed to the similar size and increased electronegativity of
fluorine over hyderogen.2 In this context, the trifluoromethyl group represents important structural motif
in agrochemicals, pharmaceuticals, and drug candidates. The CF3 moieties can enhance in metabolic
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stability, increase lipophilicity, bioavailability, and hydrolytic stability. Further, the trifluoromethyl-
containing organic compounds are commonly applied in material such as liquid crystals.3
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Over the past decade, due to the importance of trifluoromethylation process, several methods
have been developed, using various radical, nucleophilic, and electrophilic trifluoromethylating agents
such as CF3I,4 CF3SO2Cl,5 CF3COOH,6 Ruppert-Prakash reagent (TMSCF3),7 Tognis’ reagent,8
Umemotos’ reagent9 and Baran reagent (CF3SO2)2Zn10 and Langlois’ (CF3SO2Na)11. Among these,
Langlois’ reagent is benchtop-stable, inexpensive, easy to handle and convenient reagent for
trifluoromethylation.12 Despite these developments, the approach for radical trifluoromethylation of
arenes and heteroarenes have achieved over the past years.13
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a) Radical C-H functioalization on 2H-Indazole
X
H
Ag, PC, Fe, TBHP
N
N
N
N
X= COPh, PO(Ph)2, SCN, CF3
b) Our previous report (radical C-H nitration)
H
NO2
Fe(NO3)3.9H2O
N
N
N
N
c) Present Method (Photoredox Catalysed trifluoromethylation)
CF3
H
PC, PIDA
N
N
Visible Light
N
N
Scheme 1: Regioselective C3-H functionalization of 2H-indazole
In recent years, the visible light induced photoredox catalytic activation of organic molecules has been
established as a powerful strategy in modern organic synthesis which provide attractive features, like
mild, environmentally benign, excellent functional group tolerance, and high reactivity.14 The
photoredox strategy can involve via single-electron-transfer (SET) process upon irradiation with visible
light using metal complexes and organic dyes as photocatalyst.15 Moreover, the usage of organic dyes
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is inexpensive and easy to handle as photoredox catalysts, and hence this would be an excellent
substitute to inorganic transition-metal photocatalyst.
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Nitrogen-containing heterocycle compounds have gained significant importance in natural products and
they exhibit a wide range of biological activities.16 Among them, indazoles are broadly known for their
bioactivities17 such as antitumor,18 antimicrobial,19 anti-inflammatory,20 anti-HIV,21 anti-platelet22 and
anti-contraceptive.23 Considering the immense importance of derivatives of 2H-indazoles, extensive
efforts have been devoted for the synthesis and functionalization of 2H-indazole.24 Recently, Oh et.al
have reported the silver-catalyzed direct acyl radical addition to 2H-indazole25a and Hajra et al. have
also realized the construction of carbon-phosphorus (C-P)25b and carbon-sulfur (C-S)25c bond formations
on 2H-indazole (Scheme 1a). Very recently, Hajra et.al have described a new approach for the direct
C3-trifluoromethylation of 2H-indazole mediated by peroxides (Scheme 1a).25d The C3-H
functionalization of 2H-indazoles has few disadvantages such as usage of transition-metal catalyst,
peroxides and high temperature. Encouraged by the significant advances in the recent radical C-H
functionalization,26 our group initiated the research program on the C-H functionalization of indazoles.27
Herein, we report a novel metal-free visible-light-promoted organic dye catalyzed regioselective C3-
trifluoromethylation of 2H-indazole. An initial version of this work was deposited in ChemRxiv on 5th
March-2019.28
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Results and Discussion
Table 1. Optimization of Reaction Conditions for the Synthesis of 2aa
CF3
N
H
Photocatalyst, Oxidant
N
N
1a
CF3 Source, Solvent,
24 h, rt
N
2a
entry
1
catalyst
rose bengal
oxidants
PIDA
CF3 Source
NaSO2CF3
Solvent
DCM
yield (%)b
60
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2
rose bengal
rose bengal
K2S2O8
TBHP
IBA-OAc
PhIO
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
NaSO2CF3
TMSCF3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CH3CN
DCE
n.d
n.d
3
4
rose bengal
Trace
Trace
n.d
5
rose bengal
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rose bengal
-
7
-
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
Trace
Trace
Trace
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Ru(bpy)3Cl2
Ir(ppy)3
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eosin-Y
rhodamine B
methylene blue
azure-B
Trace
75
55
riboflavin
Trace
30
methylene blue
methylene blue
methylene blue
methylene blue
methylene blue
methylene blue
methylene blue
methylene blue
methylene blue
methylene blue
methylene blue
methylene blue
50
Acetone
DMSO
Toluene
MeOH
EtOH
Dioxane
DMF
Trace
n.d
n.d
n.d
n.d
n.d
n.d
DCM
DCM
DCM
n.d
ICH2CF3
n.d
CF3SO2Cl
n.d
aReaction conditions:1a (1 mmol), methylene blue (1 mol%), PIDA (2 mmol), NaSO2CF3 (2 mmol), DCM (1
mL), 60 W CFL blub, rt, 24 h. bIsolated yield of chromatographically pure products. n.d = not detected.
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In the initial experiments, we have chosen 2-phenyl-2H-indazole as the model substrate,
Langlois’ reagent as radical CF3 source and phenyliodine(III) diacetate (PIDA) as an oxidant with 2
mol% rose bengal as a photocatalyst in MeCN and irradiated with 60 W Compact Fluorescent Bulb
(CFL) at room temperature for 24 h. Delightfully, we observed C3-trifluoromethylated product 2a with
60% yield (Table 1, entry 1). Then, the effect of other oxidants such as K2S2O8, TBHP, IBA-OAc, and
PhIO was examined (table 1, entry 2-5). Unfortunately, our attempts went in vain. To improve the
reaction efficiency in terms of yield, we have tested the various photocatalysts. Among all, methylene
blue (Table 1, entry 12) was found to be effective photocatalyst and provided the desired product 2a
with 75% yield. Among the solvents screened (table 1, entry 15-23), DCM was found to be the most
efficient solvent for this strategy. To improve the yield, a variety of CF3 sources were examined, but
without much success (table 1, entry 24-26).
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Table 2. Substrate scope for the C3-trifluoromethylation of 2H-indazole a,b
CF3
H
methylene blue
NaSO2CF3, PIDA
R1
N
R1
N
CFL 60W, DCM,
rt, 24 h
N
R2
R2
N
1
2
CF3
CF3
CF3
R
N
N
N
R
N
N
R
N
2e
2a
R = F
45%
R = H
75%
2i
R = o-CH3
45%
2f
2b
2c
R = Cl
R = Br
R = I
53%
62%
68%
R = 6-Cl
R = 6-Br
35%
37%
2j
R = o-OMe
R = m-CH3
R = m-OMe
R = p-CH3
R = p-OMe
42%
64%
70%
83%
83%
40%
2g
2h
2k
2l
2d
R = 5-Br
43%
2m
2n
2o
CF3
N
CF3
Br
R = m-(CO)CH3
R = o, m, p-OCH3
N
N
2p
80%
N
H3C
R
2q
(42%)
2r
R = H
55%
45%
2s
R = CH3
aReaction Conditions: 1a (1 mmol), methylene blue (1 mol%), PIDA (2 mmol), NaSO2CF3 (2 mmol), DCM (1
mL), 60 W CFL blub, rt, 24 h. bIsolated yield of chromatographically pure products.
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With the established optimized reaction conditions (table 1, entry 12), we have examined the
scope of this protocol with various substitutions on 2H-indazoles (table 2). Initially, we checked the
halogen substitution on 2H-indazole (2b-h). The presence of halogen at C5 and C6-positions of 2H-
indazoles (2b-d) gave poor yields. The halogen substituent at para position of the amine partner of 2H-
indazoles (2e-h) gave 45% to 68% yields. Likewise, the amine partner of 2H-indazoles bearing electron-
donating groups (-Me, -OMe) resulted in the products with very good yields (2i-n & 2p). This might
be due to the increased electron density at C3-position of 2H-indazole. This observation was similar to
our earlier report.27a
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However, the electron donating groups (-Me, -OMe) at ortho position (2i, 2j) gave moderate yields;
this is due to the steric hindrance of the ortho substitution. We observed poor yield, while the electron-
withdrawing group substituted on 2H-indazole (2o), because the electron density might be reduced at
C3-position on 2H-indazole. In the case of benzylamine partner, the C3-H trifluoromethylated indazoles
(2r, 2s) were obtained in low yield.
Scheme 2. Gram-scale synthesis of 2-phenyl-3-(trifluoromethyl)-2H-indazole 2a
H
CF3
N
methylene blue (1 mol%)
NaSO2CF3 (2 equiv.)
N
N
N
PIDA (2 equiv.)
1a
CFL 60 W, DCM, rt, 24 h
2a
1 g, 5.15mmol
0.932 g, 69 %
Due to the presence of 2H-indazole skeleton in various biologically relevant compounds, we have also
evaluated the scalability of our protocol. Consequently, when we performed the reaction on 1g scale, it
produced the C3-trifluoromethylation of 2H-indazole 2a with 69% yield (Scheme 2).
Scheme 3. Control Experiments
CF3
N
H
Standard conditions
N
O
N
N
1a
radical scanvenger
( 2.0 equiv)
N
CF3
2a
TEMPO-CF3
TEMPO = 0%
BHT
BQ
= 0%
= Trace
19F NMR = -78.21 ppm
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To investigate the reaction mechanism, we performed few control experiments as shown in
scheme 3. We observed that 2-phenyl-2H-indazole 1a failed to produce the corresponding
trifluoromethylation product 2a in the presence of radical scavengers such as TEMPO, BHT and BQ.
Also, we observed the intermediate C and TEMPO-CF3 adduct in 19F NMR. These results indicate that
the reaction mechanism proceeded through the radical pathway as depicted in scheme 4. Moreover, we
have performed NMR experiments to confirm intermediates, however we did not observe the peaks
corresponding to any hypervalent iodine complexes other than iodobenzene peaks in NMR spectra. In
addition, we measured the redox potentials for the 2H-indazole 1a (Ered = −0.71 V vs Ag/AgCl),
Langlois’ reagent (Ered = −1.39 V vs Ag/AgCl), photocatalyst (PC) (Ered = −1.74 V vs Ag/AgCl), using
cyclic voltammetry (see SI) and reduction potential for excited state photocatalyst (PC*) (Ered = 1.60 V
vs Ag/AgCl).29 The reduction potentials of 2H-indazole and excited state photocatalyst (PC*) clearly
signifies that 2H-indazole 1a has the potential to transfer a single electron to excited state photocatalyst
(PC*), thus supporting the proposed mechanism.
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Based on the control experiment results and the previous literature reports,27 a plausible reaction
mechanism of the present trifluoromethylation of 2-phenyl-2H-indazole is depicted in scheme 4.
Initially, the CF3 radical species would be generated by the reaction of NaSO2CF3 (B) with PIDA (A)
via intermediate C. Meanwhile, the photocatalyst (PC) converted to its excited state PC* upon the
absorption of photons from visible light. The PC* produce the indazole radical cation D from the
oxidation of indazole along with the generation of photocatalytic radical anion PC∙− through single-
electron-transfer (SET) process. After that, the photocatalyst radical anion (PC∙−) is oxidized to PC by
reducing acetate radical to acetate anion. Then the generated CF3 radical would attack intermediate D
to form intermediate E which on deprotonation would result in trifluoromethylation product 2a.
Scheme 4. Plausible reaction mechanism
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19F NMR= -88.88 ppm
CH3
N
CH3
S
N
PhI(OAc)2
OSOCF3
H3C
CH3
Ered = -1.39 V vs Ag/AgCl
A
B
Cl
N
PC = Methylene Blue dye
OAc
9
Ered = -1.74 V vs Ag/AgCl
OAc
19F NMR= -77.99 ppm
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I
Ph
SO2CF3
C
PhI(OAc)
OAc
F
CF3OSO
PhI
E
SO2
CF3
H
CF3
N
N
N
N
N
N
E
Ered = -0.71 V vs Ag/AgCl
D
OAc
PC
1a
PC
OAc
HOAc
CF3
PC
excited state PC*
Ered = 1.60 V vs Ag/AgCl
OAc
N
N
19F NMR= -54.45 ppm
2a
Conclusions
We have successfully demonstrated a novel photoredox catalyzed regioselective C3-H
trifluoromethylation of 2H-indazoles. This protocol offers the transition metal-free photoredox
catalyzed C3-H trifluoromethylation of 2H-indazole. This method utilizes an inexpensive and benchtop-
stable Langlois’ reagent under mild reaction conditions. Further the developed protocol for
regioselective trifluoromethylation of 2H-indazole would be great significance in pharmaceutical
chemistry and material sciences.
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Experimental Section
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General Considerations
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1
IR spectra were recorded on an FTIR spectrophotometer. H NMR spectra were recorded on
400 MHz spectrometers at 295 K in CDCl3; chemical shifts (δ ppm) and coupling constants (Hz) are
reported in standard fashion concerning either internal standard tetramethylsilane (TMS) (δH = 0.00
ppm) or CHCl3 (δH = 7.25 ppm). 13C NMR spectra were recorded on 100 MHz spectrometers at RT in
CDCl3; chemical shifts (δ ppm) are reported relative to CHCl3 [δC = 77.00 ppm (central line of the
triplet)]. In the 1HNMR, the following abbreviations were used throughout: s = singlet, d = doublet, t
= triplet, q = quartet, qui = quintet, m = multiplet and br s. = broad singlet. The assignment of signals
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was confirmed by H, 13C and DEPT spectra. High-resolution mass spectra (HR-MS) were recorded
using a Q-TOF multimode source. Melting points were determined on an electrothermal melting point
apparatus and are uncorrected. All dry solvents were used, toluene was dried over sodium metal and
DMSO, CH3CN and DMF were dried over calcium hydride and which are commercially available.
All small scale dry reactions were carried out using a standard syringe-septum technique.
Reactions were monitored by TLC on silica gel using a combination of petroleum ether and ethyl acetate
as eluents. Reactions were generally run under argon, nitrogen and oxygen atmosphere wherever
necessary. Solvents were distilled before use; petroleum ether with a boiling range of 40 to 60 ˚C was
used. Acme’s silica gel (60–120 mesh) was used for column chromatography (approximately 20g per
one gram of crude material). All 2-azidobenzaldehydes (A-B and C) except D have been synthesized
by using literature known procedures. 30,27c
General procedure (GP-I) for the synthesis of 2-phenyl-2H-indazole:27f
Azidobenzaldehyde 1 (1 mmol), aniline 2 (1 mmol) were taken in a 10 mL oven dried schlenck
tube and it was closed with stopcock with argon balloon and placed in an external heating oil bath at
120 ˚C for 1-3 hrs (oil bath temperature). After completion of the starting material, the mixture was
cooled to room temperature and was purified on a silica gel column chromatography
(hexane/ethylacetate 90:10) which furnished the respective products 1a-s.
General procedure (GP-II) for the synthesis of 2-phenyl-3-(trifluoromethyl)-2H-indazole:
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In an oven-dried reaction vessel equipped charged with 2-phenyl-2H-indazole (1 mmol), PIDA
(2 mmol), sodium triflate (2 mmol) were added and followed by addition of DCM (1 mL). The resulting
reaction mixture was irradiated using a 60 W CFL bulb. The progress of the reaction was monitored by
TLC until the reaction was completed. The reaction mixture was quenched by addition of aq. NH4Cl
solution and extracted with ethyl acetate (3  10 mL). The organic layer was dried (Na2SO4) and
concentrated in a vacuum. Purification of the residue on a silica gel column chromatography using
petroleum ether/ethyl acetate as (petroleum ether/ethylacetate 97:3 to 95:5) eluent furnished the product
trifluoromethylated indazoles 2a-s.
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Characterization Data of the Products
2-phenyl-3-(trifluoromethyl)-2H-indazole (2a) Dark yellow Solid (50 mg, 75%), mp 40-42
℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3736, 3673, 3613, 3565, 3032, 2968, 2381, 1734, 1700,
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1650, 1556, 1540, 1521, 1508, 1458, 1420, 1218, 1120, 940, 757, 667, 631; H NMR (CDCl3, 400
MHz): δH = 7.79 - 7.87 (m, 2H), 7.52 - 7.63 (m, 5H), 7.39 - 7.45 (m, 1H), 7.28 - 7.34 (m, 1H); 13C{1H}
NMR (CDCl3, 100 MHz): 148.2, 139.6, 130.0, 29.1, 127.3, 126.1, 125.1, 123.5 (q, JC-F = 40.0 Hz),
121.3 (q, JC-F = 269.0 Hz), 119.4, 118.4; 19F NMR (CDCl3, 376 MHz): −54.5; HR-MS (ESI-TOF) m/z:
[M+H]+ calcd for [C14H10F3N2]+ = 263.0791; found: 263.0794.
6-chloro-2-phenyl-3-(trifluoromethyl)-2H-indazole (2b): Dark orange Solid (29 mg, 35%),
mp 44-46 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3673, 3613, 3565, 3525, 3068, 2926, 2854, 2355,
1695, 1634, 1596, 1549, 1502, 1470, 1439, 1314, 1290, 1222, 1178, 1126, 1104, 999, 768, 691, 621,
544; 1H NMR (CDCl3, 400 MHz): δH = 7.73 (d, 1H, J = 8.8 Hz), 7.56 - 7.41 (m, 5H), 7.34 (s, 1H), 6.95
- 6.87 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 148.4, 139.6, 139.3, 135.5, 129.8 (q, JC-F = 36.0
Hz), 127.7, 126.0, 121.4 (q, JC-F = 252.0 Hz), 119.4, 119.3, 105.7; 19F NMR (CDCl3, 376 MHz): −54.7;
HR-MS (ESI-TOF) m/z: [M+H]+ calcd for [C14H9ClF3N2]+ = 297.0401; found: 297.0408.
6-bromo-2-phenyl-3-(trifluoromethyl)-2H-indazole (2c): Yellow Solid (27 mg, 37%), mp
42-44 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 2116, 2032, 1596, 1540, 1502, 1462, 1432, 1305,
1220, 1179, 1127, 1106, 998, 934, 798, 768, 692, 571, 515; 1H NMR (CDCl3, 400 MHz): δH = 8.04 -
7.98 (m, 1H), 7.71 (dd, 1H, Ja = 1.5 and Jb= 9.8 Hz), 7.62 - 7.51 (m, 5H), 7.38 (dd, 1H, Ja = 1.7 and Jb
= 9.0 Hz); 13C{1H} NMR (CDCl3, 100 MHz): δ = 148.7, 139.2, 129.8 (q, JC-F = 42.0 Hz), 128.9, 126.0,
121.9 (q, JC-F = 268.0 Hz), 120.7, 120.0, 119.2; 19F NMR (CDCl3, 376 MHz): −54.7; HR-MS (ESI-
TOF) m/z: [M+H]+ calcd for [C14H9BrF3N2]+ = 340.9896; found: 340.9914.
5-bromo-2-phenyl-3-(trifluoromethyl)-2H-indazole (2d): Dark yellow Solid (31 mg, 43%),
mp 52-54 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3648, 3588, 3547, 3070, 2924, 2321, 1735, 1596,
1502, 1420, 1271, 1216, 1169, 1124, 1107, 1043, 996, 861, 804, 768, 692, 634, 596; 1H NMR (CDCl3,
400 MHz) δH = 8.01 (s, 1H), 7.70 (d, 1H, J = 9.3 Hz), 7.62 - 7.50 (m, 4H), 7.50 - 7.42 (m, 2H); 13C{1H}
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NMR (CDCl3, 100 MHz): δ = 146.6, 139.3, 137.9, 132.5, 129.8 (q, JC-F = 36.0 Hz), 124.6, 123.0, 122.6,
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121.9 (q, JC-F = 248.0 Hz), 120.1, 118.6, 116.5, 112.7; F NMR (CDCl3, 376 MHz): −54.6; HR-MS
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(ESI-TOF) m/z: [M+H]+ calcd for [C14H9BrF3N2]+ = 340.9896; found: 340.9900.
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2-(4-fluorophenyl)-3-(trifluoromethyl)-2H-indazole (2e): Yellow Solid (50 mg, 45%), mp
52-54 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3689, 3620, 3568, 3036, 2938, 2321, 1717, 1540,
1502, 1454, 1252, 1216, 1156, 1118, 1107, 1032, 987, 861, 767, 659, 631; 1H NMR (CDCl3, 400 MHz):
δH = 7.86 - 7.75 (m, 2H), 7.62 - 7.53 (m, 2H), 7.45 - 7.39 (m, 1H), 7.31 (dd, 1H, Ja = 6.8 and Jb = 8.3
Hz,), 7.26 - 7.21 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 164.5 (d, JC-F = 249.0 Hz), 149.7,
148.2, 135.6 (d, JC-F = 2.0 Hz), 128.1 (d, JC-F = 9.0 Hz), 127.4, 125.5, 123.6 (q, JC-F = 40.0 Hz), 121.5,
121.0 (q, JC-F = 268.0 Hz), 119.4, 118.4, 116.5 (d, JC-F = 24.0 Hz); 19F NMR (CDCl3, 376 MHz): −54.5,
-110.2; HR-MS (ESI-TOF) m/z: [M+H]+ calcd for [C14H9F4N2]+ = 281.0696; found: 281.0690.
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2-(4-chlorophenyl)-3-(trifluoromethyl)-2H-indazole (2f): Dark yellow solid (35 mg, 53%),
mp 46-48 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3673, 3613, 3547, 3068, 2317, 2089, 1552, 1522,
1498, 1432, 1298, 1220, 1176, 1118, 1089, 1017, 998, 929, 832, 746, 728, 583, 537; 1H NMR (CDCl3,
400 MHz): δH = 7.76 - 7.68 (m, 2H), 7.49 - 7.39 (m, 4H), 7.34 - 7.29 (m, 1H), 7.24 - 7.17 (m, 1H);
13C{1H} NMR (CDCl3, 100 MHz): δ = 148.4, 138.0, 136.1, 129.8 (q, JC-F = 47.0 Hz), 127.5, 127.4,
125.7, 123.9, 122.3, 122.2, 121.7, 119.9 (q, JC-F = 231.0 Hz), 118.4; 19F NMR (CDCl3, 376 MHz):
−54.3; HR-MS (ESI-TOF) m/z: [M+H]+ calcd for [C14H9ClF3N2]+ = 297.0401; found: 297.0401.
2-(4-bromophenyl)-3-(trifluoromethyl)-2H-indazole (2g): Dark yellow (45 mg, 62%), mp
44-46 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3673, 3613, 3547, 3068, 1521, 1495, 1432, 1298,
1222, 1176, 1119, 1099, 1068, 1015, 996, 929, 829, 743, 711, 576, 535; 1H NMR (CDCl3, 400 MHz):
δH = 7.84 - 7.78 (m, 2H), 7.70 - 7.64 (m, 2H), 7.46 (d, 2H, J = 8.3 Hz), 7.43 - 7.37 (m, 1H), 7.31 - 7.25
(m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 148.4, 138.6, 132.8 (q, JC-F = 43.0 Hz), 127.8, 127.6,
125.3, 124.2, 123.9, 122.5 (q, JC-F = 223.0 Hz), 119.4, 118.4; 19F NMR (CDCl3, 376 MHz): −54.3; HR-
MS (ESI-TOF) m/z: [M+H]+ calcd for [C14H9BrF3N2]+ = 340.9896; found: 340.9900.
2-(4-iodophenyl)-3-(trifluoromethyl)-2H-indazole (2h): Light yellow (40 mg, 68%), mp
100-102 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3736, 3547, 3462, 3032, 2917, 2356, 2154, 1716,
1683, 1556, 1540, 1509, 1362, 1257, 999, 821, 800, 740, 521; 1H NMR (CDCl3, 400 MHz): δH = 7.94
- 7.86 (m, 2H), 7.85 - 7.78 (m, 2H), 7.45 - 7.38 (m, 1H), 7.38 - 7.28 (m, 3H); 13C{1H} NMR (CDCl3,
100 MHz): δ = 148.4, 139.3, 138.8 (q, JC-F = 43.0 Hz), 127.7, 125.3, 123.8, 122.7, 122.2, 121.7, 119.5
(q, JC-F = 224.0 Hz), 118.4, 95.8; 19F NMR (CDCl3, 376 MHz): −54.3; HR-MS (ESI-TOF) m/z: [M+H]+
calcd for [C14H9F3IN2]+ = 388.9757; found: 388.9756.
2-(o-tolyl)-3-(trifluoromethyl)-2H-indazole (2i): Dark yellow Solid (30 mg, 45%), mp 52-54
℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax =3057, 2927, 1603, 1564, 1501, 1386, 1337, 1306, 1158,
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1114, 1039, 969, 957, 863, 810, 751, 716, 663, 605, 573; 1H NMR (CDCl3, 400 MHz): δH = 7.90 - 7.78
(m, 2H), 7.51 - 7.28 (m, 6H), 2.02 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 148.1, 139.6, 138.3,
137.1, 135.8, 130.5, 127.3 (q, JC-F = 36.0 Hz), 125.0, 122.1, 119.4 (q, JC-F = 228.0 Hz), 116.0, 114.9,
16.8; 19F NMR (CDCl3, 376 MHz): −56.2; HR-MS (ESI-TOF) m/z: [M+H]+ calcd for [C15H12F3N2]+ =
277.0947; found: 277.0952.
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2-(2-methoxyphenyl)-3-(trifluoromethyl)-2H-indazole (2j): Yellow Solid (27 mg, 42%), mp
40-42 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3673, 3614, 3525, 2930, 2846, 2316, 1603, 1510,
1437, 1335, 1283, 1202, 1120, 1093, 1021, 966, 804, 753, 653, 603; 1H NMR (CDCl3, 400 MHz): δH =
8.03 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.53 (dt, Ja = 1.7 and Jb = 7.9 Hz, 1H), 7.44 (dd, Ja =
1.5 and Jb = 7.8 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.13 - 7.04 (m, 2H), 3.74 (m, 3H); 13C{1H} NMR (CDCl3,
100 MHz): δ =154.8, 143.5, 132.0, 128.7, 127.9 (q, JC-F = 42.0 Hz), 125.3, 124.8, 123.9, 123.2, 121.8
(q, JC-F = 267.0 Hz), 119.0, 112.0, 55.7; 19F NMR (CDCl3, 376 MHz): −54.3; HR-MS (ESI-TOF) m/z:
[M+H]+ calcd for [C15H12F3N2O]+ = 293.0896; found: 293.0901.
2-(m-tolyl)-3-(trifluoromethyl)-2H-indazole (2k): Brown oil (43 mg, 64%). IR (MIR-ATR,
4000–600 cm-1): ʋmax = 3648, 3565, 3525, 3065, 2924, 2322, 1611, 1592, 1495, 1476, 1431, 1302,
1221, 1202, 1169, 1118, 1016, 880, 787, 745, 693, 693, 627, 605, 521; 1H NMR (CDCl3, 400 MHz): δH
= 7.74 (d, 2H J = 8.8 Hz), 7.39 - 7.24 (m, 5H), 7.20 (dd, 1H, Ja = 7.8 and Jb = 15.2 Hz), 2.37 (s, 3H).
13C{1H} NMR (CDCl3, 100 MHz): δ = 148.2, 139.3, 130.7, 129.5, 128.8, 127.1, 126.7, 125.3, 123.1 (q,
JC-F = 44.0 Hz), 119.6 (q, JC-F = 250.0 Hz), 118.3, 21.2; 19F NMR (CDCl3, 376 MHz): −54.2; HR-MS
(ESI-TOF) m/z: [M+H]+ calcd for [C15H12F3N2]+ = 277.0947; found: 277.0960.
2-(3-methoxyphenyl)-3-(trifluoromethyl)-2H-indazole (2l): Brownish yellow Solid (53 mg,
80%), mp 74-76 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3614, 3547, 2925, 2846, 2323, 2134,
1734, 1593, 1498, 1468, 1288, 1250, 1201, 1163, 1122, 1044, 976, 885, 755, 688, 521; 1H NMR (CDCl3,
400 MHz): δH = 8.04 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 6.8 Hz, 1H), 7.45 (t, J = 8.3 Hz, 1H), 7.40 - 7.32
(m, 1H), 7.19 (d, J = 7.3 Hz, 1H), 7.15 - 7.08 (m, 2H), 3.87 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz):
δ = 160.0, 143.4, 140.0, 129.9, 125.6 (q, JC-F = 40.0 Hz), 123.7, 122.4, 122.1 (q, JC-F = 268.0 Hz), 118.5,
116.4, 112.0, 55.6; 19F NMR (CDCl3, 376 MHz): −54.7; HR-MS (ESI-TOF) m/z: [M+H]+ calcd for
[C15H12F3N2O]+ = 293.0896; found: 293.0901.
2-(p-tolyl)-3-(trifluoromethyl)-2H-indazole (2m): Yellow Solid (50 mg, 83%), mp 42-44 ℃;
IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3673, 3614, 3043, 2925, 2324,1553, 1515, 1471, 1431, 1383,
1298, 1219, 1174, 1117, 1100, 999, 930, 820, 745, 610, 547; 1H NMR (CDCl3, 400 MHz): δH = 7.86 -
7.78 (m, 2H), 7.50 - 7.42 (m, 2H), 7.42 - 7.36 (m, 1H), 7.36 - 7.25 (m, 3H), 2.48 - 2.44 (m, 3H); 13C{1H}
NMR (CDCl3, 100 MHz): δ = 148.1, 140.2, 137.2, 130.2, 128.2, 127.1, 125.9 (q, JC-F = 39.0 Hz), 123.8,
122.3, 121.5 (q, JC-F = 267.0 Hz), 119.6, 118.4, 21.3; 19F NMR (CDCl3, 376 MHz): −54.5; HR-MS
(ESI-TOF) m/z: [M+H]+ calcd for [C15H12F3N2]+ = 277.0947; found: 277.0948.
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2-(4-methoxyphenyl)-3-(trifluoromethyl)-2H-indazole (2n): Yellow Solid (53 mg, 83%), mp
74-76 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 2969, 2887, 2839, 2303, 2043, 1608, 1513, 1433,
1299, 1252, 1175, 11148, 1030, 1015, 998, 928, 834, 736, 703, 611, 557, 536; 1H NMR (CDCl3, 400
MHz): δH = 7.85 - 7.79 (m, 2H), 7.53 - 7.47 (m, 2H), 7.43 - 7.37 (m, 1H), 7.32 - 7.24 (m, 1H), 7.07 -
6.99 (m, 2H), 3.89 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 160.6, 148.0, 132.5, 127.4 (q, JC-F
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39.0 Hz), 124.9, 123.5, 122.7, 122.3, 121.4, 119.6 (q, JC-F = 244.0 Hz), 114.8, 55.6; 19F NMR (CDCl3,
376 MHz): −54.6; HR-MS (ESI-TOF) m/z: [M+H]+ calcd for [C15H12F3N2O]+ = 293.0896; found:
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1-(3-(3-(trifluoromethyl)-2H-indazol-2-yl)phenyl)ethanone (2o): Light brown Solid (25 mg,
40%), mp 74-76 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3648, 3589, 3504, 3074, 2925, 2323,
1716, 1690, 1589, 1522, 1493, 1430, 1359, 1302, 1256, 1222, 1178, 1149, 1012, 748, 691, 587, 562;
1H NMR (CDCl3, 400 MHz): δH = 8.23 - 8.12 (m, 2H), 7.88 - 7.76 (m, 3H), 7.72 - 7.64 (m, 1H), 7.47 -
7.40 (m, 1H), 7.36 - 7.29 (m, 1H), 2.66 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 196.4, 148.4,
140.0, 138.0, 130.3, 129.5, 128.2, 127.6, 126.1, 125.4, 123.6 (q, JC-F = 40.0 Hz), 120.5, 119.5 (q, JC-F
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209.0 Hz), 118.4, 26.7; 19F NMR (CDCl3, 376 MHz): −54.2; HR-MS (ESI-TOF) m/z: [M+H]+ calcd for
[C16H12F3N2O]+ = 305.0896; found: 305.0914.
3-(trifluoromethyl)-2-(3,4,5-trimethoxyphenyl)-2H-indazole (2p): Yellow Solid (48 mg,
78%), mp 126-128 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3673, 3648, 3565, 2971, 2881, 2835,
1596, 1556, 1505, 1462, 1415, 1307, 1265, 1233, 1170, 1125, 1106, 1016, 945, 897, 837, 794, 733,
702, 613; 1H NMR (CDCl3, 400 MHz): δH = 7.87 - 7.78 (m, 2H), 7.46 - 7.38 (m, 1H), 7.31 (dd, 1H, Ja
= 6.8 and Jb = 8.3 Hz,), 6.83 (s, 2 H), 3.93 (s, 3H), 3.90 (s, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δH
= 153.2, 148.0, 139.3, 134.9, 127.3, 125.1 (q, JC-F = 42.0 Hz), 121.5, 119.6 (q, JC-F = 215.0 Hz), 03.8,
61.0, 56.3; 19F NMR (CDCl3, 376 MHz): −54.5; HR-MS (ESI-TOF) m/z: [M+H]+ calcd for
[C17H16F3N2O3]+ = 353.1108; found: 353.1104.
6-bromo-2-(o-tolyl)-3-(trifluoromethyl)-2H-indazole (2q): Pale yellow Solid (48 mg, 78%),
mp 82-84 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 2116, 2032, 1596, 1540, 1502, 1462, 1432, 1305,
1220, 1179, 1127, 1106, 998, 934, 798, 768, 692, 571, 515; 1H NMR (CDCl3, 400 MHz): δH = 8.00 (d,
1H, J = 1.0 Hz), 7.88 - 7.79 (m, 1H), 7.77 - 7.70 (m, 1H), 7.67 (d, 1H, J = 7.8 Hz), 7.40 - 7.27 (m, 3H),
2.63 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 158.3, 150.9, 148.8, 138.9, 129.1, 124.8 (q, JC-F
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44.0 Hz), 122.1, 121.7 (q, JC-F = 246.0 Hz), 120.9, 119.4, 115.6, 23.9; F NMR (CDCl3, 376 MHz):
−54.5; HR-MS (ESI-TOF) m/z: [M+H]+ calcd for [C15H11BrF3N2]+ = [M+H]+: 355.0052; found:
355.0063.
2-benzyl-3-(trifluoromethyl)-2H-indazole (2r): Yellow Solid (29 mg, 55%), mp 42-44 ℃; IR
(MIR-ATR, 4000–600 cm-1): ʋmax =3673, 3614, 3547, 3067, 3035, 2926, 2323, 1521, 1483, 1436,
1327, 1286, 1219, 1165, 1112, 1036, 970, 881, 746, 706, 627; 1H NMR (CDCl3, 400 MHz): δH = 7.82
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- 7.72 (m, 2H), 7.39 - 7.19 (m, 7H), 5.73 (s, 2H); 13C{1H} NMR (CDCl3, 100 MHz): δH = 147.8, 135.2,
128.9 (q, JC-F = 42.0 Hz), 127.7 (d, JC-F = 8.0 Hz), 126.7, 124.7, 123.7 (q, JC-F = 207.0 Hz), 121.2,
120.0, 119.2, 118.3, 56.3; 19F NMR (CDCl3, 376 MHz): −55.8; HR-MS (ESI-TOF) m/z: [M+H]+ calcd
for [C15H12F3N2]+ = 277.0947; found: 277.0943.
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2-(4-methylbenzyl)-3-(trifluoromethyl)-2H-indazole (2s): Brown oil (29 mg, 45%), mp 90-
92 ℃; IR (MIR-ATR, 4000–600 cm-1): ʋmax = 3673, 3648, 3613, 2925, 2858, 2359, 1717, 1969, 1622,
1539, 1511, 1475, 1433, 1385, 1337, 1305, 1201, 1160, 1123, 1015, 967, 813, 749, 689, 608; 1H NMR
(CDCl3, 400 MHz): δH = 7.73 - 7.63 (m, 2H), 7.26 (ddd, 1H, Ja = 1.2, Jb = 7.0 and Jc = 8.4 Hz), 7.20 -
7.00 (m, 5H), 5.61 (s, 2H), 2.24 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 147.8, 138.2, 132.2,
129.4 (q, JC-F = 44.0 Hz), 127.7 (q, JC-F = 9.0 Hz), 124.6, 122.6, 121.2 (q, JC-F = 266.0 Hz), 119.2,
118.3, 56.1, 21.1; 19F NMR (CDCl3, 376 MHz): −55.8; HR-MS (ESI-TOF) m/z: [M+H]+ calcd for
[C16H14F3N2]+ = 291.1104; found: 291.1110.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Cyclic Voltammetry data, Copies of NMR (PDF).
AUTHOR INFORMATION
Corresponding Author
* E-mail: sharada@iith.ac.in
*E-mail: E-mail: bhakthadoss@yahoo.com
ORCID
Duddu S. Sharada: 0000-0001-5861-4126
Manickam Bakthadoss: 0000-0003-4184-3947
Notes
The authors declare no competing financial interest
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ACKNOWLEDGMENT
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We gratefully acknowledge the Department of Science and Technology-Science and
Engineering Research Board (DST-SERB-EMR/2016/000952) New Delhi, India and Indian Institute
of Technology Hyderabad (IITH) for financial support. AVM and VNB thanks to UGC, AP thanks to
DST-SERB, New Delhi, India for the award of research fellowship. We thank Prof. Ch. Subrahmanyam
and Mr. Palyam Subramanyam, IIT Hyderabad, India, for their help in cyclic voltammetry. We would
like to thank the reviewer for his/her comments which helped us to improve our manuscript.
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