Metal-Free Trifluoromethylation of Indazoles

Article abstract of DOI:10.1021/acs.joc.8b02312

A simple and efficient tert-butyl hydroperoxide-mediated direct trifluoromethylation of indazoles using sodium trifluoromethanesulfinate has been developed under metal-free conditions. A library of trifluoromethylated products with broad functionalities has been synthesized with moderate to good yields. A radical mechanistic pathway has been proposed for the present protocol.

Full text of DOI:10.1021/acs.joc.8b02312

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Metal-Free Trifluoromethylation of Indazoles
Payel Ghosh, Susmita Mondal, and Alakananda Hajra
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 15 Oct 2018
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Metal-Free Trifluoromethylation of Indazoles
Payel Ghosh, Susmita Mondal, and Alakananda Hajra*
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Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India
Email: alakananda.hajra@visva-bharati.ac.in
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H
CF3
C(sp2)-H functionalization
TBHP
regioselective
CF3SO2Na
N R
N R
+
DMSO, 60 °C
12 h
mild reaction conditions
radical pathway
scale-up synthesis
N
N
24 examples
up to 85% yield
R = aryl, alkyl
Abstract: A simple and efficient tert-butyl hydroperoxide mediated direct trifluoromethylation
of indazoles using sodium trifluoromethanesulfinate has been developed under metal-free
conditions. A library of trifluoromethylated products with broad functionalities has been
synthesized with moderate to good yields. A radical mechanistic pathway has been proposed for
the present protocol.
Incorporation of fluorine-containing group into organic molecules has gained much
attention to the organic chemists because the presence of fluorine atom or fluorine-containing
group often changes the chemical, physical, and biological properties of parent molecules.1
Fluorinated compounds are widely applicable in pharmaceutical and agrochemical industries as
well as in material sciences.2 Among the different F-containing groups, trifluoromethyl group
becomes more interesting in organic synthesis owing to its strong electron-withdrawing power,
metabolic stability, and high lipophilicity.3 Therefore, tremendous efforts have been done for the
direct trifluoromethylation of heterocycles via C-H bond functionalization using various radical,
nucleophilic, and electrophilic trifluoromethylating agents like Togni’s reagent,4 Umemoto’s
reagent,5 Ruppert’s reagent,6 Langlois’ reagent7 etc. Among these, Langlois’ reagent is the most
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preferable as it is less expensive and easy to handle.8 In 1991, Langlois first reported
trifluoromethylation of aromatic compounds using sodium trifluoromethanesulfinate (Langlois’
reagent) as trifluoromethylating agent.8a After that several trifluoromethylation reactions have
been reported using Langlois’ reagent.9 Recently, Kumar and co-workers reported visible-light-
induced trifluoromethylation of 1,6-enynes using Langlois’ reagent.9e However, most of the
reported methods are involved the use of different metal-catalysts like Cu, Ag, Mn, Fe etc.
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Indazole, a nitrogen-containing fused heterocycle has been gained a lot importance in
medicinal chemistry as it shows a number of pharmacological and biological activities like
antitumor,10a antimicrobial,10b anti-inflammatory,10c anticancer,10d HIV-protease inhibition,10e
anti-depressant,10f anti-platelet10g etc. Indazoles are also known as efficient bioisosteres of
indoles and benzimidazoles in pharmaceutical chemistry.10 Several marketed drugs containing
this moiety are MK-4827 (anticancer agent),11a pazopanib,11b bendazac (votrient, tyrosine kinase
inhibitor),11c and gamendazole.11d It is also used as estrogen receptors12a and bacterial gyrase β-
inhibitors.12b Therefore, various approaches have been made for the synthesis of indazole
moieties.13 However, there are only few methods for the functionalization of indazoles.14 To the
best of our knowledge there is no method for the direct trifluoromethylation of indazoles.
Considering the importance of both indazole moiety and trifluoromethyl group, herein we report
a C-3 trifluoromethylation of indazoles under metal-free conditions using TBHP as an oxidant
(Scheme 1).
Scheme 1. Direct Trifluoromethylation of Indazoles
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CF3
N
TBHP (2 equiv)
N
+
CF3SO2Na
N
N
DMSO, 60 °C
12h
2a
1a
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We started our investigation taking 2-phenyl-2H-indazole (1a) as model substrate and
sodium trifluoromethanesulfinate (Langlois’ reagent) as trifluoromethylating reagent (Table 1).
Initially we performed the reaction using 1a (0.2 mmol), Langlois’ reagent (2 equiv), and 2 equiv
tert-butyl hydrogen peroxide (TBHP) in CH3CN solvent at 60 °C. To our delight 2-phenyl-3-
(trifluoromethyl)-2H-indazole (2a) was obtained in 56% yield after 12 h. No further
improvement of the yield was obtained after 24 h. Inspired by this initial result we carried out the
reaction in different conditions to optimize the reaction conditions. At first we screened the
effect of solvents such as 1,2-DCE, THF, 1,4-dioxane, toluene, ethanol, DCB, DMF, DMSO, and
DMAc (Table 1, entries 2-10). Better result was achieved in DMSO solvent affording the desired
product in 81% yield (Table 1, entry 9). Next, we carried out the reaction using different
oxidants like di-tert-butyl peroxide (DTBP), tert-butyl peroxybenzoate (TBPB), dicumyl
peroxide (DCP), and K2S2O8 (Table 1, entries 11-14). But these were not suitable like TBHP.
Moreover, the reaction was carried out under O2 atmosphere without TBHP but the desired
product was not formed (Table 1, entry 15). The yield was diminished with decreasing the
loading of both TBHP and CF3SO2Na (Table 1, entry 16). No significant improvement of the
yield was obtained at 80 °C but lowering of the yield was observed at room temperature (Table
1, entry 17). Finally, the optimized reaction condition was achieved using 2 equiv CF3SO2Na and
2 equiv TBHP in DMSO at 60 °C for 12 h (Table 1, entry 9).
Table 1. Optimization of the Reaction Conditionsa
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CF3
N
N
2a
Oxidant
N
+
CF3SO2Na
N
Solvent, 60 °C
12h
1a
9
entry
oxidant (equiv)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP(2)
TBHP (2)
TBHP (2)
DTBP (2)
TBPB (2)
DCP (2)
solvent
CH3CN
1,2- DCE
THF
Yield (%)
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3
trace
4
1,4-dioxane
toluene
EtOH
no reaction
trace
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trace
7
DCB
no reaction
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8
DMF
9
DMSO
DMAc
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
81
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trace
61
trace
K2S2O8 (2)
O2
trace
no reaction
51, 45b
82c, 63d
TBHP (1)
TBHP (2)
aAll reactions were carried out with 1a (0.2 mmol), CF3SO2Na (2 equiv), oxidant (2 equiv), and
solvent (2 mL) for 12 h at 60 °C. b1 equiv CF3SO2Na used. cAt 80 °C. dAt room temperature.
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With this optimized reaction conditions we explored the substrates scope of the present
methodology as shown in Scheme 2. We first examined the effect of the different N-2 substituent
of 2H-indazoles. 2-Phenyl-2H-indazoles containing electron-donating substituents like -Me and -
OMe at the different positions of phenyl ring efficiently produced the trifluoromethylated
products in good yields (2b-2e). Halogen substituted 2-phenyl-2H-indazoles were also
underwent the reaction very smoothly (2f-2j). Highly electron-withdrawing group (4-CN)
substituted 2H-indazole was also well tolerable for such transformation (2k). Ethyl 4-(2H-
indazol-2-yl)benzoate (1l) effectively reacted with CF3SO2Na to provide the desired product (2l)
in good yield. In addition, 2H-indazoles with alkyl (n-butyl and tert-butyl) and cyclohexyl
substitution at N-2 position also afforded the trifluoromethylated products in moderate to good
yields (2m-2o). Ortho substituted 2-phenyl-2H-indazoles and 1H-indazole (5a) were unable to
produce the desired products. p-Methoxy benzyl substituted indazole produced an inseparable
mixture of products under the optimized reaction conditions. The gram-scale reaction of the
present method was carried out under the normal laboratory setup taking 2-phenyl-2H-indazole
(1a, 5 mmol) under the optimized reaction conditions. To our delight, the trifluoromethylated
product (2a) was obtained without a significant decrease in yield (78%) which clearly
demonstrates the practical applicability of our proposed method.
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Scheme 2. Substrates Scope of the Present Methoda
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CF3
N
TBHP (2 equiv)
N
R
+
CF3SO2Na
(2 equiv)
R
N
DMSO, 60 °C
12 h
N
1
2
7
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9
CF3
N
CF3
CF3
N
Me
N
N
2b,
Me
N
N
b
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85%
2c
, 82%
2a
, 81%, (78%)
CF3
CF3
OMe
CF3
N
N
OMe
Cl
N
N
F
N
N
2d
, 84%
2e
, 79%
2f
, 77%
CF3
CF3
CF3
Cl
Cl
N
N
N
N
F
N
N
2h
, 78%
2g
, 80%
2i
, 75%
CF3
CF3
CF3
N
CN
N
Br
N
N
CO2Et
N
N
2j
, 76%
CF3
2k
, 71%
2l
, 79%
CF3
CF3
N
N
N
N
N
N
N
N
5a
Ph
2m
, 65%
2n
2o, 73%
, 61%
aReaction conditions: 1 (0.2 mmol), CF3SO2Na (2 equiv), TBHP (2 equiv), and DMSO (2 mL)
for 12 h at 60 °C. bOn a 5 mmol scale.
Next, we checked the effect of different substituents at the arene part of 2H-indazoles
(Scheme 3). 5-Methoxy-substituted 2H-indazole gave the desired trifluoromethylated products in
good yields (4a). The single crystal X-ray analysis of 4a was performed to confirm the structure
of the 5-methoxy-2-(4-methoxyphenyl)-3-(trifluoromethyl)-2H-indazole.15 2H-indazoles bearing
halogens like -F and -Cl on C-5 position of arene successfully reacted with Langlois’ reagent to
produce the desired products (4b-4e) in moderate to good yields. 2-(p-Tolyl)-2H-
[1,3]dioxolo[4,5-f]indazole (3f) was also suitable for this trifluoromethylation reaction.
Cyclohexyl and n-butyl substituted 2H-indazoles reacted very well (4g and 4h). It is notable that
1H-pyrazolo[3,4-d]pyrimidin-4-amine produced the trifluoromethylated product in good yield
(4i).
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Scheme 3. Substrates Scopea
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6
7
8
R2
CF3
N
R2
TBHP (2 equiv)
R1
R1
N
CF3SO2Na
+
N
DMSO, 60 °C
N
(2 equiv)
12 h
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CF3
CF3
MeO
F
N
N
OMe
N
Me
N
4a,
81%
4b
, 78%
4a
CF3
CF3
CF3
F
Cl
O
N
R2
N
OMe
N
Me
N
N
O
N
4c
R2 = H, 4d, 80%
, 77%
4f
, 69%
2
4e
R = Me, , 81%
NH2
CF3
CF3
CF3
N
MeO
Cl
N
N
N
N
N
N
N
H
4g
, 78%
4h
, 71%
4i
, 77%
aReaction conditions: 3 (0.2 mmol), CF3SO2Na (2 equiv), TBHP (2 equiv), and DMSO (2 mL)
for 12 h at 60 °C.
To get the mechanistic pathway of the proposed reaction, few control experiments were
carried out (Scheme 4). The reaction did not proceed in the presence of radical scavengers like
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 2,6-di-tert-butyl-4-methyl phenol (BHT), and p-
benzoquinone (BQ). These observations suggest that the reaction probably proceeds through a
radical pathway.
Scheme 4. Control Experiments
CF3
standard conditions
N Ph
+
CF3SO2Na
N Ph
N
radical scavenger
(3.0 equiv)
N
1a
2a
(1) TEMPO: , 0%
2a
(2) BHT: , trace
2a
(3) BQ: , trace
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Based on the control experiments and previous literature reports,8d a plausible
mechanistic pathway of the trifluoromethylation reaction has been described in Scheme 5. Initial
step involves the formation of CF3-radical from sodium trifluoromethanesulfinate in presence of
TBHP. Next, CF3 radical reacts at C-3 position of 2H-indazole (1a) to form the radical
intermediate A. Then, tert-butoxy radical abstracts a hydrogen radical from C-3 position of
intermediate A to produce the desired product (2a).
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Scheme 5. Plausible Mechanistic Pathway
O OH
O
+
+ CF3SO2Na
SO2
+
CF3
NaOH
CF3
N
N
+
CF3
N
1a
N
A
O
CF3
N
HO
N
2a
In conclusion, we have developed a straightforward method for the regioselective direct
trifluoromethylation of 2H-indazoles using inexpensive Langlois’ reagent as a source of
trifluoromethyl group under metal-free conditions. Mild reaction conditions, high functional
group tolerance, regioselectivity, and scalability are the important features of our present
protocol. To the best of our knowledge this is the first report for the direct trifluoromethylation
of 2H-indazoles. We believe this strategy will gain much importance in organic synthesis,
medicinal chemistry, and as well as in material sciences.
Experimental Section:
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General Information: All reagents were purchased from commercial sources and used without
further purification. 1H NMR spectra were determined on 400 MHz spectrometer as solutions in
CDCl3 and DMSO-d6. Chemical shifts were expressed in parts per million (δ) and the signals
were reported as s (singlet), d (doublet), dd (doublet of doublet), t (triplet), m (multiplet), q
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(quartet), and coupling constants (J) were given in Hz. C{1H} NMR spectra were recorded at
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100 MHz in CDCl3 and DMSO-d6 solution. F NMR spectra were recorded at 376 MHz in
CDCl3 and DMSO-d6 solution. Chemical shifts as internal standard were referenced to CDCl3 (δ
= 7.26 for 1H and δ = 77.16 for 13C{1H} NMR) and DMSO-d6 (δ = 2.50 for 1H and δ = 39.52 for
13C{1H} NMR) as internal standard. TLC was done on silica gel coated glass slide. All solvents
were dried and distilled before use. Commercially available solvents were freshly distilled before
the reaction. All reactions involving moisture sensitive reactants were executed using oven dried
glassware. All the 2H-indazoles were prepared by reported method.13b Commercially available
TBHP (70 wt % in water) was used as an oxidant.
Typical experimental procedure for the compound 2-phenyl-3-(trifluoromethyl)-2H-
indazole (2a):
A mixture of 2-phenyl-2H-indazole (1a) (0.2 mmol, 38.8 mg), CF3SO2Na (2.0 equiv, 0.4 mmol,
62 mg), and TBHP (70 wt % in water, 2.0 equiv, 0.4 mmol, 0.055 mL) was taken in a reaction
tube. Then DMSO (2.0 mL) was added to it and stirred at 60°C for 12 h. After completion of the
reaction (TLC), the reaction mixture was quenched with water (2.0 mL). The reaction mixture
was then extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4 and
concentrated under reduced pressure to get the crude residue which was purified by column
chromatography on silica gel (60-120 mesh) using petroleum ether:ethyl acetate = 98:02 as an
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eluent to afford the pure product 2-phenyl-3-(trifluoromethyl)-2H-indazole (2a) (42.4 mg, 81%)
as a yellow liquid.
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2-Phenyl-3-(trifluromethyl)-2H-indazole (2a): Yellow liquid (81%, 42.4 mg); Rf = 0.50 (PE:EA
1
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= 98:02); H NMR (400 MHz, CDCl3): δ 7.85-7.82 (m, 2H), 7.60-7.53 (m, 5H), 7.43-7.39 (m,
1H), 7.32-7.28 (m, 1H), 13C{1H} NMR (100 MHz, CDCl3): δ 148.3, 139.7, 130.1, 129.2, 127.3,
126.2, 125.2, 123.8 (q, JC-F = 40.0 Hz), 121.7, 121.0 (q, JC-F = 269.0 Hz), 119.5, 118.5; 19F NMR
(376 MHz, CDCl3) δ -54.5; Anal. Calcd for C14H9F3N2: C, 64.12%; H, 3.46; N, 10.68; Found: C,
64.31; H, 3.40; N, 10.79%.
2-(p-Tolyl)-3-(trifluoromethyl)-2H-indazole (2b): White soild (85%, 46.9 mg); Rf = 0.55
(PE:EA = 98:02); M.p. 83-84 °C; 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 8.8 Hz, 2H), 7.47
(d, J = 8.4 Hz, 2H), 7.42-7.38 (m, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.31-7.27(m, 1H), 2.46 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 148.1, 140.2, 137.2, 129.6, 127.1, 125.8, 124.9, 123.5 (q,
19
JC-F = 39.0 Hz), 121.5, 121.0 (q, JC-F = 269.0 Hz), 119.3, 118.4, 21.2; F NMR (376 MHz,
CDCl3) δ -54.5; HRMS (ESI-TOF) m/z: [M + H]+Calcd for C15H12F3N2: 277.0947; found:
277.0962.
2-(m-Tolyl)-3-(trifluoromethyl)-2H-indazole (2c): Yellow liquid (82%, 45.2 mg); Rf = 0.45
1
(PE:EA = 97:03); H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 9.2 Hz, 2H), 7.44-7.35 (m, 5H),
7.31-7.27 (m, 1H), 2.45 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 148.2, 139.6, 139.4, 130.8,
128.9, 127.3, 126.8, 125.1, 123.7 (q, JC-F = 41.0 Hz), 123.2, 121.6, 121.0 (q, JC-F = 267.0 Hz),
119.5, 118.5, 21.3; 19F NMR (376 MHz, CDCl3) δ -54.5; Anal. Calcd for C15H11F3N2: C, 65.22;
H, 4.01; N, 10.14%; Found: C, 65.00; H, 4.05; N, 10.07%.
2-(4-Methoxyphenyl)-3-(trifluoromethyl)-2H-indazole (2d):13g Yellow gummy mass (84%, 49.0
mg); Rf = 0.45 (PE:EA = 98:02); 1H NMR (400 MHz, CDCl3): δ 7.83-7.80 (m, 2H), 7.50 (d, J =
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8.8 Hz, 2H), 7.42-7.38 (m, 1H), 7.30-7.27 (m, 1H), 7.05-7.01 (m, 2H), 3.88 (s, 3H); C{1H}
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121.4, 121.1 (q, JC-F = 268.0 Hz), 119.3, 118.3, 114.1, 55.6; F NMR (376 MHz, CDCl3) δ -
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54.6.
2-(3-Methoxyphenyl)-3-(trifluoromethyl)-2H-indazole (2e): Yellow liquid (79%, 46.1 mg); Rf =
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0.40 (PE:EA = 97:03); H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 9.2 Hz, 2H), 7.45-7.39 (m,
2H), 7.31-7.27 (m, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.14-7.08 (m, 2H), 3.86 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 160.0, 148.2, 140.6, 129.9, 127.3, 125.1, 123.7 (q, JC-F = 41.0 Hz), 121.6,
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121.04 (q, JC-F = 269.0 Hz), 121.03, 119.5, 118.5, 118.4, 116.2, 55.6; F NMR (376 MHz,
CDCl3) δ -54.5; Anal. Calcd for C15H11F3N2O: C, 61.65; H, 3.79; N, 9.59%; Found: C, 61.80; H,
3.73; N, 9.67%.
2-(4-Fluorophenyl)-3-(trifluoromethyl)-2H-indazole (2f): White solid (77%, 43.1 mg); Rf =
1
0.50 (PE:EA = 98:02); M.p. 68-69 °C; H NMR (400 MHz, CDCl3): δ 7.83-7.80 (m, 2H), 7.58-
7.55 (m, 2H), 7.44-7.40 (m, 1H), 7.32-7.29 (m, 1H), 7.26-7.20 (m, 2H); C{1H} NMR (100
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MHz, CDCl3): δ 163.4 (d, JC-F = 249.0 Hz), 148.3, 135.7 (d, JC-F = 2.0 Hz), 128.2 (d, JC-F = 9.0
Hz), 127.5, 125.3, 123.9 (q, JC-F = 40.0 Hz), 121.6, 121.0 (q, JC-F = 268.0 Hz), 119.5, 118.5,
116.3 (d, JC-F = 24.0 Hz); 19F NMR (376 MHz, CDCl3) δ -54.5, -110.2; Anal. Calcd for
C14H8F4N2: C, 60.01; H, 2.88; N, 10.00%; Found: C, 60.17; H, 2.92; N, 9.91%.
2-(4-Chlorophenyl)-3-(trifluoromethyl)-2H-indazole (2g): Yellow solid (80%, 47.3 mg); Rf =
1
0.55 (PE:EA = 99:01); M.p. 81-82 °C; H NMR (400 MHz, CDCl3): δ 7.83-7.80 (m, 2H), 7.56-
7.51 (m, 4H), 7.44-7.40 (m, 1H), 7.33-7.29 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 148.5,
138.1, 136.3, 132.4, 129.5, 127.6, 127.5, 125.4, 122.0 (q, JC-F = 53.0 Hz), 121.0 (q, JC-F = 271.0
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Hz), 119.5, 118.5; 19F NMR (376 MHz, CDCl3) δ -54.4; Anal. Calcd for C14H8ClF3N2: C, 56.68;
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2-(3-Chlorophenyl)-3-(trifluoromethyl)-2H-indazole (2h): Yellow liquid (78%, 46.1 mg); Rf =
0.45 (PE:EA = 98:02); 1H NMR (400 MHz, CDCl3): δ 7.83-7.80 (m, 2H), 7.63 (s, 1H), 7.56-7.48
(m, 3H), 7.44-7.40 (m, 1H), 7.31 (t, J = 8.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 148.5,
140.6, 135.0. 130.3, 130.1, 127.7, 126.7, 125.5, 124.48 (q, JC-F = 32.0 Hz), 124.43, 121.8, 120.9
(q, JC-F = 268.0 Hz), 119.5, 118.5; 19F NMR (376 MHz, CDCl3) δ -54.4; Anal. Calcd for
C14H8ClF3N2: C, 56.68; H, 2.72; N, 9.44%; Found: C, 56.83; H, 2.67; N, 9.54%.
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2-(4-Chloro-3-fluorophenyl)-3-(trifluoromethyl)-2H-indazole (2i): White solid (75%, 47.1 mg);
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Rf = 0.55 (PE:EA = 98:02); M.p. 84-85 °C; H NMR (400 MHz, CDCl3): δ 7.82-7.79 (m, 2H),
7.70 (dd, J = 6.4 Hz, 2.4 Hz, 1H), 7.51-7.47 (m, 1H), 7.44-7.40 (m, 1H), 7.33-7.29 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 159.0 (d, JC-F = 252.0 Hz), 148.5, 136.0 (d, JC-F = 3.0 Hz),
128.9, 127.8, 126.1 (d, JC-F = 8.0 Hz), 125.6, 132.9 (q, JC-F = 40.0 Hz), 121.8 (d, JC-F = 26.0 Hz),
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120.8 (q, JC-F = 271.0 Hz), 119.4, 118.5, 117.1, 116.9; F NMR (376 MHz, CDCl3) δ -54.4, -
112.1; Anal. Calcd for C14H7ClF4N2: C, 53.44; H, 2.24; N, 8.90%; Found: C, 53.21; H, 2.30; N,
8.83%.
2-(4-Bromophenyl)-3-(trifluoromethyl)-2H-indazole (2j):13g Yellow liquid (76%, 51.8 mg); Rf =
1
0.45 (PE:EA = 98:02); H NMR (400 MHz, CDCl3): δ 7.90-7.80 (m, 2H), 7.70-7.66 (m, 2H),
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7.47 (d, J = 8.4 Hz, 2H), 7.43-7.39 (m, 1H), 7.34-7.28 (m, 1H); C{1H} NMR (100 MHz,
CDCl3): δ 148.5, 138.7, 138.4, 132.4, 127.7, 127.6, 125.4, 123.7 (q, JC-F = 40.0 Hz), 124.3, 120.9
(q, JC-F = 268.0 Hz), 119.5, 118.5; 19F NMR (376 MHz, CDCl3) δ -54.3.
4-(3-(Trifluoromethyl)-2H-indazol-2-yl)benzonitrile (2k): Yellow gummy mass (71%, 40.7
1
mg); Rf = 0.50 (PE:EA = 97:03); H NMR (400 MHz, CDCl3): δ 7.88-7.85 (m, 2H), 7.83-7.80
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(m, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.46-7.42 (m, 1H), 7.35-7.31 (m, 1H); C{1H} NMR (100
MHz, CDCl3): δ 148.9, 143.0, 133.2, 128.9, 128.1, 126.9, 125.9, 123.8 (q, JC-F = 40.0 Hz), 122.1,
120.8 (q, JC-F = 268.0 Hz), 118.6, 117.7, 114.1; 19F NMR (376 MHz, CDCl3) δ -54.0; Anal.Calcd
for C15H8F3N3: C, 62.72; H, 2.81; N, 14.63%; Found: C, 62.87; H, 2.85; N, 14.56%.
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Ethyl 4-(3-(trifluoromethyl)-2H-indazol-2-yl)benzoate (2l): Yellow liquid (79%, 52.7 mg); Rf =
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0.45 (PE:EA = 98:02); H NMR (400 MHz, CDCl3): δ 8.25-8.22 (m, 2H), 7.84-7.81 (m, 2H),
7.68 (d, J = 8.4 Hz, 2H), 7.44-7.40 (m, 1H), 7.33-7.29 (m, 1H), 4.43 (q, J = 7.2 Hz, 2H), 1.43 (t,
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J = 7.2 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 165.5, 148.6, 143.0, 132.0, 130.6, 127.7,
126.1, 125.5, 121.8 (q, JC-F = 28.0 Hz), 121.6, 120.9 (q, JC-F = 269.0 Hz), 119.5, 118.5, 61.6,
14.4; 19F NMR (376 MHz, CDCl3) δ -54.2; Anal. Calcd for C17H13F3N2O2: C, 61.08; H, 3.92; N,
8.38%; Found: C, 61.29; H, 3.85; N, 8.49%.
2-Butyl-3-(trifluoromethyl)-2H-indazole (2m): Colourless liquid (65%, 31.4 mg); Rf = 0.45
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(PE:EA = 98:02); H NMR (400 MHz, CDCl3): δ 7.75-7.72 (m, 2H), 7.35-7.31 (m, 1H), 7.24-
7.20 (m, 1H), 4.52 (t, J = 7.6 Hz, 2H), 2.05-1.98 (m, 2H), 1.46-1.37 (m, 2H), 0.97 (t, J = 7.6 Hz,
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3H); C{1H} NMR (100 MHz, CDCl3): δ 147.6, 126.5, 124.5, 122.9 (q, JC-F = 28.0 Hz), 122.3
(q, JC-F = 265.0 Hz), 120.1, 119.2 (d, JC-F = 1.0 Hz), 118.1, 52.8, 32.8, 20.0, 13.6; 19F NMR (376
MHz, CDCl3) δ -56.3; Anal. Calcd for C12H13F3N2: C, 59.50; H, 5.41; N, 11.56%; Found: C,
59.36; H, 5.44; N, 11.61%.
2-(Tert-butyl)-3-(trifluoromethyl)-2H-indazole (2n): Yellow liquid (61%, 29.5 mg); Rf = 0.50
(PE:EA = 98:02); 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.56 (dd,
J= 7.2 Hz, 2.0 Hz, 1H), 7.07 (t, J = 8.4 Hz, 1H), 1.76 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3):
δ 143.5 126.0, 124.8, 123.7 (q, JC-F = 5.0 Hz), 122.5 (d, JC-F = 22.0 Hz), 120.2 (q, JC-F = 266.0
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Hz), 119.7, 118.5, 60.9, 30.2; 19F NMR (376 MHz, CDCl3) δ -62.2; Anal. Calcd for C12H13F3N2:
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2-Cyclohexyl-3-(trifluoromethyl)-2H-indazole (2o): Yellow liquid (73%, 39.1 mg); Rf = 0.60
(PE:EA = 99:01); 1H NMR (400 MHz, CDCl3): δ 7.78-7.73 (m, 2H), 7.34-7.30 (m, 1H), 7.21 (t,
J = 8.0 Hz, 1H), 4.56-4.48 (m, 1H), 2.23-2.07 (m, 4H), 1.99-1.95 (m, 2H), 1.80-1.76 (m, 1H),
1.53-1.45 (m, 2H), 1.43-1.33 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.5, 126.2, 124.4,
121.72 (q, JC-F = 39.0 Hz), 121.70 (q, JC-F = 270.0 Hz), 120.5, 119.2, 118.2, 61.9, 33.6, 25.7,
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25.2; F NMR (376 MHz, CDCl3) δ -56.2; Anal. Calcd for C14H15F3N2: C, 62.68; H, 5.64; N,
10.44%; Found: C, 62.45; H, 5.60; N, 10.52%.
5-Methoxy-2-(4-methoxyphenyl)-3-(trifluoromethyl)-2H-indazole (4a): Yellow solid (81%,
52.1 mg); Rf = 0.50 (PE:EA = 97:03); M.P. 117-118 °C; 1H NMR (400 MHz, CDCl3): δ 7.68 (d,
J = 9.6 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.08 (dd, J = 9.6 Hz, 2.4 Hz, 1H), 7.02-7.00 (m, 2H),
6.95 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 160.6, 157.3, 145.0,
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132.7, 127.4, 122.9, 122.6, 122.1, 121.3 (q, JC-F = 267.0 Hz), 119.8, 114.2, 95.3, 55.7, 55.5; F
NMR (376 MHz, CDCl3) δ -54.5; Anal. Calcd for C16H13F3N2O2: C, 59.63; H, 4.07; N, 8.69%;
Found: C, 59.84; H, 4.16; N, 8.82%.
5-Fluoro-2-(p-tolyl)-3-(trifluoromethyl)-2H-indazole (4b): Yellow solid (78%, 45.8 mg); Rf =
1
0.50 (PE:EA = 98:02); M.P. 85-86 °C; H NMR (400 MHz, CDCl3): δ 7.81-7.78 (m, 1H), 7.44
(d, J = 8.4 Hz, 2H), 7.40-7.38 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.22-7.17 (m, 1H), 2.46 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 160.1 (d, JC-F = 243.0 Hz), 145.6, 140.5, 137.1, 129.8,
125.8, 124.1 (d, JC-F = 48.0 Hz), 121.4 (q, JC-F = 12.0 Hz), 120.9 (q, JC-F = 268.0 Hz), 120.8 (d,
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CDCl3) δ -54.7, -114.7; HRMS (ESI-TOF) m/z: [M + H]+Calcd for C15H11F4N2: 295.0853;
found: 295.0856.
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mg); Rf = 0.45 (PE:EA = 98:02); M.p. 91-92°C; H NMR (400 MHz, CDCl3): δ 7.80-7.76 (m,
1H), 7.47 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 9.2 Hz, 1H), 7.21-7.16 (m, 1H), 7.03-7.01 (m, 2H),
3.88 (s, 3H); C{1H} NMR (100 MHz, CDCl3): δ 161.3, 159.9 (d, JC-F = 196.0 Hz), 145.5,
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120.7 (d, JC-F = 9.0 Hz), 119.0 (d, JC-F = 29.0 Hz), 114.3, 102.3 (d, JC-F = 27.0 Hz), 55.7; F
NMR (376 MHz, CDCl3) δ -54.9, -114.8; Anal. Calcd for C15H10F4N2O: C, 58.07; H, 3.25; N,
9.03%; Found: C, 58.24; H, 3.31; N, 8.95%.
5-Chloro-2-phenyl-3-(trifluoromethyl)-2H-indazole (4d): Yellow solid (80%, 47.3 mg); Rf =
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0.50 (PE:EA = 99:01); M.P. 90-91 °C; H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.77-7.75
(m, 1H), 7.60-7.53 (m, 5H), 7.35 (dd, J = 9.2 Hz, 2.0 Hz, 1H); C{1H} NMR (100 MHz,
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CDCl3): δ 146.6, 139.4, 131.2, 130.5, 129.3, 129.0, 126.1, 123.5 (q, JC-F = 41.0 Hz), 122.0, 120.7
(q, JC-F = 269.0 Hz), 120.1, 118.3 (d, JC-F = 18.0 Hz); 19F NMR (376 MHz, CDCl3) δ -54.6; Anal.
Calcd for C14H8ClF3N2: C, 56.68; H, 2.72; N, 9.44%; Found: C, 56.46; H, 2.68; N, 9.51%.
5-Chloro-2-(p-tolyl)-3-(trifluoromethyl)-2H-indazole (4e): Yellow solid (81%, 50.2 mg); Rf =
0.60 (PE:EA = 98:02); M.p. 98-99 °C; 1H NMR (400 MHz, CDCl3): δ 7.80 (s, 1H), 7.75 (d, J =
9.2 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.34-7.32 (m, 3H) 2.46 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 146.5, 140.6, 136.9, 131.0, 129.8, 128.8, 125.8 , 123.5 (q, JC-F = 40.0 Hz), 122.0,
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120.7 (q, JC-F = 268.0 Hz), 120.0, 118.3, 21.4; F NMR (376 MHz, CDCl3) δ -54.7; HRMS
(ESI-TOF) m/z: [M + H]+Calcd for C15H11ClF3N2: 311.0557; found: 311.0555.
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2-(p-Tolyl)-3-(trifluoromethyl)-2H-[1,3]dioxolo[4,5-f]indazole (4f): Off white gummy mass
(69%, 44.2 mg); Rf = 0.45 (PE:EA = 98:02); 1H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 8.4 Hz,
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NMR (100 MHz, CDCl3): δ 149.9, 148.0, 145.8, 139.9, 137.3, 129.7, 125.8, 121.1 (q, JC-F
=
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269.0 Hz), 120.3, 119.7 (q, JC-F = 6.0 Hz), 101.5, 94.4, 94.3 (d, JC-F = 3.0 Hz), 21.3; F NMR
(376 MHz, CDCl3) δ -54.8; Anal. Calcd for C16H11F3N2O2: C, 60.00; H, 3.46; N, 8.75%; Found:
C, 59.84; H, 3.51; N, 8.84%.
2-Cyclohexyl-5-methoxy-3-(trifluoromethyl)-2H-indazole (4g): Yellow liquid (78%, 46.4 mg);
Rf = 0.50 (PE:EA = 99:01); 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.8 Hz, 1H), 7.01 (dd, J
= 9.6 Hz, 2.4 Hz, 1H), 6.9 (s, 1H), 4.49-4.42 (m, 1H), 3.84 (s, 3H), 2.15-2.05 (m, 4H), 1.98-
1.93 (m, 2H), 1.78-1.74 (m, 1H), 1.52-131 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 157.0,
144.2, 121.9 (q, JC-F = 269.0 Hz), 121.3, 120.9, 120.5, 119.6, 95.5, 61.7, 55.5, 33.6, 25.7, 25.2;
19F NMR (376 MHz, CDCl3) δ -56.0; Anal. Calcd for C15H17F3N2O: C, 60.40; H, 5.74; N,
9.39%; Found: C, 60.59; H, 5.69; N, 9.48%.
2-Butyl-5-chloro-3-(trifluoromethyl)-2H-indazole (4h): Yellow liquid (71%, 40.3 mg); Rf =
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0.55 (PE:EA = 98:02); H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.67 (d, J = 9.2 Hz, 1H),
7.28-7.25 (m, 1H), 4.50 (t, J = 7.6 Hz, 2H), 2.05-1.96 (m, 2H), 1.46-1.36 (m, 2H), 0.96 (t, J =
7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 145.9, 130.5, 128.1, 122.2 (q, JC-F = 40.0 Hz),
121.4, 121.0 (q, JC-F = 267.0 Hz), 119.6, 118.0 (d, JC-F = 2.0 Hz), 53.0, 32.6, 19.9, 13.6; 19F NMR
(376 MHz, CDCl3) δ -56.5; Anal. Calcd for C12H12ClF3N2: C, 62.68; H, 5.64; N, 10.44%; Found:
C, 62.45; H, 5.60; N, 10.52%.
3-(Trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4i): Light yellow gummy mass
1
(77%, 31.3 mg); Rf = 0.50 (PE:EA = 30:70); H NMR (400 MHz, DMSO-d6): δ 14.32 (s, 1H),
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(q, JC-F = 40.0 Hz), 121.0 (q, JC-F = 267.0 Hz), 95.7; F NMR (376 MHz, DMSO-d6) δ -59.1;
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Anal. Calcd for C6H4F3N5: C, 35.48; H, 1.98; N, 34.48%; Found: C, 35.61; H, 2.01; N, 34.43%.
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1
Supporting information: Scanned copies of H, 13C{1H}, and 19F NMR spectra of the
synthesized compounds, CIF file for compound 4a are available as supporting information. This
material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment: A.H. acknowledges the financial support from SERB-DST, (Grant no.
EMR/2016/001643). P.G. thanks UGC-New Delhi (UGC-JRF) and S.M. thanks CSIR-New
Delhi (CSIR-SRF) for their fellowship.
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15. Further information can be found in the CIF file. This crystal was deposited in the
Cambridge Crystallographic Data Centre and assigned as CCDC 1872608.
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