Metal-free regioselective C-H amination for the synthesis of pyrazole-containing 2H-indazoles

Article abstract of DOI:10.1039/d0ob02485f

A general and practical regioselective approach for the C-H amination of 2H-indazoles under transition-metal-free conditions was developed. A series of substrates were tested showing eminent functional group tolerance and affording the C-N functionalization products in good to excellent yields. Mechanism studies revealed that a radical process was involved in this transformation.

Full text of DOI:10.1039/d0ob02485f

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Metal-free regioselective C–H amination for the
synthesis of pyrazole-containing 2H-indazoles†
Cite this: Org. Biomol. Chem., 2021,
19, 1787
Kai Wang,a Tingting Wei,b Yujia Zhang,b Jiahao Hou,b Renren Baib and
a,b
Yuanyuan Xie
*
Received 11th December 2020,
Accepted 21st January 2021
A general and practical regioselective approach for the C–H amination of 2H-indazoles under transition-
metal-free conditions was developed. A series of substrates were tested showing eminent functional
group tolerance and affording the C–N functionalization products in good to excellent yields. Mechanism
studies revealed that a radical process was involved in this transformation.
DOI: 10.1039/d0ob02485f
rsc.li/obc
research and application. Although great achievements have
been achieved,11–14 these reactions are always carried out with
Introduction
As a distinctly important group of nitrogen-containing hetero- transition metal catalysts, resulting in some disadvantages and
cycles, indazole and its derivatives have attracted a fair amount limitations.
of attention due to their wide use in the field of pharmaceuti-
Herein, we report a metal-free regioselective C–H amination
cals,1 such as antit-tumor,1e anti-inflammatory,1f and anti- for the synthesis of pyrazole-containing 2H-Indazoles via C–H
cancer therapies.1g Besides, they could also be used in syn- bond functionalization to afford the desired products in good
thesis,2 materials chemistry,3 and coordination chemistry.4 to excellent yields under mild conditions.
Based on these unique characterstics, the development of
efficient synthetic methods as well as novel molecules of inda-
zole containing organic compounds has attracted more atten-
tion than ever before from organic synthesis workers.5
Recently, with the development of C–H functionalization
strategies, attention on the functionalization of 2H-indazoles
in the C3 position has grown. A great number of works have
been performed based on this highly efficient strategy6–10
(Fig. 1). Despite these persistent efforts, methodologies for
the selective C–N bond formation have still rarely been
established.
Results and discussion
We commenced our investigations by taking 2-phenyl-2H-inda-
zole 1a and pyrazole 2a as model substrates to react in the
presence of 2.0 equivalent K2S2O8 in 1,2-dichloroethane (DCE).
Delightfully, the C–N cross-coupling product 3a was obtained
Likewise, pyrazole-containing compounds also have been
attracting lots of interest due to their specific bioactivities,
whereby developing an efficient method for the introduction
of pyrazoles would provide more possibilities for their appli-
cation. Over the past several decades, the direct C–H/N–H
functionalization strategy has become an effective way to
construct C–N bonds. Unlike traditional methods, such as
Buchwald–Hartwig, Chan–Lam, and Ullmann–Goldberg amin-
ations, the prefunctionalization of substrates can be effectively
avoided in this strategy, making the method more valuable for
aCollaborative Innovation Center of Yangtze River Delta Region Green
Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China
bCollege of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou,
China. E-mail: xyy@zjut.edu.cn; Fax: (+86)571-88320878
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob02485f
Fig. 1 Functionalizations at the C3 position of 2H-indazoles.
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Table 1 Optimization of the reaction conditionsa,b
Table 2 Scope of the pyrazole substratesa,b
Entry
Solvent
Oxidant
Yieldb [%]
1
2
3
4
5
6
7
8
DCE
DMSO
THF
CH3CN
H2O
H2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
(NH4)2S2O8
Na2S2O8
TBHP
63
70
Trace
97(95)c
31(61)d
81e
69
72
Trace
13
24
9
10
11
12
13
DTBP
PhI(OAc)2
PhI(TFA)2
—
Trace
n.r.
a Reaction conditions: 1a (0.2 mmol), 2a (1.5 equiv.), oxidant (2.0
equiv.), solvent (2.0 mL), stirred at 80 °C, under air, 5 h. b Isolated
yields. c K2S2O8 (1.5 equiv.). d 12 h. e K2S2O8 (3.0 equiv.), 15 h.
in a 63% yield (Table 1, entry 1). Subsequently, solvents,
including DMSO, THF, and CH3CN, were then screened, and
the best yield was found to be 97% in CH3CN (entries 2–4),
and it was noticed that this transformation could also occur in
H2O, providing the desired product in a 31% yield (entry 5).
Pleasantly, the yield increased to 61% as the reaction time was
extended to 12 h (entry 5). With further increasing the dosage
of K2S2O8 and prolonging the reaction time, the yield was
raised to 81%, thus showing good reactivity under the current
a Reaction conditions A: 1 (0.3 mmol), 2 (1.5 equiv.), K2S2O8 (1.5
equiv.), CH3CN (3.0 mL), stirred at 80 °C, under air, 5 h. Conditions B:
1 (0.3 mmol), 2 (1.5 equiv.), K2S2O8 (3.0 equiv.), H2O (3.0 mL), stirred
at 80 °C, under air, 15 h. b Isolated yields.
conditions (entry 6). Encouraged by this satisfying result, formation and produced the products in 82%, 85%, and 17%
follow-up studies were carried out on the screening of oxidants yields, respectively (3h, 3i, 3k). Unfortunately, 1H-indole could
and these showed that K2S2O8 had superior performance to not undertake this reaction (3j).
other oxidants, like (NH4)2S2O8, Na2S2O8, tert-butyl hydroper-
Further studies were carried out with different 2H-indazoles
oxide (TBHP), di-tert-butyl peroxide (DTBP), PhI(OAc)2, and to further confirm the scope of our methodologies (Table 3).
PhI(TFA)2 (entries 7–12). Pleasantly, when the dosage of Similar to the previous research, the yields under conditions A
K2S2O8 was reduced to 1.5 equiv., the yield of 3a slightly were higher than under conditions B. Substrates containing
dropped to 95% (entry 4). As expected, no product could be electron-donating groups (–Me and –OMe) and electron-
detected in the absence of oxidants (entry 13).
withdrawing groups (–F, –Cl, –Br, –I, and –CF3) on both the
With the aforementioned optimized reaction protocol in benzene ring and indazole ring could tolerate the reaction con-
hand and considering water is a green and friendly solvent ditions and give the desired products in up to 98% yields
for chemical reactions,15 both methods were studied in sub- (4aa–4ax). However, no products (4af, 4ag) could be detected
sequent experiments. First of all, the scope of pyrazole sub- when –CO2Et– and –CN-substituted 2H-indazoles were tested.
strates was screened (Table 2). Various pyrazoles with different However, when the substituents were in the ortho-position
substituents were investigated under both sets of optimal reac- of the phenyl ring, the yields of the products were sharply
tion conditions, resulting in the desired products in up to 98% reduced to 52% and 56% (4an–4ao), respectively, which indi-
yields (3a–3e) and demonstrating excellent substrate tolerance. cated that steric factors had a significant influence on the reac-
Furthermore, the more electron-absorbent the substituent, the tion potency. It is beyond our expectations that indazoles con-
less favorable the reaction. Also, strong electron-withdrawing taining methoxy could not take part in this reaction under con-
groups, such as 4-nitro-1H-pyrazol, could not work in this ditions B due to their poor solubility (4av–4ax). Satisfactorily,
transformation (3f). Ultimately, steric hindrance also played a this problem could be solved by the addition of TBAHS, and
vital role in this reaction and the yelid of product (3g) was only the desired products were obtained in 53%–65% yields.15d
55%. Satisfactorily, 1H-indazole, 1H-benzotriazole and N-(phe- Subsequent investigations were implemented with aliphatic-
nylsulfonyl)benzenesul-fonamide could also bear this trans- amine-substituted indazoles and only 2-cyclohexyl-3-(1H-
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Table 3 Scope of the indazole substratesa,b
Scheme 2 Plausible mechanistic pathway.
To gain more insights into the reaction mechanism, several
control experiments were then conducted (Scheme 1). With
the addition of the radical scavengers 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) (up to 4.0 equiv.), no desired product
could be detected, while compound 5 was detected by
ESI-HRMS.
Based on the aforementioned experiments and previous
reports,6d,16 a plausible mechanism was proposed via a radical
pathway (Scheme 2). Primarily, pyrazole-radical (A) was gener-
ated in the presence of K2S2O8. Then, (A) attacked 1a at the C3
position to form the radical intermediate (B), which via a
hydrogen radical extraction by sulfate radical ion with persul-
fate to generate the desired product 3a.
a Reaction conditions A: 1 (0.3 mmol), 2a (1.5 equiv.), K2S2O8 (1.5
equiv.), CH3CN (3.0 mL), stirred at 80 °C, under air, 5 h. Conditions B:
1 (0.3 mmol), 2a (1.5 equiv.), K2S2O8 (3.0 equiv.), H2O (3.0 mL), stirred
at 80 °C, under air, 15 h. Conditions C: 1 (0.3 mmol), 2a (1.5 equiv.),
K2S2O8 (3.0 equiv.), TBAHS (2.0 equiv.), H2O (3.0 mL), stirred at 80 °C,
under air, 15 h. b Isolated yields.
pyrazol-1-yl)-2H-indazole (4az–4ba) could be obtained in a 53%
yield. Furthermore, when the benzene ring and indazole ring
were changed to pyridine and imidazopyridine, no product
could be detected (4ay, 4bb).
Next, a gram-scale reaction was conducted with 2-phenyl-
2H-indazole 1a and pyrazole 2a to demonstrate the synthesis
using this protocol, and the desired product could be obtained
in up to an 83% yield (Scheme 1).
Experimental section
General information
All the chemicals were obtained commercially and used
1
without any prior purification. H NMR spectra were recorded
on a Bruker Avance II 400 spectrometer. All the products
were isolated by short chromatography on
a silica gel
(200–300 mesh) column using petroleum ether (60–90 °C) and
ethyl acetate, unless otherwise noted. All the compounds
were characterized by 1H NMR, 13C NMR, 19F NMR, and
HRGC-HRMS, consistent with other studies reported in the
literature.
General procedure for the synthesis of 2H-indazoles.17
A
dried round-bottom flask was charged with aryl aldehydes
(4.0 mmol), the appropriate anilines (4.0 mmol), molecular
sieves 4 Å MS (1 g/1.0 mmol aldehyde), and dichloromethane
(20 mL). The reaction mixture was stirred at ambient tempera-
ture for 24 h. The mixture was filtered through Celite and the
filtrate was concentrated under reduced pressure to provide
the pure imines without additional purification. The desired
imine (4.0 mmol, 1 equiv.) was dissolved in dry DMSO
(20 mL), and then copper iodide (152 mg, 20 mol%), TMEDA
(120 μL, 20 mol%), and sodium azide (520 mg, 2.0 equiv.) were
added and the reaction mixture was stirred at 120 °C for 24 h.
Scheme 1 Gram-scale reaction and mechanistic studies. Reaction con-
ditions A: 1a (1.16 g, 6 mmol), 2a (0.61 g, 1.5 equiv.), K2S2O8 (2.43 g, 1.5
equiv.), CH3CN (30.0 mL), 24 h. Conditions C: 1a (1.16 g, 6 mmol), 2a
(0.61 g, 1.5 equiv.), K2S2O8 (4.86 g, 3.0 equiv.), TBAHS (4.07 g, 2.0
equiv.), H2O (30.0 mL), 15 h.
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The brown mixture was then allowed to reach room tempera- 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.44–7.37 (m, 6H), 7.31 (s, 1H),
ture, then diluted with ethyl acetate (20 mL) and water 7.18 (dd, J = 8.2, 6.8 Hz, 1H), 2.14 (s, 3H). 13C NMR (151 MHz,
(20 mL). The precipitate was filtered through a short pad of CDCl3) δ 148.03, 143.38, 138.71, 130.58, 130.38, 129.19, 128.67,
Celite and the filtrates were extracted with ethyl acetate. The 127.43, 124.25, 123.52, 118.95, 118.45, 118.11, 117.56, 8.83.
combined organic layers were concentrated under reduced HRMS (ESI) ([M + H]+) calcd for C17H15N4: 275.1291. Found:
pressure and the crude mixtures were purified by column 275.1299.
chromatography using ethyl acetate in hexane (3%–5%) as an
3-(4-Chloro-1H-pyrazol-1-yl)-2-phenyl-2H-indazole
(3c).
eluent to give relatively pure indazoles.
Obtained as a white solid (A: 78%; B: 61%); M.p. 133–134 °C.
General procedure for the synthesis of 3a. Conditions A: A 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.8 Hz, 1H), 7.78 (s,
mixture of 1a (0.3 mmol), 2a (1.5 equiv.), and K2S2O8 1H), 7.59–7.56 (m, 2H), 7.47–7.40 (m, 6H), 7.24 (t, J = 2.0 Hz,
(1.5 equiv.) in CH3CN (3.0 mL) was placed in a Schlenk tube 1H). 13C NMR (100 MHz, CDCl3) δ 147.98, 141.13, 138.31,
and stirred at 80 °C under air atmosphere for 5 h. Then the 130.03, 129.40, 129.24, 129.08, 127.59, 124.31, 124.15, 118.42,
mixture was allowed to reach room temperature and concen- 118.32, 117.66, 112.85. HRMS (ESI) ([M + H]+) calcd for
trated under reduced pressure after filtration. The product 3a C16H12ClN4: 295.0745. Found: 295.0749.
was purified by silica gel column flash chromatography using
PE/AcOEt (30 : 1) as an eluent.
3-(4-Bromo-1H-pyrazol-1-yl)-2-phenyl-2H-indazole
Obtained as a white solid (A: 73%; B: 57%); M.p. 128–129 °C.
(3d).
Conditions B: A mixture of 1a (0.3 mmol), 2a (1.5 equiv.), 1H NMR (400 MHz, CDCl3) δ 7.83–7.80 (m, 2H), 7.61–7.55 (m,
and K2S2O8 (3.0 equiv.) in H2O (3.0 mL) was placed in a 2H), 7.49–7.38 (m, 6H), 7.23 (t, J = 2.0 Hz, 1H). 13C NMR
Schlenk tube and stirred at 80 °C under an air atmosphere for (100 MHz, CDCl3) δ 147.97, 143.15, 138.31, 132.22, 129.40,
15 h. Then the mixture was cooled to room temperature, and 129.13, 129.07, 127.60, 124.30, 124.16, 118.42, 118.33, 117.66,
extracted with ethyl acetate (5.0 × 3 mL). The combined 96.07. HRMS (ESI) ([M + H]+) calcd for C16H12BrN4: 339.0240.
organic solvent was dried over Na2SO4, filtered, and concen- Found: 339.0247.
trated under reduced pressure. The product 3a was purified by
silica gel column flash chromatography using PE/AcOEt (30 : 1) Obtained as a white solid (A: 69%; B: 51%); M.p. 145–146 °C.
as an eluent.
1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.81 (d, J = 8.8 Hz,
3-(4-Iodo-1H-pyrazol-1-yl)-2-phenyl-2H-indazole
(3e).
General procedure for the gram-scale synthesis of product 1H), 7.62 (s, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.46–7.37 (m, 6H),
3a. Conditions A: A mixture of 1a (1.16 g, 6.0 mmol), 2a 7.21 (t, J = 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 147.90,
(0.61 g, 1.5 equiv.), and K2S2O8 (2.43 g, 1.5 equiv.) in CH3CN 147.47, 138.26, 136.48, 129.42, 129.07, 128.92, 127.64, 124.24,
(30.0 mL) was placed in a 50 mL round-bottom flask and 124.15, 118.47, 118.30, 117.60, 59.52. HRMS (ESI) ([M + H]+)
stirred at 80 °C under an air atmosphere for 5 h. Then the calcd for C16H12IN4: 387.0101. Found: 387.0100.
mixture was then allowed to reach room temperature and con-
3-(3,5-Diphenyl-1H-pyrazol-1-yl)-2-phenyl-2H-indazole (3g).
centrated under reduced pressure after filtration. The product Obtained as a white solid (A: 55%; B: 42%); M.p. 143–144 °C.
3a was purified by silica gel column flash chromatography 1H NMR (400 MHz, CDCl3) δ 8.05–7.99 (m, 2H), 7.82 (dd, J =
using PE/AcOEt (30 : 1) as an eluent.
15.6, 8.7 Hz, 2H), 7.51 (t, J = 7.5 Hz, 2H), 7.47–7.42 (m, 2H),
Conditions C: A mixture of 1a (1.16 g, 6.0 mmol), 2a (0.61 g, 7.28–7.15 (m, 5H), 7.07–7.05 (m, 2H), 7.02–6.99 (m, 2H), 6.85
1.5 equiv.), and K2S2O8 (4.86 g, 3.0 equiv.) TBAHS (4.07 g, (s, 1H), 6.76–6.69 (m, 2H). 13C NMR (100 MHz, CDCl3)
2.0 equiv.) in H2O (30.0 mL) was placed in a 50 mL round- δ 154.07, 148.27, 147.85, 138.33, 132.48, 129.43, 128.87,
bottom flask and stirred at 80 °C under an air atmosphere for 128.81, 128.78, 128.65, 128.51, 128.41, 128.22, 127.41, 127.22,
15 h. Then the mixture was cooled to room temperature, and 126.07, 123.86, 119.08, 118.90, 118.35, 104.35. HRMS (ESI)
extracted with ethyl acetate (20.0 × 3 mL). The combined ([M + H]+) calcd for C28H21N4: 413.1761. Found: 413.1766.
organic solvent was dried over Na2SO4, filtered and concen-
2′-Phenyl-2′H-1,3′-biindazole (3h). Obtained as a white solid
trated under reduced pressure. The product 3a was purified by (A: 82%; B: 64%); M.p. 137–138 °C. 1H NMR (400 MHz, CDCl3)
silica gel column flash chromatography using PE/AcOEt (30 : 1) δ 8.30 (s, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H),
as an eluent.
7.46–7.42 (m, 2H), 7.40–7.36 (m, 3H), 7.33–7.30 (m, 3H),
2-Phenyl-3-(1H-pyrazol-1-yl)-2H-indazole (3a). Obtained as a 7.29–7.27 (m, 1H), 7.21–7.15 (m, 2H). 13C NMR (100 MHz,
white solid (A: 95%; B: 81%); M.p. 102–103 °C. 1H NMR CDCl3) δ 148.23, 141.47, 138.82, 137.64, 129.18, 128.62, 128.52,
(400 MHz, CDCl3) δ 7.86 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 8.8 Hz, 128.03, 127.44, 124.38, 124.01, 123.64, 122.33, 121.38, 118.92,
1H), 7.60 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.46–7.37 118.52, 118.37, 109.78. HRMS (ESI) ([M + H]+) calcd for
(m, 6H), 7.21 (dd, J = 8.2, 6.8 Hz, 1H), 6.50 (t, J = 2.0 Hz, 1H). C20H15N4: 311.1291. Found: 311.1293.
13C NMR (100 MHz, CDCl3) δ 148.02, 142.46, 138.53, 132.44,
1-(2-Phenyl-2H-indazol-3-yl)-1H-benzo[d][1,2,3]triazole (3i).
130.04, 129.25, 128.79, 127.51, 124.22, 123.75, 118.81, 118.16, Obtained as a white solid (A: 85%; B: 63%); M.p. 133–134 °C.
117.66, 107.95. HRMS (ESI) ([M + H]+) calcd for C16H13N4: 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.2 Hz, 1H), 7.91 (d,
261.1135. Found: 261.1139.
3-(4-Methyl-1H-pyrazol-1-yl)-2-phenyl-2H-indazole
J = 8.8 Hz, 1H), 7.48–7.44 (m, 3H), 7.42–7.37 (m, 3H), 7.31 7.29
(3b). (m, 3H), 7.24–7.20 (m, 2H). 13C NMR (100 MHz, CDCl3)
Obtained as a white solid (A: 98%; B: 85%); M.p. 108–110 °C. δ 148.32, 145.39, 138.21, 134.42, 129.36, 129.21, 129.15,
1H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 8.8 Hz, 1H), 7.64 (s, 127.68, 125.13, 124.87, 124.54, 124.32, 120.54, 118.69, 118.66,
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118.24, 109.50. HRMS (ESI) ([M + H]+) calcd for C19H14N5: p. 131–132 °C. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 1.6 Hz,
312.1244. Found: 312.1245. 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.69–7.65 (m, 3H), 7.56 (d, J =
N-(2-(3-Fluorophenyl)-2H-indazol-3-yl)-N-(phenylsulfonyl) 8.6 Hz, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.45–7.39 (m, 1H), 7.22
ben-zenesulfonamide (3k). Obtained as a white solid (A: 17%; (dd, J = 8.4, 6.8 Hz, 1H), 6.57 (t, J = 2.0 Hz, 1H). 13C NMR
B: 0%); M.p. 161–163 °C. 1H NMR (400 MHz, CDCl3) δ 7.82 (m, (100 MHz, CDCl3) δ 148.34, 142.87, 141.30, 132.57, 130.61 (q,
4H), 7.77 (d, J = 8.8 Hz, 1H), 7.69 (m, 2H), 7.60 (d, J = 8.1 Hz, JC–F = 32.3 Hz), 130.07, 128.06, 126.46 (q, JC–F = 4.0 Hz), 124.98
1H), 7.47 (m, 4H), 7.34 (m, 3H), 7.13 (m, 1H), 7.02–6.93 (m, (q, JC–F = 272.7 Hz), 124.30, 124.10, 118.64, 118.28, 117.99,
1H), 6.59 (d, J = 8.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) 108.47. 19F NMR (376 MHz, CDCl3) δ −62.75. HRMS (ESI)
δ 163.51(d, JC–F = 246.0 Hz), 148.30, 139.86 (d, JC–F = 10.0 Hz), ([M + H]+) calcd for C17H12F3N4: 329.1009. Found: 329.1007.
138.42, 134.70, 130.22 (d, JC–F = 8.0 Hz), 129.31, 129.07, 127.26,
3-(1H-Pyrazol-1-yl)-2-(p-tolyl)-2H-indazole (4ah). Obtained as
124.33, 123.83, 121.93 (d, JC–F = 4.0 Hz), 120.98, 119.21, 118.87, a white solid (A: 85%; B: 74%); M.p. 113–114 °C. 1H NMR
116.36 (d, JC–F = 20.0 Hz), 114.14 (d, JC–F = 25.0 Hz). 19F NMR (400 MHz, CDCl3) δ 7.84 (d, J = 1.6 Hz, 1H), 7.80 (d, J = 8.8 Hz,
(376 MHz, CDCl3) δ −110.67. HRMS (ESI) ([M + H]+) calcd for 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.42–7.37
C25H19N3O4S2: 508.0796. Found: 508.0799.
2-(4-Fluorophenyl)-3-(1H-pyrazol-1-yl)-2H-indazole
(m, 1H), 7.30–7.26 (m, 2H), 7.21–7.17 (m, 3H), 6.48 (t, J =
(4aa). 2.0 Hz, 1H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 147.91,
Obtained as a yellow liquid (A: 71%; B: 63%); M.p. 90–91 °C. 142.35, 138.85, 136.13, 132.43, 129.96, 129.81, 127.33, 124.01,
1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 1.6 Hz, 1H), 7.79 (d, 123.58, 118.79, 118.11, 117.64, 107.83, 21.15. HRMS (ESI)
J = 8.8 Hz, 1H), 7.60–7.55 (m, 2H), 7.40 (dt, J = 9.0, 5.7 Hz, 3H), ([M + H]+) calcd for C17H15N4: 275.1291. Found: 275.1297.
7.21 (dd, J = 8.2, 6.9 Hz, 1H), 7.14–7.07 (m, 2H), 6.52 (t, J =
2.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 163.67 (d, JC–F
2-(4-Methoxyphenyl)-3-(1H-pyrazol-1-yl)-2H-indazole
Obtained as a white solid (A: 93%; B: 77%); M.p. 120–121 °C.
(4ai).
=
250.0 Hz), 148.02, 142.52, 134.74(d, JC–F = 3.0 Hz), 132.43, 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 1.6 Hz, 1H), 7.79 (d,
130.08, 127.57, 126.17(d, JC–F = 9.0 Hz), 123.87, 118.65, 118.14, J = 8.8 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H),
117.66, 116.29(d, JC–F = 23.0 Hz), 108.02. 19F NMR (376 MHz, 7.41–7.36 (m, 1H), 7.35–7.31 (m, 2H), 7.19 (dd, J = 8.2, 7.0 Hz,
CDCl3) δ −111.99. HRMS (ESI) ([M + H]+) calcd for C16H12FN4: 1H), 6.48 (t, J = 2.0 Hz, 1H), 3.84 (s, 3H). 13C NMR (100 MHz,
279.1041. Found: 279.1043.
CDCl3) δ 159.79, 147.82, 142.30, 132.39, 131.65, 129.97, 127.23,
2-(4-Chlorophenyl)-3-(1H-pyrazol-1-yl)-2H-indazole
(4ab). 125.59, 123.51, 118.74, 118.03, 117.55, 114.37, 107.76, 55.49.
Obtained as a white solid (A: 77%; B: 68%); M.p. 126–127 °C. HRMS (ESI) ([M + H]+) calcd for [C17H15N4]+: 291.1240. Found:
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 1.8 Hz, 1H), 7.80 (d, 291.1240.
J = 8.8 Hz, 1H), 7.60 (d, J = 2.6 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H),
2-(3-Fluorophenyl)-3-(1H-pyrazol-1-yl)-2H-indazole
(4aj).
7.45–7.36 (m, 3H), 7.36–7.31 (m, 2H), 7.21 (m, 1H), 6.54 (t, J = Obtained as a white solid (A: 68%; B: 51%); M.p. 133–134 °C.
2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 148.13, 142.61, 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.80 (d, J = 8.8 Hz,
137.13, 134.67, 132.48, 129.98, 129.39, 127.69, 125.32, 123.98, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.43–7.34
118.63, 118.19, 117.83, 108.13. HRMS (ESI) ([M + H]+) calcd for (m, 2H), 7.24–7.09 (m, 4H), 6.55 (t, J = 2.0 Hz, 1H). 13C NMR
C16H12ClN4: 295.0745. Found: 295.0748.
(100 MHz, CDCl3) δ 163.85 (d, JC–F = 250.5 Hz), 148.11, 142.76,
2-(4-Bromophenyl)-3-(1H-pyrazol-1-yl)-2H-indazole
(4ac). 139.78 (d, JC–F = 10.0 Hz), 132.54, 130.55 (d, JC–F = 9.0 Hz),
Obtained as a white solid (A: 80%; B: 65%); M.p. 146–147 °C. 129.99, 127.87, 124.10, 119.56 (d, JC–F = 4.0 Hz), 118.70, 118.22,
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 1.6 Hz, 1H), 7.79 (d, 117.85, 115.86 (d, JC–F = 21.0 Hz), 111.92 (d, JC–F = 26.0 Hz),
J = 8.8 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.58–7.50 (m, 3H), 108.31. 19F NMR (376 MHz, CDCl3) δ −110.50. HRMS (ESI)
7.44–7.38 (m, 1H), 7.26 (d, J = 8.6 Hz, 2H), 7.21 (dd, J = 8.4, 6.8 ([M
Hz, 1H), 6.54 (t, J = 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) 279.1050.
δ 148.11, 142.72, 137.54, 132.54, 132.42, 129.90, 127.80, 2-(3-Chlorophenyl)-3-(1H-pyrazol-1-yl)-2H-indazole
125.50, 124.04, 122.73, 118.66, 118.17, 117.82, 108.27. HRMS Obtained as a white solid (A: 74%; B: 55%); M.p. 93–94 °C. H
(ESI) ([M + H]+) calcd for C16H12BrN4: 339.0240. Found: NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H),
+
H]+) calcd for C16H12FN4: 279.1041. Found: 349.
(4ak).
1
339.0245.
7.62 (d, J = 1.8 Hz, 1H), 7.59–7.54 (m, 1H), 7.48 (d, J = 1.8 Hz,
2-(4-Iodophenyl)-3-(1H-pyrazol-1-yl)-2H-indazole
(4ad). 1H), 7.44–7.36 (m, 2H), 7.34–7.28 (m, 1H), 7.25–7.16 (m, 2H),
Obtained as a white solid (A: 78%; B: 61%); M.p. 151–152 °C. 6.60–6.52 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 148.16,
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 1.6 Hz, 1H), 7.79 (d, 142.75, 139.46, 134.99, 132.54, 130.16, 130.01, 128.85, 127.87,
J = 8.8 Hz, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 1.8 Hz, 1H), 124.46, 124.11, 121.92, 118.68, 118.21, 117.78, 108.31. HRMS
7.55 (d, J = 8.4 Hz, 1H), 7.43–7.38 (m, 1H), 7.24–7.18 (m, 1H), (ESI) ([M + H]+) calcd for C16H12ClN4: 295.0745. Found:
7.12 (d, J = 8.6 Hz, 2H), 6.54 (t, J = 2.0 Hz, 1H). 13C NMR 295.0747.
(100 MHz, CDCl3) δ 148.13, 142.71, 138.36, 138.25, 132.55,
3-(1H-Pyrazol-1-yl)-2-(m-tolyl)-2H-indazole (4al). Obtained as
127.79, 125.62, 125.51, 124.04, 118.66, 118.18, 117.87, 108.27, a light yellow liquid (A: 82%; B: 72%); 1H NMR (400 MHz,
94.31. HRMS (ESI) ([M + H]+) calcd for C16H12IN4: 387.0101. CDCl3) δ 7.84 (d, J = 1.6 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.60
Found: 387.0106.
(d, J = 8.6 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.42–7.37 (m, 1H),
3-(1H-Pyrazol-1-yl)-2-(4-(trifluoromethyl)phenyl)-2H-indazole 7.31 (s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.23–7.16 (m, 2H), 7.09 (d,
(4ae). Obtained as a white solid (A: 54%; B: 42%); M. J = 7.8 Hz, 1H), 6.49 (t, J = 2.0 Hz, 1H), 2.37 (s, 3H). 13C NMR
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(100 MHz, CDCl3) δ 147.98, 142.31, 139.43, 138.48, 132.42, (ESI) ([M + H]+) calcd for C16H11ClFN4: 313.0651. Found:
130.04, 129.52, 128.89, 127.38, 124.95, 123.62, 121.07, 118.81, 313.0655.
118.14, 117.64, 107.79, 21.27. 19F NMR (376 MHz, CDCl3)
5-Fluoro-2-(4-methoxyphenyl)-3-(1H-pyrazol-1-yl)-2H-inda-
δ −113.37. HRMS (ESI) ([M + H]+) calcd for C17H15N4: zole (4ar). Obtained as a white solid (A:80%; B: 55%);
275.1291. Found: 275.1299.
M.p. 111–112 °C. 1H NMR (400 MHz, CH2Cl2) δ 7.84 (d, J =
2-(3-Methoxyphenyl)-3-(1H-pyrazol-1-yl)-2H-indazole (4am). 1.6 Hz, 1H), 7.78–7.75 (m, 1H), 7.49 (d, J = 2.4 Hz, 1H),
Obtained as a white solid (A: 88%; B: 75%); M.p. 93–94 °C. 7.31–7.28 (m, 2H), 7.21–7.16 (m, 2H), 6.95–6.87 (m, 2H), 6.48
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 1.8 Hz, 1H), 7.81 (d, (t, J = 2.0 Hz, 1H), 3.83 (s, 3H). 13C NMR (100 MHz, CDCl3)
J = 8.8 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H),
δ
13C NMR (100 MHz, CDCl3) δ 160.53 (d, JC–F = 243.4 Hz),
7.41 (dd, J = 8.2, 7.2 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.21 (dd, 159.82, 145.12, 142.52, 132.40, 131.36, 130.30 (d, JC–F = 9.0 Hz),
J = 8.4, 6.8 Hz, 1H), 6.98–6.93 (m, 3H), 6.51 (t, J = 2.0 Hz, 1H), 125.42, 120.40 (d, JC–F = 10.0 Hz), 119.24 (d, JC–F = 28.0 Hz),
3.77 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.07, 147.93, 117.08 (d, JC–F = 11.0 Hz), 114.41, 108.01, 101.55 (d, JC–F
=
142.47, 139.42, 132.57, 129.97, 127.57, 123.81, 118.80, 118.15, 25.0 Hz), 55.53. 19F NMR (376 MHz, CDCl3) δ −117.06. HRMS
117.76, 116.24, 115.39, 109.19, 108.01, 55.50. HRMS (ESI) (ESI) ([M + H]+) calcd for C17H14FN4O: 309.1146. Found:
([M + H]+) calcd for C17H15N4O: 291.1240. Found: 291.1244.
309.1151.
3-(1H-Pyrazol-1-yl)-2-(o-tolyl)-2H-indazole (4an). Obtained as
5-Chloro-2-phenyl-3-(1H-pyrazol-1-yl)-2H-indazole
(4as).
a light yellow liquid (A: 52%; B: 43%); 1H NMR (400 MHz, Obtained as a white solid (A: 75%; B: 53%); M.p. 133–134 °C.
CDCl3) δ 7.78 (dd, J = 8.6, 4.4 Hz, 2H), 7.74 (d, J = 1.6 Hz, 1H), 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 1.6 Hz, 1H), 7.74 (d,
7.42–7.35 (m, 4H), 7.30 (d, J = 7.6 Hz, 2H), 7.22 (dd, J = 8.6, J = 9.2 Hz, 1H), 7.61 (d, J = 1.3 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H),
6.6 Hz, 1H), 6.37 (t, J = 2.0 Hz, 1H), 2.02 (s, 3H). 13C NMR 7.43–7.41 (m, 3H), 7.39–7.36 (m, 2H), 7.33 (dd, J = 9.2, 1.9 Hz,
(100 MHz, CDCl3) δ 148.21, 142.11, 137.68, 135.50, 131.76, 1H), 6.50 (t, J = 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3)
131.10, 130.99, 129.93, 127.38, 127.33, 126.65, 123.34, 119.48, δ 146.32, 142.72, 138.22, 132.36, 129.71, 129.50, 129.37,
118.03, 115.52, 107.56, 17.25. HRMS (ESI) ([M + H]+) calcd for 129.09, 129.07, 124.14, 119.79, 117.96, 117.66, 108.23. HRMS
C17H15N4: 275.1291. Found: 275.1290.
(ESI) ([M + H]+) calcd for C16H12ClN4: 295.0745. Found: 295.0753.
2-(2-Methoxyphenyl)-3-(1H-pyrazol-1-yl)-2H-indazole (4ao).
5-Chloro-2-(4-chlorophenyl)-3-(1H-pyrazol-1-yl)-2H-indazole
Obtained as a yellow liquid (A: 56%; B: 46%); 1H NMR (4at). Obtained as
a white solid (A: 72%; B: 43%);
(400 MHz, CDCl3) δ 7.76 (m, 3H), 7.59 (dd, J = 7.8, 1.4 Hz, 1H), M.p. 139–140 °C. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J =
7.55 (d, J = 2.4 Hz, 1H), 7.48–7.36 (m, 2H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.56–7.51 (m, 2H), 7.39 (d,
7.2 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), J = 8.6 Hz, 2H), 7.34–7.29 (m, 3H), 6.54 (t, J = 2.0 Hz, 1H). 13C
6.39 (t, J = 2.0 Hz, 1H), 3.57 (s, 3H). 13C NMR (100 MHz, NMR (100 MHz, CDCl3) δ 146.39, 142.93, 136.75, 134.97,
CDCl3) δ 153.80, 148.39, 141.81, 132.19, 131.09, 130.95, 128.61, 132.44, 129.80, 129.60, 129.55, 129.33, 125.21, 119.81, 118.12,
127.65, 127.24, 123.18, 120.98, 119.27, 118.03, 115.56, 111.66, 117.46, 108.49. HRMS (ESI) ([M + H]+) calcd for C16H11Cl2N4:
107.13, 55.68. HRMS (ESI) ([M + H]+) calcd for C17H15N4O: 329.0355. Found: 329.0354.
291.1240. Found: 291.1248.
5-Chloro-3-(1H-pyrazol-1-yl)-2-(p-tolyl)-2H-indazole
(4au).
5-Fluoro-2-phenyl-3-(1H-pyrazol-1-yl)-2H-indazole
(4ap). Obtained as a white solid (A: 82%; B: 62%); M.p. 137–138 °C.
Obtained as a white solid (A: 71%; B: 52%); M.p. 107–108 °C. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 1.6 Hz, 1H), 7.73 (d,
1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 1.6 Hz, 1H), 7.78 (dd, J = 9.2 Hz, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H),
J = 9.2, 4.2 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.45–7.39 (m, 3H), 7.32–7.29 (m, 1H), 7.22 (m, 4H), 6.48 (t, J = 2.0 Hz, 1H), 2.39 (s,
7.39–7.34 (m, 2H), 7.19 (m, 2H), 6.49 (t, J = 2.0 Hz, 1H). 13C 3H). 13C NMR (100 MHz, CDCl3) δ 146.21, 142.58, 139.21,
NMR (100 MHz, CDCl3) δ 160.64 (d, JC–F = 244.4 Hz), 145.41, 135.82, 132.33, 129.90, 129.64, 129.34, 128.86, 123.93, 119.72,
142.55, 138.40, 132.40, 130.44 (d, JC–F = 9.0 Hz), 129.28, 128.92, 117.93, 117.64, 108.07, 21.18. HRMS (ESI) ([M + H]+) calcd for
124.10, 120.58 (d, JC–F = 10.0 Hz), 119.48 (d, JC–F = 29.0 Hz), C17H14Cl4N4: 309.0902. Found: 309.0903.
117.28 (d, JC–F = 12.0 Hz), 108.05, 101.54 (d, JC–F = 25.0 Hz). 19
NMR (376 MHz, CDCl3) δ −116.68. HRMS (ESI) ([M + H]+) Obtained as a white solid (A: 75%; C: 53%); M.p. 124–125 °C.
calcd for C16H12FN4: 279.1041. Found: 279.1044.
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 1.8 Hz, 1H), 7.69 (d,
2-(4-Chlorophenyl)-5-fluoro-3-(1H-pyrazol-1-yl)-2H-indazole J = 9.4 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.40–7.32 (m, 5H), 7.09
(4aq). Obtained as white solid (A: 54%; B: 41%); (dd, J = 9.4, 2.2 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H), 6.48 (t, J =
F
5-Methoxy-2-phenyl-3-(1H-pyrazol-1-yl)-2H-indazole
(4av).
a
M.p. 155–156 °C.1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 2.0 Hz, 1H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 156.58,
1.6 Hz, 1H), 7.78 (dd, J = 9.4, 4.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 144.95, 142.36, 138.55, 132.66, 129.22, 128.48, 123.81, 123.01,
1H), 7.41–7.37 (m, 2H), 7.32–7.29 (m, 2H), 7.21 (td, J = 9.2, 119.65, 118.01, 107.86, 94.14, 55.46. HRMS (ESI) ([M + H]+)
1.0 Hz, 1.0 Hz, 1H), 7.14 (dd, J = 8.4, 2.0 Hz, 1H), 6.54 (t, J = calcd for C17H15N4O: 291.1240. Found: 291.1244.
2.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 160.76 (d, JC–F
=
5-Methoxy-3-(1H-pyrazol-1-yl)-2-(p-tolyl)-2H-indazole (4aw).
244.4 Hz), 145.50, 142.77, 136.92, 134.85, 132.46, 130.33 (d, Obtained as a white solid (A: 83%; C: 61%); M.p. 137–138 °C.
JC–F = 9.0 Hz), 129.47, 125.16, 120.63 (d, JC–F = 10.0 Hz), 119.80 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 1.8 Hz, 1H), 7.69 (d,
(d, JC–F = 29.0 Hz), 117.47 (d, JC–F = 11.0 Hz), 108.31, 101.37 (d, J = 9.4 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.23–7.17 (m, 4H), 7.08
JC–F = 26.0 Hz). 19F NMR (376 MHz, CDCl3) δ −116.15. HRMS (dd, J = 9.3, 2.2 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.48 (t, J =
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2.0 Hz, 1H), 3.82 (s, 3H), 2.37 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 156.49, 144.78, 142.29, 138.55, 136.10, 132.64, 129.81,
129.02, 123.61, 122.80, 119.60, 117.91, 107.78, 94.18, 55.47,
21.18. HRMS (ESI) ([M + H]+) calcd for C18H17N4: 305.1397.
Found: 305.1390.
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5-Methoxy-2-(4-methoxyphenyl)-3-(1H-pyrazol-1-yl)-2H-inda-
zole (4ax). Obtained as a white solid (A:89%; C: 65%);
M.p. 125–126 °C. 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H),
7.68 (d, J = 9.2 Hz, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.29 (s, 2H),
7.08 (dd, J = 9.2, 2.0 Hz, 1H), 6.90 (d, J = m, 2H), 6.72 (t, J =
2.0 Hz, 1H), 6.49 (t, J = 2.0 Hz, 1H), 3.83 (s, 6H). 13C NMR
(100 MHz, CDCl3) δ 159.49, 156.45, 144.65, 142.30, 132.62,
131.62, 129.03, 125.22, 122.69, 119.53, 117.78, 114.32, 107.77,
3 C. Queffélec, M. Petit, P. Janvier, D. A. Knight and B. Bujoli,
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4 L. Weber, Coord. Chem. Rev., 2005, 249, 741.
94.18, 55.52, 55.48. HRMS (ESI) ([M
C18H17FN4O2: 321.1346. Found: 321.1351.
+
H]+) calcd for
2-Cyclohexyl-3-(1H-pyrazol-1-yl)-2H-indazole (4bb). Obtained
as a white solid (A:53%; B:48%); M.p. 74–75 °C. 1H NMR
(400 MHz, CDCl3) δ 7.92 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 2.4 Hz,
1H), 7.76 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.36–7.30
(m, 1H), 7.16–7.10 (m, 1H), 6.61 (t, J = 2.0 Hz, 1H), 4.37–4.30
(m, 1H), 2.21–2.05 (m, 4H), 1.92–1.90 (m, 2H), 1.72 (m, 1H),
1.48–1.16 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 146.93,
142.51, 132.51, 129.22, 126.27, 122.82, 118.02, 117.94, 116.25,
107.68, 59.10, 33.24, 25.58, 25.12. HRMS (ESI) ([M + H]+) calcd
for C16H19N4: 267.1604. Found: 267.1600.
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6 Selected examples for C–C functionalization, see:
(a) M. Singsardar, S. Laru, S. Mondal and A. Hajra, J. Org.
Chem., 2019, 84, 4543; (b) A. Murugan, V. N. Babu, A. Polu,
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Conclusions
In summary, we developed an efficient metal-free method for
selective C–H amination for realizing the synthesis of pyrazole-
containing 2H-indazole at the C3 position. This process could
tolerate a broad scope of substrates and a series of substrates
were tested, affording the desired products in good to excellent
yields with high atom economy. Control experiments revealed
that a radical pathway was included in this transformation,
and the gram-scale reaction showed that this ideal method has
further application value.
7 Selected examples for C–S/Se functionalization, see:
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Conflicts of interest
There are no conflicts to declare.
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