Synthesis of 4-chalcogenyl pyrazoles via electrophilic chalcogenation/cyclization of α,β-alkynic hydrazones

Article abstract of DOI:10.1039/d0ob00050g

A facile method for the synthesis of 4-chalcogenylated pyrazoles has been developed via electrophilic chalcogenation/cyclization of α,β-alkynic hydrazones. The cyclization of α,β-alkynic aldehyde hydrazones could be induced by using either sulfenyl chloride or the S-electrophiles generated in situ from the reaction of NCS and arythiol. The developed method was successfully applied to the synthesis of the sulfenyl analogue of celecoxib.

Full text of DOI:10.1039/d0ob00050g

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Synthesis of 4-chalcogenyl pyrazoles via
electrophilic chalcogenation/cyclization of
Cite this: DOI: 10.1039/d0ob00050g
α,β-alkynic hydrazones†
Xinzhang Yu,a Yu-Zhu Shang,b Yu-Fei Cheng,b Jun Tian,b Yulan Niu*a and
b
Wen-Chao Gao
*
A facile method for the synthesis of 4-chalcogenylated pyrazoles has been developed via electrophilic
chalcogenation/cyclization of α,β-alkynic hydrazones. The cyclization of α,β-alkynic aldehyde hydrazones
could be induced by using either sulfenyl chloride or the S-electrophiles generated in situ from the reac-
tion of NCS and arythiol. The developed method was successfully applied to the synthesis of the sulfenyl
analogue of celecoxib.
Received 9th January 2020,
Accepted 17th February 2020
DOI: 10.1039/d0ob00050g
rsc.li/obc
left in the pyrazole ring, are usually inevitable (Scheme 1, eqn
(1)).7 Therefore, construction of sulfenylated pyrazoles from
Introduction
As one kind of essential azaheterocycles, pyrazoles and their readily available starting materials and sulfenyl modification
derivatives have attracted much attention of synthetic chemists of pyrazole-containing drugs under mild reaction conditions
due to their frequent occurrences in pharmaceuticals and are still limited.
agrochemicals and high utility for further design of biologi-
Electrophilic cyclization of α,β-alkynic hydrazones has
cally active compounds (Fig. 1).1 For example, apixaban, the emerged as a promising strategy for the synthesis of multi-sub-
second-top-selling drug in the US market in 2018, is a highly stituted pyrazoles in recent decades (Scheme 1, eqn (2)).
selective factor Xa (FXa) inhibitor that was used for the preven- Several kinds of useful groups including trifluoromethyl
tion and treatment of thromboembolic diseases.2 Celecoxib, a (CF3),8a,b iodo (I),8c,d fluoro (F)8e and boryl (B)8f substituents
selective cyclooxygenase-2 (COX-2) inhibitor, is one of the have been regioselectively introduced to the 4-position of the
most successful non-steroidal anti-inflammatory drugs.3 target pyrazole ring. Furthermore, this cyclization could also
Agrochemicals bearing a functionalized pyrazole skeleton like provide 4-unsubstituted pyrazoles by using CuI/Et3N in the
fipronil and fluazolate have been widely used to improve the absence of any electrophiles.8g Inspired by these precedent
production of crops. Therefore, numerous methods have been works, we envisaged that the cyclization of α,β-alkynic hydra-
developed for the construction of the pyrazole framework as zones could be induced by an appropriate sulfur-electrophile.
well as the functionalization of pyrazoles.4 Due to the orbital However, considering the nucleophilic effect of the nitrogen
interactions of the sulfur atom with the electron donors of atom, the formation of unexpected sulfenamide derived from
targets, how to incorporate the sulfenyl group into heterocycles
has the priority to be considered in drug design,5 and sulfenyl
modification of pyrazoles is highly desirable for drug discov-
ery.6 In general, synthetic methods for sulfenylated pyrazoles
are mainly focused on the direct sulfenylation of pre-existing
pyrazolones or pyrazoles through oxidative cross-dehydrogena-
tive coupling, and undesired aspects such as high reaction
temperature, the use of smelly thiols, and the 5-hydroxy group
aDepartment of Chemistry and Chemical Engineering,
Taiyuan Institute of Technology, Taiyuan, 030008, P.R. China.
E-mail: niuyulan@163.com
bCollege of Biomedical Engineering, Taiyuan University of Technology, Taiyuan,
030024, P.R. China. E-mail: gaowenchao@tyut.edu.cn
†Electronic supplementary information (ESI) available: Copies of NMR spectra
for all new compounds. See DOI: 10.1039/d0ob00050g
Fig. 1 Bioactive molecules containing the pyrazole framework.
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Table 1 Condition optimization for the sulfenylation/cyclization of
3-phenyl propynal hydrazonesa
Entry
Additive (1 eq.)
Solvent
Temp. (°C)
Yieldb (%)
1c
2d
3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
TFA
BF3Et2O
ZnCl2
Et3N
DABCO
AlCl3
AlCl3
AlCl3
AlCl3
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH2Cl2
CH3CN
THF
r.t.
r.t.
r.t.
60
60
60
60
60
60
60
r.t.
r.t.
r.t.
60
51
10
65
75
17
19
33
49
0
4
5e
6
7
8
9
10
11
12
13
14f
Scheme 1 Strategies for the synthesis of 4-substituted pyrazoles.
0
30
47
32
53
N-sulfenylation9 competed with the electrophilic cyclization,
which makes the synthesis of 4-sulfenylated pyrazoles unfeasi-
ble. With our continuous interest in the studies of sulfur elec-
trophiles,10 herein we would like to report our results on the
synthesis of 4-sulfenylated pyrazoles through the cyclization of
α,β-alkynic hydrazones induced by S-electrophiles or sulfenyl
chlorides generated in situ.
CH3NO2
a Reaction conditions: 1a (0.1 mmol), S-electrophile (0.15 mmol), addi-
tive (0.1 mmol) in the solvent (2 mL) at the indicated temperature for
6–8 h. b Isolated yields. c 0.225 mmol of 4 was used instead of 2a.
d 0.15 mmol of 5 was used instead of 2a. e 20 mol% of AlCl3 was
employed. f Reaction conditions: NCS (0.15 mmol) and p-tolylthiol
(0.15 mmol) in MeNO2 (1 mL) at 60 °C for 0.5 h, and then 1a in
MeNO2 (1 mL) was added for another 6–8 h.
Results and discussion
In our previous work, N-sulfenylsuccinimides were proved as
effective sulfur-electrophiles to induce cyclization of various
alkynyl derivatives.10b–e However, when 1.5 equiv. of N-(p-
tolylthio)succinimide (4) were employed for the cyclization of
1a, the target product 3a was only obtained in 51% yield t-butyl groups could react with p-tolylthio chloride to give the
(Table 1, entry 1). N-(p-Tolylthio)phthalimide (5) were less reac- desired 4-sulfenyl pyrazoles in moderate to good yields (3a–e).
tive than 4, while p-tolylthio chloride 2a could give the desired Different arylsulfenyl chlorides with electron-donating or
product in 65% yield (entries 2 and 3). A higher reaction temp- -withdrawing substituents also proceeded well in this trans-
erature could accelerate the reaction process, and 3a was pro- formation, delivering the corresponding products in moderate
duced in 75% yield at 60 °C (entry 4). The cyclization only gave yields (3f–h). Notably, the hydrazone derived from 4-nitrophe-
3a in 17% yield when a catalytic amount of AlCl3 was used nylhydrazine and 1,3-diphenylprop-2-yn-1-one was a suitable
(entry 5). Different additives like TFA, BF3Et2O, ZnCl2, Et3N or substrate for this cyclization and afforded the product 3i in
DABCO were also tried in this reaction, but none of them 62% yield. In addition, phenylselenyl chloride was also
could give
a better result (entries 6–10). Notably, the attempted for this reaction, and the desired 4-selenylated pyra-
N-sulfenylation of 1a was detected when Et3N or DABCO was zole 3j was obtained in 65% yield. In addition, the sulfenyla-
used. The influence of solvents was next evaluated, and the tion/cyclization process was also tried by using sulfenyl chlor-
reaction efficiency obtained in solvents such as CH2Cl2, ides generated in situ (conditions B), and all the sulfenylated
CH3CN and THF was inferior to that in MeNO2 (entries 11–13). pyrazoles were obtained in moderated yields. When
Furthermore, due to the sensitivity of sulfenyl chloride to air 1-(1,3-diphenylprop-2-yn-1-ylidene)-2-phenylhydrazine 6a was
and water, a straightforward procedure in which p-tolylthiochlor- employed as a substrate, it was found that the cyclization pro-
ide 2a was generated in situ from N-chlorosuccinimide (NCS) moted by N-sulfenylsuccinimides gave a better result than that
and p-tolylthiol11 was thereby developed, and it gave the target by N-sulfenyl chlorides, and the desired fully substituted pyra-
product 3a in 53% yield (entry 14).
zole 7a could be obtained even in 98% yield (Table 3). Thus,
After the optimal reaction conditions for the sulfenylation/ N-sulfenylsuccinimides 4 bearing various substituents such as
cyclization of 3-phenylpropynal hydrazones were established methoxy, bromo, nitro and azide groups were consequently
(Table 1, entry 4), the scope and the generality of the present attempted for the sulfenylation/cyclization of propynone
protocol were then investigated. As shown in Table 2, a series hydrazones, and the corresponding products 7b–f were pro-
of 3-substituted propynal hydrazones bearing aryl, thienyl and duced in moderate to good yields. However, the reaction of
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Table 2 Substrate scope for the chalcogenation/cyclization of 3-sub-
stituted propynal hydrazonesa,b
Scheme 2 Synthesis of a sulfenylated analogue of celecoxib.
Furthermore, the replacement of the N-phenyl group with the
N-sulfonyl group failed to give the sulfenyl product, although
the cyclization occurred.13
The success in the synthesis of 4-sulfenylated pyrazoles
inspired us to explore the synthetic utility of the present
method. With the trifluoromethyl acetylenic hydrazone 8 in
hand,12 the cyclization induced by N-phenylthio succinimide
(4b) was performed smoothly to give the 4-phenylthio ana-
logue of the anti-inflammatory drug celecoxib in 55% yield
(Scheme 2). Therefore, the present protocol has provided a
convenient way for the structural modification of pyrazole-
based drugs.
a Reaction condition A: 1 (0.1 mmol), 2 (0.15 mmol), AlCl3 (0.1 mmol)
in MeNO2 (2 mL) at 60 °C for 4–6 h. b Reaction condition B: NCS
(0.15 mmol) and arylthiol (0.15 mmol) were mixed in MeNO2 (1 mL) at
room temperature for 0.5 h, and then 1 (0.1 mmol) and AlCl3
(0.1 mmol) in MeNO2 (1 mL) were added. c Benzeneselenenyl chloride
(0.15 mmol) was used.
Conclusions
In summary, a novel and facile method for the synthesis of
4-chalcogenyl pyrazoles via the cyclization of α,β-alkynic hydra-
zones induced by S-electrophiles or Se-electrophiles has been
developed. Moreover, from the readily available NCS and
arythiols, S-electrophiles could be generated in situ and used
directly for the cyclization of arylpropynal hydrazones. The
developed method was further applied to the modification of
the anti-inflammatory drug celecoxib and gave the sulfenylated
analogue of celecoxib. The convenience and practicability for
introducing an organochalcogen moiety to the pyrazole skel-
eton make the present method much attractive in synthetic
and pharmaceutical chemistry.
Table 3 Substrate scope for the chalcogenation/cyclization of 3-aryl-
propyn-1-one hydrozonesa
Experimental
General information
1H NMR spectra were obtained at 400 MHz and 13C NMR
spectra were obtained at 100 MHz employing Bruker
AVANCE III NMR spectrometers with CDCl3 as the solvent.
Chemical shifts (δ) were measured in ppm and referenced to
the deuterated chloroform (1H: δ = 7.26 ppm, 13C: δ =
77.00 ppm).
a Reaction conditions:
6 (0.1 mmol), 4 (0.15 mmol), and AlCl3
(0.1 mmol) in CH3CN (2 mL) at 60 °C for 2–4 h. b N-p-Tolylthio chloride
was used as a sulfur source. c 1.5 equiv. of benzeneselenenylchloride
were used instead of N-sulfanylsuccinimides.
The multiplicities of signals were described using the fol-
lowing abbreviations: s = singlet, d = doublet, t = triplet, q =
ketone hydrazone 6a with N-ethylthio succinimide failed to quartet, m = multiplet, dd = doublet of doublets, tt = triplet of
give the cyclic product 7g, probably owing to the lower stability triplets. High-resolution mass spectra (HRMS) were obtained
of the aliphatic sulfenium cation. Similarly, the cyclization of on a micrOTOF-Q II instrument with an ESI source. Melting
α,β-alkynic ketone hydrazones could also be promoted by phe- points were measured with an RD-II type melting point appar-
nylselenyl chloride to give the desired product 7h in 52% yield. atus without correction.
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General procedure for the sulfenylation/cyclization of 3-phenyl 1-Phenyl-5-(thiophen-3-yl)-4-(p-tolylthio)-1H-pyrazole (3d)
propynal hydrazones
Yield: 24.7 mg (71%); time: 4.0 h; brown liquid; TLC, Rf = 0.40
1
A 10 ml round-bottomed flask, equipped with a magnetic (PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 7.77 (s, 1H),
stirrer bar and fitted with a rubber septum, was flame-dried 7.33–7.24 (m, 5H), 7.19 (s, 1H), 7.14–7.12 (m, 1H), 7.00 (s, 4H),
and purged with dry nitrogen. To this flask were added 6.72 (dd, 1H, J = 4.8, 0.8 Hz), 2.22 (s, 3H); 13C NMR (CDCl3,
N-phenyl 3-phenyl propyn-1-al hydrazone (1a, 0.1 mmol), 100 MHz): δ 145.9, 141.3, 140.0, 135.4, 135.0, 129.8, 129.0,
p-tolylthiol chloride (2a, 0.15 mmol), and AlCl3 (0.1 mmol) fol- 128.4, 127.99, 127.96, 126.8, 126.6, 125.4, 125.1, 108.9, 20.9;
lowed by MeNO2 (1 mL). The mixture was stirred at 60 °C for HRMS (ESI) m/z calcd for C20H17N2S2 [M + H]+: 349.0828,
4 h under nitrogen. After the reaction was complete by TLC found: 349.0828.
analysis, the crude reaction mixture was directly charged on
5-(tert-Butyl)-1-phenyl-4-(p-tolylthio)-1H-pyrazole (3e)
silica gel and purified by column chromatography (SiO2, pet-
roleum ether/ethyl acetate, 95 : 5) to afford the desired product
3a. Yield: 25.6 mg (75%).
Yield: 17.4 mg (54%); time: 6.0 h; brown liquid; TLC, Rf = 0.42
1
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 7.87 (s, 1H),
7.10 (t, 2H, J = 8.0 Hz), 7.01 (d, 3H, J = 2.4 Hz), 6.90(s, 1H), 6.84
(t, 1H, J = 7.2 Hz), 6.28 (d, 2H, J = 8.0 Hz), 2.20 (s, 3H), 1.11 (s,
9H); 13C NMR (CDCl3, 100 MHz): δ 148.7, 135.9, 132.9, 129.7,
129.5, 128.9, 128.1, 128.0, 126.8, 121.5, 116.3, 113.8, 44.0, 28.8,
21.0; HRMS (ESI) m/z calcd for C20H23N2S [M + H]+: 323.1576,
found: 322.1590.
General procedure for the sulfenylation/cyclization of 3-phenyl
propynal hydrazones using sulfenyl chloride generated in situ
A 10 mL flask, sealed and equipped with a magnetic stirrer
bar, was charged with p-toluenethiol (0.225 mmol),
N-chlorosuccinimide (0.225 mmol), and MeNO2 (1 mL). After
the mixture was stirred for 30 min, 1a (0.15 mmol) and AlCl3
(0.15 mmol) in MeNO2 (1 mL) were added via a syringe under
a nitrogen atmosphere. After the reaction was complete by TLC
analysis, the reaction mixture was quenched with saturated
aqueous Na2CO3 solution (5.0 mL) and extracted with EtOAc
(10 × 3 mL). The organic layers were concentrated and purified
by column chromatography (SiO2, petroleum ether/ethyl
acetate, 95 : 5) to afford the desired product 3a. Yield: 18 mg
(53%).
1,5-Diphenyl-4-(phenylthio)-1H-pyrazole (3f)
Yield: 22.0 mg (67%); time: 4.0 h; brown liquid; TLC, Rf = 0.39
1
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 7.87 (s, 1H),
7.33 (d, 1H, J = 2.8 Hz), 7.30 (d, 2H, J = 4.0 Hz), 7.27 (m, 2H),
7.25 (m, 1H), 7.23–7.20 (m, 4H), 7.18–7.17 (m, 1H), 7.16–7.12
(m, 4H); 13C NMR (CDCl3, 100 MHz): δ 138.3, 133.3, 129.9,
129.09, 129.06, 129.0, 128.9, 128.5, 128.44, 128.37, 126.5,
125.9, 125.4, 109.2; HRMS (ESI) m/z calcd for C21H16N2SNa [M
+ Na]+: 351.0926, found: 351.0933.
1,5-Diphenyl-4-(p-tolylthio)-1H-pyrazole (3a)
4-((4-Methoxyphenyl)thio)-1,5-diphenyl-1H-pyrazole (3g)
Time: 4.0 h; brown liquid; TLC, Rf = 0.38 (PE : EtOAc = 95 : 5);
1H NMR (CDCl3, 400 MHz): δ 7.78 (s, 1H), 7.23–7.20 (m, 8H),
7.11 (dd, 2H, J = 7.6, 1.2 Hz), 6.98 (s, 4H), 2.22 (s, 3H); 13C{1H}
NMR (CDCl3, 100 MHz): δ 145.6, 135.4, 135.0, 130.0, 129.7,
128.9, 128.8, 128.3, 127.5, 127.0, 124.9, 20.9; HRMS (ESI) m/z
calcd for C22H19N2S [M + H]+: 343.1263, found: 343.1296.
Yield: 22.9 mg (64%); time: 4.0 h; brown liquid; TLC, Rf = 0.39
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 7.82 (s, 1H),
1
7.34–7.28 (m, 7H), 7.25–7.24 (m. 1H), 7.19 (dd, 2H, J = 7.6, 1.6
Hz), 7.13(d, 2H, J = 8.8 Hz), 6.79 (d, 2H, J = 8.8 Hz), 3.77 (s,
3H); 13C NMR (CDCl3, 100 MHz): δ 158.3, 145.2, 139.9, 135.9,
130.3, 130.1, 129.9, 128.9, 128.8, 128.5, 128.3, 127.6, 127.5,
125.1, 124.9, 115.2, 114.6, 111.0, 55.4; HRMS (ESI) m/z calcd
for C22H18N2OSNa [M + Na]+: 381.1032, found: 381.1026.
1-Phenyl-5-(p-tolyl)-4-(p-tolylthio)-1H-pyrazole (3b)
Yield: 25.3 mg (71%); time: 4.0 h; brown liquid; TLC, Rf = 0.40
1
4-((4-Nitrophenyl)thio)-1,5-diphenyl-1H-pyrazole (3h)
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 7.84 (s, 1H),
7.30–7.28 (m, 5H), 7.07 (t, 8H, J = 2.6 Hz), 2.32 (s, 3H), 2.29 (s,
3H); 13C NMR (CDCl3, 100 MHz): δ 145.8, 145.7, 140.0, 138.8,
135.3, 135.1, 129.9, 129.7, 129.1, 128.8, 127.5, 126.9, 125.7,
124.9, 109.1, 21.3, 20.9; HRMS (ESI) m/z calcd for C23H21N2S
[M + H]+: 357.1420, found: 357.1415.
Yield: 21.6 mg (58%); time: 5.0 h; brown liquid; TLC, Rf = 0.40
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 8.07 (d, 2H,
1
J = 8.8 Hz), 7.92 (s, 1H), 7.34–7.28 (m, 8H), 7.19 (d, 2H, J =
8.8 Hz), 7.14 (d, 2H, J = 6.8 Hz); 13C NMR (CDCl3, 100 MHz):
δ 149.0, 145.8, 139.6, 129.7, 129.3, 129.0, 128.5, 128.1, 128.0,
125.1, 124.9, 124.1, 105.3; HRMS (ESI) m/z calcd for
C21H15N3O2SNa [M + Na]+: 396.0777, found: 396.0774.
5-(4-Methoxyphenyl)-1-phenyl-4-(p-tolylthio)-1H-pyrazole (3c)
Yield: 25.3 mg (68%); time: 4.0 h; brown liquid; TLC, Rf = 0.41
1
1-(4-Nitrophenyl)-5-phenyl-4-(p-tolylthio)-1H-pyrazole (3i)
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 7.84 (s, 1H),
7.31–7.29 (m, 5H), 7.10 (d, 2H, J = 8.8 Hz), 7.06 (s, 4H), 6.81 (d, Yield: 24.0 mg (62%); time: 4.0 h; brown liquid; TLC, Rf = 0.42
1
2H, J = 8.8 Hz), 3.78 (s, 3H), 2.29 (s, 3H); 13C NMR (CDCl3, (PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 8.17 (d, 2H,
100 MHz): δ 159.9, 145.7, 140.0, 135.23, 135.19, 131.3, 129.7, J = 9.2 Hz), 7.88 (s, 1H), 7.44 (d, 2H, J = 9.2 Hz), 7.42–7.35 (m,
128.9, 127.4, 126.8, 124.9, 113.8, 55.2, 20.9; HRMS (ESI) m/z 3H), 7.19 (d, 2H, J = 6.8 Hz), 7.06 (s, 4H), 2.30 (s, 3H); 13C NMR
calcd for C23H21N2OS [M + H]+: 373.1369, found: 373.1372.
(CDCl3, 100 MHz): δ 145.7, 144.5, 136.0, 133.9, 129.9, 129.8,
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129.5, 128.8, 127.7, 124.44, 124.40, 112.3, 20.9; HRMS (ESI) 4-((4-Azidophenyl)thio)-1,3-diphenyl-5-(p-tolyl)-1H-pyrazole
m/z calcd for C22H18N3O2S [M
+
H]+: 388.1114, found: (7e)
388.1108.
Yield: 26.2 mg (57%); time: 3.0 h; brown liquid; TLC, Rf = 0.32
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 7.90 (d, 2H,
1
1,5-Diphenyl-4-(phenylselanyl)-1H-pyrazole (3j)
J = 8.4 Hz), 7.34–7.30 (m, 8H), 7.19 (d, 4H, J = 7.2 Hz), 7.07 (d,
2H, J = 8.4 Hz), 6.87 (d, 2H, J = 8.8 Hz), 2.36 (s, 3H); 13C NMR
(CDCl3, 100 MHz): δ 154.4, 148.1, 139.7, 138.3, 137.0, 135.5,
130.0, 129.1, 129.06, 129.03, 128.8, 128.3, 127.7, 127.6, 127.2,
124.9, 119.7, 105.5, 21.3; HRMS (ESI) m/z calcd for
C28H21N5SNa [M + Na]+: 482.1410, found: 482.1423.
Yield: 23.3 mg (62%); time: 4.0 h; brown liquid; TLC, Rf = 0.39
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 7.88 (s, 1H),
1
7.31–7.27 (m, 10H), 7.23–7.21 (m, 2H), 7.18–7.15 (m, 3H); 13C
NMR (CDCl3, 100 MHz): δ 146.4, 145.9, 139.9, 133.2, 130.2,
129.5, 129.3, 129.1, 128.83, 128.76, 127.5, 126.2, 124.8, 103.6;
HRMS (ESI) m/z calcd for C21H16N2SeNa [M + Na]+: 399.0371,
found: 399.0365.
1,3,5-Triphenyl-4-(p-tolylthio)-1H-pyrazole (7f)
Yield: 22.6 mg (54%); time: 2.5 h; brown liquid; TLC, Rf = 0.27
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 8.76 (s, 1H),
1
1,3-Diphenyl-4-(phenylthio)-5-(p-tolyl)-1H-pyrazole (7a)
7.98 (d, 2H, J = 7.6 Hz), 7.66–7.63 (m, 2H), 7.46–7.34 (m, 9H),
7.21 (d, 2H, J = 8.8 Hz), 7.15 (d, 2H, J = 8.0 Hz), 7.07 (d, 2H, J =
8.0 Hz), 2.31 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 143.4,
135.9, 135.6, 134.7, 134.5, 131.9, 129.7, 129.1, 128.7, 128.4,
126.6, 125.6, 121.4, 114.3, 104.0, 100.0, 21.0; HRMS (ESI) m/z
calcd for C28H22N2SNa [M + Na]+: 441.1396, found: 441.1407.
Yield: 40.9 mg (98%); time: 2.0 h; brown liquid; TLC, Rf = 0.25
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 7.90 (d, 2H,
1
J = 8.0 Hz), 7.35–7.15 (m, 15H), 7.11–7.06 (m, 3H), 2.33 (s, 3H);
13C NMR (CDCl3, 100 MHz): δ 154.6, 148.2, 139.8, 139.3, 138.1,
130.1, 129.3, 129.1, 129.0, 128.98, 128.90, 128.8, 128.2, 127.8,
127.5, 125.6, 124.93, 124.87, 105.4, 21.3; HRMS (ESI) m/z calcd
for C28H22N2SK [M + K]+: 457.1135, found: 457.1141.
1,3-Diphenyl-4-(phenylselanyl)-5-(p-tolyl)-1H-pyrazole (7h)
Yield: 24.2 mg (52%); time: 2.0 h; brown liquid; TLC, Rf = 0.26
4-((4-Methoxyphenyl)thio)-1,3-diphenyl-5-(p-tolyl)-1H-pyrazole
(7b)
1
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 7.87 (d, 2H,
J = 8 Hz), 7.34–7.28 (m, 9H), 7.19 (d, 9H, J = 6.8 Hz);2.37 (s,
3H); 13C NMR (CDCl3, 100 MHz): δ 148.4, 139.9, 138.1, 134.3,
130.3, 129.9, 129.8, 129.1, 128.9, 128.78, 128.76, 128.4, 128.2,
127.4, 125.7, 124.9, 101.4, 21.3; HRMS (ESI) m/z calcd for
C28H22N2SeK [M + K]+: 489.0840, found: 489.0853.
Yield: 31.8 mg (71%); time: 2.0 h; brown liquid; TLC, Rf = 0.25
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 8.10 (d, 2H,
1
J = 8.0 Hz), 7.49–7.42 (m, 8H), 7.38–7.34 (m, 4H), 7.17 (d, 2H,
J = 8.8 Hz), 6.90 (d, 2H, J = 8.8 Hz), 3.88 (s, 3H), 2.52 (s, 3H);
13C NMR (CDCl3, 100 MHz): δ 130.2, 129.7, 129.5, 129.3, 129.0,
128.8, 128.2, 128.0, 127.9, 127.4, 124.9, 114.6, 107.1, 55.2, 21.3;
HRMS (ESI) m/z calcd for C29H24N2OSNa [M + Na]+: 471.1502,
found: 471.1511.
4-(4-(Phenylthio)-5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)
benzenesulfonamide (9)
Yield: 27 mg (55%). Time: 6 h. White solid. TLC Rf = 0.21
(PE : EtOAc = 5 : 1) 1H NMR (CDCl3, 400 MHz): δ 7.88(d, 2H, J =
8.0 Hz), 7.44 (d, 2H, J = 12.0 Hz), 7.21 (t, 2H, J = 8.0 Hz), 7.15
(m, 3H), 7.07 (d, 2H, J = 8.0 Hz), 7.03 (d, 2H, J = 8.0 Hz), 4.95
(brs, 2H), 2.30 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 149.5,
142.3, 141.3, 140.3, 137.0, 129.8 (q, JCF = 22.0 Hz), 128.9, 127.5,
127.2, 126.0, 125.2, 125.0(q, JCF = 256.0 Hz), 124.1, 108.8, 21.4;
19F NMR (CDCl3, 376.3 MHz): δ −62.0; HRMS (ESI) m/z calcd
for C23H19F3N3O2S2 [M + H]+: 490.0865 found: 490.0876.
4-((2-Bromophenyl)thio)-1,3-diphenyl-5-(p-tolyl)-1H-pyrazole
(7c)
Yield: 32.3 mg (65%); time: 2.5 h; brown liquid; TLC, Rf = 0.26
1
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 7.87 (d, 2H,
J = 8.4 Hz), 7.46 (d, 1H, J = 8.0 Hz), 7.35–7.26 (m, 9H), 7.16 (d,
3H, J = 7.2 Hz), 7.12 (dd, 1H, J = 7.6, 1.6 Hz), 6.93 (t, 2H, J =
8.0 Hz), 2.33 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 154.6,
148.4, 140.3, 139.8, 138.4, 132.8, 130.0, 129.2, 129.1, 129.0,
128.93, 128.87, 128.4, 127.8, 127.7, 126.3, 125.9, 125.0, 119.9,
104.9; HRMS (ESI) m/z calcd for C28H21BrN2SNa [M + Na]+:
519.0506, 521.0486, found: 519.0511, 521.0489.
Conflicts of interest
There are no conflicts to declare.
4-((4-Nitrophenyl)thio)-1,3-diphenyl-5-(p-tolyl)-1H-pyrazole (7d)
Yield: 35.7 mg (77%); time: 2.0 h; brown liquid; TLC, Rf = 0.30
(PE : EtOAc = 95 : 5); H NMR (CDCl3, 400 MHz): δ 7.98 (d, 2H,
J = 8.8 Hz), 7.76 (d, 2H, J = 8.0 Hz), 7.28–7.24 (m, 8H),
1
Acknowledgements
7.13–7.10 (m, 6H), 2.28 (s, 3H); 13C NMR (CDCl3, 100 MHz): This work was supported by the Natural Science Foundation of
δ 154.5, 149.1, 148.4, 145.1, 139.5, 138.7, 130.9, 129.8, 129.3, China (No. 21901179), the Key Research and Development
129.2, 129.0, 128.8, 128.6, 128.5, 127.8, 127.6, 125.0, 124.9, Program of Shanxi Province (International Cooperation) (No.
124.1, 103.0, 21.3; HRMS (ESI) m/z calcd for C28H22N3O2S 201803D421093) and the Natural Science Foundation of
[M + H]+: 464.1427, found: 464.1420.
Shanxi Province (No. 201901D211052).
This journal is © The Royal Society of Chemistry 2020
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