(2 + 1 + 1 + 1)-Annulation Reactions of Aryldiazonium Tetrafluoroborates with Sulfur Ylides to Polysubstituted Pyrazoles

Article abstract of DOI:10.1021/acs.joc.1c00949

Novel divergent domino annulation reactions of sulfur ylides with aryldiazonium tetrafluoroborates have been developed, affording various tetra- and trisubstituted pyrazole derivatives in moderate to good yields. Three molecules of sulfur ylides were appl

Full text of DOI:10.1021/acs.joc.1c00949

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(2 + 1 + 1 + 1)-Annulation Reactions of Aryldiazonium
Tetrafluoroborates with Sulfur Ylides to Polysubstituted Pyrazoles
Fengkai Qiu, Yu Cao, Linghui Zeng, Chong Zhang, Liping Fu, Jiankang Zhang,* Huajian Zhu,*
and Jiaan Shao*
Cite This: J. Org. Chem. 2021, 86, 8997−9006
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ABSTRACT: Novel divergent domino annulation reactions of
sulfur ylides with aryldiazonium tetrafluoroborates have been
developed, affording various tetra- and trisubstituted pyrazole
derivatives in moderate to good yields. Three molecules of sulfur
ylides were applied as C1 synthon to construct the complex
products with five new chemical bonds formed in these one-pot reactions.
Inspired by Xu’s work, we deduced that new chemical
transformations might be realized when aryldiazonium salts are
reacting with multiple equivalents of sulfur ylides. In view of
our long-standing interests in exploring new methodologies of
sulfur ylides,7 we herein reported a type of (2 + 1 + 1 + 1)-
annulation reaction, in which various polysubstituted pyrazoles
were obtained from reactions of aryldiazonium tetrafluorobo-
rates with three molecules of sulfur ylides (Scheme 1, eq 3).
INTRODUCTION
■
Sulfur ylides are readily accessible and classical reagents widely
used as one-carbon units. Due to their inherent zwitterionic
property and reactivity, sulfur ylide-initiated reactions are
considered as effective approaches to achieve varieties of
organic transformations in organic chemistry.1 Over the past
decades, the development of tandem reactions with sulfur
ylides has provided one of the most advantageous strategies for
the construction of structurally diverse carbo- or heterocyclic
compounds.2 Although great progress has been made in sulfur
ylide-related chemistry, there is still room for researchers to
extend the application of sulfur ylides in organic synthesis, as
new reagents or reaction types are emerging successively.
Aryldiazonium salts are known as readily available and
inexpensive chemicals that have been applied as versatile
building blocks for a number of organic syntheses.3 One of the
reaction modes of aryldiazonium salts is acting as highly
reactive electrophiles. Under this mechanism, aryldiazonium
salts are usually attacked by nucleophiles to generate a range of
nitrogen-containing compounds.4 Aryldiazonium salts have
been reported to react with stabilized sulfur ylides, resulting in
nitrilimine intermediates, which could further proceed a 1,3-
dipolar dimerization or react with another reactive functional
reagent to construct a variety of nitrogen-containing
heterocyclic compounds (Scheme 1, eq 1). In the above
cases, aryldiazonium salts and sulfur ylides usually reacted
equivalently with each other.5 Recently, Xu’s group reported an
interesting synthesis of highly functionalized hydrazones using
α-diazo-β ketoesters/ketones and dimethylsulfonium ylides as
starting materials. In this transformation, zwitterionic inter-
mediates generated from addition of dimethylsulfonium ylides
with diazo compounds could be further attacked by another
molecule of dimethylsulfonium ylides. As a result, two
molecules of dimethylsulfonium ylides were involved during
the reaction process (Scheme 1, eq 2).6
RESULTS AND DISCUSSION
■
Our inquiry began with the reaction of stabilized sulfur ylide 1a
with aryldiazonium tetrafluoroborate 2a. First, a 2:1 mixture of
1a and 2a was stirred in acetonitrile at 20 °C for 48 h in the
presence of TEA, DBU, or DABCO; no major products were
generated (Table 1, entries 1−3). To our delight, when 3.0
equiv of NaHCO3 was used as an additive, two major products
were isolated in 16 and 28% yields, respectively (Table 1, entry
4). A similar result was gained when Na2CO3 was applied in
the reaction (Table 1, entry 5). The products were further
identified as polysubstitutedpyrazole 3a and 4a. As we all
know, pyrazole is a privileged scaffold with broad pharma-
ceutical activities in medicinal chemistry. Commercial drugs
such as Celecoxib, Difenamizole, Ruxolitinib, as well as
Crizotinib are featured with pyrazole moieties.8 Besides,
functional pyrazoles are valuable building blocks which could
be further transferred to more complex drug-like molecules by
late-stage modifications. In this sense, the development of a
synthesis method for functional pyrazoles would be an
important advance.
Received: April 23, 2021
Published: June 16, 2021
https://doi.org/10.1021/acs.joc.1c00949
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 8997−9006
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Scheme 1. Reactions of Sulfur Ylides or Sulfonium Ylides with Diazo Compounds
Encouraged by the initial results, other inorganic bases were
then screened for further optimization of these trans-
formations. As listed in Table 1, in the presence of K2CO3,
KOH, NaH, or NaOH, 4a was obtained as a major product
(Table 1, entries 6−9). NaOH was proven to be superior to
other bases with an 80% yield of 4a (Table 1, entry 9). Besides,
the amount of base seemed to be an influencing factor for the
conversions of these reactions. Reducing the amount of bases
led to the formation of major product 3a (Table 1, entries 10−
12), among which NaOH was still the most effective base
(Table 1, entry 11). As we expected, increasing the amount of
NaOH led to 4a as the major product with a yield of 64%
(Table 1, entry 13). Further screening of solvents showed that
acetonitrile was the best solvent (Table 1, entries 9 and 14−
20). Furthermore, reducing or increasing the amount of 2a was
not conducive to the yields of products (Table 1, entries 21
and 22). It should be pointed out that each molecule of
diazonium salt would react with three molecules of sulfur ylide
to afford products theoretically; however, due to the instability
of diazonium salts in the presence of bases, the amount of
diazonium salts was set to be excessive in comparison with that
of sulfur ylides, so a 2:1 ration of 1a and 2a was considered to
be the most suitable. Based on the above investigation, the
optimal conditions for synthesis of 3a and 4a were set as
entries 11 and 9 in Table 1, respectively. Besides, previous
work has been reported that 1,4-dihydrotetrazin-1,2,4,5-
tetrazines can be obtained as major products when the
methanol solution of sulfur ylides was added dropwise to the
solution of diazonium salts.5b Interestingly, only a trace of 1,4-
dihydrotetrazin-1,2,4,5-tetrazines was detected under the
optimal conditions; this is possibly due to the fact that sulfur
ylides were always in a higher concentration than the key
intermediate during the reaction process, thus effectively
avoiding the 1,3-dipolar dimerization of nitrilimine intermedi-
ates to form 1,4-dihydrotetrazin-1,2,4,5-tetrazines as the
literature reported.
With the optimal conditions in hand, we then explored the
scope of substrates for these sequential (2 + 1 + 1 + 1) tandem
reactions. As listed in Table 2, some kinds of tetrasubstituted
pyrazole derivatives 3 could be obtained in accepted yields in
the presence of 1.0 mmol of NaOH. Phenyldiazonium
tetrafluoroborate and aryldiazonium tetrafluoroborates with a
methyl or methoxyl group on the benzene ring (Table 2, 3a, 3i,
and 3b) could be carried out in slightly better yields than that
with a fluorine substituent (Table 2, 3k). A strong electron-
withdrawing substitute, such as a nitro group on the benzene
ring of aryldiazonium tetrafluoroborate, was intolerant to the
reaction, and only a trace of the product was observed (Table
2, 3l). Sulfur ylides with electron-donating substitutes on the
benzene ring led to slightly higher yields than those with
halogen substitutes (Table 2, 3f−3h vs 3c−3e); however, all of
them were obtained in lower yields than unsubstituted sulfur
ylides (Table 2, 3b). As expected, the positions of methyl on
the benzene ring of sulfur ylides had little effect on the yields
(Table 2, 3f−3h). In addition, sulfur ylide with 2-naphthyl
attached at the carbonyl was found to be tolerable to the
reaction (Table 2, 3j). Unfortunately, when 1-(dimethyl-l4-
sulfanylidene)-4-phenylbutan-2-one or methyl 2-(dimethyl-l4-
sulfanylidene)acetate was applied as a starting material, only a
trace amount of products was detected. Besides, it should be
pointed out that trisubstituted pyrazole compounds were
detected as major byproducts under the standard reaction
conditions when 2.0 equiv of NaOH was used as an additive,
which was responsible for the relatively lower yields of some
tetrasubstituted pyrazoles 3.
Trisubstituted pyrazole compounds 4 could be obtained in
the presence of 1.5 mmol of NaOH. As listed in Table 3, some
kinds of aryldiazonium tetrafluoroborates could be applied in
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a
Table 1. Optimization of the Reaction Conditions
b
entry
solvent
base/equiv
major product (yield, %)
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Et2O
TEA/3.0
DBU/3.0
3a (<5%), 4a (<5%)
3a (<5%), 4a (<5%)
3a (<5%), 4a (<5%)
3a (16%), 4a (28%)
3a (22%), 4a (34%)
4a (55%)
4a (62%)
4a (69%)
4a (80%)
3a (51%)
3a (70%)
3a (65%)
4a (64%)
3a (<5%), 4a (<5%)
4a (30%)
4a (65%)
4a (60%)
4a (57%)
4a (71%)
DABCO/3.0
NaHCO3/3.0
Na2CO3/3.0
K2CO3/3.0
KOH/3.0
NaH/3.0
9
NaOH/3.0
NaOH/1.6
NaOH/2.0
K2CO3/2.0
NaOH/4.0
NaOH/3.0
NaOH/3.0
NaOH/3.0
NaOH/3.0
NaOH/3.0
NaOH/3.0
NaOH/3.0
NaOH/3.0
NaOH/3.0
10
11
12
13
14
15
16
17
18
19
20
CH2Cl2
THF
DMF
EtOH
MeOH
DMSO
CH3CN
CH3CN
3a (<5%), 4a (<5%)
4a (30%)
4a (71%)
c
21
22
d
a
The reaction was carried out with 1a (0.2 mmol, 2.0 equiv), 2a (0.1 mmol, 1.0 equiv), base and solvent (2 mL), 20 °C, 48 h, under air
b
c
d
atmosphere. Isolated yields were calculated according to 1a after column chromatography. 1a (0.2 mmol), 1a:2a = 3:1. 1a (0.2 mmol), 1a:2a =
3:2. TEA = Triethylamine. DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene. Dabco = 1,4-Diazabicyclo[2.2.2]octane.
the reactions to generate the products 4 in moderate to good
yields. Among them, aryldiazonium tetrafluoroborates with
electron-donating groups on the benzene ring were generally
proceeded better than those with electron-withdrawing
substituents (Table 3, 4a vs 4b−4g; 4q vs 4i). The reactions
can also be applied to sulfur ylides with −F, −Cl, −Br, −NO2,
or −CN on the benzene ring in moderate yields (Table 3, 4h−
4l). To our surprise, sulfur ylides bearing an electron-donating
group such as a methyl group on the benzene ring were
unfavorable for the transformations; tetrasubstituted pyrazoles
3f and 3g were obtained as major products instead of the
desired products even when increasing the amounts of NaOH
or prolonging the reaction time. The possible reason is that a
methyl group might weaken the electrophilic ability of a
carbonyl group and further affect the subsequent removal of
aroyl groups. To our delight, diazonium tetrafluoroborate with
biphenyl, sulfur ylides with 2-naphthyl or 2-thienyl attached to
the carbonyl can also be well tolerated (Table 3, 4p, 4o, and
4m).
d]pyridazine compound 4fb could be efficiently obtained in 70
and 97% yield, respectively (Scheme 2, eq 1).
At last, to gain insight into the reaction mechanism, a
control experiment was carried out (Scheme 2, eq 2). When 3a
(1.0 equiv) was treated with NaOH (0.5 equiv) in CH3CN at
20 °C for 24 h, 4a was generated in 22% yield.
Based on the above-mentioned results, a possible mecha-
nism for this domino reaction is proposed in Scheme 3.
Initially, nucleophilic attack of sulfur ylides 1 on aryldiazonium
tetrafluoroborates 2 leads to formation of a new C−N bond to
generate the intermediate I′. Intermediate I′ would further
convert to the zwitterionic nitrilimine II,5b which could be
attacked by the other two molecules of sulfur ylides through a
repeated SN2 reaction process to form intermediate IV. A
subsequent intramolecular nucleophilic attack of intermediate
IV provides the dihydropyrazole intermediate V. Aromatiza-
tion of intermediates V under the air atmosphere leads to the
desired product 3. However, there may be two possible
pathways for the formation of product 4. In pathway a,
breaking of the C−C bond between 5-arylformyl and the
pyrazole nucleus in the presence of NaOH results in the
transformation from 3 to 4. However, pathway b cannot be
excluded either. In this pathway, intermediate IV might
undergo a deacylation process in the presence of NaOH to
afford intermediate V′ which would go through an intra-
molecular cyclization followed by aromatization to provide
product 4.
1
The structures of all products were characterized by H
NMR, 13C NMR, and HRMS. Moreover, the structures of 3k
and 4h were further identified by single-crystal X-ray
diffraction (Table 2, 3k, CCDC 2064733; Table 3, 4h,
CCDC 2064734).
In order to better expand the application of these methods,
4f was selected for the late-stage modifications. As displayed in
Scheme 2, aryl methanol compound 4fa and pyrazolo[3,4-
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a
Table 2. Substrate Scope of Tetrasubstituted Pyrazole Compounds 3
a
Reaction conditions: 1 (1.0 mmol, 2.0 equiv), 2 (0.5 mmol, 1.0 equiv), NaOH (1.0 mmol, 2.0 equiv), and CH3CN (10 mL), 20 °C, 48 h, under
air atmosphere. Isolated yields were calculated according to sulfur ylides after column chromatography.
buffer B in A (B, CH3OH containing 0.1% formic acid; A, H2O
containing 0.1% formic acid). Mobile phase B was increased linearly
from 5 to 95% over 7 min and 95% over the next 2 min, after which
the column was equilibrated to 5% for 1 min. The X-ray diffraction
CONCLUSIONS
■
In conclusion, we have developed novel divergent domino
annulation reactions of stabilized sulfur ylides and aryldiazo-
nium tetrafluoroborates for the synthesis of polysubstituted
pyrazole derivatives in moderate to good yields under mild
conditions. In these (2 + 1 + 1 + 1)-annulation reactions, three
molecules of sulfur ylides were applied as C1 synthon to
construct the complex products with five new chemical bonds
formed in the one-pot reactions. Good generality, mild
reaction conditions, easily manufactured start materials, as
well as no need for precious catalysts are all advantages for this
method. We believe that these interesting chemical trans-
formations will be a supplement to the synthetic diversities of
sulfur ylides and attract research interest from organic chemists
and pharmacologists.
measurements were carried out on a Rigaku RAXIS-RAPID single-
crystal diffractometer. The reactions were monitored by thin layer
chromatography (TLC) using silica gel GF254. Aryldiazonium
tetrafluoroborates and sulfur ylides were synthesized according to
the literature procedure.9,10
Typical Procedure for Synthesis of Product 3. A mixture of
sulfur ylide (1.0 mmol, 2.0 equiv), aryl diazonium tetrafluoroborate
(0.5 mmol, 1.0 equiv), and NaOH (1.0 mmol, 2.0 equiv) was stirred
in 10 mL of CH3CN at 20 °C for 48 h under an air atmosphere. After
the completeness of the reaction, the solvent was removed, and the
crude product was carried out by chromatography to afford 3a−3k as
desired products.
(1-(p-Tolyl)-1H-pyrazole-3,4,5-triyl)tris(phenylmethanone)
(3a). Purified by column chromatography (silica gel, petroleum:-
1
EtOAc = 8:1), white solid (110 mg, 70%), mp 128.9−130.8 °C. H
EXPERIMENTAL SECTION
■
NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.2 Hz, 2H), 7.67 (d, J = 7.2
Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H), 7.59−7.54 (m, 1H), 7.47−7.42 (m,
4H), 7.37 (d, J = 7.6 Hz, 2H), 7.30−7.26 (m, 4H), 7.19 (d, J = 7.2
Hz, 2H), 2.35 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 189.7,
186.9, 186.8, 149.8, 141.4, 139.5, 138.0, 136.5, 136.5, 136.4, 134.4,
133.5, 133.2, 130.7, 130.1, 129.7, 129.1, 128.8, 128.5, 126.9, 124.5,
21.3. HRMS (ESI) m/z: [M + H]+ calcd for C31H23N2O3 471.1703;
found 471.1700.
General Information. Unless otherwise noted, all reagents and
solvents were purchased from commercial sources and used without
purification. Purifications of reaction products were carried out by
chromatography using silica gel (200−300 mesh). Melting points
̈
were recorded on a BUCHI B-540 melting point apparatus. NMR
spectra were recorded for 1H NMR at 400 MHz and for 13C NMR at
100 MHz. For 1H NMR, tetramethylsilane (TMS) served as the
internal standard (δ = 0) and data are reported as follows: chemical
shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), and coupling constant(s) in Hz. For 13C
NMR, CDCl3 (δ = 77.26) or DMSO-d6 (δ = 39.6) was used as the
internal standard and spectra were obtained with complete proton
decoupling. HPLC analysis and the HRMS of all final products were
confirmed on an Agilent 1290 HPLC-6224 Time of Fight Mass
Spectrometer using a PhenomenexLuna 5μ C18, 100 Å, 150 × 4.60
mm 5 μm column at a flow rate of 0.5 mL/min using linear gradient
(1-Phenyl-1H-pyrazole-3,4,5-triyl)tris(phenylmethanone)
(3b). Purified by column chromatography (silica gel, petroleum:-
1
EtOAc = 8:1), white solid (108 mg, 71%), mp 128.9−130.8 °C. H
NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.2 Hz, 2H), 7.68 (d, J = 7.6
Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.52−7.38
(m, 9H), 7.30 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.6 Hz, 2H). 13C{1H}
NMR (100 MHz, CDCl3) δ 189.5, 186.7, 186.5, 149.8, 141.2, 138.7,
137.8, 136.2, 136.2, 134.3, 133.4, 133.1, 130.5, 129.5, 129.3, 129.1,
9000
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a
Table 3. Substrate Scope of Trisubstituted Pyrazole Compounds 4
a
Reaction conditions: 1 (1.0 mmol, 2.0 equiv), 2 (0.5 mmol, 1.0 equiv), NaOH (1.5 mmol, 3.0 equiv), and CH3CN (10 mL), 20 °C, 48 h, under
b
air atmosphere. Scale-up reaction with 10 mmol of sulfur ylide and 5 mmol of aryldiazonium tetrafluoroborate. Isolated yields were calculated
according to sulfur ylides after column chromatography.
Scheme 2. Late-Stage Modifications of 4f and Control Reaction
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Scheme 3. Plausible Mechanisms for the Formation of 3 and 4
128.9, 128.6, 128.3, 126.9, 124.5. HRMS (ESI) m/z: [M + H]+ calcd
for C30H21N2O3 457.1547; found 457.1550.
J = 22.0 Hz), 115.9 (d, J = 22.0 Hz), 115.8 (d, J = 21.7 Hz). HRMS
(ESI) m/z: [M + H]+ calcd for C30H18F3N2O3 511.1264; found
511.1270.
(1-Phenyl-1H-pyrazole-3,4,5-triyl)tris((4-bromophenyl)-
methanone) (3c). Purified by column chromatography (silica gel,
petroleum:EtOAc = 8:1), white solid (106 mg, 46%), mp 138.2−
(1-Phenyl-1H-pyrazole-3,4,5-triyl)tris((4-chlorophenyl)-
methanone) (3e). Purified by column chromatography (silica gel,
petroleum:EtOAc = 8:1), white solid (86 mg, 46%), mp 185.2−187.0
1
140.1 °C. H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.8 Hz, 2H),
1
7.62 (d, J = 8.8 Hz, 2H), 7.55 (t, J = 8.8 Hz, 4H), 7.50−7.44 (m, 6H),
7.43−7.40 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 188.5,
185.4, 185.1, 149.4, 140.9, 138.5, 136.3, 134.7, 134.6, 132.2, 132.1,
131.9, 131.8, 130.9, 130.4, 130.2, 129.6, 129.5, 129.2, 128.8, 126.8,
124.4. HRMS (ESI) m/z: [M + H]+ calcd for C30H18Br3N2O3
690.8862; found 690.8864.
°C. H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 6.8 Hz, 2H), 7.70−
7.58 (m, 4H), 7.50−7.38 (m, 7H), 7.35−7.25 (m, 4H). 13C{1H}
NMR (100 MHz, CDCl3) δ 188.2, 185.1, 184.8, 149.3, 141.3, 140.9,
140.3, 139.9, 138.4, 135.9, 134.3, 134.2, 132.1, 130.8, 130.3, 129.5,
129.5, 129.2, 128.9, 128.8, 126.8, 124.3. HRMS (ESI) m/z: [M + H]+
calcd for C30H18Cl3N2O3 559.0378; found 559.0382.
(1-Phenyl-1H-pyrazole-3,4,5-triyl)tris((4-fluorophenyl)-
methanone) (3d). Purified by column chromatography (silica gel,
petroleum:EtOAc = 8:1), a white solid (73 mg, 43%), mp 151.0−
(1-Phenyl-1H-pyrazole-3,4,5-triyl)tris(o-tolylmethanone)
(3f). Purified by column chromatography (silica gel, petroleum:-
1
EtOAc = 8:1), white solid (83 mg, 50%), mp 138.2−140.1 °C. H
1
151.9 °C. H NMR (400 MHz, CDCl3) δ 8.34 (dd, J = 8.8, 5.6 Hz,
NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.2
Hz, 3H), 7.41−7.36 (m, 4H), 7.35−7.29 (m, 2H), 7.23−7.17 (m,
3H), 7.16−7.12 (m, 1H), 7.11−7.06 (m, 2H), 7.01 (d, J = 7.4 Hz,
1H), 2.40 (s, 3H), 2.22 (s, 3H), 2.08 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 190.6, 190.0, 187.6, 151.0, 142.5, 140.6, 139.5, 139.4,
138.7, 137.4, 136.4, 135.8, 133.0, 132.0, 131.8, 131.7, 131.6, 131.5,
131.3, 131.2, 130.8, 129.2, 129.1, 127.5, 125.7, 125.3, 125.2, 124.7,
2H), 7.74−7.70 (m, 4H), 7.49−7.41 (m, 5H), 7.15 (t, J = 8.6 Hz,
2H), 7.02−6.97 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 188.2,
185.0, 184.7, 166.5 (d, J = 256.9 Hz), 166.3 (d, J = 254.5 Hz), 166.0
(d, J = 254.3 Hz), 149.6, 141.0, 138.7, 134.2 (d, J = 2.8 Hz), 133.6 (d,
J = 9.5 Hz), 132.6 (d, J = 2.8 Hz), 132.5 (d, J = 10.0 Hz), 132.4 (d, J
= 2.8 Hz), 131.8 (d, J = 9.5 Hz), 129.6, 129.5, 127.0, 124.5, 116.3 (d,
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20.9, 20.6, 20.5. HRMS (ESI) m/z: [M + H]+ calcd for C33H27N2O3
499.2016; found 499.2020.
CH3CN at 20 °C for 48 h under an air atmosphere. After the
completeness of the reaction, the solvent was removed, and the crude
product was carried out by chromatography (silica gel, petroleum:-
EtOAc = 10:1) to afford 4f as a white solid (430 mg, 30%).
(1-Phenyl-1H-pyrazole-3,4,5-triyl)tris(m-tolylmethanone)
(3g). Purified by column chromatography (silica gel, petroleum:-
1
EtOAc = 8:1), white solid (85 mg, 51%), mp 150.2−152.1 °C. H
(1-(p-Tolyl)-1H-pyrazole-3,4-diyl)bis(phenylmethanone)
NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.87 (s, 1H),
7.53−7.46 (m, 4H), 7.42−7.36 (m, 6H), 7.34−7.38 (m, 2H), 7.25−
7.14 (m, 3H), 2.36 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 189.5, 187.3, 186.7, 150.0, 141.4, 138.8, 138.6,
138.1, 138.1, 137.9, 136.4, 136.3, 135.0, 134.2, 133.7, 130.6, 129.9,
129.3, 129.0, 128.6, 128.2, 127.8, 126.9, 126.8, 126.2, 124.5, 21.3,
21.0, 21.0. HRMS (ESI) m/z: [M + H]+ calcd for C33H27N2O3
499.2016; found 499.2010.
(4a). Purified by column chromatography (silica gel, petroleum:-
1
EtOAc = 8:1), white solid (98 mg, 80%), mp 99.3−101.0 °C. H
NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.14−7.99 (m, 2H), 7.89−
7.76 (m, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.60−7.48 (m, 2H), 7.48−
7.35 (m, 4H), 7.31 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 189.2, 188.1, 151.2, 138.3, 138.2, 136.7, 136.7,
133.2, 132.9, 130.2, 130.2, 130.1, 129.1, 128.5, 128.3, 125.0, 119.9,
21.0. HRMS (ESI) m/z: [M + H]+ calcd for C24H19N2O2 367.1441;
found 367.1438.
(1-Phenyl-1H-pyrazole-3,4,5-triyl)tris(p-tolylmethanone)
(3h). Purified by column chromatography (silica gel, petroleum:-
(1-(2-Fluorophenyl)-1H-pyrazole-3, 4-diyl)bis-
(phenylmethanone) (4b). Purified by column chromatography
(silica gel, petroleum:EtOAc = 8:1), white solid (76 mg, 62%), mp
1
EtOAc = 8:1), white solid (85 mg, 51%), mp 203.2−204.9 °C. H
NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0
Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.53−7.47 (m, 2H), 7.39−7.35 (m,
3H), 7.26−7.23 (m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0
Hz, 2H), 2.41 (s, 3H), 2.33 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 189.2, 186.4, 186.4, 149.9, 145.6, 144.3, 143.9,
141.3, 138.9, 135.4, 133.9, 133.8, 130.7, 129.8, 129.4, 129.3, 129.2,
129.1, 129.0, 129.0, 126.7, 124.4, 21.8, 21.8, 21.7. HRMS (ESI) m/z:
[M + H]+ calcd for C33H27N2O3 499.2016; found 499.2021.
(1-(4-Methoxyphenyl)-1H-pyrazole-3,4,5-triyl)tris-
(phenylmethanone) (3i). Purified by column chromatography
(silica gel, petroleum:EtOAc = 6:1), white solid (104 mg, 64%),
mp 119.3−121.0 °C. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 7.2
Hz, 2H), 7.69−7.61 (m, 4H), 7.57 (t, J = 7.4 Hz, 1H), 7.50−7.40 (m,
6H), 7.31−7.28 (m, 2H), 7.27−7.24 (m, 2H), 6.89 (d, J = 9.2 Hz,
2H), 3.79 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 189.5, 186.8,
186.7, 160.0, 149.5, 141.3, 137.8, 136.3, 136.3, 134.3, 133.7, 133.0,
131.8, 130.5, 129.5, 128.9, 128.6, 128.3, 126.5, 125.9, 114.4, 55.5.
HRMS (ESI) m/z: [M + H]+ calcd for C31H23N2O4 487.1652; found
487.1645.
1
118.3−119.5 °C. H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.08
(d, J = 7.2 Hz, 2H), 7.98 (t, J = 7.4 Hz, 1H), 7.84 (d, J = 7.2 Hz, 2H),
7.65−7.52 (m, 2H), 7.49−7.36 (m, 5H), 7.34−7.25 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ 188.8, 188.2, 154.0 (d, J = 250.3
Hz), 151.5, 138.2, 136.7, 134.3 (d, J = 10.4 Hz), 133.5, 133.1, 130.4,
129.6 (d, J = 7.9 Hz), 129.2, 128.6, 128.5, 127.3 (d, J = 9.5 Hz), 125.4
(d, J = 3.8 Hz), 125.0, 124.9, 117.2 (d, J = 20.2 Hz). HRMS (ESI) m/
z: [M + H]+ calcd for C23H16FN2O2 371.1190; found 371.1183.
(1-(3-Fluorophenyl)-1H-pyrazole-3, 4-diyl)bis-
(phenylmethanone) (4c). Purified by column chromatography
(silica gel, petroleum:EtOAc = 8:1), white solid (79 mg, 64%), mp
1
105.6−107.1 °C. H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H),
8.02 (d, J = 7.6 Hz, 2H), 7.97−7.85 (m, 4H), 7.73−7.66 (m, 2H),
7.64−7.50 (m, 5H), 7.31 (t, J = 8.2 Hz, 1H). 13C{1H} NMR (100
MHz, DMSO-d6) δ 193.4, 193.1, 167.7 (d, J = 244.4 Hz), 156.6,
145.3 (d, J = 10.6 Hz), 142.5, 141.3, 139.1, 138.5, 136.8 (d, J = 9.7
Hz), 135.0, 134.4, 134.0 (d, J = 3.5 Hz), 129.2, 120.9, 119.9 (d, J =
21.0 Hz), 112.5 (d, J = 26.3 Hz), 112.3 (d, J = 3.5 Hz). HRMS (ESI)
m/z: [M + H]+ calcd for C23H16FN2O2 371.1190; found 371.1192.
(1-(4-Fluorophenyl)-1H-pyrazole-3, 4-diyl)bis-
(phenylmethanone) (4d). Purified by column chromatography
(silica gel, petroleum:EtOAc = 8:1), a white solid (80 mg, 65%), mp
92.3−94.1 °C. 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.06 (d, J
= 7.2 Hz, 2H), 7.81 (m, 4H), 7.64−7.48 (m, 2H), 7.46−7.32 (m,
4H), 7.30−6.98 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 189.0,
188.0, 162.1 (d, J = 248.6 Hz), 151.6, 138.1, 136.6, 135.3 (d, J = 2.8
Hz), 133.4, 133.0, 130.2, 129.1, 128.5, 128.4, 125.3, 121.9 (d, J = 8.5
Hz), 116.7 (d, J = 23.3 Hz). HRMS (ESI) m/z: [M + H]+ calcd for
C23H16FN2O2 371.1190; found 371.1196.
(1-Phenyl-1H-pyrazole-3,4,5-triyl)tris(naphthalen-2-ylme-
thanone) (3j). Purified by column chromatography (silica gel,
petroleum:EtOAc = 8:1), light pink solid (51 mg, 25%), mp 183.9−
185.8 °C. 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.25 (s, 1H),
8.13 (d, J = 9.2 Hz, 2H), 7.94 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 8.2 Hz,
2H), 7.78−7.70 (m, 4H), 7.69−7.65 (m, 2H), 7.62−7.58 (m, 5H),
7.56−7.50 (m, 3H), 7.46−7.35 (m, 5H). 13C{1H} NMR (100 MHz,
CDCl3) δ 189.6, 186.9, 186.7, 150.3, 141.6, 139.0, 136.2, 135.9, 135.7,
135.5, 133.9, 133.8, 133.3, 133.0, 132.5, 132.3, 132.2, 131.4, 130.1,
129.8, 129.6, 129.5, 129.4, 129.3, 129.0, 128.9, 128.6, 128.5, 128.4,
127.9, 127.8, 127.3, 127.2, 126.8, 126.7, 125.5, 124.6, 124.2, 123.9.
HRMS (ESI) m/z: [M + H]+ calcd for C42H27N2O3 607.2016; found
607.2013.
(1-(4-Fluorophenyl)-1H-pyrazole-3,4,5-triyl)tris-
(phenylmethanone) (3k). Purified by column chromatography
(silica gel, petroleum:EtOAc = 8:1), white solid (88 mg, 56%), mp
163.9−164.8 °C. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 6.0 Hz,
2H), 7.66−7.57 (m, 5H), 7.50−7.45 (m, 6H), 7.35−7.26 (m, 4H),
7.14−7.06 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 189.4,
186.6, 186.4, 162.6 (d, J = 250.2 Hz), 149.8, 141.3, 137.7, 136.2,
136.1, 134.9 (d, J = 3.1 Hz), 134.5, 133.5, 133.2, 130.5, 129.5, 128.9,
128.7, 128.4, 126.9, 126.6 (d, J = 8.9 Hz), 116.4 (d, J = 23.2 Hz).
HRMS (ESI) m/z: [M + H]+ calcd for C30H20FN2O3 475.1452;
found 475.1460.
(1-(4-Chlorophenyl)-1H-pyrazole-3, 4-diyl)bis-
(phenylmethanone) (4e). Purified by column chromatography
(silica gel, petroleum:EtOAc = 10:1), white solid (93 mg,72%), mp
1
105.6−106.8 °C. H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.06
(d, J = 7.6 Hz, 2H), 7.80 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H),
7.59−7.45 (m, 5H), 7.44−7.38 (m, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 188.9, 187.8, 151.6, 138.0, 137.5, 136.5, 133.9, 133.4, 133.0,
130.2, 130.0, 129.9, 129.0, 128.5, 128.3, 125.4, 121.0. HRMS (ESI)
m/z: [M + H]+ calcd for C23H16ClN2O2 387.0895; found 387.0901.
(1-(4-Bromophenyl)-1H-pyrazole-3, 4-diyl)bis-
(phenylmethanone) (4f). Purified by column chromatography
(silica gel, petroleum:EtOAc = 10:1), white solid (143 mg, 79% for 1
mmol scale reaction; 430 mg, 30% for 10 mmol scale reaction), mp
1
Typical Procedure for Synthesis of Product 4. A mixture of
sulfur ylide (1.0 mmol, 2.0 equiv), aryl diazonium tetrafluoroborate
(0.5 mmol, 1.0 equiv), and NaOH (1.5 mmol, 3.0 equiv) was stirred
in 10 mL of CH3CN at 20 °C for 48 h under an air atmosphere. After
the completeness of the reaction, the solvent was removed, and the
crude product was carried out by chromatography to afford 4a−4q as
desired products.
115.6−117.0 °C. H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.06
(d, J = 7.2 Hz, 2H), 7.80 (d, J = 7.2 Hz, 2H), 7.71−7.62 (m, 4H),
7.60−7.56 (m, 1H), 7.55−7.51 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H),
7.39 (t, J = 7.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 188.9,
187.8, 151.7, 138.0, 138.0, 136.5, 133.4, 133.0, 132.8, 130.2, 129.9,
129.0, 128.5, 128.3, 125.4, 121.7, 121.3. HRMS (ESI) m/z: [M + H]+
calcd for C23H16BrN2O2 431.0390; found 431.0397.
Typical procedure for scale-up synthesis of product 4f. A mixture of
2-(dimethyl-l4-sulfanylidene)-1-phenylethan-1-one (10 mmol, 2.0
equiv), 4-bromobenzenediazonium tetrafluoroborate (5 mmol, 1.0
equiv), and NaOH (15 mmol, 3.0 equiv) were stirred in 80 mL of
4-(3,4-Dibenzoyl-1H-pyrazol-1-yl)benzonitrile (4g). Purified
by column chromatography (silica gel, petroleum:EtOAc = 8:1),
white solid (88 mg, 70%), mp 118.9−120.5 °C. 1H NMR (400 MHz,
CDCl3) δ 8.41 (s, 1H), 8.06 (d, J = 7.6 Hz, 2H), 7.95 (d, J = 8.4 Hz,
9003
https://doi.org/10.1021/acs.joc.1c00949
J. Org. Chem. 2021, 86, 8997−9006

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
2H), 7.87−7.75 (m, 4H), 7.64−7.52 (m, 2H), 7.46 (t, J = 7.4 Hz,
2H), 7.41 (t, J = 7.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ
188.6, 187.6, 152.3, 141.8, 137.8, 136.3, 133.9, 133.6, 133.2, 130.2,
130.0, 129.1, 128.6, 128.5, 126.0, 119.9, 117.8, 111.7. HRMS (ESI)
m/z: [M + H]+ calcd for C24H16N3O2 378.1237; found 378.1240.
(1-Phenyl-1H-pyrazole-3,4-diyl)bis((4-fluorophenyl)-
methanone) (4h). Purified by column chromatography (silica gel,
petroleum:EtOAc = 10:1), white solid (84 mg, 65%), mp 134.5−
8.05 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.72
(d, J = 7.6 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H),
7.45 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.29 (t, J = 7.8 Hz,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 187.7, 186.1, 150.7, 139.8,
138.8, 138.2, 136.2, 135.8, 133.1, 131.9, 130.3, 130.1, 129.9, 129.8,
128.8, 128.5, 127.5, 124.8, 122.9, 122.7, 120.0. HRMS (ESI) m/z: [M
+ H]+ calcd for C23H15Br2N2O2 508.9495; found 508.9499.
(1-Phenyl-1H-pyrazole-3,4-diyl)bis(naphthalen-2-ylmetha-
none) (4o). Purified by column chromatography (silica gel,
petroleum:EtOAc = 8:1), white solid (47 mg, 31% yield), mp
1
136.5 °C. H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.26−8.18
(m, 2H), 7.92−7.85 (m, 2H), 7.78 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.6
Hz, 2H), 7.46−7.41 (m, 1H), 7.14 (t, J = 8.6 Hz, 2H), 7.09 (t, J = 8.6
Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 187.9, 186.1, 167.16
(d, J = 254.1 Hz), 164.6 (d, J = 253.5 Hz), 151.1, 139.0, 134.5 (d, J =
2.9 Hz), 133.3 (d, J = 9.4 Hz), 132.9 (d, J = 2.9 Hz), 131.9 (d, J = 9.4
Hz), 130.1, 130.0, 128.5, 125.3, 120.1, 115.9 (d, J = 21.9 Hz), 115.7
(d, J = 21.7 Hz). HRMS (ESI) m/z: [2M + Na]+ calcd for
C46H28F4N4NaO4 799.1939; found 799.1946.
1
138.5−140.0 °C. H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.46
(s, 1H), 8.30 (s, 1H), 8.04−8.01(m, 1H), 7.95−7.73 (m, 9H), 7.68−
7.50 (m, 5H), 7.49−7.41 (m, 2H). 13C{1H} NMR (100 MHz,
CDCl3) δ 187.8, 186.0, 167.3, 167.0, 164.8, 164.5, 151.0, 138.9, 134.4,
134.4, 133.2, 133.1, 132.9, 132.8, 131.8, 131.7, 129.9, 129.9, 128.4,
125.2, 119.9, 115.9, 115.7, 115.6, 115.5. HRMS (ESI) m/z: [2M +
Na]+ calcd for C62H40N4NaO4 927.2942; found 927.2943.
(1-Phenyl-1H-pyrazole-3,4-diyl)bis((4-bromophenyl)-
methanone) (4i). Purified by column chromatography (silica gel,
petroleum:EtOAc = 10:1), white solid (117 mg, 69%), mp 182.1−
(1-([1,1′-Biphenyl]-2-yl)-1H-pyrazole-3,4-diyl)bis-
(phenylmethanone) (4p). Purified by column chromatography
(silica gel, petroleum:EtOAc = 8:1), white solid (101 mg, 71%), mp
115.3−116.5 °C. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 4.4 Hz,
2H), 7.72 (s, 1H), 7.59−7.50 (m, 7H), 7.49−7.46 (m, 4H), 7.43−
7.38 (m, 2H), 7.35−7.27 (m, 2H), 7.26−7.22 (m, 2H). 13C{1H}
NMR (100 MHz, CDCl3) δ 188.4, 188.0, 151.1, 138.3, 137.9, 137.4,
137.3, 136.6, 135.0, 133.2, 132.8, 131.3, 130.3, 129.6, 129.2, 129.0,
128.8, 128.7, 128.4, 128.3, 128.0, 126.4, 123.9. HRMS (ESI) m/z: [M
+ H]+ calcd for C29H21N2O2 429.1598; found 429.1603.
1
182.7 °C. H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.03 (d, J =
8.4 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.62
(d, J = 8.4 Hz, 2H), 7.58−7.50 (m, 4H), 7.46−7.42 (m, 1H). 13C{1H}
NMR (100 MHz, CDCl3) δ 188.2, 186.4, 150.7, 138.8, 136.7, 135.1,
131.9, 131.7, 130.5, 130.1, 129.8, 128.8, 128.4, 128.3, 125.0, 119.9.
HRMS (ESI) m/z: [M + H]+ calcd for C23H15Br2N2O2 508.9495;
found 508.9495.
(1-Phenyl-1H-pyrazole-3,4-diyl)bis((4-chlorophenyl)-
methanone) (4j). Purified by column chromatography (silica gel,
petroleum:EtOAc = 10:1), white solid (63 mg, 45%), mp 162.3−
(1-(4-Methoxyphenyl)-1H-pyrazole-3,4-diyl)bis((4-
bromophenyl)methanone) (4q). Purified by column chromatog-
raphy (silica gel, petroleum:EtOAc = 7:1), white solid (167 mg, 93%),
1
164.0 °C. H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.19−8.02
(m, 2H), 7.88−7.65 (m, 4H), 7.56−7.52 (m, 2H), 7.46−7.42 (m,
3H), 7.40−7.35 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 188.0,
186.2, 150.8, 140.0, 139.6, 138.7, 136.4, 134.8, 131.8, 130.5, 130.1,
129.9, 128.9, 128.8, 128.4, 125.1, 120.0. HRMS (ESI) m/z: [2M +
Na]+ calcd for C46H28Cl2N4NaO4 863.0757; found 863.0753.
4,4′-(1-Phenyl-1H-pyrazole-3,4-dicarbonyl)dibenzonitrile
(4k). Purified by column chromatography (silica gel, petroleum:-
1
mp 158.0−160.0 °C. H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H),
8.01 (d, J = 8.8 Hz, 2H), 7.77−7.65 (m, 4H), 7.61 (d, J = 8.6 Hz,
2H), 7.55 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 188.3, 186.4, 159.7, 150.5,
136.9, 135.3, 132.4, 132.0, 131.9, 131.7, 130.5, 130.1, 128.8, 128.2,
121.6, 114.9, 55.7. HRMS (ESI) m/z: [M + H]+ calcd for
C24H17Br2N2O3 538.9600; found 538.9605.
1
EtOAc = 5:1), white solid (67 mg, 50%), mp 140.5−141.6 °C. H
NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.29 (d, J = 8.4 Hz, 2H),
7.94 (d, J = 8.4 Hz, 2H), 7.78 (t, J = 8.6 Hz, 4H), 7.74 (d, J = 8.4 Hz,
2H), 7.56 (t, J = 7.7 Hz, 2H), 7.47 (t, J = 7.3 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 187.8, 185.5, 150.1, 141.1, 139.3, 138.6, 132.5,
132.2, 130.8, 130.6, 130.0, 129.4, 128.9, 124.9, 120.0, 118.0, 117.8,
116.7, 116.4. HRMS (ESI) m/z: [M + H]+ calcd for C25H15N4O2
403.1190; found 403.1192.
General Procedure for Synthesis of Product 4fa. A mixture of
4f (0.25 mmol, 1.0 equiv) and NaBH4 (1.25 mmol, 5.0 equiv) was
stirred in 5 mL of THF at 110 °C (oil bath) for 8 h. After the
completeness of the reaction, the reaction mixture was poured into
water and then extracted with EtOAc and dried by Na2SO4. The
crude product was carried out by chromatography to afford 4fa.
(1-(4-Bromophenyl)-1H-pyrazole-3, 4-diyl)bis-
(phenylmethanol) (4fa). Purified by column chromatography
(silica gel, petroleum:EtOAc = 3:1), a white solid (76 mg, 70%),
(1-Phenyl-1H-pyrazole-3,4-diyl)bis((4-nitrophenyl)-
methanone) (4l). Purified by column chromatography (silica gel,
petroleum:EtOAc = 3:1), brown solid (64 mg, 43%), mp 154.3−
1
1
mp 137.0−137.5 °C. H NMR (400 MHz, CDCl3) δ 7.52−7.45 (m,
156.0 °C. H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.00 (d, J =
7H), 7.44−7.26 (m, 8H), 6.04 (s, 1H), 5.73 (s, 1H), 3.55 (s, 1H),
2.72 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.7, 142.7,
141.9, 138.8, 132.5, 128.7, 128.6, 128.0, 127.3, 127.1, 126.4, 125.1,
120.4, 119.7, 71.1, 68.2. HRMS (ESI) m/z: [M + H]+ calcd for
C23H20BrN2O2 435.0703; found 435.0700.
General Procedure for Synthesis of Product 4fb. A mixture of
4f (0.25 mmol, 1.0 equiv) and N2H4·H2O (1.0 mmol, 4.0 equiv) was
stirred in 5 mL of EtOH at 90 °C (oil bath) for 8 h. After the
completeness of the reaction, the product was filtered out to afford
4fb.
2-(4-Bromophenyl)-4,7-diphenyl-2H-pyrazolo[3,4-d]-
pyridazine (4fb). Filtered to afford 4fb as a green solid (103 mg,
97%), mp 216.2−217.0 °C. 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J
= 4.4 Hz, 2H), 8.77 (s, 1H), 8.14 (d, J = 4.8 Hz, 2H), 7.90 (d, J = 7.2
Hz, 2H), 7.72 (d, J = 7.6 Hz, 2H), 7.64−7.48 (m, 6H). 13C{1H}
NMR (100 MHz, CDCl3) δ 154.2, 150.4, 143.6, 138.6, 136.8, 135.0,
133.2, 130.6, 130.5, 129.6, 129.2, 128.7, 128.5, 123.5, 123.1, 122.6,
118.2. HRMS (ESI) m/z: [M + H]+ calcd for C23H16BrN4 427.0553;
found 427.0549.
7.6 Hz, 2H), 7.75−7.74 (m, 2H), 7.69 (d, J = 7.6 Hz, 2H), 7.61 (d, J
= 7.6 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H). 7.25−7.17 (m, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 188.1, 186.3, 150.9, 136.7, 135.1, 132.0,
131.9, 131.8, 130.5, 130.2, 128.9, 128.4, 125.2, 122.0, 121.9, 117.0,
116.7. HRMS (ESI) m/z: [M + Na]+ calcd for C23H14N4NaO6
465.0806; found 465.0814.
(1-Phenyl-1H-pyrazole-3,4-diyl)bis(thiophen-2-ylmetha-
none) (4m). Purified by column chromatography (silica gel,
petroleum:EtOAc = 7:1), white solid (90 mg, 74%), mp 150.2−
152.0 °C. 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.28 (s, 1H),
7.82 (d, J = 7.2 Hz, 2H), 7.74 (d, J = 3.6 Hz, 1H), 7.69 (d, J = 3.6 Hz,
1H), 7.62 (s, 1H), 7.55 (t, J = 6.6 Hz, 2H), 7.43 (t, J = 6.6 Hz, 1H),
7.19 (s, 1H), 7.10 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
181.0, 178.4, 149.9, 144.5, 142.2, 139.0, 135.8, 135.3, 134.5, 134.0,
129.9, 129.3, 128.3, 128.1, 125.0, 119.9. HRMS (ESI) m/z: [2M +
Na]+ calcd for C38H24N4NaO4S4 751.0573; found 751.0570.
(1-Phenyl-1H-pyrazole-3,4-diyl)bis((3-bromophenyl)-
methanone) (4n). Purified by column chromatography (silica gel,
petroleum:EtOAc = 8:1), white solid (110 mg, 65%), mp 122.6−
125.9 °C. 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.24 (s, 1H),
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Article
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00949.
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AUTHOR INFORMATION
Corresponding Authors
■
Jiankang Zhang − School of Medicine, Zhejiang University
City College, Hangzhou 310015, P. R. China;
Email: zjk0125@yeah.net
Huajian Zhu − School of Medicine, Zhejiang University City
College, Hangzhou 310015, P. R. China; Email: zhuhj@
zucc.edu.cn
Jiaan Shao − School of Medicine, Zhejiang University City
College, Hangzhou 310015, P. R. China; orcid.org/0000-
0001-8735-3236; Email: shaoja@zucc.edu.cn
Authors
Fengkai Qiu − School of Medicine, Zhejiang University City
College, Hangzhou 310015, P. R. China; College of
Pharmaceutical Sciences, Zhejiang University, Hangzhou
310058, P. R. China
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Yu Cao − School of Medicine, Zhejiang University City College,
Hangzhou 310015, P. R. China; College of Pharmaceutical
Sciences, Zhejiang University, Hangzhou 310058, P. R.
China
Linghui Zeng − School of Medicine, Zhejiang University City
College, Hangzhou 310015, P. R. China
Chong Zhang − School of Medicine, Zhejiang University City
College, Hangzhou 310015, P. R. China
Liping Fu − Department of Pharmacy, Shaoxing Hospital of
Traditional Chinese Medicine, Shaoxing 312000, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00949
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by Zhejiang Provincial Natural
Science Foundation of China under Grant No. LY20H300001;
Agricultural and Social Development Fundation of Hangzhou
Science and Technology Committee under Grant No.
20201203B148; Medical Health Science and Technology
Project of Zhejiang Provincial Health Commission under
Grant Nos. 2020KY681, 2020KY679, and 2019RC085; The
Scientific Research Foundation of Zhejiang University City
College under Grant No. J-20011 and J-20010; The Second
Round of “West Lake Scholar” Introduction Plan of Hangzhou
Municipal University in 2019 for J.S.; The Second Round of
Excellent Innovation Team of Hangzhou Municipal University
in 2019 for L.Z.
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