Metal-Free Direct C–H Thiolation and Thiocyanation of Pyrazolones

Article abstract of DOI:10.1002/ejoc.201901770

Metal-free approach for direct C–H thiolation and thiocyanation of N-substituted pyrazolones with disulfides and thiocyanate salts, respectively, are developed. These reactions allow the C–S bond coupling to proceed effectively under mild conditions, providing useful and convenient methods for preparation of a series of 4-thio-substituted pyrazolone analogues, which have potential applications in organic, medicinal and material chemistry. Preliminary mechanistic investigation suggested that radical processes are likely to involve in these transformations.

Full text of DOI:10.1002/ejoc.201901770

A Journal of
Accepted Article
Title: Metal-Free Direct C−H Thiolation and Thiocyanation of
Pyrazolones
Authors: Tanakorn Kittikool and Sirilata Yotphan
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901770
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10.1002/ejoc.201901770
European Journal of Organic Chemistry
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Metal-Free Direct C−H Thiolation and Thiocyanation of
Pyrazolones
Tanakorn Kittikool[a] and Sirilata Yotphan[a]*
Dedication ((optional))
Abstract: Metal-free approach for direct C−H thiolation and
thiocyanation of N-substituted pyrazolones with disulfides and
thiocyanate salts, respectively, are developed. These reactions allow
the C−S bond coupling to proceed effectively under mild conditions,
providing useful and convenient methods for preparation of a series
of 4-thio-substituted pyrazolone analogues, which have potential
applications in organic, medicinal and material chemistry. Preliminary
mechanistic investigation suggested that radical processes are likely
to involve in these transformations.
Introduction
Thiol moieties are widely distributed in natural products,
pharmaceutical and bioactive compounds and polymer materials.
[1] These moieties also play important roles in organic synthesis,
coordination chemistry and agrochemistry, as they can modify
physical and biological properties of the parent compounds.[2]
Among many effective methods available for incorporating
thioether motifs into the organic compounds, a direct formation of
C−S bond through C−H functionalization reaction has recently
received considerable attention.[3] In particular, the development
of transition-metal-free strategies has appeared to be an
attractive route for synthetic chemists in both academic and
industrial fields as it could offer a milder, cheaper and more
practical synthetic alternative to transition metal-mediated
reactions. [4]
Scheme 1. Direct C−S Bond Coupling of N-Substituted Pyrazolones.
of inflammation and fever.[6] In addition, many pyrazolone
analogues have been used as valuable scaffolds in drug
[7]
discovery, combinatorial chemistry, and organic synthesis.
Owing to their fascinating profiles and their promising impact in
many research areas, exploration of new synthetic methodology
for the preparation and modification of pyrazolones can increase
their structure diversity as well as enhance further utilizations.
Throughout the past decade, good progress has been made
toward the direct C−C bond coupling of bioactive pyrazolone
cores (such as phenazone) via C−H functionalization. These
examples include Pd-catalyzed direct arylation[8] and
alkenylation,[9] Au-catalyzed alkynylation of pyrazolones with
hypervalent iodide [10] , Cu-promoted direct acylation reactions[11]
as well as Ru-catalyzed oxidative double C−H activation and
annulation reaction.[12] On the other hand, the direct
carbon−heteroatom bond coupling of N-substituted pyrazolone
compounds has not been found in literature until recently. Under
oxidative coupling conditions, Ackermann and our groups
reported the silver-mediated direct C−H thiolation of N-alkylated
pyrazolone derivatives at C4 position with disulfides to afford 4-
Pyrazolones and their derivatives have drawn much
attention because of their diverse biological and pharmaceutical
activities such as antibacterial, antiviral and antitumor activities. [5]
Particularly, phenazone and its derivatives, such as
propylphenazone and aminophenazone, are important non-
steroidal anti-inflammatory drugs (NSAIDs) used for a treatment
[a]
Department of Chemistry and Center of Excellence for Innovation in
Chemistry, Faculty of Science, Mahidol University, Rama VI Road,
Bangkok 10400, Thailand.
Corresponding author: Dr. Sirilata Yotphan
E-mail: sirilata.yot@mahidol.ac.th
http://chemistry.sc.mahidol.ac.th/en/people/faculty/sirilata-yotphan/
thio substituted pyrazolones (Scheme 1).[13] However,
a
stoichiometric amount of silver(I) salt, which is rather expensive
and harmful to health and environment, was necessary to drive
the successful C−S bond coupling. Thus, it is highly desirable to
develop more practical and efficient protocols using readily
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under
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10.1002/ejoc.201901770
European Journal of Organic Chemistry
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available innocuous reagents under mild and eco-friendly
conditions to access these useful compounds.
]
Table 1. Optimization of Reaction Conditions.[a
On the basis of our interest in metal-free oxidative cross-
coupling,[14] herein, we wish to disclose a metal-free approach for
direct C−H thiolation and thiocyanation of pyrazolone derivatives
with disulfides and thiocyanate salts to access of a series of 4-
thio-substituted pyrazolones in moderate to excellent yields.
These reactions proceed very well under relatively benign and air-
tolerant conditions, thus they can be used as an alternative
synthetic protocol to prepare potent biologically active analogues
for a number of applications.
Entry
Reagent
Oxidant
Solvent
Yield (%)[b]
1
2
NIS
K2S2O8
K2S2O8
CH3CN
CH3CN
84
90
NH4I
3
TBAI
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Na2S2O8
(NH4)2S2O8
K2S2O8
K2S2O8
K2S2O8
-
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
DMSO
H2O
18
4
NaI
95
Results and Discussion
5
KI
99
6
I2
97
In order to obtain the optimal reaction conditions for
metal-free direct C−S bond coupling, 2,3-dimethyl-1-phenyl-
3-pyrazolin-5-one (phenazone, 1a) and diphenyl disulfide
7
KI
31
8
KI
63
9
KI
69
(2a) were chosen as the model substrates to test reactions.
10
11
12
13
14
15
16
KI
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
94
Using potassium persulfate (K2S2O8) as the oxidant, several
inexpensive and environment-friendly iodine/iodide additives
were examined under air (Table 1, entries 1–6). To our
delight, one equivalent of potassium iodide (KI) was the best
choice to afford the desired thiolating product 3aa in
acetonitrile (CH3CN) in excellent yield at 60 °C (entry 5,
99%). Alternatively, molecular iodine (I2) could be employed
in the reaction to provide a very high quantity of the product
(entry 6), while other forms of iodine additives gave lower
yields. Other solvents and oxidants including Na2S2O8,
(NH4)2S2O8 or peroxide (i.e. H2O2, TBHP, DTBP) were less
effective for this transformation (entries 7−12).[15] Carrying
out the reaction at room temperature resulted in much lower
conversion (entry 13). In addition, the amount of KI used in
the reaction had a crucial effect on the conversion as
reduction of product yield was obtained when using KI less
than 1 equivalent (entries 14 and 15). Lastly, in the absence
of either KI or persulfate, no desired product was detected by
TLC and GC-MS methods, indicating that both KI and K2S2O8
oxidant were necessary for this transformation (entries 16
and 17).
KI
35
KI
88
16[c]
KI
KI (20%)
KI (50%)
KI
15
50
No reaction
17
K2S2O8
CH3CN
No reaction
-
[a] Conditions: 1a (0.25 mmol, 1.0 equiv), 2a (1.0 equiv), reagent (1.0 equiv),
oxidant (2.0 equiv) in 1 mL solvent at 60 °C under an air atmosphere for 16
h, as monitored by TLC. [b] GC yield. [c] reaction at room temperature.
however, under the standard conditions, slightly low yield
was isolated from the substrate bearing phenyl group (3cc).
The reactions also proceeded with a good quantity of desired
products when R1 on pyrazolone is a methyl group (e.g. 3da
and 3db). For the 5-unsubstituted pyrazolone substrates,
the direct thiolation proceeded selectively at C-4 position
(3ea, 28%). On the other hand, no reaction was observed in
case of unsubstituted 5-pyrazolone (3eb).
Next, the scope of disulfides was examined. In general,
various diaryl disulfides were successfully coupled with
pyrazolones to provide corresponding 4-thio-substituted
products in moderate to excellent yields. The disulfides with
With the optimal reaction conditions established, we
further investigated the scope as well as the limitation of the
methodology by examining various N-substituted pyrazolone
substrates (Table 2). Upon treating diphenyl disulfide (2a),
several 1-phenyl pyrazolones with different alkyl
substitutions (including the benzyl group and allyl group) on
the nitrogen atom (R2) can be readily transformed to the 4-
thio substituted compounds in moderate to decent yields
electron-donating,
substituents on the aryl ring can be installed on the substrate,
producing the desired products with no difficulty (3fa 3jb).
electron-withdrawing,
halogen
−
Notably, functional groups such as amide, hydroxyl, amino
groups, were well tolerated under the optimized reaction
conditions (3i−3jb). In addition, heteroaromatic disulfides, for
(
3aa−3ae). Pyrazolone analogues possessing different
instance, thiophene and benzothioazole were smoothly
reacted with pyrazolone substrates, affording the products in
quantitative yields (3k and 3l). We also tested the reactions
with dialkyl disulfides, and the dipropyl and dibenzyl
disulfides were viable to the direct C−S coupling (3ma and
3mb). Nonetheless, the direct thiolation reactions were not
well compatible with diallyl, di-isopropyl and di-tert-butyl
disulfides. Only small or trace amounts of the products were
substitutions on the ortho-, meta-, or para-position at the N-
aryl moiety (R1) all worked well to afford the corresponding
products (3ba−3bf) in good to high amounts. No crucial
effect from the substituents (electron donating, electron
withdrawing, or halogen groups) was observed. Likewise, the
substrate bearing n-propyl, iso-propyl or phenyl groups at the
R3 position could undergo direct thiolation (3ca−3cc),
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10.1002/ejoc.201901770
European Journal of Organic Chemistry
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product under mild conditions. This metal-free methodology
could provide a useful building block and a pivotal synthetic
intermediate to a variety of sulfur-containing compounds.[17]
obtained under the optimized systems (3mc−3me). The
direct chalcogenation was further inspected with diphenyl
diselenide and ditelluride, unfortunately, quite low yield of the
product was found for the direct selenylation (3na, 22%).
Meanwhile, no reaction was observed with ditelluride (3nb).
These results could be due to the stability of the radical
intermediates.[16]
The scope of thiocyanation with respect to pyrazolones
is illustrated in Table 3. Substituents on carbon and nitrogen
atoms of pyrazolone substrates with different aryl and alkyl
groups appeared to have a dramatic impact on the reactivity
towards the reaction. Despite various alkyl groups at R2
position, thiocyanation reactions of pyrazolones bearing
Table 2. Metal-Free Direct Thiolation of Pyrazolones with Disulfides.[a,b]
phenyl moiety at R1 on nitrogen proceeded well (4a−4e). In
particular, benzyl and allyl groups on R2 were both suitable
for the reactions, providing high yields of products (4d and
4e). However, low yield was obtained in the case of substrate
with N-alkyl ester functional group at R2 (4f). It is also
noteworthy that substrates bearing electron donating,
electron withdrawing, or halogen groups on phenyl ring (R1)
of pyrazolones all underwent smooth transformations,
yielding good to excellent amounts of products (4g−4l).
Moreover, the reaction proceeded with a tolerance of steric
hindrance from the alkyl group on adjacent carbon (R3) (4m
and 4n). Unfortunately, when R3 group is phenyl, the
substrate was incompetent to the reaction under the
established conditions (4o). Meanwhile, when R1 group is not
arene, pyrazolone exhibited a decreased reactivity towards
the reaction, and a reduced yield was observed (4p and 4q).
Table 3. Substrate Scope of the Direct Thiocyanation.[a,b]
[a] Conditions: pyrazolone (1 mmol, 1.0 equiv), disulfide (1.0 equiv), KI (1.0
equiv), K2S2O8 (2.0 equiv) in CH3CN (4 mL) at 60 °C under an air atmosphere
for 16 h, as monitored by TLC. [b] Isolated yields. [c] Using I2 (1.0 equiv)
instead of KI. [d] Using 4-bromothiphenol as a thiolating reagent.
[a] Conditions: pyrazolone (1 mmol, 1.0 equiv), NH4SCN (1.5 equiv), K2S2O8
(3.0 equiv) in CH3CN (4 mL) at room temperature under an air atmosphere, 16
h. [b] Isolated yield. [c] Reaction was conducted at 60 °C.
For preliminary insight into the reaction mechanism, a well-
known radical scavenger, BHT (butylated hydroxytoluene) and
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy), was added into
the reaction systems, and the yields from both the thiolation and
thiocyanation reactions were significantly reduced, which
indicative of free radical processes. Based on the above
observation and previous literature,[14f,18,19] possible reaction
mechanisms were illustrated in Scheme 3. These
transformations presumably involve an initial generation of
the thiyl radical or thiocyanate radical species (•SY, Y = R or
CN) induced by persulfate (S2O82−) or sulfate radical anion
(SO4•−). Next, the reactive sulfur radical intermediates could
couple with pyrazolone substrate leading to a formation of
Scheme
2 Metal-Free Direct Thiocyanation of Pyrazolone with
Thiocyanate salt.
The direct thiocyanation of pyrazolone compounds with
thiocyanate salts was also investigated. Luckily, as shown in
Scheme 2, positive results were achieved even at room
temperature by simply using K2S2O8 to induce the
incorporation of thiocyanate group to the 4-position of
pyrazolone. Apart from NH4SCN, NaSCN and KSCN were
very well effective, giving good to excellent yields of the
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10.1002/ejoc.201901770
European Journal of Organic Chemistry
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intermediate A, in which the radical could be stabilized by the
method, and only partial data are listed. Melting points were determined
on Buchi Melting Point M-565 apparatus. High resolution mass
spectroscopy (HRMS) data were analyzed by a high-resolution micrOTOF
instrument with electrospray ionization (ESI). The structures of known
compounds were corroborated by comparing their 1H NMR, 13C NMR data
with those of literature.[13b]
adjacent nitrogen atom. Then, further oxidation of the
intermediate by sulfate radical anion via a SET process
could form a cationic intermediate . Lastly, a subsequent
A
B
loss of proton would afford the final product.
General Procedure for the Metal-Free Promoted Direct Thiolation of
Pyrazolones with Disulfides. To a 20 mL scintillation vial equipped with
a magnetic stir bar, pyrazolone 1 (1.0 mmol, 1.0 equiv), disulfide 2 (1.0
mmol, 1.0 equiv), potassium iodide (KI) (1.0 mmol, 1.0 equiv), potassium
persulfate (K2S2O8) (2.0 mmol, 2.0 equiv) and acetonitrile (CH3CN) (4 mL)
were added, respectively. The reaction mixture was stirred at 60 °C for 16
h. Upon completion (monitored by TLC), distilled deionized H2O (20 mL)
and sat. Na2S2O3 (10 mL) was added, and the mixture was extracted with
ethyl acetate (EtOAc) (2 × 40 mL). The combined organic layer was
washed with saturated NaCl, dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified by SiO2 column
chromatography to afford the thiolated pyrazolone product 3.
General Procedure for the Metal-Free Promoted Direct Thiocyanation
of Pyrazolones with Ammoniumthiocyanate. To a 20 mL scintillation
vial equipped with a magnetic stir bar, pyrazolone 1 (1.0 mmol, 1.0 equiv),
ammonium thiocyanate (NH4SCN) (1.5 mmol, 1.5 equiv), potassium
persulfate (K2S2O8) (3.0 mmol, 3.0 equiv) and acetonitrile (CH3CN) (4 mL)
were added, respectively. The reaction mixture was stirred at room
temperature for 16 h. Upon completion (monitored by TLC), distilled
deionized H2O (20 mL) was added, and the mixture was extracted with
ethyl acetate (EtOAc) (2 × 40 mL). The combined organic layer was
washed with saturated NaCl, dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified by SiO2 column
chromatography to afford the thiocyanated pyrazolone product 4.
Scheme 3. Control Experiments and Possible Reaction Mechanisms.
Conclusions
In summary, we have successfully described a metal-
free direct C−
S bond coupling of the C(sp2)−H bond of N-
substituted pyrazolones with disulfides and thiocyanate salts
under mild conditions. Both thiolation and thiocyanation
approaches employ readily accessible substrates and
reagents and are applicable to a broad range of substrates,
affording the products in moderate to excellent yields.
Preliminary mechanistic studies indicate that the
transformations are likely to proceed via radical processes.
These methods provide an alternative and facile synthetic
route to access a series of 4-thio-substituted pyrazolone
derivatives, which might have potential applications in
organic, material and pharmaceutical areas.
1,5-Dimethyl-2-phenyl-4-(phenylthio)-1,2-dihydro-3H-pyrazol-3-one
1
(3aa).[13b] White solid (293 mg, 99% yield); H NMR (400 MHz, CDCl3): δ
7.49−7.45 (m, 2H), 7.39 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H),
7.28−7.20 (m, 4H), 7.10 (t, J = 7.2 Hz, 1H), 3.22 (s, 3H), 2.38 (s, 3H); 13
C
NMR (100 MHz, CDCl3): δ 165.4, 159.7, 137.4, 134.9, 129.3, 128.9, 127.3,
127.1, 125.6, 124.8, 98.2, 35.7, 12.1; HRMS (ESI): calcd for
C17H16N2OSNa [M+Na]+ 319.0876, found 319.0874.
1-Ethyl-5-methyl-2-phenyl-4-(phenylthio)-1,2-dihydro-3H-pyrazol-3-
one (3ab). White solid (180 mg, 58% yield); mp = 121.2 ̶
123.0 °C; 1H NMR
(400 MHz, CDCl3): δ 7.49−7.41 (m, 4H), 7.31 (t, J = 7.2 Hz, 1H), 7.24−7.19
(m, 4H), 7.09 (t, J = 7.2 Hz, 1H), 3.71 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 0.96
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 166.1, 159.4, 137.4,
135.1, 129.4, 129.0, 127.2, 127.0, 125.6, 124.8, 100.4, 43.2, 12.0, 11.4;
IR (KBr, cm-1): ν = 3028, 2992, 1870, 1669, 1597, 1341, 1245, 1113, 1024,
746, 694, 657, 599, 498; HRMS (ESI): calcd for C18H18N2OSNa [M+Na]+
333.1032, found 333.1031.
Experimental Section
General Information: Unless otherwise noted, all reagents were obtained
from commercial suppliers and used without further purification. All
experiments were carried out under air atmosphere, and oven-dried
glasswares were used in all cases. Column chromatography was
performed over silica gel (SiO2; 60 Å silica gel, Merck Grade, 70–230
Mesh). 1H and 13C NMR spectra were recorded on Bruker-AV400
spectrometers in CDCl3 or DMSO-d6 solution, at 400 and 100 MHz,
respectively. NMR chemical shifts are reported in ppm, and were
measured relative to CHCl3 (7.26 ppm for 1H and 77.16 ppm for 13C) or
DMSO (2.50 ppm for 1H and 39.52 ppm for 13C). IR spectra were recorded
on PerkinElmer FT-IR Spectrometer Model Frontier by KBr pallet or neat
5-Methyl-1-pentyl-2-phenyl-4-(phenylthio)-1,2-dihydro-3H-pyrazol-3-
one (3ac). White solid (159 mg, 45% yield); mp = 101.4 ̶
102.2 °C; 1H NMR
(400 MHz, CDCl3): δ 7.49−7.45 (m, 2H), 7.40 (d, J = 7.2 Hz, 2H), 7.32 (t,
J = 7.4 Hz, 1H), 7.24−7.19 (m, 4H), 7.11−7.08 (m, 1H), 3.65 (t, J = 7.4 Hz,
2H), 2.37 (s, 3H), 1.42−1.34 (m, 2H), 1.24−1.17 (m, 2H), 1.13−1.06 (m,
2H), 0.81 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 16661, 1.961,
1.161, 1..61, 11961, 11961, 11161, 11669, 11.6., 11.61, 9.61, 1.61, 1.61,
166., 116., 1.6., 1161; IR (KBr, cm-1): ν = 3068, 2925, 2856, 1668, 1582,
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10.1002/ejoc.201901770
European Journal of Organic Chemistry
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1538, 1436, 1342, 1250, 1118, 1024, 753, 736, 607, 506; HRMS (ESI):
calcd for C21H24N2OSNa [M+Na]+ 375.1502, found 375.1503.
3-(2-Ethyl-3-methyl-5-oxo-4-(phenylthio)-2,5-dihydro-1H-pyrazol-1-
yl)benzenesulfonamide (3be). Pale orange solid (354 mg, 91% yield);
mp = 155.9 ̶
156.6 °C; 1H NMR (400 MHz, CDCl3): δ 7.90 (s, 1H), 7.78 (d,
J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.22−7.16
(m, 4H), 7.11−7.07 (m, 1H), 5.56 (s, 2H), 3.69 (q, J = 6.9 Hz, 2H), 2.37 (s,
3H), 0.94 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 166.3, 160.8,
144.0, 136.8, 135.5, 130.2, 129.2, 128.2, 126.9, 125.9, 125.0, 122.4, 100.2,
43.6, 12.1, 11.4; IR (KBr, cm-1): ν = 3321, 3161, 3062, 1654, 1592, 1478,
1335, 1164, 912, 742, 688, 592; HRMS (ESI): calcd for C18H20N3O3S2
[M+H]+ 390.0941, found 390.0944.
1-Benzyl-5-methyl-2-phenyl-4-(phenylthio)-1,2-dihydro-3H-pyrazol-3-
one (3ad). White solid (198 mg, 53% yield); mp = 118.7 ̶
119.9 °C; 1H NMR
(400 MHz, CDCl3): δ 7.49−7.52 (m, 2H), 7.40 (d, J = 7.2 Hz, 2H), 7.35−7.28
(m, 4H), 7.17−7.13 (m, 2H), 7.09−7.04 (m, 3H), 6.95 (d, J = 6.4 Hz, 2H),
4.81 (s, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.7, 159.8,
137.2, 135.0, 134.0, 129.5, 129.0, 128.9, 128.7, 127.5, 127.4, 126.7, 125.4,
125.1, 100.7, 51.6, 12.6; IR (KBr, cm-1): ν = 3034, 2988, 2920, 1678, 1569,
1494, 1390, 1191, 1022, 816, 743, 690, 638, 500; HRMS (ESI): calcd for
C23H20N2OSNa [M+Na]+ 395.1189, found 395.1190.
2-(3,4-Dimethylphenyl)-1-ethyl-5-methyl-4-(phenylthio)-2,1dihydro-
3H-pyrazol-3-one (3bf). White solid (261 mg, 77% yield); mp = 144.8
145.5 °C; 1H NMR (400 MHz, CDCl3): δ 7.24−7.18 (m, 6H), 7.11−7.07 (m,
2H), 3.69 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H), 0.97
(t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 166.1, 158.4, 137.9,
137.7, 136.2, 132.7, 130.4, 128.9, 126.9, 126.5, 125.4, 122.6, 99.7, 42.9,
20.0, 19.5, 11.9, 11.7; IR (KBr, cm-1): ν = 2969, 2918, 1877, 1662,1551,
1498, 1410, 1351, 1109, 1024, 812, 749, 694, 598; HRMS (ESI): calcd for
C20H23N2OS [M+H]+ 339.1526, found 339.1527.
̶
1-Allyl-5-methyl-2-phenyl-4-(phenylthio)-1,2-dihydro-3H-pyrazol-3-
one (3ae). Pale orange solid (162 mg, 50% yield); mp = 117.0 ̶ 118.3 °C;
1H NMR (400 MHz, CDCl3): δ 7.47−7.43 (m, 2H), 7.39 (d, J = 7.6 Hz, 2H),
7.31 (t, J = 7.2 Hz, 1H), 7.24−7.18 (m, 4H), 7.09 (t, J = 6.4 Hz, 1H),
5.61−5.52 (m, 1H), 5.18 (d, J = 10.4 Hz, 1H), 5.03 (d, J = 16.8 Hz, 1H),
4.21 (d, J = 5.6 Hz, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.7,
159.6, 137.3, 134.9, 129.9, 129.3, 128.9, 127.4, 126.9, 125.5, 125.1, 119.9,
100.1, 50.2, 12.0; IR (KBr, cm-1): ν = 3066, 2991, 2951, 1667, 1555, 1495,
1410, 1356, 1225, 1114, 982, 927, 740, 697, 650; HRMS (ESI): calcd for
C19H18N2OSNa [M+Na]+ 345.1032, found 345.1034.
1-Ethyl-2-phenyl-4-(phenylthio)-5-propyl-1,2-dihydro-3H-pyrazol-3-
one (3ca). Pale orange solid (136 mg, 40% yield); mp = 122.7 ̶ 124.0 °C.
1H NMR (400 MHz, CDCl3): δ 7.48−7.41 (m, 4H), 7.37−7.29 (m, 1H),
7.24−7.18 (m, 4H), 7.10−7.01 (m, 1H), 3.71 (q, J = 7.1 Hz, 2H), 2.73 (t, J
= 7.8 Hz, 2H), 1.72−1.62 (m, 2H), 1.01−0.94 (m, 6H); 13C NMR (100 MHz,
CDCl3): δ 166.1, 163.3, 137.6, 135.2, 129.4, 128.9, 127.1, 126.9, 125.5,
124.7, 100.3, 43.3, 27.9, 22.5, 13.9, 11.7; IR (KBr, cm-1): ν = 2963, 2931,
1870, 1671, 1592, 1534, 1478, 1374, 1217, 1105, 818, 747, 691; HRMS
(ESI): calcd for C20H23N2OS [M+H]+ 339.1526, found 339.1527.
1-Ethyl-2-(4-methoxyphenyl)-5-methyl-4-(phenylthio)-1,2-dihydro-
3H-pyrazol-3-one (3ba). Pale orange solid (266 mg, 78% yield); mp =
1
153.0
̶
154.5 °C; H NMR (400 MHz, CDCl3): δ 7.31 (d, J = 9.2 Hz, 2H),
7.23−7.18 (m, 4H), 7.12−7.06 (m, 1H), 6.98 (d, J = 8.8 Hz, 2H), 3.82 (s,
3H), 3.66 (q, J = 6.9 Hz, 2H), 2.34 (s, 3H), 0.97 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 166.2, 159.1, 157.9, 137.7, 128.9, 127.7, 127.2,
126.8, 125.4, 114.8, 99.2, 55.7, 42.7, 11.8, 11.8; IR (KBr, cm-1): ν = 3056,
2960, 1890, 1675, 1582, 1556, 1510, 1306, 1255, 1119, 1023, 835, 739,
691; HRMS (ESI): calcd for C19H21N2O2S [M+H]+ 341.1318, found
341.1319.
1-Ethyl-5-isopropyl-2-phenyl-4-(phenylthio)-1,2-dihydro-3H-pyrazol-
3-one (3cb). White solid (163 mg, 48% yield); mp = 183.8 ̶
185.0 °C; 1H
NMR (400 MHz, CDCl3): δ 7.49−7.42 (m, 4H), 7.31 (t, J = 7.0 Hz, 1H),
7.21−7.18 (m, 4H), 7.11−7.06 (m, 1H), 3.78 (q, J = 6.9 Hz, 2H), 3.28 (sep,
J = 7.1 Hz, 1H), 1.42 (d, J = 7.2 Hz, 6H), 0.99 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 167.5, 166.3, 137.7, 135.0, 129.4, 128.9, 127.2,
126.7, 125.3, 124.9, 99.0, 43.4, 27.7, 20.9, 12.2; IR (KBr, cm-1): ν = 3032,
2970, 2930, 1948, 1667, 1582, 1478, 1438, 1303, 1234, 1090, 741, 698;
HRMS (ESI): calcd for C20H23N2OS [M+H]+ 339.1526, found 339.1524.
1-Ethyl-5-methyl-2-(4-nitrophenyl)-4-(phenylthio)-1,2-dihydro-3H-
pyrazol-3-one (3bb). Yellow solid (292 mg, 82% yield); mp = 158.2
159.0 °C; 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 9.2 Hz, 2H), 7.46 (d,
J = 9.2 Hz, 2H), 7.23−7.20 (m, 4H), 7.16−7.10 (m, 1H), 3.75 (q, J = 7.1 Hz,
2H), 2.42 (s, 3H), 0.97 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
166.0, 162.9, 145.4, 140.8, 136.3, 129.2, 127.5, 126.1, 125.0, 123.0, 102.9,
44.2, 12.4, 10.7; IR (KBr, cm-1): ν = 2979, 2918, 2850, 1686, 1595, 1509,
1335, 1218, 1113, 1085, 843, 743, 693; HRMS (ESI): calcd for
C18H17N3O3SNa [M+Na]+ 378.0883, found 378.0884.
̶
1-Ethyl-2,5-diphenyl-4-(phenylthio)-1,2-dihydro-3H-pyrazol-3-one
1
(3cc). Pale orange solid (105 mg, 28% yield); mp = 157.0
̶
158.3 °C; H
NMR (400 MHz, CDCl3): δ 7.59−7.54 (m, 4H), 7.50−7.47 (m, 5H), 7.31 (t,
J = 7.4 Hz, 1H), 7.25−7.18 (m, 4H), 7.09 (t, J = 7.2 Hz, 1H), 3.61 (q, J =
6.9 Hz, 2H), 0.76 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.6,
162.4, 137.2, 135.2, 130.9, 129.7, 129.4, 129.0, 128.9, 128.6, 127.4, 127.0,
125.7, 124.1, 103.1, 45.7, 10.2; IR (KBr, cm-1): ν = 3059, 2978, 2925, 1680,
1582, 1486, 1457, 1340, 1212, 1118, 1083, 740, 691, 530; HRMS (ESI):
calcd for C23H20N2OSNa [M+Na]+ 395.1189, found 395.1185.
2-(4-Chlorophenyl)-1-ethyl-5-methyl-4-(phenylthio)-1,2-dihydro-3H-
pyrazol-3-one (3bc). White solid (266 mg, 77% yield); mp = 169.5
170.7 °C;1H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 8.4 Hz, 2H), 7.37 (d, J
= 8.8 Hz, 2H), 7.22−7.19 (m, 4H), 7.13−7.08 (m, 1H), 3.70 (q, J = 7.0 Hz,
2H), 2.37 (s, 3H), 0.96 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
166.1, 160.2, 137.1, 133.7, 132.8, 129.6, 129.0, 127.1, 125.7, 125.7, 100.9,
43.3, 12.1, 11.2; IR (KBr, cm-1): ν = 3054, 2983, 2928, 1676, 1548, 1495,
1411, 1335, 1087, 837, 734, 687, 508; HRMS (ESI): calcd for
C18H17ClN2OSNa [M+Na]+ 367.0642, found 367.0644.
̶
1,2,5-Trimethyl-4-(phenylthio)-1,2-dihydro-3H-pyrazol-3-one
(3da).
White solid (169 mg, 72% yield); mp = 132.2
̶
133.4 °C; 1H NMR (400 MHz,
CDCl3): δ 7.19−7.14 (m, 4H), 7.07−7.03 (m. 1H), 3.40 (s, 3H), 3.39 (s, 3H),
2.23 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.6, 154.3, 138.1, 128.8,
126.5, 125.3, 95.5, 33.5, 29.5, 11.3; IR (KBr, cm-1): ν = 3057, 3001, 2921,
1633, 1511, 1475, 1422, 1384, 1310, 1232, 744, 733, 688; HRMS (ESI):
calcd for C12H14N2OSNa [M+Na]+ 257.0719, found 257.0717.
2-(2-Chlorophenyl)-1-ethyl-5-methyl-4-(phenylthio)-1,2-dihydro-3H-
pyrazol-3-one (3bd). White solid (242 mg, 70% yield); mp = 149.7
151.0 °C; 1H NMR (400 MHz, CDCl3): δ 7.54−7.52 (m, 1H), 7.44−7.37 (m,
3H), 7.24−7.19 (m, 4H), 7.09 (t, J = 7.0 Hz, 1H), 3.68−3.59 (m, 1H),
̶
3.55−3.46 (m, 1H), 2.35 (s, 3H), 1.09 (t, J = 7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 166.0, 157.3, 138.0, 133.9, 132.9, 131.1, 131.0, 130.7,
128.9, 127.9, 126.7, 125.4, 97.5, 42.5, 12.6, 11.7; IR (KBr, cm-1): ν = 3059,
3026, 2967, 1657, 1535, 1477, 1343, 1242, 1113, 769, 743, 692, 605;
HRMS (ESI): calcd for C18H17ClN2OSNa [M+Na]+ 367.0642, found
1-Ethyl-2,5-dimethyl-4-(phenylthio)-1,2-dihydro-3H-pyrazol-3-one
1
(3db). White solid (206 mg, 83% yield); mp = 114.7
̶
115.3 °C; H NMR
(400 MHz, CDCl3): δ 7.21−7.14 (m, 4H), 7.07 (t, J = 7.0 Hz, 1H), 3.83 (q,
J = 7.1 Hz, 2H), 3.40 (s, 3H), 2.26 (s, 3H), 1.14 (q, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 166.4, 154.9, 138.0, 128.9, 126.4, 125.3, 97.4,
41.7, 29.6, 12.8, 11.2; IR (KBr, cm-1): ν = 3052, 2983, 2959, 1647, 1580,
1539, 1479, 1438, 1215, 1067, 747, 693, 607; HRMS (ESI): calcd for
C13H16N2OSNa [M+Na]+ 271.0876, found 271.0879.
367.0641.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901770
European Journal of Organic Chemistry
FULL PAPER
White solid (105 mg, 28% yield); mp = 128.4 ̶
129.2 °C; 1H NMR (400 MHz,
CDCl3): δ 7.51 (s, 1H), 7.35−7.31 (m, 6H), 7.23 (d, J = 4.4 Hz, 4H),
7.20−7.18 (m, 2H), 7.15−7.10 (m, 1H), 7.03−7.01 (m, 2H), 5.05 (s, 2H),
4.70 (s, 2H); 13C NMR (100 MHz, CDCl3): δ166.1, 145.3, 137.8, 135.9,
133.2, 129.3, 129.1, 129.0, 128.9, 128.3, 127.5, 127.3, 126.9, 125.6, 97.7,
53.7, 46.4; IR (KBr, cm-1): ν = 3110, 3046, 1642, 1540, 1454, 1237, 1168,
1115, 909, 744, 696, 636; HRMS (ESI): calcd for C23H20N2OSNa [M+Na]+
395.1189, found 395.1185.
1,2-Dibenzyl-4-(phenylthio)-1,2-dihydro-3H-pyrazol-3-one
(3ea).
1H NMR (400 MHz, CDCl3): δ 10.89 (s, 1H), 8.27 (d, J = 6.8 Hz, 2H),8.14
(d, J = 8.4 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.51−7.35 (m, 7H), 7.31−7.28
(m, 2H), 7.09−7.05 (m, 1H), 3.13 (s, 3H), 2.49 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 166.3, 165.7, 157.4, 141.0, 136.2, 136.1, 135.0, 134.5, 131.6,
130.0, 129.4, 128.5, 128.2, 127.6, 126.5, 125.1, 125.0, 102.3, 35.6, 12.0;
HRMS (ESI): calcd for C24H22N3O2S [M+H]+ 416.1427, found 416.1428.
4-((4-Hydroxyphenyl)thio)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (3ja). White solid (110 mg, 35% yield); mp = 246.7
̶
247.9 °C; 1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 7.53−7.49 (m,
2H), 7.38−7.32 (m, 3H), 7.08 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H),
3.22 (s, 3H), 2.38 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 164.7, 159.5,
156.1, 135.0, 129.4, 129.1, 127.0, 125.5, 124.7, 116.0, 96.2, 35.3, 11.6;
IR (KBr, cm-1): ν = 3435, 2920, 1856, 1628, 1576, 1493, 1363, 1273, 1237,
1166, 821, 755, 695; HRMS (ESI): calcd for C17H17N2O2S [M+H]+ 313.1005,
found 313.1002.
1,5-Dimethyl-2-phenyl-4-(p-tolylthio)-1,2-dihydro-3H-pyrazol-3-one
1
(3fa).[13b] White solid (307 mg, 99% yield); H NMR (400 MHz, CDCl3): δ
7.47−7.43 (m, 2H), 7.37 (d, J = 7.2 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.21
(d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 3.19 (s, 3H), 2.36 (s, 3H), 2.26
(s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.5, 159.5, 135.7, 135.1, 133.7,
129.7, 129.3, 128.0, 127.2, 124.8, 99.5, 35.8, 21.0, 12.1; HRMS (ESI):
calcd for C18H19N2OS [M+H]+ 311.1213, found 311.1210.
4-((4-Aminophenyl)thio)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
4-((4-Methoxyphenyl)thio)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (3fb).[13b] White solid (320 mg, 98% yield); 1H NMR (400
MHz, CDCl3): δ 7.46−7.42 (m, 2H), 7.37−7.34 (m, 4H), 7.29 (t, J = 7.4 Hz,
1H), 6.77 (d, J = 8.8 Hz, 2H), 3.74 (s, 3H), 3.16 (s, 3H), 2.83 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 165.5, 159.1, 158.6, 135.1, 131.0, 129.3, 127.7,
127.1, 124.6, 114.6, 100.9, 55.4, 35.8, 12.1; HRMS (ESI): calcd for
C18H18N2O2SNa [M+Na]+ 349.0981, found 349.0984.
pyrazol-3-one (3jb). White solid (125 mg, 40% yield); mp = 183.6
̶
1
184.9 °C; H NMR (400 MHz, CDCl3): δ 7.46−7.42 (m, 2H), 7.36 (d, J =
7.6 Hz, 2H), 7.31−7.26 (m, 3H), 6.54 (d, J = 8.4 Hz, 2H), 3.66 (s, 2H), 3.15
(s, 3H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.6, 159.0, 145.7,
135.1, 131.9, 129.3, 127.0, 124.7, 124.6, 115.7, 102.0, 35.8, 12.1; IR (KBr,
cm-1): ν = 3413, 3323, 3037, 1630, 1593, 1540, 1295, 1137, 1119, 757,
696, 532; HRMS (ESI): calcd for C17H18N3OS [M+H]+ 312.1165, found
312.1163.
1,5-Dimethyl-4-((4-nitrophenyl)thio)-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (3fc).[13b] White solid (243 mg, 71% yield); 1H NMR (400
MHz, CDCl3): δ 8.07 (d, J = 8.8 Hz, 2H), 7.52−7.48 (m, 2H), 7.40−7.35 (m,
3H), 7.28 (d, J = 8.8 Hz, 2H), 3.31 (s, 3H), 2.39 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 164.8, 159.0, 147.7, 145.4, 134.5, 129.6, 128.0, 125.8,
125.4, 124.1, 94.9, 35.6, 12.1; HRMS (ESI): calcd for C17H15N3O3SNa
[M+Na]+ 364.0726, found 364.0727.
4-(Benzo[d]thiazol-2-ylthio)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (3k).[13b] White solid (343 mg, 97% yield); 1H NMR (400
MHz, CDCl3): δ 7.87 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.56−7.52
(m, 2H), 7.45−7.39 (m, 4H),7.29−7.26 (m, 1H), 3.37 (s, 3H), 2.48 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 171.0, 164.5, 159.2, 154.8, 135.6, 134.6,
129.6, 128.1, 126.1, 125.8, 124.1, 121.8, 120.9, 94.5, 35.3, 12.1; HRMS
(ESI): calcd for C18H16N3OS2 [M+H]+ 354.0729, found 354.0728.
4-((4-Chlorophenyl)thio)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
1
pyrazol-3-one (3fd).[13b] White solid (315 mg, 95% yield); H NMR (400
1,5-Dimethyl-2-phenyl-4-(thiophen-2-ylthio)-1,2-dihydro-3H-pyrazol-
3-one (3l).[13b] Pale orange solid (297 mg, 98% yield); 1H NMR (400 MHz,
CDCl3): δ 7.44−7.40 (m, 2H), 7.33−7.32 (m, 2H), 7.31−7.28 (m, 1H),
7.24−7.22 (m, 1H), 7.21−7.19 (m, 1H), 6.90−6.87 (m, 1H), 3.14 (s, 3H),
2.43 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.0, 158.4, 135.5, 135.0,
132.1, 129.3, 128.2, 127.6, 127.2, 124.8, 101.5, 35.7, 12.1; HRMS (ESI):
calcd for C15H15N2OS2 [M+H]+ 303.0620, found 303.0619.
MHz, CDCl3): δ 7.48−7.44 (m, 2H), 7.37−7.30 (m, 3H), 7.21−7.15 (m, 4H),
3.22 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.3, 159.3,
136.0, 134.9, 131.6, 129.4, 129.0, 128.7, 127.5, 125.0, 98.1, 35.7, 12.1;
HRMS (ESI): calcd for C17H16ClN2OS [M+H]+ 331.0666, found 331.0668.
4-((4-Bromophenyl)thio)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (3fe).[13b] Colorless solid (334 mg, 89% yield); 1H NMR
(400 MHz, CDCl3): δ 7.48−7.44 (m, 2H), 7.37 (d, J = 7.2 Hz, 2H), 7.34−7.30
(m, 3H), 7.13 (d, J = 8.4 Hz, 2H), 3.22 (s, 3H), 2.35 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 165.3, 159.3, 136.7, 134.8, 131.9, 129.4, 128.9, 127.5,
125.0, 119.4, 97.8, 35.7, 12.1; HRMS (ESI): calcd for C17H16BrN2OS
[M+H]+ 375.0161, found 375.0159.
1,5-Dimethyl-2-phenyl-4-(propylthio)-1,2-dihydro-3H-pyrazol-3-one
(3ma). White solid (189 mg, 72% yield); mp = 72.5 ̶
73.7 °C; 1H NMR (400
MHz, CDCl3): δ 7.47−7.43 (m, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.30−7.37 (m,
1H), 3.12 (s, 3H), 2.70 (t, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.60−1.51 (m, 2H),
0.97 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.5, 158.8, 135.3,
129.2, 126.8, 124.2, 101.7, 36.2, 35.9, 23.2, 13.3, 12.1; IR (KBr, cm-1): ν =
2963, 2918, 1662, 1594, 1562, 1493, 1455, 1404, 1335, 1144, 1117, 757,
694, 590; HRMS (ESI): calcd for C14H19N2OS [M+H]+ 263.1213, found
263.1209.
4-((3,5-Dichlorophenyl)thio)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (3g).[13b] White solid (337 mg, 92% yield); 1H NMR (400
MHz, CDCl3): δ 7.50−7.46 (m, 2H), 7.39−7.33 (m, 3H), 7.08−7.06 (m, 3H),
3.28 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.0, 159.2,
141.5, 135.3, 134.7, 129.5, 127.8, 125.7, 125.4, 124.6, 95.8, 35.6, 12.1;
HRMS (ESI): calcd for C17H15Cl2N2OS [M+H]+ 365.0277, found 365.0279.
4-(Benzylthio)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one
1
(3mb). White solid (202 mg, 65% yield); mp = 106.4
̶
107.7 °C; H NMR
(400 MHz, CDCl3): δ 7.48−7.44 (m, 2H), 7.35 (d, J = 7.6 Hz, 2H), 7.30 (t,
J = 7.4 Hz, 1H), 7.25−7.19 (m, 3H), 7.15−7.13 (m, 2H), 3.83 (s, 2H), 3.00
(s, 3H), 1.75 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.7, 160.5, 138.8,
135.3, 129.5, 129.3, 128.2, 127.0, 126.8, 124.4, 99.8, 38.0, 35.9, 11.4; IR
(KBr, cm-1): ν = 3034, 2921, 1942, 1659, 1592, 1558, 1455, 1425, 1332,
1116, 755, 707, 659, 591; HRMS (ESI): calcd for C18H18N2OSNa [M+Na]+
333.1032, found 333.1034.
1,5-Dimethyl-2-phenyl-4-((2,4,5-trichlorophenyl)thio)-1,2-dihydro-3H-
pyrazol-3-one (3f).[13b] White solid (212 mg, 53% yield); 1H NMR (400
MHz, CDCl3): δ 7.52−7.48 (m, 2H), 7.40−7.35 (m, 4H), 7.03 (s, 1H), 3.31
(s, 3H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.8, 159.0, 137.2,
134.6, 131.7, 130.7, 130.0, 129.6, 129.5, 128.0, 127.8, 125.6, 94.5, 35.6,
12.1; HRMS (ESI): calcd for C17H14Cl3N2OS [M+H]+ 398.9887, found
398.9889.
4-(Allylthio)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one
(3mc). White solid (29 mg, 11% yield); mp = 104.2 ̶
105.5 °C; 1H NMR (400
MHz, CDCl3): δ 7.46−7.42 (m, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.28 (t, J = 7.4
Hz, 1H), 5.90−5.69 (m, 1H), 4.96−4.89 (m, 2H), 3.32 (d, J = 7.2 Hz, 2H),
N-(2-((1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
yl)thio)phenyl)benzamide (3i).[13b] Pale orange solid (412 mg, 99% yield);
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901770
European Journal of Organic Chemistry
FULL PAPER
3.11 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.6, 159.8,
135.3, 134.4, 129.3, 126.9, 124.4, 117.2, 100.3, 36.9, 36.2, 12.3; IR (KBr,
cm-1): ν = 3039, 2920, 1660, 1593, 1491, 1404, 1340, 1253, 1123, 915,
757, 694, 639; HRMS (ESI): calcd for C14H17N2OS [M+H]+ 261.1056, found
261.1057.
2903, 2896, 2163, 1747, 1643, 1378, 1273, 1218, 1086, 1044, 879, 695;
HRMS (ESI): calcd for C15H15N3O3SNa [M+Na]+ 340.0726, found 340.0728.
1-Ethyl-2-(4-methoxyphenyl)-5-methyl-4-thiocyanato-1,2-dihydro-3H-
pyrazol-3-one (4g). White solid (287 mg, 99% yield); mp = 153.0
154.2 °C; 1H NMR (400 MHz, CDCl3): δ 7.24 (d, J = 8.8 Hz, 2H), 6.99 (d,
J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.71 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.02 (t,
J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 163.9, 160.0, 155.6, 128.3,
126.6, 115.1, 110.8, 87.4, 55.7, 42.6, 12.8, 11.8; IR (KBr, cm-1): ν = 3108,
3013, 2971, 2152, 1868, 1672, 1515, 1262, 1115, 1023, 839, 742, 608;
̶
1,5-Dimethyl-2-phenyl-4-(phenylselanyl)-1,2-dihydro-3H-pyrazol-3-
one (3na).[13b] White solid (76 mg, 22% yield); 1H NMR (400 MHz, CDCl3):
δ 7.48−7.38 (m, 6H), 7.32−7.28 (m, 1H), 7.22−7.13 (m, 3H), 3.20 (s, 3H),
2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 166.0, 160.1, 135.3, 132.3,
130.3, 129.3, 129.2, 127.1, 126.5, 124.6, 96.0, 36.0, 13.3; HRMS (ESI):
calcd for C17H16N2OSeNa [M+Na]+ 367.0320, found 367.0318.
HRMS (ESI): calcd for C14H15N3O2SNa [M+Na]+ 312.0777, found 312.0780.
1-Ethyl-5-methyl-2-(4-nitrophenyl)-4-thiocyanato-1,2-dihydro-3H-
1,5-Dimethyl-2-phenyl-4-thiocyanato-1,2-dihydro-3H-pyrazol-3-one
pyrazol-3-one (4h). Yellow solid (238 mg, 78% yield); mp = 159.4
160.6 °C; 1H NMR (400 MHz, CDCl3): δ 8.36 (d, J = 9.2 Hz, 2H), 7.57 (d,
J = 8.8 Hz, 2H), 3.81 (q, J = 7.1 Hz, 2H), 3.53 (s, 3H), 1.00 (t, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 163.7, 161.6, 146.2, 139.8, 125.1,
123.9, 109.7, 91.6, 44.3, 12.5, 11.6; IR (KBr, cm-1): ν = 3113, 2970, 2930,
2153, 1691, 1593, 1519, 1495, 1344, 1115, 848, 746, 695, 602; HRMS
(ESI): calcd for C13H12N4O3SNa [M+Na]+ 327.0522, found 327.0520.
̶
(4a). White solid (241 mg, 98% yield); mp = 142.9 ̶
143.6 °C; 1H NMR (400
MHz, CDCl3): δ 7.49−7.45 (m, 2H), 7.39−7.35 (m, 1H), 7.30−7.28 (m, 2H),
3.26 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.1, 157.1,
133.8, 129.6, 128.5, 126.0, 110.8, 86.0, 35.1, 12.1; IR (KBr, cm-1): ν = 3066,
2813, 2153, 1652, 1489, 1416, 1352, 1320, 1277, 1103, 924, 762, 735,
509; HRMS (ESI): calcd for C12H11N3OSNa [M+Na]+ 268.0515, found
268.0518.
2-(4-Chlorophenyl)-1-ethyl-5-methyl-4-thiocyanato-1,2-dihydro-3H-
1-Ethyl-5-methyl-2-phenyl-4-thiocyanato-1,2-dihydro-3H-pyrazol-3-
one (4b). Yellow oil (234 mg, 90% yield); H NMR (400 MHz, CDCl3): δ
pyrazol-3-one (4i). Colorless solid (288 mg, 98% yield); mp = 144.0
145.3 °C; 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 8.8 Hz, 2H), 7.29 (d,
J = 8.8 Hz, 2H), 3.74 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H), 0.99 (t, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 163.8, 158.3, 134.1, 132.6, 129.9,
126.7, 110.4, 89.1, 43.3, 12.3, 12.1; IR (KBr, cm-1): ν = 3089, 2981, 2156,
1666, 1534, 1496, 1352, 1260, 1989, 979, 847, 743; HRMS (ESI): calcd
for C13H12ClN3OSNa [M+Na]+ 316.0282, found 316.0280.
̶
1
7.51−7.47 (m, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.2 Hz, 2H), 3.75
(q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 0.99 (t, J = 7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 163.8, 157.3, 134.1, 129.7, 128.4, 125.8, 110.6, 88.4, 43.0,
12.4, 12.0; IR (neat, cm-1): ν = 2975, 2932, 2160, 1637, 1594, 1455, 1385,
1086, 1045, 879, 695, 603; HRMS (ESI): calcd for C13H13N3OSNa [M+Na]+
282.0672, found 282.0674.
2-(2-Chlorophenyl)-1-ethyl-5-methyl-4-thiocyanato-1,2-dihydro-3H-
5-Methyl-1-pentyl-2-phenyl-4-thiocyanato-1,2-dihydro-3H-pyrazol-3-
one (4c). Yellow oil (275 mg, 91% yield); 1H NMR (400 MHz, CDCl3): δ
7.51−7.47 (m, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 8.9 Hz, 2H), 3.68
(t, J = 7.4 Hz, 2H), 2.48 (s, 3H), 1.41−1.34 (m, 2H), 1.20−1.13 (m, 2H),
1.10−1.03 (m, 2H), 0.80 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
163.8, 156.9, 134.1, 129.7, 128.5, 126.0, 110.7, 87.2, 47.9, 28.5, 27.5,
22.1, 13.8, 12.2; IR (neat, cm-1): ν = 3061, 2957, 2861, 2155, 1594, 1488,
1418, 1344, 1096, 797, 754, 695, 604; HRMS (ESI): calcd for
C16H19N3OSNa [M+Na]+ 324.1141, found 324.1144.
pyrazol-3-one (4j). White solid (197 mg, 67% yield); mp = 137.8 ̶ 138.7 °C;
1H NMR (400 MHz, CDCl3): δ 7.56−7.53 (m, 1H), 7.46−7.37 (m, 3H),
3.74−3.65 (m, 1H), 3.60−3.51 (m, 1H), 2.48 (s, 3H), 1.10 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 163.6, 155.3, 134.1, 131.7, 131.5,
131.2, 131.1, 128.1, 111.0, 85.8, 42.4, 13.4, 11.7; IR (neat, cm-1): ν = 3067,
2967, 2153, 1674, 1480, 1417, 1251, 1111, 1081, 758, 695, 643, 604;
HRMS (ESI): calcd for C13H12ClN3OSNa [M+Na]+ 316.0282, found
316.0282.
3-(2-Ethyl-3-methyl-5-oxo-4-thiocyanato-2,5-dihydro-1H-pyrazol-1-
yl)benzenesulfonamide (4k). White solid (230 mg, 68% yield); mp =
104.2 ̶
105.3 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.85 (d, J = 8.0 Hz, 1H),
1-Benzyl-5-methyl-2-phenyl-4-thiocyanato-1,2-dihydro-3H-pyrazol-3-
one (4d). Yellow oil (235 mg, 73% yield); H NMR (400 MHz, CDCl3): δ
1
7.50−7.46 (m, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.31−7.28 (m, 5H), 6.87−6.85
(m, 2H), 4.89 (s, 2H), 2.53 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.4,
157.1, 133.9, 133.5, 129.7, 129.3, 128.9, 128.7, 126.7, 126.4, 110.5, 88.5,
51.0, 12.4; IR (neat, cm-1): ν = 3032, 2962, 2154, 1661, 1593, 1533, 1494,
1345, 1100, 1026, 740, 694, 640; HRMS (ESI): calcd for C18H15N3OSNa
[M+Na]+ 344.0828, found 344.0829.
7.77−7.73 (m, 2H), 7.63 (d, J = 7.6 Hz, 1H), 7.52 (s, 2H), 3.81 (q, J = 6.8
Hz, 2H), 2.50 (s, 3H), 0.91 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, DMSO-
d6): δ 163.4, 159.7, 145.3, 134.5, 130.4, 128.6, 124.8, 122.0, 111.5, 86.3,
42.9, 12.0, 11.7; IR (KBr, cm-1): ν = 3256, 3072, 2982, 2157, 1655, 1542,
1477, 1341, 1250, 1162, 911, 796, 746, 688, 592; HRMS (ESI): calcd for
C13H14N4O3S2Na [M+Na]+ 361.0400, found 361.0401.
1-Allyl-5-methyl-2-phenyl-4-thiocyanato-1,2-dihydro-3H-pyrazol-3-
one (4e). Yellow oil (239 mg, 88% yield); 1H NMR (400 MHz, CDCl3): δ
7.50−7.46 (m, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 7.6 Hz, 2H),
5.61−5.51 (m, 1H), 5.21 (d, J = 10.4 Hz, 1H), 5.00 (d, J = 16.8 Hz, 1H),
4.25 (d, J = 5.6 Hz, 2H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.4,
157.6, 133.9, 129.7, 129.6, 128.7, 126.2, 120.1, 110.5, 88.6, 49.9, 12.1;
IR (neat, cm-1): ν = 2974, 2930, 2157, 1642, 1593, 1531, 1489, 1414, 1349,
1254, 1087, 1046, 879, 699; HRMS (ESI): calcd for C14H13N3OSNa
[M+Na]+ 294.0672, found 294.0673.
2-(3,4-Dimethylphenyl)-1-ethyl-5-methyl-4-thiocyanato-1,2-dihydro-
3H-pyrazol-3-one (4l). White solid (121 mg, 42% yield); ); mp = 91.7
̶
1
92.8 °C; H NMR (400 MHz, CDCl3): δ 7.23 (d, J = 8.0 Hz, 1H), 7.10 (s,
1H) 7.04−7.01 (m, 1H), 4.72 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 2.29 (s, 6H),
1.01 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 163.9, 156.0, 138.4,
137.7, 131.6, 130.7, 127.5, 123.8, 110.8, 87.7, 42.7, 20.0, 19.6, 12.7, 11.9;
IR (KBr, cm-1): ν = 2976, 2930, 2159, 1637, 1499, 1452, 1346, 1266, 1086,
1044, 878, 599; HRMS (ESI): calcd for C15H17N3OSNa [M+Na]+ 310.0985,
found 310.0987.
Ethyl
2-(5-methyl-3-oxo-2-phenyl-4-thiocyanato-2,3-dihydro-1H-
1-Ethyl-2-phenyl-5-propyl-4-thiocyanato-1,2-dihydro-3H-pyrazol-3-
pyrazol-1-yl)acetate (4f). Orange oil (48 mg, 15% yield); 1H NMR (400
MHz, CDCl3): δ 7.50−7.46 (m, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 7.6
Hz, 2H), 4.35 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 1.21 (t, J = 7.0
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.8, 163.4, 159.3, 133.7, 129.9,
128.8, 126.0, 110.2, 89.7, 62.6, 48.6, 14.2, 12.2; IR (neat, cm-1): ν = 2975,
one (4m). White solid (262 mg, 91% yield); mp = 81.1 ̶
82.4 °C; 1H NMR
(400 MHz, CDCl3): δ 7.49−7.45 (m, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.31 (d,
J = 7.6 Hz, 2H), 3.74 (q, J = 6.9 Hz, 2H), 2.79 (t, J = 7.8 Hz, 2H), 1.83−1.74
(m, 2H), 1.09 (t, J = 7.4 Hz, 3H), 0.97 (t, J = 7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 163.9, 161.2, 134.1, 129.6, 128.3, 125.7, 110.7, 88.0, 43.1,
27.9, 22.1, 13.9, 12.8; IR (KBr, cm-1): ν = 2959, 2870, 2155, 1672, 1595,
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10.1002/ejoc.201901770
European Journal of Organic Chemistry
FULL PAPER
1543, 1455, 1207, 1110, 966, 749, 608, 488; HRMS (ESI): calcd for
C15H17N3OSNa [M+Na]+ 310.0985, found 310.0983.
2011, 76, 8999; (c) T. Gensch, F. J. R. Klauck, F. Glorius, Angew. Chem.,
Int. Ed. 2016, 55, 11287; (d) X. Wang, R. Qiu, C. Yan, V. P. Reddy, L.
Zhu, X. Xu, S.-F. Yin, Org. Lett. 2015, 17, 1970; (e) X. Zhu, Y. Yang, G.
Xiao, J. Song, Y. Liang, G. Deng, Chem. Commun. 2017, 53, 11917; (f)
L. Chen, P. Liu, J. Wu, B. Dai, Tetrahedron 2018, 74, 1513; (g) M.
Noikham, S. Yotphan, Eur. J. Org. Chem. 2019, 2759; (h) Y.-S. Kang, P.
Zhang, M.-Y. Li, Y.-K. Chen, H.-J. Xu, J. Zhao,W.-Y. Sun, J.-Q. Yu, Y.
Lu, Angew. Chem., Int. Ed. 2019, 58, 9099; (g) M. Klecka, L. Slavetinská,
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2015, 6, 576.
1-Ethyl-5-isopropyl-2-phenyl-4-thiocyanato-1,2-dihydro-3H-pyrazol-
3-one (4n). White solid (230 mg, 80% yield); mp = 114.0 ̶
115.0 °C; 1H
NMR (400 MHz, CDCl3): δ 7.50−7.47 (m, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.33
(d, J = 7.2 Hz, 2H), 3.80 (q, J = 6.9 Hz, 2H), 3.28 (sep, J = 7.1 Hz, 1H),
1.54 (d, J = 7.2 Hz, 6H), 1.00 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 165.3, 164.2, 133.9, 129.7, 128.4, 125.9, 111.0, 86.8, 43.2, 27.6,
20.7, 13.3; IR (KBr, cm-1): ν = 2972, 2932, 2155, 1879, 1677, 1595, 1527,
1488, 1303, 1237, 1094, 970, 753, 696, 622; HRMS (ESI): calcd for
C15H17N3OSNa [M+Na]+ 310.0985, found 310.0988.
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For selected examples: (a) K. M. Schlosser, A. P. Krasutsky, H. W.
Hamilton, J. E. Reed, K. Sexton, Org. Lett. 2004, 6, 819; (b) A. M.
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1,2,5-Trimethyl-4-thiocyanato-1,2-dihydro-3H-pyrazol-3-one
White solid (65 mg, 35% yield); mp = 117.0
(4p).
̶
118.2 °C; 1H NMR (400 MHz,
CDCl3): δ 3.49 (s, 3H), 3.40 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 163.1, 152.5, 111.0, 84.6, 33.3, 29.4, 11.4; IR (KBr, cm-1): ν =
3039, 2923, 2851, 2152, 1638, 1514, 1418, 1307, 1035, 741, 646, 595,
500; HRMS (ESI): calcd for C7H9N3OSNa [M+Na]+ 206.0359, found
206.0358.
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For selected examples: (a) G. Varvounis, in Pyrazol-3-ones, Part IV:
Synthesis and Applications in Advances in Heterocyclic Chemistry, A. R.
Katritzky, Ed.; Academic Press, New York, 2009, vol.98, pp. 143−224;
(b) G. H. Sayed, S. A. Shiba, A. Radwan, S. M. Mohameda, M. Khalil,
Chin. J. Chem. 1992, 10, 475; (c) R. Tripathy, A. Ghose, J. Singh, E. R.
Bacon,T. S. Angeles, S. X. Yang, M. S. Albom, L. D. Aimone, J. L.
Herman, J. P. Mallamo, Bioorg. Med. Chem. Lett. 2007, 17, 1793; (d) R.
L. Dow, P. A. Carpino, D. Gautreau, J. R. Hadcock, P. A. Iredale, D.
Kelly-Sullivan, J. S. Lizano, R. E. O’Connor, S. R. Schneider, D. O. Scott,
K. M. Ward, ACS Med. Chem. Lett. 2012, 3, 397; (e) P. Gupta, J. K.
Gupta, A. K. Halve, Int. J. Pharm. Sci. Res. 2015, 6, 2291.
1-Ethyl-2,5-dimethyl-4-thiocyanato-1,2-dihydro-3H-pyrazol-3-one
(4q). White solid (36 mg, 18% yield); mp = 91.5 ̶
92.3 °C; 1H NMR (400
MHz, CDCl3): δ 3.81 (q, J = 7.1 Hz, 2H), 3.39 (s, 3H), 2.38 (s, 3H), 1.20 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 163.9, 152.9, 110.9, 86.2,
41.7, 29.6, 13.6, 11.3; IR (KBr, cm-1): ν = 2976, 2923, 2151, 1650, 1532,
1416, 1387, 1255, 1081, 906, 746, 602; HRMS (ESI): calcd for
C8H11N3OSNa [M+Na]+ 220.0515, found 220.0516.
Acknowledgements
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For selected examples: (a) K. Brune, Acute Pain 1997, 1, 33; (b) M. Himly,
B. Jahn-Schmid, K. Pittertschatscher, B. Bohle, K. Grubmayr, F. Ferreira,
H. Ebner, C. Ebner, J. Allergy Clin. Immunol. 2003, 111, 882; (c) N.
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Cardiovasc. Ther. 2008, 26, 101; (e) V. Marković, S. Eric, T. Stanojković,
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R. Jelić, M. D. Joksović, Bioorg. Med. Chem. Lett. 2011, 21, 4416.
This work was supported by Thailand Research Fund
(RSA6280024 and DBG6080007), the Center of Excellence
for Innovation in Chemistry (PERCH-CIC), Ministry of Higher
Education, Science, Research and Innovation, Central
Instrument Facility (CIF), Faculty of Science, Mahidol
University and the Science Achievement Scholarship of
Thailand (to T. K.).
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For selected examples: (a) Y. Kakiuchi, N. Sasaki, M. Satoh-Masuoka,
H. Murofushi, K. Murakami-Murofushi, Biochem. Biophys. Res. Commun.
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Keywords: metal-free/ pyrazolone/disulfide / thiolation /
thiocyanation
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European Journal of Organic Chemistry
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[15] For the effect of the oxidant, K2S2O8 gave 99%, (NH4)2S2O8 gave 88%,
while Na2S2O8 gave 35%. Comparing with the other persulfate oxidants,
the decrease in the yield of the product was found when using Na2S2O8.
We were uncertain for the exact reason. However, it is likely due to the
difference in ionic radius of the counter ion (Na+ vs. K+ or NH4+), which
could influence the solvation and have a critical impact on the reaction.
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10.1002/ejoc.201901770
European Journal of Organic Chemistry
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Tanakorn Kittikool, Sirilata Yotphan*
Page No. – Page No.
Metal-Free Direct C−H Thiolation and
Thiocyanation of Pyrazolones
Metal-free direct thiolation and thiocyanation of pyrazolones with disulfides and
thiocyanate salts, respectively, have been successfully developed under mild
conditions.
Key Topic: Synthetic Methodology
This article is protected by copyright. All rights reserved.