Copper/Persulfate-Promoted Oxidative Decarboxylative C?H Acylation of Pyrazolones with α-Oxocarboxylic Acids: Direct Access to 4-Acylpyrazolones under Mild Conditions

Article abstract of DOI:10.1002/adsc.201800464

A facile and efficient oxidative C?H acylation of N-substituted pyrazolones using α-oxocarboxylic acids as an acyl group source was developed. A combination of Cu(OAc)₂ and K₂S₂O₈ enables the reaction to proceed smoothly under air and provides a wide array of 4-acylpyrazolone products in moderate to excellent yields. The mechanism of this transformation is believed to proceed via a copper-induced decarboxylation to form the acyl-copper species. This method provides a convenient and useful route for a direct installation of an acyl moiety into bioactive pyrazolone derivatives, which can be further utilized in many applications. (Figure presented.).

Full text of DOI:10.1002/adsc.201800464

Title: Copper/Persulfate-Promoted Oxidative Decarboxylative C−H
Acylation of Pyrazolones with α-Oxocarboxylic Acids: Direct
Access to 4-Acylpyrazolones under Mild Conditions
Authors: Tanakorn Kittikool, Akkharaphong Thupyai, Khamphee
Phomphrai, and Sirilata Yotphan
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800464
Link to VoR: http://dx.doi.org/10.1002/adsc.201800464

10.1002/adsc.201800464
Advanced Synthesis & Catalysis
r
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper/Persulfate-Promoted Oxidative Decarboxylative C−H
Acylation of Pyrazolones with α-Oxocarboxylic Acids: Direct
Access to 4-Acylpyrazolones under Mild Conditions
Tanakorn Kittikool,a Akkharaphong Thupyai,a Khamphee Phomphraib and Sirilata
Yotphana*
a
Center of Excellence for Innovation in Chemistry (PERCH-CIC), Department of Chemistry, Faculty of Science,
Mahidol University, Bangkok 10400, Thailand.
Phone number: +662-201-5154, Fax number: + 662-354-7151, E-mail: sirilata.yot@mahidol.ac.th
Department of Materials Science and Engineering, School of Molecular Science and Engineering, Vidyasirimedhi
b
Institute of Science and Technology (VISTEC), Wangchan, Rayong, 21210, Thailand.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A facile and efficient oxidative C−H acylation of
N-substituted pyrazolones using α-oxocarboxylic acids as an
acyl group source was developed. A combination of
Cu(OAc)2 and K2S2O8 enables the reaction to proceed
smoothly under air and provides a wide array of 4-
acylpyrazolone products in moderate to excellent yields. The
mechanism of this transformation is believed to proceed via
a copper-induced decarboxylation to form the acyl-copper
species. This method provides a convenient and useful
route for a direct installation of an acyl moiety into
bioactive pyrazolone derivatives, which can be further
utilized in many applications.
Keywords: copper; pyrazolone; α-oxocarboxylic acid;
decarboxylative coupling; acylation
acid precursors to construct
a
new C–C
Introduction
(carbon−carbon) or C−X (carbon−heteroatom) bond.
Pyrazolones and their structurally related
analogues represent highly privileged structural
motifs with a broad spectrum of biological and
pharmacological activities, such as analgesic, anti-
inflammatory, antitumor, antiviral and antibacterial
effects.[9] Well-known examples of pyrazolones are
non-steroidal anti-inflammatory drugs (NSAIDs)
phenazone (or antipyrine), propylphenazone and
Carboxylic acids are important class of organic
compounds with a broad applications in synthesis,
pharmaceutical, polymer and industrial processes.[1] A
large number of carboxylic acids have been exploited
as versatile and eco-friendly starting materials. They
have become alternatives to the organic halides or
organometallic reagents in many chemical
transformations due to their remarkable features
including the ready availability, low toxicity, high
stability, and ease of storage and handling.[2] Among
them, α-oxocarboxylic acids or α-keto acids are vital
carboxylic acids in organic synthesis and biological
systems.[3] They have been used as a readily
accessible source of acylating agent to deliver a
carbonyl moiety into organic molecules via the
decarboxylative coupling process.[4] Since the
pioneering work on decarboxylative acylation by
Minisci,[5] several efficient protocols involving
metal,[6] metal-free[7] and visible-light photoredox
catalysis[8] have been explored using α-oxocarboxylic
aminophenazone.[10]
A
number of pyrazolone
derivatives have also been used extensively in many
areas including drug discovery, medicinal and
combinatorial
chemistry,
organic
synthesis,
coordination chemistry, dyes and pigments and
agrochemicals.[11] Traditional syntheses[12] of
bioactive pyrazolone derivatives usually employ
excess and toxic stoichiometric organometallic
reagents via multistep routes, raising environmental
concerns and leading to poor atom- and step-
economy. Additionally, some functional groups are
1
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10.1002/adsc.201800464
Advanced Synthesis & Catalysis
not well tolerated which particularly limits their
structural diversity and further utilization.
experimental procedure, accommodates a wide range
of substrates, generates innocuous by-products, and
offers a useful synthetic route to directly access a
series of the acylated pyrazolones in fair to excellent
yields in a short reaction time.
Over past few decades, direct C−H bond
functionalization has emerged as one of the most
efficient and atom-economical synthetic strategies in
modern organic synthesis.[13] Despite a substantial
progress in this field,[14] only a few reports were
Results and Discussion
found in literature on
a
direct C−H bond
functionalization of N-substituted pyrazolone
analogues (Scheme 1a).[15, 16] Therefore, development
of new, efficient, and expedient methods for a direct
functionalization and manipulation of this bioactive
pharmacophore are highly desired.
Table 1. Optimization of Reaction Conditions.
Catalyst
(equiv.)
Yield[b]
Entry
Oxidant
Solvent
(%)
1
2
CuCl (0.2)
CuBr (0.2)
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Na2S2O8
(NH4)2S2O8
-
MeOH
MeOH
30
22
3
CuI (0.2)
MeOH
22
4
CuTC (0.2)
MeOH
39
5
CuO (0.2)
MeOH
32
6
CuBr2 (0.2)
MeOH
30
7
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.5)
Cu(OAc)2 (1.0)
-
MeOH
40
8
EtOH
33
9
H2O
27
10
11
12
13
14
15
16
17
18
19
20
CH3CN
38
DCE
17
Toluene
20
Dioxane
13
DMSO
trace
56
1:1 MeOH:H2O
1:1 MeOH:H2O
1:1 MeOH:H2O
1:1 MeOH:H2O
1:1 MeOH:H2O
1:1 MeOH:H2O
88c (90d)
54c
75c
no reaction
trace
K2S2O8
Scheme 1. Metal-Catalyzed Direct C−H Bond
Functionalization/C−C Bond Coupling of N-Substituted
Pyrazolones.
[a] Conditions: 1a (0.25 mmol), 2a (0.37 mmol), K2S2O8 (0.37 mmol),
copper catalyst (0.12 mmol, 50 mol%), solvent (1 mL), 60 °C, 16 h.
[b] GC yield.
[c] 4 h.
[d] Isolated yield.
Our group have been focused on the C−H
functionalization/oxidative coupling reactions of N-
heterocycles.[17] Recently, we employed pyrazolones
in direct C−H thiolation reaction under mild
conditions.[18] As a continuation of our research
interest, we envisioned that introducing the acyl
moiety, which is essential for many biochemical,
physiological in cellular processes,[19] into the
pyrazolone scaffold can greatly increase molecular
complexity, thereby enhancing a potential utilization
in many applications. Herein, we wish to disclose a
novel copper-catalyzed direct C−H acylation of
pyrazolones with α-oxocarboxylic acids via an
oxidative decarboxylative coupling process (Scheme
1b). The present method is air-tolerant, can be
performed under mild conditions, features simple
We began our study on C−H acylation of N-
substituted pyrazolones by probing an oxidative
decarboxylative
coupling of phenazone (1a) and benzoyl formic acid
(2a) under various conditions (Table 1). After
extensive screening, we found that the use of catalytic
amounts of Cu(OAc)2 along with K2S2O8 as the
oxidant in MeOH provided the 4-acylpyrazolone
product (3a) in a promising quantity (entry 7, 40%)
even under air atmosphere. Other copper or
transition-metal sources such as Fe, Ni and Pd were
much less effective.[20] Further optimization revealed
that a co-solvent system of 1:1 MeOH:H2O helped
improve solubility and product yield of this copper-
2
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10.1002/adsc.201800464
Advanced Synthesis & Catalysis
Table 2. Scope of α-Oxocarboxylic Acids.[a]
catalyzed oxidative C–H acylation (entry 15).
Moreover, when using 50 mol% of Cu(OAc)2, the
reaction was essentially complete after 4 hours and
gave the corresponding product 3a in 90% isolated
yield (entry 16). In contrast, a change in reaction
temperature as well as the use of other oxidants led to
a decrease in product yield (entries 17−18). Lastly,
control experiments verified the importance of both
Cu(OAc)2 and K2S2O8 as no reaction was observed in
the absence of either copper catalyst or persulfate
oxidant (entries 19−20).
Next, the substrate scope of the α-oxocarboxylic
acids[20] was examined. In general, a number of
arylglycoxylic acids (3a−3l) proved to be viable in
this decarboxylative acylation reaction. In particular,
phenylglycoxylic acids bearing halogen substituents
such as Cl and Br, which are useful for a late-stage
functionalization, are well-tolerated (3c−d and 3h).
Dehalogenation or other side reactions were not
observed under the established conditions. It is also
noteworthy that electron withdrawing groups (such as
p-CN, p-NO2, p-Cl) on the arene portion of α-
oxocarboxylic acids exhibited better reactivity,
thereby resulting in considerably higher yields and
conversions than electron rich arylglycoxylic acids
(p- CH3, p-OCH3).These results could be a
consequence of a stability of the anion or the
intermediate that was generated during the course of
reaction. In case of ortho-methyl substituted
phenylglycoxylic acid substrate, much lower yield of
acylpyrazolone product (3j) was obtained, suggesting
that both electronic effect and steric hindrance are
likely to impede the reaction process.[21] We also
found that the copper-catalyzed decarboxylative
coupling reaction with oxo-(thiophenyl)acetic acid
proceeded quite well, affording desired product 3m in
acceptable quantity. Remarkably, this oxidative
coupling showed a good compatibility with aliphatic
α-keto acid substrates such as pyruvic acid, 2-oxo-
valeric acid and 3-bromopyruvic acid (3n−3p) under
the optimal conditions.
[a]
Conditions: 1a (1 mmol), α-oxocarboxylic acid
2 (1.5 mmol),
Cu(OAc)2 (0.5 mmol, 50 mol%), K2S2O8 (1.5 mmol), MeOH:H2O
(1:1 v/v, 4 ml), 60 °C, 4−16 h, as monitored by TLC. Isolated yields
after chromatography purification.
containing electron withdrawing functionality on
N-aryl group (4f and 4g). These outcomes
indicate that the electronic effect from the
substitution at R1 on nitrogen is crucial for the
efficiency of the transformation. Furthermore, the
copper-catalyzed C−H acylation was found to be
applicable for the synthesis of 4-acylpyrazolone
compounds (4h−4m) with different alkyl groups
on R2 and R3, providing the expected products in
satisfactory yields, with the exception of the N-
The scope of the C–H acylation of various
pyrazolones[20] with benzoyl formic acid (2a) was
also evaluated (Table 3). The effect of
substituents on carbon and nitrogen atoms of
pyrazolone substrates was examined with
different aryl and alkyl groups, and the results
revealed that both electronic and steric nature of
substituents have a dramatic influence on the
reactivity of pyrazolone substrates towards the
reaction. When R1 is the arene motif bearing
electron donating groups (methyl or methoxy) or
chloro substituent at ortho or para position, the
pyrazolones were readily converted to the
benzyl protected pyrazolone (4i). Meanwhile,
a
pyrazolone substrate with R3 is an n-propyl group
gave a reduced yield of product (4a vs 4m).
Unfortunately, as R3 groups become more hindered
(R3 = i-propyl or phenyl groups, 4n−4p vs 4m), the
pyrazolone substrates were eventually incompetent to
undergo acylation reaction under the established
conditions due to a steric interference which might
prevent the acylation to take place at the C4 position
of pyrazolone. We also tried a reaction of pyrazolone
substrate in which R3 is H (4q). Disappointingly, this
pyrazolone was unable to elaborate via oxidative
acylation. We suspected a side-reaction (e.g.
conjugated addition) might occur, which could cause
a decomposition of the substrate.
corresponding products (4a−4e) in moderate to
high yields. On the other hand, relatively low
yields were obtained from pyrazolone substrates
3
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10.1002/adsc.201800464
Advanced Synthesis & Catalysis
Table 3. Variation of Substituents on Pyrazolones
1a) X-ray structure of compound 3a
Entry
Product
R1
R2
R3
Yield
(%)[b]
64
1
2
4a
4b
Ph
Et
Et
Me
Me
3,4-Me2C6H3
66
3
4
5
6
7
8
4c
4d
4e
4f
o-ClC6H4
p-ClC6H4
Et
Et
Me
Me
Me
Me
Me
Me
48
63
87
21
38
67
1b) X-ray structure of compound 3g
p-MeOC6H4
p-O2NC6H4
m-SO2NH2C6H5
Et
Et
4g
4h
Et
Ph
n-C5H11
9
4i
4j
Ph
Ph
Bn
allyl
Me
Et
Me
Me
Me
Me
n-Pr
i-Pr
Ph
29
60
10
11
12
13
14
15
16
17
4k
4l
Me
Me
Ph
62
51
4m
4n
4o
4p
4q
Et
39
Ph
Et
trace
trace
trace
trace
1c) X-ray structure of compound 4e
Ph
Et
Me
Me
Me
Me
Ph
H
[a] Conditions: pyrazolone (1 mmol), 2a (1.5 mmol), Cu(OAc)2 (0.5 mmol,
50 mol%), K2S2O8 (1.5 mmol), MeOH:H2O (1:1 v/v, 4 ml), 60 °C, 4−16 h,
as monitored by TLC.
[b]Isolated yields after chromatography purification.
Apart from the NMR elucidation, we acquired
the X-ray analysis of selected products (3a, 3g and
4e) to confirm the structures of the products (Figure
1).[22] Assuming through a common reaction
pathway, the structure of the other products was
assigned by analogy.
Figure 1. X-Ray Crystal Structures of 3a, 3g and 4e with
Thermal Ellipsoids Drawn at 50% Probability Level
(Hydrogen Atoms are Omitted for Clarity).
were no trapped intermediates being detected.
Given the possibility that the acyl radical
intermediate might be produced in the reaction,
we replaced the α- oxocarboxylic acid by
common carbonyl group sources, which are
known to generate the benzoyl radical
intermediate under oxidative conditions,[23] such
as benzaldehyde, benzyl alcohol, toluene, and
benzylamine. However, neither successful
reaction nor any acyl radical intermediate was
observed (Scheme 2b). Though the evidence from
the inhibition study was rather ambiguous, we
carried out a competition experiment as shown in
In regards to possible mechanisms of this
decarboxylative acylation, two reaction pathways are
usually hypothesized, involving either a free acyl
radical intermediate (RCO▪) or an acyl metal species
(RCO−M).[4a] To elucidate the mechanism of this
reaction, we conducted some preliminary
experiments. Under the assumption that the
reaction proceeded by a free radical pathway, we
subjected BHT (butylated hydroxytoluene) or
TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl),
a typical-radical scavenger, to the standard
reaction. Under these conditions, a significant
reduction of product yield was observed (Scheme
2a), which is indicative of possible involvement
of a radical or single electron transfer process
(SET) in this transformation. Unfortunately, there
Scheme
2c.
In
accordance
with
the
aforementioned substrate scope investigation, the
more electron-deficient α-oxocarboxylic acid, the
better reactivity and higher yield of
corresponding 4-acylated products were noted.
This result was consistent with the previous study
on
the
copper-catalyzed
non-radical
4
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10.1002/adsc.201800464
Advanced Synthesis & Catalysis
decarboxylative method by Gooßen and co- metallation process between Cu(OAc)2 species
workers.[24] Thus, in this transformation, the acyl
copper species (RCO−Cu) is more easily
and pyrazolone. Thus, the C−H bond activation at
C4 position of pyrazolone under the copper
generated and the decarboxylation of α- catalysis should not be considered as a rate-
oxocarboxylic acid should be involved in the rate
determining step.
determining step.[25]
Scheme 3. Kinetic and Labelling Experiments.
Based on our observations along with other
relevant literature,[4,6,16,24, 26] plausible mechanisms are
depicted in Scheme 4 (pathway A and pathway B).
For pathway A, the Cu(II) species initially interacts
with pyrazolone substrate leading to a facile C−H
bond metallation to produce the Cu(II) pyrazolone
complex (intermediate I). Next, a protonolysis of the
copper intermediate I by the α-oxocarboxylic acid
would result in a complexation between the
pyrazolone Cu(II) complex with the α-
Scheme 2. Inhibition and Competition Experiments.
oxocarboxylate,
which
further
drives
a
We further evaluated the kinetic isotope
effect of this reaction by monitoring and
comparing the reaction progress on two parallel
reactions of normal pyrazolone and deuterium
labelled pyrazolone substrates (1a and 1ad) under
standard conditions as shown in Scheme 3a.
However, no kinetic isotope effect (KIE) was
observed (KIE ≈ 1). In addition, we found a
significant H/D scrambling occurred at C4
position of pyrazolone substrate in the absence of
the acid coupling partner, but no deuterium
incooperation was detected in the product
(Scheme 3b). These results suggested a facile and
reversible C−H bond cleavage/metallation,[16]
which is probably due to an electrophilic-type
decarboxylation to release CO2 and form the acyl-
copper complex (intermediate II).[6a] Then, this
copper intermediate II is oxidized by a persulfate
anion or a sulfate radical anion[27] through an electron
transfer process to generate a highly unstable Cu(III)
species (intermediate III).[28] Spontaneous reductive
elimination of the Cu(III) complex could furnish 4-
acylpyrazolone product and Cu(I) species,[29] which is
ultimately re-oxidized to Cu(II) to resume the
reaction.[30] In pathway B, particularly in case of less
reactive pyrazolones such as steric hindered and
electron poor substrates, copper(II) acetate could
interact with the α-oxocarboxylic acid first and form
complex IV, which undergoes a decarboxylation to
5
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10.1002/adsc.201800464
Advanced Synthesis & Catalysis
afford the acyl copper species (intermediate V).[6c, 31]
Then, a reaction of the intermediate V with
pyrazolone in the presence of persulfate oxidant
could generate Cu(III) complex (intermediate VI) via
a single electron transfer process.[6d] Finally, a
reductive elimination occurs to give the product and
Cu(I), which can be converted to Cu(II) under
oxidation conditions. In the presence of the radical
scavenger such as TEMPO, the single electron
oxidation of Cu(II) to Cu(III) could be inhibited,
therefore, trace amount of product was detected.
Conclusion
In summary, we have developed a new and highly
efficient protocol for a direct C–H acylation of
pyrazolones with α-oxocarboxylic acids via a copper-
catalyzed oxidative decarboxylative coupling process.
A combination of Cu(OAc)2 and K2S2O8 facilitates
the C–H/C–C bond cleavage and C–C bond
formation, providing
a
diverse range of 4-
acylpyrazolone products in fair to decent yields. The
notable features of this approach include the use of
simple starting materials and reagents in a green
solvent system under mild and air-tolerant conditions
with the generation of innocuous by-products. These
features make this method attractive for a direct
modification of bioactive pyrazolone heterocycles in
a discovery research and other related applications.
Further
mechanistic
investigation
and
pharmacological evaluation of new pyrazolone
analogues are currently on going in our laboratory.
Experimental Section
General Information
Unless otherwise noted, all reagents were used as received
from commercial suppliers. 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; 60Å silica gel, 70–230 Mesh). GC
experiments were carried out with a GC-FID on
chromatograph equipped with HP-1 dimethylpolysiloxane
1
column (30.0 m × 0.25 mm ID × 0.25 µm). H and 13C
NMR spectra were recorded at 400 and 100 MHz,
respectively, in CDCl3 or DMSO-d6 solution. NMR
chemical shifts are reported in ppm, and were measured
relative to CHCl3 (7.26 ppm for 1H and 77.00 ppm for 13C)
1
or DMSO (2.50 ppm for H and 39.52 ppm for 13C). IR
spectra were recorded on Bruker FT-IR Spectrometer
Model ALPHA by neat 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).
X-ray crystallography data was collected at 293 K on a
Bruker D8 venture diffractometer using Mo ᴋα radiation (λ
= 0.71073 Å).[22]
General Procedure for Copper/Persulfate-Promoted
Oxidative Decarboxylative C−H Acylation of
Pyrazolones with α-Oxocarboxylic Acids: Synthesis of
4-Acylpyrazolones
A 20 ml oven-dried scintillation vial equipped with a
magnetic stir bar was charged with a mixture of pyrazolone
substrate (1.00 mmol, 1.00 equiv.), α-oxocarboxylic acid
(1.50 mmol, 1.50 equiv.), Cu(OAc)2 (90 mg, 0.50 mmol,
50 mol %), K2S2O8 (450 mg, 1.50 mmol, 1.50 equiv.), and
MeOH: H2O (1:1 v/v, 4.00 ml). The vial was loosely
Scheme 4. Possible Reaction Mechanisms.
6
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10.1002/adsc.201800464
Advanced Synthesis & Catalysis
capped and the reaction mixture was heated and stirred at
60 °C. Upon completion (ca. 4 h to 16 h) as monitored by
TLC, saturated NaHCO3 (5 mL), distilled deionized H2O
(12 mL), and saturated NaCl were added respectively to
the reaction. The mixture was extracted with ethyl acetate
(EtOAc) (2 × 25 ml). The combined organic layer was
dried over anhydrous Na2SO4, and concentrated in vacuo.
The crude product was purified by column
chromatography on silica gel to afford a desired 4-
acylpyrazolone product.
7.37−7.31 (m, 3H), 6.90 (d, J = 9.2 Hz, 2H), 3.82 (s, 3H),
3.32 (s, 3H), 2.58 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
188.9, 163.0, 163.0, 157.2, 134.2, 132.0, 131.1, 129.3,
128.1, 126.1, 113.0, 107.4, 55.3, 34.0, 12.3. IR (neat, cm-1)
ν = 2919, 1737, 1666, 1617, 1596, 1225, 1164, 1028, 752,
593. HRMS (ESI) calcd for C19H18N2O3Na [M+Na]+
345.1210, found 345.1211.
1,5-Dimethyl-4-(4-nitrobenzoyl)-2-phenyl-1,2-dihydro-
3H-pyrazol-3-one (3f): Yellow solid (155 mg, 46% yield).
1
mp = 208.3−209.1 °C. H NMR (400 MHz, CDCl3) δ 8.22
(d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 7.50−7.46 (m,
2H), 7.42−7.38 (m, 1H), 7.28 (d, J = 7.6 Hz, 2H), 3.41 (s,
3H), 2.71 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 188.7,
162.9, 156.5, 149.2, 144.3, 133.3, 129.9, 129.6, 128.9,
126.7, 122.8, 105.2, 33.7, 12.5. IR (neat, cm-1) ν = 3054,
1657, 1620, 1596, 1342, 1217, 843, 751, 692, 600. HRMS
(ESI) calcd for C18H15N3O4Na [M+Na]+ 360.0955, found
360.0959.
4-Benzoyl-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (3a): Colorless solid (263 mg, 90% yield).
1
mp = 148.7
̶
149.4 °C. H NMR (400 MHz, CDCl3) δ 7.88
(d, J = 6.8 Hz, 2H), 7.49−7.44 (m, 3H), 7.41−7.36 (m, 3H),
7.30 (d, J = 7.2 Hz, 2H), 3.32 (s, 3H), 2.60 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 190.5, 163.0, 157.1, 138.5,
134.0, 132.0, 129.3, 129.1, 128.4, 128.2, 127.9, 127.6,
126.2, 106.7, 33.9, 12.3. IR (neat, cm-1) ν = 2923, 1665,
1624, 1417, 1222, 867, 749, 693. HRMS (ESI) calcd for
C18H16N2O2Na [M+Na]+ 315.1104, found 315.1111.
4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazole-4-carbonyl)benzonitrile (3g): Light yellow
solid (257 mg, 81% yield). mp = 180.6−181.0 °C. 1H NMR
(400 MHz, CDCl3): δ 7.90 (d, J = 8.0 Hz, 2H), 7.68 (d, J =
8.0 Hz, 2H), 7.51−7.47 (m, 2H), 7.43−7.38 (m, 1H), 7.29
(d, J = 7.2 Hz, 2H), 3.41 (s, 3H), 2.70 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 188.9, 162.9, 156.7, 142.5, 133.5,
131.5, 129.6, 129.6, 128.9, 126.7, 118.6, 114.6, 105.3, 33.8,
12.6. IR (neat, cm-1) ν = 3062, 2229, 1653, 1619, 1219,
1062, 844, 745, 693. HRMS (ESI) calcd for C19H15N3O2Na
[M+Na]+ 340.1056, found 340.1060.
1,5-Dimethyl-4-(4-methylbenzoyl)-2-phenyl-1,2-
dihydro-3H-pyrazol-3-one (3b): Off-white solid (150 mg,
1
49% yield). mp = 189.7−190.1 °C. H NMR (400 MHz,
CDCl3) δ 7.81 (d, J = 8.0 Hz, 2H), 7.48−7.44 (m, 2H), 7.35
(t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.2 Hz, 2H), 7.21 (d, J =
8.0 Hz, 2H), 3.33 (s, 3H), 2.60 (s, 3H), 2.36 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 190.2, 163.1, 157.3, 142.7,
135.8, 134.2, 129.6, 129.3, 128.4, 128.1, 126.1, 107.3, 34.1,
21.6, 12.4. IR (neat, cm-1) ν = 2887, 1667, 1620, 1493,
1412, 1225, 872, 746, 695, 594. HRMS (ESI) calcd for
C19H18N2O2Na [M+Na]+ 329.1260, found 329.1265.
4-(3-Bromobenzoyl)-1,5-dimethyl-2-phenyl-1,2-
dihydro-3H-pyrazol-3-one (3h): Pale orange solid (182
1
mg, 49% yield). mp = 150.0−150.9 °C. H NMR (400
4-(4-Chlorobenzoyl)-1,5-dimethyl-2-phenyl-1,2-
MHz, CDCl3) δ 7.98 (t, J = 1.6 Hz, 1H), 7.83 (d, J = 8.0
Hz, 1H), 7.61−7.59 (m, 1H), 7.51−7.47 (m, 2H), 7.42−7.38
(m, 1H), 7.33−7.28 (m, 3H), 3.37 (s, 3H), 2.64 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 188.9, 162.9, 156.9, 140.5,
134.6, 133.8, 131.9, 129.5, 129.2, 128.5, 128.2, 126.5,
121.8, 106.0, 33.8, 12.4. IR (neat, cm-1) ν = 3021, 1650,
1617, 1498, 1416, 1249, 1062, 874, 715, 671. HRMS (ESI)
calcd for C18H15BrN2O2Na [M+Na]+ 393.0209, found
393.0210.
dihydro-3H-pyrazol-3-one (3c): White solid (235 mg,
72% yield). mp = 183.6−184.1 °C. H NMR (400 MHz,
1
CDCl3) δ 7.83 (d, J = 8.4 Hz, 2H), 7.49−7.45 (m, 2H),
7.39−7.35 (m, 3H), 7.29 (d, J = 7.2 Hz, 2H), 3.35 (s, 3H),
2.62 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 189.1, 162.9,
156.9, 138.1, 136.8, 133.8, 130.9, 129.4, 128.4, 127.9,
126.4, 106.2, 33.8, 12.4. IR (neat, cm-1) ν = 2918, 1656,
1620, 1483, 1411, 1219, 1087, 872, 837, 756. HRMS (ESI)
calcd for C18H15ClN2O2Na [M+Na]+ 349.0714, found
349.0719.
4-(3-Methoxybenzoyl)-1,5-dimethyl-2-phenyl-1,2-
dihydro-3H-pyrazol-3-one (3i): Pale orange solid (193
4-(4-Bromobenzoyl)-1,5-dimethyl-2-phenyl-1,2-
1
mg, 60% yield). mp = 140.7
̶
141.4 °C. H NMR (400
dihydro-3H-pyrazol-3-one (3d): Pale orange solid (130
1
MHz, CDCl3) δ 7.51 (d, J = 7.6 Hz, 1H), 7.48−7.44 (m,
2H), 7.41 (dd, J = 2.4, 1.6 Hz, 1H), 7.38−7.34 (m, 1H),
7.33−7.29 (m, 3H), 7.03 (ddd, J = 8.0, 2.8, 0.8 Hz, 1H),
3.82 (s, 3H), 3.34 (s, 3H), 2.60 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 190.3, 163.0, 159.1, 157.1, 139.8, 134.1,
129.4, 128.7, 128.2, 126.2, 122.4, 118.6, 113.5, 107.0, 55.3,
34.0, 12.4. IR (neat, cm-1) ν = 2926, 1651, 1619, 1575,
1495, 1243, 1050, 756, 601. HRMS (ESI) calcd for
C19H18N2O3Na [M+Na]+ 345.1210, found 345.1217.
mg, 35% yield). mp = 193.5−194.2 °C. H NMR (400
MHz, CDCl3) δ 7.75 (d, J = 8.4 Hz, 2H), 7.54−7.50 (m,
2H), 7.47 (d, J = 8.0 Hz, 2H), 7.40−7.36 (m, 1H), 7.30 (d,
J = 7.2 Hz, 2H), 3.37 (s, 3H), 2.65 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 189.3, 163.0, 157.1, 137.3, 133.8, 131.0,
130.9, 129.5, 128.5, 126.4, 124.6, 106.3, 33.9, 12.5. IR
(neat, cm-1) ν = 2921, 1652, 1607, 1220, 1067, 873, 771,
750, 689. HRMS (ESI) calcd for C18H15BrN2O2Na
[M+Na]+ 393.0209, found 393.0206.
1,5-Dimethyl-4-(2-methylbenzoyl)-2-phenyl-1H-
4-(4-Methoxybenzoyl)-1,5-dimethyl-2-phenyl-1,2-
pyrazol-3(2H)-one (3j): Colorless solid (25 mg, 8%
dihydro-3H-pyrazol-3-one (3e): Off-white solid (68 mg,
21% yield). mp = 186.5−187.3 °C. H NMR (400 MHz,
1
1
yield). mp = 191.3
̶
192.2 °C. H NMR (400 MHz, CDCl3)
δ 7.46−7.42 (m, 2H), 7.38−7.31 (m, 2H), 7.29−7.25 (m,
CDCl3) δ 7.94 (d, J = 8.8 Hz, 2H), 7.48−7.44 (m, 2H),
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800464
Advanced Synthesis & Catalysis
3H), 7.19 (t, J = 7.6 Hz, 2H), 3.37 (s, 3H), 2.72 (s, 3H),
2.39 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 193.1, 163.1,
156.7, 140.2, 135.4, 133.9, 130.4, 129.6, 129.3, 128.2,
127.7, 126.2, 125.1, 106.8, 33.8, 19.7, 12.6. IR (neat, cm-1)
ν = 2922, 1665, 1627, 1526, 1486, 1411, 1218, 1057, 750,
696. HRMS (ESI) calcd for C19H18N2O2Na [M+Na]+
339.1260, found 339.1259.
7.6 Hz, 2H), 3.32 (s, 3H), 2.98 (t, J = 7.4 Hz, 2H), 2.67 (s,
3H), 1.72−1.63 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 197.6, 164.0, 156.0, 133.9, 129.5,
128.4, 126.3, 106.2, 43.6, 33.5, 17.5, 14.0, 12.5. IR (neat,
cm-1) ν = 2925, 1741, 1643, 1518, 1351, 1156, 878, 734,
670. HRMS (ESI) calcd for C15H18N2O2Na [M+Na]+
281.1260, found 281.1258.
4-(2-Naphthoyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-
4-(2-Bromoacetyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-
3H-pyrazol-3-one (3k): Pale orange solid (86 mg, 25%
3H-pyrazol-3-one (3p): Off-white solid (108 mg, 35%
1
yield). mp = 172.0
̶
172.8 °C. 1H NMR (400 MHz, CDCl3)
yield). mp = 121.6
̶
122.5 °C. H NMR (400 MHz, CDCl3)
δ 8.47 (s, 1H), 7.98−7.93 (m, 2H), 7.86−7.81 (m, 2H),
δ 7.54−7.50 (m, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.30 (d, J =
7.53−7.45 (m, 4H), 7.37−7.32 (m, 3H), 3.34 (s, 3H), 2.63
7.2 Hz, 2H), 4.64 (s, 2H), 3.36 (s, 3H), 2.69 (s, 3H). 13C
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 190.4, 163.1, 157.0, NMR (100 MHz, CDCl3) δ 186.9, 163.4, 155.6, 133.3,
135.9, 135.3, 134.1, 130.9, 129.7, 129.4, 128.3, 127.6,
127.5, 127.3, 126.3, 126.0, 125.6, 124.6, 107.1, 33.9, 12.4.
IR (neat, cm-1) ν = 2921, 1658, 1610, 1485, 1407, 1189,
1056, 779, 745. HRMS (ESI) calcd for C22H18N2O2Na
[M+Na]+ 365.1260, found 365.1260.
129.7, 129.1, 126.9, 103.7, 35.7, 33.4, 12.5. IR (neat, cm-1)
ν = 2943, 1640, 1517, 1383, 1233, 1083, 765, 702, 602.
HRMS (ESI) calcd for C13H13BrN2O2Na [M+Na]+
331.0053, found 331.0050.
4-Benzoyl-1-ethyl-5-methyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (4a): Off-white solid (196 mg, 64% yield),
4-(2,3-Dihydrobenzo[b][1,4]dioxine-6-carbonyl)-1,5-
dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (3l):
1
mp = 190.6
̶
191.3 °C. H NMR (400 MHz, CDCl3) δ 7.89
Pale orange solid (158 mg, 45% yield). 179.6
̶
180.6 °C. 1H
(d, J = 7.2 Hz, 2H), 7.48−7.44 (m, 3H), 7.42−7.39 (m, 2H),
7.38−7.32 (m, 3H), 3.81 (q, J = 7.2 Hz, 2H), 2.63 (s, 3H),
1.09 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
190.6, 163.8, 157.4, 138.5, 134.3, 132.0, 129.4, 129.4,
128.1, 127.7, 126.1, 108.0, 41.6, 12.6, 12.2. IR (neat, cm-1)
ν = 2922, 1729, 1658, 1611, 1486, 1207, 1060, 747, 691,
NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.6 Hz, 2H),
7.48−7.44 (m, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.31 (d, J =
7.6 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.24 (dd, J = 13.2,
5.2 Hz, 4H), 3.32 (s, 3H), 2.56 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 188.8, 163.0, 157.0, 147.4, 142.8, 134.1,
132.0, 129.3, 128.1, 126.1, 124.0, 119.1, 116.4, 107.4, 64.6, 602. HRMS (ESI): calcd for C19H18N2O2Na [M+Na]+
64.0, 34.0, 12.3. IR (neat, cm-1) ν = 2924, 1668, 1616,
1541, 1489, 1279, 1254, 1059, 886, 778. HRMS (ESI)
calcd for C20H18N2O4Na [M+Na]+ 373.1159, found
373.1160.
329.1260, found 329.1260.
4-Benzoyl-2-(3,4-dimethylphenyl)-1-ethyl-5-methyl-1,2-
dihydro-3H-pyrazol-3-one (4b): Orange solid (221 mg,
1
66% yield). mp = 165.4
̶
166.2 °C. H NMR (400 MHz,
CDCl3) δ 7.90−7.88 (m, 2H), 7.49−7.45 (m, 1H),
7.41−7.37 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 7.11 (d, J =
2.0 Hz, 1H), 7.03 (dd, J = 8.0, 2.0 Hz, 1H), 3.79 (q, J = 7.2
Hz, 2H), 2.62 (s, 3H), 2.27 (s, 6H), 1.11 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 190.7, 163.8, 156.2, 138.6,
138.0, 137.3, 131.9, 131.7, 130.4, 129.4, 127.8, 127.6,
123.9, 107.5, 41.3, 19.8, 19.4, 12.9, 12.2. IR (neat, cm-1) ν
= 2919, 1662, 1621, 1500, 1226, 1060, 830, 692, 644.
HRMS (ESI) calcd for C21H22N2O2Na [M+Na]+ 357.1573,
found 357.1572.
1,5-Dimethyl-2-phenyl-4-(thiophene-3-carbonyl)-1,2-
dihydro-3H-pyrazol-3-one (3m): Pale yellow solid (167
1
mg, 56% yield). mp = 173.0
̶
174.0 °C. H NMR (400
MHz, CDCl3) δ 8.59 (dd, J = 2.8, 1.2 Hz, 1H), 7.66 (dd, J
= 5.0, 1.0 Hz, 1H), 7.51−7.46 (m, 2H), 7.39 (t, J = 7.6 Hz,
1H), 7.32 (d, J = 7.6 Hz, 2H), 7.20 (dd, J = 5.0, 3.0 Hz,
1H), 3.33 (s, 3H), 2.61 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 182.9, 162.8, 157.1, 142.0, 134.2, 134.0, 129.5,
128.4 (2C), 126.4, 124.2, 107.5, 33.9, 12.5. IR (neat, cm-1)
ν = 2917, 1640, 1591, 1489, 1405, 1226, 1075, 849, 743,
696. HRMS (ESI) calcd for C16H14N2O2SNa [M+Na]+
321.0668, found 321.0671.
4-Benzoyl-2-(2-chlorophenyl)-1-ethyl-5-methyl-1,2-
dihydro-3H-pyrazol-3-one (4c): Yellow solid (163 mg,
1
48% yield). mp = 161.5
̶
162.3 °C. H NMR (400 MHz,
4-Acetyl-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (3n): Pale yellow solid (120 mg, 52%
CDCl3) δ 7.89 (d, J = 7.6 Hz, 2H), 7.54−7.52 (m, 1H),
7.48−7.42 (m, 3H), 7.40−7.36 (m, 3H), 3.83−3.74 (m, 1H),
3.62−3.53 (m, 1H), 2.64 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 190.5, 163.4, 155.1, 138.5,
134.2, 131.9, 131.6, 131.3, 130.8, 129.4, 127.9, 127.6,
127.1, 106.2, 41.0, 13.4, 12.1. IR (neat, cm-1) ν = 2920,
1737, 1659, 1621, 1474, 1211, 1061, 938, 750, 604.
HRMS (ESI) calcd for C19H17ClN2O2Na [M+Na]+
363.0871, found 363.0870.
1
yield). mp = 149.8
̶
150.5 °C. H NMR (400 MHz, CDCl3)
δ 7.50−7.46 (m, 2H), 7.40−7.36 (m, 1H), 7.28 (d, J = 7.2
Hz, 2H), 3.30 (s, 3H), 2.64 (s, 3H), 2.54(s, 3H). 13C NMR
(100 MHz, CDCl3) δ 194.7, 164.2, 155.6, 133.8, 129.5,
128.4, 126.4, 106.3, 33.4, 29.6, 12.4. IR (neat, cm-1) ν =
2982, 1655, 1630, 1487, 1333, 1165, 1101, 760, 699, 590.
HRMS (ESI) calcd for C13H14N2O2Na [M+Na]+ 253.0947,
found 253.0956.
4-Butyryl-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
4-Benzoyl-2-(4-chlorophenyl)-1-ethyl-5-methyl-1,2-
pyrazol-3-one (3o): Off-white solid (122 mg, 48% yield).
dihydro-3H-pyrazol-3-one (4d): Yellow solid (214 mg,
1
1
mp = 111.7
̶
112.5 °C. H NMR (400 MHz, CDCl3) δ
63% yield). mp = 161.5
̶
162.3 °C. H NMR (400 MHz,
7.52−7.48 (m, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.30 (d, J =
CDCl3) δ 7.87 (d, J = 7.2 Hz, 2H), 7.51−7.48 (m, 1H),
8
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10.1002/adsc.201800464
Advanced Synthesis & Catalysis
7.44−7.39 (m, 4H), 7.28 (d, J = 8.8 Hz, 2H), 3.79 (q, J =
7.2 Hz, 2H), 2.61 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 190.4, 163.8, 158.4, 138.3,
J = 7.2 Hz, 2H), 7.50−7.42 (m, 3H), 7.40−7.33 (m, 3H),
7.31−7.30 (m, 3H), 7.24 (d, J = 7.2 Hz, 2H), 6.95−6.93 (m,
2H), 4.93 (s, 2H), 2.66 (s, 3H). 13C NMR (100 MHz,
133.7, 132.9, 132.2, 129.5, 129.4, 127.8, 126.9, 108.4, 41.9, CDCl3) δ 190.6, 163.4, 157.4, 138.4, 134.0, 133.7, 132.1,
12.4, 12.3. IR (neat, cm-1) ν = 2929, 1660, 1635, 1551,
1489, 1211, 1124, 794, 664, 597. HRMS (ESI) calcd for
C19H17ClN2O2Na [M+Na]+ 363.0871, found 363.0870.
129.4, 129.4, 129.0, 128.5, 128.4, 127.7, 126.6, 126.5,
107.9, 49.6, 12.7. IR (neat, cm-1) ν = 2921, 1666, 1633,
1530, 1352, 1223, 1026, 870, 761, 691. HRMS (ESI) calcd
for C24H20N2O2Na [M+Na]+ 391.1417, found 391.1419.
4-Benzoyl-1-ethyl-2-(4-methoxyphenyl)-5-methyl-1,2-
dihydro-3H-pyrazol-3-one (4e): Off white solid (293 mg,
1-Allyl-4-benzoyl-5-methyl-2-phenyl-1,2-dihydro-3H-
1
87% yield). mp = 137.3
̶
138.1 °C. H NMR (400 MHz,
pyrazol-3-one (4j): Pale orange solid (191 mg, 60%
1
CDCl3) δ 7.92 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H),
7.44−7.40 (m, 2H), 7.29 (d, J = 3.6 Hz, 2H), 7.00 (d, J =
8.8 Hz, 2H), 3.85 (s, 3H), 3.80 (q, J = 7.2 Hz, 2H), 2.65 (s,
3H), 1.14 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 190.6, 163.9, 159.7, 155.7, 138.5, 131.9, 129.4, 128.5,
127.6, 126.7, 114.7, 107.2, 55.5, 41.1, 12.9, 12.2. IR (neat,
cm-1) ν = 2936, 1658, 1617, 1499, 1248, 1026, 813, 748,
583. HRMS (ESI) calcd for C20H20N2O3Na [M+Na]+
359.1366, found 359.1365.
yield). mp = 139.3
̶
140.3 °C. H NMR (400 MHz, CDCl3)
δ 7.90 (d, J = 7.2 Hz, 2H), 7.50−7.44 (m, 3H), 7.43−7.35
(m, 3H), 7.32 (d, J = 7.2 Hz, 2H), 5.70−5.60 (m, 1H), 5.25
(d, J = 10.4 Hz, 1H), 5.05 (d, J = 17.2 Hz, 1H), 4.32 (d, J =
5.2 Hz, 2H), 2.61 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
190.5, 163.3, 157.6, 138.4, 134.0, 132.1, 129.7, 129.4,
129.4, 128.4, 127.7, 126.5, 119.5, 107.9, 48.5, 12.3. IR
(neat, cm-1) ν = 2922, 1668, 1612, 1485, 1415, 1215, 939,
756, 687, 629. HRMS (ESI) calcd for C20H18N2O2Na
[M+Na]+ 341.1260, found 341.1259.
4-Benzoyl-1-ethyl-5-methyl-2-(4-nitrophenyl)-1,2-
dihydro-3H-pyrazol-3-one (4f): Brown solid (74 mg,
21% yield). Decomposed at 105.6 °C. H NMR (400 MHz,
4-Benzoyl-1,2,5-trimethyl-1,2-dihydro-3H-pyrazol-3-
1
one (4k): Yellow solid (143 mg, 62% yield). mp = 150.2 ̶
1
CDCl3): δ 8.33 (d, J = 9.2 Hz, 2H), 7.86 (d, J = 7.2 Hz,
2H), 7.57−7.52 (m, 3H), 7.46−7.42 (m, 2H), 3.87 (q, J =
6.9 Hz, 2H), 2.63 (s, 3H), 1.10 (t, J = 7.0 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 190.0, 163.7, 161.9, 145.7,
151.0 °C. H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 6.8
Hz, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.41−7.37 (m, 2H), 3.49
(s, 3H), 3.37 (s, 3H), 2.50 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 190.5, 162.4, 152.0, 138.7, 131.9, 129.3, 127.6,
140.1, 138.0, 132.6, 129.3, 128.0, 124.8, 123.9, 109.9, 42.9, 106.0, 31.9, 28.6, 11.7. IR (neat, cm-1) ν = 2924, 1614,
12.5, 11.7. IR (neat, cm-1) ν = 2918, 1680, 1639, 1511,
1337, 1208, 1109, 929, 748. HRMS (ESI) calcd for
C19H17N3O4Na [M+Na]+ 374.1111, found 374.1122.
1559, 1504, 1410, 1208, 1176, 932, 748, 601. HRMS (ESI)
calcd for C13H14N2O2Na [M+Na]+ 253.0947, found
253.0951.
3-(4-Benzoyl-2-ethyl-3-methyl-5-oxo-2,5-dihydro-1H-
4-Benzoyl-1-ethyl-2,5-dimethyl-1,2-dihydro-3H-
pyrazol-1-yl)benzenesulfonamide (4g): White solid (146
pyrazol-3-one (4l): White solid (125 mg, 51% yield). mp
1
mg, 38% yield). mp = 116.0
̶
116.8 °C. H NMR (400
= 101.1 ̶
101.2 °C. 1H NMR (400 MHz, CDCl3) δ
MHz, DMSO-d6) δ 7.84 (d, J = 8.0 Hz, 1H), 7.79−7.71 (m,
4H), 7.61 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.51
(s, 2H), 7.45 (t, J = 7.6 Hz, 2H), 3.87 (q, J = 6.8 Hz, 2H),
2.58 (s, 3H), 1.02 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6) 189.2, 163.3, 159.0, 145.2, 138.4, 134.8, 132.1,
130.2, 129.1, 128.9, 127.8, 124.7, 122.5, 106.4, 41.8, 12.1,
11.9. IR (neat, cm-1) ν = 3231, 3067, 2922, 1737, 1626,
1337, 1222, 1160, 687, 591. HRMS (ESI) calcd for
C19H19N3O4SNa [M+Na]+ 408.0988, found 408.0988.
7.86−7.84 (m, 2H), 7.51−7.47 (m, 1H), 7.43−7.39 (m, 2H),
3.94 (q, J = 7.2 Hz, 2H), 3.38 (s, 3H), 2.54 (s, 3H), 1.28 (t,
J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 190.6,
163.4, 152.6, 138.7, 132.0, 129.4, 127.7, 107.1, 40.4, 28.8,
13.6, 11.5. IR (neat, cm-1) ν = 2921, 1616, 1502, 1204,
1072, 932, 749, 688, 647. HRMS (ESI) calcd for
C14H16N2O2Na [M+Na]+ 267.1104, found 267.1106.
4-Benzoyl-1-ethyl-2-phenyl-5-propyl-1,2-dihydro-3H-
pyrazol-3-one (4m): Orange solid (130 mg, 39% yield).
1
mp = 118.7
̶
119.5 °C. H NMR (400 MHz, CDCl3) δ 7.88
4-Benzoyl-5-methyl-1-pentyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (4h): Orange solid (233 mg, 67% yield).
(d, J = 7.2 Hz, 2H), 7.50−7.44 (m, 3H), 7.42−7.35 (m, 3H),
7.33 (d, J = 7.6 Hz, 2H), 3.81 (q, J = 7.2 Hz, 2H), 2.95 (t, J
= 7.8 Hz, 2H), 1.87−1.77 (m, 2H), 1.13−1.09 (m, 6H). 13C
NMR (100 MHz, CDCl3) δ 190.4, 164.1, 161.5, 138.6,
134.4, 131.9, 129.3, 129.3, 128.0, 127.7, 126.0, 107.5, 41.8,
27.6, 22.6, 14.1, 13.1. IR (neat, cm-1) ν = 2923, 1663, 1630,
1527, 1455, 1359, 1212, 995, 753, 690. HRMS (ESI) calcd
for C21H22N2O2Na [M+Na]+ 357.1573, found 357.1572.
1
mp = 104.7
̶
105.3 °C. H NMR (400 MHz, CDCl3) δ 7.88
(d, J = 7.2 Hz, 2H), 7.49−7.44 (m, 3H), 7.42−7.34 (m, 3H),
7.31 (d, J = 7.2 Hz, 2H), 3.74 (t, J = 7.6 Hz, 2H), 2.63 (s,
3H), 1.52−1.44 (m, 2H), 1.27−1.18 (m, 2H), 1.16−1.08 (m,
2H), 0.82 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 190.6, 163.7, 157.2, 138.6, 134.3, 131.9, 129.3, 129.1,
128.2, 127.6, 126.2, 106.9, 46.4, 28.3, 27.5, 22.0, 13.7,
12.4. IR (neat, cm-1) ν = 2918, 1663, 1629, 1518, 1485,
1218, 1056, 754, 693, 604. HRMS (ESI) calcd for
C22H24N2O2Na [M+Na]+ 371.1730, found 371.1733.
Acknowledgements
This work was supported by Thailand
Research
Fund
4-Benzoyl-1-benzyl-5-methyl-2-phenyl-1,2-dihydro-3H-
(RSA5980008 and DBG6080007), Center of Excellence for
Innovation in Chemistry (PERCH-CIC), Office of the Higher
Education Commission (OHEC), Ministry of Education, Central
pyrazol-3-one (4i): Orange solid (107 mg, 29% yield). mp
1
= 148.4
̶
149.2 °C. H NMR (400 MHz, CDCl3) δ 7.88 (d,
9
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10.1002/adsc.201800464
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Instrument Facility, Faculty of Science, Mahidol University and
the Science Achievement Scholarship of Thailand (to T. K.). We
also thank Dr. Andy S. Tsai for a helpful discussion.
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11
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FULL PAPER
Copper/Persulfate-Promoted Oxidative
Decarboxylative C−H Acylation of Pyrazolones
with α-Oxocarboxylic Acids: Direct Access to 4-
Acylpyrazolones under Mild Conditions
Adv. Synth. Catal. Year, Volume, Page – Page
Tanakorn Kittikool, Akkharaphong Thupyai,
Khamphee Phomphrai and Sirilata Yotphan *
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