Iodine-Catalyzed Regioselective Oxidative Cyclization of Aldehyde Hydrazones with Electron-Deficient Olefins for the Synthesis of Mefenpyr-Diethyl

Article abstract of DOI:10.1021/acs.joc.9b01499

A regioselective synthesis of polysubstituted dihydropyrazoles and pyrazoles through an iodine-catalyzed oxidative cyclization strategy of aldehyde hydrazones with electron-deficient olefins is described. The protocol adopts very mild reaction conditions and provides desirable yields. The reaction is supposed to proceed via a cascade C-H functionalization, C-N bond formation, and oxidation sequential processes. The overall simplicity and regioselectivity of the catalytic system make this approach a valuable and step-economical tool to construct a C-C bond for the synthesis of Mefenpyr-Diethyl.

Full text of DOI:10.1021/acs.joc.9b01499

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Article
Iodine-Catalyzed Regioselective Oxidative Cyclization
of Aldehyde Hydrazones with Electron-Deficient
Olefins for the Synthesis of Mefenpyr-Diethyl
Jia-Nan Zhu, Wen-Kang Wang, Jian Zheng, Hao-Peng Lin, Yun-Xia Deng, and Sheng-Yin Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01499 • Publication Date (Web): 23 Jul 2019
Downloaded from pubs.acs.org on July 23, 2019
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Page 1 of 14
1
The Journal of Organic Chemistry
Iodine-Catalyzed
Regioselective
Oxidative
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9
Cyclization of Aldehyde Hydrazones with Electron-
Deficient Olefins for the Synthesis of Mefenpyr-
Diethyl
Jia-Nan Zhu, Wen-Kang Wang, Jian Zheng, Hao-Peng Lin, Yun-Xia Deng and Sheng-Yin Zhao*
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College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai
201620, P. R. China.
E-mail: syzhao8@dhu.edu.cn
O
O
R3
R1
HN
R4
O
R4
R1
I2 (20 mol %)
I2 (20 mol %)
O
R1
N
+
R4
N
O
N
N
BPO, CH3CN
80 °C, 6 h
TBHP, CH3CN
80 °C, 2 h
CO2Et
R2
N
R3
COR2
R3
H

R2
Me
R3
H

21 examples
up to 90% yield
9 examples
up to 86% yield
N
EtO2C
N
Cl
Cl
Mefenpyr-diethyl, a herbicide safener
ABSTRACT: A regioselective synthesis of polysubstituted dihydropyrazoles and pyrazoles through
iodine-catalyzed oxidative cyclization strategy of aldehyde hydrazones with electron-deficient olefins is
described. The protocol adopts very mild reaction conditions and provides desirable yields. The reaction
is supposed to proceed via a cascade C−H functionalization, C−N bond formation and oxidation
sequential processes. The overall simplicity and regioselectivity of the catalytic system make this
approach a valuable and step-economical tool to construct C−C bond for the synthesis of Mefenpyr-
Diethyl.
■ INTRODUCTION
Arguably, polyfunctional dihydropyrazoles and
pyrazoles represent one of the most important
CO2Me
Me
N
Me
classes of N-heterocycles found in numerous
natural products,1-3 bioactive compounds,4-6 and
functional materials.7,8 For example, RH3421 is
an insecticide that can block both peripheral and
central neuronal activities in insects.9 Mefenpyr-
diethyl, a herbicide safener, which was used to
against ACCase inhibitors.10,11 On the other hand,
the polysubstituted pyrazoles are found in
commercially available drugs such as
Rimonabant, Celecoxib and Sildenafil citrate
(Figure 1). In addition, they can act as
luminescent materials,12,13 coordination polymer
gels,14 building blocks in supramolecular
assembly15 and also work as ligands for some
cross-coupling reaction,16,17 precursors to N-
heterocyclic carbenes (NHCs),18-20 and directed
groups for C−H activetions.21-23 Given the
usefulness of these privileged skeleton,
development of efficient and operationally
simple approaches are of great significance.
CO2Et
H
N
N
N
N
EtO2C
Cl
Cl
O
Cl
Mefenpyr-diethyl
CF3
RH 3421
SO2NH2
Cl
Cl
Cl
N
N
Me
NH
N
N
O
N
Me
CF3
Rimonabant
Celecoxib
Figure 1. Selected examples of functional
dihydropyrazoles and pyrazoles.
Traditional
strategies
for
constructing
polysubstituted pyrazoles are annulations
initiated by the condensation of hydrazine
compounds with carbonyl derivatives (Scheme
1a),24-27 or 1,3-dipolar cycloadditions of diazo
molecules with alkenes or alkynes (Scheme
1b).28-38 For example, chloramine-T was
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commonly used to generate 1,3-dipolar species
combination of the iodine/peroxide mediated
1
and subsequent 1,3-dipolar cycloadditions for the
synthesis of pyrazoles would smoothly occur. All
these reactions were mainly focus on
bisarylhydrazones in the presence of excessive
chloramine-T. In addition, hydrazones have also
been employed as the starting materials for the
synthesis of pyrazoles (Scheme 1c).39-43 Apart
from these methods, transition-metal-catalyzed
oxidative C-H bond functionalization was always
used to construct pyrazole derivatives (Scheme
1d).44-47 However, these approaches have the
defects of requiring precious metal, harsh
reaction conditions or inferior regioselectivity.
As far as we know, related single electron
oxidation of (N=CH) of diverse aldehyde
hydrazones to electron-deficient olefins in
dihydropyrazoles or pyrazoles synthesis was not
examined to date. Hence, development of a one-
pot regioselective avenue for the efficient
construction of the pyrazole skeleton is highly
desirable.
oxidative coupling reactions have been
investigated to some extent.56-64 Despite the
compelling progress, the examination of direct
catalytic transformation via a iodine catalyzed
strategy for the construction of privileged
heterocyclic compounds are still promising.
Inspired by our previous work,65-67 and literature
reports, we herein report a I2-catalyzed pyrazoles
synthesis by an oxidative radical relay strategy.
2
3
4
5
6
7
8
9
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50
51
52
53
54
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57
58
59
60
Table 1. Optimization of the Reaction
Conditionsa
O
catalysts
oxidant
H
O
Ph
N
O
EtO2C
+
N
solvent
80 °C, 6 h
O
N
N
CO2Et
Ph
1a
2a
3a
entry
1
2
3
4
5
6
7
8
catalyst
oxidant
solvent
yield (%)
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
K2S2O8
DTBP
BTI
DMF
35
21
58
0
0
0
0
0
trace
0
16
64
81
53
68
57
70
77
73
61
DMSO
CH3CN
dioxane
DME
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Scheme 1. Strategies for the Synthesis of
Pyrazoles
R3
R3
R4
R2
Previous work:
O
O
9
condensation
and/or
R1
R2
+
R4
NH2
R2
R4
N
N
(a)24-27
N
N
10
11
12
13
14
15
16
17b
18c
19d
20e
H2O2
N
R3
H
N
R1
R1
m-CPBA
TBPB
BPO
BPO
BPO
BPO
BPO
BPO
BPO
R2
R2
R1
R3
R1
R1
R2
cycloaddition
+
EWG
and/or
(b)28-31
N
R3
N
N
I2
R3
H
N
H
N
H
NaI
NIS
TBAI
I2
I2
I2
1. t-BuOK, THF
-78 °C, N2
R2
N
R3
R4
R3
R4
H
NO2
R4
R1
R2
(c)34
N
+
N
H
R3
2. TFA (2 equiv)
-78 °C-rt, N2
N
R1
R1
HN
R2
N
(d)40
N
5 % [RuCl2(p-cymene)]2
R4
R2
DMSO, 2 equiv NaHCO3
1 atm O2, 60-100 °C, 5-6 h
N
R1
R3
I2
BPO
This work:
aReactions were carried out with 1a (0.5 mmol), 2a (0.75
mmol), catalyst (20 mol %), oxidant (3.0 equiv.) in a
solvent (2.0 mL) under air condition at 80 oC for 6 h. b10
O
I2 (20 mol %)
BPO (3 equiv)
O
I2 (20 mol %)
TBHP (3 equiv)
R3
O
H
R1
N
R4
R1
R4
R1
R4
+
N
O
CH3CN
80 °C, 6 h
CH3CN
80 °C, 2 h
O
N
N
COR2
R3
N
N
R2
R2
R3 H
c
d
R3  H
mol % I2 was used. 50 mol % I2 was used. 2.0 equiv.
 Low-cost catalyst
 Broad substrate scope
 Metal-free
 Oxidative radical relay cyclization
 Good regioselectivity
e
o
BPO was used. The reaction was conducted at 60 C.
TBHP = 70% t-BuOOH in water, DTBP = 2-(t-

Atom and step economy
buytlperoxy)-2-methylpropane, BTI
=
[Bis(trifluo-
acetoxy)iodo]benzene. m-CPBA = m-Chloroperoxyben-
zoic acid, TBPB = tert-Butyl peroxybenzoate, BPO =
Dibenzoyl peroxide.
In recent years, metal-free catalyzed oxidative
C−H functionalization has been gained
considerable attention due to its low costs and the
formation of environmentally acceptable
byproducts.48-51 Molecular iodine, which
possesses various oxidation states and mild redox
potential, has been widely utilized in oxidative
■ RESULTS AND DISCUSSION
We started our studies by examining various
reaction conditions for this oxidative radical relay
reaction of phenylhydrazone 1a and tert-butyl
acrylate 2a, selected results are summarized in
Table 1. To our delight, the target molecule 3a
coupling
reactions.52-55
Furthermore,
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was obtained in 35% yield when the
Due to the formation of dihydropyrazoles is
1
transformation proceeded in the presence of 20
mol % I2 and 3.0 equiv. of TBHP in DMF at
80 °C (entry 1). The screening of solvents
revealed that CH3CN was the best selection,
giving 3a in 58% yield (entries 2-6). The
structure of 3a was confirmed by X-ray single
crystal diffraction.68 Then, a variety of oxidants
were tested, and the results showed that none of
the other oxidants was superior to BPO, with an
up to 81% yield (entries 7-13). The replacement
of iodine with other iodides, including NaI, NIS
or TBAI, the yield of 3a decreased (entries 14-
16). Varying the quantity of the catalyst, the yield
decreased slightly (entries 17-18). Reducing the
amount of BPO to 2.0 equiv. afford 73% yield of
the desired product 3a (entry 19). Lowering the
temperature to 60 °C, the yield decreased to 61%
(entry 20).
With the optimized reaction conditions in hand
(Table 1, entry 13), the scope of this oxidative
radical relay reaction was then investigated
(Scheme 2). Obviously, diverse electron-deficient
olefins are feasible coupling partners for this
transformation, and moderate to good yields
could be achieved (3a-i). A series of electron-
withdrawing olefins, such as α,β-unsaturated
esters, amides, ketones, nitrile and terminal
alkyne ester underwent the desired radical relay
smoothly, furnishing pyrazole derivatives with
high efficiency in 60-90% yields. Next, a wide
range of aldehyde hydrazones were evaluated.
First, the transformation proceeded smoothly in
regard to hydrazons from diversely substituted
aromatic hydrazine. Both electron-donating and
electron-deficient substituents were all well
compatible in moderate yields (3j-o). More
importantly, electron-deficient substituents such
as bromo, cyano and carboxyl groups can offer
the opportunity for further downstream
diversification. Notably, replacement of the aryl
hydrazine with diverse alkyl hydrazine including,
cyclohexyl, isopropyl, and benzyl were perfectly
tolerable with tert-butyl acrylate, thus affording
the corresponding pyrazoles 3p-r in high yields.
After validating the scope with hydrazine,
glyoxal and phenylglyoxal were further
examined. Delightedly, the yields of products 3s,
3t and 3u were in 78%, 69% and 56%,
respectively.
considerably fast. A mild oxidant may probably
has no impact on other functional groups of the
substrates so we choose TBHP as the terminal
oxidant. Indeed, α-alkyl substituted acrylates are
well compatible in dihydropyrazoles synthesis in
the presence of TBHP with moderate to good
yields 4a-i (Scheme 3). It is noteworthy that the
free NH and OH in dihydropyrazoles could be
used for further functionalization. To further
demonstrate the synthetic applicability of this
oxidative radical relay protocol, we present the
facile synthesis of mefenpyr-diethyl using ethyl
2
3
4
5
6
7
8
9
10
11
12
13
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15
16
17
18
19
20
21
22
23
24
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Results of I2-Catalyzed Pyrazoles
(3) Synthesisa
O
I2 (20 mol %)
H
O
BPO (3 equiv)
R1
N
O
R2
+
N
R3
N
R1
CH3CN, 80 °C, 6 h
COR2
N
O
1
2
O
O
O
O

N
Ph
EtO2C
N
EtO2C
EtO2C
EtO2C
N
Ph
N
CCDC 1904618
3a (81%)
3b (79%)
O
O
O
N
O
O
Ph
N
N
N
Ph
N
N
EtO2C
EtO2C
EtO2C
Ph
Ph
N
N
3c (90%)
3d (82%)
3e (72%)
O
O
CN
N
NH2
Ph
N
Ph
N
N
Ph
EtO2C
N
N
3h (61%)
3g (80%)
3f (65%)
O
O
O
O
O
N
O
N
N
N
Ph
N
EtO2C
OMe
EtO2C
EtO2C
N
3i (60%)
3j (76%)
3k (66%)
O
O
O
OPh
O
N
OPh
N
N
N
EtO2C
EtO2C
EtO2C
CF3
N
N
Br
CN
3m (65%)c
3n (59%)c
3l (68%)b
O
O
O
O
OPh
N
O
N
N
N
EtO2C
EtO2C
EtO2C
N
Cy
N
CO2H
3q (85%)
3o (75%)c
3p (84%)
O
O
O
N
Cy
O
Bn
Ph
O
N
EtO2C
N
N
3r (81%)
3s (78%)
O
O
OPh
Ph
OPh
Ph
O
N
N
OHC
Ph
N
N
3t (69%)
3u (56%)
aReactions were carried out with 1 (1.0 mmol), 2a (1.5
mmol), catalyst (20 mol %), BPO (3.0 equiv) in a
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o
solvent (4.0 mL) under air atmosphere at 80 C for 6 h.
the thermal conditions, followed by C-C, C-N
1
2
3
4
5
6
7
8
bthe reaction time was 12 h. cThe reaction time was 20 h.
bond formation. Then the model reaction was
implemented in the absence of molecular iodine.
Expectedly, a trace of product 3a was observed
(Scheme 5B). These results indicated that
molecular iodine play a significant role in the
methacrylate 2f with 1f under our I2-catalyzed
conditions directly delivering 4f in a simple and
one-pot operation with 65% yield (Scheme 4).
The method was convnient and practical. A
reaction.
Subsequently,
radical
trapping
experiments were carried out. The addition of
TEMPO drastically shut down the desired
coupling reaction, with the formation of the
TEMPO-adduct 5a in 64% yield, indicating the
involvement of the hydrazone radical (Scheme
5C).
preactivation precursor,
ethyl-2-chloro-(2,4-
phenylhydrazono)acetate, was
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
dichloro-
avoided.69
Scheme 3. Results of I2-Catalyzed
Dihydropyrazoles (4) Synthesisa
I2 (20 mol %)
TBHP (3 equiv)
O
Scheme 4. One-pot Synthesis of Mefenpyr-
H
O
R4
R1
Ph
N
Diethyl
+
N
R4
Br
CH3CN, 80 °C, 2 h
N
O
CO2Et
EtO2C
O
R3
N
I2 (20 mol %)
TBHP (3 equiv)
H
N
O
O
1a
2
N
CO2Et
+
N
O
EtO2C
N
CH3CN, 80 °C, 4 h
O
Cl
Cl
Cl
O
OH
Cl
4f
1f
2f
O
OEt
OEt
Ph
65% yield
Mefenpyr-diethyl
N
N
Ph
Ph
N
EtO2C
N
EtO2C
N
EtO2C
N
4b (86%)
4c (63%)
4a (77%)
Scheme 5. Control Experiments
O
H
O
I2 (20 mol %)
BPO (3 equiv)
O
I
Br
H
Ph
N
I
Ph
N
Ph N
O
HN
N
OEt
+
A
B
C
N
N
NH2
CO2Et
O
CH3CN, 80°C, 6 h
CO2Et
CO2Et
N
N
1a
EtO2C
N
N
not detected
not detected
Ph
EtO2C
Ph
N
EtO2C
N
4d (74%)
4e (57%)
4g (73%)
O
O
H
N
O
O
BPO (3 equiv)
O
O
Ph
+
OH
Br
OH
N
CH3CN, 80°C, 6 h
N
CO2Et
EtO2C
O
O
Ph
N
1a
2a
O
3a (trace)
N
N
N
EtO2C
N
Ph
Ph
Ph
HN
NH
N
O
I2 (20 mol %)
BPO (3 equiv)
O
4h (69%)
4i (52%)
CO2Et
+
N
O
O
N
aReactions were carried out with 1a (1.0 mmol), 2
+
CH3CN, 80 °C, 6 h
TEMPO (1.5 equiv)
O
CO2Et
1a
EtO2
C
Ph
N
N
(1.5 mmol), catalyst (20 mol %), TBHP (3.0 equiv) in
2a
3a trace
a solvent (4.0 mL) under air atmosphere at 80 oC for 2
h.
5a (64% yield)
confirmed by NMR
and HRMS
Ph
HN
O
O
O
I2 (20 mol %)
TBHP (3 equiv)
To further achieve some insights into the
reaction mechanism, a variety of control
experiments were conducted (Scheme 5). First,
considering that molecular iodine can be
involved in the formation of hydrazonoyl iodide
or N-iodo hydra-zone intermediates, subsequent
oxidative cyclization reaction may proceed via
SET process. The model reaction was operated in
the absence of tert-butyl acrylate 2a.
Unfortunately, the reaction system was very
complex forming a mixture of inseparable
compounds and related hydrazonoyl iodide or N-
iodo hydrazone was not detected via LC-MS,
showing that these intermediates were not
involved (Scheme 5A). Next, because of BPO
can be converted into benzoyloxy radical under
N
+
O
+
O
N
D
O
N
CH3CN, 80 °C, 2 h
EtO2
C
EtO2C
Ph
Ph
CO2Et
N
N
1a
2a
3a (major)
6a (trace)
Ph
O
HN
O
I2 (20 mol %)
TBHP (3 equiv)
N
+
O
O
CO2Et
DMF, 80 °C, 2 h
N
E
EtO2
C
Ph
N
6a (83%)
1a
2a
confirmed by NMR
and HRMS
O
O
BPO (3 equiv)
CH3CN, 80 °C, 3 h
O
O
F
N
N
EtO2
C
Ph
EtO2C
Ph
N
N
3a 94%
6a
Scheme 6. Proposed Reaction Mechanism
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O
electron-deficient olefin under mild conditions.
O
Ph
1
2
3
4
5
6
7
8
I+
+
Ph
R2
O
1/2I2
H
PhCO2
PhCO2
+
+
The reaction is believed to proceed through a
cascade C−H functionalization, C−N bond
formation and oxidation sequential processes.
Notably, an expedient and operationally simple,
one-pot synthesis of mefenpyr-diethyl has been
successfully achieved.
O
H
R1
N
PhCO2
PhCO2
R1
N
-H
PhCO2H
N
N
R2
PhCO2 PhCO
+
(PhCO2)2
2
O
R1
NH
N
H
R1
N
O
I+
1/2 I2
SET
R3
N
R2
R3
■ EXPERIMENTAL SECTION
9
radical addition
R2
I
II
10
11
12
13
14
15
16
17
18
19
General Information and Method. All
reagents were purchased from commercial sources and
used without treatment, unless otherwise indicated.
Petroleum ether (PE) refers to a hydrocarbon mixture
with a boiling range of 60-90 ºC. TLC was performed on
silica gel polygram SILG/UV 254 plates and visualized
by quenching of UV fluorescence (λmax = 254 nm).
Silica gel (100-200 microns) was used for all
chromatographic separations. Melting points were
determined with RY-1 apparatus and uncorrected. IR
spectra were recorded as KBr pellets on a Shimadzu
model 470 spectrophotometer. NMR (1H and 13C)
spectra were recorded using a Bruker AV 400 MHz or
600 MHz spectrometer in CDCl3 or DMSO-d6 with
TMS as internal standard. Chemical shifts (δ) were
recorded in ppm. Mass spectra were acquired on thermo
Fisher scientific LTQ FTICR-MS and Agilent 6210
ESI/TOF MS.
O
O
R1
NH
R3 BPO
O
-H+
R2
R3
R2
N
N
N
N
R3
N
R1
R1
R2
III
IV
V
To demonstrate the existence of intermediate 6a,
the model reaction was conducted in CH3CN in
the presence of TBHP at 80 °C for 2 h. A trace of
intermediate 6a was detected (Scheme 5D). In
contrast, when the reaction was operated in DMF
for 2 h, the single intermediate 6a was isolated in
83% yield (Scheme 5E). Subsequently, the
intermediate 6a was treated with 3.0 equiv. of
BPO in CH3CN for 3 h affording the final
product 3a in 94% yield (Scheme 5F). These
observations verified the reasonable intermediacy
of 6a.
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Preparation of starting hydrazones 1.72
A
suspension of hydrazine hydrochloride (10.0 mmol) in
anhydrous THF (20.0 mL) was treated with
triethylamine (12.0 mmol, 1214 mg) before a solution of
glyoxylate (10.0 mmol) was dropwise added into the
reaction mixture at 0 ºC. The mixture was stirred at this
temperature for 30 minutes and then overnight. The
reaction was filtered under vacuum to collect the
triethylamine hydrochloride salt. The filtrates were
concentrated in vacuo and the resulting solids dissolved
in ethyl acetate (50 mL) and washed with water (2 x 30
mL). The resulting organic layer was dried over Na2SO4
and concentrated in vacuo, the crude product was
purified by flash chromatography (petroleum ether
/ethyl acetate = 25:1-1:1) or recrystallized from ethyl
acetate to give the desired hydrazones in good yields.
Synthetic Procedure for the Synthesis of
3. A mixture of hydrazone 1 (1.0 mmol), electron-
deficient olefines 2 (1.5 mmol), I2 (50.8 mg, 0.2 mmol),
BPO (726.7 mg, 3.0 mmol) and CH3CN (4 mL) were
added into the 25 ml round-bottom flask, then the
mixture was stirred in oil bath at 80 ºC for 6 h. After the
starting material 1 was consumed as indicated by TLC,
the reaction mixture was poured into water and then
extracted with ethyl acetate (3 × 30 mL). The combined
organic phase was washed with water (3 × 10 mL), dried
over anhydrous MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by
flash chromatography (silica gel, petroleum ether : ethyl
acetate = 8:1-1:1) to give 3.
Based on these experimental results and
previous reports,65,67 a plausible mechanism for
this oxidative radical relay reaction is shown in
Scheme 6. Initially, aldehyde hydrazone is
presumably involved a hydrogen abstraction
from the N=CH via single-electron oxidation to
give a carbon radical I. The succedent single-
electron addition to C=C of acrylate to form C−C
propagation II, which is further oxidized by I+ to
obtain
a
carbocation III.63 Subsequent
intramolecular cyclization leads to the formation
of dihydropyrazole compounds IV. Finaly, the
dihydropyrazoles were oxidized by BPO to
provide the Pyrazole derivatives V. In a word, the
I2−I+ redox process through promoting reductive
cleavage of the O−O bond in the peroxide played
a crucial role in the C−N bond formations.70,71
■ CONCLUSIONS
We have developed an efficient strategy to the
synthesis of polysubstituted dihypyrazoles or
pyrazoles via a iodine-catalyzed oxidative radical
relay reaction of aldehyde hydrazones with
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Page 6 of 14
= 3:1) to give the yellow solid; 55% yield, 1.2 g (known
Synthetic Procedure for the Synthesis of
compound). Literature data: 1H NMR (300 MHz,
CDCl3) δ = 8.79 (s, 1H), 7.18-6.99 (m, 3H), 6.81 (d, J =
9.0 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 1.32
(t, J = 7.1 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ =
164.7, 155.4, 136.3, 124.4, 115.5, 114.7, 60.8, 55.6,
14.3. our reporting data: 1H NMR (600 MHz,
Chloroform-d) δ = 12.31 (s, 1H), 7.17–7.14 (m, 2H),
6.91–6.89 (m, 2H), 6.62 (s, 1H), 4.26 (q, J = 7.1 Hz,
2H), 3.82 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (151 MHz, Chloroform-d) δ = 164.0, 155.6,
136.8, 117.2, 115.1, 114.7, 60.2, 55.6, 14.2.
1
2
3
4
5
6
7
8
4. A mixture of hydrazone 1 (1.0 mmol), electron-
deficient olefins 2 (1.5 mmol), I2 (50.8 mg, 0.2 mmol),
TBHP (70% aq. 386.3 mg, 3.0 mmol) and CH3CN (4
mL) were added into the 25 ml round-bottom flask, then
the mixture was stirred in oil bath at 80 ºC for 2 h. After
the starting material 1 was consumed as indicated by
TLC, the reaction mixture was poured into water and
then extracted with ethyl acetate (3 × 30 mL). The
combined organic phase was washed with water (3 × 10
mL), dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. The crude product
was purified by flash chromatography (silica gel,
petroleum ether : ethyl acetate = 10:1-1:1) to give 4.
Synthetic Procedure for the Synthesis of
4f. A mixture of 2,4-dichlorophenylhydrazone 1f (261.1
mg, 1.0 mmol), ethyl methacrylate 2f (171.2 mg, 1.5
mmol), I2 (50.8 mg, 0.2 mmol), TBHP (70% aq. 386.3
mg, 3.0 mmol) and CH3CN (4 mL) were added into the
25 ml round-bottom flask, then the mixture was stirred
in oil bath at 80 ºC for 4 h. After the starting material 1f
was consumed as indicated by TLC, the reaction mixture
was poured into water and then extracted with ethyl
acetate (3 × 30 mL). The combined organic phase was
washed with water (3 × 10 mL), dried over anhydrous
MgSO4, filtered and concentrated under reduced
pressure. The crude product was purified by flash
chromatography (silica gel, petroleum ether : ethyl
acetate = 12: 1) to give 4f (243 mg, 65%) as a yellow
viscous oil.
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Ethyl (E)-2-(2-(o-tolyl)hydrazono)acetate (1k).
Recrystallized from ethyl acetate to give the yellow
solid; 76% yield, 1.6 g. 1H NMR (600 MHz,
Chloroform-d) δ = 12.43 (s, 1H), 7.58 (d, J = 8.1 Hz,
1H), 7.25 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.3 Hz, 1H),
6.96 (t, J = 7.4 Hz, 1H), 6.74 (s, 1H), 4.30 (q, J = 7.1
Hz, 2H), 2.33 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (151 MHz, Chloroform-d) δ = 164.0, 141.0,
130.6, 127.2, 122.4, 122.2, 119.1, 112.9, 60.5, 17.0,
14.2.
Ethyl
(E)-2-(2-(4-
bromophenyl)hydrazono)acetate (1l).73 Purified by
flash chromatography (petroleum ether /ethyl acetate =
5:1) to give the yellow solid; 85% yield, 2.3 g (known
compound). Literature data: 1H NMR (400 MHz,
CDCl3): (ppm) δ = 1.34 (t, J = 5.6 Hz, 3H), 4.30 (q, J =
5.6 Hz, 2H), 7.03 (d, J = 6.8 Hz, 2H), 7.09 (s, 1H), 7.36
(m, J = 6.8 Hz, 2H), 8.77 (s, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ = 14.4, 61.2, 114.7, 115.7, 126.6, 132.3,
Ethyl (E)-2-(2-phenylhydrazono)acetate (1a).73
Recrystallized from ethyl acetate to give the yellow
solid; 81% yield, 1.6g (known compound). Literature
1
141.8, 164.4. Our reporting data: H NMR (600 MHz,
Chloroform-d) δ = 12.30 (s, 1H), 7.43 (d, J = 8.7 Hz,
2H), 7.09 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 4.27 (q, J =
7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(151 MHz, Chloroform-d) δ = 163.7, 142.1, 132.2,
119.3, 115.5, 114.8, 60.6, 14.2.
1
data: H NMR (300 MHz, CDCl3) δ = 8.63 (s, 1H),
7.37-7.23 (m, 2H), 7.21-7.12 (m, 2H), 7.09 (s, 1H), 6.97
(dd, J = 10.3, 4.2 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.35
(t, J = 7.1 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ =
164.4, 142.5, 129.4, 125.7, 122.4, 114.0, 60.9, 14.3. our
Ethyl
(E)-2-(2-(4-
1
(trifluoromethyl)phenyl)hydrazono)acetate (1m).
Recrystallized from ethyl acetate to give the yellow
solid; 85% yield, 2.2 g. 1H NMR (600 MHz,
Chloroform-d) δ = 12.40 (s, 1H), 7.58 (d, J = 8.5 Hz,
2H), 7.27 (d, J = 8.5 Hz, 2H), 6.74 (s, 1H), 4.29 (q, J =
7.1 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR
(151 MHz, Chloroform-d) δ = 163.5, 145.6, 126.7 (q, J
= 3.9 Hz), 125.3, 124.2 (q, J = 32.5 Hz), 123.5, 120.6,
113.6, 60.8, 14.1.
reporting data: H NMR (600 MHz, DMSO-d6) δ =
11.27 (s, 1H), 7.29 (t, J = 7.8 Hz, 2H), 7.20 (s, 1H), 7.11
(d, J = 8.2 Hz, 2H), 6.92 (t, J = 7.3 Hz, 1H), 4.19 (q, J =
7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(151 MHz, DMSO-d6) δ = 164.2, 143.8, 129.8, 125.5,
121.7, 113.6, 60.3, 14.7.
Ethyl
(E)-2-(2-(2,3-
dichlorophenyl)hydrazono)acetate (1f). Purified
by flash chromatography (petroleum ether /ethyl acetate
1
Ethyl
(E)-2-(2-(4-
= 7:1) to give the yellow solid; 45% yield, 1.2 g. H
cyanophenyl)hydrazono)acetate
(1n).
NMR (600 MHz, DMSO-d6) δ = 10.94 (s, 1H), 7.67 (s,
1H), 7.56 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H),
7.39 (dd, J = 9.0, 2.4 Hz, 1H), 4.21 (d, J = 7.1 Hz, 2H),
1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz,
DMSO-d6) δ = 163.8, 139.6, 130.3, 129.4, 128.8, 125.4,
118.6, 116.8, 60.7, 14.7.
Recrystallized from ethyl acetate to give the brown
solid; 81% yield, 1.8 g. 1H NMR (600 MHz, Chloroform-
d) δ = 12.43 (s, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.25 (dd, J =
8.9, 2.6 Hz, 2H), 6.78 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H),
1.38 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz,
Chloroform-d) δ = 163.4, 146.4, 133.7, 121.9, 119.4, 114.0,
104.9, 61.0, 14.1.
Ethyl
(E)-2-(2-(4-
methoxyphenyl)hydrazono)acetate (1j).73 Purified
by flash chromatography (petroleum ether /ethyl acetate
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The Journal of Organic Chemistry
7.7 Hz, 2H), 7.41-7.36 (m, 4H), 7.12 (tt, J = 6.7, 2.0 Hz,
(E)-4-(2-(2-ethoxy-2-
oxoethylidene)hydrazinyl)benzoic acid (1o).
Recrystallized from methanol to give the yellow solid;
1
2
3
4
1H) ； 13C{1H} NMR (151 MHz, Chloroform-d) δ =
186.4, 142.6, 137.3, 132.9, 129.5, 128.9, 128.0, 123.9,
122.4, 115.0.
1
84% yield, 2.0 g. H NMR (600 MHz, DMSO-d6) δ =
(E)-1-phenyl-2-(2-phenylhydrazono)ethan-1-one
12.55 (s, 1H), 11.57 (d, J = 11.8 Hz, 1H), 7.90–7.88 (m,
2H), 7.28 (dd, J = 8.8, 1.1 Hz, 1H), 7.15 (dd, J = 8.7, 1.9
Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (151 MHz, DMSO-d6) δ = 167.5,
163.8, 147.6, 131.7, 128.1, 123.5, 113.1, 60.6, 14.7.
Ethyl (E)-2-(2-isopropylhydrazono)acetate (1p).
Purified by flash chromatography (petroleum ether
/ethyl acetate = 4:1) to give the colorless liquid; 53%
5
6
7
8
(1u). Purified by flash chromatography (petroleum
ether /ethyl acetate = 8:1) to give the brown solid; 50%
1
yield, 0.74 g. H NMR (600 MHz, DMSO-d6) δ = 11.73
(s, 1H), 9.48 (d, J = 7.9 Hz, 1H), 7.38–7.31 (m, 3H),
7.21 (d, J = 8.4 Hz, 2H), 7.00 (t, J = 7.3 Hz, 1H);
13C{1H} NMR (151 MHz, DMSO-d6) δ = 190.7, 143.2,
135.9, 129.9, 122.9, 114.4.
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1
yield, 0.84 g. H NMR (600 MHz, DMSO-d6) δ = 8.69
(5-(tert-butyl) 3-ethyl 1-phenyl-1H-pyrazole-3,5-
(d, J = 5.4 Hz, 1H), 6.78 (s, 1H), 4.09 (q, J = 7.1 Hz,
2H), 3.68–3.39 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H), 1.10 (d,
J = 6.5 Hz, 6H); 13C{1H} NMR (151 MHz, DMSO-d6) δ
= 164.7, 120.0, 59.5, 49.0, 21.4, 14.8.
dicarboxylate (3a). White solid; Yield: 81% (256 mg);
Mp: 60-62 ºC; IR (thin film): ν 2981, 1717, 1600, 1542,
1506, 1367, 1297, 1231, 1161, 1077, 1022, 841, 765,
690, 623 cm-1; 1H NMR (400 MHz, Chloroform-d) δ =
7.48–7.41 (m, 6H), 4.44 (q, J = 7.1 Hz, 2H), 1.41 (t, J =
7.2 Hz, 3H ), 1.40 (s, 9H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ = 161.7, 157.5, 143.6, 140.2, 136.5,
129.2, 128.6, 126.2, 114.4, 83.0, 61.3, 27.9, 14.4.
Please see the single crystal.
Ethyl (E)-2-(2-cyclohexylhydrazono)acetate (1q).
Purified by flash chromatography (petroleum ether
/ethyl acetate = 3:1) to give the colorless liquid; 62%
yield, 1.2 g. 1H NMR (600 MHz, DMSO-d6) δ = 8.76 (d,
J = 5.5 Hz, 1H), 6.81 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H),
3.29–3.23 (m, 1H), 1.86–1.82 (m, 2H), 1.70–1.66 (m,
2H), 1.58–1.54 (m, 1H), 1.33–1.25 (m, 2H), 1.23 (d, J =
3.4 Hz, 1H), 1.19 (t, J = 7.1 Hz, 4H), 1.17–1.12 (m, 1H);
13C{1H} NMR (151 MHz, DMSO-d6) δ = 164.8, 119.8,
59.5, 56.4, 31.6, 25.7, 24.4, 14.8.
3-ethyl 5-methyl 1-phenyl-1H-pyrazole-3,5-
dicarboxylate (3b). White solid; Yield: 79% (216 mg);
Mp: 112-114 ºC; IR (thin film): ν 3174, 2984, 1726,
1500, 1442, 1376, 1222, 1131, 1037, 1013, 941, 907,
1
844, 750, 705, 684, 659, 602 cm-1; H NMR (400 MHz,
Ethyl (E)-2-(2-benzylhydrazono)acetate (1r).74
Purified by flash chromatography (petroleum ether
/ethyl acetate = 2:1) to give the yellow liquid; 71%
Chloroform-d) δ = 7.52 (s, 1H), 7.49–7.43 (m, 5H), 4.44
(q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, Chloroform-d) δ = 161.5,
158.9, 143.9, 139.7, 134.5, 129.4, 128.6, 126.2, 114.7,
61.4, 52.3, 14.4. HRMS (ESI): m/z calcd for
C14H15N2O4 [M+H]+: 275.1026; found: 275.1027.
1
yield, 1.5 g (known compound). Literature data: H
NMR (CDCl3) δ = 1.28 (3H, t, J = 7.0 Hz), 4.23 (2H, q,
J = 7.0 Hz), 4.37 (2H, d, J = 4.6 Hz), 6.74 (1H, br t),
1
6.75 (1H, s), 7.2-7.4 (5H, m); our reporting data: H
3-ethyl 5-phenyl 1-phenyl-1H-pyrazole-3,5-
NMR (600 MHz, DMSO-d6) δ = 9.27 (t, J = 4.5 Hz, 1H),
7.37 (t, J = 7.5 Hz, 2H), 7.33–7.27 (m, 3H), 6.71 (s, 1H),
4.42 (d, J = 4.5 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 1.19 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, DMSO-d6) δ
= 164.8, 137.2, 129.0, 128.2, 127.7, 119.7, 59.7, 50.8,
14.7.
dicarboxylate (3c). White solid; Yield: 90% (303 mg);
Mp: 88-90 ºC; IR (thin film): ν 3147, 1748, 1723, 1600,
1494, 1370, 1279, 1216, 1188, 1122, 1080, 1001, 847,
1
741, 684cm-1; H NMR (400 MHz, Chloroform-d) δ =
7.75 (s, 1H), 7.52–7.45 (m, 5H), 7.38 (t, J = 7.9 Hz, 2H),
7.23 (d, J = 7.5 Hz, 1H), 7.11 (d, J = 7.9 Hz, 2H), 4.47
(q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (101 MHz, Chloroform-d) δ = 161.5, 156.8, 149.8,
144.0, 139.5, 134.0, 129.6, 128.8, 126.4, 126.3, 121.3,
115.6, 61.6, 14.4. HRMS (ESI): m/z calcd for
C19H17N2O4 [M+H]+: 337.1183; found: 337.1177.
(E)-2-(2-cyclohexylhydrazono)-1-phenylethan-1-
one (1s). Purified by flash chromatography (petroleum
ether /ethyl acetate = 2:1) to give the yellow liquid; 89%
yield, 2.0 g. 1H NMR (600 MHz, DMSO-d6) δ = 12.99 (d,
J = 5.3 Hz, 1H), 7.99 (d, J = 7.4 Hz, 2H), 7.63 (s, 1H),
7.60–7.56 (m, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.44 (q, J =
7.5, 6.0 Hz, 1H), 3.46 (tq, J = 9.7, 4.2 Hz, 1H), 2.01–1.85
(m, 2H), 1.71–1.66 (m, 2H), 1.55 (dt, J = 13.2, 4.3 Hz, 1H),
1.47–1.37 (m, 2H), 1.37–1.24 (m, 2H), 1.23–1.09 (m, 1H);
13C{1H} NMR (151 MHz, DMSO-d6) δ = 184.6, 137.6,
132.8, 129.2, 128.0, 119.9, 59.1, 32.1, 25.7, 25.4, 24.5,
24.4.
Ethyl
5-(dimethylcarbamoyl)-1-phenyl-1H-
pyrazole-3-carboxylate (3d). Yellow viscous oil;
Yield: 82% (236 mg); IR (thin film): ν 2984, 2936, 1714,
1642, 1500, 1370, 1222, 1170, 1119, 1010, 904, 832,
1
768, 690, 669; H NMR (400 MHz, Chloroform-d) δ =
7.52 (dt, J = 8.2, 1.7 Hz, 2H), 7.44–7.34 (m, 3H), 7.01
(d, J = 1.5 Hz, 1H), 4.40 (qd, J = 7.2, 1.7 Hz, 2H), 2.96
(s, 3H), 2.71 (s, 3H), 1.38 (td, J = 7.1, 1.7 Hz, 3H);
13C{1H} NMR (151 MHz, Chloroform-d) δ = 161.8,
161.6, 144.3, 139.1, 138.0, 129.3, 128.8, 123.5, 110.0,
61.3, 38.1, 35.0, 14.4. HRMS (ESI): m/z calcd for
C15H18N3O3 [M+H]+: 288.1343; found: 288.1340.
(E)-1-phenyl-2-(2-phenylhydrazono)ethan-1-one
(1t). Recrystallized from ethyl acetate to give the
1
yellow solid; 70% yield, 1.6 g. H NMR (600 MHz,
Chloroform-d) δ = 14.52 (s, 1H), 8.03 (d, J = 7.5 Hz,
2H), 7.76 (s, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.54 (t, J =
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= 161.4, 157.6, 143.9, 139.5, 133.7, 129.5, 128.7, 126.2,
Ethyl 5-(morpholine-4-carbonyl)-1-phenyl-1H-
1
2
3
4
5
6
7
8
115.2, 76.6, 75.7, 61.5, 52.8, 14.4. HRMS (ESI): m/z
calcd for C16H14N2O4Na [M+Na]+: 321.0846; found:
321.0844.
pyrazole-3-carboxylate (3e). Yellow solid; Yield: 72%
(237 mg); Mp: 102-104 ºC; IR (thin film): ν 3144, 1748,
1723, 1639, 1603, 1494, 1276, 1216, 1191, 1083, 1001,
844, 762, 741,684 cm-1; 1H NMR (400 MHz,
Chloroform-d) δ = 7.58–7.54 (m, 2H), 7.52–7.42 (m,
3H), 7.06 (s, 1H), 4.45 (q, J = 7.1 Hz, 2H), 3.62 (dt, J =
38.4, 4.7 Hz, 4H), 3.13 (dt, J = 32.9, 4.6 Hz, 4H), 1.42 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, Chloroform-
d) δ = 161.6, 160.3, 144.6, 138.9, 137.3, 129.5, 129.1,
123.7, 110.4, 66.2, 66.1, 61.4, 47.0, 42.4, 14.4. HRMS
(ESI): m/z calcd for C17H20N3O4 [M+H]+: 330.1448;
found: 330.1442.
5-(tert-butyl) 3-ethyl 1-(4-methoxyphenyl)-1H-
pyrazole-3,5-dicarboxylate (3j). White solid; Yield:
76% (263 mg); Mp: 76-78 ºC; IR (thin film): ν 2978,
2845, 1729, 1711, 1515, 1460, 1373, 1285, 1231, 1164,
1
1125, 1092, 1025, 1004, 856, 768, 626, 542 cm-1; H
9
NMR (400 MHz, Chloroform-d) δ = 7.42 (s, 1H), 7.34
(d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 4.43 (q, J =
7.1 Hz, 2H), 3.85 (s, 3H), 1.43 (s, 9H), 1.41 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ =
161.8, 160.0, 157.6, 143.3, 136.4, 133.2, 127.4, 114.3,
113.7, 82.9, 61.3, 55.5, 28.0, 14.4. HRMS (ESI): m/z
calcd for C18H23N2O5 [M+H]+: 347.1601; found:
347.1603.
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Ethyl
5-carbamoyl-1-phenyl-1H-pyrazole-3-
carboxylate (3f). White solid; Yield: 65% (169 mg);
Mp: 175-177 ºC; IR (thin film): ν 3407, 3141, 2987,
1748, 1726, 1596, 1479, 1367, 1282, 1222, 1194, 1086,
1
1025, 1010, 850, 771, 690, 629, 608, 566 cm-1; H NMR
5-(tert-butyl) 3-ethyl 1-(o-tolyl)-1H-pyrazole-3,5-
dicarboxylate (3k). Yellow solid; Yield: 66% (218
mg); Mp: 122-124 ºC; IR (thin film): ν 2984, 1720, 1705,
1539, 1370, 1297, 1249, 1170, 1143, 1077, 1019, 835,
(400 MHz, Chloroform-d) δ = 7.51-7.46 (m, 5H), 7.33 (s,
1H), 5.91 (s, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.41 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ
= 161.7, 159.9, 143.8, 139.3, 137.4, 129.4, 129.0, 125.6,
111.9, 61.5, 14.4. HRMS (ESI): m/z calcd for
C13H14N3O3 [M+H]+: 260.1030; found: 260.1032.
1
765, 723,626 cm-1; H NMR (600 MHz, Chloroform-d)
δ = 7.49 (s, 0H), 7.39 (t, J = 7.4 Hz, 2H), 7.31–7.28 (m,
2H), 7.26 (d, J = 7.7 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H),
2.03 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H), 1.34 (s, 9H);
13C{1H} NMR (151 MHz, Chloroform-d) δ = 161.7,
157.3, 143.6, 139.9, 137.3, 135.1, 130.4, 129.6, 127.2,
126.3, 113.7, 82.8, 61.3, 27.8, 17.1, 14.4. HRMS (ESI):
m/z calcd for C18H22N2O4Na [M+Na]+: 353.1472; found:
353.1476.
Ethyl
5-cyano-1-phenyl-1H-pyrazole-3-
carboxylate (3g). Yellow solid; Yield: 80% (193 mg);
Mp: 69-71 ºC; IR (thin film): ν 3147, 2987, 2240, 1745,
1726, 1596, 1473, 1367, 1285, 1222, 1167, 1122, 1013,
983, 856, 768, 690 cm-1; 1H NMR (400 MHz,
Chloroform-d) δ = 7.75–7.72 (m, 2H), 7.58–7.50 (m,
4H), 4.46 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, Chloroform-d) δ = 160.5,
145.0, 137.9, 129.9, 129.7, 123.5, 118.2, 115.7, 110.1,
61.9, 14.3. HRMS (ESI): m/z calcd for C13H11N3O2Na
[M+Na]+: 264.0743; found: 264.0747.
5-(tert-butyl) 3-ethyl 1-(4-bromophenyl)-1H-
pyrazole-3,5-dicarboxylate (3l). White solid; Yield:
68% (269 mg); Mp: 92-94 ºC; IR (thin film): ν 2975,
1729, 1708, 1494, 1470, 1367, 1291, 1231, 1161, 1131,
1086, 1028, 850, 838, 823, 762, 729 cm-1; 1H NMR (400
MHz, Chloroform-d) δ = 7.60 (d, J = 8.6 Hz, 2H), 7.44
(s, 1H), 7.32 (d, J = 8.6 Hz, 2H), 4.44 (q, J = 7.1 Hz,
2H), 1.45 (s, 9H), 1.41 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (101 MHz, Chloroform-d) δ = 161.5, 157.4, 143.9,
139.0, 136.4, 131.8, 127.8, 123.2, 114.7, 83.3, 61.5, 27.9,
14.4. HRMS (ESI): m/z calcd for C17H20BrN2O4
[M+H]+: 395.0601; found: 395.0608.
Ethyl
1-phenyl-5-propionyl-1H-pyrazole-3-
carboxylate (3h). White solid; Yield: 61% (166 mg);
Mp: 122-124 ºC; IR (thin film): ν 3132, 2981, 2942,
1717, 1690, 1596, 1524, 1497, 1454, 1406, 1364, 1243,
1204, 1025, 931, 868, 838, 777, 702, 539 cm-1; 1H NMR
(600 MHz, Chloroform-d) δ = 7.52 (s, 1H), 7.50–7.46
(m, 3H), 7.41–7.39 (m, 2H), 4.47 (q, J = 7.1 Hz, 2H),
2.93 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H), 1.17 (t,
J = 7.3 Hz, 3H); 13C{1H} NMR (151 MHz, Chloroform-
d) δ = 190.6, 161.6, 143.7, 140.5, 140.2, 129.3, 128.7,
126.1, 114.0, 61.5, 34.1, 14.4, 7.7. HRMS (ESI): m/z
calcd for C15H16N2O3Na [M+Na]+: 295.1053; found:
295.1054.
3-ethyl 5-phenyl 1-(4-(trifluoromethyl)phenyl)-
1H-pyrazole-3,5-dicarboxylate (3m). Yellow solid;
Yield: 65% (263 mg); Mp: 110-112 ºC; IR (thin film): ν
3144, 1745, 1723, 1615, 1524, 1485, 1330, 1291, 1222,
1191, 1161, 1119, 1101, 1064, 859, 759, 741, 684,
587cm-1; 1H NMR (600 MHz, Chloroform-d) δ = 7.80 (s,
1H), 7.76 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H),
7.44–7.41 (m, 2H), 7.31–7.28 (m, 1H), 7.16–7.14 (m,
2H), 4.50 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (151 MHz, Chloroform-d) δ = 161.2,
156.8, 149.7, 144.7, 142.1, 134.0, 131.7, 131.4, 129.7,
126.8, 126.6, 126.0 (q, J = 3.6 Hz), 124.5, 122.7, 121.2,
116.0, 61.7, 14.4. HRMS (ESI): m/z calcd for
C20H15F3N2O4Na [M+Na]+: 427.0876; found: 427.0881.
3-ethyl 5-(prop-2-yn-1-yl) 1-phenyl-1H-pyrazole-
3,5-dicarboxylate (3i). White solid; Yield: 60% (179
mg); Mp: 116-118 ºC; IR (thin film): ν 3268, 3141, 3011,
2119, 1742, 1711, 1509, 1470, 1373, 1288, 1228, 1131,
1095, 1043, 1022, 1007, 962, 913, 850, 762, 687, 681,
560cm-1; 1H NMR (600 MHz, Chloroform-d) δ = 7.61 (s,
0H), 7.51–7.45 (m, 5H), 4.83 (d, J = 2.4 Hz, 2H), 4.47
(q, J = 7.1 Hz, 2H), 2.53 (t, J = 2.4 Hz, 1H), 1.43 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (151 MHz, Chloroform-d) δ
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The Journal of Organic Chemistry
δ = 7.29 (d, J = 4.7 Hz, 1H), 7.27–7.22 (m, 5H), 5.81 (s,
3-ethyl 5-phenyl 1-(4-cyanophenyl)-1H-pyrazole-
1
2
3
4
2H), 4.40 (q, J = 7.1 Hz, 2H), 1.49 (s, 9H), 1.39 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ
= 160.7, 157.2, 141.2, 135.3, 133.9, 127.5, 126.8, 126.5,
113.2, 81.9, 60.2, 54.7, 27.0, 13.4. HRMS (ESI): m/z
calcd for C18H23N2O4 [M+H]+: 331.1652; found:
331.1658.
3,5-dicarboxylate (3n). White solid; Yield: 59% (213
mg); Mp: 130-132 ºC; IR (thin film): ν 3150, 2996, 2231,
1748, 1723, 1612, 1515, 1479, 1367, 1282, 1228, 1188,
1118, 1080, 1010, 907, 847, 744, 684, 557 cm-1; H
1
5
NMR (600 MHz, Chloroform-d) δ = 7.82–7.79 (m, 3H),
7.70 (d, J = 8.5 Hz, 2H), 7.43 (t, J = 7.9 Hz, 2H), 7.30 (t,
J = 7.5 Hz, 1H), 7.16 (d, J = 7.8 Hz, 2H), 4.50 (q, J =
7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(151 MHz, Chloroform-d) δ = 161.0, 156.7, 149.6,
145.0, 142.6, 134.0, 132.7, 129.7, 127.1, 126.7, 121.2,
117.8, 116.3, 113.4, 61.8, 14.4. HRMS (ESI): m/z calcd
for C20H15N3O4Na [M+Na]+: 384.0955; found: 384.0957.
4-(3-(ethoxycarbonyl)-5-(phenoxycarbonyl)-1H-
6
7
8
9
butyl
3-benzoyl-1-cyclohexyl-1H-pyrazole-5-
carboxylate (3s). Yellow solid; Yield: 78% (276 mg);
Mp: 36-38 ºC; IR (thin film): ν 3156, 3078, 2939, 2860,
1723, 1642, 1578, 1448, 1258, 1228, 1188, 1095, 901,
771, 717, 684, 629cm-1; 1H NMR (400 MHz,
Chloroform-d) δ = 8.31–8.28 (m, 2H), 7.61–7.57 (m,
1H), 7.53–7.48 (m, 3H), 5.19 (tt, J = 11.3, 3.8 Hz, 1H),
4.32 (t, J = 6.6 Hz, 2H), 2.11–2.05 (m, 2H), 2.01–1.89
(m, 4H), 1.78–1.71 (m, 3H), 1.50–1.42 (m, 3H), 1.35–
1.23 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C{1H} NMR
(101 MHz, Chloroform-d) δ = 187.0, 159.6, 148.9,
137.1, 132.8, 132.7, 130.7, 128.1, 114.5, 65.1, 60.5, 33.1,
30.6, 25.5, 25.2, 19.2, 13.7. HRMS (ESI): m/z calcd for
C21H27N2O3 [M+H]+: 355.2018; found: 355.2016.
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pyrazol-1-yl)benzoic acid (3o). White solid; Yield:
75% (285 mg); Mp: 180-182 ºC; IR (thin film): ν 3132,
1733, 1690, 1612, 1494, 1430, 1285, 1234, 1197, 1092,
1
998, 865, 768, 735, 684, 548 cm-1; H NMR (600 MHz,
Chloroform-d) δ = 8.25 (d, J = 8.4 Hz, 2H), 7.81 (s, 1H),
7.68 (d, J = 8.4 Hz, 2H), 7.42 (t, J = 7.8 Hz, 2H), 7.29
(d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 4.51 (q, J =
7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(151 MHz, Chloroform-d) δ = 170.7, 161.2, 156.7,
149.7, 144.7, 143.6, 134.1, 130.8, 130.1, 129.7, 126.5,
126.4, 121.2, 116.1, 61.8, 14.4. HRMS (ESI): m/z calcd
for C20H16N2O6Na [M+Na]+: 403.0901; found:
403.0908.
Phenyl
3-benzoyl-1-phenyl-1H-pyrazole-5-
carboxylate (3t). White solid; Yield: 69% (254 mg);
Mp: 120-122 ºC; IR (thin film): ν 3156, 3075, 1745,
1645, 1600, 1494, 1451, 1279, 1219, 1176, 1086, 1034,
1013, 995, 898, 759, 714, 681, 656 cm-1; H NMR (600
1
MHz, Chloroform-d) δ = 8.37 (d, J = 7.5 Hz, 2H), 7.93
(s, 1H), 7.65–7.62 (m, 1H), 7.60–7.57 (m, 2H), 7.55–
7.51 (m, 5H), 7.43–7.40 (m, 2H), 7.29–7.28 (m, 1H),
7.18–7.15 (m, 2H); 13C{1H} NMR (151 MHz,
Chloroform-d) δ = 186.8, 157.1, 150.8, 149.9, 139.7,
136.6, 133.8, 133.2, 130.7, 129.6, 129.5, 128.8, 128.4,
126.4, 126.2, 121.3, 116.3. HRMS (ESI): m/z calcd for
C23H16N2O3Na [M+Na]+: 391.1053; found: 391.1057.
5-(tert-butyl) 3-ethyl 1-isopropyl-1H-pyrazole-
3,5-dicarboxylate (3p). Yellow viscous oil; Yield: 84%
(237 mg); IR (thin film): ν 2978, 2936, 1717, 1524,
1439, 1370, 1270, 1246, 1155, 1089, 1074, 1025, 847,
753, 662 cm-1; 1H NMR (400 MHz, Chloroform-d) δ =
7.21 (s, 1H), 5.57-5.47 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H),
1.56 (s, 9H), 1.53 (s, 3H), 1.51 (s, 3H), 1.38 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ =
161.0, 157.5, 140.7, 133.1, 112.9, 81.6, 60.0, 52.1, 27.2,
21.5, 13.4. HRMS (ESI): m/z calcd for C14H23N2O4
[M+H]+: 283.1652; found: 283.1652.
Phenyl
3-formyl-1-phenyl-1H-pyrazole-5-
carboxylate (3u). White solid; Yield: 56% (164 mg);
Mp: 88-90 ºC; IR (thin film): ν 3072, 2917, 2848, 1748,
1702, 1684, 1600, 1581, 1494, 1451, 1436, 1330, 1270,
1219, 1185, 1122, 1071, 1019, 938, 907, 808, 750, 705,
681 cm-1; 1H NMR (600 MHz, Chloroform-d) δ = 10.14
(s, 1H), 7.75 (s, 1H), 7.56-7.53 (m, 5H), 7.41 (t, J = 7.9
Hz, 2H), 7.28 (t, J = 3.6 Hz, 1H), 7.14 (d, J = 8.5 Hz,
2H); 13C{1H} NMR (151 MHz, Chloroform-d) δ = 185.9,
156.8, 150.9, 149.8, 139.5, 134.7, 129.8, 129.6, 129.0,
126.5, 125.9, 121.2, 112.5. HRMS (ESI): m/z calcd for
C17H12N2O3Na [M+Na]+: 315.0740; found: 315.0742.
Diethyl (R)-5-methyl-1-phenyl-4,5-dihydro-1H-
5-(tert-butyl) 3-ethyl 1-cyclohexyl-1H-pyrazole-
3,5-dicarboxylate (3q). White solid; Yield: 85% (274
mg); Mp: 64-66 ºC; IR (thin film): ν 2984, 2933, 2860,
1742, 1714, 1448, 1373, 1258, 1201, 1164, 1146, 1095,
1
1028, 901, 841, 768, 596 cm-1; H NMR (400 MHz,
Chloroform-d) δ = 7.23 (s, 1H), 5.12 (tt, J = 9.0, 6.2 Hz,
1H), 4.40 (q, J = 7.1 Hz, 2H), 2.09–1.96 (m, 4H), 1.89
(dt, J = 12.5, 3.6 Hz, 2H), 1.71 (dq, J = 12.9, 3.6 Hz,
1H), 1.58 (s, 9H), 1.46 (dddd, J = 13.2, 10.4, 7.6, 3.6
Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.30 (tt, J = 13.1, 3.5
Hz, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ =
162.0, 158.5, 141.6, 134.2, 113.9, 82.6, 61.0, 60.5, 32.8,
28.2, 25.6, 25.1, 14.4. HRMS (ESI): m/z calcd for
C17H27N2O4 [M+H]+: 323.1965; found: 323.1969.
pyrazole-3,5-dicarboxylate (4a). Yellow solid;
Yield: 77% (234 mg); Mp: 62-64 ºC; IR (thin film): ν
2990, 1729, 1696, 1600, 1563, 1503, 1303, 1255, 1104,
1013, 856, 753, 696, 684cm-1; H NMR (400 MHz,
1
Chloroform-d) δ = 7.25 (d, J = 8.5 Hz, 1H), 7.13 (d, J =
8.0 Hz, 2H), 6.97 (t, J = 7.3 Hz, 1H), 4.35 (q, J = 7.1 Hz,
2H), 4.23 (q, J = 6.9, 6.4 Hz, 2H), 3.56 (d, J = 17.7 Hz,
2H), 3.18 (d, J = 17.7 Hz, 2H), 1.66 (s, 3H), 1.38 (t, J =
7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(101 MHz, Chloroform-d) δ = 172.5, 162.5, 141.3,
5-(tert-butyl) 3-ethyl 1-benzyl-1H-pyrazole-3,5-
dicarboxylate (3r). White solid; Yield: 81% (267 mg);
Mp: 57-59 ºC; IR (thin film): ν 2978, 2929, 1717, 1457,
1370, 1273, 1216, 1158, 1080, 1022, 1001, 841, 759,
720, 690, 629 cm-1; 1H NMR (400 MHz, Chloroform-d)
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136.5, 129.1, 122.1, 115.6, 70.5, 62.3, 61.3, 47.0, 21.5,
Page 10 of 14
121.8, 115.5, 71.4, 61.0, 47.4, 20.1, 14.7. HRMS (ESI):
m/z calcd for C14H17N3O3Na [M+Na]+: 298.1162; found:
298.1169.
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2
3
4
5
6
7
8
14.4, 14.0. HRMS (ESI): m/z calcd for C16H20N2O4Na
[M+Na]+: 327.1315; found: 327.1317.
Diethyl
(R)-5-(bromomethyl)-1-phenyl-4,5-
Diethyl (R)-1-(2,4-dichlorophenyl)-5-methyl-4,5-
dihydro-1H-pyrazole-3,5-dicarboxylate
(4b).
dihydro-1H-pyrazole-3,5-dicarboxylate
(4f).
Yellow solid; Yield: 86% (329 mg); Mp: 86-88 ºC; IR
Yellow viscous oil; Yield: 65% (242 mg); 1H NMR (400
MHz, Chloroform-d) δ = 7.42 (d, J = 2.0 Hz, 1H), 7.28–
7.20 (m, 2H), 4.34 (q, J = 7.1, 6.5 Hz, 2H), 4.20 (q, J =
7.1 Hz, 2H), 3.74 (d, J = 17.7 Hz, 1H), 3.14 (d, J = 17.7
Hz, 1H), 1.47 (s, 1H), 1.36 (t, J = 7.2 Hz, 3H), 1.25 (t, J
= 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, Chloroform-d)
δ = 171.3, 162.2, 140.0, 137.8, 133.5, 133.2, 130.3,
130.1, 127.4, 73.5, 62.1, 61.4, 45.0, 22.0, 14.4, 14.0.
HRMS (ESI): m/z calcd for C16H19Cl2N2O4 [M+H]+:
373.0716; found: 373.0711.
(thin film): ν 2984, 1729, 1690, 1600, 1563, 1503, 1300,
1
1246, 1101, 1013, 747, 696, 684 cm-1; H NMR (400
MHz, Chloroform-d) δ = 7.29 (t, J = 7.5 Hz, 2H), 7.14
(d, J = 7.9 Hz, 2H), 7.04 (t, J = 7.3 Hz, 1H), 4.36 (q, J =
7.1 Hz, 2H), 4.29-4.20 (m, 2H), 4.05 (d, J = 11.6 Hz,
1H), 3.89 (d, J = 11.6 Hz, 1H), 3.62 (s, 2H), 1.39 (t, J =
7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(101 MHz, Chloroform-d) δ = 169.9, 162.0, 141.1,
137.5, 129.2, 123.1, 116.6, 73.0, 62.9, 61.5, 44.6, 34.4,
14.4, 14.0. HRMS (ESI): m/z calcd for
C16H19BrN2O4Na [M+Na]+: 405.0420; found: 405.0426.
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Diethyl
(R)-5-(bromomethyl)-1-(o-tolyl)-4,5-
(4g).
dihydro-1H-pyrazole-3,5-dicarboxylate
3-ethyl
5-(2-hydroxyethyl)
(R)-5-methyl-1-
Yellow solid; Yield: 73% (289 mg); Mp: 80-82 ºC; IR
(thin film): ν 3050, 2993, 1739, 1690, 1554, 1476, 1424,
1270, 1234, 1104, 1028, 1010, 904, 868, 805, 777, 744,
732 cm-1;1H NMR (600 MHz, Chloroform-d) δ = 7.24–
7.19 (m, 2H), 7.16 (td, J = 7.4, 2.1 Hz, 1H), 7.04 (dd, J
= 7.7, 1.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.12 (m,
2H), 3.95 (d, J = 18.2 Hz, 1H), 3.89 (d, J = 10.3 Hz, 1H),
3.68 (d, J = 10.3 Hz, 1H), 3.49 (d, J = 18.2 Hz, 1H),
2.27 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (151 MHz, Chloroform-d) δ = 168.0,
162.2, 139.2, 137.4, 136.6, 131.7, 127.9, 127.0, 126.2,
62.5, 61.3, 41.7, 34.5, 18.6, 14.4, 13.7. HRMS (ESI):
m/z calcd for C17H21BrN2O4Na [M+Na]+: 419.0577;
found: 419.0574.
phenyl-4,5-dihydro-1H-pyrazole-3,5-
dicarboxylate (4c). Yellow solid; Yield: 63% (202
mg); Mp: 64-66 ºC; IR (thin film): ν 3501, 2987, 2942,
1736, 1708, 1560, 1500, 1297, 1246, 1194, 1092, 1071,
1013, 814, 747, 690, 678 cm-1; H NMR (400 MHz,
1
Chloroform-d) δ = 7.28 (td, J = 7.2, 1.7 Hz, 2H), 7.15 (d,
J = 8.2 Hz, 2H), 6.99 (t, J = 7.3 Hz, 1H), 4.41–4.32 (m,
3H), 4.18 (ddd, J = 11.7, 6.0, 3.3 Hz, 1H), 3.66 (td, J =
5.7, 3.3 Hz, 2H), 3.61 (d, J = 17.8 Hz, 1H), 3.20 (d, J =
17.8 Hz, 1H), 1.72 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (151 MHz, Chloroform-d) δ = 172.5,
162.3, 141.5, 136.8, 129.3, 122.3, 115.2, 70.5, 67.5, 61.4,
60.7, 47.1, 22.0, 14.4. HRMS (ESI): m/z calcd for
C16H21N2O5 [M+H]+: 321.1445; found: 321.1439.
3-ethyl 5-(2-hydroxyethyl) (R)-1-(4-bromophenyl)-
3-ethyl 5-methyl (R)-5-acetamido-1-phenyl-4,5-
5-methyl-4,5-dihydro-1H-pyrazole-3,5-
dihydro-1H-pyrazole-3,5-dicarboxylate
(4d).
dicarboxylate (4h). Brown viscous oil; Yield: 69%
(275 mg); IR (thin film): ν 3455, 2990, 1790, 1742,
1699, 1587, 1560, 1491, 1306, 1252, 1185, 1095, 1007,
829, 768, 744 cm-1; 1H NMR (600 MHz, Chloroform-d)
δ = 7.41–7.37 (m, 2H), 7.06–7.04 (m, 2H), 4.38–4.35 (m,
3H), 4.28 (ddd, J = 11.8, 6.1, 3.2 Hz, 1H), 3.79–3.71 (m,
2H), 3.63 (d, J = 17.8 Hz, 1H), 3.22 (d, J = 17.8 Hz, 1H),
1.69 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(151 MHz, Chloroform-d) δ = 172.4, 162.1, 140.5,
137.6, 132.1, 116.9, 114.7, 70.5, 67.5, 61.6, 60.7, 47.2,
21.6, 14.3. HRMS (ESI): m/z calcd for
C16H19BrN2O5Na [M+Na]+: 421.0370; found: 421.0376.
Yellow solid; Yield: 74% (246 mg); Mp: 120-124 ºC; IR
(thin film): ν 3389, 2993, 1739, 1690, 1566, 1494, 1433,
1297, 1258, 1204, 1140, 1125, 1052, 974, 904, 823, 753,
696, 672, 554 cm-1; 1H NMR (400 MHz, Chloroform-d)
δ = 7.23 (d, J = 7.7 Hz, 2H), 7.15 (s, 1H), 7.09 (d, J =
8.2 Hz, 2H), 6.98 (s, 1H), 4.35 (q, J = 6.8 Hz, 2H), 3.84
(s, 3H), 3.69 (d, J = 18.2 Hz, 1H), 3.53 (d, J = 18.1 Hz,
1H), 1.92 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (101 MHz, Chloroform-d) δ = 171.1, 168.6, 162.1,
140.5, 137.8, 129.0, 122.7, 115.9, 78.9, 61.3, 54.4, 44.7,
23.4, 14.3. HRMS (ESI): m/z calcd for C16H19N3O5Na
[M+Na]+: 356.1217; found: 356.1213.
2-hydroxyethyl
(R)-3-benzoyl-1-cyclohexyl-5-
Ethyl
(R)-5-carbamoyl-5-methyl-1-phenyl-4,5-
methyl-4,5-dihydro-1H-pyrazole-5-carboxylate
dihydro-1H-pyrazole-3-carboxylate (4e). Yellow
solid; Yield: 57% (157 mg); Mp: 222-224 ºC; IR (thin
film): ν 3380,3202, 2990, 1726, 1587, 1572, 1503, 1375,
1252, 1294, 1213, 1098, 1071, 808, 756, 696, 662, 605
(4i). Yellow viscous oil; Yield: 52% (186 mg); IR (thin
film): ν 3431, 2936, 2860, 1739, 1596, 1572, 1506, 1445,
1261, 1179, 1116, 910, 892, 847, 732, 705, 672 cm-1; 1H
NMR (600 MHz, Chloroform-d) δ = 8.14–8.10 (m, 2H),
7.53–7.49 (m, 1H), 7.43 (dd, J = 8.3, 7.0 Hz, 2H), 4.35–
4.26 (m, 2H), 3.86 (t, J = 4.7 Hz, 2H), 3.63 (d, J = 17.1
Hz, 1H), 3.28 (tt, J = 11.5, 3.7 Hz, 1H), 3.11 (d, J = 17.1
Hz, 1H), 2.65 (s, 1H), 2.05–1.95 (m, 1H), 1.91–1.79 (m,
3H), 1.71–1.62 (m, 3H), 1.58 (s, 3H), 1.36–1.28 (m, 3H);
13C{1H} NMR (151 MHz, Chloroform-d) δ = 186.2,
1
cm-1; H NMR (600 MHz, DMSO-d6) δ = 7.72 (s, 1H),
7.47 (s, 1H), 7.31–7.28 (m, 2H), 7.10–7.08 (m, 2H),
6.95 (t, J = 7.3 Hz, 1H), 4.26 (qd, J = 7.1, 2.6 Hz, 2H),
3.31 (d, J = 17.6 Hz, 1H), 3.16 (d, J = 17.5 Hz, 1H),
1.38 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(151 MHz, DMSO-d6) δ = 174.3, 162.3, 141.9, 137.9,
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The Journal of Organic Chemistry
172.6, 140.6, 137.6, 131.6, 129.9, 127.8, 72.2, 67.2, 60.7,
and
biological
significance.
Eur.
J.
Med.
57.9, 43.2, 34.5, 32.9, 25.9, 25.7, 25.3, 22.6. HRMS
Chem. 2013, 69, 735-753.
2
3
4
5
6
7
(ESI): m/z calcd for C20H27N2O4 [M+H]+: 359.1965;
found: 359.1966.
Ethyl
tetramethylpiperidin-1-yl)oxy)acetate (5a). Brown
viscous oil; Yield: 64% (111 mg); H NMR (400 MHz,
DMSO-d6) δ = 7.73 (dd, J = 6.7, 3.0 Hz, 2H), 7.59 (dt, J
= 4.7, 2.6 Hz, 3H), 5.49 (s, 1H), 4.20 (qd, J = 7.1, 2.2
Hz, 2H), 1.63–1.26 (m, 6H), 1.23–1.15 (m, 12H), 0.88 (s,
3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ = 166.0,
150.6, 132.2, 129.5, 122.4, 107.0, 61.3, 60.4, 59.6, 33.9,
32.3, 20.3, 19.9, 16.5, 14.0. HRMS (ESI): m/z calcd for
C19H30N3O3 [M+H]+: 348.2282; found: 348.2281.
(2) Mokhlesi, A.; Hartmann, R.; Kurtan, T.; Weber, H.;
Lin, W.; Chaidir, C.; Muller, W. E. G.; Daletos, G.;
Proksch, P. New 2-methoxy acetylenic acids and
pyrazole alkaloids from the marine sponge cinachyrella
sp. Mar. Drugs. 2017, 15, 356/1-356/10.
(E)-2-(2-phenylhydrazono)-2-((2,2,6,6-
1
(3) Kikuchi, T.; Ikedaya, A.; Toda, A.; Ikushima, K.;
Yamakawa, T.; Okada, R.; Yamada, T.; Tanaka, R.
Pyrazole alkaloids from watermelon (Citrullus lanatus)
seeds. Phytochem. Lett. 2015, 12, 94-97.
(4) Silva, V. L. M.; Elguero, J.; Silva, A. M. S. Current
progress on antioxidants incorporating the pyrazole core.
Eur. J. Med. Chem. 2018, 156, 394-429.
(5) Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.;
Mabkhot, Y. N.; Al-aizari, F. A.; Ansar, M. Synthesis
and pharmacological activities of pyrazole derivatives: a
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8
9
10
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56
57
58
59
60
5-(tert-butyl) 3-ethyl (S)-1-phenyl-4,5-dihydro-
1H-pyrazole-3,5-dicarboxylate (6a). Yellow solid;
Yield: 83% (264 mg); 1H NMR (400 MHz, Chloroform-
d) δ = 7.30 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H),
6.96 (t, J = 7.3 Hz, 1H), 4.82 (dd, J = 13.6, 6.8 Hz, 1H),
4.35 (q, J = 7.1 Hz, 2H), 3.51 (dd, J = 18.1, 13.6 Hz,
1H), 3.28 (dd, J = 18.1, 6.8 Hz, 1H), 1.39 (s, 9H), 1.38 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, Chloroform-
d) δ = 169.2, 162.3, 142.6, 138.2, 129.1, 121.6, 114.1,
83.0, 63.3, 61.3, 37.1, 27.8, 14.3. HRMS (ESI): m/z
calcd for C17H22N2O4Na [M+Na]+: 341.1472; found:
341.1475.
(6) Faria, J. V.; Vegi, P. F.; Miguita, A. G. C.; Santos,
M. S. D.; Boechat, N.; Bernardino, A. M. R. Recently
reported biological activities of pyrazole compounds.
Bioorg. Med. Chem. 2017, 25, 5891-5903.
(7) Qu, Y.; Babailov, S. P. Azo-linked high-nitrogen
energetic materials. J. Mater. Chem. A. 2018, 6, 1915-
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(8) Castro, I.; Barros, W. P.; Calatayud, M. L.; Lloret, F.;
Marino, N.; De Munno, G.; Stumpf, H. O.; Ruiz-Garcia,
R.; Julve, M. Dicopper(II) pyrazolenophanes: Ligand
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Coordin. Chem. Rev. 2016, 315, 135-152.
■ ASSOCIATED CONTENT
푆
○
SUPPORTING INFORMATION
(9) Tsurubuchi, Y.; Zhao, X.; Nagata, K.; Kono, Y.;
Nishimura, K.; Yeh, J. Z.; Narahashi, T. Modulation of
The Supporting Information is available free of
charge on the ACS Publications website at DOI:
10.1021/acs. joc.
tetrodotoxin-resistant
sodium
channels
by
dihydropyrazole insecticide RH-3421 in rat dorsal root
ganglion neurons. Neurotoxicology. 2001, 22, 743-753.
(10) Taylor, V. L.; Cummins, I.; Brazier-Hicks, M.;
Edwards, R. Protective responses induced by herbicide
safeners in wheat. Environ. Exp. Bot. 2013, 88, 93-99.
(11) Bartucca, M. L.; Celletti, S.; Astolfi, S.; Mimmo,
T.; Cesco, S.; Panfili, I.; Del Buono, D. Effect of three
safeners on sulfur assimilation and iron deficiency
response in barley (Hordeum vulgare) plants. Pest
Manag. Sci. 2017, 73, 240-245.
(12) Wang, Y.; Yang, T.-Z.; Liu, X.-M.; Li, G.-F.; Che,
W.-L.; Zhu, D.-X.; Su, Z.-M. New cationic Ir(III)
complexes without "any soft substituents": aggregation-
induced emission and piezochromic luminescence. J.
Mater. Chem. C. 2018, 6, 12217-12223.
1
Mechanism studies, copies of H and 13C NMR
spectra, X-ray crystallography data and CIF file.
■ AUTHOR INFORMATION
Corresponding Author
* E-mail:syzhao8@dhu.edu.cn
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
The authors acknowledge financial support from
Shanghai Municipal Natural Science Foundation (No.
15ZR1401400), and the Fundamental Research Funds
for the Central Universities (2232018D3-40) and the
Fundamental Research Funds for the Central
Universities and Graduate Student Innovation Fund of
Donghua University (CUSF-DH-D-2018063 and
BCZD2019004).
(13) Narayana, Y. S. L. V.; Baumgarten, M.; Müllen, K.;
Chandrasekar, R. Tuning the solid state emission of thin
films/microspheres obtained from alternating oligo(3-
octylthiophenes)
and
2,6-bis(pyrazole)pyridine
copolymers by varying conjugation length and Eu3+
/Tb3+ metal coordination. Macromolecules. 2015, 48,
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(14) Berdiell, I. C.; Kulak, A. N.; Warriner, S. L.;
Halcrow, M. A. Heterometallic coordination polymer
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