Direct Access for the Regio- And Stereoselective Synthesis of N-Alkenylpyrazoles and Chromenopyrazoles

Article abstract of DOI:10.1021/acs.joc.0c02421

A highly regio- and stereoselective method was developed for the preparation of N-alkenylpyrazoles and chromenopyrazoles by the reaction of N-tosylhydrazones and salicyl N-tosylhydrazones with alkynes under neat conditions in the presence of La(OTf)3. The present study was found to be efficient and convenient for direct access to N-alkenylpyrazoles and chromenopyrazoles through C-C, C-N, and C-O bond forming reactions. Structure assignment of N-alkenylpyrazole compound 5c was confirmed by X-ray analysis.

Full text of DOI:10.1021/acs.joc.0c02421

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Direct Access for the Regio- and Stereoselective Synthesis of
N‑Alkenylpyrazoles and Chromenopyrazoles
Siva Hariprasad Kurma, Balasubramanian Sridhar, and China Raju Bhimapaka*
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ABSTRACT: A highly regio- and stereoselective method was
developed for the preparation of N-alkenylpyrazoles and
chromenopyrazoles by the reaction of N-tosylhydrazones and
salicyl N-tosylhydrazones with alkynes under neat conditions in the
presence of La(OTf)3. The present study was found to be efficient
and convenient for direct access to N-alkenylpyrazoles and
chromenopyrazoles through C−C, C−N, and C−O bond forming
reactions. Structure assignment of N-alkenylpyrazole compound 5c
was confirmed by X-ray analysis.
fore, method developments for construction of N-alkenylpyr-
azoles have high priority and potential demand.
INTRODUCTION
■
Pyrazole heterocyclic compounds are an attractive class of
compounds1 and are key components of several drug
molecules (Celebrex, Viagra, Zometapine, Cyenopyrafen,
Fenpyroximate, Tebufenpyrad, Apixaban) and insecticide
(Fipronil).2 Pyrazole compounds possess a broad spectrum
of biological properties,3a−d serve as ligands in coordination
chemistry, and act as optical brighteners.3e,f Therefore,
synthesis of pyrazoles has become an important area of
study. Two classical approaches are available for the synthesis
of pyrazoles, namely, (1) Knorr condensation of 1,3-
dicarbonyls with hydrazines4 and (2) 1,3-dipolar cycloaddition
of diazo compounds with alkynes or electron-deficient
alkenes.5 Later efforts have been made to achieve various
pyrazoles from N-tosylhydrazones with ethynylbenzene, 2-
bromo-3,3,3-trifluoroprop-1-ene, and activated alkynes.6 These
methods have one or more major drawbacks, such as
hazardous reagents, limited substrate scope, and regioselectiv-
ity.
On the other hand, N-alkenylpyrazoles are predominantly
heterocyclic compounds, and limited reports are available in
the literature. These compounds are prepared by addition of
alkynes to pyrazoles. In 2008, Tsuchimoto et al. reported7 the
Lewis acid-catalyzed addition of pyrazoles with alkynes (Figure
1). Das et al. developed the Ru-catalyzed regio- and
stereoselective vinylation of pyrazoles with alkynes (Figure 1,
A).8 Later, Garg et al.9 constructed (E)- and (Z)-vinylated
pyrazoles by reacting pyrazoles with activated and unactivated
alkynes in the presence of KOH/DMSO at 120 °C (Figure 1,
B). There is no straightforward single-step method available in
the literature for the synthesis of N-alkenylpyrazoles. There-
In a continuation of our research interest in the synthesis of
heterocyclic compounds10 and pyrazoles,11 herein, we report a
regio- and stereoselective synthesis of N- alkenylpyrazoles,
chromenopyrazolyl acrylates, and chromenopyrazole-4-carbox-
ylates starting from N-tosylhydrazones12a−g and salicyl N-
tosylhydrazones12h,i,16 with alkynes in the presence of La-
(OTf)313 in one pot under neat conditions, and the results are
discussed below.
RESULTS AND DISCUSSION
■
To establish the reaction conditions, we have chosen N′-
benzylidene-4-methylbenzenesulfonohydrazide 3a as a model
substrate which was prepared from benzaldehyde 1a and 4-
methylbenzenesulfonohydrazide 2. The substrate 3a (1.0
equiv) was stirred with ethyl propiolate 4a (1.0 equiv) in the
presence of 5 mol % of La(OTf)3 in toluene under reflux
conditions. The usual workup gave compound 5a in a 20%
yield. Then the reaction was repeated with 2.0 equiv of 4a
under similar conditions, and compound 5a was obtained with
a 44% yield (Scheme 1). The compound structure was
assigned as (E)-ethyl 1-(3-ethoxy-3-oxoprop-1-enyl)-5-phenyl-
1H-pyrazole-4-carboxylate 5a on the basis of spectral and
Received: October 13, 2020
Published: January 19, 2021
https://dx.doi.org/10.1021/acs.joc.0c02421
© 2021 American Chemical Society
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Table 1. Optimization Study
quantity
time
(h)
yield
a
entry
catalyst
(mol %)
solvent
temp
rt
reflux
reflux
(%)
1
2
3
4
5
6
7
8
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
Bi(OTf)3
Sc(OTf)3
Cu(OTf)2
Sn(OTf)2
Yb(OTf)3
In(OTf)3
AlCl3
FeCl3
InCl3
CuI
CuBr
Ag2CO3
PdCl2
Pd(OAc)2
Rucl3
5
5
5
5
5
5
5
5
10
3
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
toluene
toluene
CH3OH
THF
CH3CN
DCM
48
24
24
44
40
32
35
21
73
70
73
67
65
73
67
61
63
54
59
60
28
22
17
43
39
48
49
52
68
reflux
reflux
24
24
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
100 °C
100 °C
100 °C
100 °C
80 °C
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
120 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
Figure 1. Previous approaches for preparation of N-alkenylpyrazoles
and the present work.
Scheme 1. Synthesis of (E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-
enyl)-5-phenyl-1H-pyrazole-4-carboxylate 5a
a
Isolated yields.
h, an intractable mixture of products was observed. Lowering
the temperature of the neat reaction to 80 °C led to a low yield
(Table 1, entry 11), and no improvement of the yield was
observed when the reaction was carried out at 120 °C or above
(Table 1, entry 12).
Having studied the reaction with various solvents, next,
reaction of 3a with 4a was carried out at 100 °C in the
presence of various catalysts (Table 1). The triflates have
provided compound 5a in the range of 54−67% yield (Table 1,
entries 13−18). Al, Fe, In, and Cu halides and Ag2CO3
produced compound 5a in moderate yield (entries 19−24).
Compound 5a was obtained in a moderate yield when the
reaction was carried out with Pd and Ru catalysts (Table 1,
entries 25−27). Finally, we found that La(OTf)3 (5 mol %) at
100 °C is the most suitable condition to afford compound 5a
in very good yield (73%, Table 1, entry 7). We also carried out
the reaction of 3a with other terminal alkyne, methyl
propiolate 4b under optimized conditions. This provided
compound 5b in 71% yield (Table 2). Reaction with ethynyl
benzene 4c led to complete recovery of the starting material.
With the identification of the optimal conditions, we
embarked to explore the present method with more substrates.
Accordingly, the required benzenesulfonohydrazides 3b−n
have been prepared from benzaldehydes (1b−n) with 2 (see
SI, Figure S1). Thus, obtained hydrazides 3b−n were reacted
analytical data (see SI). The pyrazole 5a was formed in a
regioselective manner with E (trans) geometry (see SI). This is
the first example for the construction of N-alkenylpyrazoles
with C−C and two C−N bond formations in one pot.
This interesting result prompted us to optimize the reaction
conditions to obtain better yields, and the results are
summarized in Table 1. The reaction at room temperature in
toluene did not provide the compound (Table 1, entry 1).
When the reaction was attempted using different solvents such
as MeOH, THF, CH3CN, and DCM under reflux conditions
(Table 1, entries 3−6), 5a was produced in moderate yields.
Interestingly, compound 5a was formed in 73% yield when the
reaction was carried out under neat conditions at 100 °C
(Table 1, entry 7). There was not much difference in the yield
of 5a when the reaction was carried out with either a higher
(10 mol %) or a lower (3 mol %) amount of La(OTf)3 (Table
1, entries 9 and 10). When the reaction time was extended to 8
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with ethyl propiolate 4a under the optimized conditions, and
the results are tabulated in Table 2. The electron-donating
groups present on the substrate (3b−3h) were well tolerated
and produced the N-alkenylpyrazoles 5c−i in very good yields,
whereas electron-withdrawing groups (3i−3n) produced
compounds 5j−o in moderate to good yields (Table 2). The
structure of compound 5c was confirmed by single-crystal X-
ray diffraction analysis (CCDC 2031798, see SI, Figure S3).
Further, we recorded the 19F NMR data for 5k and 5l (see SI,
13C NMR for 5k and 5l).14
Table 2. Synthesis of N-Alkenyl 1H-Pyrazole-4-carboxylates
5a−z
Further, we demonstrated the method with a number of
examples as shown in Table 2. We prepared the required
hydrazides 3o−r from cinnamaldehyde (1o), cyclohex-1-ene
carbaldehyde (1p), 1-naphthaldehyde (1q), and benzo[d]-
[1,3]dioxole-5-carbaldehyde (1r) with 2 (see SI, Figure S1).
The hydrazides 3o−r were reacted with 4a under optimized
reaction conditions to provide the corresponding compounds
5p−s (Table 2, see SI).
After achieving the N-alkenylpyrazoles, the method was
applied to heteroaromatic sulfonohydrazides 3s−zb, which are
depicted in Table 2 to show the diversity of the protocol.
These hydrazides were prepared from heterocyclic aldehydes
such as furan (1s), thiophene (1t and 1u), pyrazole (1v),
indole (1w), quinoline (1x), 4H-chromene (1y), 2H-
chromenes (1z amd 1za), and 2-chloronicotinaldehyde (1zb)
with 2. Hydrazides 3s−zb were then reacted with 4a under
optimized conditions. The reactions proceeded smoothly with
sulfonohydrazides 3s−y to obtain the target compounds 5t−z
(Table 2, see SI). With sulfonohydrazides 3z−zb, the reaction
did not proceed and the starting materials were recovered.
To establish the reaction mechanism, we conducted the
control experiment with 3a and 4a in the presence of NaOEt
(3.0 equiv) under reflux conditions (Scheme 2).6c This
Scheme 2. Synthesis of 5aa and 5ab
provided the ethyl 3-phenyl-1H-pyrazole-5-carboxylate 5aa.6d
Then the obtained pyrazole 5aa was subjected for N-
alkenylation with 4a in the presence of La(OTf)3. This
provided compound 5ab with a 54% yield (see SI). In our
present method we directly obtained altogether a different N-
alkenylpyrazole compound 5a. Compounds 5a and 5ab also
have been analyzed by gNOESY and HPLC analyses (see SI).
A possible reaction pathway for the formation of 5a is
illustrated in Scheme 3.15 Lewis scid [La(OTf)3] activates the
carbonyl functionality of the ester moiety of the ethyl
propiolate 4a and increases the electrophilic nature at the
terminal carbon to undergo aza-Michael addition via addition
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experiments. Next, the reaction was screened with electron-
donating and -withdrawing salicyl-N-tosylhydrazones (6b, 6d,
6f, and 6g) with 4a and 4b as per the optimized conditions.
The reactions with 6d and 6g proceeded smoothly and
provided compounds 7c and 7e in moderate yields (Table 3,
see SI). Compounds 7b, 7d, and 7f were not obtained under
the optimized reaction conditions, and the starting materials
were recovered.
Scheme 3. Proposed Mechanism for the Formation of 5a
Since reaction with 4a did not give better yields, we
investigated the reaction with activated alkynes. Accordingly,
6a was made to react with diethyl but-2-ynedioate 4d under
optimized conditions (Table 4). Interestingly, this reaction
provided a different product which was confirmed as
chromenopyrazole-4-carboxylate 8a based on spectral data.
of N-tosylhydrazone 3a to form intermediate A. Intramolecular
cyclization of intermediate A led to N-tosylpyrazoline B, and
subsequent elimination of TsH gives the pyrazole C. Another
molecule of propiolate 4a undergoes aza-Michael addition with
the pyrazole C in the presence of the catalyst to give the N-
alkenylpyrazole product 5a with E (trans) selectivity.
Table 4. Synthesis of Chromeno[4,3-c]pyrazole-4-
carboxylates 8a−m
The chromenopyrazoles are important bioactive com-
pounds,16 and we recently reported the synthesis of
chromenopyrazolones and benzoylcoumarins.17 To our knowl-
edge, there is no report of a reaction between salicyl N-
tosylhydrazones and activated alkynes for preparation of
chromenopyrazolyl acrylates and chromenopyrazole-4-carbox-
ylates. Therefore, a mild and one-pot method for the synthesis
of chromenopyrazoles is very much needed. The N-
alkenylpyrazole synthetic route prompted us to demonstrate
this reaction toward the synthesis of chromenopyrazoles.
Accordingly, salicyl N-tosylhydrazone 6a was prepared from
salicylaldehyde (1zc) with 2 as per our established procedure
(see SI, Figure S2). Thus, the obtained hydrazone 6a (1.0
equiv) was initially reacted with 4a (2.0 equiv) under our
optimized conditions (Table 3). Pleasingly, this provided fused
heterocyclic compound (E)-ethyl 3-(4-oxochromeno[4,3-c]-
pyrazol-1(4H)-yl)acrylate 7a with moderate yield (32%).
To improve the yield of 7a, a number of experiments
between 6a and 4a were carried out under various reaction
conditions. A maximum 32% yield was achieved in all of these
Table 3. Synthesis of (E)-Ethyl 3-(4-Oxochromeno[4,3-
c]pyrazol-1(4H)-yl)acrylates 7a−f
We were curious about this reaction, and the scope of the
method was studied with more hydrazones 6b−h with
activated alkynes such as diethyl but-2-ynedioate 4d, dimethyl
but-2-ynedioate 4e, ethyl 3-phenylpropiolate 4f, and ethyl but-
2-ynoate 4g under optimized reaction conditions. The results
are presented in Table 4 (see SI).
Reactions of 6b−h with activated alkynes 4d and 4e
proceeded smoothly and provided a series of chromenopyr-
azole-4-carboxylates 8b−m (Table 4, see SI). However,
alkynes such as 4f and 4g did not provide the pyrazoles
under these conditions. It is noteworthy to mention here that
the ester moiety is an essential component to furnish
chromenopyrazole-4-carboxylates (Table 4, see SI).
A possible mechanism for the formation of 8a is depicted in
Scheme 4. Oxa−Michael addition of 6a with La(OTf)3
coordinates diethyl but-2-ynedioate to provide intermediate
B. Intramolecular cyclization of B provides the chromene
intermediate C with elimination of TsH. The imine present on
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analysis was carried out by a Shimadzu SPD-M20A, PDA detector
using a C-18 column, λ 200−500 nm. Eluent: CH3CN:H2O = 90:10.
Flow rate: 0.5 mL/min. Structural assignments were made with
additional information from gNOESY experiments.
Scheme 4. Proposed Mechanism of Compound 8a
Typical Procedure for Preparation of (E)-N′-Benzylidene-4-
methylbenzenesulfonohydrazides (3a−zb). Tosylhydrazine 2
(877 mg, 4.72 mmol, 1.0 equiv) was added to a stirred solution of
benzaldehyde 1a (500 mg, 4.72 mmol, 1.0 equiv) in acetonitrile (5
mL) at room temperature, and the contents were stirred for 2 h
(TLC). The solvent was removed under reduced pressure. The
residue was purified by recrystallization with hexane and afforded (E)-
N′-benzylidene-4-methylbenzenesulfonohydrazide 3a as a colorless
solid in 96% yield. The substituted tosylhydrazones 3b−zb were
prepared by reaction of aldehydes 1b−zb with tosylhydrazine 2. The
tosylhydrazones 3a−d, 3g−t, 3w, and 3zb are known compounds and
compared with the literature data.12 The newly prepared tosylhy-
drazones 3e−f, 3u−3v, and 3x−3za were characterized by spectral
data.
intermediate C reacts with ester carbonyl providing pyrazole
intermediate D. Finally, intermediate D through aromatization
with the loss of H2O gives the chromenopyrazolecarboxylate
8a.
To further demonstrate the present protocol, two N-
alkenylpyrazoles 5a and 5h and one chromenopyrazole 8a
were prepared in gram scale by reaction of tosylhydrazones 3a
(1.0 g) with 4a and 3g (1.5 g) with 4a and salicyl
tosylhydrazone 6a (1.2 g) with 4d under our optimized
reaction conditions. The results are depicted in Scheme 5.
( E ) - 4 - M e t h y l - N ′ - ( 2 , 4 , 6 - t r i m e t h o x y b e n z y l i d e n e ) -
benzenesulfonohydrazide (3e). Colorless solid (826 mg, 89% yield);
1
mp 148−150 °C. H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H),
7.99 (s, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 6.24
(d, J = 13.9 Hz, 2H), 3.78 (s, 3H), 3.74 (s, 6H), 2.38 (s, 3H).
13C{1H} NMR (101 MHz, DMSO-d6): δ 162.2, 159.6, 142.9, 142.5,
136.4, 129.1, 127.3, 103.4, 90.9, 55.8, 55.3, 20.9. FT-IR (KBr): 3017,
2942, 1606, 1580, 1456, 1415, 1334, 1207, 1158, 1125, 751 cm−1. MS
(ESI) m/z: [M + H]+ 365. HRMS (ESI) m/z: [M + H]+ calcd for
C17H21N2O5S, 365.1165; found, 365.1150.
( E ) - 4 - M e t h y l - N ′ - ( 3 - p h e n o x y b e n z y l i d e n e ) -
benzenesulfonohydrazide (3f). Colorless solid (785 mg, 85% yield);
Scheme 5. Gram Scale Preparation of Compounds 5a, 5h,
and 8a
1
mp 124−126 °C. H NMR (500 MHz, DMSO-d6): δ 11.49 (s, 1H),
7.88 (s, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.48−7.34 (m, 5H), 7.31 (d, J
= 7.7 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.15 (s, 1H), 7.04 (d, J = 7.8
Hz, 3H), 2.37 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6): δ
157.2, 156.0, 146.1, 143.4, 135.9, 135.6, 130.5, 130.1, 129.6, 127.2,
123.9, 122.1, 120.0, 119.1, 115.4, 20.9. FT-IR (KBr): 3177, 1582,
1486, 1443, 1363, 1319, 1255, 1160, 1054, 913, 757 cm−1. MS (ESI)
m/z: [M + H]+ 367. HRMS (ESI) m/z: [M + H]+ calcd for
C20H19N2O3S, 367.1110; found, 367.1102.
(E)-N′-((5-Bromothiophen-2-yl)methylene)-4-methylbenzenesul-
fonohydrazide (3u). Colorless solid (765 mg, 81% yield); mp 126−
128 °C. 1H NMR (400 MHz, DMSO-d6): δ 11.49 (s, 1H), 8.01 (d, J
= 4.2 Hz, 1H), 7.78−7.62 (m, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.28−
7.10 (m, 2H), 2.37 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
143.5, 141.2, 140.1, 135.8, 131.2, 131.1, 129.6, 127.1, 114.5, 20.92.
FT-IR (KBr): 3190, 1598, 1444, 1354, 1322, 1202, 1158, 1050, 921,
751 cm−1. MS (ESI) m/z: [M + H]+ 359. HRMS (ESI) m/z: [M +
H]+ calcd for C12H121N2O2BrS2, 358.9518; found, 358.9516.
(E)-4-Methyl-N′-((1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)-
methylene)benzenesulfonohydrazide (3v). Colorless solid (664 mg,
CONCLUSIONS
■
In summary, a highly regio- and stereoselective new protocol
has been developed for the synthesis of N-alkenylpyrazoles,
chromenopyrazolyl acrylates, and chromenopyrazole-4-carbox-
ylates. The present method involves the synthesis of five-
membered heterocyclic compounds including a fused one
through C−C, two C−N, and C−O bond forming reactions in
one pot. Due to the importance of these heterocyclic
compounds, especially in pharmaceutical and medicinal
chemistry, the present protocol can be extended for the
synthesis of various scaffolds.
1
81% yield); mp 185−187 °C. H NMR (400 MHz, DMSO- d6): δ
11.20 (s, 1H), 8.83 (s, 1H), 8.01 (s, 1H), 7.96 (d, J = 7.9 Hz, 2H),
7.77 (d, J = 8.0 Hz, 2H), 7.52 (t, J = 7.1 Hz, 4H), 7.42−7.31 (m, 3H),
7.29 (d, J = 7.8 Hz, 2H), 2.37 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR
(101 MHz, DMSO-d6): δ 151.2, 143.2, 140.7, 138.9, 137.9, 136.2,
129.5, 129.4, 129.0, 128.9, 128.2, 127.6, 127.2, 118.7, 116.1, 20.9,
20.8. FT-IR (KBr): 3212, 1602, 1540, 1451, 1405, 1351, 1221, 1164,
1089, 1037, 922, 759 cm−1. MS (ESI) m/z: [M + H]+ 431. HRMS
(ESI) m/z: [M + H]+ calcd for C24H23N4O2S, 431.1536; found,
431.1519.
EXPERIMENTAL SECTION
■
General Information. Salicylaldehydes, activated alkynes, tosyl-
hydrazine, and triflates were procured from Sigma-Aldrich. General
chemicals, Lewis acids, and solvents were obtained from local
suppliers. All of the reactions were carried at 100 °C using an oil bath.
All of the reactions were monitored by thin layer chromatography
(TLC) on precoated silica gel 60 F254 (mesh); spots were visualized
under UV light. Merck silica gel (60−120 and 100−200 mesh) was
(E)-N′-((2-Chloro-6-methoxyquinolin-3-yl)methylene)-4-methyl-
benzenesulfonohydrazide (3x). Colorless solid (704 mg, 80% yield);
1
used for column chromatography. H NMR and 13C NMR spectra
1
mp 203−205 °C. H NMR (300 MHz, DMSO-d6): δ 12.00 (s, 1H),
8.64 (s, 1H), 8.32 (s, 1H), 7.84 (t, J = 9.5 Hz, 3H), 7.61 (d, J = 2.5
Hz, 1H), 7.45 (d, J = 7.7 Hz, 3H), 3.91 (s, 3H), 2.37 (s, 3H).
13C{1H} NMR (76 MHz, DMSO-d6): δ 157.9, 145.3, 143.7, 143.1,
141.8, 136.1, 133.9, 129.8, 128.9, 127.9, 127.2, 125.3, 124.2, 106.3,
55.7, 20.9. FT-IR (KBr): 3672, 3568, 1497, 1229, 1164, 1061, 1016,
924, 763 cm−1. MS (ESI) m/z: [M + H]+ 390. HRMS (ESI) m/z: [M
+ H]+ calcd for C18H17N3O3ClS, 390.0673; found, 390.0672.
were recorded on Avance 300, 400, and 500 MHz spectrometers in
CDCl3 using TMS as the internal standard. IR spectra were recorded
on a Nicolet Nexus 670 FT spectrometer. ESI-MS results were
obtained on a quarto micro spectrometer. HRMS data were measured
on an Agilent Technologies 6510 by the Q-TOFLC/MS ESI-
Technique. Melting points were determined in open glass capillary
tubes on a Stuart melting point apparatus and are uncorrected. HPLC
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(E)-4-Methyl-N′-((4-oxo-4H-chromen-3-yl)methylene)-
benzenesulfonohydrazide (3y). Colorless solid (904 mg, 92% yield);
mp 221−223 °C. H NMR (300 MHz, DMSO-d6): δ 11.55 (s, 1H),
1588, 1470, 1388, 1283, 1216, 1182, 1132, 1039, 755 cm−1. MS (ESI)
m/z: [M + H]+ 287. HRMS (ESI) m/z: [M + H]+ calcd for
C15H15N2O4 287.1028; found, 287.1026.
1
8.63 (s, 1H), 8.15−8.03 (m, 1H), 8.02 (s, 1H), 7.83 (ddd, J = 13.7,
10.3, 4.9 Hz, 3H), 7.69 (d, J = 8.1 Hz, 1H), 7.58−7.48 (m, 1H), 7.42
(d, J = 8.1 Hz, 2H), 2.37 (s, 3H). 13C{1H} NMR (76 MHz, DMSO-
d6): δ 174.7, 155.7, 154.4, 143.5, 139.5, 135.9, 134.7, 129.7, 127.2,
126.1, 125.1, 123.2, 118.7, 117.8, 20.9. FT-IR (KBr): 3114, 1618,
1589, 1461, 1353, 1311, 1226, 1163, 1095, 1050, 912, 763 cm−1. MS
(ESI) m/z: [M + H]+ 343. HRMS (ESI) m/z: [M + H]+ calcd for
C17H15N2O4S, 343.0747; found, 343.0740.
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-(4-methoxyphenyl)-
1H-pyrazole-4-carboxylate (5c). Colorless solid (89 mg, 79%
1
yield); mp 116−118 °C. H NMR (400 MHz, CDCl3): δ 8.12 (s,
1H), 7.74 (d, J = 13.7, 1H), 7.36−7.30 (m, 2H), 7.05−7.00 (m, 2H),
6.64 (d, J = 13.7 Hz, 1H), 4.20 (qd, J = 7.0, 3.3 Hz, 4H), 3.88 (s, 3H),
1.30−1.26 (m, 3H), 1.24−1.20 (m, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 166.3, 162.1, 160.9, 147.5, 144.0, 136.5, 131.9, 118.6,
114.7, 113.9, 109.2, 60.5, 60.2, 55.3, 14.1, 14.0. FT-IR (KBr): 3416,
3045, 2967, 1718, 1792, 1459, 1369, 1301, 1234, 1170, 1146, 1084,
1019, 970, 714 cm−1. MS (ESI) m/z: [M + H]+ 345. HRMS (ESI) m/
z: [M + H]+ calcd for C18H21N2O5 345.1449; found, 345.1445.
(E)-Ethyl 5-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-3-oxoprop-1-
enyl)-1H-pyrazole-4-carboxylate (5d). Colorless solid (91 mg, 81%
(E)-N′-((4-Chloro-2-oxo-2H-chromen-3-yl)methylene)-4-methyl-
benzenesulfonohydrazide (3z). Colorless solid (804 mg, 89% yield);
1
mp 161−163 °C. H NMR (400 MHz, DMSO-d6): δ 11.97 (s, 1H),
8.08 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.74
(d, J = 7.9 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.44 (d, J = 7.7 Hz, 2H),
7.39 (d, J = 8.1 Hz, 1H), 2.39 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 161.5, 158.7, 153.9, 144.6, 134.9, 133.6, 129.9, 129.5,
127.8, 127.3, 125.2, 124.3, 122.8, 117.0, 21.0. FT-IR (KBr): 3669,
3483, 1729, 1573, 1403, 1219, 1024, 1007, 968, 731 cm−1. MS (ESI)
m/z: [M + H]+ 377. HRMS (ESI) m/z: [M + H]+ calcd for
C17H14N2O4ClS, 377.0357; found, 377.0355.
1
yield); mp 132−134 °C. H NMR (400 MHz, CDCl3): δ 8.13 (s,
1H), 7.76 (d, J = 13.7 Hz, 1H), 6.97 (dt, J = 8.2, 5.1 Hz, 2H), 6.91 (d,
J = 1.8 Hz, 1H), 6.64 (d, J = 13.7 Hz, 1H), 4.20 (q, J = 7.1, 4H), 3.96
(s, 3H), 3.90 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 166.3, 162.1, 150.5, 148.7,
147.4, 144.1, 136.6, 123.5, 118.8, 114.8, 113.5, 110.9, 109.3, 60.6,
60.3, 56.0, 55.9, 14.2, 14.1. FT-IR (KBr): 3395, 3129, 3103, 3072,
2985, 2936, 2838, 1712, 1653, 1605, 1563, 1523, 1465, 1438, 1357,
1261, 1168, 1125, 1030, 770 cm−1. MS (ESI) m/z: [M + H]+ 375.
HRMS (ESI) m/z: [M + H]+ calcd for C19H23N2O6 375.1556; found,
375.1550.
(E)-N′-((4-Chloro-2H-chromen-3-yl)methylene)-4-methylbenze-
nesulfonohydrazide (3za). Colorless solid (867 mg, 93% yield); mp
192−194 °C. 1H NMR (400 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.03
(s, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.47 (t, J = 6.9 Hz, 1H), 7.44 (d, J =
8.1 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.94 (t,
J = 15.3 Hz, 1H), 4.95 (s, 2H), 2.38 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 154.5, 143.6, 141.2, 135.6, 131.6, 129.7, 128.7,
127.1, 124.8, 123.5, 122.0, 120.5, 115.9, 64.5, 20.9. FT-IR (KBr):
3626, 3472, 1563, 1459, 1417, 1286, 1124, 1033, 1023, 973, 765
cm−1. MS (ESI) m/z: [M + H]+ 363. HRMS (ESI) m/z: [M + H]+
calcd for C17H16N2O3ClS, 363.0564; found, 363.0557.
General Procedure for Preparation of (E)-Ethyl 1-(3-Ethoxy-
3-oxoprop-1-en-1-yl)-5-phenyl-1H-pyrazole-4-carboxylates
(5a−z). La(OTf)3 (14 mg, 5 mol %) was added to the reaction
mixture of (E)-N′-benzylidene-4-methylbenzenesulfonohydrazide 3a
(100 mg, 0.36 mmol, 1.0 equiv) and ethyl propiolate 4a (72 mg, 0.73
mmol, 2.0 equiv) at room temperature. The contents were heated at
100 °C, and the reaction was monitored by TLC. After completion of
the reaction (TLC, 5 h), the residue was purified by column
chromatography using silica gel (60:120, ethyl acetate/hexane 10:90)
and afforded (E)-ethyl 1-(3-ethoxy-3-oxoprop-1-en-1-yl)-5-phenyl-
1H-pyrazole-4-carboxylate 5a as a colorless solid in 73% yield. The
oxopropenyl-1H-pyrazole-4-carboxylates 5b−z were prepared by
reaction of tosylhydrazones 3b−y with ethyl propiolate 4a under
above optimized reaction conditions. The hydrazone 3a was also
reacted with methyl propiolate 4b and provided compound 5b. The
newly prepared compounds 5a−z were characterized by spectral data.
Compound 5c was dissolved in chloroform and kept for slow
evaporation at room temperature. The crystals were grown after 3
days and analyzed by single-crystal X-ray diffraction.
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-(3,4,5-trimethoxy-
phenyl)-1H-pyrazole-4-carboxylate (5e). Colorless solid (111 mg,
85% yield); mp 185−187 °C. 1H NMR (400 MHz, CDCl3): δ 8.13 (s,
1H), 7.77 (d, J = 13.7 Hz, 1H), 6.65 (d, J = 13.7 Hz, 1H), 6.59 (s,
2H), 4.24−4.18 (m, 4H), 3.95−3.94 (s, 3H), 3.87 (s, 6H), 1.30−1.26
(m, 3H), 1.24−1.20 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
166.3, 162.1, 153.1, 147.2, 144.0, 139.5, 136.5, 121.8, 115.0, 109.5,
107.9, 60.9, 60.7, 60.3, 56.3, 14.2, 14.1. FT-IR (KBr): 2981, 2941,
1714, 1652, 1615, 1589, 1469, 1420, 1293, 1274, 1230, 1205, 1157,
1033 cm−1. MS (ESI) m/z: [M + H]+ 405. HRMS (ESI) m/z: [M +
H]+ calcd for C20H25N2O7 405.1685; found, 405.1656.
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-(2,4,6-trimethoxy-
phenyl)-1H-pyrazole-4-carboxylate (5f). Colorless solid (92 mg,
83% yield); mp 148−150 °C. 1H NMR (400 MHz, CDCl3): δ 8.15 (s,
1H), 7.57 (d, J = 13.7, 1H), 6.59 (d, J = 13.7 Hz, 1H), 6.19 (s, 2H),
4.22−4.13 (m, 4H), 3.88 (s, 3H), 3.70 (s, 6H), 1.28 (dd, J = 9.2, 5.0
Hz, 3H), 1.17 (dd, J = 9.2, 5.0 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 166.7, 163.5, 162.2, 159.3, 144.0, 141.5, 137.3, 115.9,
107.6, 97.1, 90.6, 60.3, 59.7, 55.1, 55.3, 14.1, 14.0. FT-IR (KBr):
2981, 2940, 2845, 1715, 1652, 1616, 1589, 1469, 1421, 1294, 1275,
1230, 1205, 1158, 1033, 772 cm−1. MS (ESI) m/z: [M + H]+ 405.
HRMS (ESI) m/z: [M + H]+ calcd for C20H25N2O7 405.1685; found,
405.1656.
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-(3-phenoxyphenyl)-
1H-pyrazole-4-carboxylate (5g). Colorless solid (83 mg, 75%
1
yield); mp 108−110 °C. H NMR (500 MHz, CDCl3): δ 8.11 (s,
(E)-Ethyl 1-(3-ethoxy-3-oxoprop-1-en-1-yl)-5-phenyl-1H-pyra-
zole-4-carboxylate (5a). Colorless solid (83 mg, 73% yield); mp
124−126 °C. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.93 (d, J
= 13.9 Hz, 1H), 7.82 (dd, J = 2.5, 1.2 Hz, 1H), 7.80 (t, J = 3.0 Hz,
1H), 7.46−7.41 (m, 3H), 6.60 (d, J = 13.9 Hz, 1H), 4.31−4.24 (m,
4H), 1.35−1.28 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ
165.9, 162.1, 155.5, 138.5, 135.8, 131.1, 129.3, 129.1, 127.8, 114.9,
108.6, 60.8, 60.6, 14.2, 14.1. FT-IR (KBr): 3126, 2986, 1730, 1703,
1658, 1539, 1444, 1289, 1208, 1174, 1124, 1111, 1042, 966, 773
cm−1. MS (ESI) m/z: [M + H]+ 315. HRMS (ESI) m/z: [M + H]+
calcd for C17H19N2O4 315.1350; found, 315.1339.
1H), 7.72 (d, J = 13.7 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.36 (dd, J =
8.4, 7.6 Hz, 2H), 7.18−7.12 (m, 2H), 7.11−7.08 (m, 3H), 7.04−7.00
(m, 1H), 6.64 (d, J = 13.7 Hz, 1H), 4.24−4.17 (m, 4H), 1.29 (t, J =
7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz,
CDCl3): δ 166.2, 161.9, 157.5, 156.3, 146.6, 144.0, 136.3, 129.9,
128.4, 124.9, 123.9, 120.4, 120.0, 119.4, 115.2, 109.7, 60.7, 60.4, 14.2,
14.0. FT-IR (KBr): 2982, 2933, 1713, 1651, 1580, 1562, 1490, 1456,
1279, 1228, 1153, 1120, 1038, 757 cm−1. MS (ESI) m/z: [M + H]+
407. HRMS (ESI) m/z: [M + H]+ calcd for C23H23N2O5 407.1602;
found, 407.1601.
(E)-Methyl 1-(3-Methoxy-3-oxoprop-1-en-1-yl)-5-phenyl-1H-pyr-
azole-4-carboxylate (5b). Colorless solid (74 mg, 71% yield); mp
164−166 °C. 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.70 (d, J
= 13.7 Hz, 1H), 7.5−7.49 (m, 3H), 7.41−7.38 (m, 2H), 6.66 (d, J =
13.7 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 166.6, 162.5, 147.6, 144.0, 136.5, 130.4, 130.3, 128.6,
126.6, 114.8, 109.2, 51.8, 51.4. FT-IR (KBr): 2982, 2930, 1742, 1626,
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-p-tolyl-1H-pyrazole-4-
carboxylate (5h). Colorless solid (86 mg, 76% yield); mp 126−128
1
°C. H NMR (400 MHz, CDCl3): δ 8.20 (s, 1H), 7.92 (d, J = 13.8
Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 6.56 (d, J
= 13.8 Hz), 4.27 (qd, J = 7.1, 3.4 Hz, 4H), 2.40 (s, 3H), 1.32 (dt, J =
8.9, 7.1 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 165.9, 162.1,
155.5, 139.1, 138.5, 135.8, 129.1, 128.6, 128.2, 114.8, 108.4, 60.7,
2276
https://dx.doi.org/10.1021/acs.joc.0c02421
J. Org. Chem. 2021, 86, 2271−2282

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
60.5, 21.3, 14.2. FT-IR (KBr): 2983, 2926, 1734, 1620, 1595, 1562,
1511, 1465, 1450, 1367, 1325, 1217, 1189, 1110, 1035, 753 cm−1. MS
(ESI) m/z: [M + H]+ 329. HRMS (ESI) m/z: [M + H]+ calcd for
C18H21N2O4 329.1511; found, 329.1495.
J = 13.9 Hz, 1H), 4.28 (qd, J = 7.1, 4.3 Hz, 4H), 1.32 (q, J = 7.1 Hz,
6H). 13C{1H} NMR (101 MHz, CDCl3): δ 165.9, 162.0, 154.4, 138.3,
135.9, 131.1, 130.9, 130.1, 123.7, 114.9, 109.1, 60.9, 60.8, 14.2. FT-IR
(KBr): 2982, 2931, 1716, 1655, 1567, 1445, 1386, 1365, 1285, 1254,
1208, 1156, 1135, 1027, 769 cm−1. MS (ESI) m/z: [M + H]+ 393.
HRMS (ESI) m/z: [M + H]+ calcd for C17H18N2O4Br 393.0470;
found, 393.0444.
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-(4-isopropylphenyl)-
1H-pyrazole-4-carboxylate (5i). Colorless solid (88 mg, 78%
1
yield); mp 120−122 °C. H NMR (500 MHz, CDCl3): δ 8.20 (s,
1H), 7.92 (d, J = 13.8 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.29 (d, J =
8.2 Hz, 2H), 6.56 (d, J = 13.8 Hz, 1H), 4.32−4.23 (m, 4H), 2.95
(hept, J = 6.9 Hz, 1H), 1.32 (dt, J = 10.7, 7.1 Hz, 6H), 1.28 (d, J = 6.9
Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 166.1, 162.2, 155.7,
150.1, 138.5, 135.7, 129.3, 128.6, 126.1, 114.9, 108.6, 60.8, 60.6, 34.0,
23.9, 14.3, 14.2. FT-IR (KBr): 3192, 2964, 1721, 1653, 1538, 1450,
1301, 1281, 1264, 1172, 1038, 777 cm−1. MS (ESI) m/z: [M + H]+
357. HRMS (ESI) m/z: [M + H]+ calcd for C20H25N2O4 357.1828;
found, 357.1808.
(E)-Ethyl 5-(4-Cyanophenyl)-1-(3-ethoxy-3-oxoprop-1-enyl)-1H-
pyrazole-4-carboxylate (5j). Colorless solid (75 mg, 66% yield);
mp 180−182 °C. 1H NMR (500 MHz, CDCl3): δ 8.25 (s, 1H), 8.01
(d, J = 8.5 Hz, 2H), 7.93 (d, J = 13.9 Hz, 1H), 7.73 (d, J = 8.4 Hz,
2H), 6.59 (d, J = 13.9 Hz, 1H), 4.34−4.25 (m, 4H), 1.33 (q, J = 7.2
Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 165.7, 161.8, 153.5,
138.1, 135.7, 136.0, 131.7, 130.0, 118.7, 115.2, 112.7, 109.7, 61.0,
60.9, 14.3, 14.2. FT-IR (KBr): 3139, 2984, 2919, 2227, 1713, 1655,
1537, 1462, 1287, 1268, 1176, 1132, 1037, 850, 773 cm−1. MS (ESI)
m/z: [M + H]+ 340. HRMS (ESI) m/z: [M + H]+ calcd for
C18H18N3O4 340.1297; found, 340.1304.
(E)-Ethyl 5-(2-Bromophenyl)-1-(3-ethoxy-3-oxoprop-1-enyl)-1H-
pyrazole-4-carboxylate (5o). Colorless solid (76 mg, 68% yield); mp
118−120 °C. 1H NMR (500 MHz, CDCl3): δ 8.16 (s, 1H), 7.73 (d, J
= 13.6 Hz, 1H), 7.49−7.44 (m, 2H), 7.41 (td, J = 7.7, 1.8 Hz, 1H),
7.32 (dd, J = 7.4, 1.8 Hz, 1H), 6.65 (d, J = 13.6 Hz, 1H), 4.22−4.17
(m, 2H), 4.16−4.10 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 166.1, 161.7, 145.7,
143.7, 135.9, 132.9, 132.0, 131.7, 128.8, 127.4, 124.2, 116.1, 109.9,
60.6, 60.3, 14.1, 13.8. FT-IR (KBr): 2982, 2927, 2854, 1714, 1652,
1566, 1444, 1284, 1253, 1207, 1154, 1119, 1061, 1025, 769 cm−1. MS
(ESI) m/z: [M + H]+ 393. HRMS (ESI) m/z: [M + H]+ calcd for
C17H18N2O4Br 393.0465; found, 393.0444.
Ethyl 1-((E)-3-Ethoxy-3-oxoprop-1-enyl)-5-styryl-1H-pyrazole-4-
carboxylate (5p). Colorless solid (92 mg, 81% yield); mp 156−158
1
°C. H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.89 (d, J = 13.8
Hz, 1H), 7.63 (t, J = 7.3 Hz, 2H), 7.61−7.56 (m, 2H), 7.38 (dd, J =
10.1, 4.6 Hz, 2H), 7.33−7.28 (m, 1H), 6.59 (d, J = 13.8 Hz,), 4.35 (q,
J = 7.1 Hz), 4.28 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.34 (t,
J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 166.0, 162.4,
152.9, 138.4, 136.6, 134.9, 134.1, 128.7, 128.5, 127.2, 117.0, 115.1,
108.7, 60.8, 60.6, 14.3, 14.2. FT-IR (KBr): 3130, 2979, 1702, 1651,
1546, 1484, 1427, 1310, 1297, 1280, 1221, 1162, 1120, 1104, 778
cm−1. MS (ESI) m/z: [M + H]+ 341. HRMS (ESI) m/z: [M + H]+
calcd for C19H21N2O4 341.1501; found, 341.1495.
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-(4-(trifluoromethyl)-
phenyl)-1H-pyrazole-4-carboxylate (5k).14 Colorless solid (76 mg,
1
68% yield); mp 96−98 °C. H NMR (500 MHz, CDCl3): δ 8.16 (s,
1H), 7.79 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 13.6 Hz, 1H), 7.55 (d, J =
8.0 Hz, 2H), 6.69 (d, J = 13.6 Hz, 1H), 4.23−4.17 (m, 4H), 1.28 (t, J
= 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz,
CDCl3): (ppm) 166.1, 161.8, 145.7, 144.0, 135.8, 132.3 (C−F, 2JC−F
= 33.0 Hz), 131.1, 130.6, 125.5, 123.6 (C−F, 1JC−F = 272.4 Hz),
115.7, 110.4, 60.8, 60.6, 14.2, 14.0. 19F NMR (377 MHz, CDCl3): δ
−62.99. FT-IR (KBr): 3105, 3066, 2983, 1706, 1651, 1623, 1565,
1518, 1465, 1417, 1333, 1273, 1245, 1131, 1070, 1029, 847 cm−1. MS
(ESI) m/z: [M + H]+ 387. HRMS (ESI) m/z: [M + H]+ calcd for
C18H20N2O4F3 387.1227; found, 387.1213.
(E)-Ethyl 5-cyclohexenyl-1-(3-ethoxy-3-oxoprop-1-enyl)-1H-pyr-
azole-4-carboxylate (5q). Colorless solid (88 mg, 77% yield); mp
122−124 °C. 1H NMR (500 MHz, CDCl3): δ 8.09 (s, 1H), 7.85 (d, J
= 13.9 Hz, 1H), 6.47 (d, J = 13.9 Hz, 1H), 6.38 (dt, J = 5.7, 1.8 Hz,
1H), 4.27 (dq, J = 14.3, 7.1 Hz, 4H), 2.47−2.40 (m, 2H), 2.23 (dt, J =
6.1, 3.7 Hz, 2H), 1.81−1.74 (m, 2H), 1.73−1.66 (m, 2H), 1.33 (dt, J
= 13.8, 7.1 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 166.1,
162.3, 157.6, 138.5, 135.4, 131.4, 129.6, 114.8, 108.0, 60.7, 60.5, 27.4,
25.6, 22.5, 21.8, 14.3, 14.2. FT-IR (KBr): 3395, 3126, 3072, 2925,
2858, 1714, 1648, 1529, 1450, 1337, 1267, 1162, 1114, 1026, 776
cm−1. MS (ESI) m/z: [M + H]+ 319. HRMS (ESI) m/z: [M + H]+
calcd for C17H23N2O4 319.1666; found, 319.1652.
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-(naphthalen-1-yl)-1H-
pyrazole-4-carboxylate (5r). Colorless solid (93 mg, 83% yield); mp
140−142 °C. 1H NMR (500 MHz, CDCl3): δ 8.28 (s, 1H), 8.01 (t, J
= 14.3 Hz, 1H), 7.99−7.89 (m, 1H), 7.58 (dt, J = 17.1, 8.5 Hz, 1H),
7.56−7.50 (m, 1H), 7.48−7.41 (m, 3H), 7.34 (d, J = 8.4 Hz, 1H),
6.66 (d, J = 13.7 Hz, 1H), 4.16−4.08 (m, 2H), 4.03−3.91 (m, 2H),
1.20 (t, J = 7.1 Hz, 3H), 0.82 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126
MHz, CDCl3): δ 166.1, 161.9, 145.7, 144.1, 136.3, 133.4, 132.1,
130.7, 128.9, 128.5, 127.2, 126.5, 124.9, 124.8, 124.6, 116.9, 109.6,
60.5, 60.1, 14.1, 13.5. FT-IR (KBr): 2983, 2824, 1720, 1652, 1583,
1559, 1463, 1385, 1279, 1256, 1240, 1216, 1154, 1140, 1085, 951,
775 cm−1. MS (ESI) m/z: [M + H]+ 365. HRMS (ESI) m/z: [M +
H]+ calcd for C21H21N2O4 365.1520; found, 365.1495.
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-(3-fluorophenyl)-1H-
pyrazole-4-carboxylate (5l).14 Colorless solid (80 mg, 70% yield);
mp 140−142 °C. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.92
(d, J = 13.9 Hz, 1H), 7.65 (ddd, J = 9.8, 5.4, 4.3 Hz, 1H), 7.59 (ddd, J
= 10.1, 2.5, 1.6 Hz, 1H), 7.40 (td, J = 8.0, 5.9 Hz, 1H), 7.13 (tdd, J =
8.4, 2.6, 0.9 Hz, 1H), 6.57 (d, J = 13.9 Hz, 1H), 4.36−4.22 (m, 4H),
1.37−1.28 (m, 6H). 13C NMR (101 MHz, CDCl3): (ppm) 165.8,
162.3 (C−F, 1JC−F = 244.3 Hz), 161.9, 154.1, 138.3, 135.9, 133.2
(C−F, 4JC−F = 8.2 Hz), 129.4 (C−F, 4JC−F = 8.2 Hz), 125.1 (C−F,
5JC−F = 1.8 Hz), 116.6 (C−F, 2JC−F = 23.6 Hz), 116.1 (C−F, 3JC−F
=
20.9 Hz), 115.1, 109.1, 60.9, 60.8, 14.2, 14.1. 19F NMR (377 MHz,
CDCl3): δ −113.54. FT-IR (KBr): 2983, 2925, 2855, 1714, 1660,
1555, 1538, 1462, 1289, 1220, 1207, 1177, 1149, 1122, 1042, 774
cm−1. MS (ESI) m/z: [M + H]+ 333. HRMS (ESI) m/z: [M + H]+
calcd for C17H18N2O4F 333.1261; found, 333.1245.
(E)-Ethyl 5-(4-Chlorophenyl)-1-(3-ethoxy-3-oxoprop-1-enyl)-1H-
pyrazole-4-carboxylate (5m). Colorless solid (80 mg, 71% yield);
mp 120−122 °C. 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.65
(d, J = 13.6 Hz, 1H), 7.54−7.48 (m, 2H), 7.37−7.31 (m, 2H), 6.66
(d, J = 13.6 Hz, 1H), 4.23−4.17 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H),
1.21 (t, J = 7.1 Hz). 13C{1H} NMR (101 MHz, CDCl3): δ 166.2,
161.9, 146.2, 144.1, 136.7, 136.0, 131.9, 128.9, 125.3, 115.3, 110.0,
60.8, 60.5, 14.2, 14.1. FT-IR (KBr): 2981, 2884, 1720, 1656, 1451,
1281, 1266, 1241, 1207, 1158, 1128, 1094, 1034, 775 cm−1. MS (ESI)
m/z: [M + H]+ 349. HRMS (ESI) m/z: [M + H]+ calcd for
C17H18N2O2Cl 349.0967; found, 349.0949.
(E)-Ethyl 5-(Benzo[d][1,3]dioxol-5-yl)-1-(3-ethoxy-3-oxoprop-1-
enyl)-1H-pyrazole-4-carboxylate (5s). Colorless solid (83 mg, 74%
1
yield); mp 126−128 °C. H NMR (500 MHz, CDCl3): δ 8.11 (s,
1H,), 7.73 (d, J = 13.7 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.89−6.80
(m, 2H), 6.64 (d, J = 13.7 Hz, 1H), 6.07 (s, 2H), 4.21 (qd, J = 7.1, 3.2
Hz, 4H), 1.28 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (126 MHz, CDCl3): δ 166.3, 162.1, 149.3, 147.8, 147.2, 144.0,
136.4, 124.8, 119.9, 115.0, 110.8, 109.5, 108.5, 101.7, 60.7, 60.3, 14.2,
14.1. FT-IR (KBr): 2924, 2853, 1711, 1650, 1567, 1504, 1461, 1278,
1231, 1203, 1151, 1118, 1098, 1031, 779 cm−1. MS (ESI) m/z: [M +
H]+ 359. HRMS (ESI) m/z: [M + H]+ calcd for C18H19N2O6
359.1260; found, 359.1237.
(E)-Ethyl 5-(4-Bromophenyl)-1-(3-ethoxy-3-oxoprop-1-enyl)-1H-
pyrazole-4-carboxylate (5n). Colorless solid (78 mg, 70% yield); mp
128−130 °C. 1H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H,), 7.91 (d, J
= 13.9 Hz, 1H), 7.79−7.70 (m, 2H), 7.56 (d, J = 8.5 Hz, 2H), 6.57 (d,
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-(furan-2-yl)-1H-pyra-
zole-4-carboxylate (5t). Colorless solid (91 mg, 79% yield); mp
2277
https://dx.doi.org/10.1021/acs.joc.0c02421
J. Org. Chem. 2021, 86, 2271−2282

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Article
166−168 °C. 1H NMR (500 MHz, CDCl3): δ 8.20 (s, 1H), 7.94 (d, J
= 13.9 Hz, 1H), 7.59 (d, J = 3.3 Hz, 1H), 7.57 (s, 1H), 6.58 (d, J =
13.9 Hz, 1H), 6.54 (dd, J = 3.2, 1.6 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H),
4.27 (q, J = 7.1 Hz, 2H), 1.37 (q, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (126 MHz, CDCl3): δ 165.8, 161.6, 145.8, 145.4,
143.5, 138.3, 135.5, 114.4, 113.9, 111.6, 109.1, 60.8, 60.8, 14.3, 14.2.
FT-IR (KBr): 3125, 2992, 1725, 1707, 1660, 1541, 1447, 1305, 1283,
1221, 1184, 1159, 1136, 1046, 1009, 774 cm−1. MS (ESI) m/z: [M +
H]+ 305. HRMS (ESI) m/z: [M + H]+ calcd for C15H17N2O5
305.1140; found, 305.1132.
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-(thiophen-2-yl)-1H-
pyrazole-4-carboxylate (5u). Colorless solid (88 mg, 77% yield);
mp 140−142 °C. 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 8.16
(d, J = 3.8 Hz, 1H), 7.87 (d, J = 13.8 Hz, 1H), 7.39 (d, J = 4.9 Hz,
1H), 7.16−7.07 (m, 1H), 6.57 (d, J = 13.8 Hz, 1H), 4.35 (q, J = 7.1
Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.35 (dt, J = 14.5, 7.1 Hz, 6H).
13C{1H} NMR (101 MHz, CDCl3): δ 165.9, 161.9, 149.5, 138.1,
[M + H]+ 430. HRMS (ESI) m/z: [M + H]+ calcd for C21H21N3O5Cl
430.1195; found, 430.1164.
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-(4-oxo-4H-chromen-
3-yl)-1H-pyrazole-4-carboxylate (5z). Colorless solid (64 mg, 57%
yield); mp 118−120 °C. 1H NMR (500 MHz, CDCl3): δ 8.29 (dd, J
= 8.0, 1.4 Hz, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.93 (d, J = 13.9 Hz,
1H), 7.73−7.69 (m, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.44 (t, J = 7.5 Hz,
1H), 6.52 (d, J = 13.9 Hz, 1H), 4.29−4.25 (m, 2H), 4.22 (q, J = 6.7
Hz, 2H), 1.33 (t, J = 6.7 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (126 MHz, CDCl3): δ 174.5, 166.3, 162.0, 157.8, 156.3, 144.1,
138.4, 136.5, 134.5, 126.4, 124.2, 124.0, 118.3, 116.3, 112.8, 109.7,
60.7, 60.6, 14.2, 14.1. FT-IR (KBr): 2986, 1717, 1657, 1613, 1559,
1552, 1465, 1368, 1289, 1246, 1191, 1050, 771 cm−1. MS (ESI) m/z:
[M + H]+ 383. HRMS (ESI) m/z: [M + H]+ calcd for C20H19N2O6
383.1262; found, 383.1237.
Typical Procedure for Preparation of (E)-N′-(2-Hydroxyben-
zylidene)-4-methylbenzenesulfonohydrazides (6a−h). Tosyl-
hydrazine 2 (762 mg, 4.10 mmol, 1.0 equiv) was added to a stirred
solution of salicylaldehyde 1zc (500 mg, 4.10 mmol, 1.0 equiv) in
acetonitrile (5 mL) at room temperature. The contents were stirred at
the same temperature for 2 h. The reaction was monitored by TLC,
after completion of the reaction; the solvent was removed under
reduced pressure. The residue was purified by recrystallization with
hexane and afforded (E)-N′-benzylidene-4-methylbenzenesulfonohy-
drazide 6a as a colorless solid in 95% yield. The substituted
tosylhydrazones 6b−g were prepared by reaction of substituted
salicylaldehyde 1zd-zj with tosylhydrazine 2. The prepared tosylhy-
drazones 6b−g are known compounds and were compared with the
literature data.12
General Procedure for the Preparation of (E)-Ethyl 3-(4-
oxochromeno[4,3-c]pyrazol-1(4H)-yl)acrylate (7a). La(OTf)3
(10 mg, 5 mol %) was added to the reaction mixture of ((E)-N′-
(2-hydroxybenzylidene)-4-methylbenzenesulfonohydrazide 6a (100
mg, 0.34 mmol, 1.0 equiv) and ethyl propiolate 4a (68 mg, 0.69
mmol, 2.0 equiv) at room temperature, and the contents were heated
at 100 °C. The reaction was monitored by TLC, and after completion
of the reaction (10 h), the residue was purified by column
chromatography using silica gel (60:120, ethyl acetate/hexane
5:95), affording (E)-ethyl 3-(4-oxochromeno[4,3-c]pyrazol-1(4H)-
yl)acrylate 7a as colorless solid in 32% yield. The chromenopyrazolyl
acrylates 7c and 7e were prepared by reaction of hydrazones 6d and
6g with ethyl propiolate 4a under the above optimized reaction
conditions. The newly prepared compounds 7a, 7c, and 7e were
characterized by spectral data.
(E)-Ethyl 3-(4-Oxochromeno[4,3-c]pyrazol-1(4H)-yl)acrylate
(7a). Colorless solid (31 mg, 32% yield); mp 176−178 °C. 1H
NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.10 (t, J = 11.7 Hz, 1H),
8.04 (d, J = 13.8 Hz, 1H), 7.54 (dd, J = 11.4, 4.2 Hz, 1H), 7.37 (dd, J
= 15.7, 7.9 Hz, 2H), 6.79 (d, J = 13.8 Hz, 1H), 4.32 (q, J = 7.1 Hz,
2H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
165.4, 157.0, 153.3, 150.9, 138.2, 133.3, 131.5, 124.9, 123.3, 117.7,
113.8, 111.6, 110.3, 61.2, 14.2. FT-IR (KBr): 2954, 2358, 1720, 1705,
1662, 1565, 1453, 1405, 1297, 1280, 1241, 1217, 1162, 953, 776
cm−1. MS (ESI) m/z: [M + H]+ 285. HRMS (ESI) m/z: [M + H]+
calcd for C15H13N2O4 285.0875; found, 285.0875.
136.1, 133.0, 130.2, 127.5, 114.1, 109.0, 60.9, 60.8, 14.3, 14.2. FT-IR
(KBr): 3133, 2978, 1715, 1650, 1564, 1528, 1299, 1273, 1180, 1156,
1113, 772 cm−1. MS (ESI) m/z: [M + H]+ 321. HRMS (ESI) m/z:
[M + H]+ calcd for C15H17N2O6S 321.0915; found, 321.0903.
(E)-Ethyl 5-(5-Bromothiophen-2-yl)-1-(3-ethoxy-3-oxoprop-1-
enyl)-1H-pyrazole-4-carboxylate (5v). Colorless solid (77 mg, 69%
1
yield); mp 176−178 °C. H NMR (400 MHz, CDCl3): δ 8.15 (s,
1H), 7.95 (d, J = 4.0 Hz, 1H), 7.85 (d, J = 13.8 Hz, 1H), 7.05 (d, J =
4.0 Hz, 1H), 6.55 (d, J = 13.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.28
(q, J = 7.1 Hz, 2H), 1.36 (dt, J = 14.1, 7.1 Hz, 6H). 13C{1H} NMR
(101 MHz, CDCl3): δ 165.8, 161.9, 148.6, 137.9, 136.1, 134.7, 130.5,
130.2, 115.1, 113.9, 109.3, 60.9, 14.3, 14.2. FT-IR (KBr): 2925, 2853,
1721, 1707, 1648, 1532, 1470, 1296, 1267, 1225, 1174, 1111, 1063,
1021, 974, 774 cm−1. MS (ESI) m/z: [M + H]+ 399. HRMS (ESI) m/
z: [M + H]+ calcd for C15H16N2O4BrS 399.0010; found, 399.0008.
(E)-Ethyl 2-(3-Ethoxy-3-oxoprop-1-enyl)-1′-phenyl-3′-p-tolyl-
1′H,2H-3,4′-bipyrazole-4-carboxylate (5w). Colorless solid (58 mg,
51% yield); mp 142−144 °C. 1H NMR (400 MHz, CDCl3): δ 8.40 (s,
1H), 8.18 (s, 1H), 7.87 (d, J = 13.8 Hz, 1H), 7.85−7.78 (m, 2H),
7.53 (d, J = 8.1 Hz, 2H), 7.47 (t, J = 8.0 Hz, 2H), 7.31 (t, J = 7.4 Hz,
1H), 7.14 (d, J = 7.9 Hz, 2H), 6.42 (d, J = 13.8 Hz, 1H), 4.27 (q, J =
7.1 Hz, 2H), 4.02 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 1.33 (t, J = 7.1
Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 165.9, 161.9, 152.1, 148.3, 139.9, 138.4, 137.6, 135.0,
130.5, 129.4, 129.2, 128.7, 127.8, 126.5, 119.2, 116.3, 112.1, 108.7,
60.8, 60.6, 21.2, 14.2, 13.9. FT-IR (KBr): 2981, 2933, 1712, 1651,
1598, 1550, 1507, 1298, 1261, 1222, 1173, 1078, 1057, 963, 757
cm−1. MS (ESI) m/z: [M + H]+ 471. HRMS (ESI) m/z: [M + H]+
calcd for C27H27N2O4 471.2064; found, 471.2026.
(E)-Ethyl 1-(3-Ethoxy-3-oxoprop-1-enyl)-5-(1H-indol-3-yl)-1H-
pyrazole-4-carboxylate (5x). Colorless solid (88 mg, 78% yield);
mp 172−174 °C. 1H NMR (400 MHz, CDCl3): δ 9.09 (s, 1H), 8.22
(s, 1H), 7.98−7.86 (m, 1H), 7.32 (dd, J = 10.2, 4.0 Hz, 2H), 7.28
(dd, J = 6.1, 1.7 Hz, 1H), 7.23−7.13 (m, 2H), 6.72−6.64 (m, 1H),
4.19 (qd, J = 7.1, 3.7 Hz, 4H), 1.28−1.21 (m, 3H), 1.19−1.13 (m,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 166.1, 161.9, 144.1, 142.0,
136.7, 135.1, 126.6, 125.7, 122.2, 120.3, 118.7, 114.2, 111.1, 107.8,
100.6, 60.0, 59.7, 13.8, 13.4. FT-IR (KBr): 3347, 3272, 2982, 1709,
1649, 1580, 1524, 1435, 1423, 1291, 1264, 1222, 1159, 1088, 1026,
771 cm−1. MS (ESI) m/z: [M + H]+ 354. HRMS (ESI) m/z: [M +
H]+ calcd for C19H20N3O4 354.1472; found, 354.1448.
(E)-Ethyl 3-(8-Methyl-4-oxochromeno[4,3-c]pyrazol-1(4H)-yl)-
acrylate (7c). Colorless solid (33 mg, 35% yield); mp 145−147 °C.
1H NMR (500 MHz, CDCl3): δ 9.76 (s, 1H), 7.85 (s, 1H), 7.37 (d, J
= 10.9 Hz, 1H), 7.31 (dd, J = 8.5, 1.7 Hz, 1H), 7.27 (d, J = 3.5 Hz,
1H), 5.77 (d, J = 10.9 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H),
1.34 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 164.1,
157.4, 151.4, 149.7, 136.3, 136.2, 134.5, 132.2, 122.9, 117.4, 113.4,
109.9, 108.7, 61.3, 20.8, 14.1. FT-IR (KBr): 3021, 1754, 1652, 1481,
1425, 1215, 1140, 1024, 761 cm−1. MS (ESI) m/z: [M + H]+ 299.
HRMS (ESI) m/z: [M + H]+ calcd for C16H15N2O4 299.1041; found,
299.1026.
(E)-Ethyl 5-(2-Chloro-6-methoxyquinolin-3-yl)-1-(3-ethoxy-3-ox-
oprop-1-enyl)-1H-pyrazole-4-carboxylate (5y). Colorless solid (70
1
mg, 64% yield); mp 170−173 °C. H NMR (400 MHz, CDCl3): δ
8.22 (s, 1H), 8.09 (d, J = 7.0 Hz, 1H), 8.02 (d, J = 13.6 Hz, 1H), 7.51
(ddd, J = 5.2, 4.7, 1.8 Hz, 2H), 7.12 (d, J = 2.7 Hz, 1H), 6.71 (d, J =
13.6 Hz, 1H), 4.22−4.12 (m, 4H), 3.95 (s, 3H), 1.25 (t, J = 6.9 Hz,
3H), 1.08 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
165.9, 161.6, 158.8, 146.2, 144.3, 143.8, 142.5, 139.9, 135.5, 130.0,
127.1, 124.9, 120.9, 117.0, 110.4, 105.3, 60.7, 60.6, 55.7, 14.2, 13.9.
FT-IR (KBr): 2981, 2932, 2824, 1717, 1655, 1562, 1497, 1348, 1293,
1272, 1254, 1229, 1203, 1159, 1083, 1027, 836 cm−1. MS (ESI) m/z:
(E)-Ethyl 3-(8-Bromo-4-oxochromeno[4,3-c]pyrazol-1(4H)-yl)-
acrylate (7e). Colorless solid (21 mg, 21% yield); mp 244−246 °C.
1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H), 8.25 (s, 1H), 8.03 (d, J
= 13.7 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H),
2278
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Article
6.80 (d, J = 13.7 Hz, 1H), 4.32 (dd, J = 13.9, 6.8 Hz, 2H), 1.37 (t, J =
7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 165.3, 156.4,
152.2, 149.8, 138.0, 134.3, 133.4, 126.0, 119.5, 117.7, 115.5, 112.2,
110.1, 61.3, 14.2. FT-IR (KBr): 3660, 3296, 2984, 1765, 1720, 1654,
1596, 1467, 1263, 1219, 1181, 771 cm−1. MS (ESI) m/z: [M + H]+
363. HRMS (ESI) m/z: [M + H]+ calcd for C15H12N2O4Br 362.9980;
found, 362.9981.
General Procedure for the Preparation of Ethyl 3-
Ethoxychromeno[4,3-c]pyrazole-4-carboxylates (8a−m). La-
(OTf)3 (10 mg, 5 mol %) was added to the reaction mixture of
((E)-N′-(2-hydroxybenzylidene)-4-methylbenzenesulfonohydrazide
6a (100 mg, 0.34 mmol, 1.0 equiv) and diethyl but-2-ynedioate 4d
(59 mg, 0.34 mmol, 1.0 equiv) at room temperature, and the contents
were heated at 100 °C. The reaction was monitored by TLC, and
after completion of the reaction (10 h), the residue was purified by
column chromatography using silica gel (60:120, ethyl acetate/hexane
10:90), affording ethyl 3-ethoxychromeno[4,3-c]pyrazole-4-carboxy-
late 8a as a colorless solid in 69% yield. The chromenopyrazole-4-
carboxylates 8b−m were prepared by reaction of hydrazones 6b−g
with activated alkynes 4d−e under the above optimized reaction
conditions. The newly prepared compounds 8a−m were characterized
by spectral data.
13.9. FT-IR (KBr): 2955, 2834, 1749, 1650, 1604, 1556, 1521, 1454,
1397, 1339, 1315, 1269, 1223, 1159, 1117, 1092, 1034, 825, 760
cm−1. MS (ESI) m/z: [M + H]+ 317. HRMS (ESI) m/z: [M + H]+
calcd for C16H17N2O5 317.1146; found, 317.1132.
Ethyl 3-Ethoxy-8-methylchromeno[4,3-c]pyrazole-4-carboxylate
1
(8f). Colorless solid (71 mg, 72% yield); mp 142−144 °C. H NMR
(400 MHz, CDCl3): δ 7.88 (d, J = 0.8 Hz, 1H), 7.29−7.22 (m, 2H),
4.64 (q, J = 7.2 Hz, 2H), 4.57−4.50 (m, 2H), 2.43 (s, 3H), 1.58 (t, J =
7.2 Hz, 3H), 1.52−1.47 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3):
δ 159.0, 155.8, 150.9, 148.4, 134.2, 134.1, 131.4, 122.4, 116.9, 113.7,
107.3, 62.8, 48.3, 20.8, 15.8, 13.9. FT-IR (KBr): 2960, 2923, 2851,
1735, 1597, 1562, 1523, 1501, 1461, 1445, 1399, 1367, 1273, 1223,
1187, 1091, 1018, 914, 761 cm−1. MS (ESI) m/z: [M + H]+ 301.
HRMS (ESI) m/z: [M + H]+ calcd for C16H17N2O4 [M + H]+
301.1191; found, 301.1182.
Methyl 3-Methoxy-8-methylchromeno[4,3-c]pyrazole-4-carbox-
1
ylate (8g). Colorless solid (62 mg, 70% yield); mp 196−198 °C. H
NMR (400 MHz, CDCl3): δ 7.86−7.82 (m, 1H), 7.30−7.23 (m, 2H),
4.29 (s, 3H), 4.08 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 159.4, 155.6, 150.7, 148.3, 134.1, 134.0, 131.4, 122.3,
116.8, 113.4, 107.3, 53.1, 40.5, 20.8. FT-IR (KBr): 2960, 2924, 2863,
1751, 1723, 1684, 1623, 1594, 1557, 1521, 1497, 1457, 1434, 1307,
1271, 1237, 1199, 1095, 1013, 926, 760 cm−1. MS (ESI) m/z: [M +
H]+ 273. HRMS (ESI) m/z: [M + H]+ calcd for C14H13N2O4
273.0877; found, 273.0869.
Ethyl 3-Ethoxychromeno[4,3-c]pyrazole-4-carboxylate (8a). Col-
1
orless solid (68 mg, 69% yield); mp 100−102 °C. H NMR (400
MHz, CDCl3): δ 8.09 (dd, J = 7.8, 1.5 Hz, 1H), 7.48 (ddd, J = 8.7,
7.3, 1.6 Hz, 1H), 7.33 (ddd, J = 15.0, 8.4, 4.3 Hz, 2H), 4.65 (q, J = 7.2
Hz, 2H), 4.54 (q, J = 7.1 Hz, 2H), 1.58 (t, J = 7.2 Hz, 3H), 1.50 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 158.9, 155.7,
152.7, 148.3, 134.2, 130.5, 124.3, 122.5, 117.2, 114.2, 107.2, 62.8,
48.3, 15.8, 13.9. FT-IR (KBr): 2984, 2940, 2873, 1752, 1620, 1592,
1557, 1516, 1455, 1402, 1367, 1304, 1271, 1229, 1157, 1103, 1047,
1031, 968, 750 cm−1. MS (ESI) m/z: [M + H]+ 287. HRMS (ESI) m/
z: [M + H]+ calcd for C15H15N2O4 287.1040; found, 287.1026.
Methyl 3-Methoxychromeno[4,3-c]pyrazole-4-carboxylate (8b).
Ethyl 3-Ethoxy-6-methylchromeno[4,3-c]pyrazole-4-carboxylate
1
(8h). Colorless solid (63 mg, 64% yield); mp 93−95 °C. H NMR
(400 MHz, CDCl3): δ 7.93 (dd, J = 7.7, 0.9 Hz, 1H), 7.33 (dd, J =
7.4, 0.7 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 4.65 (q, J = 7.2 Hz, 2H),
4.53 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.58 (s, 3H), 1.50 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 159.1, 155.7, 151.2,
148.8, 134.0, 131.8, 126.6, 123.9, 120.2, 113.9, 107.2, 62.7, 48.3, 16.1,
15.8, 13.9. FT-IR (KBr): 2984, 2924, 2854, 1754, 1618, 1558, 1523,
1457, 1423, 1393, 1368, 1307, 1248, 1227, 1190, 1149, 1125, 1038,
974, 745 cm−1. MS (ESI) m/z: [M + H]+ 301. HRMS (ESI) m/z: [M
+ H]+ calcd for C16H17N2O4 301.1191; found, 301.1182.
1
Colorless solid (59 mg, 66% yield); mp 168−170 °C. H NMR (400
MHz, CDCl3): δ 8.05 (d, J = 7.7 Hz, 1H), 7.52−7.44 (m, 1H), 7.39−
7.28 (m, 2H), 4.30 (s, 3H), 4.08 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 159.4, 155.5, 152.7, 148.3, 134.1, 130.6, 124.4, 122.5,
117.2, 113.9, 107.4, 53.2, 40.6. FT-IR (KBr): 2956, 2923, 2854, 1755,
1718, 1620, 1556, 1510, 1455, 1316, 1307, 1272, 1232, 1154, 1098,
1031, 972, 757 cm−1. MS (ESI) m/z: [M + H]+ 259. HRMS (ESI) m/
z: [M + H]+ calcd for C13H11N2O4 259.0727; found, 259.0713.
Ethyl 3-Ethoxy-8-methoxychromeno[4,3-c]pyrazole-4-carboxy-
Methyl 3-Methoxy-6-methylchromeno[4,3-c]pyrazole-4-carbox-
1
ylate (8i). Colorless solid (57 mg, 64% yield); mp 154−156 °C. H
NMR (400 MHz, CDCl3): δ 7.91 (dd, J = 7.8, 0.9 Hz, 1H), 7.33 (dd,
J = 7.4, 0.7 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 4.30 (s, 3H), 4.08 (s,
3H), 2.48 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 159.5,
155.5, 151.1, 148.7, 134.0, 131.9, 126.6, 123.9, 120.0, 113.6, 107.4,
53.1, 40.6, 16.1. FT-IR (KBr): 2970, 2921, 2846, 1756, 1615, 1559,
1524, 1483, 1450, 1379, 1320, 1283, 1254, 1192, 1113, 1077, 1040,
946, 771 cm−1. MS (ESI) m/z: [M + H]+ 273. HRMS (ESI) m/z: [M
+ H]+ calcd for C14H13N2O4 273.0883; found, 273.0869.
1
late (8c). Colorless solid (70 mg, 71% yield); mp 116−118 °C. H
NMR (400 MHz, CDCl3): δ 7.52 (d, J = 2.9 Hz, 1H), 7.30 (d, J = 9.1
Hz, 1H), 7.05 (dd, J = 9.1, 3.0 Hz, 1H), 4.65 (q, J = 7.2 Hz, 2H), 4.54
(q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 1.58 (t, J = 7.0 Hz, 3H), 1.49 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 159.0, 156.2,
155.9, 134.3, 118.6, 118.4, 114.5, 107.4, 104.6, 62.8, 55.9, 48.3, 15.9,
13.9. FT-IR (KBr): 2994, 2943, 2837, 1747, 1603, 1556, 1521, 1485,
1462, 1432, 1391, 1367, 1302, 1232, 1216, 1156, 1092, 1052, 998,
770 cm−1. MS (ESI) m/z: 317 [M + H]+. HRMS (ESI) m/z: calcd for
C16H17N2O5 [M + H]+ 317.1139; found, 317.1132.
Ethyl 8-Chloro-3-ethoxychromeno[4,3-c]pyrazole-4-carboxylate
1
(8j). Colorless solid (60 mg, 61% yield); mp 110−112 °C. H NMR
(400 MHz, CDCl3): δ 8.07 (d, J = 2.5 Hz, 1H), 7.42 (dd, J = 8.8, 2.5
Hz, 1H), 7.33−7.27 (m, 1H), 4.65 (q, J = 7.2 Hz, 2H), 4.54 (q, J =
7.1 Hz, 2H), 1.58 (t, J = 7.2 Hz, 3H), 1.49 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 158.8, 155.1, 151.2, 147.4,
134.4, 130.5, 129.8, 122.3, 118.7, 115.4, 107.2, 62.9, 48.5, 15.8, 13.9.
FT-IR (KBr): 2955, 2924, 2854, 1761, 1556, 1511, 1454, 1383, 1368,
1299, 1236, 1117, 1073, 1052, 989, 759 cm−1. MS (ESI) m/z: [M +
H]+ 321. HRMS (ESI) m/z: [M + H]+ calcd for C15H14N2O2Cl
321.0654; found, 321.0636.
Methyl 3,8-Dimethoxychromeno[4,3-c]pyrazole-4-carboxylate
(8d). Colorless solid (62 mg, 69% yield); mp 203−205 °C. 1H
NMR (500 MHz, CDCl3): δ 7.49 (d, J = 3.0 Hz, 1H), 7.32−7.28 (m,
1H), 7.08−7.03 (m, 1H), 4.31 (s, 3H), 4.08 (s, 3H), 3.89 (s, 3H) .
13C{1H} NMR (101 MHz, CDCl3): δ 159.4, 156.2, 155.6, 148.3,
147.0, 134.2, 129.8, 114.2, 107.4, 104.4, 55.8, 53.2, 40.6. FT-IR
(KBr): 2955, 2925, 2848, 1741, 1624, 1594, 1513, 1455, 1438, 1396,
1312, 1286, 1272, 1251, 1151, 1085, 1027, 989, 759 cm−1. MS (ESI)
m/z: [M + H]+ 289. HRMS (ESI) m/z: [M + H]+ calcd for
C14H13N2O5 289.0833; found, 289.0819.
Methyl 8-Chloro-3-methoxychromeno[4,3-c]pyrazole-4-carbox-
1
ylate (8k). Colorless solid (51 mg, 57% yield); mp 207−209 °C. H
NMR (400 MHz, CDCl3): δ 8.02 (d, J = 2.4 Hz, 1H), 7.43 (dd, J =
8.8, 2.4 Hz, 1H), 7.34−7.28 (m, 1H), 4.31 (s, 3H), 4.08 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 159.2, 154.9, 151.2, 147.2,
134.4, 130.6, 129.9, 122.2, 118.6, 115.2, 107.4, 53.3, 40.8. FT-IR
(KBr): 2962, 2923, 2859, 1740, 1555, 1509, 1448, 1311, 1284, 1256,
1231, 1137, 1114, 1075, 1038, 999, 757 cm−1. MS (ESI) m/z: [M +
H]+ 293. HRMS (ESI) m/z: [M + H]+ calcd for C13H10N2O4Cl
293.0339; found, 293.0323.
Ethyl 3-Ethoxy-7-methoxychromeno[4,3-c]pyrazole-4-carboxy-
1
late (8e). Colorless solid (62 mg, 63% yield); mp 121−123 °C. H
NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.5 Hz, 1H), 6.88 (dt, J =
6.7, 2.3 Hz, 2H), 4.62 (q, J = 7.2 Hz, 2H), 4.53 (q, J = 7.1 Hz, 2H),
3.87 (s, 3H), 1.57 (t, J = 7.2 Hz, 3H), 1.49 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 161.6, 159.0, 155.9, 154.2,
148.6, 134.1, 123.5, 112.2, 107.2, 106.1, 101.4, 62.7, 55.6, 48.2, 15.8,
Methyl 8-Bromo-3-methoxychromeno[4,3-c]pyrazole-4-carbox-
1
ylate (8l). Colorless solid (54 mg, 59% yield); mp 231−233 °C. H
NMR (400 MHz, CDCl3): δ 8.17 (d, J = 2.3 Hz, 1H), 7.56 (dd, J =
2279
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pubs.acs.org/joc
Article
8.8, 2.3 Hz, 1H), 7.28−7.22 (m, 1H), 4.31 (s, 3H), 4.08 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 159.2, 154.8, 151.6, 147.1,
134.4, 133.4, 125.2, 118.9, 117.2, 115.6, 107.4, 53.3, 40.8. FT-IR
(KBr): 2957, 2941, 2863, 1744, 1692, 1614, 1586, 1554, 1509, 1449,
1378, 1311, 1284, 1257, 1230, 1134, 1109, 1038, 997, 753 cm−1. MS
(ESI) m/z: [M + H]+ 337. HRMS (ESI) m/z: [M + H]+ calcd for
C13H10N2O4Br 336.9831; found, 336.9818.
Methyl 6,8-Dichloro-3-methoxychromeno[4,3-c]pyrazole-4-car-
boxylate (8m). Colorless solid (46 mg, 51% yield); mp 238−240 °C.
1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 2.4 Hz, 1H), 7.54 (d, J =
Scientific and Innovative Research (AcSIR), Ghaziabad
201002, India
Balasubramanian Sridhar − Department of Analytical and
Structural Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500 007, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02421
Notes
2.4 Hz, 1H), 4.32 (s, 3H), 4.08 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 159.1, 153.6, 147.2, 146.9, 134.6, 130.8, 129.7, 123.1,
120.7, 116.3, 107.4, 53.4, 40.9. FT-IR (KBr): 2956, 2927, 2863, 1774,
1546, 1509, 1457, 1432, 1404, 1312, 1164, 1133, 1086, 1000, 827,
771 cm−1. MS (ESI) m/z: [M + H]+ 327. HRMS (ESI) m/z: [M +
H]+ calcd for C13H14N2O4Cl2 326.9946; found, 326.9933.
Ethyl 3-Phenyl-1H-pyrazole-5-carboxylate (5aa). Colorless solid
(60 mg, 76% yield); mp 108−109 °C. 1H NMR (400 MHz, CDCl3):
δ 7.75 (t, J = 6.5 Hz, 2H), 7.45−7.38 (m, 2H), 7.37−7.33 (m, 1H),
7.09 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 160.6, 149.3, 139.1, 130.7,
128.9, 128.5, 125.7, 105.5, 61.3, 14.2. FT-IR (KBr): 3569, 3120, 2911,
1764, 1529, 1509, 1477, 1458, 1365, 1337, 1147, 1026 cm−1. MS
(ESI) m/z: [M + H]+ 217. HRMS (ESI) m/z: [M + H]+ calcd for
C12H13N2O2 217.0971; found, 217.0968.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Director, CSIR-IICT, for providing the required
facilities to carry out the research (Communication no. IICT/
Pubs./2020/173). The authors are thankful to Mr. T. Ramesh
Babu for HPLC analysis. C.R.B. acknowledges SERB-DST,
India for financial support (EEQ/2017/000314).
REFERENCES
■
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1
138−140 °C. H NMR (400 MHz, CDCl3): δ 8.97 (d, J = 13.7 Hz,
1H), 7.91−7.85 (m, 2H), 7.47−7.37 (m, 3H), 7.32 (s, 1H), 6.75 (d, J
= 13.7 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H),
1.44 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 166.5, 158.9, 153.1, 137.9, 134.7, 131.2, 129.2,
128.8, 126.1, 111.5, 109.0, 61.8, 60.6, 14.32, 14.2. FT-IR (KBr): 3077,
2919, 2812, 1741, 1713, 1665, 1574, 1541, 1451, 1330, 1289, 1267,
1193, 1159, 1042 cm−1. MS (ESI) m/z: [M + H]+ 315. HRMS (ESI)
m/z: [M + H]+ calcd for C17H19N2O4 315.1339; found, 315.1331.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02421.
■
sı
1H and 13C NMR spectra, HRMS spectra, gNOESY
spectra, structures of the tosylhydrazones 3a−zb and
6a−h, HPLC chromatograms, and X-ray crystallography
data (PDF)
Accession Codes
CCDC 2031798 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
China Raju Bhimapaka − Department of Organic Synthesis
and Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500 007, India; Academy of
Scientific and Innovative Research (AcSIR), Ghaziabad
201002, India; orcid.org/0000-0001-6905-809X;
Email: chinaraju@iict.res.in
Authors
Siva Hariprasad Kurma − Department of Organic Synthesis
and Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500 007, India; Academy of
2280
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