Formal [4 + 1] Annulation of α-Arylhydrazonoketones and Dimethylsulfoxonium Methylide: One-pot Synthesis of Substituted Pyrazoles and Dihydropyrazoles

Article abstract of DOI:10.1021/acs.joc.6b01127

A formal [4 + 1] annulation of readily available α-arylhydrazonoketones and trimethylsulfoxonium iodide in the presence of cesium carbonate is described involving a sequential Corey-Chaykovsky reaction and intramolecular nucleophilic cyclization process. Substituted pyrazoles were obtained exclusively from the reactions of α-arylhydrazono-β-oxo-amides and trimethylsulfoxonium iodide in moderate to good yields, whereas the reactions of α-arylhydrazono-β-oxo-ketone/α-arylhydrazono- β-oxo-ester afforded the corresponding dihydropyrazoles in good yields.

Full text of DOI:10.1021/acs.joc.6b01127

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Article
Formal [4+1] Annulation of alpha-Arylhydrazonoketones
and Dimethylsulfoxonium Methylide: One-pot Synthesis
of Substituted Pyrazoles and Dihydropyrazoles
Qian Zhang, Mangfei Yu, Jingwen Yuan, Rui Zhang, Yongjiu Liang, Jiamei Tian, and Dewen Dong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01127 • Publication Date (Web): 21 Jun 2016
Downloaded from http://pubs.acs.org on June 24, 2016
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The Journal of Organic Chemistry
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Formal [4+1] Annulation of α-Arylhydrazonoketones and
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Dimethylsulfoxonium Methylide: One-pot Synthesis of
Substituted Pyrazoles and Dihydropyrazoles
Qian Zhang,a,b Mangfei Yu,a Jingwen Yuan,a,b Rui Zhang,a* Yongjiu Liang,a Jiamei Tian,c and Dewen
Donga*
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a Key Laboratory of Synthetic Rubber, Changchun Institute of Applied Chemistry, Chinese Academy
of Sciences, Changchun, 130022, China;
b University of Chinese Academy of Sciences, Beijing 100039, China
c Department of Chemistry, Northeast Normal University, Changchun 130024, China
E-mail: ariel@ciac.ac.cn; dwdong@ciac.ac.cn.
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract
A formal [4+1] annulation of readily available α-arylhydrazonoketones and trimethylsulfoxonium
iodide in the presence of cesium carbonate is described involving a sequential Corey-Chaykovsky
reaction and intramolecular nucleophilic cyclization process. Substituted pyrazoles were obtained
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exclusively from the reactions of α-arylhydrazono-β-oxo-amides and trimethylsulfoxonium iodide in
moderate to good yields, whereas the reactions of α-arylhydrazono-β-oxo-ketone/α-arylhydrazono-
β-oxo-ester afforded the corresponding dihydropyrazoles in good yields.
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Introduction
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Over the past decades, pyrazole chemistry has attracted considerable interest of research for
their broad range of properties. 1,2 Pyrazole is a key unit found in a number of natural products and
other small molecules along with important bioactivities, such as cyclooxygenase-2 (Cox-2)
inhibitors, HIV-1 reverse transcriptase inhibitors, and protein kinase inhibitors.3 In addition, some
functionalized pyrazoles have been used in supramolecular and polymer chemistry, in the food
industry, as cosmetic colorings, UV stabilizers, and ligands for the transition metal-catalyzed
reactions.4-6 The conventional approaches have been well-established for the preparation of such
aza-heterocycles, involving either the modification of the pre-constructed pyrazole ring by their
cross-coupling reactions with electrophiles to create C-N and C-C bonds,7-9 or the construction of
the pyrazole skeleton from appropriately substituted acyclic precursors. The latter becomes more
attractive for its general applicability to achieve more flexible substitution, which include the
condensation of hydrazines with 1,3-dicarbonyl compounds or their 1,3-dielectrophilic
equivalents,10,11 cycloaddition of electron-rich diazo compounds,12 nitrile imines13 or sydnones
with alkynes or alkenes,14 metal-catalyzed intramolecular nitrogen addition to alkynes.15 In our
previous work, we developed efficient synthesis of pyrazoles,16 pyrazolin-5-ones17 and
pyrazolin-5-one N-oxides18 from enaminones and 1-carbamoyl-1-oximyl cyclopropanes, respectively.
On the other hand, dimethylsulfoxonium methylide (DSM), i.e. Corey−Chaykovsky reagent,19 have
been widely used as a methylene-transfer reagent in organic conversion to three-membered ring
compounds, such as epoxides, aziridines and cyclopropanes.20-23 Most recently, we investigated the
reaction of α,α-dialkyl β-oxo amides and trimethylsulfoxonium iodide in the presence of NaH, and
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The Journal of Organic Chemistry
achieved efficient synthesis of γ-lactams via tandem Corey−Chaykovsky reaction and intramolecular
lactamization (Scheme 1a), 24 and Chen and co-workers developed an unprecedented strategy to access
dihydropyrazoles by a formal [4+1] cycloadditions of in-situ-derived azoalkenes and sulfur ylides
(Scheme 1b).25 Encouraged by these results and in continuation with our research interest in the
synthesis of highly valuable heterocycles, we are interested to investigate the reaction of
3-oxo-2-arylhydrazonobutanamides with trimethylsulfoxonium iodide in the presence of Cs2CO3 in
N,N-dimethylformamide (DMF). As a result of these studies, we developed a facile one-pot synthesis
of substituted pyrazoles and dihydropyrazoles from α-arylhydrazonoketones with varied substituted
groups (Scheme 1c). Herein, we wish to report our experimental results and present a proposed
mechanism involved in the formal [4+1] annulation reaction.
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Scheme 1. [4+1] Annulation Reactions.
(a) Previous work: Formal [4+1] Annulation of β-Oxo Amides and Sulfur Ylide.
(b) Previous work: Formal [4+1] Cycloaddition of Azoalkenes and Sulfur Ylides.
(c) This work: Formal [4+1] Annulation of α-Arylhydrazonoketones and Sulfur Ylide.
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Results and Discussion
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The substrates, α-arylhydrazonoketones 1, were prepared from commercially available
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1,3-dicarbonyl compounds and diazonium chloride salt in the presence of sodium acetate according to
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a reported procedure.26 We then selected 3-oxo-N-phenyl-2-(2-phenylhydrazono)butanamide 1a as a
model compound to examine its reaction behavior. Thus, the reaction of 1a and trimethylsulfoxonium
iodide 2 (1.2 equiv.) in the presence of Cs2CO3 (1.5 equiv.) in DMF was first attempted at room
temperature. As indicated by TLC results, the reaction yielded a yellow solid along with the recovery
of some starting material after work-up and purification of the resulting mixture by column
chromatography. The product was characterized as 4-hydroxy-4-methyl-N,1-diphenyl-
4,5-dihydro-1H-pyrazole-3-carboxamide 3a on the basis of its spectral and analytical data (Table 1,
entry 1). It was noted that when the load amount of Cs2CO3 was increased to 3.0 equivalents, there
was still quite a lot of starting material remaining intact although the yield of 3a was slightly increased
(Table 1, entry 2). Very interestingly, when the reaction temperature was increased to 60 °C , another
product was obtained along with 3a, which was characterized as 4-methyl-N,
1-diphenyl-1H-pyrazole-3-carboxamide 4a (Table 1, entry 3). Obviously, 1H-pyrazole 4a was derived
from 4,5-dihydro-1H-pyrazole 3a upon a dehydration process.
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Table 1. Reaction of α-Arylhydrazono-β-oxo-amide 1a and Trimethylsulfoxonium Iodide 2
under Different Conditions.a
Entry
1
Base
Solvent
DMF
Temp.
(oC)
rt
Time
(h)
Yield b (%)
(equiv)
3a
28(64)
4a
Cs2CO3(1.5)
26.0
0
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2
Cs2CO3(3.0)
Cs2CO3(3.0)
Cs2CO3(3.0)
Cs2CO3(3.0)
Cs2CO3(3.0)
Cs2CO3(1.5)
NaH(3.0)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
xylene
DCEc
rt
26.0
26.0
23.0
12.5
5.0
37(60)
0
1
2
3
4
5
6
7
8
3
60
35(15)
30
81
84
87
82
45
43
80
83
72
58
4
100
130
150
150
150
150
150
150
reflux
reflux
0
0
5
9
6
0
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7
7.0
0
8
13.0
14.0
8.0
0
9
NaOH(3.0)
DBU(3.0)
0
10
11
12
0
Cs2CO3(3.0)
Cs2CO3(3.0)
Cs2CO3(3.0)
5.0
0
15.0
24.0
0
13
16
a
Reagents and conditions: (1) 1a (1.0 mmol), 2 (1.2 mmol), solvent (4.0 mL); entries 1-3 and 13:
b
c
under air; entries 4-12: under N2. Isolated yield (data in parentheses for the recovery of 1a). DCE
=1,2-Dichloroethane.
The optimization of the reaction conditions, including the reaction temperature, solvent and base,
was then investigated as shown in Table 1. The experiments revealed that the reaction temperature had
significant influence on the reaction. At 100 °C under nitrogen, the reaction could be completed and
exclusively afforded pyrazole 4a in 81% yield (Table 1, entry 4), and further increase of temperature
could even reduce the reaction time to 5.0 h (Table 1, entries 5 and 6). Reducing the loading of
Cs2CO3 would result in slightly low yield of 4a (Table 1, entry 7). Other inorganic and organic bases,
such as NaH, NaOH and DBU, were also examined, but either lower yield of 4a was obtained or
prolonged reaction time was required (Table 1, entry 8-10 ). It should be mentioned that the nature of
the solvent played a crucial role during the cyclization process, and the further dehydration reaction
was favoured to proceed at higher reaction temperature (entries 11-13).
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Table 2. Synthesis of Pyrazoles
Trimethylsulfoxonium Iodide 2.a
4
from α-Arylhydrazono-β-oxo-amides
1
and
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Entry
1
1
R1
R2
R3
Time(h)
5.0
4
Yield(%)b
87
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Pr
C6H5
C6H5
4a
4b
4c
4d
4e
4f
2
2-MeOC6H4 C6H5
4.0
78
3
3-MeC6H4
3-ClC6H4
4-ClC6H4
C6H5
C6H5
C6H5
6.0
89
4
11.0
5.0
81
5
83
6
4-MeOC6H4 C6H5
5.0
90
7
1g
1h
1i
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2-MeC6H4
6.0
4g
4h
4i
84
8
2-ClC6H4
3-MeC6H4
Me
5.0
75
9
6.0
80
10
11
12
1j
10.0
3.0
4j
72
1k
1l
C6H5
4k
4l
71
CF3
C6H5
C6H5
9.0
64
13
1m
C6H5
6.0
4m
70
a
Reagents and conditions: 1 (1.0 mmol), 2 (1.2 mmol), Cs2CO3 (3.0 mmol), DMF (4.0 mL),
150 °C , N2. b Isolated yields.
Under the optimal conditions as for 4a in entry 6 (Table 1), a range of reactions of
α-arylhydrazono-β-oxo-amides 1 and trimethylsulfoxonium iodide 2 were carried out, and some of the
results are summarized in Table 2. It was found that the reactions of 1b–i bearing varied aryl groups
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R2 and R3 could proceed smoothly to afford the corresponding 1H-pyrazole 4b-i in good to high yields
(Table 2, entries 2–9). In the case of the reaction of 1j bearing an alkyl group R3 could undergo formal
[4+1] annulation reaction to furnish the corresponding 1H-pyrazole 4j in good yield (Table 2, entry
10). The versatility of this 1H-pyrazole synthesis was further evaluated by performing substrate 1k-1m
bearing varied alkyl and aryl group R1 with 2 under the identical conditions (Table 2, entries 11-13). It
should be noted that the structure of 4e was further confirmed by X-ray single crystal analysis (See
Supporting Information) and its spectral and analytical data. In contrast to our previous work,24 the
preferential formation of pyrazole ring in the present work over a γ-lactam ring implies that the
cyclization occurs in a chemoselective manner.
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a
Table 3. Expansion of the Scope of the Formal [4+1] Annulation.
Entry
1
R
3
Yield(%)b
4
Yield(%)c
1
2
1n
1o
1p
COOEt
COMe
COPh
3n
3o
3p
84
88
80
4n
4o
4p
89
93
87
3
a
Reagents and conditions: i) 1 (1.0 mmol), 2 (1.2 mmol), Cs2CO3 (3.0 mmol), DMF
o
(4.0 mL), 60 C, 1.0-2.0 h. ii) concentrated HCl (aq., 0.2 mL ), DMF (4.0 mL), rt, 0.5
b
h. Isolated yields for 3; c Isolated yields for 4.
To further expand the scope of the cyclization protocol, we investigated the reaction of
α-arylhydrazono-β-oxo-ester 1n in the same fashion (Table 3). As indicated by TLC results, the
reaction of 1n and sulfur ylide 2 could proceed smoothly at 60 °C to furnish a product, which was
characterized as dihydropyrazole 3n. However, further increasing of reaction temperature to 100 °C ,
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for example, would lead to the formation of a complex mixture, which might be attributed to the
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decomposition of 3n. Then, a separate experiment was performed by treatment of 3n with
concentrated aqueous HCl (2.4 equiv.) in DMF at room temperature. The reaction was completed
within half an hour and furnished a product, which was characterized as ethyl 4-methyl-1-phenyl-1H-
pyrazole-3-carboxylate 4n.27 Similarly, dihydropyrazoles 3o and 3p and pyrazoles 4o and 4p were
synthesized in high yields, respectively (Table 3).28 It should be mentioned that one-pot two-step
synthesis of 4n-p from 1n-p was achieved by acidification of the reaction system after 1n-p was
completely converted into 3n-p.
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On the basis of the above experimental results together with some reported literature, a
mechanism for the formal [4+1] annulation of readily available α-arylhydrazonoketones and
trimethylsulfoxonium iodide was proposed as depicted in Scheme 2. In the presence of Cs2CO3,
trimethylsulfoxonium iodide 2 is converted into sulfur ylide, i.e. Corey–Chaykovsky reagent DSM.24
The attack of the in-situ generated sulfur ylide on the carbonyl group of 1 forms intermediate A, which
is followed by an intramolecular chemoselective aza-cyclization to afford 4,5-dihydro-1H-pyrazole 3
with the elimination of DMSO,19,24 and further to gives rise to 1H-pyrazole 4 through a dehydration
process.
Scheme 2. Plausible Mechanism for the Formal [4+1] Annulation of α-Arylhydrazonoketones 1
and Trimethylsulfoxonium Iodide 2.
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The Journal of Organic Chemistry
Conclusions
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In summary, a facile and efficient synthesis of substituted pyrazoles and dihydropyrazoles from
α-arylhydrazonoketones and trimethylsulfoxonium iodide in the presence of cesium carbonate is
developed, which involves via a Corey–Chaykovsky reaction and intramolecular nucleophilic
cyclization reaction sequence. The ready availability of substrates, simplicity of execution, and
synthetic potential of the products make this novel protocol very attractive. Further work on the
utilization and extension of the scope of the methodology is currently under investigation in our
laboratory.
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Experimental Section
General Experimental
All reagents were purchased from commercial sources and used without treatment, unless
1
otherwise indicated. The products were purified by column chromatography over silica gel. H NMR
and 13C NMR spectra were recorded at 25 oC at 300 MHz (400 MHz or 600 MHz) and 100 MHz ( or
150 MHz), respectively, with TMS as internal standard. IR spectra (KBr) were recorded on
-1
FTIR-spectrophotometer in the range of 400-4000 cm . High resolution mass spectra were recorded
on a mass spectrometer. All melting points were determined in open capillary tubes in a Thiele
apparatus and are uncorrected. Melting points were uncorrected.
Synthesis and analytical data of compounds 3 and 4
Procedure A for the synthesis of 4,5-dihydro-1H-pyrazoles 3a: The Corey−Chaykovsky
reagent was prepared by adding Cs2CO3 (3.0 mmol) in one portion into a solution of
trimethylsulfoxonium iodide 2 (1.2 mmol) in DMF (4.0 mL) under stirring for 15 min at room
temperature. To the above Corey−Chaykovsky reagent was added 1a (1.0 mmol), which was stirred
for 26.0 h at room temperature. After the reaction was completed, the resulting mixture was poured
into saturated aqueous NaCl (100 mL), which was extracted with dichloromethane (3×30 mL). The
combined organic phase was washed with water, dried over anhydrous MgSO4, filtered, and
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evaporated in vacuo. The crude product was purified by flash silica gel chromatography (silica gel,
petroleum ether/ethyl acetate = 4:1) to give 3a as a yellow solid (109 mg, 37%).
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2
3
4
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4-Hydroxy-4-methyl-N,1-diphenyl-4,5-dihydro-1H-pyrazole-3-carboxamide (3a). Yellow solid,
m.p. 142-143 °C; 1H-NMR (300 MHz, CDCl3): δ 1.82 (s, 3H), 3.44 (s, 1H), 3.90 (d, J = 11.7 Hz, 1H),
4.09 (d, J = 11.7 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 7.12-7.19 (m, 3H), 7.33-7.40 (m, 4H), 7.62 (d, J =
8.1, 2H), 8.32 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ 25.2, 62.0, 79.1, 112.7, 118.7, 120.7, 123.4,
128.1, 128.3, 136.3, 141.7, 143.5, 159.2; IR (KBr): ν = 3394, 3384, 3058, 2925, 1646, 1596, 1537,
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-1
1498 cm ; HRMS (ESI-TOF) calcd for M = C17H17N3O2 [M+Na]+, 318.1213; found, 318.1218.
Ethyl 4-hydroxy-4-methyl-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate (3l). Prepared
according to the general procedure A using 1l (1.0 mmol) as substrate. To the Corey−Chaykovsky
reagent was added 1l, which was stirred for 2.0 h at 60 °C. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 4:1) to give 3l as a light yellow solid (208
mg, 84%). Light yellow solid, m.p. 154-156 °C; 1H-NMR (300 MHz, CDCl3): δ 1.41 (t, J = 7.2 Hz,
3H), 1.75 (s, 3H), 2.99 (s, 1H), 3.87 (d, J = 12.0 Hz, 1H), 4.09 (d, J = 12.0 Hz, 1H), 4.38 (q, J = 7.2 Hz,
2H), 6.99 (t, J = 7.2 Hz, 1H), 7.17-7.21 (m, 2H), 7.29-7.35 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ
13.3, 24.9, 60.1, 61.7, 78.8, 113.1, 121.0, 128.2, 140.7, 141.4, 161.7; IR (KBr): ν = 3471, 3005, 2982,
-1
2932, 1682, 1523, 1504, 1494 cm ; HRMS (ESI-TOF) calcd for M = C13H16N2O3 [M+Na]+, 271.1053;
found, 271.1057.
1-(4-hydroxy-4-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)ethanone (3m). Prepared according
to the general procedure A using 1m (1.0 mmol) as substrate. To the Corey−Chaykovsky reagent was
added 1m, which was stirred for 1.5 h at 60 °C. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 4:1) to give 3m as a yellow solid (192 mg,
88%). Yellow solid, m.p. 75-77 °C; 1H-NMR (300 MHz, CDCl3): δ 1.74 (s, 3H), 2.49 (s, 3H), 3.18 (s,
1H), 3.86 (d, J = 12.0 Hz, 1H), 4.08 (d, J = 12.0 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 7.18-7.22 (m, 2H),
7.32-7.38 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ 24.8, 25.2, 62.3, 78.6, 113.2, 121.4, 128.3, 141.2,
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148.2, 193.8; IR (KBr): ν = 3491, 2971, 1647, 1595, 1498 cm ; HRMS (ESI-TOF) calcd for M =
1
2
3
C12H14N2O2 [M+Na]+, 241.0947; found, 241.0952.
4
5
6
7
8
(4-hydroxy-4-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)(phenyl)methanone (3p). Prepared
according to the general procedure A using 1p (1.0 mmol) as substrate. To the Corey−Chaykovsky
reagent was added 1p, which was stirred for 2.0 h at 60 °C. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 4:1) to give 3p as a yellow solid (224 mg,
80%). Yellow solid, m.p. 104-105 °C; 1H-NMR (300 MHz, CDCl3): δ 1.83 (s, 3H), 3.78 (s, 1H), 3.91
(d, J = 12.0 Hz, 1H), 4.14 (d, J = 12.0 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.36
(t, J = 8.1 Hz, 2H), 7.50 (t, J = 7.2 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 8.21 (d, J = 7.5 Hz, 2H);
13C-NMR (150 MHz, CDCl3): δ 9.2, 118.3, 122.1, 126.1(2), 127.0, 128.5, 129.7, 131.4, 137.0, 138.7,
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147.8, 188.3; IR (KBr): ν = 3483, 2932, 1600, 1504, 1353, 1288, 1177, 1149 cm ; HRMS (ESI-TOF)
calcd for M = C17H16N2O2 [M+Na]+, 303.1104; found, 303.1097.
Procedure B for the synthesis of 1H-pyrazoles 4a: The Corey−Chaykovsky reagent was
prepared by adding Cs2CO3 (3.0 mmol) in one portion into a solution of trimethylsulfoxonium iodide 2
(1.2 mmol) in DMF (4.0 mL) under stirring for 15 min at room temperature. To the above
Corey−Chaykovsky reagent was added 1a (1.0 mmol), which was heated to reflux and stirred for 5.0 h
under N2. After the reaction was completed, the resulting mixture was poured into saturated aqueous
NaCl (100 mL), which was extracted with dichloromethane (3×30 mL). The combined organic phase
was washed with water, dried over anhydrous MgSO4, filtered, and evaporated in vacuo. The crude
product was purified by flash silica gel chromatography (silica gel, petroleum ether/ethyl acetate = 7:1)
to give 4a as a white solid (240 mg, 87%).
4-Methyl-N,1-diphenyl-1H-pyrazole-3-carboxamide (4a). White solid, m.p. 157-159 °C;
1H-NMR (300 MHz, CDCl3): δ 2.47 (d, J = 0.6 Hz, 3H), 7.12 (t, J = 7.5 Hz, 1H), 7.33-7.39 (m, 3H),
7.47-7.53 (m, 2H), 7.70-7.73 (m, 4H), 7.76 (d, J = 0.6 Hz, 1H), 8.86 (s, 1H); 13C-NMR (100 MHz,
CDCl3): δ 8.7, 118.3, 118.7, 120.4, 122.9, 126.2, 127.2, 128.0, 128.5, 137.0, 138.5, 143.5, 159.7; IR
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(KBr): ν = 3391, 3097, 3053, 1671, 1595, 1521, 1503 cm ; HRMS (MALDI-TOF) calcd for M =
1
2
3
C17H15N3O [M+H]+, 278.1288; found, 278.1285.
4
5
6
7
8
1-(2-Methoxyphenyl)-4-methyl-N-phenyl-1H-pyrazole-3-carboxamide (4b). Prepared according to
the general procedure B using 1b (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 6:1) to give 4b as a yellow oil (239 mg,
78%). Yellow oil; 1H-NMR (300 MHz, CDCl3): δ 2.47 (d, J = 0.6 Hz, 3H), 3.92 (s, 3H), 7.07-7.13 (m,
3H), 7.33-7.40 (m, 3H), 7.68-7.73 (m, 3H), 7.83 (d, J = 0.6 Hz, 1H), 8.85 (s, 1H); 13C-NMR (100
MHz, CDCl3): δ 8.6, 54.9, 111.3, 118.6, 118.8, 120.1, 122.8, 124.3, 127.9(2), 128.0, 132.1, 137.1,
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-1
142.7, 150.6, 159.9; IR (KBr): ν = 3382, 3054, 2927, 1678, 1595, 1528, 1502 cm ; HRMS
(MALDI-TOF) calcd for M = C18H17N3O2 [M+Na]+, 330.1213; found, 330.1214.
4-Methyl-N-phenyl-1-(m-tolyl)-1H-pyrazole-3-carboxamide (4c). Prepared according to the
general procedure B using 1c (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 7:1) to give 4c as a yellow solid (259 mg,
89%). Yellow solid, m.p. 139-141 °C; 1H-NMR (300 MHz, CDCl3): δ 2.46 (s, 6H), 7.09-7.18 (m, 2H),
7.34-7.39 (m, 3H), 7.48-7.55 (m, 2H), 7.71-7.75 (m, 3H), 8.85 (s, 1H); 13C-NMR (100 MHz, CDCl3):
δ 8.7, 20.5, 115.5, 118.7, 119.1, 120.2, 122.9, 127.0, 127.2, 127.9, 128.3, 137.0, 138.5, 138.7, 143.4,
-1
159.8; IR (KBr): ν = 3373, 3140, 2972, 1682, 1592, 1530 cm ; HRMS (MALDI-TOF) calcd for M =
C18H17N3O [M+H]+, 292.1444; found, 292.1441.
1-(3-Chlorophenyl)-4-methyl-N-phenyl-1H-pyrazole-3-carboxamide (4d). Prepared according to
the general procedure B using 1d (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 7:1) to give 4d as a yellow solid (252 mg,
81%). Yellow solid, m.p. 159-161 °C; 1H-NMR (300 MHz, CDCl3): δ 2.46 (d, J = 0.9 Hz, 3H), 7.13 (t,
J = 7.5 Hz, 1H), 7.30-7.45 (m, 4H), 7.56-7.60 (m, 1H), 7.70-7.74 (m, 2H), 7.75 (d, J = 0.9 Hz, 1H),
7.78 (t, 1H), 8.81 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ 8.7, 116.0, 118.6, 118.7, 120.8, 123.0,
126.1, 127.1, 128.0, 129.6, 134.4, 136.8, 139.4, 144.0, 159.4; IR (KBr): ν = 3371, 3098, 3053, 1679,
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1594, 1531 cm ; HRMS (MALDI-TOF) calcd for M = C17H14ClN3O [M+H]+, 312.0898; found,
312.0894.
-1
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2
3
4
5
6
7
8
1-(4-Chlorophenyl)-4-methyl-N-phenyl-1H-pyrazole-3-carboxamide (4e). Prepared according to
the general procedure B using 1e (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 7:1) to give 4e as a yellow solid (258 mg,
83%). Yellow solid, m.p. 160-162 °C; 1H-NMR (300 MHz, CDCl3): δ 2.46 (d, J = 0.6 Hz, 3H), 7.13 (t,
J = 7.2 Hz, 1H), 7.37-7.39 (m, 2H), 7.47 (d, J = 9.0 Hz, 2H), 7.66 (d, J = 9.0 Hz, 2H), 7.69-7.72 (m,
2H), 7.73 (d, J = 0.6 Hz, 1H), 8.80 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ 8.6, 118.7, 119.4, 120.7,
123.0, 127.1, 128.0, 128.6, 131.7, 136.8, 137.0, 143.8, 159.5; IR (KBr): ν = 3384, 3093, 3045, 1671,
9
10
11
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60
-1
1591, 1520, 1497 cm ; HRMS (MALDI-TOF) calcd for M = C17H14ClN3O [M+H]+, 312.0898; found,
312.0893.
1-(4-Methoxyphenyl)-4-methyl-N-phenyl-1H-pyrazole-3-carboxamide (4f). Prepared according to
the general procedure B using 1f (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 6:1) to give 4f as a yellow solid (276 mg,
90%). Yellow solid, m.p. 158-161 °C ; 1H-NMR (300 MHz, CDCl3): δ 2.46 (d, J = 0.9 Hz, 3H), 3.87 (s,
3H), 7.00 (d, J = 9.0 Hz, 2H), 7.12 (t, J = 7.2 Hz, 1H), 7.34-7.39 (m, 2H), 7.61 (d, J = 9.0 Hz, 2H),
7.66 (d, J = 0.9 Hz, 1H), 7.69-7.73 (m, 2H), 8.84 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ 8.6, 54.6,
113.6, 118.6, 120.0(2), 122.8, 127.3, 127.9, 132.2, 137.0, 143.0, 157.8, 159.8; IR (KBr): ν = 3311,
-1
3129, 2955, 1659, 1597, 1538, 1514 cm ; HRMS (MALDI-TOF) calcd for M = C18H17N3O2 [M+H]+,
308.1394; found, 308.1390.
4-Methyl-1-phenyl-N-(o-tolyl)-1H-pyrazole-3-carboxamide (4g). Prepared according to the
general procedure B using 1g (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 7:1) to give 4g as a white solid (244 mg,
84%). White solid, m.p. 99-100 °C; 1H-NMR (300 MHz, CDCl3): δ 2.40 (s, 3H), 2.47 (d, J = 0.6 Hz,
3H), 7.07 (t, J =7.5 Hz, 1H), 7.21-7.28 (m, 4H), 7.35 (t, J =7.5 Hz, 1H), 7.47-7.52 (m, 2H), 7.69-7.23
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(m, 2H), 7.78 (d, J = 0.6 Hz, 1H), 8.18 (d, 1H), 8.87 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ 8.6, 16.7,
118.1, 120.3, 120.7, 123.3, 125.8, 126.1, 126.9, 127.0, 128.5, 129.3, 135.0, 138.5, 143.8, 159.6; IR
1
2
3
4
5
6
-1
(KBr): ν = 3399, 3085, 3053, 2974, 1683, 1587, 1533, 1503 cm ; HRMS (MALDI-TOF) calcd for M
= C18H17N3O [M+H]+, 292.1444; found, 292.1440.
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8
9
N-(2-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-3-carboxamide (4h). Prepared according to
the general procedure B using 1h (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 7:1) to give 4h as a white solid (233 mg,
75%). White solid, m.p. 135-136 °C; 1H-NMR (300 MHz, CDCl3): δ 2.47 (d, J = 0.9 Hz, 3H), 7.05 (t,
J = 7.5 Hz, 1H), 7.28-7.43 (m, 3H), 7.50 (t, J = 7.5 Hz, 2H), 7.72-7.75 (m, 2H), 7.79 (d, J = 0.9 Hz,
1H), 8.57-8.61 (m, 1H), 9.58 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ 8.6, 118.0, 120.0, 120.4, 121.9,
123.1, 126.1, 126.6, 126.9, 128.1, 128.5, 133.9, 138.4, 143.3, 159.7; IR (KBr): ν = 3374, 3050, 2926,
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1692, 1591, 1533, 1520 cm ; HRMS (MALDI-TOF) calcd for M = C17H14ClN3O [M+H]+, 312.0898;
found, 312.0906.
4-Methyl-1-phenyl-N-(m-tolyl)-1H-pyrazole-3-carboxamide (4i). Prepared according to the
general procedure B using 1i (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 7:1) to give 4i as a yellow solid (232 mg,
80%). Yellow solid, m.p. 96-99 °C; 1H-NMR (300 MHz, CDCl3): δ 2.38 (s, 3H), 2.47 (d, J = 0.9 Hz,
3H), 6.84 (d, J = 7.5 Hz, 1H), 7.21-7.27 (m, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.45-7.52 (m, 3H), 7.63 (s,
1H), 7.69-7.73 (m, 2H), 7.76 (d, J = 0.9 Hz, 1H), 8.83 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ 8.7,
20.5, 115.7, 118.3, 119.3, 120.3, 123.7, 126.2, 127.1, 127.8, 128.5, 136.9, 137.9, 138.5, 143.6, 159.7;
IR (KBr): ν = 3314, 2960, 2919, 1669, 1591, 1539, 1532, 1501 cm-1; HRMS (MALDI-TOF) calcd for
M = C18H17N3O [M+H]+ 292.1444 found 292.1441.
N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide (4j). Prepared according to the general
procedure B using 1j (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 6:1) to give 4j as a white solid (155 mg,
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72%). White solid, m.p. 100-102 °C; 1H-NMR (300 MHz, CDCl3): δ 2.42 (d, J = 0.9 Hz, 3H), 2.99 (d,
J = 5.1 Hz, 3H), 7.01 (s, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.42-7.48 (m, 2H), 7.63-7.68 (m, 2H), 7.71 (d, J
= 0.9 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 8.5, 24.5, 118.1, 119.6, 125.9, 126.6, 128.4, 138.6,
1
2
3
4
5
6
-1
7
8
143.7, 162.5; IR (KBr): ν = 3345, 3058, 2927, 1644, 1598, 1544, 1504 cm ; HRMS (MALDI-TOF)
9
calcd for M = C12H13N3O [M+Na]+, 238.0951; found, 238.0948.
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60
N,1-diphenyl-4-propyl-1H-pyrazole-3-carboxamide (4k). Prepared according to the general
procedure B using 1k (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 8:1) to give 4k as a white solid (216 mg,
71%). White solid, m.p. 95-97 °C; 1H-NMR (600 MHz, CDCl3): δ 1.03 (t, J = 7.8 Hz, 3H), 1.72-1.76
(m, 2H), 2.92 (t, J = 7.8 Hz, 2H), 7.12 (t, J = 7.8 Hz, 1H), 7.34-7.38 (m, 3H), 7.50 (t, J = 7.2 Hz, 2H),
7.70-7.73 (m, 4H), 7.77 (s, 1H), 8.88 (s, 1H); 13C-NMR (150 MHz, CDCl3): δ 13.0, 22.4, 25.3, 118.4,
118.7, 122.9, 125.6, 126.2, 126.5, 128.0, 128.5, 137.0, 138.6, 143.1, 159.6; IR (KBr): ν = 3389, 2966,
-1
2938, 2878, 1686, 1603, 1532, 1504, 760 cm ; HRMS (ESI-TOF) calcd for M =C19H19N3O [M+H]+,
306.1601; found, 306.1596.
N,1-diphenyl-4-(trifluoromethyl)-1H-pyrazole-3-carboxamide (4l). Prepared according to the
general procedure B using 1l (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 8:1) to give 4l as a yellow solid (211 mg,
64%). Yellow solid, m.p. 122-124 °C; 1H-NMR (600 MHz, CDCl3): δ 7.15 (t, J = 7.2 Hz, 1H), 7.37 (t,
J = 7.8 Hz, 2H), 7.46 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 7.23 (d, J = 7.8 Hz, 4H), 8.25 (s, 1H),
8.76 (s, 1H); 13C-NMR (150 MHz, CDCl3): δ 114.8 (q, 2JCF = 30), 118.8, 119.1, 120.6 (q, 1JCF = 270),
123.5, 127.7, 128.0, 128.9, 129.0, 136.3, 137.5, 143.2, 156.2; IR (KBr): ν = 3383, 3122, 1700, 1603,
-1
1544, 1441, 760 cm ; HRMS (ESI-TOF) calcd for M =C17H12F3N3O [M+H]+, 332.1005; found,
332.0997.
N,1,4-triphenyl-1H-pyrazole-3-carboxamide (4m). Prepared according to the general procedure B
using 1m (1.0 mmol) as substrate. The crude product was purified by flash chromatography (silica gel,
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petroleum ether/ethyl acetate = 6:1) to give 4m as a light yellow solid (237 mg, 70%). Light yellow
solid, m.p. 149-150 °C; 1H-NMR (300 MHz, CDCl3): δ 7.12 (t, 1H), 7.32-7.45 (m , 6H), 7.55 (t, 2H),
7.67-7.71 (m, 4H), 7.79 (d, 2H), 8.03 (s, 1H), 8.92 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ118.6,
118.9, 123.0, 125.7, 126.6, 127.1, 127.2, 127.9, 128.4, 128.6, 130.1, 136.9, 138.2, 142.3, 158.7; IR
1
2
3
4
5
6
7
8
9
-1
(KBr): ν = 3320, 3305, 1671, 1602, 1534, 1506, 761, 700 cm ; HRMS (ESI-TOF) calcd for M
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=C22H17N3O [M+Na]+, 362.1264; found, 362.1241.
Procedure C for the synthesis of 4n: To a 50 mL round-bottomed flask was added 3n (1.0
mmol), DMF (4 mL) and concentrated HCl (0.2 mL). Then the mixture was stirred at room
temperature for 1.0 h. After the reaction was completed, the resulting mixture was poured into
saturated aqueous NaCl (100 mL), which was extracted with dichloromethane (3×30 mL). The
combined organic phase was washed with water, dried over anhydrous MgSO4, filtered, and
evaporated in vacuo. The crude product was purified by flash silica gel chromatography (silica gel,
petroleum ether/ethyl acetate = 8:1) to give 4n as a white solid (204 mg, 89%).
Ethyl 4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (4n). White solid, m.p. 72-74 °C; 1H-NMR
(300 MHz, CDCl3): δ 1.43 (t, J = 7.2 Hz, 3H), 2.37 (d, J = 0.9 Hz, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.32
(t, J = 7.5 Hz, 1H), 7.43-7.48 (m, 2H), 7.69-7.73 (m, 2H), 7.74 (d, J = 0.9 Hz, 1H); 13C-NMR (100
MHz, CDCl3): δ 8.9, 13.4, 59.7, 118.8, 121.2, 126.2, 126.6, 128.4, 138.6, 141.7, 162.0; IR (KBr): ν =
-1
3134, 3077, 2981, 1714, 1595, 1506, 1366, 1278, 1241 cm ; HRMS (MALDI-TOF) calcd for M =
C13H14N2O2 [M+Na]+, 253.0947; found, 253.0943.
1-(4-Methyl-1-phenyl-1H-pyrazol-3-yl)ethanone (4o). Prepared according to the general
procedure C using 3o (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 8:1) to give 4o as a white solid (186 mg,
93%). White solid, m.p. 65-68 °C; 1H-NMR (300 MHz, CDCl3): δ 2.37 (d, J = 0.6 Hz, 3H), 2.66 (s,
3H), 7.34 (t, J = 7.2 Hz, 1H), 7.45-7.50 (m, 2H), 7.70-7.74 (m, 3H); 13C-NMR (100 MHz, CDCl3): δ
8.9, 26.1, 118.4, 120.2, 126.1, 126.6, 128.5, 138.8, 148.4, 194.6; IR (KBr): ν = 3133, 3095, 3059,
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2956, 1667, 1504 cm ; HRMS (MALDI-TOF) calcd for M = C12H12N2O [M+Na]+, 223.0842; found,
223.0844.
-1
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(4-methyl-1-phenyl-1H-pyrazol-3-yl)(phenyl)methanone (4p). Prepared according to the general
procedure C using 3p (1.0 mmol) as substrate. The crude product was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 6:1) to give 4p as a light yellow solid (227
mg, 87%). Light yellow solid, m.p. 93-96 °C; 1H-NMR (300 MHz, CDCl3): δ 2.46 (s, 3H), 7.33 (t, J =
7.5 Hz, 1H), 7.45-7.52 (m, 4H), 7.59 (t, J = 7.5 Hz, 1H), 7.73 (d, J = 7.8 Hz, 2H), 7.82 (s, 1H), 8.30 (d,
J = 7.2 Hz, 2H); 13C-NMR (150 MHz, CDCl3): δ 25.2, 61.5, 79.9, 113.4, 121.5, 127.1, 128.4, 129.1,
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131.6, 136.1, 141.2, 147.6, 187.0; IR (KBr): ν = 3145, 3105, 1652, 1603, 1512, 1370, 1277 cm ;
HRMS (ESI-TOF) calcd for M = C17H14N2O [M+Na]+, 285.0998; found, 285.0996.
AssociatedContent
Supporting Information
The supporting Information is available free of charge on the ACS Publication website at
DOI:10.1021/acs.joc.XXXXXXXX.
1H and 13C NMR spectra of products 3 and 4 (PDF). X-ray crystallographic data (CIF file) of 4e.
Author Information
Corresponding Author
E-mail: ariel@ciac.ac.cn; dwdong@ciac.ac.cn.
Note
The authors declare no competing financial interest.
Acknowledgement
Financial support of this research by the National Natural Science Foundation of China
(21502185 and 21542006) is greatly acknowledged.
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