Substituent-Oriented Synthesis of Substituted Pyrazoles/Chromeno[3,2- c]pyrazoles via Sequential Reactions of Chromones/3-Chlorochromones and Tosylhydrazones

Article abstract of DOI:10.1021/acs.joc.9b00282

A facile and efficient synthetic strategy for the chemoselective synthesis of monocyclic/tricyclic-fused pyrazoles was developed, and it was oriented by different 3-position substituents (H or Cl) on the chromones. The reaction proceeded in a one-pot sequential way with a broad substrate scope and moderate to excellent yields.

Full text of DOI:10.1021/acs.joc.9b00282

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Note
Substituent-Oriented Synthesis of Substituted Pyrazoles/
Chromeno[3,2-c]Pyrazoles via Sequential Reactions of
Chromones/3-chlorochromones and Tosylhydrazones.
Tianzi Dai, Qunyi Li, Xiaofei Zhang, and Chunhao Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00282 • Publication Date (Web): 28 Mar 2019
Downloaded from http://pubs.acs.org on March 28, 2019
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The Journal of Organic Chemistry
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Substituent-Oriented Synthesis of Substituted Pyrazoles/
Chromeno[3,2-c]Pyrazoles via Sequential Reactions of Chromones/3-
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chlorochromones and Tosylhydrazones
Tianzi Dai†‡, Qunyi Li§, Xiaofei Zhang*†‡, and Chunhao Yang*†‡
† State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555
Zuchongzhi Road, Shanghai 201203, China.
‡ School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
§Department of Pharmacy, Huashan Hospital North, Fudan University, 108 Luxiang Road, Shanghai 201907, China.
*†‡ E-mail: chyang@simm.ac.cn.
*†‡ E-mail: xiaofeizhang@simm.ac.cn.
OH
O
O
O
O
O
H
N
X
N
X = H
X = Cl
NH
R2
R1
R1
R1
N
H
N
N
H
N
Ts
R2
R2
Ts
N
R2
Substituent-oriented
Metal-free
High chemoselectivity
Broad scope
27 examples
up to 98% yield
13 examples
up to 94% yield
ABSTRACT: A facile and efficient synthetic strategy for chemoselective synthesis of monocyclic/tricyclic-fused pyrazoles was
developed and it was oriented by different 3-position substituents (H or Cl) on the chromones. The reaction proceeded in a one-pot
sequential way with a broad substrate scope and moderate to excellent yields.
Chromone and its derivatives, which are found in a wide variety of synthetic and natural products exhibiting important biological
activities, are greatly useful building blocks for synthesis of various heterocycles due to their three strong electrophilic centres that could
react with numerous nucleophilic reagents, especially as an excellent Michael reaction acceptor accompanied by ring-opening process.1
Accordingly, simple, effective diversity-oriented synthesis based on chromones to construct bioactive heterocyclic scaffolds has piqued
enough interest of synthetic chemists.
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O
NH2
O
O
O
N
N
1
2
3
NH
N
COOEt
O
4
5
anticancer agent
nNOS and iNOS inhibitor
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7
8
9
O
O
O
N
H
N
N
N
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O
antipsychotic agent
anticancer/antimicrobial agent
Figure 1. Representative examples of bioactive monocyclic/tricyclic-fused pyrazole derivatives.
Among those bioactive heterocyclic scaffolds, pyrazoles are fascinating and versatile examples of five-membered heterocycles with
broad pharmaceutical and agrochemical activities including antitumor2, antimicrobial3, anti-hypercholesterolemia4, anti-inflammatory5, and
inhibitory activity towards nNOS/iNOS6 (Figure 1). Additionally, as an important subset of fused compounds, tricyclic-fused pyrazoles
have also shown excellent properties such as lower toxicity and higher activity due to the introduction of other heterocycles,7 which
enables themselves to become promising structural cores of various pharmacologically active substances (Figure 1).8 Besides the classic
numerous accesses to monocyclic pyrazoles (condensation reaction and 1, 3-dipolar cycloaddition reaction using alkynes or alkenes with
appropriate leaving groups)9, this scaffold also had been synthesized via the reaction of cinnamaldehyde and tosylhydrazone recently, only
two examples being given with lower regioselectivity and moderate yields (Scheme 1a).10 However, the synthesis of tricyclic
chromeno[3,2-c]pyrazoles is extremely limited. The reported procedure involved a side reaction of 3-acetylchromone with diazomethane11
(Scheme 1c) or a multistep synthesis starting from 1, 1-difluoroethylene12 (Scheme 1b), which have been known to suffer from obvious
drawbacks. Recently, an attempt using N-tosylhydrazones and chromone-3-carboxaldehyde had been made to synthesize this kind of
compounds, but xanthones instead of chromeno[3,2-c]pyrazoles were obtained.13 Owing to all mentioned above, it is still challenging and
highly desirable to design a practical and straightforward synthetic method for constructing monocyclic/tricyclic-fused pyrazoles
simultaneously, especially by substituent-oriented synthesis strategy with a tunable atom (H or Cl) from easily obtained starting materials.
Scheme 1. Strategies for Synthesis of Monocyclic Pyrazoles/ Chromeno[3,2-c]Pyrazoles
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Previous work
O
H
1
2
3
a)
N
H
NNHTs
O
N
Cs2CO3
only 2 examples
68% or 72% yield
Ph
Ph
H
R1
R1
4
5
6
b)
F
O
O
H
N
H
N
SnBu3
F
5 steps
2 steps
N
N
F
7
8
c)
O
O
O
O
H
N-tosylhydrazones
N
9
N
O
10
11
12
13
14
15
16
17
18
19
20
21
2%
This work
OH
O
X = H
O
d)
R1
X
R2
N
NH
Ts
NH
R2
R1
O
O
methanol, rt
30 min
N
+
O
O
Cs2CO3, DMF
110 oC, 1 h
one-pot
R1
Not isolated
H
TsNHNH2
N
X = Cl
R2
N
R1
Inspired by our previous studies on constructing bioactive heterocyclic scaffolds based on chromones14, we envisioned that a one-pot
reaction of tosylhydrazones and chromones/3-halogenated chromones in the presence of a base could be achieved to prepare ring-opening
and ring-closing products under the same reaction conditions (Scheme 1d). As we expected, monocyclic/tricyclic-fused pyrazoles were
chemoselectively obtained respectively, which was controlled by using different substituents on 3-position of chromones (H or Cl). The
structures of two products 4ao15 and 5a16 were unambiguously confirmed by X-ray crystallographic analysis (shown in Supporting
Information).
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At the outset of our study, we treated chromone (3aa) with benzaldehyde (1a) and tosylhydrazide (2) as the model substrates in a one-
pot, two-step sequential version to optimize the reaction conditions (Table 1). To our delight, NaOH as the base and DMF as the solvent at
110 °C for 1 h led to a 72% yield (Table 1, entry 1). Motivated by this result, a range of bases were tested, suggesting that the bases of this
reaction had a significant effect on the isolated yields of the product (Table 1, entries 1-6). Among them Cs2CO3 was found to be the
optimal base with an excellent yield of 98% (Table 1, entry 2), while no desired product was detected as for Na3PO4, Na2CO3, and Et3N
(Table 1, entries 3, 5, and 6). Subsequently, screening of solvents indicated that polar solvents were favorite in the reactions and DMF was
the best choice as well as DMSO (Table 1, entries 7-11 vs 2). Besides, further studies showed that increasing the amount of 1a and 2 had
no obvious effect on the yield (Table 1, entry 12), whereas a decrease for 1a and 2 led to incomplete full conversion of the starting material
(Table 1, entry 13). Taking temperature into consideration, we found lower the temperature to 80 °C could decrease the yield obviously
(Table 1, entry 14). Actually, we have also investigated the one-pot, one-step way and one-pot, two-step way without the concentration
process of tosylhydrazone intermediate respectively, however, the yield of pyrazole 4aa was not satisfactory (Table 1, entries 15 and 16).
Therefore, the optimal reaction conditions were found to include benzaldehyde (1.2 equiv.), tosylhydrazide (1.4 equiv.) and Cs2CO3 (3.0
equiv.) in DMF (2.0 mL) at 110 °C for 1 h.
Table 1. Optimization of Reaction Conditionsa
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O
O
Ts
1
2
3
4
NH
OH
O
N
O
methanol, rt
30 min
3aa
1a
+
TsNHNH2
N
NH
base, solvent
temp, 1h
4aa
Not isolated
2
5
I
6
7
8
temp
entry
base
solvent
yieldb (%)
(°C)
110
110
110
110
110
110
110
110
110
110
110
110
110
80
9
1
2
NaOH
Cs2CO3
Na3PO4
t-BuONa
Na2CO3
Et3N
DMF
DMF
72
98
10
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3
DMF
n.d.
78
4c
5
DMF
DMF
n.d.
n.d.
10
6
DMF
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
EtOH
toluene
dioxane
DMSO
MeCN
DMF
8
n.d.
52
9
10
11
12 c
13 d
14
15e
95
33
97
DMF
90
DMF
58
DMF
110
48
methanol
/DMF
16 f
Cs2CO3
110
82
a
Reaction conditions: 1a (0.36 mmol, 1.2 equiv.) and 2 (0.42 mmol, 1.4 equiv.) in methanol (2.0 mL) were stirred for 30 min at rt and
evaporated to dryness; then compound 3aa (0.3 mmol, 1.0 equiv.), base (0.9 mmol, 3.0 equiv.) and solvent (2.0 mL) were added, heated
for another 1 h. b Isolated yields. c 1.5 equiv. of 1a and 1.8 equiv. of 2 were used. d 1.0 equiv. of 1a and 1.2 equiv. of 2 were used. e A one-
pot, one-step method was used. f A one-pot, two-step method without concentration was used.
With the optimal conditions identified, we embarked on exploring the scope of this method with a variety of substrates. The results for 29
successful examples are summarized in Scheme 2. Pleasingly, various substituted chromones with electron-donating groups or electron-
withdrawing groups were broadly tolerated, furnishing pyrazoles 4aa–4bh in good to excellent yields regardless of steric hindrances and
substitution positions on the aromatic ring. Moreover, multi-substituted chromones including fused-chromones such as naphthalene
derivatives also delivered the corresponding products in excellent yields (Scheme 2, 4aq-4at,). To further explore the one-pot, two-step
sequential synthesis of pyrazoles, the scope of aldehydes was then surveyed (Scheme 2, 4au-4bh). As illustrated in Scheme 2, the aromatic
aldehydes bearing electron-withdrawing group afforded better yield of the corresponding product than that with electron-donating group
(Scheme 2, 4au vs 4ba), whereas strong electron-withdrawing groups such as cyano group gave a relatively lower yield (Scheme 2, 4bb).
Heteroaromatics were also compatible with the reaction (Scheme 2. 4bc-4be). Gratifyingly, aliphatic aldehydes were found to be suitable
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substrates as well under the standard conditions leading to the desired products in acceptable yields (Scheme 2, 4bf-4bh), which provided a
1
2
novel strategy for introduction of various aliphatic chains or alicyclic rings to pyrazole skeleton.
3
4
Scheme 2. Synthesis of Monocyclic Pyrazoles via One-Pot, Two-Step Reaction of Aldehydes, Tosylhydrazide, and
5
6
Chromonesa, b
7
8
9
O
R2
Ts
NH
OH O
R1
O
O
methanol, rt
30 min
3a
10
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1
N
R1
R2
N
+
NH
Cs2CO3, DMF
110 oC, 1 h
R1
TsNHNH2
4
Not isolated
2
I
OH
O
OH
O
OH O
N
N
N
NH
NH
NH
4aa R = H
4ab R = Me
4ac R = Pr
98% 95%c
R
R
4af
R = F
94%
91%
91%
4ag R = Cl 91%
4ah R = Br 93%
4ai R = Ph 93%
4aj R = CF3 65%
4ak 97%
4ad R = i-Pr 96%
4ae R = OMe 87%
OH
O
OH
O
OH O
N
N
N
NH
NH
NH
R
R
4al R = F
4am R = Cl 82%
4an R = Br 85%
98%
4ao R = Me
4ap R = OMe 94%
95%
4aq 92%
OH
O
OH
O
OH O
R1
R2
R
N
N
N
NH
NH
NH
R3
4au R = F
97%
4as R1 = H, R2 = Me, R3 = Cl
4at R1 = Me, R2 = H, R3 = Me
97%
98%
4ba R = OMe 75%
4ar 97%
4bb R = CN
63%
OH
O
OH O
OH O
S
S
N
N
N
N
N
NH
NH
NH
4bc 97%
4bd 78%
4be 96%
OH
O
OH
O
OH O
N
N
N
NH
NH
NH
4bf 73%
4bg 50%
4bh 59%
a
Reaction conditions: 1 (0.36 mmol, 1.2 equiv.) and 2 (0.42 mmol, 1.4 equiv.) in methanol (2.0 mL) were stirred for 30 min at rt and
evaporated to dryness; then compound 3a (0.3 mmol, 1.0 equiv.), base (0.9 mmol, 3.0 equiv.) and solvent (2.0 mL) were added, heated for
another 1 h. b Isolated yields. c The procedure was scaled up to a gram scale.
After successfully synthesizing monocyclic pyrazoles from 3-unsubstituted-chromones, we turned our attention to 3-chlorochromones
(Scheme 3). As expected, the reaction underwent further cyclization to form the tricyclic system, and the yield of the product 5a was 86%
under previous optimized conditions (Scheme 3, 5a). Notably, the efficiency of this transformation was significantly influenced by the
electronic properties of the substituents on the chromone ring, on which with electron-donating groups showing more favorable reactivity
than those electron-withdrawing groups in terms of isolated yields (Scheme 3, 5b, 5c vs 5f, 5h, 5i; 5d vs 5e, 5g). In addition, both
substrates of aromatic aldehydes with electron-donating groups and electron-withdrawing substituents performed well to give similar
results (Scheme 3, 5k, 5l), while no desired product was obtained for 4-nitrobenzaldehyde. This may be caused by the unstability of 4-
nitrobenzaldehyde in the presence of base and nucleophile. The reaction of heteroaromatic aldehyde also proceeded smoothly and provided
very good yield (Scheme 3, 5m). However, a relatively lower yield was obtained when aliphatic aldehyde such as cyclohexanaldehyde was
used, and quite a few ring-opening byproducts were produced simultaneously (Scheme 3, 5n).
Scheme 3. Synthesis of Tricyclic Chromeno[3,2-c]Pyrazoles a, b
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O
Cl
1
2
3
4
R2
O
O
Ts
R1
O
H
O
NH
N
methanol, rt
30 min
3b
1
N
R2
N
+
Cs2CO3, DMF
110 oC, 1 h
R1
TsNHNH2
R1
Not isolated
5
2
5
I
6
7
8
9
O
O
H
N
O
H
N
O
O
H
H
O
N
N
N
N
N
N
O
O
O
O
10
11
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13
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53
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60
86% 81%c
63%
69%
5a
5b
5c
5d
93%
O
O
O
O
H
N
O
O
H
N
H
H
Cl
Br
N
N
N
N
N
N
F
O
Cl
O
5e
5f
5g
5h
58%
79%
42%
78%
O
O
O
O
O
O
H
N
H
H
N
H
N
Cl
F3
C
N
N
N
N
N
O
O
O
F
5i
45%
5j
76%
5k
94%
5l
90%
O
O
H
H
N
N
N
N
O
O
S
5n
4bf
19%
27% +
5m
83%
a
Reaction conditions: 1 (0.36 mmol, 1.2 equiv.) and 2 (0.42 mmol, 1.4 equiv.) in methanol (2.0 mL) were stirred for 30 min at rt and
evaporated to dryness; then compound 3b (0.3 mmol, 1.0 equiv.), base (0.9 mmol, 3.0 equiv.) and solvent (2.0 mL) were added, heated for
another 1 h. b Isolated yields. c The procedure was scaled up to a gram scale.
To demonstrate the synthetic utility of our protocol, we scaled up the reaction to a gram scale, whereby the monocyclic and tricyclic-
fused pyrazole 4aa and 5a were furnished with yields of 95% and 81%, respectively (Scheme 2, Scheme 3).
Differential formation of monocyclic or tricyclic-fused pyrazoles could be explained by plausible mechanisms as depicted in Scheme 4.
The common steps involve the formation of hydrazone intermediate A generated from condensation of aldehyde 1 and tosylhydrazine 2,
which subsequently transforms into intermediate B in the presence of Cs2CO3. Then an intermolecular Michael addition between 3 and B
affords intermediate C which undergoes ring opening to give intermediate D based on the literature precedents (path a)14a,c,d. However,
different pathways appear when chromones with different atoms/groups on position 3 are introduced. 3-Unsubstituted undergo an
intramolecular cyclization reaction under alkaline conditions followed by a 1, 3-hydrogen shift to yield the monocyclic pyrazole products
4, while 3-chlorochromones experience more complicated procedures, including an intramolecular Michael addition and keto-enol
tautomerism to produce intermediate I. Afterwards, Clˉ would be eliminated from I to provide intermediate J. Finally, J could be
converted to the tricyclic pyrazole products 5 via an intramolecular cyclization and a 1, 5-hydrogen shift similar to monocyclic products 4.
Moreover, intermediate I might be obtained from intermediate C directly without the ring-opening/ring-closing process to furnish the
tricyclic-fused pyrazoles as well (path b). Besides, the possibility of a [3 + 2]-cycloaddition mechanism for synthesis of the two skeletons
could not be excluded.
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Scheme 4. Proposed Mechanism
1
2
3
2
R
N
Ts
Cs2CO3
N
H
1
A
4
5
6
7
8
9
N
N
R
O
N
B
NH
3
R
Michael
addition
OH
4
O
X
N
N
O
O
N
N
R
C
R
10
11
12
13
14
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OH
B
F
(a)
X=Cl
O
H
R
R
O
O
HO
O
N
N
N
X
N
X=H
E
D
R
O
N
N
Cl
O
(b)
H
G
Michael
addition
N
N
O
R
5
O
Cl
N
H
N
O
O
R
N
H
N
O
R
B
K
O
O
Cl
H
N
N
R
N
N
O
O
H
R
I
J
B
In conclusion, we have demonstrated a one-pot sequential reaction for chemoselective synthesis of monocyclic pyrazoles and tricyclic-
fused pyrazoles, which was oriented by different substituents on position 3 of chromones. This practical and easily handled protocol, with
good substrate availability and great regioselectivity, could occur under a broad substrate scope in short reaction time without any extra
additive metal. Moreover, the reactions could be carried out in moderate to excellent yields and scaled-up easily. Further studies on the
application of these products are under investigation in our laboratory.
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all solvents and other reagents are commercially available and used without further
purification. All reagents were weighed and handled in air at room temperature. Thin layer chromatography (TLC) employed glass 0.25
mm silica gel plates. Flash chromatography columns were packed with 300-400 mesh silica gel in petroleum ether. NMR spectra were
recorded on Brucker AVANCE 300 NMR spectrometer or Brucker AVANCE III 400 NMR spectrometer or Brucker AVANCE III 500
NMR spectrometeror or Brucker AVANCE III 600 NMR spectrometer. Chemical shifts were reported in parts per million (ppm, δ). Proton
coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), heptet (hept), multipet (m) and broad (br). Low and high-
resolution mass spectra (LRMS and HRMS) were recorded on a Finnigan/MAT-95 (EI), Finnigan LCQ/DECA and Micromass Ultra Q-
TOF (ESI) spectrometer. Melting points were measured by Büchi 510 melting point apparatus.
General procedure for the synthesis of chromones. All synthesized starting chromenones 3aa-3at were known compounds. However,
only a CAS Registry Number existed for 3aj by SciFinder searching. The chromones were prepared by the addition of the corresponding
substituted o-hydroxyacetophenone (2 mmol) with N, N-dimethylformamide dimethyl acetal (DMF-DMA), followed by cyclization by
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hydrogen chloride according to a reported protocol except compound 3aq and 3ar.14c,17 The cyclization process of 3aq and 3ar was
1
2
completed without anything18 or by T3P®19, respectively.
3
4
5
6
7
8
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6-(trifluoromethyl)-4H-chromen-4-one (3aj): As a light yellow solid (317 mg, 74%), m. p. 50-53 °C. 1H NMR (500 MHz,
Chloroform-d) δ 8.52 (s, 1H), 7.93 – 7.87 (m, 2H), 7.59 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 6.1 Hz, 1H). 13C{1H} NMR (126 MHz,
Chloroform-d) δ 176.4, 158.0, 155.6, 130.2 (d, J = 3.2 Hz), 127.8 (q, J = 33.7 Hz), 124.7, 124.0 (q, J = 4.0 Hz), 123.4 (d, J = 272.4 Hz),
119.4, 113.5. HRMS (EI-DFS) m/z: [M]+ calcd for C10H5F3O2, 214.0236; found 214.0238.
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General procedure for the synthesis of 3-chlorochromones. All synthesized starting 3-chlorochromenones 3ba-3bh were known
compounds except compound 3bi, and 3bj also only had a CAS Registry Number. 3-Chlorochromones were prepared by the addition of
the corresponding substituted o-hydroxyacetophenone (2 mmol) with N, N-dimethylformamide dimethyl acetal (DMF-DMA), followed by
cyclization and an chlorination process by iodine monochloride (3ba-3bc, 3be-3bh)14a,20 or N-Chlorosuccinimide (NCS) (3bd, 3bi,
3bj)1b,21 according to a reported protocol.
3-chloro-6-(trifluoromethyl)-4H-chromen-4-one (3bi): As a white solid (278 mg, 56%), m. p. 121-123 °C. 1H NMR (600 MHz,
Chloroform-d) δ 8.60 – 8.57 (m, 1H), 8.21 (s, 1H), 7.94 (dd, J = 8.8, 2.1 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H). 13C{1H} NMR (126 MHz,
Chloroform-d) δ 171.4, 157.4, 152.4, 130.6 (d, J = 3.1 Hz), 128.4 (q, J = 33.9 Hz), 124.5 (q, J = 4.1 Hz), 123.3, 123.2 (q, J = 272.5 Hz),
121.7, 119.5. HRMS (EI-DFS) m/z: [M]+ calcd for C10H4ClF3O2, 247.9846; found 247.9845.
3,6-dichloro-7-methyl-4H-chromen-4-one (3bj): As a white solid (420 mg, 92%), m. p. 148-150 °C. 1H NMR (600 MHz, Chloroform-
d) δ 8.19 (s, 1H), 8.12 (s, 1H), 7.37 (s, 1H), 2.51 (s, 3H). 13C{1H} NMR (151 MHz, Chloroform-d) δ 154.2, 151.9, 143.6, 132.5, 125.6,
122.3, 120.6, 119.8, 20.8. HRMS (EI-DFS) m/z: [M]+ calcd for C10H6Cl2O2, 227.9739; found 227.9732.
General procedure for the synthesis of monocyclic substituted-pyrazoles(4aa–4bh). A 5 mL reaction tube equipped with a magnetic
stirrer was charged with aldehyde (0.36 mmol), tosylhydrazide (78 mg, 0.42 mmol), methanol (2 mL). The mixture was stirred at room
temperature for 30 min. After removing the solvent in vacuo, chromones (0.3 mmol), Cs2CO3 (293 mg, 0.9 mmol), and DMF (2 mL) were
added, and the reaction mixture was heated at 110 °C under open atmosphere until pyrazole formation was complete. Then the mixture was
extracted with EtOAc (10 mL × 3), and washed with brine (10 mL), dried over anhydrous Na2SO4 and evaporated to dryness to yield a
crude reaction product, which was purified by silica gel chromatography eluted with PE: EtOAc = 5:1 to give the product as yellow solid.
Gram-scale preparation of 4aa. A 100 mL reaction tube equipped with a magnetic stirrer was charged with benzaldehyde (836 μL, 8.22
mmol), tosylhydrazide (1786 mg, 9.59 mmol), methanol (40 mL). The mixture was stirred at room temperature for 30 min. After removing
the solvent in vacuo, chromones (1000 mg, 6.85 mmol), Cs2CO3 (6696 mg, 20.55 mmol), and DMF (40 mL) were added, and the reaction
mixture was heated at 110 °C under open atmosphere until pyrazole formation was complete. Then the mixture was extracted with EtOAc
(40 mL × 3), and washed with brine (40 mL), dried over anhydrous Na2SO4 and evaporated to dryness to yield a crude reaction product,
which was purified by silica gel chromatography eluted with PE: EtOAc = 5:1 to give the product as yellow solid (1719 mg, 95%).
(2-hydroxyphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4aa): As a light yellow solid (78 mg, 98%), m. p. 155-157 °C. 1H NMR
(500 MHz, Chloroform-d) δ 12.02 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 7.78 – 7.71 (m, 2H), 7.54 (ddd, J = 8.7, 7.2, 1.7 Hz, 1H), 7.49 – 7.43
(m, 2H), 7.43 – 7.38 (m, 1H), 7.21 (s, 1H), 7.07 (dd, J = 8.4, 1.2 Hz, 1H), 7.01 – 6.95 (m, 1H). 13C{1H} NMR (126 MHz, Chloroform-d) δ
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189.4, 163.4, 136.7, 132.4, 130.1, 129.1, 129.0, 125.7, 119.2, 119.1, 118.5, 106.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H14N2O2,
265.0972; found 265.0965.
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(2-hydroxy-5-methylphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4ab): As a light yellow solid (76 mg, 91%), m. p. 171-173 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.24 – 8.15 (m, 1H), 7.93 – 7.85 (m, 2H), 7.50 (t, J = 7.7 Hz, 2H), 7.45 – 7.33 (m, 3H), 6.94 (d, J = 8.3
Hz, 1H), 2.30 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 189.8, 158.7, 145.9, 136.4, 132.4, 130.0, 129.5, 129.0, 128.0, 125.9, 121.5,
117.7, 106.3, 20.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H16N2O2, 279.1128; found 279.1121.
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(2-hydroxy-5-propylphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4ac): As a light yellow solid (83 mg, 91%), m. p. 109-110 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.42 – 8.16 (m, 1H), 7.90 (d, J = 7.7 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.46 – 7.33 (m, 3H), 6.96 (d, J =
8.4 Hz, 1H), 2.59 – 2.51 (m, 2H), 1.60 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.0, 159.2,
135.9, 132.8, 132.1, 129.5, 129.0, 125.9, 121.3, 117.7, 106.4, 36.8, 24.7, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H20N2O2,
307.1441; found 307.1449.
(2-hydroxy-5-isopropylphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4ad): As a light yellow solid (87 mg, 96%), m. p. 144-146
°C. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.92 – 7.86 (m, 2H), 7.54 – 7.47 (m, 2H), 7.47 – 7.38 (m, 2H), 7.35 (s, 1H), 6.97 (d, J =
8.5 Hz, 1H), 2.97 – 2.84 (m, 1H), 1.23 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 189.9, 159.01, 145.6, 139.0, 133.9,
130.0, 129.5, 129.0, 125.9, 121.4, 117.8, 106.3, 33.0, 24.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H20N2O2, 307.1441; found
307.1445.
(2-hydroxy-5-methoxyphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4ae): As a light yellow solid (77 mg, 87%), m. p. 136-139 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.11 – 7.74 (m, 3H), 7.50 (t, J = 7.6 Hz, 2H), 7.44 – 7.37 (m, 1H), 7.36 (s, 1H), 7.19 (dd, J = 9.0, 3.2 Hz,
1H), 6.97 (d, J = 9.0 Hz, 1H), 3.77 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 189.4, 154.8, 151.9, 129.5, 129.0, 125.9, 122.8, 121.8,
118.8, 115.6, 106.4, 56.0. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H16N2O3, 295.1077; found 295.1081.
(5-fluoro-2-hydroxyphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4af): As a light yellow solid (79 mg, 94%), m. p. 183-185 °C. 1H
NMR (400 MHz, DMSO-d6) δ 8.72 – 8.34 (m, 1H), 7.94 – 7.85 (m, 2H), 7.56 – 7.47 (m, 2H), 7.46 – 7.35 (m, 2H), 6.93 – 6.84 (m, 2H).
13C{1H} NMR (126 MHz, DMSO-d6) δ 188.9, 166.4 (d, J = 252.7 Hz), 163.4, 135.6, 129.5, 129.1, 126.0, 118.8, 107.2 (d, J = 22.2 Hz),
106.4, 104.5 (d, J = 23.9 Hz). HRMS (EI-DFS) m/z: [M]+calcd for C16H11FN2O2, 282.0799; found 282.0797.
(5-chloro-2-hydroxyphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4ag): As a light yellow solid (82 mg, 91%), m. p. 191-193 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.60 – 8.04 (m, 1H), 7.88 (d, J = 7.6 Hz, 2H), 7.58 – 7.47 (m, 3H), 7.42 (t, J = 7.4 Hz, 1H), 7.34 (s, 1H),
7.05 (d, J = 8.8 Hz, 1H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 188.9, 158.5, 134.2, 131.2, 129.6, 129.2, 125.9, 124.3, 122.8, 119.5,
106.1. HRMS (EI-DFS) m/z: [M]+ calcd for C16H11ClN2O2, 298.0504; found 298.0509.
(5-bromo-2-hydroxyphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4ah): As a light yellow solid (96 mg, 93%), m. p. 202-205 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.69 – 8.15 (m, 1H), 7.91 – 7.80 (m, 2H), 7.63 (dd, J = 8.8, 2.5 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.40 (t,
J = 7.3 Hz, 1H), 7.32 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 189.4, 158.8, 137.0, 134.1, 129.6, 129.2,
125.9, 124.6, 120.0, 110.2, 106.0. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H13BrN2O2, 343.0077; found 343.0079.
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(4-hydroxy-[1, 1'-biphenyl]-3-yl)(5-phenyl-1H-pyrazol-3-yl)methanone (4ai): As a light yellow solid (96 mg, 93%), m. p. 156-158
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°C. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.94 – 7.88 (m, 2H), 7.85 (dd, J = 8.6, 2.4 Hz, 1H), 7.70 – 7.63 (m, 2H), 7.54 – 7.44 (m,
4H), 7.44 – 7.31 (m, 3H), 7.14 (d, J = 8.5 Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 189.4, 159.6, 139.3, 133.0, 130.9, 130.2, 129.0,
128.9, 128.6, 127.0, 126.1, 125.4, 122.0, 117.9, 105.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C22H18N2O2, 341.1285; found 341.1293.
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(2-hydroxy-5-(trifluoromethyl)phenyl)(5-phenyl-1H-pyrazol-3-yl)methanone(4aj): As a light yellow solid (44 mg, 65%), m. p. 151-
154 °C. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.88 (d, J = 7.4 Hz, 2H), 7.66 (d, J = 7.7 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.36 (t,
J = 7.3 Hz, 1H), 7.30 (s, 1H), 7.03 (d, J = 8.5 Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 185.8, 165.6, 148.8, 131.2, 130.5, 129.8,
129.4, 128.6, 125.8, 125.3 (d, J = 270.5 Hz), 124.0, 121.3, 116.9, 105.5. HRMS (EI-DFS) m/z: [M]+ calcd for C17H11F3N2O2, 332.0767;
found 332.0763.
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(2-hydroxy-3-methylphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4ak): As a light yellow solid (81 mg, 97%), m. p. 143-145 °C.
1H NMR (500 MHz, DMSO-d6) δ 8.66 – 8.52 (m, 1H), 7.95 – 7.86 (m, 2H), 7.60 – 7.46 (m, 3H), 7.46 – 7.36 (m, 2H), 6.94 (t, J = 7.7 Hz,
1H), 2.25 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.9, 160.9, 145.3, 137.4, 131.3, 129.5, 129.1, 126.6, 126.0, 119.2, 118.9,
106.6, 15.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H16N2O2, 279.1128; found 279.1120.
(4-fluoro-2-hydroxyphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4al): As a light yellow solid (82 mg, 98%), m. p. 167-170 °C. 1H
NMR (400 MHz, DMSO-d6) δ 8.83 – 8.30 (m, 1H), 7.93 – 7.83 (m, 2H), 7.50 (dd, J = 8.3, 6.8 Hz, 2H), 7.45 – 7.39 (m, 1H), 7.36 (s, 1H),
6.94 – 6.84 (m, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 189.3, 166.4 (d, J = 252.4 Hz), 163.3, 135.6, 129.5, 129.1, 126.0, 118.8, 107.2
(d, J = 22.0 Hz), 106.3, 104.5 (d, J = 23.8 Hz). HRMS (EI-DFS) m/z: [M]+ calcd for C16H11FN2O2, 282.0799; found 282.0798.
(4-chloro-2-hydroxyphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4am): As a light yellow solid (74 mg, 82%), m. p. 190-192 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.47 – 8.21 (m, 1H), 7.96 (dd, J = 7.3, 1.7 Hz, 2H), 7.58 (dd, J = 8.3, 6.8 Hz, 2H), 7.54 – 7.46 (m, 1H),
7.42 (s, 1H), 7.22 – 7.10 (m, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 188.8, 160.7, 139.0, 133.8, 129.5, 129.1, 125.9, 121.8, 119.6,
117.4, 106.2. HRMS (EI-DFS) m/z: [M]+ calcd for C16H11ClN2O2, 298.0504; found 298.0509.
(4-bromo-2-hydroxyphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4an): As a light yellow solid (88 mg, 85%), m. p. 200-202 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.29 – 8.00 (m, 1H), 7.94 – 7.85 (m, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.34 (s, 1H),
17.25 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 8.4, 1.9 Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 189.5, 160.3, 133.7, 129.5, 129.1, 127.8,
125.9, 122.4, 120.3, 106.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H13BrN2O2, 343.0077; found 343.0085.
(2-hydroxy-4-methylphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4ao):As a light yellow solid (80 mg, 95%), m. p. 155-158 °C. 1H
NMR (500 MHz, Chloroform-d) δ 12.10 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 7.4 Hz, 2H), 7.49 – 7.41 (m, 2H), 7.41 – 7.35 (m,
1H), 7.18 (s, 1H), 6.87 (s, 1H), 6.77 (dd, J = 8.3, 1.6 Hz, 1H), 2.38 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 188.8, 163.6, 148.5,
132.2, 130.3, 129.1, 128.9, 125.8, 120.6, 118.5, 116.8, 106.6, 22.1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H16N2O2, 279.1128;
found 279.1133.
(2-hydroxy-4-methoxyphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4ap): As a light yellow solid (83 mg, 94%), m. p. 139-141 °C.
1H NMR (400 MHz, Chloroform-d) δ 12.71 (s, 1H), 11.64 (s, 1H), 8.51 – 8.17 (m, 1H), 7.73 (d, J = 7.8 Hz, 2H), 7.48 – 7.32 (m, 3H), 7.19
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– 7.09 (m, 1H), 6.55 – 6.42 (m, 2H), 3.85 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 166.7, 166.6, 134.1, 129.0, 128.8, 125.7,
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(2-hydroxynaphthalen-1-yl)(5-phenyl-1H-pyrazol-3-yl)methanone (4aq): As a light yellow solid (87 mg, 92%), m. p. 124-127 °C.
1H NMR (400 MHz, DMSO-d6) δ 7.94 – 7.85 (m, 2H), 7.85 – 7.77 (m, 2H), 7.48 – 7.28 (m, 6H), 7.25 (d, J = 8.9 Hz, 1H), 7.13 (s, 1H).
13C{1H} NMR (126 MHz, DMSO-d6) δ 153.1, 131.8, 131.0, 129.0, 128.4, 128.3, 127.6, 127.1, 125.5, 123.2, 123.0, 120.0, 118.7, 105.2.
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H16N2O2, 315.1128; found 315.1133.
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(1-hydroxynaphthalen-2-yl)(5-phenyl-1H-pyrazol-3-yl)methanone (4ar): As a yellow solid (92 mg, 97%), m. p. 185-188 °C. 1H
NMR (400 MHz, DMSO-d6) δ 8.89 – 8.67 (m, 1H), 8.38 (dd, J = 8.4, 1.2 Hz, 1H), 7.94 – 7.84 (m, 3H), 7.71 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H),
7.59 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.49 (dd, J = 8.4, 6.9 Hz, 2H), 7.45 – 7.36 (m, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.8,
163.0, 152.0, 143.9, 137.2, 130.9, 129.6, 129.2, 128.0, 127.7, 126.6, 126.0, 124.8, 124.2, 118.6, 113.2, 106.4. HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C20H16N2O2, 315.1128; found 315.1127.
(5-chloro-2-hydroxy-3-methylphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4as): As a light yellow solid (90 mg, 97%), m. p. 194-
196 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.87 – 8.30 (m, 1H), 7.89 – 7.80 (m, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 7.34
(s, 1H), 7.01 (s, 1H), 2.34 (s, 3H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 188.6, 159.8, 143.9, 132.4, 129.6, 129.2, 125.9, 123.5, 120.2,
106.1, 20.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H15ClN2O2, 313.0738; found 313.0743.
(2-hydroxy-3,5-dimethylphenyl)(5-phenyl-1H-pyrazol-3-yl)methanone (4at): As a yellow solid (86 mg, 98%), m. p. 135-137 °C. 1H
NMR (400 MHz, Chloroform-d) δ 12.08 (s, 1H), 8.01 – 7.90 (m, 1H), 7.73 (d, J = 7.4 Hz, 2H), 7.46 – 7.34 (m, 3H), 7.23 – 7.19 (m, 1H),
7.16 (s, 1H), 2.27 (s, 3H), 2.26 (s, 3H). 13C{1H} NMR (151 MHz, Chloroform-d) δ 159.8, 138.9, 129.4, 129.0, 128.8, 127.6, 127.2, 125.8,
118.1, 106.8, 20.6, 15.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H18N2O2, 293.1285; found 293.1293.
(5-(4-fluorophenyl)-1H-pyrazol-3-yl)(2-hydroxyphenyl)methanone (4au): As a light yellow solid (82 mg, 97%), m. p. 155-158 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.31 – 8.16 (m, 1H), 7.90 (dd, J = 8.5, 5.4 Hz, 2H), 7.51 (ddd, J = 9.1, 7.3, 1.7 Hz, 1H), 7.36 – 7.24 (m,
3H), 7.06 – 6.92 (m, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 188.96, 162.07 (d, J = 245.6 Hz), 159.92, 134.96, 131.97, 127.59 (d, J =
8.4 Hz), 126.41, 121.64, 118.89, 117.36 (d, J = 4.2 Hz), 115.86 (d, J = 21.7 Hz), 105.97. HRMS (EI-DFS) m/z: [M]+ calcd for
C16H11FN2O2, 282.0799; found 282.0798.
(2-hydroxyphenyl)(5-(4-methoxyphenyl)-1H-pyrazol-3-yl)methanone (4ba): As a light yellow solid (65 mg, 75%), m. p. 155-157
°C. 1H NMR (400 MHz, DMSO-d6) δ 8.57 – 8.28 (m, 1H), 7.84 – 7.75 (m, 2H), 7.53 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.23 (s, 1H), 7.11 –
6.94 (m, 4H), 3.80 (s, 3H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 190.4, 160.8, 160.0, 135.6, 132.8, 127.4, 121.7, 119.4, 117.8, 114.9,
105.4, 55.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H16N2O3, 295.1077; found 295.1081.
4-(3-(2-hydroxybenzoyl)-1H-pyrazol-5-yl)benzonitrile (4bb): As a light yellow solid (55 mg, 63%), m. p. 170-172 °C. 1H NMR (600
MHz, DMSO-d6) δ 8.14 – 8.04 (m, 3H), 7.90 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 7.4 Hz, 1H), 7.44 (s, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.92 (t, J
= 7.2 Hz, 1H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 187.2, 160.2, 148.2, 146.8, 136.5, 134.9, 133.2, 132.0, 126.2, 123.2, 119.3, 118.7,
118.6, 110.2, 107.5. HRMS (EI-DFS) m/z: [M]+ calcd for C17H15N2O3, 295.1077; found 295.1081.
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(2-hydroxyphenyl)(5-(thiazol-4-yl)-1H-pyrazol-3-yl)methanone (4bc): As a light yellow solid (80 mg, 97%), m. p. 222-225 °C. 1H
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NMR (400 MHz, DMSO-d6) δ 9.26 (d, J = 1.9 Hz, 1H), 8.51 – 8.24 (m, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.54 (ddd, J = 8.6, 7.2, 1.7 Hz, 1H),
7.30 (s, 1H), 7.08 – 6.95 (m, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 189.8, 160.4, 155.8, 146.1, 135.5, 132.6, 122.1, 119.4, 117.8,
116.5, 106.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H11N3O2S, 272.0488; found 272.0496.
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(2-hydroxyphenyl)(5-(pyridin-4-yl)-1H-pyrazol-3-yl)methanone (4bd): As a light yellow solid (62 mg, 78%), m. p. 231-233 °C. 1H
NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 5.3 Hz, 2H), 8.07 (s, 1H), 7.93 – 7.84 (m, 2H), 7.59 – 7.48 (m, 2H), 7.08 – 6.96 (m, 2H).
13C{1H} NMR (126 MHz, DMSO-d6) δ 188.2, 159.6, 150.8, 135.3, 131.9, 122.7, 120.1, 119.6, 117.7, 108.4. HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C15H13N3O2, 266.0924; found 266.0928.
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(2-hydroxyphenyl)(5-(thiophen-3-yl)-1H-pyrazol-3-yl)methanone (4be): As a light yellow solid (78 mg, 96%), m. p. 170-172 °C. 1H
NMR (500 MHz, DMSO-d6) δ 8.44 – 8.23 (m, 1H), 8.00 (d, J = 3.2 Hz, 1H), 7.69 (dd, J = 5.0, 2.9 Hz, 1H), 7.62 (dd, J = 5.0, 1.3 Hz, 1H),
7.53 (ddd, J = 8.7, 7.2, 1.8 Hz, 1H), 7.24 (s, 1H), 7.07 – 6.95 (m, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 189.7, 160.3, 135.2, 132.4,
131.0, 127.7, 126.0, 122.2, 121.7, 119.1, 117.5, 106.0. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H12N2O2S, 271.0536; found 271.0538.
(5-cyclohexyl-1H-pyrazol-3-yl)(2-hydroxyphenyl)methanone (4bf): As a light yellow solid (59 mg, 73%), m. p. 107-109 °C. 1H
NMR (500 MHz, DMSO-d6) δ 8.53 – 8.43 (m, 1H), 7.57 – 7.51 (m, 1H), 7.04 – 6.94 (m, 2H), 6.70 (s, 1H), 2.76 (tt, J = 11.3, 3.7 Hz, 1H),
2.05 – 1.99 (m, 2H), 1.82 (dq, J = 10.9, 3.6 Hz, 2H), 1.74 (dd, J = 12.4, 4.0 Hz, 1H), 1.58 – 1.23 (m, 6H). 13C{1H} NMR (126 MHz,
DMSO-d6) δ 189.9, 161.3, 151.1, 149.2, 135.1, 132.7, 121.4, 118.4, 118.0, 104.7, 34.8, 32.4, 25.7, 25.6. HRMS (ESI-TOF) m/z: [M+H]+
calcd for C16H20N2O2, 271.1441; found 271.1443.
(5-cyclopentyl-1H-pyrazol-3-yl)(2-hydroxyphenyl)methanone (4bg): As a light yellow solid (43 mg, 56%), m. p. 113-115 °C. 1H
NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 7.8 Hz, 1H), 7.55 – 7.45 (m, 1H), 7.01 – 6.89 (m, 2H), 6.66 (s, 1H), 3.10 (p, J = 8.1 Hz, 1H),
2.11 – 1.97 (m, 2H), 1.78 – 1.66 (m, 2H), 1.67 – 1.51 (m, 4H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.8, 161.3, 150.0, 135.6, 133.2,
121.4, 119.2, 117.8, 105.5, 36.5, 33.1, 25.1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H16N2O2, 257.1285; found 257.1285.
(5-benzyl-1H-pyrazol-3-yl)(2-hydroxyphenyl)methanone (4bh): As a light yellow solid (50 mg, 59%), m. p. 116-117 °C. 1H NMR
(400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.56 (ddd, J = 8.6, 7.2, 1.7 Hz, 1H), 7.42 – 7.27 (m, 5H), 7.07 – 6.97 (m, 2H), 6.72 (s, 1H), 4.11 (s,
2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 190.6, 160.7, 138.8, 135.2, 132.6, 128.7, 128.6, 126.6, 121.2, 119.0, 117.5, 107.5, 31.3.
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H16N2O2, 279.1128; found 279.1133.
General procedure for the synthesis of chromeno[3,2-c]pyrazoles (5a-5n). A 5 mL reaction tube equipped with a magnetic stirrer was
charged with aldehyde (0.36 mmol), tosylhydrazide (78 mg, 0.42 mmol), methanol (2 mL). The mixture was stirred at room temperature
for 30 min. After removing the solvent in vacuo, 3-chlorochromone (0.3 mmol), Cs2CO3 (293 mg, 0.9 mmol),and DMF (2 mL) were
added, and the reaction mixture was heated at 70 °C under open atmosphere until chromeno[3,2-c]pyrazoles formation was complete. Then
the mixture was extracted with EtOAc (10 mL × 3), and washed with brine (10 mL), dried over anhydrous Na2SO4 and evaporated to
dryness to yield a crude product, which was purified by silica gel chromatography eluted with PE: EtOAc = 2:1 to give the product as a
yellow solid.
Gram-scale preparation of 5a. A 100 mL reaction tube equipped with a magnetic stirrer was charged with benzaldehyde (676 μL, 6.65
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mmol), tosylhydrazide (1444 mg, 7.76 mmol), methanol (40 mL). The mixture was stirred at room temperature for 30 min. After removing
the solvent in vacuo, 3-chlorochromone (1000 mg, 5.54 mmol), Cs2CO3 (5412 mg, 16.61 mmol), and DMF (40 mL) were added, and the
reaction mixture was heated at 110 °C under open atmosphere until pyrazole formation was complete. Then the mixture was extracted with
EtOAc (40 mL × 3), and washed with brine (40 mL), dried over anhydrous Na2SO4 and evaporated to dryness to yield a crude reaction
product, which was purified by silica gel chromatography eluted with PE: EtOAc = 2:1 to give the product as yellow solid (1180 mg,
81%).
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3-phenylchromeno[3,2-c]pyrazol-9(1H)-one (5a): As a light yellow solid (67 mg, 86%), m. p. 270-272 °C. 1H NMR (500 MHz,
DMSO-d6) δ 14.47 (s, 1H), 8.34 – 8.26 (m, 1H), 8.14 (d, J = 7.6 Hz, 2H), 7.95 – 7.85 (m, 2H), 7.62 – 7.52 (m, 3H), 7.45 (t, J = 7.4 Hz, 1H).
13C{1H} NMR (126 MHz, DMSO-d6) δ 168.3, 156.6, 143.5, 136.6, 135.3, 131.2, 129.5, 128.8, 127.9, 126.4, 126.1, 125.0, 122.6, 119.4.
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H12N2O2, 263.0815; found 263.0818.
7-methyl-3-phenylchromeno[3,2-c]pyrazol-9(1H)-one (5b): As a light yellow solid (52 mg, 63%), m. p. >300 °C. 1H NMR (400 MHz,
DMSO-d6) δ 14.44 (s, 1H), 8.17 – 8.09 (m, 2H), 8.07 – 8.03 (m, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.70 (dd, J = 8.7, 2.2 Hz, 1H), 7.56 (t, J =
7.7 Hz, 2H), 7.48 – 7.41 (m, 1H), 2.46 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 168.2, 154.9, 143.5, 136.5, 136.3, 134.4, 131.2,
129.5, 128.7, 127.9, 126.0, 125.6, 122.3, 119.1, 20.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H14N2O2, 277.0972; found 277.0972.
7-methoxy-3-phenylchromeno[3,2-c]pyrazol-9(1H)-one (5c): As a light yellow solid (60 mg, 69%), m. p. 265-268 °C. 1H NMR (400
MHz, DMSO-d6) δ 14.45 (s, 1H), 8.13 (d, J = 7.7 Hz, 2H), 7.85 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 3.1 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H), 7.50
(dd, J = 9.2, 3.2 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 3.90 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 168.0, 156.3, 151.3, 143.6, 136.4,
131.2, 129.5, 128.7, 127.6, 126.1, 124.3, 123.2, 120.9, 106.2, 56.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H14N2O3, 293.0921;
found 293.0926.
6-methoxy-3-phenylchromeno[3,2-c]pyrazol-9(1H)-one (5d): As a light yellow solid (81 mg, 93%), m. p. 276-278 °C. 1H NMR (500
MHz, DMSO-d6) δ 8.19 – 8.09 (m, 3H), 7.56 (t, J = 7.7 Hz, 2H), 7.49 – 7.40 (m, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.9, 2.4 Hz,
1H), 3.94 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 167.7, 164.5, 158.3, 142.9, 135.2, 130.6, 129.1, 128.3, 127.3, 125.6, 116.0,
113.9, 101.2, 56.3. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H14N2O3, 293.0921; found 293.0927.
6-fluoro-3-phenylchromeno[3,2-c]pyrazol-9(1H)-one (5e): As a light yellow solid (67 mg, 79%), m. p. 237-240 °C. 1H NMR (500
MHz, DMSO-d6) δ 8.31 (dd, J = 8.9, 6.5 Hz, 1H), 8.13 – 8.07 (m, 2H), 7.78 (dd, J = 9.9, 2.4 Hz, 1H), 7.55 (t, J = 7.7 Hz, 2H), 7.46 – 7.41
(m, 1H), 7.39 (td, J = 8.5, 2.5 Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 167.9, 165.8 (d, J = 252.5 Hz), 157.8 (d, J = 14.0 Hz),
143.5, 130.6, 129.4, 129.1 (d, J = 11.1 Hz), 128.8, 126.0, 119.9, 113.5 (d, J = 22.9 Hz), 106.1 (d, J = 26.2 Hz). HRMS (EI-DFS) m/z: [M]+
calcd for C16H9FN2O2, 280.0643; found 280.0640.
7-chloro-3-phenylchromeno[3,2-c]pyrazol-9(1H)-one (5f): As a light yellow solid (37 mg, 42%), m. p. 250-253 °C. 1H NMR (400
MHz, DMSO-d6) δ 8.13 (d, J = 1.5 Hz, 1H), 8.11 – 8.05 (m, 2H), 7.91 – 7.86 (m, 2H), 7.54 (t, J = 7.6 Hz, 2H), 7.46 – 7.40 (m, 1H).
13C{1H} NMR (126 MHz, DMSO-d6) δ 167.5, 155.1, 143.4, 134.9, 130.5, 129.4, 129.2, 128.8, 126.0, 125.2, 123.9, 121.7, 110.0. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C16H10ClN2O2, 296.0347; found 296.0343.
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6-chloro-3-phenylchromeno[3,2-c]pyrazol-9(1H)-one (5g): As a light yellow solid (69 mg, 78%), m. p. 252-255 °C. 1H NMR (500
MHz, DMSO-d6) δ 8.20 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 7.7 Hz, 2H), 7.96 (d, J = 2.1 Hz, 1H), 7.55 – 7.48 (m, 3H), 7.41 (dd, J = 8.2, 6.4
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Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 1687.0, 156.7, 143.2, 139.4, 135.4, 130.6, 129.4, 128.9, 128.7, 128.1, 126.0, 125.3, 121.6,
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119.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H11ClN2O2, 297.0425; found 297.0427.
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7-bromo-3-phenylchromeno[3,2-c]pyrazol-9(1H)-one (5h): As a light yellow solid (60 mg, 58%), m. p. 278-280 °C. 1H NMR (400
MHz, DMSO-d6) δ 8.29 (d, J = 2.6 Hz, 1H), 8.12 – 8.06 (m, 2H), 8.01 (dd, J = 9.0, 2.6 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.56 (t, J = 7.7
Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 167.4, 155.5, 143.3, 137.6, 135.5, 130.0, 129.5, 128.8, 128.3,
126.0, 124.3, 121.9, 117.0. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H10BrN2O2, 339.9842; found 339.9822.
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3-phenyl-7-(trifluoromethyl)chromeno[3,2-c]pyrazol-9(1H)-one (5i): As a light yellow solid (45 mg, 45%), m. p. 155-157 °C. 1H
NMR (600 MHz, DMSO-d6) δ14.63 (s, 1H), 8.54 – 8.46 (m, 1H), 8.22 (d, J = 7.3 Hz, 1H), 8.18 – 8.07 (m, 3H), 7.57 (d, J =
6.5 Hz, 2H), 7.45 (d, J = 6.3 Hz, 1H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 167.2, 158.2, 143.5, 136.6, 131.2, 130.8, 130.0,
129.4, 128.8, 127.8, 126.0, 124.1 (q, J = 272.2, 271.6 Hz), 123.8, 122.7, 121.2. HRMS (EI-DFS) m/z: [M]+ calcd for C17H9F3N2O2,
330.0609; found 330.0611.
7-chloro-5-methyl-3-phenylchromeno[3,2-c]pyrazol-9(1H)-one (5j): As a light yellow solid (71 mg, 76%), m. p. 286-287 °C. 1H
NMR (500 MHz, DMSO-d6) δ 8.03 – 7.99 (m, 2H), 7.95 (s, 1H), 7.67 (s, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 2.37 (s,
3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 166.8, 154.3, 143.1, 142.8, 135.0, 130.3, 129.7, 129.0, 128.4, 125.6, 125.0, 121.4, 120.9, 20.2.
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H13ClN2O2, 311.0582; found 311.0579.
3-(4-methoxyphenyl)chromeno[3,2-c]pyrazol-9(1H)-one (5k): As a light yellow solid (82 mg, 94%), m. p. 250-253 °C. 1H NMR (500
MHz, DMSO-d6) δ 8.28 (dd, J = 7.9, 1.7 Hz, 1H), 8.08 – 8.01 (m, 2H), 7.89 (ddd, J = 8.6, 6.8, 1.8 Hz, 1H), 7.83 (dd, J = 8.5, 1.1 Hz, 1H),
7.52 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.16 – 7.09 (m, 2H), 3.84 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 168.7, 159.7, 156.6, 142.8,
135.2, 127.4, 126.4, 124.8, 123.3, 122.7, 119.3, 114.9, 55.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H13N2O3, 292.0842; found
292.0842.
3-(4-fluorophenyl)chromeno[3,2-c]pyrazol-9(1H)-one (5l): As a light yellow solid (75 mg, 90%), m. p. >300 °C. 1H NMR (500 MHz,
DMSO-d6) δ 8.27 (dd, J = 8.0, 1.6 Hz, 1H), 8.17 – 8.10 (m, 2H), 7.88 (ddd, J = 8.7, 6.9, 1.7 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.52 (t, J =
7.4 Hz, 1H), 7.38 (t, J = 8.8 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 168.2, 162.0 (d, J = 245.5 Hz), 156.2, 142.7, 134.9, 134.6,
128.1, 127.7 (d, J = 8.2 Hz), 127.1, 126.0, 124.6, 122.3, 118.9, 116.1 (d, J = 21.7 Hz). HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C16H10FN2O2, 280.0643; found 280.0647.
3-(thiophen-3-yl)chromeno[3,2-c]pyrazol-9(1H)-one (5m): As a yellow solid (66 mg, 83%), m. p. 250-252 °C. 1H NMR (500 MHz,
DMSO-d6) δ 8.26 (dd, J = 8.0, 1.8 Hz, 1H), 8.16 – 8.10 (m, 1H), 7.89 – 7.81 (m, 2H), 7.77 – 7.72 (m, 2H), 7.49 (ddd, J = 8.0, 6.6, 1.6 Hz,
1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 168.3, 156.2, 142.3, 134.8, 131.1, 127.4, 126.1, 125.4, 124.5, 122.5, 122.4, 119.0. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C14H10N2O2S, 269.0379; found 269.0377.
3-cyclohexylchromeno[3,2-c]pyrazol-9(1H)-one (5n): As a light yellow solid (22 mg, 27%), m. p. 180-181 °C. 1H NMR (500 MHz,
DMSO-d6) δ 8.29 (dd, J = 8.0, 1.8 Hz, 1H), 7.89 (ddd, J = 8.7, 7.0, 1.8 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.56 – 7.50 (m, 1H), 3.01 (tt, J =
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11.7, 3.6 Hz, 1H), 2.12 – 2.04 (m, 2H), 1.86 (dq, J = 10.7, 3.5 Hz, 2H), 1.80 – 1.65 (m, 3H), 1.53 – 1.42 (m, 2H), 1.40 – 1.31 (m, 1H).
13C{1H} NMR (126 MHz, DMSO-d6) δ 168.8, 156.4, 143.2, 135.0, 126.4, 124.6, 122.7, 119.1, 35.4, 31.8 26.2, 26.0. HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C16H18N2O2, 269.1285; found 269.1280.
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website.
Crystallographic data and characterization of new compounds (1H and 13C NMR spectra).
X-ray data for compound 4ao.
X-ray data for compound 5a.
AUTHOR INFORMATION
Corresponding Author
*†‡ E-mail: chyang@simm.ac.cn.
*†‡ E-mail: xiaofeizhang@simm.ac.cn.
PresentAddresses
† State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China.
‡ School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by the NSFC (No. 81872722), National Science & Technology Major Project “Key New Drug
Creation and Manufacturing Program”, China (No. 2018ZX09711002), and SKLDR/SIMM (SIMM1803KF-07).
REFERENCES
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Electron-Demand Diels–Alder Reaction of Chromone Heterodienes Using 3-Vinylindoles as Dienophiles. J. Org. Chem. 2013, 78, 10233-
10239; (b) Xiang, H.; Yang, C. A Facile and General Approach to 3-((Trifluoromethyl)thio)-4H-chromen-4-one. Org. Lett. 2014, 16,
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5686-5689; (c) Liu, Y.; Jin, S.; Huang, L.; Hu, Y. Phase Transfer Reagent Promoted Tandem Ring-Opening and Ring-Closing Reactions
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a
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