Iodine-Catalyzed Ring Opening of 1,1-Diacylcyclopropanes for Synthesis of Fully Substituted Pyrazole Derivatives

Article abstract of DOI:10.1002/ejoc.202000496

An iodine-catalyzed [3+2] cycloaddition/ring opening reaction of 1,1-diacylcyclopropanes with sulfonyl hydrazides has been reported. In the presence of 20 mol-% iodine, a range of structurally diverse fully substituted pyrazoles with a hydroxy functional group are obtained in moderate to excellent yields with extremely high regioselectivity.

Full text of DOI:10.1002/ejoc.202000496

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Iodine-Catalyzed Ring Opening of 1,1-Diacylcyclopropanes for
Synthesis of Fully Substituted Pyrazole Derivatives
Authors: Xiuqin Yang, Jin Zhu, Yishu Bao, Ziyu Ding, Fulai Yang, Ming
Chen, and Qingfa Zhou
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000496
Link to VoR: https://doi.org/10.1002/ejoc.202000496
01/2020

10.1002/ejoc.202000496
European Journal of Organic Chemistry
FULL PAPER
Iodine-Catalyzed Ring Opening of 1,1-Diacylcyclopropanes for
Synthesis of Fully Substituted Pyrazole Derivatives
Xiuqin Yang,[a] Jin Zhu,[a] Yishu Bao,[a] Ziyu Ding,[a] Fulai Yang,*[a] Ming Chen*[a] and Qingfa Zhou*[a]
[a]
X. Yang, J. Zhu, Y. Bao, Z. Ding, Dr. F. Yang, Dr M. Chen, Prof. Dr. Q. Zhou.
State Key Laboratory of Natural Medicines, Department of Organic Chemistry,
China Pharmaceutical University
Nanjing 210009, P. R. China.
E-mail: zhouqingfa@cpu.edu.cn; chm@cpu.edu.cn;fly1986@ustc.edu.cn
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: An iodine-catalyzed [3+2] cycloaddition/ring opening
reaction of 1,1-diacylcyclopropanes with sulfonyl hydrazides has been
reported. In the presence of 20 mol % iodine, a range of structurally
diverse fully substituted pyrazoles with a hydroxy functional group are
obtained in moderate to excellent yields with extremely high
regioselectivity.
carbonyl compounds.[9] However, little has been published on
synthesis of fully substituted pyrazole derivatives with a hydroxy
functional group in one step.[7g]
As a mild oxidant and mild Lewis acid property, iodine is
widely used in organic synthesis.[10] Recently, Chang's group has
realized iodine-mediated synthesis of pyrazole derivatives using
α,β-unsaturated aldehydes or ketones and hydrazine under
metal-free conditions in the form of oxidative C-N bond
formation.[11] Encouraged by this method, in this context, we
envisioned that sulfonyl hydrazides reacted with 1,1-
diacylcyclopropanes via cycloaddition to afford pyrazole ring,
which then undergo ring opening reaction to give fully substituted
pyrazole derivatives with a hydroxy functional group.
Introduction
Pyrazole is an extensively utilized moiety, particularly in the field
of medicinal chemistry, both as a pendant functional group and as
a core template in a wide variety of therapeutic areas.[1] At present,
many pyrrole skeleton-containing compounds have been
developed as marketed drugs or clinical research.[2] Among a
group of pyrazole derivatives, pyrazolol is a very special class,
because it not only can be oxidized into aldehydes or carboxylic
acids, but also be further modified into various alkoxypyrazoles.[3]
For example (Figure 1), BKI 1708 (I), as a synaptic kinase inhibitor,
can be used for the treatment of cryptosporidiosis.[4] Lonazolac
(II), as a nonsteroidal anti-inflammatory drug (NSAID), it can be
used to relieve pain caused by joints and spine, such as arthritis
and ankylosing spondylitis.[5] In addition, 3-alkoxypyrazoles (III)
can be used as an inhibitor of human dihydroorotate
dehydrogenase (DHODH) and shows activity against measles
virus.[6]
Results and Discussion
We initiated our investigation with the cyclization of cyclopropyl
ketone 1a and p-toluenesulfonyl hydrazide 2a in the presence of
iodine (Table 1). First, we selected dichloromethane as solvent,
disappointingly, no desired product was obtained at room
temperature. Then raising the reaction temperature to 70 ℃, the
target product was observed in 60% yield. Encouraged by this
result, various solvents were examined, and a 64% yield was
achieved when using acetonitrile as solvent. Moreover, replacing
iodine with other catalysts, such as N-iodosuccinimide (NIS),
sodium iodide, ammonium iodide, etc., gave much lower yields.
Finally, screening additives revealed that the additives have great
impact on the reaction. The highest yield, 81%, was obtained
when ammonium iodide was used as additive. Thus, the optimal
reaction conditions were 1 equiv. of 1a, 2 equiv. of 2a, 0.2 equiv.
of I2, and 2 equiv. of NH4I in CH3CN at 70 ℃. It is worth noting that
when ammonium iodide and iodine were added, the solution
showed a colorless state, so we speculated that the presence of
iodide ions can form iodine triple negative ions with iodine,
thereby improving the reaction yield.
Figure 1. Some inhibitors and drug active molecules.
During the course of a medicinal chemistry campaign, much
attention has been paid to the synthesis of substituted fully
substituted pyrazole derivatives.[7] On the other hand, the
synthesis of fully substituted pyrazole derivatives with a hydroxy
functional group via a highly efficient and convergent method
endured some challenges. The construction of alcohol motifs has
received intensive attention owing to the fact that these
compounds are versatile precursors of various functionalities and
moieties in organic synthesis.[8] The traditional method used
preformed organometallic reagents to couple with various
With the optimal reaction conditions secured, a series of 1,1-
diacylcyclopropanes were investigated for this reaction (Table 2).
First, a range of cyclopropylketones bearing various aromatic
ketones (R2 = aryl) proved to work well in this reaction, in
moderate to good yields (54-88%) with extremely high
regioselectivity. Notably, the reaction tolerated a variety of
functional groups, such as alkoxy, fluoro, chloro, bromo, iodo.
Methyl substituted cyclopropylketones (R2 = Me) gave 3r with a
lower yield (48%). However, when both substitutions of the
1
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10.1002/ejoc.202000496
European Journal of Organic Chemistry
FULL PAPER
Table 2. Scope of 1,1-diacylcyclopropanes.[a]
cyclopropane were benzoyl, no product (3s) was found under the
standard conditions. The extra substituent (R1) on the cyclopropyl
ketones also have a great influence on the yield. When a series
of aryl-, vinyl-, or alkyl-substituted cyclopropyl ketones (1a-1r)
were treated, the desired products (3a-3r) were obtained in
moderate to good yields. When the substituent (R1 = H, Me), the
desired products (3t-3v) were obtained in moderate to good yields.
Subsequently, the scope of sulfonyl hydrazides was tested
(Table 3). A range of aryl sulfonyl hydrazides that have electron-
donating and electron-withdrawing groups gave the desired
products in moderate to good yields (4a-4l). In addition, alkyl
sulfonyl hydrazides proved to be suitable reaction partners, giving
products (4m-4q) with similar efficiency. In addition to a variety of
sulfonyl hydrazides, simple aliphatic hydrazides, phenyl
hydrazines and hydrazine hydrate can also react under our
standard condition to obtain the corresponding products (4r-4t).
Table 1. Optimization on Reaction Conditions.[a]
[a] Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), I2 (0.02 mmol), NH4I (0.2
mmol), solvent (1.0 mL), under air in a sealed tube at 70 ℃ (oil bath) for 16 h.
[b] Isolated yield based on 1.
Catalyst
(equiv.)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.3)
I2 (0.4)
NBS (0.2)
NIS (0.2)
NH4I (2.0)
NaI (2.0)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
Temp.
( ℃ )
70
70
70
70
70
70
70
70
70
70
80
90
70
70
70
70
70
70
70
70
70
70
70
70
70
70
60
Entry
Solvent
Yield[b] (%)
Table 3. Scope of sulfonyl hydrazides.[a]
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
60
48
43
41
46
EtOAc
Toluene
CH3NO2
CH3CN
DMSO
DMF
64
trace
trace
33
40
59
trace
30
59
54
56
42
58
35
62
trace
53
77
81
trace
35
Dioxane
THF
10
11
12
13[c]
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
d]
14[
15
16
17
18
19
20
21[e]
22[f]
23[g]
24[h]
25[i]
26[j]
27[k]
56
[a] Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), I2 (0.02 mmol), NH4I (0.2
mmol), solvent (1.0 mL), under air in a sealed tube at 70 ℃ (oil bath) for 16 h.
[b] Isolated yield based on 2.
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), I2 (0.02 mmol), solvent
(1.0 mL), under air in a sealed tube at 70 ℃ (oil bath) for 16 h. [b] Isolated yield
based on 1a. [c] 1a (0.12 mmol), 2a (0.1 mmol). [d] 1a (0.1 mmol),2a (0.3 mmol).
[e] TBHP (2 equiv.) as additive. [f] KI (2 equiv.) as additive. [g] NaI (2 equiv.) as
additive. [h] NH4I (2 equiv.) as additive. [i] TsOH (1 equiv.) as additive. [j] Et3N
(1 equiv) as additive. [k] NH4I (2 equiv.) as additive.
mixture of diacylcyclopropane and sulfonyl hydrazide had no
effect on the reaction efficiency, indicating that the reaction
process might not involve radical intermediates (Scheme 1, eq 2).
Furthermore, we also used Intermediate 5a alone to react under
standard conditions and found that the target product could not
be obtained. Combined with our previous screening experiments,
without adding any catalyst, only adding 2 equiv of sulfonyl
hydrazide can not get the target product (Scheme 1,eq 3).
Therefore, we exclude the catalysis of sulfonyl hydrazide.
To gain insight into the reaction mechanism, a series of
control experiments with possible intermediates was performed
(Scheme 1). Compound 5a was easily obtained under the
standard conditions. Treatment of 5a with sulfonyl hydrazides
gave the product 3a in 74% yield, which substantially
demonstrates that the reaction went through a sulfonylhydrazone
intermediate (Scheme 1, eq 1). Moreover, the addition of the free
radical inhibitor 2,6-di-tert-butyl-p-cresol (BHT) to the reaction
2
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10.1002/ejoc.202000496
European Journal of Organic Chemistry
FULL PAPER
According to the results of the above control experiments, a
proposed pathway is illustrated (Scheme 2). Initially,
diacylcyclopropane 1 reacts with sulfonyl hydrazide to give
p-toluenesulfonyl can be easily removed, affording the compound
14 in 71% yield (Scheme 3).
sulfonylhydrazone
6,
which
undergoes
intramolecular
condensation to offer 7. Then intermediate 7 reacts with iodine to
afford intermediate 8 and at the same time iodine is converted into
hypoiodic acid[12-13]. Due to the ring tension, 8 undergoes ring
opening to give 9, which is attacked by the previously removed
hydroxyl anion to give the desired product 3 or 4.
Scheme 3. Gram scale and synthetic transformations.
Conclusion
Scheme 1. Control experiments.
In conclusion, we have developed a highly effective strategy to
achieve
iodine-catalyzed
[3+2]
cycloaddition
of
diacylcyclopropanes with sulfonyl hydrazide. This reaction
tolerates a broad range of cyclopropyl ketones and sulfonyl
hydrazides to afford useful and densely functionalized pyrazole
derivatives with an hydroxy functional group. The easy handle
process, high synthetic value of resulting products, and intriguing
mechanism of the titled process render it not only conceptually
novel, but also synthetically useful.
Experimental Section
General Procedure for Synthesis of 3 or 4: To a solution of sulfonyl
hydrazide 2 (0.2 mmol) in CH3CN (1.0 mL) was added NH4I (28.98 mg, 0.2
mmol), diacylcyclopropane 1 (0.1 mmol) and I2 (5.08 mg, 0.02 mmol). The
resulting mixture was stirred at 70 ℃ (oil bath) under air for 16 h, cooled
Scheme 2. Proposed mechanism.
to room temperature, and purified by silica gel chromatography, eluting
with petroleum ether/ethyl acetate (10/1 to 5/1) to give mainly desired
product 3 or 4. 3a: 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H),
7.52 (dd, J = 6.5, 2.9 Hz, 2H), 7.40 – 7.33 (m, 3H), 7.29 (d, J = 8.2 Hz, 2H),
7.19 – 7.07 (m, 3H), 7.02 – 6.93 (m, 2H), 4.55 (t, J = 6.8 Hz, 1H), 2.95 (dd,
J = 14.4, 6.9 Hz, 1H), 2.77 (dd, J = 14.4, 6.7 Hz, 1H), 2.41 (s, 3H), 2.17 (s,
3H), 2.13 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 155.4, 145.2, 143.2, 142.3,
135.4, 132.5, 129.9, 128.7, 128.5, 128.4, 128.3, 127.8, 127.7, 125.6, 116.8,
74.0, 33.7, 21.7, 11.2; HRMS (ESI) calcd for C25H25N2O3S+ (M+H)+
433.1580, found 433.1579.
To demonstrate the practicality of this protocol, a gram-scale
reaction proceeded smoothly without apparent yield loss
(Scheme 3). In the end, to indicate the synthetic utility of reaction,
we undertook a series of reactions using the representative
product 4a. The vinyl-bearing product 4a can form a vinyl α-
addition product 10 in 86% yield under the action of 2-generation
Grubbs catalyst. At the same time, the double bond can be
selectively reduced by H2 and Pd/C, obtaining a double bond
reduction product 12 in 70% yield, while 4a can undergo
intramolecular enol-type interconversion and isomerization to
carbonyl compound 11. In addition, it can also be selectively
oxidized to ketone by Dess-Martin oxidant to obtain oxidation
product 13 in 85% yield. Moreover, at high temperature, the group
3
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10.1002/ejoc.202000496
European Journal of Organic Chemistry
FULL PAPER
Synthesis of 10: To a solution of 4a (38.25 mg, 0.1 mmol) in toluene (1.0
mL) was added methyl acrylate (86.09 mg, 1.0 mmol), phenol (4.70 mg,
0.05 mmol) and Grubbs2nd catalyst (2.12 mg, 0.0025 mmol). The resulting
mixture was stirred at 110 ℃ (oil bath) under air for 30 min, cooled to room
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (Grant Nos. 21102179 and
21572271), Qing Lan Project of Jiangsu Province, and the
“Double First-Class” University project (CPU2018GY35,
CPU2018GF02) and Postgraduate Scientific Research
Innovation Projects of Jiangsu Province (KYCX19_0624).
temperature, and purified by silica gel chromatography, eluting with
petroleum ether/ethyl acetate (8:1) to give 10 in 86% yield. 1H NMR (400
MHz, CDCl3) δ 7.88 (d, J = 8.3 Hz, 2H), 7.58 – 7.50 (m, 2H), 7.42 – 7.36
(m, 3H), 7.32 (d, J = 8.3 Hz, 2H), 6.79 – 6.73 (dd, J = 15.6, 4.8 Hz, 1H),
5.93 – 5.82 (dd, J = 15.6, 1.6 Hz, 1H), 4.29 – 4.19 (m, 1H), 3.71 (s, 3H),
2.82 – 2.65 (m, 2H), 2.52 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 166.6, 155.2, 148.7, 145.5, 142.4, 135.0, 132.1, 130.0, 128.9, 128.6,
128.4, 127.8, 120.3, 116.0, 70.7, 51.7, 31.0, 21.8, 11.9; HRMS (ESI) calcd
for C23H25N2O5S+ (M+H)+ 441.1479, found 441.1480.
Keywords: Iodine catalysis • Cycloaddition • Ring opening •
Pyrazole derivatives
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Synthesis of 11 and 12: To a solution of 4a (38.25 mg, 0.1 mmol) and
Pd/C (15.96 mg) in MeOH (1.0 mL) was stirred at room temperature under
1.0 atm hydrogen atmosphere. After being stirred for 2 h, the mixture was
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yield.11:1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 8.3 Hz, 2H), 7.46 – 7.36
(m, 5H), 7.34 (d, J = 7.8 Hz, 2H), 3.53 (s, 2H), 2.47 (s, 3H), 2.42 (s, 3H),
2.36 (q, J = 7.3 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 207.4, 155.3, 145.4, 142.3, 135.2, 132.0, 130.0, 128.8, 128. 6,
128.4, 127.9, 114.0, 37. 8, 35.4, 21.7, 11.8, 7.8; HRMS (ESI) calcd for
C21H23N2O3S+ (M+H)+ 383.1424, found 383.1426; 12: 1H NMR (300 MHz,
CDCl3) δ 7.90 (d, J = 8.3 Hz, 2H), 7.64 – 7.54 (m, 2H), 7.44 – 7.36 (m, 3H),
7.32 (d, J = 8.2 Hz, 2H), 3.57 – 3.39 (m, 1H), 2.71 – 2.57 (m, 2H), 2.54 (s,
3H), 2.42 (s, 3H), 1.44 – 1.35 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 155.4, 145.3, 141.9, 135.3, 132.5, 129.9, 128.7, 128.5,
128.4, 127.9, 117.5, 73.0, 31.3, 29.8, 21.7, 11.8, 9.8; HRMS (ESI) calcd
for C21H25N2O3S+ (M+H)+ 385.1580, found 385.1582.
[2] E. Yen-Pon, P. A. Champagne, L. Plougastel, S. Gabillet, P. Thuery, M.
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Synthesis of 13: To a solution of 4a (38.25 mg, 0.1 mmol) in CH2Cl2 (2.0
mL) was added Dess-Martin reagent (50.90 mg, 0.12 mmol). The resulting
mixture was stirred at room temperature for 1.5 h, and purified by silica gel
chromatography, eluting with petroleum ether/ethyl acetate (10:1) to give
13 in 85% yield. 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 8.2 Hz, 2H), 7.44
– 7.35 (m, 5H), 7.32 (d, J = 8.0 Hz, 2H), 6.42 – 6.12 (m, 2H), 5.81 (dd, J =
10.1, 1.4 Hz, 1H), 3.71 (s, 2H), 2.46 (s, 3H), 2.42 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 196.1, 155.4, 145. 5, 142.6, 135.2, 135.1, 131.9, 130.0,
129.4, 128.8, 128.6, 128.4, 127.8, 113.5, 35.5, 21.7, 11.8; HRMS (ESI)
calcd for C21H21N2O3S+ (M+H)+ 381.1267, found 381.1269.
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Synthesis of 14: To a solution of 3a (43.25 mg, 0.1 mmol) in DMSO (1.0
mL). The resulting mixture was stirred at 120 ℃ for 1 h, cooled to room
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temperature, and purified by silica gel chromatography, eluting with
petroleum ether/ethyl acetate (3:1) to give 14 in 71% yield. 1H NMR (500
MHz, DMSO-d6) δ 7.59 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.33
(t, J = 7.5 Hz, 1H), 7.24 (t, J = 7.2 Hz, 2H), 7.21 – 7.14 (m, 3H), 4.58 (t, J
= 6.8 Hz, 1H), 2.91 (dd, J = 14.3, 7.2 Hz, 1H), 2.71 (dd, J = 14.3, 6.6 Hz,
1H), 1.90 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 144.0, 132.3, 128.7, 128.3,
128.0, 127.9, 127.5, 125.8, 111.4, 74.3, 33.9, 10.7; HRMS (ESI) calcd for
C18H19N2O+ (M+H)+ 279.1492, found 279.1496.
4
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10.1002/ejoc.202000496
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Entry for the Table of Contents
Heterocycles Synthesis: Iodine-catalyzed ring opening of 1,1-diacylcyclopropanes for synthesis of fully substituted pyrazole
derivatives have been reported. This reaction tolerates a broad range of cyclopropyl ketones and sulfonyl hydrazides to afford useful
and densely functionalized pyrazole derivatives with an hydroxy functional group.
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