A facile and expeditious approach to substituted 1H-pyrazoles catalyzed by iodine

Article abstract of DOI:10.1016/j.tetlet.2016.05.020

A facile and expeditious method for the synthesis of 1H-pyrazoles by the reaction of α,β-unsaturated aldehydes/ketones and sulfonyl hydrazide catalyzed by as low as 2 mol % I₂ has been demonstrated. This synthetic system features simple operation and mild reaction conditions, and displays a broad functional group tolerance furnishing good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2016.05.020

Accepted Manuscript
A facile and expeditious approach to substituted 1H-pyrazoles catalyzed by io-
dine
Hailei Zhang, Qian Wei, Guodong Zhu, Jingping Qu, Baomin Wang
PII:
S0040-4039(16)30532-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.020
TETL 47639
Reference:
Tetrahedron Letters
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3 May 2016
Please cite this article as: Zhang, H., Wei, Q., Zhu, G., Qu, J., Wang, B., A facile and expeditious approach to
substituted 1H-pyrazoles catalyzed by iodine, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.05.020
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Tetrahedron Letters
A facile and expeditious approach to substituted 1H-pyrazoles catalyzed by iodine
Hailei Zhang, Qian Wei, Guodong Zhu, Jingping Qu, Baomin Wang
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, 2 Linggong Road, Dalian
116024, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile and expeditious method for the synthesis of 1H-pyrazoles by the reaction of α,β-
unsaturated aldehydes/ketones and sulfonyl hydrazide catalyzed by as low as 2 mol% I2 has
been demonstrated. This synthetic system features simple operation and mild reaction
conditions, and displays a broad functional group tolerance furnishing good to excellent yields.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Metal-free
α,β-Unsaturated carbonyl compounds
Sulfonyl hydrazides
Iodine catalysis
Pyrazoles
Introduction
efficiency limitations. For instance, formation of two
regioisomers by the condensation routes is an inevitable
While the relative incapacity of Nature to cope with the N-N
bond results in pyrazole containing natural products a real
infrequency, such heterocycles, which are not only of
drawback and methods based on nucleophilic reactions
necessitate multistep procedures to secure the starting material,
while methodologies depending on dipolar cycloaddition
reactions usually characterize regioselective disadvantages, and
diazo compounds are considered to be poisonous and potentially
explosive.
considerable application but also
a perennial source of
fascination and inspiration to scientists for more than a century,
represent a diverse array of significantly functional compounds
of unnatural origin abundantly featured in agrochemicals,
pharmaceuticals, material and synthetic chemistry.1 Compounds
bearing the pyrazole nucleus, in particular, have exhibited a wide
spectrum of therapeutic application and a plethora of drugs have
progressed to the market,2,3 such as lonazolac,2b fipronil,2c
Viagra,2d celecoxib,2e and many others. Pyrazoles also constantly
act as essential building blocks of ligands for transition metals,
supermolecules and liquid crystals.4 Owing to their multifarious
and prominent properties, the discovery of environmentally
benign, efficient and practical approaches for the construction
Among these popular procedures for pyrazole synthesis,
hydrazine hydrate is applied as a predominant nitrogen source,
nevertheless, most of these transformations are dependent on a
large excess amount of hydrazine hydrate and oxidant or base. In
1987, Shechter et al. published the early report in which only 1.1
eq. of tosyl hydrazide with unsaturated ketone was used as
nitrogen source for the preparation of 1H-cyclooctapyrazoles.9
Then, a remarkable number of novel 1H-pyrazoles synthesis
using substituted hydrazides, especially sulfonyl hydrazides as
nitrogen transfer reagents have been reported. In 2011, Yu and
co-workers established a highly efficient and eco-friendly
protocol for the preparation of substituted 1H-pyrazoles by one-
pot condensation reaction of α,β-unsaturated carbonyl
compounds with tosyl hydrazide promoted by stoichiometric
tetrabutylammonium bromide in water (Scheme 1).10 In 2014,
Chang et al. developed an efficient method for regioselective
pyrazole preparation from α,β-unsaturated aldehydes/ketones and
hydrazines through I2-promoted oxidative intramolecular C−N
bond formation (Scheme 1).7c Although these approaches
resolved some of the conventional problems inherent in the
cycloaddition of diazo compounds to α,β-unsaturated carbonyl
and functionalization of pyrazole cores, especially in
a
regioselective manner, has always been an active field of
research of high impact in synthetic chemistry.5
The most commonly used approaches for the acquisition of
substituted pyrazoles include: 1) condensation of hydrazines with
1,3-dicarbonyl compounds or their synthetic equivalents,6 2)
condensation of α,β-unsaturated carbonyl compounds with
hydrazines followed by dehydrogenation,7 3) [3
+
2]
cycloadditions of 1,3-dipoles to dipolarophiles like alkenes and
alkynes,5g 4) the nucleophilic attack of hydrazines to flavones,
chromones, or isoxazoles.8 Although appealingly general, these
approaches have their own safety, eco-friendliness, scope or
———
Corresponding author: Tel.: +86-0411-8498-6190; fax: +86-0411-8498-6186; e-mail: bmwang@dlut.edu.cn

2
Tetrahedron
Scheme 1 Methods toward the preparation of substituted
Table 1 Optimization of reaction conditions a
pyrazoles between α,β-unsaturated carbonyl compounds and
substituted hydrazides
Entry Additive
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtOAc
H2O
t (h)
Yieldb (%)
49
1
2
3
4
5
TBHP
8
8
3
8
8
3
3
8
1.5
1.5
3
3
1.5
2
2
2
8
8
H2O2
K2CO3
Na2CO3
CH3COONa
KOH
53
75
36
Trace
72
75
Trace
93
84
78
88
95
95
71
Trace
23
76
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
---
EtOH
DMSO
DCE
10
11
12
13c
14d
15e
16f
17
18g
Scheme 2 Iodine source promoted reactions between α,β-
unsaturated carbonyl compounds and sulfonylhydrazides
THF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
K2CO3
compounds, the existing methodologies hereinabove suffer from
the requirement of metal salts, stoichiometric additives as well as
strong bases.
a Reaction conditions: benzylidenacetone 1a (0.50 mmol), TsNHNH2
(1.2 mmol), iodine (0.1 mmol), additive (1.5 mmol), solvent (2.0
o
mL), 75 C, open to air. b Isolated yield. c 5 mol% I2 was used. d 2
mol% I2 was used. e 1 mol% I2 was used. f No catalyst. g At 60 oC.
According to the published literature, sulfonyl hydrazides
constantly served for the construction of C-S bond with α,β-
unsaturated carbonyl compounds mediated by iodine source,
however, such preeminent transformations for the generation of
C-C bond or two C-N bonds remain comparatively infrequent to
date (Scheme 2).11 To the best of our knowledge, however, there
is no precedent study enabling the preparation of 1H-pyrazoles
from readily available α,β-unsaturated carbonyl compounds and
p-toluenesulfonyl hydrazide catalyzed by iodine. Herein, we
report the first example of an efficient and generally applicable
route for the construction of diversely substituted 1H-pyrazoles
via the annulation of α,β-unsaturated aldehydes/ketones along
with p-toluenesulfonyl hydrazine with a broad substrate scope,
simple reaction conditions and excellent yields. Notably, the
utilization of EtOH as a green medium and only 2 mol% iodine
as a highly efficient catalyst to prepare the pyrazole moiety in a
one-pot sequence make this reaction a green procedure.
to 2 mol% made no difference to the yield, while 1 mol% iodine
resulted in the decreasing yield of the pyrazole (Table 1, entries
14-15). Trace amount of the product was generated without
iodine catalyst on account of the difficult formation of the tosyl
hydrazone only in the presence of K2CO3, which indicated that
iodine was crucial to the condensation between α,β-unsaturated
carbonyl compounds and TsNHNH2 (Table 1, entry 16). By
assessing the base loading and temperature, it was found that
both were critical to this transformation (Table 1, entries 17-18).
Based on the optimal conditions, the scope and generality of
this transformation was conducted with an array of α,β-
unsaturated carbonyl compounds. As outlined in Table 2, a vast
variety of substitution patterns and functional groups smoothly
tolerated iodine-catalyzed conditions with TsNHNH2 to afford
the 1H-pyrazole products in high yields with excellent
regioselectivity. Satisfactorily, chalcones bearing functional
groups like -OH, -OMe, -Me, -X, and -NO2 were commendably
applied to the established reaction conditions to furnish the
desired products in satisfactory yields (Table 2, 2b-2l). Of note
was that o-hydroxyphenylpyrazole (Table 2, 2b), which is
conventionally synthesized by treatment of chromone, alkynone
or 1,3-diketone with hydrazine, and possesses broad bioactivities,
could be easily obtained in high yield.1a,1o The steric hindrance
was studied and proved to be all but negligible (Table 2, 2d and
2o). Meanwhile, significant electronic effects of the substituents
on the reactivity were observed. The result revealed that slightly
lower yields for substrates with strongly electron-withdrawing or
electron-donating substitutions, such as -OH and -NO2, in the R2
ring were got (Table 2, 2b and 2l), and the electronic effect of
substituent groups on the benzoyl ring has an insignificant impact
on the yields. It is worth mentioning that thienyl and naphthyl
substituted chalcones efficiently reacted with TsNHNH2 to afford
the corresponding pyrazoles under present catalytic conditions
(Table 2, 2m, 2n and 2r). Furthermore, we were delighted to
disclose that gratifying yield was also acquired from cinnamyl
Results and discussion
The investigation commenced with
a model reaction
employing chalcone 1a and p-toluenesulfonyl hydrazide in the
presence of various additives and solvents using iodine as the
selected catalyst to acquire the optimized reaction conditions, and
the results are summarized in Table 1. In consideration of
dehydrogenation of the 4,5-dihydro-1H-pyrazole formed by
condensation/Michael addition sequence, the initial optimization
was screened between different oxidants and bases.
Disappointedly, addition of different kinds of oxidants to the
reaction system did not lead to dramatically increased yields.
Then, we turned to bases, and thankfully, K2CO3 exhibited the
best performance to produce 3,5-diphenyl-1H-pyrazole 2a in
o
75% yield at 75 C under air, which indicated that deprotonation
by base had absolute predominance compared with oxidative
dehydrogenation via oxidant (Table 1, entry 3). Encouraged by
the primary result, the influence of other common solvents such
as EtOAc, H2O, EtOH, DMSO, DCE and THF were tested (Table
1, entries 7−12), and the best result (93%) was acquired in EtOH
(Table 1, entry 9). Most unexpectedly, reducing the loading of I2

Table 2 Synthesis of pyrazoles from α,β-unsaturated
carbonyl compounds and TsNHNH2
Scheme 3 Synthesis of pyrazoles from α,β-unsaturated
carbonyl compounds and PhNHNH2
a
Scheme 4 Control Experiments
entry
1
R1
R2
2
yield (%)b
95
Ph
Ph
2a
2b
2c
2d
2e
2f
2
Ph
2-HOC6H4
4-MeOC6H4
2-MeOC6H4
3-MeC6H4
4-MeC6H4
4-FC6H4
4-ClC6H4
3,4-Cl2C6H3
2-BrC6H4
4-BrC6H4
4-NO2C6H4
2-Naphthyl
2-Thienyl
Ph
70
3
Ph
86
4
Ph
93
5
Ph
94
6
Ph
96
7
Ph
2g
2h
2i
93
8
Ph
93
Scheme 5 Proposed mechanism
9
Ph
95
10
11
12
13
14
15
17
18
19
19
20
Ph
2j
91
Ph
2k
2l
96
Ph
79
Ph
2m
2n
2o
2p
2q
2r
2s
2t
92
Ph
88
Scheme 6 Gram-Scale Reaction
2-MeC6H4
3-BrC6H4
3- NO2C6H4
1-Naphthyl
H
88
Ph
94
Ph
96
Ph
89
Ph
96
A). It is noteworthy that the condensation reaction proceeded
faster than iodine-free procedure, which indicates that
condensation between α,β-unsaturated carbonyl compounds and
TsNHNH2 can be dramatically promoted by iodine (Scheme 4,
B). In a further experiment hydrazone (4a) was subjected to the
standard conditions and the relevant derivative (2a) was finally
found in 88% yield (Scheme 4, C). Nevertheless, there was
moderate yield of desired product formed without iodine, which
thereby suggests that iodine is of great importance to the
intramolecular cyclization of hydrazones.
Me
Ph
81
a Reaction conditions: 1 (0.5 mmol), TsNHNH2 (0.6 mmol), I2 (2 mol%),
K2CO3 (0.75 mmol), EtOH (2 mL) under air. Isolated yield.
aldehyde (Table 2, 2s). More importantly, 81% yield of 5-
methyl-3- phenyl-1H-pyrazole was observed when benzalacetone
was subjected to the standard condition (Table 2, 2t).13 By
comparing with previously published results, it could be easily
discerned that the new method not only saliently reduced the
reaction time, but above all successfully avoided the use of
strong base and excess additives.10
In light of the above experimental results and previously
published examples,7c,11a,12 a plausible reaction mechanism is
finally proposed (Scheme 5). At first, hydrazone (A) is generated
via condensation of α,β-unsaturated carbonyl compounds and
TsNHNH2 by the activation of iodine. Then, N-I bond (B) is
formed under K2CO3 followed by HI addition to the C-C double
bond and subsequent intramolecular cyclization to yield 4,5-
dihydro-1H-pyrazole D. Elimination of TsH from intermediate E
under the mediation of K2CO3 results in the formation of the
target product 2. Further investigations on the more detailed
mechanism are in progress in our laboratory.
Considering these inspiring results, further investigations of
this facile protocol were initiated with α,β-unsaturated
aldehydes/ketones and phenylhydrazine. Surprisingly, no
anticipated products were detected, which strongly displayed that
an alternative reaction mechanism for our process might exist in
contrast with Chang’s speculation (Scheme 3).7c
Then, several control experiments were carried out to discern
the probable mechanistic pathway thoroughly of this developed
protocol, as shown in Scheme 4. Firstly, chalcone (1a) was
treated with TsNHNH2 (1.2 eq.) in EtOH at refluxing temperature
in the presence of 2 mol% iodine and hydrazone (4a) was formed
in 73% yield in 10 minutes by way of condensation (Scheme 4,
We performed the reaction on a much larger scale to
demonstrate the practical applicability of the one-pot sequence
and a gram-scale synthesis of 2a was subjected to the our
developed experimental conditions. To our delight, the reaction

4
Tetrahedron
Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton,
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Med. Chem. 1997, 40, 1347.
proceeded smoothly, and the expected product 2a was isolated
in 93% yield (Scheme 6).
Conclusions
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In summary, a simple, green and practical system for the
regioselective preparation of 1H-pyrazole derivatives in the
presence of 2 mol% iodine using TsNHNH2 as nitrogen-transfer
reagent in EtOH under mild conditions has been demonstrated. In
contrast with reported procedures, the present procedure is
applicable and highly efficient, and has the advantage of short
reaction time and high yields. Moreover, the utilization of
catalytic amounts of iodine as an efficient catalyst to synthesize
pyrazole moiety in a one-pot condensation and cyclization
manner has been testified to be reliable. Last but not the least, the
present transformation proceeds in good yields and
commendably tolerates a wide range of functional groups, which
paves the way for the synthesis of 1H-pyrazoles and will gain
much attention in multidisciplinary fields for the preparation of
potentially bioactive derivatives.
4.
5.
Acknowledgments
We thank the National Natural Science Foundation of China
(No.21542007), the Program for New Century Excellent Talents
in University (NCET-11-0053), the Fundamental Research Funds
of the Central Universities (DUT15TD25) for support of this
work.
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M.;

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A facile and expeditious approach to
substituted 1H-pyrazoles catalyzed by iodine
Hailei Zhang, Qian Wei, Guodong Zhu, Jingping Qu, Baomin Wang*
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University
of Technology, Dalian 116024, P. R. China

Highlights



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A facile and expeditious approach to 1H-pyrazoles is developed.
Starting materials are α,β-unsaturated ketones/aldehydes and sulfonyl hydrazide.
The reaction is catalyzed by as low as 2 mol% I2.
The process features simple conditions, high yield, and broad substrate scope.