Dual roles of sulfonyl hydrazides: A three-component reaction to construct fully substituted pyrazoles using TBAI/TBHP

Article abstract of DOI:10.1021/ol501312s

A mild and rapid approach has been developed for the construction of fully substituted pyrazoles using TBAI as a catalyst and TBHP as an oxidant, in which tosylhydrazide functions as the ring component and sulfonyl precursor. This protocol features a wide substrate scope with a broad range of functional group tolerance, utilizes easily available starting materials, can be scaled-up, and is operationally simple.

Full text of DOI:10.1021/ol501312s

Letter
pubs.acs.org/OrgLett
Dual Roles of Sulfonyl Hydrazides: A Three-Component Reaction
To Construct Fully Substituted Pyrazoles Using TBAI/TBHP
Jie Zhang,† Ying Shao,*,‡ Hongxiang Wang,† Qiang Luo,† Jijun Chen,† Dongmei Xu,*,†
and Xiaobing Wan*,†
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P. R. China
‡Key Laboratory of Advanced Catalytic Materials and Technology, Changzhou University, Changzhou 213164, P. R. China
S
* Supporting Information
ABSTRACT: A mild and rapid approach has been developed for the construction of fully substituted pyrazoles using TBAI as a
catalyst and TBHP as an oxidant, in which tosylhydrazide functions as the ring component and sulfonyl precursor. This protocol
features a wide substrate scope with a broad range of functional group tolerance, utilizes easily available starting materials, can be
scaled-up, and is operationally simple.
yrazoles and their derivatives have attracted considerable
attention because of their wide applications in the phar-
as the ring component as well as a sulfonyl precursor to con-
struct a novel fully substituted pyrazole in one step. As a result,
we herein described the successful execution of this ideal and
fully substituted pyrazoles were prepared efficiently without
isolating or purifying any intermediates (Scheme 1).
P
maceutical and agrochemical sciences.1 For example, Celebrex,2
employed as a selective COX-2 inhibitor, is one of the top 200
brand name drugs by total US prescriptions in 2012.3 Addi-
tionally, pyrazoles serve as ligands in coordination chemistry,4
precursors to N-heterocyclic carbenes (NHCs),5 and direct-
ing groups for C−H activations.6 As a result, a variety of
methods have been elegantly developed for the synthesis of
pyrazoles.7−10 Among the various pyrazoles, fully substituted
pyrazoles are notably prevalent in many bioactive molecules.11
The most popular approaches toward them consist of the
cyclocondensation of a monosubstituted hydrazine with a
substituted 1,3-dielectrophile,12 the [3 + 2] cycloaddition,13 and
the functionalization of preformed trisubstituted pyrazoles.14 In
2010, Glorius et al. reported a new method for the synthesis of
fully substituted pyrazoles from enamines and nitriles via an
oxidative N−N bond formation.15 However, in the majority of
these methods, complex prefunctionalized starting materials or
multistep sequences were usually required. Therefore, a simple
and rapid protocol is still highly desirable for the construction
of fully substituted pyrazoles.
Scheme 1. Our Strategy for the Synthesis of Fully
Substituted Pyrazoles
Initially, the reaction of acetylacetone 1a and tosylhydrazide
2a using TBAI/TBHP18 afforded the desired 3,5-dimethyl-1,4-
ditosyl-1H-pyrazole 3a in moderate yield (Table 1, entry 1).
Gratifyingly, the desired product 3a was isolated in 72% and
80% yields using 30 mol % pyridine or 20 mol % Co(OAc)2·
4H2O as an additive, respectively (Table 1, entries 2−3). When
both of them were added, the yield increased slightly to 85%
(Table 1, entry 4). The reaction could not proceed in the ab-
sence of TBAI (Table 1, entries 5). Other oxidants such as air,
di-tert-butyl peroxide (DTBP), and 30% aqueous H2O2 were
also examined and were found to be less effective than TBHP
(Table 1, entries 6−8).
The sulfonyl group, a strong electron-withdrawing group, is
of great interest due to its importance in medical chemistry,
photovoltaic materials, nonlinear optics, and synthetic chem-
istry.16 Therefore, it is valuable to develop new strategies to
introduce sulfonyl groups to the designated molecular frame-
works. Recently, sulfonylation via sulfonyl radicals generated
in situ from sulfonyl hydrazides17a−e using tetrabutylammonium
iodide (TBAI) and tert-butyl hydroperoxide (TBHP) has been
well developed by several groups. As an outgrowth of these
studies, we postulated that tosylhydrazide might play dual roles
With optimized conditions identified, a series of sulfonyl
hydrazides were evaluated, as shown in Scheme 2. Sulfonyl
Received: May 8, 2014
© XXXX American Chemical Society
A
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Letter
a
a
Table 1. Optimization Studies
Scheme 3. Scope of 1,3-Diketones
b
entry
oxidant
catalyst
additives
yield (%)
1
2
3
4
5
6
7
8
TBHP
TBHP
TBHP
TBHP
TBHP
air
TBAI
TBAI
TBAI
TBAI
−
TBAI
TBAI
TBAI
−
58
72
80
85
pyrdine
Co(OAc)2·4H2O
Co(OAc)2·4H2O/pyridine
Co(OAc)2·4H2O/pyridine
Co(OAc)2·4H2O/pyridine
Co(OAc)2·4H2O/pyridine
Co(OAc)2·4H2O/pyridine
c
N.D.
31
18
38
DTBP
H2O2
a
0.5 mmol of 1a, 1.25 mmol of 2a, 0.1 mmol of TBAI, 0.1 mmol of
Co(OAc)2·4H2O, 0.15 mmol of pyridine, 1.1 mmol of oxidant, 2.0 mL
b
c
a
of ethyl acetate (EA) under air, at 70 °C for 2 h. Isolated yield. Not
detected.
0.5 mmol of 1, 1.25 mmol of 2a, 0.1 mmol of TBAI, 0.1 mmol of
Co(OAc)2·4H2O, 0.15 mmol of pyridine, 1.1 mmol of TBHP, 2.0 mL
of EA under air, at 70 °C for 2 h.
a
Scheme 2. Scope of Sulfonyl Hydrazides
obtained with excellent regioselectivity and high yield, and the
exact structure was unequivocally confirmed by single-crystal
X-ray analysis. However, the bulk steric effects related to 1,3-
diketones almost canceled this catalytic behavior, leading to a trace
amount of product 4c and 4e. Again, 1-phenylbutane-1,3-dione
could also participate in the reaction smoothly (product 4d).
To explore the reaction mechanism for this transformation,
some control experiments were conducted. When pyrazole 5
was subjected to the standard conditions, no desired product 3a
was detected (Scheme 4a). The use of ethyl 3-oxobutanoate 6
Scheme 4. Probe for Possible Mechanism
a
0.5 mmol of 1a, 1.25 mmol of 2, 0.1 mmol of TBAI, 0.1 mmol of
Co(OAc)2·4H2O, 0.15 mmol of pyridine, 1.1 mmol of TBHP, 2.0 mL
of EA under air, at 70 °C for 2 h.
hydrazides with ortho, meta, or para substitutents on the phenyl
group could be converted to corresponding pyrazoles in good
to excellent yields. Both electron-donating and -withdrawing
groups hardly influenced the reactivity of this transformation. It
is noteworthy that the presence of halide substituents (3f, 3g,
3h, 3i) on the aromatic groups had no significant effect on the
efficiency, which could be used for further functionalization
through transition-metal-catalyzed cross-coupling. To our
delight, some heteroaryl sulfonyl hydrazides such as thiophene
and quinolone resulted in smooth reactions and the corre-
sponding products 3m and 3n were furnished in satisfactory
yields. Unfortunately, aliphatic sulfonyl hydrazides (3o, 3p)
were not adaptable substrates for this protocol, presumably
owing to the relative instability of the sulfonyl radicals gener-
ated in situ from aliphatic sulfonyl hydrazides.
or ethyl 3-(2-tosylhydrazono)butanoate 7 lead to the desired
product 8 in good yields (Scheme 4b, 4c). Based upon the
above-mentioned results, we suspected that sequential con-
densation of tosylhydrazide with 1,3-diketone, sulfonylation,
and cyclization were involved in this pyrazole formation
reaction. Notably, reaction of TsI and 7 only afforded a trace
amount of 8 (Scheme 4d), thus excluding the possibility of TsI
as the reaction intermediate.
Next, we set out to survey the reactivity of symmetrical and
nonsymmetrical 1,3-diketones in this reaction, and the results
are summarized in Scheme 3. When 6-methyl-2,4-heptanedione
was used as the substrate, the corresponding product 4a was
On the basis of the above-mentioned findings and literature,
a tentative mechanism is depicted in Scheme 5. Initially, I−
t
promotes the decomposition of TBHP to generate BuO•
t
radical A and BuOO• radical B (step 5a). The sulfonyl radical
B
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Letter
Notes
Scheme 5. Proposed Reaction Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Natural Science Foundation of
China (No. 21272165).
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full spectroscopic data for all new
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: shaoying810724@163.com.
*E-mail: xdm.sd@163.com.
*E-mail: wanxb@suda.edu.cn.
C
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