Convenient access to polyfunctional pyrazoles via a highly efficient and regioselective multicomponent reaction

Article abstract of DOI:10.1021/acs.orglett.5b00605

A multicomponent reaction has been developed for the synthesis of polyfunctional pyrazole derivatives from readily available arylglyoxal monohydrates, tosylhydrazine, and aldehydes or ketones. This synthetic method has significant advantages in broad substrate scope, excellent regioselectivity, and simple operation.

Full text of DOI:10.1021/acs.orglett.5b00605

Letter
pubs.acs.org/OrgLett
Convenient Access to Polyfunctional Pyrazoles via a Highly Efficient
and Regioselective Multicomponent Reaction
Wen-Ming Shu,† Kai-Lu Zheng,† Jun-Rui Ma,† Hui-Ying Sun,† Mei Wang,† and An-Xin Wu*,†,‡
†Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Hubei, Wuhan 430079, P. R. China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: A multicomponent reaction has been developed
for the synthesis of polyfunctional pyrazole derivatives from
readily available arylglyoxal monohydrates, tosylhydrazine, and
aldehydes or ketones. This synthetic method has significant
advantages in broad substrate scope, excellent regioselectivity,
and simple operation.
Scheme 1. Strategies for the Synthesis of Pyrazole
he pyrazole moiety is widely regarded as a privileged
Theterocyclic skeleton with broad pharmaceutical activities,
including antitumor, antifungal, and inhibitory activities toward
Cyclin Dependent Kinases (CDKs) and DNA gyrase (Figure
1).1 Substituted pyrazoles have also been utilized as useful
ligands for metal catalyzed cross-coupling reactions.2
Figure 1. Some biologically active pyrazole compounds.
In the past few decades, several methods have been
developed for the preparation of substituted pyrazoles.3 The
most common synthetic routes to pyrazoles are as follows:
cyclocondensation between hydrazine derivatives and 1,3-
dicarbonyl compounds (Scheme 1a);4 1,3-dipolar cycloaddition
of diazo compounds with electron-deficient alkenes or alkynes
(Scheme 1b);3b,d,5 and three-component reaction of vinyl
azides, aldehydes, and tosylhydrazine (Scheme 1c).6 However,
these methods are somewhat limited to harsh reaction
conditions, poor regioselectivity, and narrow substrate scope.
Therefore, the development of a highly efficient and
regioselective method would be greatly valuable for the
synthesis of polyfunctionalized pyrazoles from easily available
substrates. Herein, a novel method is presented for the
synthesis of polysubstituted pyrazoles from simple arylglyoxal
monohydrates, tosylhydrazine, and aldehydes or ketones with
excellent regioselectivity and a broad substrate scope (Scheme
1d).
Initially, the reaction of phenylglyoxal monohydrate (1a),
tosylhydrazine (2), and benzaldehyde (3a) was screened in
ethylene glycol at 100 °C in the presence of Cs2CO3. To our
delight, the desired compound (4,5-diphenyl-1H-pyrazol-3-
yl)(phenyl)methanone 4aa was furnished in 81% yield (entry
1). Encouraged by the aforementioned results, other reaction
conditions were investigated, including the choice of base,
Received: February 27, 2015
Published: March 31, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00605
Org. Lett. 2015, 17, 1914−1917

Organic Letters
Letter
solvent, and temperature. The results are summarized in Table
1. It was observed that most of the bases (Cs2CO3, K2CO3,
Table 2. Substrates Scope of Three-Component Reaction
with Aldehydes
a
a
Table 1. Optimization of the Reaction Conditions
b
entry
Ar
R
4
yield (%)
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4aa
4ba
4ca
4da
4ea
4fa
85
71
45
65
81
83
80
55
68
72
75
77
81
55
57
84
86
71
75
0
b
2
4-MeC6H4
3-MeOC6H4
3,4-(OCH2O)C6H3
2-ClC6H4
4-ClC6H4
3-BrC6H4
3-NO2C6H4
2-thienyl
2-benzofuryl
1-naphthyl
2-naphthyl
Ph
entry
solvent
base
temp (°C)
yield (%)
3
1
EG
Cs2CO3
K2CO3
100
100
100
100
100
100
100
80
81
75
76
72
15
10
85
78
82
71
73
66
−
4
2
EG
5
3
EG
KOH
6
4
EG
NaOH
7
4ga
4ha
4ia
5
EG
DABCO
DBU
8
6
EG
9
7
EG
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
10
11
12
13
14
15
16
17
18
19
20
4ja
8
EG
4ka
4la
9
EG
110
78
10
11
12
13
14
15
EtOH
i-PrOH
H2O
DMSO
DMF
toluene
4-MeC6H4
4-MeOC6H4
3,4-(MeO)2C6H4
4-ClC6H4
4-BrC6H4
2-thienyl
4ab
4ac
4ad
4ae
4af
80
Ph
100
100
100
100
Ph
Ph
−
−
Ph
Ph
4ag
4ah
4ai
a
Reaction conditions: 1a (0.2 mmol, 2.0 equiv), 2 (0.2 mmol, 2.0
Ph
2-naphthyl
Et
equiv), 3a (0.15 mmol, 1.5 equiv), base (0.8 mmol, 8.0 equiv), and
Ph
b
solvent (3 mL) for 12 h. Isolated yields. EG = ethylene glycol.
a
Reactions were carried out with 1 (2.0 mmol, 2.0 equiv), 2 (2.0
mmol, 2.0 equiv), 3 (1.5 mmol, 1.5 equiv), and Na2CO3 (8.0 equiv) in
ethylene glycol (20.0 mL) at 100 °C for 12 h. Yields of the isolated
products were shown.
b
KOH, NaOH, DABCO, DBU, and Na2CO3) could successfully
promote the reaction (entries 1−7). Among these, Na2CO3 was
determined optimum, and 4aa was isolated in 85% yield (entry
7). Various solvents were screened, and the results revealed that
ethylene glycol is the best choice for the reaction (entries 10−
15). Unfortunately, the desired product 4aa was not obtained
in DMSO, DMF, and toluene (entries 13−15). Moreover, the
yield was slightly decreased when the reaction was performed at
a lower or higher temperature (entries 8 and 9).
monohydrates (1) containing different functional groups (H,
alkyl, halogen, electron-withdrawing (EWG), and electron-
donating (EDG) groups) reacted with acetylacetone (5a) to
provide the expected products 6aa−6la in excellent yields (75−
89%).
With the optimized conditions in hand, the scope of the
arylglyoxal monohydrates (1) was investigated. The results are
summarized in Table 2. The efficiency of this transformation
was significantly influenced by the electronic properties of the
substituents on the aromatic ring system. In general, electron-
neutral (H) and halogen (2-Cl, 4-Cl, 3-Br) groups were found
preferable to electron-donating (4-Me, 4-OMe, 3,4-OCH2O)
and electron-withdrawing (3-NO2) groups in terms of isolated
yields (45−85%; entries 1−8). To our delight, the arylglyoxal
monohydrates with 2-thienyl, 2-benzofuryl, 1-naphthyl, and 2-
naphthyl also gave the desired products successfully in
moderate to good yields (68−77%; entries 9−12). Next, the
scope of the aldehydes (3) was investigated. Yields of
multisubstituted pyrazoles 4ab−4ah were obtained in 55−
86% yield, when using different aldehydes (entries 13−19). To
our disappointment, the corresponding product 4ai was not
obtained when the substituent group R was ethyl (entry 20). A
more likely reason is the instability of the alkyl diazo
intermediate generated from aliphatic aldehyde with tosylhy-
drazine. The structure of 4ac was further determined by X-ray
crystallographic analysis (see Supporting Information).
Encouraged by the results achieved above, the scope of
ketones was subsequently examined (Scheme 3). The steric
hindrance of isopropyl (6ac) or tert-butyl (6ad) groups in the
1, 3-diketones was shown to significantly impair the reaction.
However, the reaction occurred smoothly for other ketones
regardless of differences in electronic properties, and the
corresponding products were obtained in good to excellent
yields (66−84%; 6ab, and 6ae−6ai). The structure of 6ah was
determined by single-crystal X-ray diffraction analysis (see SI).
To gain insight into the reaction process, control experi-
ments were performed (Scheme 4). In the presence of Na2CO3,
1,2-diphenylethanone 5j7 was obtained with a 78% yield from
benzaldehyde (3a) and tosylhydrazine (2) in ethylene glycol at
100 °C for 12 h (eq 1). It was then verified that the desired
product 4aa could be obtained in 85% yield from phenylglyoxal
monohydrate (1a), tosylhydrazine (2), and 1,2-diphenyletha-
none 5j under the same conditions (eq 2). The product 4aa
was also obtained in 76% yield from the reaction of 2-diazo-1-
phenylethanone (7a), tosylhydrazine (2), and benzaldehyde
(3a) at 100 °C for 12 h (eq 3). The reaction of 7a with 5j also
afforded the desired product 4aa in 79% yield (eq 4). These
results identified that 7a and 5j most probably are the
intermediates for this reaction. The desired product 4aa was
not obtained when using 1,2-diphenylethyne (8a) as the
This work aspired to obtain a diverse library of polyfunc-
tional pyrazoles, and ketones were thus chosen for the reaction
instead of aldehydes (Scheme 2). Pleasingly, arylglyoxal
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Letter
Scheme 2. Scope of Arylglyoxal Monohydrates for the
Reaction with Ketones
Scheme 4. Control Experiments
a
shown in Scheme 5 (4aa as an example). Initially, the
condensation of benzaldehyde 3a and tosylhydrazine 2 affords
Scheme 5. A Possible Mechanism
a
Reactions were performed with 1 (1.0 mmol, 1.0 equiv), 2 (1.0
mmol, 1.0 equiv), 5a (1.5 mmol,1.5 equiv), and Na2CO3 (8.0 equiv) in
the mixture solvent H2O/DMF (2:1) at 100 °C for 2 h. Isolated
products.
a
Scheme 3. Scope of Ketones
the corresponding hydrazone intermediate A, which sub-
sequently transforms into intermediate 9a in the presence of
Na2CO3. Then, 9a reacts with benzaldehyde 3a to afford the
intermediate B, which subsequently affords the compound 5j
via a 1,2-proton transfer with the departure of a molecule of N2.
Meanwhile, phenylglyoxal monohydrate 1a reacts with
tosylhydrazine 2 to furnish the hydrazone intermediate A′
and it further converts to α-diazophenylethanone 7a,9 which
resonates to 7a′ and reacts with 5j via a 1,3-dipolar
cycloaddition to afford intermediate C. Afterward, the
intermedidate C transforms into intermediate D by the
elimination of a molecule of H2O. Finally, the intermediate D
is converted to the desired product 4aa via a tautomerization
reaction.
a
Isolated products.
substrate under the same reaction conditions. This result
excluded the possibility of an alkyne intermediate (8a) in this
reaction (eq 5).8
On the basis of the above-mentioned experimental results, a
possible reaction mechanism for this reaction is proposed as
In summary, a highly efficient and regioselective method has
been developed for the synthesis of polysubstituted pyrazoles,
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Organic Letters
Letter
(8) (a) Ojha, D. P.; Prabhu, K. R. Org. Lett. 2014, 17, 18−21. (b) Li,
X.; Liu, X.; Chen, H.; Wu, W.; Qi, C.; Jiang, H. Angew. Chem., Int. Ed.
2014, 53, 14485−14489.
(9) Shu, W.-M.; Ma, J.-R.; Zheng, K.-L.; Sun, H.-Y.; Wang, M.; Yang,
Y.; Wu, A.-X. Tetrahedron 2014, 70, 9321−9329.
providing easy access to a library of pyrazoles from readily
available starting materials with a very simple operation.
Further studies into the applications of this method are
currently underway in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, product characterizations, crystallo-
1
graphic data, and copies of the H and 13C NMR spectra are
included. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chwuax@mail.ccnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grants 21272085 and 21472056) for financial support.
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