Efficient synthesis of dihydropyrazoles by halocyclization of β,γ-unsaturated hydrazones

Article abstract of DOI:10.1002/ejoc.201402021

An efficient halocyclization of β,γ-unsaturated hydrazones with N-bromosuccinimide was developed without the addition of any additives under mild reaction conditions to provide facile access to biologically important 4,5-dihydropyrazoles. Under the optimized conditions, a variety of highly substituted 4,5-dihydropyrazole derivatives were obtained in generally good yields. Moreover, this reaction can be further applied to the synthesis of pyrazoles in a one-pot fashion. Copyright

Full text of DOI:10.1002/ejoc.201402021

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402021
Efficient Synthesis of Dihydropyrazoles by Halocyclization of β,γ-Unsaturated
Hydrazones
Xiao-Qiang Hu,[a] Jia-Rong Chen,*[a] Qiang Wei,[a] Feng-Lei Liu,[a] Qiao-Hui Deng,[a]
You-Quan Zou,[a] and Wen-Jing Xiao*[a,b]
Keywords: Bromine / Cyclization / Hydrazones / Nitrogen heterocycles / Synthetic methods
An efficient halocyclization of β,γ-unsaturated hydrazones
azoles. Under the optimized conditions, a variety of highly
with N-bromosuccinimide was developed without the ad- substituted 4,5-dihydropyrazole derivatives were obtained in
dition of any additives under mild reaction conditions to pro-
vide facile access to biologically important 4,5-dihydropyr-
generally good yields. Moreover, this reaction can be further
applied to the synthesis of pyrazoles in a one-pot fashion.
cer, antiviral, anti-inflammatory, hypotensive, and antidia-
betic activities.[3] Not surprisingly, extensive efforts have
Introduction
Five-membered nitrogen heterocycles are an important been directed toward the synthesis of these scaffolds over
class of compounds, and this structural motif exists widely the last decades. Typically, the dihydropyrazole architecture
in many nature products, biologically active molecules, and can be constructed through the following three ways: cyclo-
pharmaceuticals.[1] These heterocycles have also been iden- addition reactions of hydrazines with α,β-unsaturated alde-
tified as valuable synthetic building blocks and chiral li- hydes or ketones (Scheme 1, method a),[4] microwave-as-
gands in asymmetric catalysis.[2] In this context, “privi- sisted cyclocondensation reactions between alkyl dihalides
leged” dihydropyrazoles and their derivatives exhibit a and hydrazines (Scheme 1, method b),[5] and 1,3-dipolar cy-
broad spectrum of biological activities, including antican- cloaddition of diazoalkanes or nitrilimines with alkenes
Scheme 1. Reaction design: intramolecular annulation of β,γ-unsaturated hydrazones with NBS; Ts = p-tolylsulfonyl.
[a] Key Laboratory of Pesticide & Chemical Biology Ministry of (Scheme 1, method c).[6] However, the relatively high reac-
Education, College of Chemistry, Central China Normal
University,
tion temperature and the limited substrate scope of meth-
ods a and b, to some extent, limit their broad application
in synthetic chemistry, whereas method c sometimes leads
to mixture of regioisomers owing to the poor regioselec-
tivity of the cycloaddition process in some cases. Therefore,
the development of new and more efficient methods for the
construction of diversely substituted dihydropyrazoles is
still desirable.
152 Luoyu Road, Wuhan, Hubei 430079, P. R. China
E-mail: chenjiarong@mail.ccnu.edu.cn
wxiao@mail.ccnu.edu.cn
http://chem-xiao.ccnu.edu.cn
[b] Collaborative Innovation Center of Chemical Science and
Engineering,
92 Weijin Road, Tianjin 300072, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402021.
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Efficient Synthesis of Dihydropyrazoles by Halocyclization
Recently, hydrazones have emerged as versatile reagents Table 1. Optimization for the synthesis of dihydropyrazole 3a.[a]
as a result of their unique properties and high reactivity.[7,8]
Despite advances, β,γ-unsaturated hydrazones remain
largely unexploited. In 2013, Loh’s group developed a radi-
cal-mediated annulation of azodicarboxylates with aryl-
hydrazines to afford highly substituted and functionalized
trans-diamines.[9] At almost the same time, Han and co-
workers independently reported an interesting (2,2,6,6-tet-
ramethylpiperidin-1-yl)oxidanyl (TEMPO-) or diisopropyl
azodicarboxylate (DIAD)-initiated intramolecular cycload-
dition of hydrazone radicals with C=C bonds at high tem-
perature to give the corresponding pyrazolines and tetra-
hydropyridazines in high yields.[10] As part of our ongoing
Entry “Br” source Solvent
t [min]
Yield[b] [%]
program on the chemistry of hydrazones[11] and the con-
struction of synthetically useful and biologically important
carbo- and heterocycles,[12] we recently reported the first ex-
ample of the [4+3] cycloaddition of diazadienes generated
in situ from α-halo hydrazones with C,N-cyclic azomethine
imines to produce various 1,2,4,5-tetrazepine deriva-
tives.[11a] Subsequently, we also developed an enantioselec-
tive inverse-electron-demand hetero-Diels–Alder reaction
between diazadienes and enol ethers by using a copper/bis-
oxazoline complex as the catalyst to give enantioenriched
pyridazine derivatives in good yields with good enantiose-
lectivities.[11b] Inspired by these works, we envisage the pos-
sibility of the intramolecular annulation of β,γ-unsaturated
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2a
2a
2a
2a
2a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Cl(CH2)2Cl
PhMe
10
10
10
60
10
10
60
30
10
96
86
75
34
87
92
80
80
30
EtOAc
THF
[a] Reaction conditions: 1a (0.30 mmol), 2 (0.36 mmol), in solvent
(3.0 mL) at room temperature. [b] Yield of isolated product after
chromatography.
hydrazones
1
with N-bromosuccinimide (NBS, 2a;
Scheme 1). In the design, the C=C bond of the β,γ-unsatu-
The generality of this intramolecular annulation reaction
rated hydrazone might be first activated by NBS to form was next investigated. As illustrated in Table 2, a wide range
bromonium ion intermediate A-1, which then undergoes of β,γ-unsaturated hydrazones bearing electron-neutral,
intramolecular addition by the nitrogen atom electron-donating, and electron-withdrawing groups at the
(Scheme 1).[13,14] Importantly, the reaction would provide 2-, 3-, or 4-position of benzene were well tolerated in this
facile access to 4,5-dihydropyrazole derivatives. In this com- transformation, and corresponding products 3b–g were de-
munication, we wish to disclose our preliminary results.
livered in high yields (Table 2, 83–95%). Notably, aliphatic
hydrazones such as those bearing cyclohexyl, benzyl, and
isopropyl groups also reacted with 2a smoothly to give de-
sired products 3h–j in good yields (Table 2, 81–98%). It was
Results and Discussion
Initially, we selected β,γ-unsaturated hydrazone 1a and previously found that protecting groups on the nitrogen
NBS (2a) as the model substrates to examine the feasibility atom of hydrazones have a substantial influence on the re-
of the intramolecular annulation reaction. To our delight, activity and reaction modes of the hydrazones.[9] Therefore,
the reaction worked smoothly without the addition of any the effects of N-protecting groups on the reaction were also
additive in CH2Cl2 at room temperature, and corresponding investigated. For example, a hydrazone substituted with an
dihydropyrazole 3a was obtained in 96% yield within ester group also proved to be suitable for this transforma-
10 min (Table 1, entry 1). To further improve the reaction tion under the standard reaction conditions, and dihydro-
efficiency, some other commonly used bromine sources pyrazole 3k was afforded in 93% yield. In addition, an
were then investigated. Commercially available bromine acetyl-substituted hydrazone also participated in this reac-
sources such as 2b, 2c, and 2d were also tolerated in this tion to give desired product 3l in moderate yield owing to
transformation, although decreased yields were observed the formation of some unidentified side products (Table 2,
(Table 1, entry 1 vs. entries 2–4). With the optimal bromine 56%), and the structure was unambiguously confirmed by
source established, that is 2a, we briefly screened the reac- X-ray analysis (Figure 1).[15] Furthermore, the substrate
tion media. It was found that halogenated solvents such as scope was successfully extended to a bulkier substrate bear-
CH2Cl2, CHCl3, and Cl(CH2)2Cl gave comparable yields ing a phenyl group at the terminal double bond to furnish
(Table 1, entries 1, 5, 6), whereas the use of PhMe or EtOAc desired 3m in 46% yield in 3 h.
as the solvent decreased the reaction efficiency (Table 1, en-
In addition to NBS, N-chlorosuccinimide (NCS) and N-
tries 7 and 8). The use of THF led to only a moderate yield iodosuccinimide (NIS) were also utilized to react with
as a result of a complex reaction mixture (Table 1, entry 9). hydrazone 1a under the standard reaction conditions
Accordingly, CH2Cl2 was chosen as the best solvent for fur- (Scheme 2). Surprisingly, the reaction with NCS gave rise
ther study.
to a very complex mixture and no desired product was de-
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J.-R. Chen, W.-J. Xiao et al.
SHORT COMMUNICATION
Table 2. Halocyclization of β,γ-unsaturated hydrazones for the syn-
thesis of dihydropyrazole derivatives.[a]
Scheme 2. Halocyclization of β,γ-unsaturated hydrazone 1a with
NCS and NIS.
To further explore the synthetic potential of this meth-
odology,
a gram-scale reaction was performed with
2.7 mmol of 1d under the standard reaction conditions
[Scheme 3, Equation (1)]. The reaction proceeded very well,
and desired product 3d was obtained in 81% yield. More
importantly, these dihydropyrazole products were easily
converted into pyrazoles through a simple operation. For
example, by using KOH as the base, N-free pyrazole 5 was
obtained from 3k in 88% yield within 30 min [Scheme 3,
Equation (2)].[16] Furthermore, the one-pot reaction with
hydrazone 1k also worked well to give pyrazole 5 in 81%
overall yield [Scheme 3, Equation (3)]. Thus, this one-pot
reaction provides a complementary, simple, and practical
way to synthesize pyrazole derivatives. Notably, all of the
products containing halogen atoms (I, Br) are amenable to
further synthetic elaborations, such as nucleophilic substitu-
tions and coupling reactions.
[a] The reaction was performed with 1 (0.30 mmol) and 2a
(0.36 mmol) in CH2Cl2 (3.0 mL) at room temperature.
Figure 1. X-ray crystal structure of 3l (thermal ellipsoids are set at
30% probability).
tected [Scheme 2, Equation (1)]. In contrast, NIS under-
went the desired halocyclization reaction smoothly to afford
product 4 in 83% yield [Scheme 2, Equation (2)].
Scheme 3. Gram-scale reaction and synthetic applications.
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Efficient Synthesis of Dihydropyrazoles by Halocyclization
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Conclusions
In conclusion, we developed an efficient halocyclization
of β,γ-unsaturated hydrazones with NBS, and a range of
dihydropyrazole derivatives were obtained in good to excel-
lent yields (46–98%) without any additives under mild reac-
tion conditions. Significantly, this methodology can be fur-
ther employed for the synthesis of pharmaceutically impor-
tant pyrazoles in a one-pot fashion. Further studies toward
an asymmetric version of this halocyclization reaction are
currently under active investigation in our laboratory.
[7]
Experimental Section
[8]
Typical Procedure: β,γ-Unsaturated hydrazone 1a (104.6 mg,
0.30 mmol) and N-bromosuccinimide (2a; 64.0 mg, 0.36 mmol)
were dissolved in CH2Cl2 (3 mL) at room temperature until the
reaction was complete, as monitored by TLC. The crude reaction
mixture was then directly purified by flash column chromatography
(petroleum ether/ethyl acetate = 10:1 to 5:1) to give 3a as a white
solid in 96% yield.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental methods and characterization data.
Acknowledgments
[9]
We are grateful to the National Natural Science Foundation of
China (grant numbers 21272087, 21202053, and 21232003) and the
National Basic Research Program of China (973 program, grant
number 2011CB808603) for support of this research.
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SHORT COMMUNICATION
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this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
See the Supporting Information for details.
Received: February 5, 2014
[16]
[15] The structure of 3l was determined by X-ray analysis. CCDC-
Published Online: March 17, 2014
981688 contains the supplementary crystallographic data for
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