Cascade reaction to 1H-pyrazoles from hydrazones via sodium Ni-trite promoted dual C–C/C–N formation, annulation and aromatization with 1,2-dichloroethane

Article abstract of DOI:10.1016/j.cclet.2021.02.025

A novel route for tandem C–C/C–N formation, annulation and aromatization of hydrazones with 1,2-dichloroethane to synthesize 1H-pyrazoles has been developed. Furthermore, the 1,2-dichloroethane serves as alkylation reagent in good to excellent yields. This methodology features mild reaction conditions and good functional group tolerance, providing a direct approach for the preparation of 1H-pyrazoles.

Full text of DOI:10.1016/j.cclet.2021.02.025

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Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Cascade reaction to 1H-pyrazoles from hydrazonesvia sodium ni-trite
promoted dual C–C/C–N formation, annulation and aromatization with
1,2-dichloroethane
Liqiang Haoa, Hongyan Liua, Zheng Zhanga, Fuqiang Wena, Chengcai Xiaa,
,
*
Zengfen Pangb,
*
a
Institute of Pharmacology, Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai’an 271016, China
Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji’nan 250117, China
b
A R T I C L E I N F O
A B S T R A C T
Article history:
A novel route for tandem C–C/C–N formation, annulation and aromatization of hydrazones with 1,2-
dichloroethane to synthesize 1H-pyrazoles has been developed. Furthermore, the 1,2-dichloroethane
serves as alkylation reagent in good to excellent yields. This methodology features mild reaction
conditions and good functional group tolerance, providing a direct approach for the preparation of 1H-
pyrazoles.
Received 8 December 2020
Received in revised form 2 February 2021
Accepted 9 February 2021
Available online xxx
© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Tandem
Hydrazones
1,2-Dichloroethane
1H-Pyrazoles
Annulation
1H-Pyrazoles are highly valuable compounds and not only are
prevalent in pharmaceuticals such as anthelmintic activity [1], 5-
HT2C receptor agonists [2], modulators of the M1 muscarinic
acetylcholine receptor [3], and inhibition of trypanosoma brucei
and trypanosoma cruzi [4],monoamine oxidase-A inhibitors [5]but
also can serve for catalytic materials [6] as ligands (Fig. 1). In view
of their great importance, development an efficient method to
formation of 1H-pyrazoles is attracting more attention in the past
decades [7].
hinder their practical application in chemical synthesis. Therefore,
developing a new type of mild, metal-free catalytic reaction is
challenging and indispensable. Herein, inspired by these works
and continuing efforts in our previous work [10,11], we design and
synthesize an metal-free annulation onto (E)-1-benzylidene-2-
methylhydrazine, which was achieved by cynalization and
aromatization of 1,2-dichloroethane with NaNO2 catalysis
(Scheme 1c). This method provides a simple and convenient
way for the construction of double C–C/C–N bonds and reduces the
generation of by-products in the reaction process.
(E)-1-Benzylidene-2-methylhydrazine (1a) was chosen as the
model substrates for the optimization of the reaction conditions,
which include the nitro source, cosolvent, amount of raw
materials, temperature and atmosphere. The optimization results
showed that the reaction is very sensitive to nitro source effects
(Table 1, entries 1À7), and the best result was obtained by using
NaNO2 as nitro source (Table 1, entry 6). Next, cosolvents were
screened, EtOH gave a better yield than other cosolvents including
MeOH, n-butanol, isobutanol, octanol, 2-propanol, DMSO and DMF
(Table 1, entries 8À14). Considering the influence of the reaction
temperature, we observed that the yield was slightly decreased
when decreasing to 80 ꢀC or increasing to 120 ꢀC (Table 1, entries 15
and 16). As nitrate can improve the reaction and the NaNO2
Hydrazones possess an excellent reactivity for cyclization
reaction. Comas-barcel's group [8] has reported the synthesis of
pyrazole compounds from alkynes and sydnones catalyzed by Cu
(OAc)2 H2O with excellent yield (Scheme 1a). Meanwhile, pyrazole
Á
compounds synthesized by ethane-1,2-diol derivatives react with
(E)-1-benzylidene-2-phenylhydrazine compounds under the ca-
talysis of FeCl3 have been reported by Panda’s group [9]
(Scheme 1b). In the past few decades, pyrazole derivatives
prepared by transition metals has obtained
a remarkable
achievement. However, the catalysis of transition metals may
* Corresponding authors.
E-mail addresses: xiachc@163.com (C. Xia), pangzf0806@163.com (Z. Pang).
https://doi.org/10.1016/j.cclet.2021.02.025
1001-8417/© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article as: L. Hao, H. Liu, Z. Zhang et al., Cascade reaction to 1H-pyrazoles from hydrazonesvia sodium ni-trite promoted dual C–
C/C–N formation, annulation and aromatization with 1,2-dichloroethane, Chin. Chem. Lett., https://doi.org/10.1016/j.cclet.2021.02.025

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Table 1
Optimization of reaction conditions.a
Entry
Nitro source
Co(NO3)2 6H2O
Cu(NO3)2
Bi(NO3)3
Cosolvent
T (oC)
Yield (%)b
1
2
3
4
5
6
7
8
Á
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
n-Butanol
Isobutanol
Octanol
2-Propanol
DMSO
DMF
EtOH
EtOH
EtOH
EtOH
110
110
110
110
110
110
110
110
110
110
110
110
110
110
80
10
nr
8
18
23
75
21
60
nr
15
nr
18
42
35
45
61
(CH3)3CONO
NH4NO3
NaNO2
Al(NO3)3
NaNO2
NaNO2
NaNO2
NaNO2
NaNO2
NaNO2
NaNO2
NaNO2
NaNO2
NaNO2
NaNO2
NaNO2
NaNO2
9
Scheme 1. Reaction from hydrazones.
10
11
12
13
14
15
16
17
18
19
20
120
110
110
110
110
13c, 41d,62e
70f, 71g
72h,61i
36j, 58k, 23l
EtOH
EtOH
a
Reaction conditions:1a (0.2 mmol), nitrate (2.0 equiv.), DCE/ EtOH = 1:2 (v/v)
(2.0 mL), air, sealed tube, 110 ꢀC for 24 h.
b
Isolated yields.
NaNO2 (0 equiv.).
NaNO2 (1.0 equiv.).
NaNO2 (3.0 equiv.).
20 h.
36 h.
N2.
O2.
c
d
e
f
g
h
i
j
DCE/EtOH = 1:10 (v/v).
DCE/EtOH = 1:1 (v/v).
DCE/EtOH = 10:1 (v/v).
k
l
Scheme 2. Scope of various substituents of hydrazones 1. Reaction conditions: 1
(0.2 mmol), NaNO2 (2.0 equiv.) and DCE/ EtOH = 1:2 (v/v) (2.0 mL), air, sealed tube,
110 ꢀC for 24 h. Isolated yields.
Fig. 1. Representative compounds of 1H-pyrazoles.
products. Meta substituents with diverse electronics also worked
well, with electron-donating groups (2p and 2q), halogens (2r–2t)
and electron-withdrawing groups (2u) all providing the pyrazole
in good yields. What we regret is that the target compound cannot
be obtained when using alkyl aldehydes (2w). Similarly, many
disubstituted compounds such as 2aa-2af also afforded the
corresponding products in synthetically useful yields (58%–68%).
In addition, 2-furaldehyde (2ag) gave a 56% yield. Unfortunately,
the methodology failed to produce any products when bearing 2-
OCH3 (2h) and 3-NO2 (2v) group. t-Butylhydrazine replaced of
methylhydrazine, we failed to produce the requisite pyrazole.
Unfortunately, under standard conditions, when 1,2-dichloropro-
pane was used instead of 1,2-dichloroethane, we did not get the
expected compound.
evidently facilitate the transformation, different amount of the
NaNO2 were examined (Table 1, entry 17). Further investigations
on the reaction did not improve the yield of product. (Table 1,
entries 18–20). With the optimized conditions in hand, we
investigated the substrate scope of this reaction, various
substituents on the benzene ring of the aromatic aldehyde were
examined and the results are summarized in Scheme 2.
Substrates with para substituents such as 4-Me(2b), 4-CH2CH3
(2c), 4-F (2d), 4-Cl (2e), 4-Br (2f), 4-CF3 (2g) afforded the
corresponding products in good yields. Furthermore ortho-
substituents bearing electron donating (2i and 2j) and halogen
substituents (2k–2m) were well tolerated, but withdrawing
character (2n and 2o) could not be converted into corresponding
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2a (Scheme 3d) about 15% yield from (Z)-1-(3-chloro-1-phenyl-
propylidene)-2-methylhydrazine 4 as starting material when
reaction temperature is 20 ꢀC or 110 ꢀC. When compound 4 was
subjected to NaNO2 under the standard reaction conditions, the
desired product 2a was formed about 85% yield (Scheme 3e). Thus,
the last step of this tandem reaction is successfully promoted by
NaNO2. Further investigations found that (Z)-1-(2-chloroethyl)-1-
methyl-2-(1-phenylethylidene)hydrazine 6 and (Z)-3-chloro-1-
phenyl-N-(piperidin-1-yl)propan-1-imine 8 were not obtained
under the standard conditions respectively, by using (Z)-1-methyl-
2-(1-phenylethylidene)hydrazine 5 and (Z)-N-morpholino-1-phe-
nylmethanimine 7 as starting material (Schemes 3f and g). But,
when the radical scavenger TEMPO (3.0 equiv.) was added under
standard conditions, the target compound 2a was obtained in 68%
yield. This suggested that it may not be a free radical mechanism
(Scheme 3h). Excitingly, we have detected of intermediate (B), (C),
(E) and 2a (Scheme 4) from reaction mixture about 10 min after the
start of the reaction by HPLC-MS (Supporting information).
On the basis of the results of our group and others [5,7], a
plausible mechanism is proposed (Scheme 4). Firstly, 1a released a
hydrogen ion to generate intermediate (A), which react with 1,2-
dichloroethane to generate intermediate (B) and intermediate (C)
under the participation of NaNO2. Secondly, intermediate (D) was
generated from intermediate (C) released a hydrogen ion. After
this, a cyclization of intermediate (D) can occur to give the
intermediate (E). Finally, the target product 2a is obtained by
oxidation of intermediate (E).
In summary, we have developed a method of sodium nitrite
promoted dual C–N, C–C coupling reaction using hydrazones and
1,2-dichloroethane as starting materials under mild conditions
providing 1H-pyrazoles as products. In these processes, 1,2-
dichloroethane serve as alkylation reagent in good to excellent
yields. Moreover, this protocol would be anticipated to construct
diversified 1H-pyrazoles for the screening of the potential
pharmaceuticals in future.
Scheme 3. Mechanistic studies.
Declaration of competing interest
The authors report no declarations of interest.
Acknowledgments
To study the mechanism of cyclization reaction, some control
experiments were conducted. Firstly, it was known that no target
product (2a) was produced in the absence of NaNO2 (Scheme 3a).
Similarly, we have not detected 1a, 3 and 4 when using many bases
such as K2CO3, Na2CO3, CsCO3 and NaOH replace NaNO2
(Scheme 3b). These results indicate that NaNO2 are crucial for
facilitating this reaction. Secondly, we obtained successfully the
intermediate (H) about 67% yield (Scheme 3c) or desired product
The authors gratefully acknowledge financial support for this
research from Shandong Provincial Natural Science Foundation
(No. ZR2017LB006) and Academic promotion programme of
Shandong First Medical University (No. 2019LJ003).
Scheme 4. Postulated reaction mechanism.
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References
(c) G.W. Zhang, Y. Zhao, H.B. Ge, Angew. Chem. Int. Ed. 52 (2013) 2559–2563;
(d) F. Punner, Y. Sohtome, M. Sodeoka, Chem. Commun. (Camb.) 52 (2016)
14093–14096;
[1] T.G. Le, A. Kundu, A. Ghoshal, et al., J. Med. Chem. 62 (2019) 3367–3380.
[2] J. Carpenter, Y. Wang, G. Wu, et al., J. Med. Chem. 60 (2017) 6166–6190.
[3] J.C.C. Dallagnol, E. Khajehali, E.T. van Der Westhuizen, et al., J. Med. Chem. 61
(2018) 2875–2894.
(e) J. Chen, R. Properzi, D.P. Uccello, et al., Org. Lett. 16 (2014) 4146–4149;
[4] S. Varghese, R. Rahmani, S. Russell, et al., ACS Med. Chem. Lett. 11 (2020) 278–
(f) J.D. Kirkham, S.J. Edeson, S. Stokes, J.P.A. Harrity, Org. Lett. 14 (2012) 5354–
5357;
285.
[5] F. Chimenti, A. Bolasco, F. Manna, et al., Chem. Biol. Drug Des. 67 (2006) 206–
214.
[6] L.L. De Oliveira, R.R. Campedelli, M.C.A. Kuhn, J.F. Carpentier, O.L. Casagrande, J.
Mol. Catal. A Chem. 288 (2008) 58–62.
[7] (a) S. Peruncheralathan, T.A. Khan, H. Ila, H. Junjappa, J. Org. Chem. 70 (2005)
10030–10035;
(g) J. Schranck, X.F. Wu, H. Neumann, M. Beller, Chem. Eur. J. 18 (2012) 4827–
4831.
[8] J. Comas-Barcel, R.S. Foster, B. Fiser, E. Gomez-Bengoa, J.P.A. Harrity, Chem. Eur.
J. 20 (2014) 1–8.
[9] N. Panda, A.K. Jena, J. Org. Chem. 77 (2012) 9401–9406.
[10] G.D. Wang, J. Sun, K. Wang, et al., Org. Chem. Front. 6 (2019) 1608–1612.
[11] L.Q. Hao, G.D. Wang, J. Sun, et al., Adv. Synth. Catal. 362 (2020) 1657–1662.
(b) C.M. Thompson, J.L. Poole, J.L. Cross, I. Akritopoulou-Zanze, S.W. Djuric,
Molecules 16 (2011) 9161–9177;
4