Visible-light promoted one-pot synthesis of pyrazoles from alkynes and hydrazines

Article abstract of DOI:10.1016/j.tetlet.2018.12.009

A visible-light promoted cascade of Glaser coupling/annulation has been developed for one-pot synthesis of polysubstituted pyrazoles from alkynes and hydrazines. The method features mild reaction conditions, readily availible starting materials and green

Full text of DOI:10.1016/j.tetlet.2018.12.009

Accepted Manuscript
Visible-Light Promoted One-Pot Synthesis of Pyrazoles from Alkynes and Hy-
drazines
Yunge Meng, Te Zhang, Xinchi Gong, Min Zhang, Chunyin Zhu
PII:
S0040-4039(18)31442-4
https://doi.org/10.1016/j.tetlet.2018.12.009
TETL 50472
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 September 2018
30 November 2018
3 December 2018
Please cite this article as: Meng, Y., Zhang, T., Gong, X., Zhang, M., Zhu, C., Visible-Light Promoted One-Pot
Synthesis of Pyrazoles from Alkynes and Hydrazines, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.12.009
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
A visible-light promoted cascade of Glaser coupling/annulation has been developed for one-pot synthesis of polysubstituted
pyrazoles from alkynes and hydrazines. The reaction features mild reaction conditions, readily availible starting materials and
green oxidant (O2).
Visible-Light Promoted One-Pot Synthesis of
Pyrazoles from Alkynes and Hydrazines
Leave this area blank for abstract info.
Yunge Meng, Te Zhang, Xinchi Gong, Min Zhang*, and Chunyin Zhu*

1
Tetrahedron Letters
Visible-Light Promoted One-Pot Synthesis of Pyrazoles from Alkynes and
Hydrazines
Yunge Menga, Te Zhanga, Xinchi Gonga, Min Zhanga,  and Chunyin Zhua,b,

a School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, PR China
b State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University, Xiamen 361005, P.R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A visible-light promoted cascade of Glaser coupling/annulation has been developed for one-pot
synthesis of polysubstituted pyrazoles from alkynes and hydrazines. The method features mild
reaction conditions, readily availible starting materials and green oxidant (O2). It works for a wide
range of substituted phenyl acetylene and hyrazines with good functional group tolerance and
efficiency. Mechanistic pathways including photochemical irridiation, intramolecular hydrogen-
atom-abstraction (HAT) and enamine-to-imine tautomerization was proposed for the
transformation.
Available online
Keywords:
Alkyne
Pyrazole
Visible-light
Cascade
2009 Elsevier Ltd. All rights reserved.
Synthesis
The synthesis of privileged pyrazole framework has gained
major research effort from the synthetic community due to their
prevalence in many natural products and synthetic
pharmaceuticals,1 as well as versatile utility as precursors to N-
heterocyclic carbenes (NHCs),2 ligands for transition-metal-
catalyzed cross-coupling reactions, 3 and directing groups for C−H
activations 4. Many traditional methods for their preparation have
mainly focused on annulations initiated by the condensation of a
characteristics of sunlight. 6 In contrast to conventional thermal
reactions, photocatalytic processes are initiated by the generation
of various reactive species, frequently without stoichiometric
activation reagents under mild conditions. Application of these
reactive intermediates can result in numerous synthetically useful
bond formations in a predictable and selective manner, thus giving
rise to the flourishment of photocatalysis in almost every subjects
of organic synthesis. It is worth mentioning that the synthesis of
heterocycle compounds has benefit a lot from the development of
such catalytic system, as the past decades have witnessed a wealth
of novel methodologies for the synthesis of different heterocycles
monosubstituted hydrazine with
a
carbonyl, such as
cyclocondensation of 1, 3-dicarbonyl or α, β-unsaturated carbonyl
compounds with hydrazines. 5 However, these methods usually
suffer from harsh conditions like high reaction temperature,
microwave irradiation or hazard oxidants, which are contrary to
the concept of green chemistry. As a result, the development of
more environmentally benign processes toward the synthesis of
pyrazole derivatives continues to be a topic of current interest in
contemporary synthetic chemistry.
7
like pyrazoles, pyridines, pyrroles, etc. For the synthesis of
pyrazoles, Xiao and Chen developed an oxidative deprotonation
electron transfer strategy for the photoredox catalytic generation
of hydrazonyl radicals from ketone hydrazones, which could
undergo intramolecular radical cyclization reaction to give
8
pyrazole derivatives. Chen group reported a practical and
efficient CF3 radical-mediated nucleophilic cyclization of β, γ-
unsaturated hydrazones for the synthesis of CF3-containing
pyrazolines employing visible-light photoredox catalysis. 9 Zhu
group accomplished a visible-light photoredox catalyzed cascade
of the C(sp2)−H/C(sp3)−H bond functionalization of aldehyde
hydrazones for the synthesis of complex fused dihydropyrazoles.10
Zhu and Yu developed a novel [4 + 1] annulation of aldehyde
hydrazones with diethyl 2-bromomalonate for the synthesis of
pyrazoloisoquinolines by exploiting a relay photoredox catalysis
strategy.11 We developed a selective and high yielding synthesis of
polysubstituted pyrazoles through a visible light photoredox
Scheme 1. A visible-light promoted cascade of Glaser
coupling/annulation of alkynes with hydrazines.
Recently, visible light-induced photocatalytic strategy has
received increasing attention from the synthetic community due to
the inexhaustible, environmentally friendly and efficient
———
 Corresponding author. e-mail: zhangmin@ujs.edu.cn
 Corresponding author. e-mail: zhucycn@gmail.com

2
Tetrahedron Letters
catalysis promoted reaction of hydrazine with Michael
copper salts including CuCl, CuCl2, Cu(OTf)2 and Cu(OAc)2 were
acceptors.12a
tested in the reaction using Ru(bpy)3Cl2 as the photocatalyst, and
they could not improve the outcome of the reaction (Table 1,
entries 5-8). The screening of solvents revealed that DMSO was
superior to THF, DMF and MeOH (Table 1, entries 9-11), while
CH3CN, AcOEt or DCM did not work for this reaction at all,
resulting in no desired product (Table 1 entries 12-14). The
reaction was further optimized by varying the equivalents of
hydrazine hydrate 2a. A decrease in the yield of the reaction was
observed when the amount of hydrazine hydrate 2a was reduced
from 4.0 equivalents to 2.0, 2.5 or 3.0 equivalents (Table 1 entries
15-17). On the other side, increasing the equivalents of hydrazine
hydrate 2a to 5 also led to inferior outcomes (Table 1, entry 18),
probably due to additional side reaction. So DMSO, CuI,
Ru(bpy)3Cl2 and 4.0 equivalents of hydrazine hydrate 2a were
chosen as the optimized conditions.
As a continuation of our interest in such area,12 herein we report
a visible-light promoted cascade of Glaser coupling/annulation of
alkynes with hydrazines for the synthesis of polysubstituted
pyrazoles (Scheme 1). Initially phenyl acetylene 1a and hydrazine
hydrate 2a were chosen as the model substrates to study the
reaction conditions. The reaction was carried out by exposing
phenyl acetylene 1a to air in the presence of copper catalyst and
photocatalyst under the irradiation of 12 w blue LED bulb,
followed by the addition of hydrazine hydrate 2a when 1a was
consumed. At first, different photocatalysts (2 mol%) were
evaluated with reactions in DMSO in the presence of CuI (20
mol%) under room temperature, and it is found that Rhodamine B,
Eosin Y and Methylene blue were able to promote the reaction to
some extent, resulting in the formation of desired product 3a with
yields from 38-51% (Table 1, entries 1-3), while Ru(bpy)3Cl2 gave
a yield up to 77% (Table 1, entry 4). Instead of CuI, different
Table 1. Optimization of reaction conditions[a]
.
X
Yield %
38
entry
solvent
[Cu]
photocatalyst
1
2
3
4
5
6
7
8
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
THF
CuI
CuI
Rhodamine B
Eosin Y
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
2.0
2.5
3.0
5.0
51
42
77
64
60
56
69
48
32
45
0
CuI
Methylene blue
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
CuI
CuCl
CuCl2
Cu(OTf)2
Cu(OAc)2
CuI
10
11
12
13
14
15
16
17
18
DMF
CuI
CH3OH
CH3CN
AcOEt
DCM
CuI
CuI
CuI
0
CuI
0
DMSO
DMSO
DMSO
DMSO
CuI
58
62
70
68
CuI
CuI
CuI
a0.5 mmol of 1a, 2.0 mmol of 2a, 0.1 mmol of copper catalyst, 0.01 mmol of photocatalyst, 2 mL of solvent, open vial, irradiated by 12 W blue LED bulb at
room temperature.
b isolated yield.
Table 2. Reaction of hydrazine hydrate 2a with different aryl acetylenes 1a
a 0.5 mmol of 1, 2.0 mmol of 2a, 0.1 mmol of CuI, 0.01 mmol of Ru(bpy)3Cl2, 2 mL of DMSO, open vial, irradiated by 12 W blue LED bulb at room
temperature.

3
With the optimized conditions in hand, we proceeded to
evaluate the scope and generality of this cascade reaction. Firstly,
a wide range of aryl acetylenes 1 could react with hydrazine
hydrate 2a, leading to desired pyrazole products with moderate to
good isolated yields(3aa–3ia). Aryl acetylenes bearing electron-
withdrawing groups on benzene ring gave relatively higher yields
than the ones with electron-donating groups (3fa–3ia vs 3ba–3ea),
and 4-ethynylbenzonitrile 1h with a –CN group could undergo this
reaction to form desired product 3ha in up to 84% yield. The steric
nature of the substrates was shown to have little influence on the
reaction efficiency, as substrates 3ba–3da with a methyl group on
para, meta and ortho position of benzene ring respectively could
be converted to the corresponding pyrazoles in nearly same yields.
Notably, a series of functional groups, such as methoxy, nitrile and
ester, were all well tolerated under the reaction conditions, leading
to desired products in good yields (3ea, 3ha and 3ia). The reaction
of two alkynes with different aryl groups was also studied,
unfortunately it gave poor selectivity for homo-/cross-coupling.
turning on/off light or photocatalyst, it is found that light is
indispensable for the first step (Glaser coupling) of the cascade
reaction, while photocatalyst can accelerate the coupling, but is not
essential. For the second step, both light and photocatalyst are
indispensable, as no desired product 3aa is detected from the
reaction in absence of photocatalyst in dark environment.
Scheme 3. Control reactions by turning on/off hv or photocatalyst
We next examined substituted hydrazines 2 in the cascade
reaction with phenyl acetylene 1a. As showed in Table 3, this
reaction allows both alkyl and aryl substitution of hydrazine,
leading to tri-substituted pyrazoles in moderate yields. The
reaction of methyl hydrazine 2b and phenyl acetylene 1a can
generate pyrazole 3ab with a yield of 65%, while the reaction of
iso-propyl or tert-butyl hydrazine did not give any desired
products, probably due to the steric hindrance (3ac and 3ad).
Notably, various aryl hydrazines with different groups on benzene
ring were also found to work for the reaction, leading to
corresponding pyrazoles 3ae-3ah. Unfortunately, electron-
deficient hydrazine, such as acetohydrazide 2i could not undergo
this transformation, probably due to its relatively lower
nucleophilicity compared to alkyl and aryl substituted hydrazines.
Table 3. Reaction of phenyl acetylene 1a with substituted
hydrazines 2[a]
a0.5 mmol of 1a, 2.0 mmol of 2, 0.1 mmol of CuI, 0.01 mmol of Ru(bpy)3Cl2,
2 mL of DMSO, open vial, irradiated by 12 W blue LED bulb at room
temperature
Scheme 4. Plausible mechanistic pathways for the reaction
Scheme 2. Stepwise results of the synthesis
On the basis of these experimental observations and our
previous study of hydrazines,12,13 a plausible mechanism is
proposed for this cascade reaction (Scheme 4). The first step
almost resembles a typical Glaser reaction, as it goes through
several copper acetylide complexes, accompanied by the valence
changes of copper which is proposed to be accomplished by
photochemical process in the presence of oxygen. By studying the
For insight into the reaction mechanism, a stepwise synthesis
(Scheme 2) was performed by firstly subjecting 1a to standard
conditions without hydrazine, and 4 was isolated in 84% yield.
Then 4 was treated with hydrazine under standard conditions in
the absence of CuI, and the desired product 3aa was obtained in
87% yield. Also
control reactions focusing on the role of
photocatalysis in this strategy were carried out (Scheme 3). By

4
Tetrahedron
Simꢀn-Fuentes, Chem. Rev. 2011, 111, 6984; e) Y. L. Janin, Chem.
Rev. 2012, 112, 3924; For recent pyrazole syntheses, see, e.g.: f) J.
J. Neumann, M. Suri, F. Glorius, Angew. Chem. Int. Ed. 2010, 49,
7790; g) G. Shan, P. Liu, Y. Rao, Org. Lett. 2011, 13, 1746; h) Y.
Wang, X. Bi, W.-Q. Li, D. Li, Q. Zhang, Q. Liu, B. S. Ondon, Org.
Lett. 2011, 13, 1722; i) J. Qian, Y. Liu, J. Zhu, B. Jiang, Z. Xu, Org.
Lett. 2011, 13, 4220; j) R. S. Foster, H. Jakobi, J. P. A. Harrity, Org.
Lett. 2012, 14, 4858; k) G. Zhang, H. Ni, W. Chen, J. Shao, H. Liu,
B. Chen, Y. Yu, Org. Lett. 2013, 15, 5967; l) X. Zhu, Y.-F. Wang,
W. Ren, F.-L. Zhang, S. Chiba, Org. Lett. 2013, 15, 3214; m) G.
Zhang, Y. Zhao, H. Ge, Angew. Chem., Int. Ed. 2013, 52, 2559; n)
Y. Kong, M. Tang, Y. Wang, Org. Lett. 2014, 16, 576; o) Y.
Schneider, J. Prévost, M. Gobin, C. Y. Legault, Org. Lett. 2014, 16,
596; p) F.-G. Zhang, Y. Wei, Y.-P. Yi, J. Nie, J.-A. Ma, Org. Lett.
2014, 16, 3122; q) J. Zhang, Y. Shao, H. Wang, Q. Luo, J. Chen, D.
Xu, X. Wan, Org. Lett. 2014, 16, 3312; r) X. Li, L. He, H. Chen,
W. Wu, H. Jiang, J. Org. Chem. 2013, 78, 3636; s) T. Zhang, W.
Bao, J. Org. Chem. 2013, 78, 1317; t) J.-R. Chen, W.-R. Dong, M.
Candy, F.-F. Pan, M. Jorres, C. Bolm, J. Am. Chem. Soc. 2012, 134,
6924; u) C. Zhu, B. Bi, D. Yao, Q.Y. Chen, Z. B. Luo, Synthesis.
2015, 47, 1877.
For selected reviews on photoredox catalysis: a) J. Xuan, W. J.
Xiao, Angew. Chem. Int. Ed. 2012, 51, 6828; b) C. K. Prier, D. A.
Rankic, D. W. MacMillan, Chem. Rev. 2013, 113, 5322; c) D. M.
Schultz, T. P. Yoon, Science. 2014, 343, 1239176; d) R. A. Angnes,
Z. Li, C. R. D. Correia, G. B. Hammond, Org. Biomol. Chem. 2015,
13, 9152; e) J. Xuan, Z. G. Zhang, W.J. Xiao, Angew. Chem. Int.
Ed. 2015, 54, 15632; f) J. Luo, J. Zhang, ACS Catal. 2016, 6, 873;
g) J. R. Chen, X. Q. Hu, L. Q. Lu, W. J. Xiao, Chem. Soc. Rev. 2016,
45, 2044; h) See a special Issue on “Photoredox Catalysis in
Organic Chemistry” on Acc. Chem. Res., 2016, 49; i) X. Sun and S.
Yu, Synlett 2016, 27, 2659; j) M. Zhang, C. Zhu, L.-W. Ye,
Synthesis 2017, 49, 1150; k) J.-R. Chen, D.-M. Yan, Q. Wei, W.-J.
Xiao, ChemPhotoChem, 2017, 1, 148. l)W. Li, W. Xu, J. Xie, S.
Yu, C. Zhu, Chem. Soc. Rev., 2018, 47, 654.
UV-Vis absorption of phenyl acetylene, CuI and the mixture of
the two (see section 6 of Supporting Information), it is found that
the absorption of the mixture is red shifted to the region almost
within the spectrum of household blue LEDs compared to phenyl
acetylene or CuI alone. This result indicates that the generated
copper complex (intermediate 5 and 6) could be irradiated by blue
light, hence be oxidized through photochemical process. The
second step is initiated by the irradiation of RuII photocatalyst to
its excited state RuII* which is then reductively quenched by 2a
with concomitant generation of radical ion 9 and RuI. Upon
deprotonation, radical ion 9 is converted to radical 10 which
attacks diyne 4 to form radical intermediate 11. Through an
intramolecular hydrogen-atom-abstraction (HAT) and enamine-
to-imine tautomerization, 11 is converted to 13 via 12 by
abstracting a proton. Then intramolecular attack of allene group by
the nitrogen radical within intermediate 13 generates radical 14.
Finally, an oxidative quench of RuI by radical 14 regenerates RuII
photocatalyst, along with the formation of 15 which readily
transforms to desired product 3aa upon proton transfer.
6.
In conclusion, we have developed a visible-light promoted
cascade of Glaser coupling/annulation for the synthesis of
polysubstituted pyrazoles from readily available alkynes and
hydrazines. The method employs very mild reaction conditions
and uses air as the terminal oxidant, which makes the process
environmentally benign. Various substituted phenyl acetylene and
hyrazines undergo this reaction smoothly, leading to desired
products with good functional group tolerance and efficiency.
Photocatalysis was proven to be essential for these transformation
and a plausible mechanism featuring intramolecular hydrogen-
atom-abstraction (HAT) and enamine-to-imine tautomerization
was proposed for this transformation.
7.
8.
For reviews: a) J.-R. Chen, X.-Q. Hu, L.-Q. Lu, W.-J. Xiao, Acc.
Chem. Res. 2016, 49, 1911; b) P. Xu, W. Li, J. Xie, C. Zhu, Acc.
Chem. Res., 2018, 51, 484.
a) X.-Q. Hu, J.-R. Chen, Q. Wei, F.-L. Liu, Q.-H. Deng, A. M.
Beauchemin and Xiao, W.-J. Angew. Chem. Int. Ed. 2014, 53,
12163; b) Q.-Q. Zhao, X.-Q. Hu, M.-N. Yang, J.-R. Chen, W.-J.
Xiao, Chem. Commun. 2016, 52, 12749; c) Q.-Q. Zhao, J. Chen, D.-
M. Yan, J.-R. Chen, W.-J. Xiao, Org. Lett. 2017, 19, 3620.
Q. Wei, J.-R. Chen, X.-Q. Hu, X.-C. Yang, B. Lu, W.-J. Xiao, Org.
Lett. 2015, 17, 4464.
Acknowledgments
We acknowledge the National Natural Science Foundation of
China (No. 31501686), the Natural Science Foundation of Jiangsu
Province (No. BK20140536), the Qing Lan Project of Jiangsu
Province and Jiangsu University Foundation (No. 13JDG059) for
financial support.
9.
10. J. Cheng, P. Xu, W. Li, Y. Cheng, C. Zhu, Chem. Commun. 2016,
52, 11901.
11. J. Cheng, W. Li, Y. Duan, Y. Cheng, S. Yu, C. Zhu, Org. Lett. 2017,
19, 214.
References and notes
12. a) Y. Ding, T. Zhang, Q.-Y. Chen, C. Zhu, Org. Lett. 2016, 18,
4206; b) T. Zhang, Y. Meng, J. Lu, Y. Yang, G.-Q. Li, C. Zhu, Adv.
Synth. Catal., 2018, 360, 3063.
13. a) Y. Ding, W. Zhang, H. Li, Y. Meng, T. Zhang, Q.-Y. Chen, C.
Zhu, Green Chem., 2017, 19, 2941; b) Y. Ding, H. Li, Y. Meng, T.
Zhang, J. Li, Q.-Y. Chen, C. Zhu. Org. Chem. Front., 2017, 4, 1611.
1.
a) A. Schmidt, Z. Guan, Synthesis 2012, 44, 3251; b) S. Schnatterer,
Phenylpyrazole-Containing Fiprole Insecticides. In Bioactive
Heterocyclic Compound Classes: Agrochemicals; Lamberth, C.,
Ed.; Wiley-VCH: Weinheim, Germany, 2012; c) F. Giornala, S.
Pazenok, L. Rodefeld, N. Lui, J.-P. Vors, F. R. Leroux, J. Fluorine
Chem. 2013, 152, 2; d) V. Kumar, K. Kaur, G. K. Gupta, A. K.
Sharma, Eur. J. Med. Chem. 2013, 69, 735; e) K. M. Kasiotis, E. N.
Tzanetou, S. A. Haroutounian, Front. Chem. 2014, 2, 78; f) R.
Pérez-Fernández, P.Goya, J. Elguero, ARKIVOC 2014, 15, 233; g)
C. Li, L. Liang, K. Wang, C. Bian, J. Zhang, Z. Zhou, J. Mater.
Chem. A 2014, 2, 18097; h) S. H. Hwang, K. M. Wagner, C.
Morisseau, J. Y. Liu, H. Dong, A. T. Wecksler, B. D. Hammock, J.
Med. Chem. 2011, 54, 3037; i) H. X. Dai, A. F. Stepan, M. S.
Plummer, Y. H. Zhang, J. Q. Yu, J. Am. Chem. Soc. 2011, 133,
7222; j) S. R. Donohue, C. Halldin, V. W. Pike, Bioorg. Med. Chem.
2006, 14, 3712.
Supplementary Material
Highlights
• Simple one-pot reaction for preparation of
pyrazoles from alkynes and hydrazines.
• Mild conditions: visible-light promoted; room
temperature; O2 as the Oxidant.
• Easy reaction set-up.
2.
3.
A. Schmidt, A. Dreger, Curr. Org. Chem. 2011, 15, 2897.
a) R. A. Singer, M. Dore, J. E. Sieser, M. A. Berliner, Tetrahedron
Lett. 2006, 47, 3727; b) R. Kowalcyk, J. Skarzewski, Tetrahedron.
2005, 61, 623; c) S. O. Ojwach, J. Darkwa, Inorg. Chim. Acta. 2011,
363, 1947.
• Functional group tolerance.
4.
5.
a) V. S. Thirunavukkarasu, K. Raghuvanshi, L. Ackermann, Org.
Lett. 2013, 15, 3286; b) P. M. Liu, C. G. Frost, Org. Lett. 2013, 15,
5862.
For reviews: a) K. Makino, H. S. Kim, Y. Kurasawa, J. Heterocycl.
Chem. 1998, 35, 489; b) J. Steve, ARKIVOC 2006, 7, 35; c) S.
Fustero, A. Simꢀn-Fuentes, J. F. Sanz-Cervera, Org. Prep. Proced.
Int. 2009, 41, 253; d) S. Fustero, M. Sꢁnchez-Rosellꢀ, P. Barrio, A.