Copper-Catalyzed Aerobic Cyclization of β,γ-Unsaturated Hydrazones with Concomitant CC Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.0c02911

A Cu-catalyzed aerobic oxidative cyclization of β,γ-unsaturated hydrazones for the preparation of pyrazole derivatives has been developed. The hydrazonyl radical promoted the cyclization, along with a concomitant CC bond cleavage of β,γ-unsaturated hydrazones. This process has been verified via several control experiments, including a radical-trapping study, an 18O-labeling method, and the identification of the possible byproducts. The advantages of this reaction include operational simplicity, a broad reaction scope, and a mild selective reaction process.

Full text of DOI:10.1021/acs.orglett.0c02911

pubs.acs.org/OrgLett
Letter
Copper-Catalyzed Aerobic Cyclization of β,γ-Unsaturated
Hydrazones with Concomitant CC Bond Cleavage
Zhenwei Fan, Jiahao Feng, Yuchen Hou, Min Rao, and Jiajia Cheng*
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ABSTRACT: A Cu-catalyzed aerobic oxidative cyclization of β,γ-unsaturated hydrazones for the preparation of pyrazole derivatives
has been developed. The hydrazonyl radical promoted the cyclization, along with a concomitant CC bond cleavage of β,γ-
unsaturated hydrazones. This process has been verified via several control experiments, including a radical-trapping study, an 18O-
labeling method, and the identification of the possible byproducts. The advantages of this reaction include operational simplicity, a
broad reaction scope, and a mild selective reaction process.
The advent of readily accessible radical species under milder
conditions has fueled a reinvigoration into radical chemistry,
resulting in the discovery of novel transformations of radical
C−C bond cleavage for the production of functional molecules
that complement conventional ionic processes.4 In this
context, nitrogen-centered radicals (NCRs) are of eminent
importance in chemical synthesis, which can be further
leveraged to enable radical addition/cyclization transforma-
tions.5 In recent years, the chemistry of NCRs has witnessed
remarkable advances, as illustrated by the flourishing field of
NCR-mediated transformations.6
From the standpoint of sustainable chemistry, the develop-
ment of an efficient and selective approach for the trans-
formation of NCRs involving C−C bond cleavage is promising,
which provided an appealing synthetic platform for the
creation of a wide array of nitrogen-containing heterocyclic
molecules.
he C−C bonds in organic molecules are ubiquitous,
Tstrong, and surrounded by C−H bonds. The C−C bond
cleavage thus represents a grand challenge, because of their
relative inertness, thermodynamic, and kinetic stability.1 The
prevalent strategies of C−C bond cleavage by transition-metal
catalysis rely on the reaction of small rings2 or a substrate with
latent coupling fragments such as tertiary alcohol,3 whereas
these strategies usually suffer from harsh reaction conditions,
together with limited functional group tolerance (Scheme 1a).
Scheme 1. Cyclization of β,γ-Unsaturated Hydrazones with
Concomitant C = C Bond Cleavage
The pyrazole moiety is widely present in the field of natural
products, biologically/pharmacologically active molecules,
agrochemicals, and synthetic ligands. Therefore, the efficient
synthesis of functionalized pyrazoles has attracted substantial
attention from both academia and industry (see Figure 1).7
Hydrazones constitute a class of structurally versatile reagents,
because of their broad modularity and ready accessibility.8
However, the conventional cyclization of hydrazones for the
preparation of pyrazole derivatives usually suffered from the
Received: August 30, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02911
© XXXX American Chemical Society
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A

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a
Table 1. Optimization of the Reaction Conditions
b
Figure 1. Selected examples of biologically active drug molecules with
a phenylpyrazole framework.
Yield (%)
temp, T
(°C)
entry
catalyst
solvent
ligand
2a
3a
employment of a stoichiometric promoter, precious metal
catalysts, harsh reaction conditions, and restricted functional
group tolerance.9 The straightforward cyclization of hydra-
zonyl radicals has recently been developed to be a new
powerful synthetic strategy to construct pyrazole scaffolds. In
this context, enormous progress has been achieved in the
employment of β,γ-unsaturated hydrazones as fascinating and
unconventional approaches toward enabling a range of
structurally diverse synthetic transformations.10 Nevertheless,
most of the reported approaches rely on the catalytic 5-exo-trig
or 6-endo-trig ring closure in the realm of β,γ-unsaturated
hydrazone chemistry (see Scheme 1b).11 The catalyst-
controlled aerobic radical cyclization of hydrazones for the
synthesis of pyrazoles via the cleavage of the CC double
bond has rarely been exploited so far.12,13 Therefore, the
fabrication of pyrazoles with readily accessible starting
materials in a controllable manner would be greatly desirable.
Recently, we report one Cu-catalyzed oxidative 6-endo-trig
annulation of β,γ-unsaturated hydrazones for the pyridazines,
and 1,6-dihydropyridazines synthesis with a different reaction
solvent.14 In this paper, we disclose a Cu-catalyzed oxidative
cyclization of β,γ-unsaturated hydrazones for the synthesis of
pyrazole with the concomitant cleavage CC bond (Scheme
1c). In this approach, O2 served as the terminal oxidant and
low-cost Cu(I) salt was employed as the catalyst. The features
of operational simplicity and mild reaction conditions, in
combination with a more general functional group tolerance,
made this Cu-catalyzed aerobic oxidative transformation
particularly synthetically advantageous, practical, and green.
Initially, β,γ-unsaturated hydrazine 1a was chosen as a model
compound and catalytic Cu(OAc)2 was evaluated under a
balloon pressure of O2 atmosphere (see Table 1). Pleasingly,
the reaction does indeed occur in CH3CN at 80 °C, thus
giving the desired pyrazole product 2a in a 25% yield (Table 1,
entry 1). It is noteworthy that an undesired side-product was
formed during the screening reactions. Further cautious
analytical characterization confirmed that it was a six-endo-
trig cyclization product 3a. Screening of the reaction solvent
could not afford better results, and 3a was obtained exclusively
with toluene or dioxane as the reaction medium (Table 1,
entries 2 and 3). Different copper(I) salts, such as CuOAc,
CuBr, Cu(acac)2, CuOTf, and Cu(OTf)2, were explored
(Table 1, entries 4−8); among these salts, CuOTf provided
the best result. We then determined that 2a could be generated
as the sole product by decreasing the reaction temperature
(Table 1, entries 9 and 10). Subsequently, various types of
ligands were tested with the expectation to stabilize the
catalytic metal center and increase the reaction outcome
(Table 1, entries 11−14). Delightedly, the optimal reaction
yield was achieved (76%) when 1,10-phenanthroline-5,6-dione
L2 (10 mol %) was added. Lowering the ligand loading to 6
mol % only led to a slight decrease in the reactivity (Table 1,
entry 15). Further exploration of alternative solvents (Table 1,
1
2
3
4
5
6
7
8
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuOAc
CuBr
CH3CN
toluene
dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
−
−
−
−
−
−
−
−
80
80
80
80
80
80
80
80
70
60
60
60
60
70
70
70
70
70
50
40
70
70
25
nd
nd
30
37
38
53
trace
67
61
25
43
nd
76
75
25
40
nd
42
trace
nd
nd
50
50
20
25
trace
trace
nd
trace
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
Cu(acac)2
CuOTf
Cu(OTf)2
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
−
−
10
11
12
13
14
15
16
17
18
19
20
2,2′-bpy
phen
L1
L2
L2
c
c
L2
L2
c
DMF
CH3OH L2
CH3CN
CH3CN
CH3CN
CH3CN
c
c
c
c
c
L2
L2
L2
L2
d
21
22
nd
a
Reaction conditions: 1a (0.1 mmol), catalyst (5 mol %), ligand (6
mol %), O2 (balloon), solvent (2.0 mL), 4 h. Isolated yield. 6 mol %
of ligand was used. The reaction was conducted under N2.
b
c
d
entries 16−18) led to inferior results, whereas lowering the
reaction temperature resulted in a obviously slower reaction
rate and decreased substrate conversion (Table 1, entries 19
and 20). The reaction delivered no product when oxygen or
copper catalyst was removed from the reaction conditions
(Table 1, entries 21 and 22). Finally, the best result was
eventually achieved with CuOTf (5 mol %) and 1,10-
phenanthroline-5,6-dione (6 mol %), under an atmosphere of
O2 (Table 1, entry 15).
A study on the substrate scope demonstrates that this
approach offers great potential and utility in the streamlined
and divergent assembly of pyrazole derivatives. It was shown
that hydrazone derivatives with a wide range of substituents at
the aromatic moiety worked well to afford pyrazole derivatives
2 with CuOTf as the catalyst (see Scheme 2). The optimized
reaction conditions showed high functional group tolerance,
and the steric and electronic properties of the substitute only
impart a slight impact on the reaction. β,γ-Unsaturated
hydrazones bearing either electron-donating (e.g., alkyl and
aryl group) or electron-withdrawing groups (e.g., Cl, Br, CN,
CO2CH3) at the para-position of the phenyl rings were
compatible with the transformation to afford the pyrazoles
2b−2j in good to high yields (55%−81%). Notably, CF3O-
substituted hydrazone also smoothly afforded the desired
product 2k. The molecular structure of 2h was elucidated by
an X-ray crystallography study. Moreover, substrates contain-
ing substitutes at the meta-position of the phenyl moiety
B
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Scheme 2. Scope of Copper-Catalyzed Oxidative Cyclization
for the Synthesis of Pyrazole Derivatives
Scheme 3. Cyclization of Various Hydrazones for the
a
a
Synthesis of Pyrazole Derivatives
a
Reaction conditions: 1 (0.1 mmol), CuOTf (5 mol %), ligand 1,10-
phenanthroline-5,6-dione (6 mol %), O2 (balloon), CH3CN (1.0 mL)
at 70 °C for 4 h.
To assess the synthetic practicality of the current procedure,
the gram-scale preparation of 1h was performed and the
reaction worked well with the production of the cyclization
product 2h in 65% yield (Scheme 4). To further showcase the
a
Reaction conditions: 1 (0.1 mmol), CuOTf (5 mol %), ligand 1,10-
phenanthroline-5,6-dione (6 mol %), O2 (balloon) in CH3CN (1.0
mL) at 70 °C for 4 h.
Scheme 4. Gram-Scale Reaction and Synthetic
Derivatization
proves to be compatible with the CuOTf (2l and 2m). When a
naphthalene ring-substituted hydrazone was prepared and
subjected to the Cu-catalyzed reaction conditions, pyrazole 2n
was delivered in a 64% yield. We then observed that the
current catalytic system was suitable for substrates derived
from 3,4-bis-substituted phenyl ketones, affording the corre-
sponding products in moderate to high yields (2o−2q).
Remarkably, a substrate containing heteroaryl frameworks
could also be applied with this oxidative cyclization reaction,
which delivered the target product in an overall good yield
(2r−2t). Finally, we are pleased to find that an olefinic
substituent could be used instead of an aryl group, leading to
the generation of the cyclization pyrazole product in 63% yield
(2u).
The structural diversity of hydrazone was further examined
by varying the substitute of the olefin moiety (see Scheme 3).
To our delight, hydrazone with a methyl or phenyl group at the
terminal olefin moiety was well-transferred to the correspond-
ing pyrazole products (2v and 2w) in good to high yields. Note
that the substrate scope could also be extended to hydrazone
with an alkyl group at the α-position (2x). Furthermore, the N-
protecting group of 1 was investigated. N-Boc-, N-CO2Bn-,
and N-CO2Et-substituted hydrazones also underwent the
reaction to deliver 2y−2aa with a promising outcome, whereas
the use of N-Ac- or N-CONHPh-based 1 resulted in a low
yield (2ab and 2ac). In addition, the reaction exhibited great
tolerance with N-arylsulfonyl-substituted hydrazone, generat-
ing 2ad in 52% yield.
utility of the present approach, the deprotection of the N-
protecting group was performed using product 2h, and the
derivatization proceeded smoothly to deliver the N−H
pyrazole derivative 3.15
To gain preliminary insight into the model reaction, we
performed additional control experiments to elucidate the
underlying mechanism (see Scheme 5). Upon addition of
radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) under the established conditions, a significantly
lower production yield of the target reaction was observed
(Scheme 5a). Notably, TEMPO-trapped adduct 4 was isolated
in 20% yield, which is indicative of the carbon-centered radical
engaged in the process. Subsequently, hydrazone 5 was added
under the standard conditions to afford an 81% yield of 6,
which directly confirmed the cleavage of the CC bond
C
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centered radical II′. Following pathway A in Scheme 6, alkyl-
hydroperoxide IV is afforded via a hydrogen abstraction, and
product 2b is formed through the elimination of aldehyde and
H2O from intermediate IV. Alternatively, a 1,5-hydrogen atom
transfer (HAT)19 may first deliver the alkyl radical V, and
subsequent C−C bond cleavage would finally lead to the
oxidative cyclization product 2b.
Scheme 5. Mechanism Study
In conclusion, a facile one-pot, copper-catalyzed aerobic
cyclization has been successively developed for the synthesis of
the pyrazoles using β,γ-unsaturated hydrazones as the readily
accessible substrates. The radical cyclization, along with the
cleavage of the CC bond of β,γ-unsaturated hydrazones
occurred, and this process has been verified by several control
experiments, including a radical-trapping study, an 18O-labeling
method, and isolation of the possible byproduct. This Cu-
catalyzed aerobic oxidative cyclization features operational
simplicity, commercially available catalysts, broad substrate
scope, and amenability to scale-up without precautions to
avoid air or moisture. More-detailed mechanistic studies and
synthetic applications of the hydrazonyl-radical-promoted
reactions are underway in our laboratory.
during the reaction process (Scheme 5b). Furthermore, when
hydrazine 1ae with a phenyl group attached to the olefin
moiety was used as the substrate (Scheme 5c), the aldehyde
byproduct 7 was furnished in 90% yield, along with the
isolation of the cyclization product 2b. To verify the origin of
oxygen in the reaction process, we performed the isotopic
labeling experiments with the addition of 5 equiv of 18O-
enriched water. The observation of the 76% yield of 18O-
unlabeled products suggested that the aldehyde O atoms
mainly originated from the atmospheric oxygen. Although the
specific reaction pathway is still not clear, the 10% yield of the
18O-labeled product indicates the partial origin of oxygen from
water, which has seldom been reported previously.16
Consistent with the result from the optimization studies that
no product was afforded in the absence of O2 (Table 1, entry
16), it is reasonable to speculate that the activation of O2 must
be one of the key steps in the catalytic process.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02911.
Detailed experimental procedure; 1H, 13C, 19F NMR and
HPLC spectra; X-ray data information (PDF)
Accession Codes
CCDC 2023937 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
The mechanistic rationale based on the literature17 and
additional control experiments is proposed in Scheme 6. The
AUTHOR INFORMATION
Scheme 6. Proposed Reaction Pathway
■
Corresponding Author
Jiajia Cheng − State Key Laboratory of Photocatalysis on Energy
and Environment, Key Laboratory of Molecule Synthesis and
Function Discovery (Fujian Province University), College of
Chemistry, Fuzhou University, Fuzhou 350116, China;
orcid.org/0000-0002-0878-7069; Email: jjcheng@
fzu.edu.cn
Authors
Zhenwei Fan − State Key Laboratory of Photocatalysis on
Energy and Environment, Key Laboratory of Molecule Synthesis
and Function Discovery (Fujian Province University), College of
Chemistry, Fuzhou University, Fuzhou 350116, China
Jiahao Feng − State Key Laboratory of Photocatalysis on Energy
and Environment, Key Laboratory of Molecule Synthesis and
Function Discovery (Fujian Province University), College of
Chemistry, Fuzhou University, Fuzhou 350116, China
Yuchen Hou − State Key Laboratory of Photocatalysis on
Energy and Environment, Key Laboratory of Molecule Synthesis
and Function Discovery (Fujian Province University), College of
Chemistry, Fuzhou University, Fuzhou 350116, China
Min Rao − State Key Laboratory of Photocatalysis on Energy
and Environment, Key Laboratory of Molecule Synthesis and
reaction is initiated by the interaction of Cu catalyst with
substrate 1b to generate intermediate I, which underwent
reversible homolysis of the N−[Cu(II)] bond to give N-
centered hydrazonyl radical I′.18 The intramolecular amino-
cupration of Cu(II)-activated substrate 1b occurs to provide
the alkyl-copper complex II. Homocleavage of intermediate II
would give the carbon-centered radical intermediates II′,
which could be readily trapped by molecular oxygen to
generate the radical intermediate III. The finding of TEMPO-
trapping adduct 4 is consistent with the generation of carbon-
D
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Function Discovery (Fujian Province University), College of
pubs.acs.org/OrgLett
Letter
Chang, J. J. Org. Chem. 2014, 79, 10170−10178. (d) Wang, Q.; He,
L.; Li, K. K.; Tsui, G. C. Org. Lett. 2017, 19, 658−661.
Chemistry, Fuzhou University, Fuzhou 350116, China
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W.-J. Org. Lett. 2015, 17, 4464−4467. (b) Zhu, M. K.; Chen, Y. C.;
Loh, T. P. Chem. - Eur. J. 2013, 19, 5250−5254.
Complete contact information is available at:
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(11) Hu, X. Q.; Qi, X.; Chen, J. R.; Zhao, Q. Q.; Wei, Q.; Lan, Y.;
Xiao, W. J. Nat. Commun. 2016, 7, 11188.
Notes
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H. Org. Lett. 2018, 20, 5094−5097. (b) Deng, Y.; Wei, X.-J.; Wang,
The authors declare no competing financial interest.
̈
H.; Sun, Y.; Noel, T.; Wang, X. Angew. Chem., Int. Ed. 2017, 56, 832−
ACKNOWLEDGMENTS
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■
We gratefully acknowledge the Science Foundation of the
Fujian Province (No. 2019J01203), the National Natural
Science Foundation of China (Nos. 22072020 and 21502019),
the Open Project Program of the State Key Laboratory of
Photocatalysis on Energy and Environment (No. SKLPEE-
KF201816), and Fuzhou University for financial support.
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