Visible-light photocatalytic aerobic annulation for the green synthesis of pyrazoles

Article abstract of DOI:10.1021/acs.orglett.6b01867

A selective and high yielding synthesis of polysubstituted pyrazoles through a VLPC (visible light photoredox catalysis)-promoted reaction of hydrazine with Michael acceptors is reported. The method employs very mild reaction conditions and uses air as the terminal oxidant, which makes the process environmentally benign. Different types of Michael acceptors with various substituents can undergo the reaction to afford corresponding pyrazoles in good to excellent yields. The reaction is proposed to go through VLPC-promoted oxidation of hydrazine to diazene followed by its addition to Michael acceptors, other than the conventional condensation of hydrazine with a carbonyl.

Full text of DOI:10.1021/acs.orglett.6b01867

Letter
pubs.acs.org/OrgLett
Visible-Light Photocatalytic Aerobic Annulation for the Green
Synthesis of Pyrazoles
Ya Ding,† Te Zhang,† Qiu-Yun Chen,† and Chunyin Zhu*,†,‡
†School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, P. R. China
‡State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University, Xiamen 361005, P. R. China
S
* Supporting Information
ABSTRACT: A selective and high yielding synthesis of
polysubstituted pyrazoles through a VLPC (visible light photo-
redox catalysis)-promoted reaction of hydrazine with Michael
acceptors is reported. The method employs very mild reaction
conditions and uses air as the terminal oxidant, which makes the
process environmentally benign. Different types of Michael
acceptors with various substituents can undergo the reaction to
afford corresponding pyrazoles in good to excellent yields. The
reaction is proposed to go through VLPC-promoted oxidation of
hydrazine to diazene followed by its addition to Michael acceptors, other than the conventional condensation of hydrazine with a
carbonyl.
Scheme 1. Strategies for the Synthesis of Pyrazoles
yrazoles and their derivatives represent an important
1
Pframework in pharmaceutical and agrochemical sciences.
For example, a number of pyrazole-containing compounds have
been successfully developed into commercial drugs including
Celebrex,2a,b Acomplia,2c and Viagra,1a and the insecticide
Fipronil.2d Additionally, substituted pyrazole derivatives have
been employed as ligands for transition-metal-catalyzed cross-
coupling reactions,3 precursors to N-heterocyclic carbenes
(NHCs),4 and directing groups for C−H activations.5 Due to
the functional versatility of the pyrazole skeleton, their
synthesis has been extensively explored.6 By far the most
prevalent strategies for constructing pyrazole rings are
annulations initiated by the condensation of a monosubstituted
hydrazine with a carbonyl, such as cyclocondensation of 1, 3-
dicarbonyl or α,β-unsaturated carbonyl compounds with
hydrazines.7 However, these methods usually involve reaction
conditions such as high reaction temperature, microwave
irradiation, and hazard oxidants, which are contrary to the
concept of green chemistry, and sometimes can lead to poor
regioselectivity (Scheme 1). Accordingly, synthetic methods for
polysubstituted pyrazoles with high selectivity employing mild
and cheap conditions are still of current interest to the synthetic
community.
involving VLPC for oxidative couplings/annulations.8n,14 For
visible light photocatalytic oxidative couplings/annulations,
VLPC usually serves as an oxidation promoter to generate
reactive intermediates which can be utilized in further
transformations to furnish complicated molecular structures.
In this context, we envision that VLPC can promote
transformation of substituted hydrazine to a diazene
intermediate which could attack Michael acceptors and cyclize
to pyrazoles (Scheme 1).
To test this rationale, we started our investigation by
studying the oxidative annulation between methyl hydrazine
(1a) and 2-benzylidenemalononitrile (2a). The desired
product, 5-amino-1-methyl-3-phenyl-1H-pyrazole-4-carbonitrile
(3a), was furnished in 75% yield when the reaction proceeded
at 25 °C in the presence of 2 mol % RuII(bpy)3Cl2·6H2O
irradiated with a 3 W blue LED in an open vial for 24 h in
MeOH (entry 1, Table 1). Encouraged by the aforementioned
result, other reaction conditions were investigated, and the
results are summarized in Table 1. First, various solvents were
Over the past decade, visible light photoredox catalysis has
evolved to be a green synthetic strategy, as it uses visible light as
a renewable energy source to promote chemical reactions
involving electron transfers.8 Since the independent seminal
reports from the MacMillan, Yoon, and Stephenson groups
almost a decade ago,9 VLPC has already found major
applications in enantioselective α-functionalization of carbonyl
compounds,10 [2 + 2] cycloadditions,11 dehalogenationreac-
tions,12 decarboxylative couplings,8e radical C−H functionaliza-
tion of aromatic compounds,13 and the synergistic catalysis
Received: June 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01867
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Letter
a
(71−90%), except for the one with an electron-donating group
which could also be converted to the desired product but in
moderate yield (4-OMe, 3m, 50%). The presence of electron-
neutral (4-H, 2-Me, 3-Me, 4-Me) and electron-deficient (2-F, 3-
F, 4-F) groups attached to the phenyl ring had little effect on
reactivity, and the corresponding pyrazoles were afforded in
good to excellent yields (3a−3d and 3j−3l). The steric nature
of the substrates was shown to have little influence on the
reaction efficiency, and substrates with ortho, meta, or para
substituents on the phenyl group could be converted to the
corresponding pyrazoles in good to excellent yields (3b−3d,
3e−3g, and 3j−3l); even the one with 2,4-dichloro substituents
could also give 81% yield (3i). It is noteworthy that the all the
substrates with halide substituents could be smoothly converted
to corresponding pyrazoles which could be used for further
functionalization through transition-metal-catalyzed cross-cou-
pling (3e−3l). Furthermore, different hydrazines were
examined for this reaction, and tert-butyl hydrazine reacted
smoothly with 2a to give corresponding pyrazole 3n in good
yield while PhNHNH2 and TsNHNH2 only led to other
unexpected structures.15
Table 1. Optimization of Reaction Conditions
b
entry
solvent
temp (°C)
time (h)
yield (%)
1
MeOH
DCM
EtOH
H2O
25
25
25
25
25
25
25
25
25
25
50
24
24
24
24
24
24
24
24
24
12
24
75
78
80
81
90
70
65
61
46
60
75
2
3
4
5
MeCN
DMSO
DMF
6
7
8
THF
9
Et2O
10
11
MeCN
MeCN
a
0.5 mmol of 2a, 0.6 mmol of 1a, 0.01 mmol of RuII(bpy)3Cl2·6H2O,
1.0 mL of solvents, with 3W blue LED, under air. Isolated yield.
b
Encouraged by the exciting results obtained between the
reactions of methyl hydrazine with different substituted
methylenemalononitriles, application of this VLPC promoted
aerobic annulation to other Michael acceptors was investigated
next (Scheme 3). Substituted chalcones (5a−5e) turned out to
screened, revealing that CH3CN was the best choice for the
reaction, though other solvents such as EtOH, DCM, DMSO,
DMF, THF, Et2O, and even H2O can also give decent yields
(entries 1−9). Additionally, shortening the reaction time
decreased the yield of 3a (entry 10). Subsequently, varying
the reaction temperature uncovered that higher temperature
can jeopardize the reaction, leading to a lower yield (entry 11).
After optimizing the reaction conditions, we turned our
attention to the generality and scope of the substrates for this
transformation. A wide range of substituted olefins bearing two
nitriles were first evaluated in the reaction with methyl
hydrazine, as shown in Scheme 2. Nearly all substrates
examined were found to undergo the desired transformation
to give the corresponding products in good to excellent yields
a
Scheme 3. Scope of Different Michael Acceptors
Scheme 2. Scope of Methylenemalononitriles Reacting with
a
Hydrazine
a
0.5 mmol of 4, 0.6 mmol of 1a, 0.01 mmol of RuII(bpy)3Cl2·6H2O,
1.0 mL of MeCN, with 3W blue LED, under air, 24 h.
be suitable substrates for this transformation, and they can be
converted to corresponding 1,3,5-triubstituted pyrazoles in
good to excellent yields (75−90%). Similarly α,β-unsaturated
ketoesters also work well for the reaction to give the
corresponding pyrazoles in good yields (5f−5g). To our
delight, diethyl 2-benzylidenemalonate was found to undergo
the desired transformation to give the corresponding 5-hydoxy
pyrazole in 85% yield (5h).
During the study of the reaction between methyl hydrazine
and Michael acceptor 2a in Et2O, an intermediate 6 was
1
isolated and confirmed by H NMR, 13C NMR, MS, and IR
(see Supporting Information), and 6 can be converted to
corresponding pyrazole when subjected to standard conditions
(eq 1, Scheme 4). This observation supports the idea that the
reaction is initiated by a pathway other than the condensation
of methyl hydrazine with the carbonyl. Another control
reaction of 1a with 2a in the absence of a photocatalyst
under a dark environment resulted in 77% starting material 2a
recovered (eq 2, Scheme 4). Also the luminescence of
a
0.5 mmol of 2, 0.6 mmol of 1, 0.01 mmol of RuII(bpy)3Cl2·6H2O, 1.0
mL of MeCN, with 3W blue LED, under air, 24 h.
B
DOI: 10.1021/acs.orglett.6b01867
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Letter
radical 8, which can also quench the excited state RuII* and lose
a proton to form diazene 9. At the same time RuI is oxidized
back to RuII by molecular oxygen. Then the addition of diazene
9 to the Michael acceptor and proton tautomerization furnish
the intermediate 6 which undergoes intramolecular condensa-
tion to form the desired product.
Scheme 4. Mechanistic Study
In conclusion, we have developed a selective and high
yielding synthesis of polysubstituted pyrazoles through a
VLPC-promoted reaction of hydrazine with Michael acceptors.
The method employs very mild reaction conditions and uses air
as the terminal oxidant, which makes the process environ-
mentally benign. Different types of Michael acceptors with
various substituents can undergo the reaction to afford
corresponding pyrazoles in good to excellent yields. The
reaction is proposed to go through VLPC-promoted oxidation
of hydrazine to diazene followed by its addition to Michael
acceptors, other than the conventional condensation of
hydrazine with a carbonyl. Further study on the reactivity of
diazene intermediate is ongoing in our laboratory.
RuII(bpy)3Cl2·6H2O with excitation at 493 nm could be readily
quenched by 1a following Stern−Volmer kinetics (Figure 1).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01867.
Experimental procedures and spectral data for all new
compounds; mechanistic study, luminescence quenching
experiment; and spectral data for intermediate 6 (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhucycn@gmail.com.
Notes
The authors declare no competing financial interest.
Figure 1. (up) Luminescence quenching of RuII(bpy)3Cl2·6H2O with
excitation at 493 nm by 1a. (down) The Stern−Volmer plot.
ACKNOWLEDGMENTS
■
We acknowledge the Natural Science Foundation of China
(Nos. 21302070 and 21271090), Jiangsu University Founda-
tion (No. 13JDG059), and the Qing Lan Project of Jiangsu
Province for finance support. Finally we want to thank Xiao
group from Central China Normal University for donating a
piece of equipment for setting up VLPC reactions.
This luminescence quenching is most likely due to photo-
induced electron transfer. On the basis of these experimental
observations, a plausible mechanism is proposed (Scheme 5).
First, the RuII photocatalyst is irradiated to the excited state
RuII* using blue LEDs, and this excited state is then reductively
quenched by 1a with concomitant generation of radical anion 7
and RuI. Upon deprotonation, radical anion 7 is converted to
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DOI: 10.1021/acs.orglett.6b01867
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