Electrochemical Palladium-Catalyzed Oxidative Sonogashira Carbonylation of Arylhydrazines and Alkynes to Ynones

Article abstract of DOI:10.1021/jacs.1c06036

Oxidative carbonylation using carbon monoxide has evolved as an attractive tool to valuable carbonyl-containing compounds, while mixing CO with a stoichiometric amount of a chemical oxidant especially oxygen is hazardous and limits its application in scale-up synthesis. By employing anodic oxidation, we developed an electrochemical palladium-catalyzed oxidative carbonylation of arylhydrazines with alkynes, which is regarded as an alternative supplement of the carbonylative Sonogashira reaction. Combining an undivided cell with constant current mode, oxygen-free conditions avoids the explosion hazard of CO. A diversity of ynones are efficiently obtained using accessible arylhydrazines and alkynes under copper-free conditions. A possible mechanism of the electrochemical Pd(0)/Pd(II) cycle is rationalized based upon cyclic voltammetry, kinetic studies, and intermediates experiments.

Full text of DOI:10.1021/jacs.1c06036

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Electrochemical Palladium-Catalyzed Oxidative Sonogashira
Carbonylation of Arylhydrazines and Alkynes to Ynones
Yong Wu,∥ Li Zeng,∥ Haoran Li, Yue Cao, Jingcheng Hu, Minghao Xu, Renyi Shi,* Hong Yi,*
and Aiwen Lei*
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ABSTRACT: Oxidative carbonylation using carbon monoxide has evolved as an attractive tool to valuable carbonyl-containing
compounds, while mixing CO with a stoichiometric amount of a chemical oxidant especially oxygen is hazardous and limits its
application in scale-up synthesis. By employing anodic oxidation, we developed an electrochemical palladium-catalyzed oxidative
carbonylation of arylhydrazines with alkynes, which is regarded as an alternative supplement of the carbonylative Sonogashira
reaction. Combining an undivided cell with constant current mode, oxygen-free conditions avoids the explosion hazard of CO. A
diversity of ynones are efficiently obtained using accessible arylhydrazines and alkynes under copper-free conditions. A possible
mechanism of the electrochemical Pd(0)/Pd(II) cycle is rationalized based upon cyclic voltammetry, kinetic studies, and
intermediates experiments.
nones are core skeletons of various natural and bioactive
compounds, as well as important synthetic building blocks
achieving an electrochemical aminocarbonylation of alkynes in
the undivided cell.9
Y
that can be converted into complex molecules (Scheme 1A).1
Thus, considerable attention has been focused toward
preparing this structural unit.2 Besides the traditional cross-
coupling reactions of terminal alkynes with acyl chlorides, the
carbonylative Sonogashira-type reaction which employs easily
available aryl halides, alkynes, and CO as coupling partners is a
conventional route for the direct preparation of ynones.3
Despite its great contribution to ynone synthesis, this
transformation suffers from the generation of halide-containing
chemical wastes, multistep processes, and harsh reaction
conditions (Scheme 1B-1).2e,4 Recently, severe environmental
problems motivate chemists to develop new synthetic
methodologies to minimize the generation of chemical wastes.
Oxidative carbonylation reactions using O2 have attracted
broad interest, which provides a direct route to carbonyl
derivatives under mild conditions.5 However, the mixture of
CO/O2 results in safety issues, limiting practical application in
industry. The Beller group developed an efficient strategy for
carbonylative Sonogashira reactions of anilines under mild
conditions, the strategy proceeds with the assistance of
As a part of continued interest in oxidative carbonylation
and synthetic methods of ynones,10 herein, we developed an
electrochemical palladium-catalyzed oxidative carbonylation of
arylhydrazines with alkynes in an undivided cell, which is
regarded as an alternative supplement of carbonylative
Sonogashira reaction (Scheme 1C). We achieved an external
oxidant-free electrochemical oxidation of Pd(0) to Pd(II),
avoiding the usage of stoichiometric amounts of chemical
oxidants.
Phenylhydrazines which could be easily prepared from
anilines have previously proved to be a potential aryl reagent
with the release of environmental-friendly N2 as a byproduct.11
We started our research by using phenylhydrazine hydro-
chloride (1a) and phenylacetylene (2a) as a model reaction to
investigate the effects of reaction parameters. Optimization of
the reaction is shown in Table 1. The reaction was carried out
in an undivided cell with a carbon felt anode and a graphite rod
cathode under 1.5 mA (4.5 F/mol) in the CO atmosphere.
Different Pd salts were used as the catalyst precursors, and only
Pd(PPh3)2Cl2 gave a 31% yield to access desired ynone
(entries 1−3). Notably, a phosphine ligand was crucial in this
transformation. Efforts were also taken to change the ligands
using PdCl2 as the catalyst precursor, indicating that PPh3 gave
the best result (entries 4−7). By combining Pd(PPh3)2Cl2 with
PPh3 ligand, the yield could be raised to 65% (entry 8).
6
t
stoichiometric BuONO (Scheme 1B-2). Organo-electrosyn-
thesis that uses electric current as redox reagents attracts
increasing attention due to its great potential in the
commitment of developing green and sustainable methods.7
Electrochemical anodic oxidation provides a great opportunity
to realize transition-metal catalyzed oxidative carbonylation
under external oxidant-free conditions.8 In the electrocatalytic
carbonylation reaction, the challenge is the deactivation of high
valent metal species in the cathodic cell, which decreases the
catalytic efficiency. Divided cells are used as a solution to
prevent the deposition of metal catalysts on the cathode. We
envision that the modification of ligand and reaction
conditions can tune the potential of the metal complex,
Received: June 13, 2021
https://doi.org/10.1021/jacs.1c06036
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© XXXX American Chemical Society
A

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Scheme 1. (A) Bioactive Products with Ynones Structure;
(B) Carbonylative Sonogashira Reaction; (C)
Electrochemical Pd-Catalyzed Oxidative Carbonylation of
Arylhydrazines and Alkynes
Table 1. Summary of the Effects of Reaction Parameters and
Conditions on the Reaction Efficiency
a
b
Entry
[Pd]
PdCl2
Pd(OAc)2
Pd(PPh)2Cl2
PdCl2
Ligands
Additives
Yield (%)
1
2
3
4
−
−
−
PPh3
−
−
−
−
trace
trace
31
56
5
6
7
8
9
10
11
12
13
PdCl2
PdCl2
PdCl2
P(p-tol)3
P(m-tol)3
Xantphos
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
−
−
−
−
53
20
trace
65
70
57
84(83)
trace
21
58
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)4
−
KI
TBAI
NH4I
NH4I
NH4I
NH4I
NH4I
c
d
e
14
15
n.d.
a
Reaction conditions: 1a (0.40 mmol), 2a (0.25 mmol), [Pd] (5.0
n
mol %), ligands (10 mol %), additives (30 mol %), Bu4NBF4 (0.20
mmol), NEt3 (0.75 mmol), and CH3CN (6 mL) in an undivided cell
with a carbon felt anode, a graphite rod cathode, CO balloon, 25 °C,
b
1.5 mA, 20 h, 4.5 F/mol. The yield of 3a was determined by GC
analysis with biphenyl as the internal standard; n.d. = not detected.
c
d
e
Isolated yield. No electricity, CO/O2 = 1/1. No electricity, BQ was
used as the oxidant.
3h). The electron-rich aryl alkynes bearing −Pentyl, −tBu,
−Ph, and −OMe were well tolerated, furnishing 3i−3l in 70−
87% yields. Strongly electron-withdrawing groups such as
−CF3, −COOMe, −COMe, and −CN proved compatible but
afforded generally lower yields as a result of lower conversion
(3m−3p). Substrates bearing naphthalenyl or thiophene were
suitable under the reaction conditions and provided corre-
sponding products 3q and 3r in 66% and 71% yields,
respectively. Both aliphatic acyclic and cyclic terminal alkynes
could be introduced as substrates for this process (3s and 3t).
Variation of the arylhydrazine hydrochlorides were also
examined, and the results were shown in Table 2. It appeared
that the position of the substituents on the phenyl ring has a
limited effect on the reaction efficiency (3aa−3ac). Disub-
stituted substrates such as 3, 5-dimethyl phenylhydrazine
hydrochlorides could also successfully undergo the electro-
chemical oxidative carbonylation reaction to afford moderate
yield (3ad). Halogen-substituted phenylhydrazine hydro-
chlorides could give desired products in moderate yields
under the standard reaction conditions (3ae−3ag), providing
us the opportunities for further functionalization. Both
electron-rich and electron-deficient phenylhydrazines were
well tolerated in this transformation (3ah−3am). Substrates
bearing 1-naphthalenyl or 2-naphthalenyl were compatible
with this electrochemical process.
Furthermore, several iodine sources were used as additives to
enhance the reaction efficiency (entries 9−11). Delightfully,
adding an additional 30 mol % of NH4I led to an excellent
yield (entry 11). A trace amount of product could be detected
when using O2, 1,4-Benzoquinone (BQ), or other oxidation
reagents as the oxidant but switching off the electricity (entries
12−13 and Table S1), indicating the specialty of electrosyn-
thesis to distinguish from the traditional oxidation method.
Pd(PPh3)4 was examined as the Pd(0) catalyst, and a
satisfactory yield could be also obtained (entry 14). Control
experiments showed that Pd(PPh3)2Cl2 was indispensable for
the electrooxidative carbonylation (entry 15).
Encouraged by these results, we next investigated the scope
of this electrooxidative carbonylative Sonogashira-type reac-
tion. Various alkynes were tested under the standard reaction
conditions (Table 2). First, the reaction of para-, meta-, and
ortho-methyl-substituted phenylacetylene all proceeded well
and afforded the corresponding ynones in 92−85% yields
(3b−3d), indicating that steric hindrance of phenylacetylene
has little influence on reaction efficiency. Notably, halogens
such as F, Cl, and Br were all tolerated in this transformation,
thus providing a possibility for further functionalization (3e−
The potential of the strategy was further documented by the
late-stage functionalization of bioactive molecules. For this
purpose, various alkyne-containing compounds were examined.
It was found that a herbicide molecule, propyzamide, could
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a
A 10 mmol scale synthesis was performed to demonstrate
the synthetic utility of this electrochemical approach. As shown
in Scheme 2, the reaction with 1a and 2a furnished the
Table 2. Evaluation of Alkynes and Phenylhydrazine Scope
Scheme 2. Gram-Scale Synthesis and Pharmaceutical
Synthesis
corresponding ynone (3a) in 51% yield (1.05 g) by using 20
mA (3.0 F/mol) (Scheme 2A). Furthermore, one of the anti-
inflammatory and analgesic drugs FSY could be obtained in
60% yield under standard electrochemical conditions, indicat-
ing that this electrosynthesis strategy had some potential in
drug preparation (Scheme 2B).
To verify the role of electricity and possible active
intermediates in the reaction system, stoichiometric reactions
were performed (Scheme 3). The arylpalladium species Pd-1
were isolated through the reaction between Pd(PPh3)4 and
PhNHNH2 under electrochemical conditions (Scheme 3A). In
addition, stoichiometric Pd-1 and acyl palladium Pd-2 reacted
with 2a smoothly to give a moderate yield under the standard
conditions but without electricity (Scheme 3B). Based on the
stoichiometric results, electric current is key for the oxidation
of Pd(0) to Pd(II) and activation of arylhydrazines. Aryl-Pd
and acyl palladium are the possible intermediates for the
electrochemical carbonylative reactions.
To further understand the mechanism, some control
experiments were carried out. When the catalytic amount of
Pd species Pd-1 and Pd-2 were utilized as the catalysts,
satisfied yields could also be obtained (Scheme 3C). These
catalytic results further verified that Pd-1 and Pd-2 are key
intermediates in the transformation. The intermolecular KIE
experiment proved that the C−H bond cleavage of phenyl-
acetylene was not involved in the rate-determining step
(Scheme 3D). The influence of the concentration has been
evaluated as shown in Scheme 3E. The reaction rate remained
unchanged when the concentration of 2a was halved, further
confirming the C−H bond activation step is fast.
a
Reaction conditions: 1 (0.40 mmol), 2 (0.25 mmol), Pd(PPh3)2Cl2
n
(5.0 mol %), PPh3 (10 mol %), NH4I (30 mol %), Bu4NBF4 (0.20
mmol), NEt3 (0.75 mmol), and CH3CN (6 mL) in an undivided cell
Cyclic voltammetry (CV) experiments were carried out to
gain insights into this carbonylation reaction as shown in
Scheme 4. First, the substrates and the additives were tested.
No obvious oxidation peaks were observed within the range 0
to 2 V for phenylacetylene and phenylhydrazine hydrochloride
(Figure S1 red and blue lines), which indicated that these
substrates are difficult to activate directly. The mixture of
phenylhydrazine hydrochloride and 1 equiv of NEt3 showed an
obvious peak at 0.65 V (Figure S1, green line). Moreover, the
oxidation peaks of NEt3, PPh3 and NH4I were recorded under
the optimized conditions showed 1.05, 1.03, and 0.42 V
respectively (Scheme 4A). The oxidation potential of the NH4I
is the lowest among these substrates and additives. Next, the
with a carbon felt anode, a graphite rod cathode, 25 °C, 1.5 mA, 20 h,
b
4.5 F/mol. Isolated yields are reported. 10 mol % Pd(PPh3)2Cl2 and
4 mL of CH3CN used.
react with phenylhydrazine hydrochloride smoothly and
afforded the ynone derivative in 87% yield (3u). Satisfyingly,
this reaction also enables the functionalization of estrone-,
naproxen-, and ibuprofen-containing alkyne, which highlighted
the potential of the strategy in the pharmaceutical intermediate
(3v−3x). Additionally, the alkyne derived from levulinic acid
was smoothly converted into the desired products in 69% yield
(3y).
C
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Scheme 3. Preliminary Mechanistic Studies
Scheme 4. Cyclic Voltammetry Studies
Pd(MeCN)2Cl2 with 2 equiv of PPh3 displayed no peaks
within the range 0 to 0.5 V due to the poor solubility (Scheme
4B, red line). Furthermore, the mixture of Pd(MeCN)2Cl2, 2
equiv of PPh3, and 3 equiv of NH4I showed an obvious peak at
0.22 V, indicating that the oxidation from Pd(0) species was
generated by the reduction of NH4I under a CO atmosphere to
Pd(II) species (Scheme 4B, blue line).12 Pd(0) species were
also formed from the reaction between Pd(II) species and
PhNHNH2 because the mixture of Pd(MeCN)2Cl2, 2 equiv of
PPh3, and 1 equiv of PhNHNH2 revealed an oxidation peak of
Pd(0)/Pd(II) at 0.14 V (Scheme 4B, green line).
The oxidation potentials during the whole reaction process
were recorded by an external voltmeter. As shown in Scheme
5, the range of oxidation potential was between 0 to 0.1 V for
the first 16 h. The oxidation potential then increased gradually
to 0.45 V for the last 4 h. These results indicated that only
Scheme 5. Eox−Time Diagrams
oxidation potentials of catalytic species were investigated. An
inconspicuous peak was observed at 0.11 V for Pd(MeCN)2Cl2
under a CO atmosphere (Scheme 4B, black line). However,
D
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Pd(0) species were oxidized by anode for most of the time
until substrates were used up.
A proposal mechanism is provided according to the above
experiments and previous related work.10b,13 As shown in
Scheme 6, PdII precursor A prefers to react with 1 to give the
Renyi Shi − School of Chemical Engineering and Technology,
Xi’an Jiaotong University, Xi’an 710049, P. R. China;
orcid.org/0000-0002-7359-0043; Email: renyi.shi@
xjtu.edu.cn
Authors
Yong Wu − The Institute for Advanced Studies (IAS), College
of Chemistry and Molecular Sciences Wuhan University,
Wuhan 430072, P. R. China
Scheme 6. Proposal Mechanism
Li Zeng − The Institute for Advanced Studies (IAS), College of
Chemistry and Molecular Sciences Wuhan University, Wuhan
430072, P. R. China
Haoran Li − The Institute for Advanced Studies (IAS), College
of Chemistry and Molecular Sciences Wuhan University,
Wuhan 430072, P. R. China
Yue Cao − The Institute for Advanced Studies (IAS), College
of Chemistry and Molecular Sciences Wuhan University,
Wuhan 430072, P. R. China
Jingcheng Hu − The Institute for Advanced Studies (IAS),
College of Chemistry and Molecular Sciences Wuhan
University, Wuhan 430072, P. R. China
Minghao Xu − The Institute for Advanced Studies (IAS),
College of Chemistry and Molecular Sciences Wuhan
University, Wuhan 430072, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c06036
aryl Pd species B along with the release of N2. Subsequent CO
insertion into the C−Pd bond of B affords the palladium
carbamoyl intermediate C. Terminal alkynes 2 then react with
species C to give ynones 3 and Pd(0) species D by reductive
elimination. Pd(0) species D may also be generated by the
reduction of NH4I. Finally, Pd catalysts undergo recycle by
anodic oxidation along with hydrogen evolution on cathode.
In summary, a novel palladium-catalyzed electrochemical
carbonylative Sonogashira-type cross-coupling reaction has
been developed. Various arylhydrazines and alkynes were well
tolerated under mild reaction conditions, giving biologically
important ynones as the products. Through mechanistic
studies, key Pd reactive intermediaters were verified and an
electric current served as a reagent for the oxidation of Pd(0)
to Pd(II). We suppose that this transformation would
contribute significantly to the development of electrochemical
carbonylative Sonogashira-type reactions.
Author Contributions
∥Y.W. and L.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (22031008, 21801195), Science
Foundation of Wuhan (2020010601012192), and the China
Postdoctoral Science Foundation (2018M632906,
2019T120678). Dedicated to Prof. Christian Bruneau for his
outstanding contribution to catalysis.
REFERENCES
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c06036.
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The experimental procedure, characterization data, and
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copies of H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Aiwen Lei − The Institute for Advanced Studies (IAS), College
of Chemistry and Molecular Sciences Wuhan University,
Wuhan 430072, P. R. China; State Key Laboratory for Oxo
Synthesis and Selective Oxidation, Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences, Lanzhou
730000, P. R. China; orcid.org/0000-0001-8417-3061;
Email: aiwenlei@whu.edu.cn
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