Electrochemical Sulfonylation of Alkynes with Sulfonyl Hydrazides: A Metal- and Oxidant-Free Protocol for the Synthesis of Alkynyl Sulfones

Article abstract of DOI:10.1002/adsc.201901607

Herein, an electrochemical oxidative cross-coupling reaction between terminal alkynes and sulfonylhydrazides has been developed. Tetrabutylammonium iodide is used as the electrolyte and redox medium. The significant advantages of this method are high atom efficiency, functional group tolerance, and transition metal- and oxidant-free conditions. Most of the compounds exhibit good inhibitory activity on tumor cell lines, and one of the compounds can inhibit cell migration and induce apoptosis in HeLa cells. (Figure presented.).

Full text of DOI:10.1002/adsc.201901607

Title: Electrochemical Sulfonylation of Alkynes with Sulfonyl
Hydrazides: A Metal- and Oxidant-free Protocol for the Synthesis
of Alkynyl Sulfones
Authors: Zu-Yu Mo, Yu-Zhen Zhang, Guo-bao Huang, Xin-Yu Wang,
Ying-ming Pan, and Hai-Tao Tang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901607
Link to VoR: http://dx.doi.org/10.1002/adsc.201901607

10.1002/adsc.201901607
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201
Electrochemical Sulfonylation of Alkynes with Sulfonyl Hydrazides: A
Metal- and Oxidant-free Protocol for the Synthesis of Alkynyl Sulfones
Zu-Yu Mo,a,c Yu-Zhen Zhang,a,c Guo-Bao Huang,b,* Xin-Yu Wanga, Ying-Ming Pana
and Hai-Tao Tanga,b,*
a
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and
Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, P. R. of China. E-mail: httang@gxnu.edu.cn
Key Laboratory of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science of Yulin
b
Normal University, Yulin 537000, P. R. of China. E-mail: lzjx0915@163.com
c
These authors contributed equally to this work
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
tolerance, and transition metal- and oxidant-free conditions.
Most of the compounds exhibit good inhibitory activity on tumor
cell lines, and one of the compounds can inhibit cell migration
and induce apoptosis in HeLa cells.
Abstract: Herein, an electrochemical oxidative cross-
coupling reaction between terminal alkynes and
sulfonylhydrazides
has
been
developed.
Tetrabutylammonium iodide is used as the electrolyte and
redox medium. The significant advantages of this method
are high atom efficiency, functional group
Keywords: Electrochemical synthesis; Cross-coupling reaction;
Terminal alkyne; Sulfonylhydrazine; Alkynyl sulfones
activities, such as anti-HIV, anticancer, antifungal,
and antibacterial properties.[4] In particular,
alkynyl sulfones not only exhibit a wide range of
pharmacological activities[5] but are also
important synthetic intermediates. They can be
converted into a variety of valuable compounds
through addition,[6] cycloaddition,[7] and cross-
coupling reaction;[8] hence, they have elicited
considerable interest from synthetic organic
chemists who have developed many effective
methods for preparing alkynyl sulfones. In recent
years, numerous studies have been conducted on
the synthesis of alkynyl sulfones (Scheme 1a).[9]
However, these methods generally require alkyl
halide or alkynic acid as substrate and use
excessive amounts of oxidants and metal catalysts.
To the best of our knowledge, the direct synthesis
of alkynyl sulfones from terminal alkynes has not
been investigated yet. Over the past decade,
electrochemical anodic oxidation, along with
Over the past decade, the cross-coupling reaction of
oxidative R1-H/R2-H has become a direct means for
constructing chemical bonds.[1] This method is one of
the most atom-economical approach for organic
synthesis because only two hydrogen atoms are not
incorporated into the final product. In this field,
however, efficient oxidative cross-coupling reactions
that involve terminal alkynes remain challenging.[2]
Reactions between terminal alkynes and nucleophiles
are still limited and require the excessive use of
oxidants and metal catalysts (Scheme 1b).[3] Therefore,
a new oxidation method for overcoming the difficulty
in direct cross-coupling reactions between terminal
alkynes and nucleophiles should be developed.
Organosulfones comprise an important class of
compounds in medicinal chemistry and drug
discovery because of their impressive biological
cathodic proton reduction, has become
a
promising approach for realizing the cross-
coupling reaction of R1–H/R2–H.[10] Our group
recently realized the asymmetric coupling
reaction
of
various
substrates
under
electrochemical conditions, motivating us to
develop a new method for synthesizing alkynyl
Figure 1. Biological activities of typical alkynyl sulfone
derivatives.
1
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10.1002/adsc.201901607
Advanced Synthesis & Catalysis
In the beginning of our investigation, we used p-
methoxyphenylacetylene 1a and p-toluenesulfonyl
hydrazide 2a as substrates for optimizing reaction
conditions. The desired product 3aa obtained a yield
of 86% (Table 1, entry 1). Moreover, nBu4NI, K2CO3
(2 equiv), and MeCN/H2O were utilized as the
electrolyte, base, and cosolvent, respectively, at a
constant potential of 1.2 V versus Ag/AgCl. K2CO3
played a key role in this reaction, and no desired
product 3aa was detected without K2CO3 (Entry 2).
Other organic bases, such as DBU (entry 3), failed to
promote the reaction. Moreover, when the reaction
was conducted in the absence of O2, a slightly
decreased yield (Entry 4) indicated that O2 plays a
positive role in this reaction and can inhibit the
formation of by-products. The reaction at 40 °C (Entry
5) or 80 °C (Entry 6) led to a significant decrease in
yield. When 1a and 2a reacted at a constant current of
10 mA, the yield decreased (Entry 7). In this study, we
replaced the MeCN/H2O mixed solvent with other
solvents, such as MeOH, DMSO, and MeCN.
However, the reaction did not progress (Entries 8–10).
For further optimization of the reaction conditions, see
Supporting Information (Table S1).
Scheme 1. Coupling reaction of indoles with sulfonyl
hydrazides.
sulfones via electrochemistry.[11] Hence, we examine
the reaction between sulfonyl hydrazines and terminal
alkynes under electricity and obtain alkynyl sulfone
compounds in the presence of tetrabutylammonium
iodide as the electrolyte and a redox catalyst (Scheme
1c). This reaction protocol uses readily available
starting
materials
without
substrate
prefunctionalization and only H2 and N2 as byproducts.
Scheme 2. Substrate scope of aryl/heteroarylsulfonyl
hydrazides.a,b
Table 1. Optimization of the reaction conditionsa,b
Entry
Variation from standard conditions Yieldb
1
2
None
86
0
Without K2CO3
3
DBU instead of K2CO3
Without O2
0
4
60
35
55
45
0
5
Reaction at 40 °C
Reaction at 80 °C
Constant current: 10 mA
MeOH as solvent
DMSO as solvent
CH3CN as solvent
6
7c
8
a
Reaction conditions: Reticulated vitreous carbon (RVC)
anode (100 PPI, 1 cm × 1 cm × 1.2 cm), Pt plate cathode (1
cm × 1 cm), undivided cell, constant potential = 1.2 V vs.
Ag/AgCl, 1a (0.25 mmol, 1.0 equiv), 2a–2k (0.5 mmol, 2
equiv), nBu4NI (2 equiv), K2CO3 (2 equiv), MeCN/H2O =
8:1 (9 mL), 60 °C, O2, 1.5 h. b Isolated yields.
9
0
10
Trace
a
Reaction conditions: Reticulated vitreous carbon
(RVC) anode (100 PPI, 1 cm × 1 cm × 1.2 cm), Pt plate
cathode (1 cm × 1 cm), undivided cell, constant
potential = 1.2 V vs. Ag/AgCl, 1a (0.25 mmol, 1.0
equiv), 2a (0.5 mmol, 2 equiv), nBu4NI (2 equiv),
K2CO3 (2 equiv), MeCN/H2O = 8:1 (9 mL), 60 °C, O2,
1.5 h (11.64–4.48 F.mol−1). b Isolated yields. cReaction
7 h.
Using the optimized conditions, we then subjected
various sulfonyl hydrazines 2a–2j to react with p-
methoxyphenylacetylene 1a to obtain the desired
alkynyl sulfones 3aa–3aj (Scheme 2). In the absence
of substitution, p-methoxyphenylacetylene 1a reacted
with benzenesulfonyl hydrazide 2b and a yield of 74%
was obtained. Benzenesulfonyl hydrazide that bears
2
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10.1002/adsc.201901607
Advanced Synthesis & Catalysis
methyl at the para- and ortho-position demonstrated
good reactivity in this transformation and obtained the
desired products with yields of 86% and 68%,
respectively (3aa and 3ac). Electron-donating groups,
such as methoxy, tertiary butyl, and phenyl, were also
tolerated and the corresponding products were
obtained with 56%–58% yields (3ad–3af). Halide
substituents, including F and Br, obtained the desired
products with excellent yields of 87% and 59%,
respectively (3ag and 3ah). Lastly, naphthalene-2
conditions, neither alkylalkynes (1l) nor alkylsulfonyl
hydrazides (2k) could produce oxidative cross-
coupling products.
To further demonstrate that alkynyl sulfones are
useful synthetic intermediates that can be transformed
into various valuable compounds, several organic
transformations were performed on the alkynyl
sulfone compound 3aa. The electrophilic behavior of
alkynyl sulfones that undergo reactions with
nucleophiles, such as nBuLi or tBuOK, followed by
sulfonohydrazide
sulfonylhydrazide
(2i)
(2j)
and
also
thiophene-2-
obtained the
–
elimination of ArSO2 moiety allow the alkynylation
corresponding polycyclic alkynyl sulfone 3ai and
heterocyclic alkynyl sulfone 3aj with 60% and 72%
yields, respectively.
of Csp3 atoms to obtain ynol ethers and other
alkynylation products (Scheme 4, a and b).[12]
Meanwhile, the sulfonyl group in alkynyl sulfone can
be readily removed by using diphenylphosphine oxide
to obtain an alkynyl-(diaryl)phosphine oxide under
mild conditions (Scheme 4, c).[13] In addition, alkynyl
sulfone can be rapidly converted into β-keto sulfone
under mild conditions (Scheme 4, d). Furthermore,
during Cu(II) catalysis, alkynyl sulfone 3aa coupled
with benzyl azide obtained the corresponding triazole
derivatives through [3+2] cycloaddition (Scheme 4,
e).[14]
Scheme 3. Substrate scope of terminal alkynes.a,b
a
Reaction conditions: Reticulated vitreous carbon (RVC)
Scheme 4. Synthetic transformations performed on
compound 3aa.
anode (100 PPI, 1 cm × 1 cm × 1.2 cm), Pt plate cathode (1
cm × 1 cm), undivided cell, constant potential = 1.2 V vs.
Ag/AgCl, 1b–1l (0.25 mmol, 1.0 equiv), 2a (0.5 mmol, 2
equiv), nBu4NI (2 equiv), K2CO3 (2 equiv), MeCN/H2O =
8:1 (9 mL), 60 °C, O2, 2 h. b Isolated yields.
To determine the reaction mechanism, several
control experiments were performed (Scheme 5).
When 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
was added to the system, no desired product 3aa was
detected (Scheme 5a). Meanwhile, reaction 2a with
styrene was conducted under our selected optimal
conditions, and the free radical adduct 4a was detected
via high-resolution mass spectrometry (Scheme 5b).[15]
The results implied that the reaction might involve a
radical pathway, and this process might obtain a
sulfonyl radical. When the reaction of 1a with 2a
commenced without K2CO3 as the base, the addition
product 5a was obtained (Scheme 5c). Furthermore, a
subsequent investigation determined that the reaction
that started from 5a can produce the desired product
3aa in the presence of K2CO3 (Scheme 5d). Thus, 5a
was confirmed as an intermediate of this reaction. The
first step of this tandem reaction is the addition
reaction of alkyne with the sulfonyl radical and iodine
to produce intermediate 5a. To determine whether any
Subsequently, the scope of alkynes was also
investigated, and the results are illustrated in Scheme
3. Satisfactorily, substrates that bear methyl and
tertiary butyl groups at the para- or ortho-positions of
the phenyl ring (1b–1d) can be used as reaction
substrates to obtain the desired products with 59%–78%
yields. Similarly, 2a was successfully coupled with 4-
fluoro/chloro/bromophenylacetylene (1e–1g) to yield
the corresponding products 3ea–3ga with 63%–76%
yields. Moreover, phenylene acetylene that bears
electron-poor substituents, such as -COOMe or
trifluoromethyl groups, at the para-position were also
suitable for this transformation and provided the
desired products 3ha and 3ia with a moderate yield.
Notably, thiophene-3-acetylene (1j) and naphthalene-
2-acetylene (1k) also obtained the corresponding
products 3ja and 3ka with 73% and 74% yield,
respectively. However, under standard reaction
other
reaction
mechanism
exists,
(iodoethynyl)benzene 6a was reacted with 2a under
standard reaction conditions. Unexpectedly, 3aa was
3
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10.1002/adsc.201901607
Advanced Synthesis & Catalysis
isolated with 88% yield. This finding suggested that
6a may be another intermediate in the present reaction
(Scheme 5e). Furthermover, a reaction of 1a with 2a
was achieved in the presence of I2, and only trace
amounts of the desired product 3aa was detected. This
finding suggested that I2 was not involved in the
reaction and the iodine radical was responsible for
oxidative coupling (Scheme 5f). Lastly, in order to
study the role of oxygen in the reaction, 5a and 6a
were reacted in oxygen and argon to obtain product
3aa under standard conditions. And the results
indicate that oxygen can promote the conversion of 5a
to 3aa. (Supporting Information).
radical, and finally alkyne radical combined with
iodine ion to form alkyne iodine.
Figure 2. EPR experiment.
From the preceding results, two possible
mechanisms are proposed in Scheme 6. In Path A, the
iodide ions were oxidized to iodide radicals at the
anode. In parallel, the anodic oxidation of sulfonyl
hydrazide 2 obtained the sulfonyl hydrazide radical,
which underwent further oxidation through the two
iodide radicals to produce the sulfonyl radical C,
which eliminated nitrogen to produce the sulfonyl
radical D.[16] Then, the addition of the sulfonyl radical
D and the iodine radical to terminal alkyne 1
generated the vinyl radical intermediate E, which was
Scheme 5. Control experiments.
Furthermore, electron paramagnetic resonance
(EPR) experiments were carried out to detect the free
radicals. When p-methoxyphenylacetylene 1a and p-
toluenesulfonyl hydrazide 2a were react for 30
minutes under standard conditions, DMPO was added
to the reaction and an EPR signal was recognized
(Figure 2). The result revealed that the formation of
sulfonyl radicals was rapidly captured by DMPO,
forming relatively stable radicals (g = 2.0063, AN =
13.68 g, AH = 13.18 g). We also carried out cyclic
voltammetry (CV) experiments. The TBAI displays
two oxidation peaks at and 0.42V and 0.67V. In the
mixture of p-toluenesulfonyl hydrazide 2a with TBAI,
an oxidation peak of 0.73V appeared, indicating that
iodine radicals promoted the production of sulfonyl
radicals (Figure S3). At the same time, base did not
promote the production of sulfonyl radicals. The
oxidation peak of p-methoxyphenylacetylene 1a
mixture of K2CO3 was 1.13V, which proved that
alkyne produced alkyne anion in the presence of base,
then iodine radical oxidized alkyne anion to alkyne
Scheme 6. Proposed mechanism.
rapidly converted into intermediate F. Lastly,
intermediate F was used to produce product 3 by
eliminating one HI in the presence of the base. In
addition, it has been proved that oxygen can promote
the conversion of intermediate E to product 3. In Path
B, terminal alkyne 1 formed alkyne anion G in the
presence of base, and then intermediate G was further
oxidized by iodine radical to alkyne radical H, which
combined with iodine ridical to form alkyne iodine I.
Subsequently, the sulfonyl radical D reacted with
(iodoethynyl)benzene I alkene to produce the radical
intermediate J, and then eliminated one iodide radical
to obtain product 3. At the cathode, reduction occurred
to release H2, completing the electrochemical cycle.
4
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10.1002/adsc.201901607
Advanced Synthesis & Catalysis
concentration of reactive oxygen species in HeLa cells,
leading to cell apoptosis.
To explore the biological activities of these series
of alkynyl sulfones, the in vitro antitumor activities of
compounds 3aa–3aj and 3ba–3ka were evaluated via
the MTT assays of the MGC-803, HpeG-2, T-24, HL-
7402, and HeLa tumor cell lines. 5-Fluorouracil (5-FU)
was used as the positive control. Most of the
compounds exhibited significant antitumor activity
against the five tumor cell lines and even
demonstrated better cytotoxic activities than the
commercial anticancer drug 5-FU. The half maximal
inhibitory concentration (IC50) values of compounds
with good antitumor activity are listed in Table S2.
Notably, the compound 3da exhibited good inhibitory
activity toward the HL-7402, HeLa, and HpeG-2 cell
lines with IC50 values of 9.2 ± 1.0, 10.6 ± 1.7, and 6.3
± 0.2 μM, respectively. Meanwhile, the compound
3ha was a powerful cytotoxic agent against the HL-
7402, T-24, and HeLa cell lines with IC50 values of
8.8 ± 1.5, 8.9 ± 0.8, and 5.6 ± 0.9 μM, respectively. In
addition, compounds 3ag and 3ja also demonstrated
good antitumor activity with IC50 values lower than 20
μM for all the tumor cells. Here, the compound 3ha
was selected to further investigate the antitumor
mechanism on HeLa cells. The results are presented
in Figures S6–S8.
Experimental Section
Synthesis of alkynylsulfonyl compounds
The alkynes (0.25 mmol, 1.0 equiv), sulfonyl hydrazides
(0.5 mmol, 2.0 equiv), K2CO3 (0.5 mmol, 2 equiv) and
nBu4NI (0.5 mmol, 2 equiv) were placed in a 25 mL four-
necked round-bottomed flask. The flask was equipped with
a RVC (100 PPI, 1 cm x 1 cm x 1.2 cm) anode and a
platinum plate (1 cm x 1 cm) cathode. MeCN (8.0 mL) and
H2O (1.0 mL) were added. The electrolysis was carried out
at 60 °C and oxygen atmosphere, which using a constant
potential of 1.2 V vs. Ag/AgCl until complete consumption
of the substrate (monitored by TLC, about 1.5 h). After the
reaction was completed, extraction was performed and the
organic fraction was dried over MgSO4, fifiltered. The
solvent was concentrated under reduced pressure.
Purification with silica gel column chromatography using
ethyl acetate/petroleum ether to afford the desired products.
Acknowledgements
We thank the National Natural Science Foundation of China
(21861006 and 21961042), the Guangxi Natural Science
Foundation
of
China
(2016GXNSFEA380001
and
2018GXNSFBA281151), the Guangxi Key R&D Program (No.
AB18221005), the Science and Technology Major Project of
Guangxi (AA17204058–21), Guangxi Science and Technology
Base and Special Talents (guike AD19110027), the State Key
Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources (CMEMR2019-A03), Guangxi Key
Laboratory of Agricultural Resources Chemistry and
Biotechnology (2019KF03). Innovation Project of Guangxi
Graduate Education (YCBZ2019030) and National college
students innovation and entrepreneurship training program
(201910602019) for financial support.
Scheme 7. IC50 (μM) values for compounds 3ag, 3da, 3ha
and 3ja.
In summary, we develop an efficient
electrochemical method for the synthesis of alkynyl
sulfones via cross-coupling reaction between terminal
alkyne and sulfonyl hydrazides. The proposed method
does not require alkyne prefunctionalization and
exhibits the following advantages: high atom
economy, metal- and oxidant-free transition
conditions, and good functional group tolerance. The
reaction proceeds through a radical pathway, as shown
in the radical trapping experiment and CV analyses. In
addition, as useful synthetic intermediates, alkynyl
sulfones can transform into various valuable
compounds through diverse types of reactions.
Moreover, most of the compounds exhibit potent
inhibitory activity against tumor cells. Further
mechanism studies have shown that compound 3ha
can inhibit cell migration and increase the
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10.1002/adsc.201901607
Advanced Synthesis & Catalysis
COMMUNICATION
Electrochemical Sulfonylation of Alkynes with
Sulfonyl Hydrazides: A Metal- and Oxidant-free
Protocol for the Synthesis of Alkynyl Sulfones
Adv. Synth. Catal. Year, Volume, Page – Page
Zu-Yu Mo,a,c Yu-Zhen Zhang,a,c Guo-Bao
Huang,b,* Xin-Yu Wanga, Ying-Ming Pana and
Hai-Tao Tanga, b,
*
7
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