Electrochemical Induced Regio- and Stereoselective Difunctionalization of Alkynes: The Synthesis of (E)-β-Iodovinyl Sulfones

Article abstract of DOI:10.1002/ejoc.202100505

An efficient, green, and oxidant-free electrochemical method for alkyne difunctionalization was described. Using undivided electrochemical cell for iodosulfonylation of alkynes with commercially available iodide radical (NaI), arylsulfonyl radical (ArSO

Full text of DOI:10.1002/ejoc.202100505

Communications
doi.org/10.1002/ejoc.202100505
Electrochemical Induced Regio- and Stereoselective
Difunctionalization of Alkynes: The Synthesis of
(E)-β-Iodovinyl Sulfones
Xinghua Zhang,*[a, b] Danna Lu,[a] and Zhenwei Wang*[a]
An efficient, green, and oxidant-free electrochemical method
for alkyne difunctionalization was described. Using undivided
electrochemical cell for iodosulfonylation of alkynes with
commercially available iodide radical (NaI), arylsulfonyl radical
(ArSO2NHNH2) sources, a variety of (E)-β-iodovinyl sulfones were
obtained in one-pot with wide substrate scope, excellent regio-
and stereoselectivity under mild and ecofriendly conditions.
Scheme 1. Application of β-iodovinyl sulfones.
Introduction
Alkyne iodosulfonylation is a powerful strategy for synthesizing
β-iodovinyl sulfone compounds that are interesting for rapid
construction of diverse functional groups in biologically active
molecules (Scheme 1).[1] Typically, the direct difunctionalization
of alkynes could provide a straightforward method for achiev-
ing scaffold diversity in organic transformations, which involves
the formation of two new vicinal chemical bonds.[2] In this
context, the choice of suitable iodine and sulfonyl sources for
the formation of CÀ I/CÀ S bonds is the key factor in achieving
these molecular skeleton. Traditional strategies for the synthesis
of β-iodovinyl sulfone often proceed via a reaction between
terminal alkyne and sulfinate (or sulfonyl hydrazide) promoted
Scheme 2. Strategies for the synthesis of β-iodovinyl sulfones.
by iodide source, such as NIS, IÀ or I2, which requires
stoichiometric chemical oxidant or high reaction temperature
(Scheme 2, eq 1).[1d,3] Obviously, the use of sacrificial reagent
inevitably leads to decreased atom economy of the overall
chemical transformation, and not accord with the increased
environmental requirements.
works, we envisioned that whether the alkyne iodosulfonylation
can be achieved under sustainable electrochemical oxidative
conditions.
Notably, Organic electrochemistry provide new opportuni-
ties for the construction of CÀ X bonds via the replacement of
common reagents by electricity.[4] Recent advances have shown Results and Discussion
that electric current can be used to induce reduction and
oxidation reactions, and difunctionalization of alkenes can be
achieved through electrochemical anodic oxidation in the
absence of oxidizing agents.[5,6] Inspired by the above elegant
We thus started to explore the practicability of the proposed
route as shown in Scheme 2, eq 2. Initially, p-toluenesulfonyhy-
drazide (1a) and phenylacetylene (2a) were chosen as the
model substrates in an undivided cell equipped with a pair of
platinum-plate electrodes (10 mm×10 mm×0.1 mm) in the
presence of iodine source. As shown in Table 1, after extensive
experiments, we identified that the optimized conditions
comprised the use of chloroform (CHCl3) and water (v/v 1/1) as
cosolvent, NaI (1.4 equiv) as iodine source and electrolyte under
a constant current (40 mA). The expected product 3a was
obtained in an optimal 88% yield along with nitrogen and
hydrogen as major byproducts after the reaction proceeded at
ambient temperature for 5 h (Table 1, entry 1). Other iodine
sources, such as n-Bu4NI and NaI, were also examined and the
[a] Dr. X. Zhang, D. Lu, Z. Wang
School of Chemical and Environmental Engineering,
Shanghai Institute of Technology,
100 Hai-Quan Road, Shanghai 201418, China
E-mail: xhzhang@sit.edu.cn
wangzhenwei@sit.edu.cn
[b] Dr. X. Zhang
Institute of Drug Discovery Technology,
Ningbo University,
Ningbo 315211, China
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100505
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Table 1. Optimization of reaction condition.[a]
Table 2. Scope of alkynes and arylsulfonohydrazides.[a]
Entry
Variation from the stand conditions
Yield [%][b]
1
2
3
4
5
6
7
8
None
KI instead of NaI
88
81
87
24
39
30
65
63
73
9
Bu4NI instead of NaI
MeCN instead of CHCl3
THF instead of CHCl3
20 mA instead of 40 mA
60 mA instead of 40 mA
2.8 equiv. of NaI was used
2.8 equiv. of 1a was used
3 h instead of 5 h
9
10
11
12
8 h instead of 5 h
No electric current
12
N.D.
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.7 mmol), NaI (0.7 mmol),
CHCl3/H2O=1:1 (3 mL); Pt (10 mm×10 mm×0.1 mm) anode and cathode,
undivided cell, rt, 5 h; [b] Isolated yield.
results indicated that all iodine salts could conduct this reaction
smoothly (Table 1, entries 2–3). Replacement of CHCl3 with
other solvents (MeCN or THF) gave inferior results (entries 4–5).
Alteration of the electric current, reaction time and the ratio of
terminal alkyne 2a and NaI did not enhance the coupling
efficiency (entries 6–11). Control experiment showed that with-
out constant current no desired product 3a was detected
(Table 1, entry 12), indicating the electric current is crucial to
this transformation.
With the optimal reaction conditions in hand, the substrate
scope of the reaction with regard to arylsulfonohydrazide 1 and
alkynes 2 was explored, and the results are summarized in
Table 2. Generally, the para- and meta- substituted aromatic
terminal alkynes bearing electron-donating (n-butyl, tert-butyl,
methoxyl or methyl) or electron-withdrawing groups (fluor-,
chloro- or bromo-) on the benzene ring readily coupled with p-
toluenesulfonylhydrazide 1a and NaI under the constant
current, affording the desired products 3a-3i in 71–88% yields.
As for the sterically hindered substrates, such as internal alkyne
2j and 2k, the steric hindrance did not significantly affect the
reaction efficiency, high regioselective (E)-β-iodovinyl sulfones
3j and 3k were obtained in 79 and 73% yields, respectively.
Furthermore, the heterocyclic compound 3-ethynylthiophene
2l was successfully employed, providing the corresponding
iodosulfonylation product 3l in 60% yield and excellent stereo-
selectivity. It should be noted that the aliphatic terminal alkyne
1m, which showed lower reactivity in difunctionalization
reactions, was also suitable for the reaction, leading to the
desired product 3m in 41% yield.
[a] Reaction conditions: for entries 3a-3v, 1 (0.5 mmol), 2 (0.7 mmol), NaI
(0.7 mmol), CHCl3/H2O=1:1 (3 mL); Pt (10 mm×10 mm×0.1 mm) anode
and cathode, undivided cell, rt, 5 h; for entry 3w, 1 (0.5 mmol), 2 (1.4
mmol), NaI (1.4 mmol), CHCl3/H2O = 1:1 (3 mL), Pt (10 mm × 10 mm × 0.1
mm) anode and cathode, undivided cell, rt, 5 h.
substituted steric effect of 2,4,6-trimethylbenzenesulfonyl
hydrazide (Table 2, 3t). Besides, introducing heteroaryl and
polycyclic aromatic substituents into sulfonyl hydrazides also
gave the coupling products 3u and 3v in moderate yields.
Notably, the bis-coupling product 3w from bis-substituted
arylsulfonohydrazides 1w was obtained in 75% yield (Table 2,
3w). As only E isomer of 3w was obtained by X-ray diffraction
analysis (CCDC No. 2055072), the regio- and stereoselectivity of
the reaction was unambiguously confirmed.
Next, we explored the compatibility of the sulfonyl reagents.
Substituted arylsulfonohydrazides with Br-, Cl-, CF3-, CH3O- and
t-Bu- groups reacted with 2a to provide products 3n-3s in 71–
82% yields regardless of their different electronic properties
(Table 2, 3n-3s). Unfortunately, the steric hindrance had a
negative influence on the reaction. For instance, β-iodovinyl
sulfone 3t was isolated in only 44% yield due to the ortho-
With the aim of evaluating the scalability of the reaction,
further study was conducted on a gram scale and the result
revealed that the electrolytic model reaction could be
performed with 77% yield under slightly modified reaction
conditions (Scheme 3).
To shine light on the reaction mechanism, some control
experiments were performed. As shown in Scheme 4, desired
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meantime, the molecular HI further underwent oxidation to
regenerate the iodide radical and release of H+. Next, radical
coupling occurred between arylsulfonyl radical D and alkyne 2a
to produce radical intermediate E, which is easily captured by
iodine radical to afford the target product 3a. At the cathode,
reduction took place to H+, providing molecular H2 to fulfill the
electrochemical cycle.
Scheme 3. Electrochemical gram-scale synthesis of (E)-β-iodovinyl sulfone.
Conclusions
In conclusion, we developed an efficient electrochemical
iodosulfonylation of alkynes under oxidant-free condition. This
protocol features a broad substrate scope, chemical oxidant
free, excellent regio- and stereoselectivity and gram-scale
synthesis. Further detailed mechanistic studies and applications
based on this efficient transformation are underway in our
laboratory.
Experimental Section
Scheme 4. Mechanistic studies.
Typical procedure for synthesis of (E)-β-iodovinyl sulfones.
Compound 1, sulfonylhydrazide (0.5 mmol), compound 2, alkyne
(0.7 mmol), NaI (0.7 mmol) and CHCl3/H2O (3 mL, v/v=1:1) were
charged into a 20 mL glass tube without exclusion of air. The tube
was equipped with platinum plates (10 mm×10 mm×0.1 mm) as
both the anode and cathode. The constant current (40 mA)
electrolysis was carried out for 5 hours at room temperature. Then,
saturated sodium thiosulfate solution was added to quench the
reaction and the mixture was extracted with ethyl acetate (5.0 mL×
3). The organic phases were combined and dried with anhydrous
MgSO4, purified by silica gel column chromatography (ether/ethyl
acetate as eluent) to afford the corresponding product 3. The
product 3a was not detected under the standard condition
when 1.0 equiv. of radical-trapping reagent, 2,2,6,6-tetrameth-
ylpiperidinooxy (TEMPO), was added into the system (Sche-
me 4a), which indicated that the reaction might proceed via a
radical pathway. In addition, using stoichiometric amount of I2
as the iodine source greatly decreased the reaction efficiency
(20% yield, Scheme 4b) and no iodosulfonylation occurred in
the absence of current (Scheme 4c). These results illustrated
that iodine radical was likely to be involved in the reaction
process and the electric current played a critical role in this
difunctionalization.
1
identity and purity of products were confirmed by H, 13C, HRMS
and X-ray single crystal diffractometer spectroscopic analysis.
Deposition Number 2055072 (for 3w) contains the supplementary
crystallographic data for this paper. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre and
Fachinformationszentrum Karlsruhe Access Structures service
www.ccdc.cam.ac.uk/structures.
Based on the mechanistic studies and preceding literature,[7]
a plausible radical-based pathway is presented for the electro-
chemical synthesis of (E)-β-iodovinyl sulfones 3a. As shown in
Scheme 5, the active catalytic species, iodine radical, was
generated via the oxidation of iodine ions in the anodic
electrode and then reacted with arylsulfonyl hydrazide 1a to
achieve the radical intermediate A, which further oxidated by Acknowledgements
iodine radical in two steps to afford arylsulfonyl radical D,
accompanied by the loss of molecular HI and N2. In the
This work was supported by the National Natural Science
Foundation of China (21871182).
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Electrochemically catalyzed · Difunctionalization ·
Iodosulfonylation · Regioselectivity · Stereoselectivity
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Manuscript received: April 23, 2021
Revised manuscript received: May 20, 2021
Accepted manuscript online: May 26, 2021
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COMMUNICATIONS
Dr. X. Zhang*, D. Lu, Z. Wang*
1 – 5
Electrochemical Induced Regio-
and Stereoselective Difunctionali-
zation of Alkynes: The Synthesis
of (E)-β-Iodovinyl Sulfones
An efficient method for electrochemi-
cal iodosulfonylation of alkynes was
developed under oxidant-free
condition. This procedure affords
valuable β-iodovinyl sulfones with
broad substrate scope, excellent
regio- and stereoselectivity. Moreover,
this facile protocol can be applied to
gram-scale synthesis of (E)-β-iodovinyl
sulfone.