TBAI/K2S2O8-facilitated reaction of sulfonylhydrazides with alkynes: Facile synthesis of (E)-β-iodovinyl sulfones

Article abstract of DOI:10.1080/00397911.2017.1337152

An efficient and convenient approach for the construction of various (E)-β-iodovinyl sulfones has been developed through potassium persulfate/tetrabutylammonium iodide-facilitated reaction of sulfonylhydrazides with alkynes. The products were obtained in good to excellent yields. The salient features of this reaction are the applications of a new iodine source, environmentally benign, safer solid oxidant, and shorter reaction time.

Full text of DOI:10.1080/00397911.2017.1337152

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
TBAI/K2S2O8-Facilitated Reaction of
Sulfonylhydrazides with Alkynes: Facile Synthesis
of (E)-β-Iodovinyl Sulfones
Chuo Tong, Bing Gan, Yiyan Yan & Yuanyuan Xie
To cite this article: Chuo Tong, Bing Gan, Yiyan Yan & Yuanyuan Xie (2017): TBAI/K2S2O8-
Facilitated Reaction of Sulfonylhydrazides with Alkynes: Facile Synthesis of (E)-β-Iodovinyl
Sulfones, Synthetic Communications, DOI: 10.1080/00397911.2017.1337152
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1337152
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Date: 20 June 2017, At: 00:11

TBAI/K2S2O8-Facilitated Reaction of Sulfonylhydrazides with Alkynes: Facile
Synthesis of (E)-β-Iodovinyl Sulfones
Chuo Tong1, Bing Gan1, Yiyan Yan1, Yuanyuan Xie1,2,
1College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou,
P.R. China
2Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals,
Zhejiang University of Technology, Hangzhou, P.R. China
Corresponding author Yuan-Yuan Xie. E-mail: xyycz@zjut.edu.cn
Abstract
An efficient and convenient approach for the construction of various (E)-β-iodovinyl
sulfones has been developed via K2S2O8/TBAI-facilitated reaction of sulfonylhydrazides
with alkynes. The products were obtained in good to excellent yields. The salient features
of this reaction are the applications of a new iodine source, environmentally benign, safer
solid oxidant and shorter reaction time.
Graphical Abstract
KEYWORDS: (E)-β-Iodovinyl Sulfones; Sulfonylhydrazides; TBAI; K2S2O8
INTRODUCTION
1

(E)-β-Iodovinyl sulfones are very useful synthons for the synthesis of a wide variety of
structures, including sulfonylacetylenes,[1] enynes,[2] and vinyl tellurides.[3] Moreover, they
have been used as a precursor for the synthesis of biologically and pharmacologically
active compounds, e.g., cysteine protease inhibitors,[4] and HIV-1 inhibitors.[5] Despite the
prevalence of (E)-β-iodovinyl sulfones, few examples for the convenient synthesis of
(E)-β-iodovinyl sulfones were reported owing to the instability of sulfonyl iodide.[6]
Generally, (E)-β-iodovinyl sulfones are synthesized by cerium (IV) ammonium nitrate
(CAN) or PhI(OAc)2 mediated reaction of alkynes with arylsulfinates in the presence of
MI (M = K or Na).[7,8] Recently, Li and co-workers reported a procedure through the
tert-butyl hydroperoxide (TBHP) mediated reaction of aryl acetylenes with
sulfonylhydrazides in the presence of I2.[9] Very recently, Wang and coworkers developed a
method via the direct difunctionalization of alkynes with sulfinic acids and molecular
iodine in 1,2-dimethoxyethane (DME) for 12-24 h.[10] However, those procedures
mentioned above suffer from certain limitations such as the use of transtion-metal catalyst,
potentially dangerous oxidants and longer reaction time. The combination of
tetrabutylammonium iodide (TBAI) and potassium persulfate (K2S2O8) has been widely
used as a powerful oxidation system in various coupling reactions. For example, it has been
applied to complete the syntheses of oxindoles[11] and 1, 2, 3-thiadiazole.[12] Meanwhle,
TBAI has been used as a source of iodine, and iodine can promote functionalization
reactions of alkynes with sulfonylhydrazides.[13] Herein, we would like to report the
2

preparation of (E)-β-iodovinyl sulfones via TBAI/K2S2O8-facilitated reaction of
sulfonylhydrazides with alkynes.
RESULTS AND DISCUSSION
We began investigation with a model reaction using phenylacetylene (1a, 0.5 mmol) and
4-methylbenzenesulfonyl hydrazide (2a, 0.6 mmol) with K2S2O8 (1 mmol) as an oxidant.
During early runs, taking advantage of I2 as the source of iodine in acetonitrile (2 mL) and
stirring in the sealed tube at 80 oC for 4 h, desired product (E)-β-iodovinyl sulfone (3aa)
was isolated in 36% yield (Table 1, entry 1). When KI was evaluated, no desired product
was observed (Table 1, entry 2). However, making use of TBAI in acetonitrile (2 mL) at 80
oC for 30 min provided the desired product in 93% yield (Table 1, entry 3). Increasing the
amount of K2S2O8 and prolonging reaction time, the yields do not fluctuate. Encouraged by
this result, we briefly screened the reaction parameters, including the reaction vessel,
solvents and oxidants to optimize the reaction performance. The investigation indicated
that reaction in the sealed tube was improved, for avoiding the volatilization of
phenylacetylene (Table 1, entry 4). Preliminary exploration found that lower yield was
obtained when the reaction temperature was decreased (Table 1, entry 5). The following
experimental results showed that solvent also had a significant impact on this reaction.
Taking into account the solubility of K2S2O8, a variety of polar solvents were tested, such
as CH3CN/H2O (1:1), DMF and tetrahydrofuran (THF), unfortunately, lower yields were
obtained (Table 1 entries 6-8). When the amount of TBAI was increased to 1.5 equivalents,
3

a relatively lower conversion was observed (Table 1 entry 9). In addition, TBHP as an
oxidant also delivered corresponding product 3aa in 88% yield (Table 1, entry 10). Thus
the following conditions were found to be the optimal reaction conditions for the desired
conversion: alkynes (1 mmol), sulfonylhydrazides (1.2 equiv), TBAI (1.2 equiv), and
K2S2O8 (2 equiv) were stirred in MeCN (2 mL) in a sealed tube at 80 oC for 30 min. The
relative configuration of 3aa was confirmed by comparison with known compound as a
trans-form.[9], [14]
After the optimal conditions were established, we focused our attention on examining the
scope and limitations of the reaction. As shown in Scheme 1, benzenesulfonyl hydrazide
with electron-donating or electron-withdrawing groups on the phenyl ring, such as methyl,
and Cl, reacted smoothly with phenylacetylene and gave the corresponding products (3aa,
3ab, 3ac, 3ad) in 91-95% yields. This indicated that substituents on the benzenesulfonyl
hydrazine imposed less effect on the reaction. The results that 2-fluorophenylacetylene
(3ba, 3bb, 3bc) in 90-93% yields and 4-ethylphenylacetylene (3ca, 3cb, 3cc) in 70-74%
yields also conform to the above findings. Meanwhile, the steric effect of the aromatic
substitution didn’t play a significant role on the yield (3ad). In addition, phenylacetylene
with the electron-withdrawing or electron-donating groups on the phenyl ring, such as F, Cl,
and ethyl, also reacted smoothly with 4-methylbenzenesulfonylhydrazide to give the
expected products (3aa, 3ba, 3ca, 3da) in 93%, 90%, 73%, 90% yields, respectively. Thus,
the electron-withdrawing groups on the phenyl rings clearly favored the reaction as
4

compared with the electron-donating groups resulting in lower yields. However, the
product of methyl propiolate was significantly reduced to only 40% yield (3ea).
Unfortunately, none of the desired product was obtained when methanesulfonyldrazide
was used as the substrate. To further confirm the configuration of the products, the olefin
hydrogen of the product 3cb was double-irradiated and found to have no NOE
enhancement with any hydrogen of the product (Scheme 2). It appears that product 3 is
trans-configuration rather than cis-configuration.
In order to gain a good insight into the mechanism of reaction, one control experiment was
conducted. The radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was
added to the preformed solution of phenylacetylene (1a) and 4-methylbenzenesulfonyl
hydrazide (2a) under the optimal conditions and the desired product 3aa was not found
(Scheme 3).
On the basis of the observations above and previous reports, [8], [9], [15], [16] we proposed a
plausible mechanism for this reaction in Scheme 4. Initially, K2S2O8 is well known to
generate the sulfate radical A in combination with TBAI. [17] Then, the resultant radicals
abstract hydrogen atoms from 4-methylbenzenssulfonylhydrazide 2a to generate sulfonyl
radical B with the release of molecular nitrogen.[18] Next, addition of sulfonyl radical B to
the phenylacetylene 1a provides the corresponding vinylsulfone free radical C. Finally,
reaction of radical C with in situ generated molecular I2 or iodine free radical affords
5

(E)-β-iodovinyl sulfone 3aa (Scheme 4).7 Therefore, it is speculated that TBAI-facilitated
the reaction of sulfonylhydrazides with alkynes via radical A.
CONCLUSIONS
In summary, we have developed an efficient and convenient protocol for the facile
synthesis of (E)-β-iodovinyl sulfones via K2S2O8/TBAI-facilitated reaction of
sulfonylhydrazides with alkynes. An environmentally benign and safer solid oxidant is
used in generating the corresponding products with good to excellent yields with shorter
reaction time. Moreover, TBAI is used as a source of iodine in the preparation of
(E)-β-iodovinyl sulfones. Further synthetic applications of this method are ongoing in our
laboratory.
EXPERIMENTAL
Melting points were determined using a Büchi B-540 capillary melting point apparatus.
1H NMR and 13C NMR were recorded with a Varian instrument at 400 and 100 MHz,
respectively, and TMS were used as internal standard. Mass spectra were measured with
Thermo Finnigan LCQ-Advantage. High resolution mass spectral (HRMS) analyses were
done on a Bruker micrOTOF-Q II instrument using ESI technique. All reagents were
obtained from commercial sources (purity > 99%) and used without further purification
except for sulfonylhydrazides. Silica gel for column chromatography was purchased from
6

Qingdao Haiyang Chemical Co., Ltd. Reactions were stirred using Teflon-coated
magnetic stir bars.
General Procedures For The Preparation Of Sulfonylhydrazides [19]
Hydrazine monohydrate (2.5 mmol) was added dropwise to a solution of an arylsulfonyl
chloride (1.0 mmol) in tetrahyrdofuran (4 mL) under nitrogen at 0°C. During the addition
the mixture became brown and a white precipitate of hydrazine hydrochloride was
deposited. The mixture was stirred at 0 °C for 30 min, added ethyl acetate (120 mL), and
washed with saturated brine (3×10 mL). The organic layer was dried over sodium sulfate,
filtered, and added slowly to stirred hexane (25 mL) over 5 min. After being stirred for 10
min, the mixture was filtered, and the collected solid was dried in vacuum. The yields for
the formation of sulfonylhydrazides range from 62% to 73%.
General Procedure For The Preparation Of (E)-Β-Iodovinyl Sulfones
Phenylacetylene 1a (0.051 g, 0.5 mmol), 4-methylbenzenssulfonylhydrazide 2a (0.112 g,
0.6 mmol), TBAI (0.222 g, 0.6 mmol ) and K2S2O8 (0.270 g, 1 mmol ) were added to
CH3CN (2 mL) in a sealed tube with magnetic stirring at 80℃(oil bath) for 30 min. After
completion of the reaction (monitored by TLC), the sealed tube was allowed to cool to
room temperature. Then, the reaction solution was filtered and removed under vacuum,
and the residue was purified by column chromatography (SiO2, petroleum ether/ethyl
acetate = 1:10) to give desired product 3aa.
7

SUPPLEMENTARY MATERIAL
Supplementary material includes full experimental details, 1H NMR, 13C NMR and Mass
spectra of the product (3aa-3ea) for this article.
ACKNOWLEDGEMENTS
We are grateful to the National Natural Science Foundation of China (No. 21576239) for
financial support. We thank Dr. Bin Mao for helpful discussions.
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9

Table 1 Optimization of the reaction conditionsa
Entry
1c
2c
3
Additive(equiv.)
I2 (0.5)
Oxidant
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
TBHP
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN/H2O
THF
Temp.( oC) Yield(%)b
80
80
80
80
60
80
80
80
80
80
36
N.R.
93
85
61
80
65
53
88
88
KI (1.2)
TBAI (1.2)
TBAI (1.2)
TBAI (1.2)
TBAI (1.2)
TBAI (1.2)
TBAI (1.2)
TBAI (1.5)
TBAI (1.2)
4d
5
6e
7
8
DMF
9
MeCN
MeCN
10
aReaction conditions: phenylacetylene 1a (0.5 mmol), 4-methylbenzenesulfonyl hydrazide
2a (0.6 mmol), oxidants (1 mmol), and solvent (2 mL) were stirred in a sealed tube at
60-80 oC for 30 min unless noted.
bIsolated yields were determined based on 1a.
cReaction time is 4h.
dReaction in the bottle.
10

eMeCN/H2O = 1/1 (v/v).
11

Scheme 1. Reaction of various alkynes with sulfonylhydrazid; aReaction conditions:
alkynes 1 (0.5 mmol), sulfonylhydrazides 2 (0.6 mmol), K2S2O8 (1 mmol), TBAI (0.6
mmol) and MeCN (2 mL) were stirred in a sealed tube at 80 oC for 30 min; bIsolated yields
were determined based on 1.
12

Scheme 2. The trans-configuration of 3cb
13

Scheme 3. Preliminary mechanistic studies
14

Scheme 4. Plausible mechanism
15