Green Chemistry: Multicomponent Hydrosulfonylation of Alkynes For The Synthesis of Vinyl Sulfones
Green Chemistry: Multicomponent Hydrosulfonylation of Alkynes For The Synthesis of Vinyl Sulfones
Green Chemistry: Multicomponent Hydrosulfonylation of Alkynes For The Synthesis of Vinyl Sulfones
Vinyl sulfones are important structural motifs with a wide range of applications in the biomedical field.
Although the hydrosulfonylations of alkynes have provided straightforward strategies for the synthesis of
vinyl sulfones, these methods still exhibit several drawbacks, such as the use of large amounts of transition
metal catalysts or/and additional additives. Herein, we report an efficient and mild multicomponent reac-
tion (MCR) for the preparation of vinyl sulfones achieved by carrying out hydrosulfonylation of alkynes
with the corresponding aryl diazonium salts, K2S2O5 and thiophenols at room temperature without any
metal catalysts or additives. This transformation was the first example of a thiophenol as a hydrogen
Received 26th June 2023, source reacting with vinyl radical with the advantages of high chemoselectivity and step-economy.
Accepted 21st September 2023
Notably, the method was found to also be applicable to aliphatic alkynes, circumventing the limitations of
DOI: 10.1039/d3gc02284f existing methods, and a gram-scale experiment proceeded smoothly, proving the practicality of the
rsc.li/greenchem methodology.
Metal-catalyst-free approaches are promising for the synthesis potential drug for the therapy of Parkinson’s disease (Nrf2 acti-
of valuable compounds uncontaminated by metal catalysts vators), radiation protection agent (Recilisib sodium), cysteine
with simplified post-treatment processes, and have garnered a protease inhibitor (WRR-483), antibacterial agent (BAY 11-
tremendous amount of attention for chemical transform- 7085) and potent anti-Chagas agent (K11777) (Fig. 1).4 Thus,
ations.1 Moreover, multicomponent reactions (MCRs) have the construction of vinyl sulfones remains a long-term goal of
gradually become a research hotspot in chemistry, due to the synthetic chemistry due to their unique pharmaceutical
ability to deploy them for constructing multiple chemical activity and vital synthetic applications.
bonds in one pot and rapidly synthesizing complex functional Over the past few decades, various classic synthetic routes
molecules, thus maximizing the incorporation of starting for the construction of vinyl sulfones have been established,
materials and avoiding the employment of hazardous and including the Knoevenagel condensations of sulfonylacetic
toxic reagents, as well as minimizing the number of steps and acids with aromatic aldehydes,5 Horne–Wadsworth–Emmons
waste generation.2 Thus, developing metal-catalyst-free MCRs reactions of sulfonyl phosphonates with carbonyl com-
for the construction of multifunctional molecules has been pounds,6 β-elimination of halosulfones or selenosulfones,7
highlighted as one of the top challenges in green chemistry. decomposition of tosylhydrazones,8 and oxidation of the
Vinyl sulfones have attracted considerable interest in corresponding vinyl sulfides.9 Recently, the cross-coupling/
organic chemistry, because they are not only versatile building addition of alkenes/alkynes with sulfonyl derivatives has
blocks in organic synthesis, but also privileged scaffolds that
have been extensively studied in a wide range of biologically
and pharmaceutically active compounds.3 For example, mole-
cules containing vinyl sulfones have been applied as a non-
adenosine triphosphate (ATP) competitive multiple-kinase-tar-
geting anticancer agent (Rigosertib) in phase III clinical trials,
rapidly emerged as an efficient and appealing strategy for the this strategy involving hydrosulfonylation of alkynes
construction of vinyl sulfones, since alkenes/alkynes are one of (Scheme 1c), initially forming aryl radicals from aryl diazo-
the most abundant and readily available chemical raw nium salts, followed by in situ generation of aryl sulfonyl rad-
materials and are highly reactive. However, the current conver- icals with inexpensive and readily available K2S2O5, and
sion methods rely on systems (1) having a transition metal,10 further synthesis of vinyl sulfones with alkynes via radical
(2) mediated by a strong oxidant,11 (3) using the cooperativity addition and extraction of hydrogen from HAT reagents (RY–H,
of a transition metal with oxidant,12 or (4) mediated by base, Y = S, O, Si). In comparison with existing methods for the syn-
Published on 22 September 2023. Downloaded by Kaohsiung Medical University on 10/12/2023 5:06:38 PM.
and are limited to activated aryl alkenes13 (Scheme 1a). Yet, thesis of vinyl sulfones, the present method has the following
the sulfonylation of alkynes is considered to be one of the distinctive advantages: (1) metal-catalyst-free and additive-free
most efficient and straightforward methods for synthesizing reaction at room temperature; (2) highly chemoselective and
vinyl sulfones (Scheme 1b).10a,e,12b,13c The sustainability and step-economical MCR; and (3) the first example of a thiophe-
practicality of these transformations, however, are impacted by nol as a hydrogen source reacting with a vinyl radical.
several factors such as their including metal catalysts, stoichio- At the outset of our investigation, we used of 4-methyl-
metric oxidants, bases and high temperatures. Additionally, phenylacetylene 1a, 4-methoxybenzenediazonium tetrafluoro-
these methods are not applicable to aliphatic alkynes, limiting borate 2a and K2S2O5 3a as the model substrates for evaluating
the versatility of these preparations of vinyl sulfones. These reaction parameters including solvent, reaction temperature
reactions have each also been found to severely suffer from and substrate dosage (Table 1). We obtained the target hydro-
one of the following drawbacks: (1) the need for prefunctiona- sulfonylation product 4a in 85% yield by using 4-(trifluoro-
lized coupling partners (such as phenylpropiolic acid),10a,12b methyl)benzenethiol (1.5 equiv.) as a hydrogen source in 1,2-
(2) the use of poorly stable and poorly available sulfinic acids dichloroethane (DCE) under N2 at room temperature for 10 h
as sulfonyl sources, and (3) the production of harmful (entry 1). Notably, the structure of 4a was unambiguously
benzene, sulfuric acid, or benzene sulfinates.10e,13c By contrast, characterized using X-ray crystallography (CCDC 2267588†). To
the realization of hydrosulfonylation of alkynes in metal-cata- further improve the yield of 4a, we screened various solvents
lyst-free and additive-free conditions has not yet been reported. and found that DCE was the best one (entries 2–10). Notably,
Notably, hydrogen atom transfer (HAT) reagents are widely we found that this medium-polarity solvent was most favorable
used in radical reactions, and especially thiophenols are con- for the reaction and the relatively good solubility of the sub-
sidered to be excellent HAT reagents owing to their weak S–H strate led to the high yield of the desired product. However,
bond dissociation energy, which can effectively provide hydro- increasing the reaction temperature from room temperature to
gen in transformations without the use of metal catalyst.14 40 °C did not significantly improve the reactivity (entry 11).
Nevertheless, to the best of our knowledge, there are few
reported examples of thiophenols as hydrogen sources used to
directly react with vinyl radicals. Herein, we developed a novel
strategy for the preparation of vinyl sulfone derivatives, with Table 1 Screening of optimal reaction conditionsa
1 None 85
2 CHCl3 instead of DCE 84
3 DCM instead of DCE 80
4 MeCN instead of DCE 78
5 THF instead of DCE 57
6 EtOAc instead of DCE 55
7 DMF instead of DCE Trace
8 MeOH instead of DCE 53
9 H2O instead of DCE 8
10 Toluene instead of DCE 45
11 40 °C 87
12 Na2S2O5 instead of 3a 81
13 1.5 equiv. of 3a 71
14 3.0 equiv. of 3a 85
15 1.5 equiv. of 2a 86
16 1.2 equiv. of 4-CF3C6H4SH 72
17 2.0 equiv. of 4-CF3C6H4SH 87
18 O2 instead of N2 11
a
Reaction conditions: 1a (0.2 mmol), 2a (1.2 equiv.), 3a (2.0 equiv.)
Scheme 1 General strategies for the synthesis of vinyl sulfones and and 4-CF3C6H4SH (1.5 equiv.) in DCE (2.0 mL) under N2 at room temp-
hydrosulfonylation of alkynes. erature for 10 h. b Isolated yields.
Next, 3a was replaced by Na2S2O5 but this replacement did not Table 3 Scope of aryldiazonium tetrafluoroboratesa
exhibit better reactivity (entry 12). In addition, we tested the
amounts of 3a and 2a and found that 2.0 equiv. of K2S2O5 and
1.2 equiv. of 4-methoxybenzenediazonium tetrafluoroborate
were optimal (entries 13–15). Furthermore, we investigated the
amount of 4-(trifluoromethyl)benzenethiol and the results
showed that, from the point of view of atom economy, using
Published on 22 September 2023. Downloaded by Kaohsiung Medical University on 10/12/2023 5:06:38 PM.
Conclusions
In conclusion, we have developed a mild, efficient and practi-
cal hydrosulfonylation of alkynes with aryldiazonium salts,
K2S2O5 and thiophenol, with this reaction proceeding in a
highly chemoselective and step-economical manner at room
temperature under metal-catalyst-free and additive-free con-
ditions, and readily scaled in batch. Mechanistic studies
showed that the thiophenol acts as a HAT reagent in this reac-
tion, and that the hydrogenation of the alkyne proceeds as a
result of a capture of the hydrogen atom from the thiophenol.
Applying this method, both aryl and aliphatic alkynes can
efficiently achieve hydrosulfonylation under mild reaction con-
Scheme 2 Mechanistic studies. ditions, delivering a range of high-value vinyl sulfones in mod-
erate to good yields. Further extensions of this hydrosulfonyla- J. C. Carretero, Chem. Soc. Rev., 2022, 51, 6774–6823;
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