Direct Synthesis of Propen-2-yl Sulfones through Cascade Reactions Using Calcium Carbide as an Alkyne Source

Article abstract of DOI:10.1021/acs.orglett.0c01915

A simple method for the construction of propen-2-yl sulfones through cascade reactions of calcium carbide with arylsulfonylhydrazones using copper as a mediator is described. The salient features of this protocol are the use of readily available and easy-to-handle alkyne source, broad substrate scope, open-air condition, and simple operation procedure.

Full text of DOI:10.1021/acs.orglett.0c01915

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Letter
Direct Synthesis of Propen-2-yl Sulfones through Cascade Reactions
Using Calcium Carbide as an Alkyne Source
Lei Gao, Zhenrong Liu, Xiaolong Ma, and Zheng Li*
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ABSTRACT: A simple method for the construction of propen-2-yl sulfones through cascade reactions of calcium carbide with
arylsulfonylhydrazones using copper as a mediator is described. The salient features of this protocol are the use of readily available
and easy-to-handle alkyne source, broad substrate scope, open-air condition, and simple operation procedure.
Scheme 1. Synthesis of Propen-2-yl Sulfones
lkenyl sulfones have long been known for their synthetic
Autilities in organic chemistry, easily participating in 1,4-
addition reactions and cycloaddition reactions. They have also
been shown to potently inhibit a variety of enzymic processes
providing unique properties for drug design and medicinal
chemistry.1 Various synthetically viable procedures have been
used for the construction of alkenyl sulfones in the literature.2
For example, the recent reported typical methods for the
synthesis of propen-2-yl sulfone include (i) the reaction of
ethylphenyl sulfone with benzoaldehyde in the presence of n-
butyllithium and diethyl chlorophosphate,3 (ii) microwave-
assisted copper triflate-catalyzed hydrosulfonylation of alkyne
with benzenesulfonic acid,4 and (iii) the copper(II)-catalyzed
three-component reaction of aryldiazonium tetrafluoroborate,
sulfur dioxide, and alkene (Scheme 1).5 However, some
drawbacks still exist for the reported methods such as use of
unavailable starting materials, rigorous reaction conditions, and
complex workup procedures. Therefore, more efficient
methods using simple steps and commercially available
materials are still necessary.
friendly, and more economical than acetylene gas in the field of
organic synthesis, calcium carbide itself is stable and difficult to
Calcium carbide is a widely utilized inexpensive industrial
material to synthesize acetylene gas. However, research in
recent years has found that the direct use of calcium carbide as
an alkyne source has a deeper and wider application value in
organic synthesis than acetylene gas.6 Our research group has
devoted great efforts to the research on organic synthesis direct
using calcium carbide as an alkyne source.7 Although calcium
carbide is safer, easier to operate, more environmentally
Received: June 7, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01915
© XXXX American Chemical Society
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A

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a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Synthesis of Propen-2-yl Sulfones
b
entry
mediator (eq)
solvent
DMF
temp. (°C)
yield (%)
1
none
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
110
130
110
0
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CuCl2 (1)
Cu(NO3)2 (1)
Cu(OAc)2 (1)
CuCl (1)
CuCl (1.2)
CuCl (1.5)
CuCl (2)
CuBr (2)
CuI (2)
CuNO3 (2)
CuOAc (2)
CuCl (2)
CuCl (2)
CuCl (2)
CuCl (2)
CuCl (2)
CuCl (2)
CuCl (2)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
xylene
chlorobenzene
DMSO
DMSO
DMSO
DMSO
DMSO
0
trace
trace
trace
12
58
65
61
55
23
36
trace
trace
68
71
82
35
0
c
19
a
Reaction conditions: 1a (1 mmol), calcium carbide (3 mmol), water
t
(6 mmol), mediator (appropriate amount), and BuOK (2 mmol) in
solvent (4 mL) were heated at appropriate temperature for 8 h under
open-air condition. Isolated yield. KF was used as an activator.
b
c
participate in organic reactions. Therefore, exploring more
effective organic reactions involving calcium carbide is still a
very challenging subject.
Herein, we report a cascade method for the synthesis of
propen-2-yl sulfones using calcium carbide as an alkyne source
and sulfonylhydrazones as starting materials.
Initially, the reaction of benzaldehyde p-tosylhydrazone (1a)
with calcium carbide was selected as a model reaction to screen
the optimal conditions. The reaction first tested in DMF at 120
°C, and the result showed that no products were observed in
the absence of a mediator (Table 1, entry 1). Then various
copper salts with different amount as mediators were tested for
the reaction. Cu(II) salt, CuCl2, Cu(NO3)2, and Cu(OAc)2 as
mediators could not give a product (entries 2−4). In contrast,
Cu(I) salt, CuCl, as a mediator could afford (E)-1-phenyl-
propen-2-yl p-tolyl sulfone (2a) as a product in different yields
depending on the amount of CuCl (entries 5−8). The E-style
structure of 2a was determined by the comparison with
literature data.4a,8 Among them, 2 equiv of CuCl could obtain
the best yield (entry 8). The other Cu(I) salts, such as CuBr,
CuI, CuNO3 and CuOAc, as mediators were also examined,
and no higher yields of 2a were observed (entries 9−12). The
solvents also played important roles in the reaction. It was
found that xylene and chlorobenzene as solvents only gave a
trace amount of 2a (entries 13, 14). DMSO was a more
efficient solvent than DMF (entry 15). The appropriate
reaction temperature was also necessary for the reaction
(entries 16−18). It was found that 2a could be obtained in
highest yield (82%) at 110 °C for 8 h (entry 17). In the case of
using fluoride, such as KF, as an activator according to
literature,9 the reaction was inversely inhibited for the
formation of 2a (entry 19). In addition, the reaction was
also affected by the amount of water. It was observed that 6
a
Reaction conditions: 1 (1 mmol), calcium carbide (3 mmol), water
t
(6 mmol), and BuOK (2 mmol) in DMSO (4 mL) were heated at
110 °C for 8 h.
B
https://dx.doi.org/10.1021/acs.orglett.0c01915
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a
Scheme 3. Synthesis of 1-Arylacetones
Scheme 5. Proposed Mechanism for Synthesis of Propen-2-
yl Sulfone or 1-Arylacetone
a
Reaction conditions: 1 (1 mmol), calcium carbide (3 mmol), water
t
(6 mmol), and BuOK (2 mmol) in DMSO (4 mL) were heated at
110 °C for 8 h.
Scheme 4. Control Experiments
situations were also observed for the substrates including
para-fluoro-, chloro-, and bromo-substituted aromatic rings,
which led to the formation of corresponding para-halopheny-
lacetones as byproducts of 2l, 2o, or 2s in low yields (3d−3f).
To investigate the reaction mechanism, several control
experiments were designed and conducted (Scheme 4). If the
reaction of 1a with calcium carbide was conducted under
nitrogen atmosphere, the desired product 2a was not observed,
and instead 1-phenylprop-1-yne (4a) was formed (Scheme 4,
eq 1). This result indicated that oxygen in the air was an
indispensable condition for the reaction. If the reaction was
conducted under air condition in the presence of TEMPO (2
equiv), the product was also 1-phenylprop-1-yne (4a), and 2a
was not observed. This implied that the reaction might
proceed through a free-radical process (Scheme 4, eq 2). In
addition, if the reaction was first conducted under air condition
at 90 °C for 5 h, the formation of 1-phenylprop-1-yne (4a)
could be detected in the reaction system. Then the system was
further stirred at 110 °C for 3 h, and the desired product 2a
could be isolated in good yield. This result meant that 1-
phenylprop-1-yne (4a) might be the intermediate for the
formation of 2a.
equiv of water based on 1a was a suitable amount for the
formation of 2a (see Supporting Information, Table S1).
By using the optimized conditions, syntheses of a series of
propen-2-yl sulfones were conducted by the reactions of
various sulfonylhydrazones with calcium carbide at 110 °C in
t
DMSO using CuCl as a mediator and BuOK as a base. The
results are summarized in Scheme 2. It was found that the
reactions could be suitable to a wide range of substrates
including various aromatic rings Ar1 and Ar2 to give the
corresponding propen-2-yl sulfones in moderate to good yield.
For example, Ar1 not only could be unsubstituted phenyl (2a,
2x, 2ag) but also could be extended to aromatic rings bearing
i
t
electron-donating groups such as Me, Et, Pr, Bu, and NH2
(2b−2i), and electron-withdrawing groups such as F, Cl, and
Br (2j−2s, 2y−2ab, 2ah, 2ai). Ar1 could also be extended to
fused ring, for example, naphthyl (2t, 2u, 2ac, 2ad, 2aj), and
heterocycle, for example, furyl (2v, 2ae) and thienyl (2w, 2af,
2ak). Ar2 was suitable to 4-tolyl (2a−2w), phenyl (2x−2af),
and 4-chlorophenyl (2ag−2ak) and afforded the expected
products in satisfactory yield.
In particular, it was noteworthy to mention that when the
substrates including para-propyn-1-yl, phenyl, or trifluoro-
methyl substituted aromatic rings in sulfonylhydrazones, the
corresponding propen-2-yl sulfones were not isolated under
standard conditions; instead, 1-aryl substituted acetones were
obtained in 75%, 70%, and 55% yields (3a−3c) (Scheme 3).
These results were attributed to the strong conjugate effect of
corresponding substituents on the aromatic rings, which
resulted in the reaction intermediates more readily to be
hydrolyzed to produce the substituted acetones. Similar
On the basis of these observations, a plausible mechanism
for the reaction of sulfonylhydrazones 1 with calcium carbide
to afford 2 or 3 is proposed in Scheme 5. Initially, diazomethyl
arene (A) is formed in situ by the reaction of arylhydrazone
t
with BuOK through the release of potassium arylsulfinate
(Bamford−Stevens reaction).10 Simultaneously, calcium car-
bide reacts with water to form calcium acetylide hydroxide
first,6d,e and then transforms into copper calcium acetylide (B)
in the presence of cuprous chloride,11 which further reacts with
A to form copper carbene species C.12 The α-migration of
C
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acetylide in species C forms intermediate D.12 Intermediate D
obtains hydrogen ion from water in the reaction system to
afford 1-arylprop-1-yne (4) as an intermediate. Meanwhile,
potassium arylsulfinate is transformed into free-radical E via
single electron transfer in the presence of air.4,13 E can easily
tautomerize to free-radical F. F reacts with 1-arylprop-1-yne
(4) by free-radical addition to afford radical species G. G
further reacts with Cu(I) to yield propen-2-yl sulfone
copper(II) complex H, which can be detected by HRMS
(see Supporting Information). Finally, the demetalation−
protonation of H with water results in the formation of
propen-2-yl sulfone 2 as the final product. In addition, for
special intermediate 4, the hydrolysis can more readily take
place to yield 1-arylacetone 3 as the final product.
In conclusion, an efficient method for the synthesis of
propen-2-yl sulfones by cascade reactions of calcium carbide
with sulfonylhydrazones has developed. The advantages of this
protocol are the easy-to-handle and inexpensive alkyne source,
open-air conditions, wide scope of substrates with high
functional group tolerance, and simple workup procedures.
This method will provide a good alternative to synthesize
propen-2-yl sulfones.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01915.
Additional data on general experimental information,
1
synthetic procedure, characterization data and H/13C
NMR spectra of all products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Zheng Li − College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu 730070, P. R.
China; orcid.org/0000-0003-1944-8270; Email: lizheng@
nwnu.edu.cn
Authors
Lei Gao − College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu 730070, P. R.
China
Zhenrong Liu − College of Chemistry and Chemical
Engineering, Northwest Normal University, Lanzhou, Gansu
730070, P. R. China
Xiaolong Ma − College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu 730070, P. R.
China
(7) (a) Fu, R.; Li, Z. Org. Lett. 2018, 20, 2342−2345. (b) Song, G.;
Li, Z. Eur. J. Org. Chem. 2018, 2018, 1326−1332. (c) Fu, R.; Li, Z.
Eur. J. Org. Chem. 2017, 2017, 6648−6651. (d) Fu, R.; Li, Z. J. Chem.
Res. 2017, 41, 341−345. (e) Li, Z.; He, L.; Fu, R.; Song, G.; Song, W.;
Xie, D.; Yang, J. Tetrahedron 2016, 72, 4321−4328. (f) Gao, L.; Li, Z.
Synlett 2019, 30, 1580−1584. (g) Lu, H.; Li, Z. Adv. Synth. Catal.
2019, 361, 4474−4482. (h) Gao, L.; Li, Z. Org. Chem. Front. 2020, 7,
702−708.
Complete contact information is available at:
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(8) (a) Wang, L.; Yue, H.; Yang, D.; Cui, H.; Zhu, M.; Wang, J.;
Wei, W.; Wang, H. J. Org. Chem. 2017, 82, 6857−6864. (b) Ojha, D.
P.; Prabhu, K. R. Org. Lett. 2015, 17, 18−21.
Notes
The authors declare no competing financial interest.
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S.; Schreiner, P. R. Org. Biomol. Chem. 2017, 15, 6800−6807.
(b) Werner, G.; Rodygin, K. S.; Kostin, A. A.; Gordeev, E. G.; Kashin,
A. S.; Ananikov, V. P. Green Chem. 2017, 19, 3032−3041.
(10) Bamford, W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4735−4740.
(11) (a) Hossain, M. L.; Ye, F.; Zhang, Y.; Wang, J. J. Org. Chem.
ACKNOWLEDGMENTS
The authors thank the National Natural Science Foundation of
China (21462038) for the financial support of this work.
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