Synthesis of vinylic sulfones in aqueous media

Article abstract of DOI:10.1021/acs.orglett.0c04257

A green method for the sulfination of allenic carbonyl compounds to access a wide variety of vinylic sulfones is developed. This reaction works in aqueous media under very mild conditions. This reaction is atom economic. A wide variety of vinylic sulfones could be obtained in moderate to excellent yields with wide functional group tolerance. The efficiency of this method is demonstrated in some reactions where the desired products can be isolated by filtration.

Full text of DOI:10.1021/acs.orglett.0c04257

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Synthesis of Vinylic Sulfones in Aqueous Media
Jeffrey Goh, Manikantha Maraswami, and Teck-Peng Loh*
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ABSTRACT: A green method for the sulfination of allenic
carbonyl compounds to access a wide variety of vinylic sulfones
is developed. This reaction works in aqueous media under very
mild conditions. This reaction is atom economic. A wide variety of
vinylic sulfones could be obtained in moderate to excellent yields
with wide functional group tolerance. The efficiency of this method
is demonstrated in some reactions where the desired products can
be isolated by filtration.
he development of truly green and practical synthetic
Tmethods is of utmost importance in the chemical and
pharmaceutical industries. The need to use metals and
flammable toxic organic solvents both in the reactions as
well as for workup and purification makes many of the organic
reactions unsafe and environmentally unfriendly. Therefore,
there has been much effort directed toward the development of
new methods that work in water under very mild reaction
conditions, are atom economic in nature, and avoid the use of
metal or/and toxic flammable organic solvent. If successful,
this metal-free approach can be employed for protein
bioconjugation since metals are also known to destroy the
tertiary structures of proteins. In this paper, we demonstrate
the feasibility of this strategy with a green and practical
synthesis of vinylic sulfones.
Vinylic sulfones are chosen as the targets as they are
important moieties featured widely in many biologically and
pharmaceutically1 active molecules (such as anticancer agents,
cysteine protease inhibitors, antibacterial agents, and TSH
receptor antagonists). They are useful building blocks in
organic synthesis2 and have also been widely used as linkers in
protein3 and material science (Figure 1). Traditionally, vinylic
sulfones are synthesized via processes such as addition−
elimination4 and the Peterson reaction.5 Other strategies
including the use of acetylenic sulfones6 and organometallic
reagents7 have also been reported. Jiang’s group investigated
the Cu(I)-catalyzed oxidative reaction of sulfonyl hydrazides8
to couple with alkenes to form vinylic sulfones (Figure 2a). In
addition, sulfonylation of carbon−carbon π bonds, such as
alkenes and alkynes, have been extensively reported.9 More
recently, vinylic sulfones synthesized from allenes were also
reported.10 However, many of these methods suffer from
various setbacks including the need to use toxic reagents/
solvents, metal catalysts, and harsh reaction conditions and
their poor atom-economy. For this reason, the establishment of
Figure 1. Applications of molecules containing the sulfone moiety.
coherent methodologies for the synthesis of these classes of
compounds in a green manner is imperative. A well-developed
green synthetic methodology to synthesize vinylic sulfones can
potentially supplement or replace existing strategies, thereby
reducing chemical waste and offering an alternative approach
to access this crucial class of compounds.
In our group, we have developed a number of metal-free
water-based green synthetic methods. These methods include
the Mukaiyama−aldol C−C bond formation reaction involving
reactive aldehdyes,11 C−S bond formation involving cysteine
bioconjugation with allenic amides12 and C−SO2R/C-
phosphorus reactions13 with reactive allylic alcohols. More
recently, we have successfully employed 2H-azirines as a linker
Received: December 25, 2020
Published: January 25, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04257
© 2021 American Chemical Society
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bioconjugation with biomolecules such as proteins. We also
found that continuous and intense stirring to ensure
interaction between the organic substrates are useful; this
observation is also in line with other reported “in water” or “on
water” reactions.15−19
With the optimized reaction conditions in hand, the
substrate scope of the sulfinic acids was investigated in an
ethanol/water solvent system. A variety of aryl and alkyl
sulfinic acids were investigated under this protocol as shown in
Scheme 1. Aryl sulfinic acids bearing electron-donating groups
a
Scheme 1. Substrate Scope of the Sulfinic Acids
Figure 2. Vinylic sulfone synthesis
for disulfide bionconjugation under biocompatible condi-
tions.14 In this investigation, we envision a highly efficient
atom-economical cross-coupling between electron-deficient
allenic carbonyl compounds and sulfinic acids for the
construction of the carbon−sulfur bond to afford the desired
vinylic sulfones (Figure 2b).
1-Phenylbuta-2,3-dien-1-one (1a) and benzene sulfinic acid
(2a) were chosen as model substrates for the cross-coupling
reaction (Table 1). The reaction was initially screened using a
Table 1. Optimization of the Sulfa-Michael Reaction
a
Conditions
b
b
entry
solvent
time (h)
conv (%)
yield (%)
1
2
3
4
5
6
7
8
9
10
PhMe
Et2O
cyclohexane
1,2-DCE
EtOH
H2O
PBS buffer (pH 7.0)
H2O:EtOH
H2O:EtOH
H2O:EtOH
12
12
12
12
12
12
12
1
100
100
100
100
100
100
100
91
13
7
18
30
75
76
75
58
a
Experimental conditions: 1a (0.15 mmol) and 2 (0.23 mmol) in
c
H2O/EtOH (1:1) (1 mL) at room temperature for 1 h. Isolated
yields. Gram-scale reaction
b
d
1
1
100
100
98(99)
e
98
a
Experimental conditions: 1a (0.15 mmol) and 2a (0.23 mmol) in the
b
(3b−3h) reacted smoothly to afford the corresponding vinylic
sulfones in good yields. Even an electron-deficient sulfinic acid
(3f) worked well under these conditions. More interestingly,
vinylic sulfones 3d−3f can be easily isolated by a simple
filtration in this transformation. In addition, aliphatic sulfinic
acids (3i−3l) also undergo this transformation to give the
vinylic sulfones in good to excellent yields.
Subsequently, the substrate scope of the electron-deficient
allenes was explored. As depicted in Scheme 2, it is evident that
a wide diversity of allenic carbonyl compounds (allenic
ketones/esters/amides) undergo a smooth transformation to
afford the desired vinylic sulfones in modest to excellent yields.
Aryl rings bearing electron-donating groups (3m−3p) reacted
smoothly under these conditions to give the corresponding
products in good yields. However, the yield of 3q is
significantly diminished when the aryl ring bears an electron-
withdrawing nitro substituent. Heterocylic allenic ketones (3s
specified solvent (1 mL) at room temperature. Conversions and
yields were determined by 1H NMR using CH2I2 as the internal
c
d
e
standard. 1.0 equiv of 2a was used. Isolated yield. 2.0 equiv of 2a
was used.
variety of nonpolar organic solvents (refer to the SI), resulting
in poor yields of the desired product 3a. The yield of 3a was
improved when polar aprotic solvents were employed (refer to
the SI). Inspired by this result, we started to screen polar protic
solvents and observed that the yields were increased
dramatically (Table 1, entries 5−7). The yield of 3a can be
improved by employing EtOH as a cosolvent along with H2O
as a 1:1 mixture (Table 1, entry 9), affording the product in
99% yield. It is important to note that the reaction conducted
in either water or buffer pH 7 (Table 1, entries 6 and 7)
afforded the desired vinylic sulfone in comparable yields.
These results suggest the possibilities of using this method for
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a
modest yield of 38% of the desired product. To our surprise, it
was observed that the allenic amide was more reactive than
allenic ester. We postulated that the increased reactivity of
allenic amides as compared to allenic esters is due to the result
of hydrogen bonding with the aqueous based medium. On the
basis of the results of the competitive study (Scheme 3), the
Scheme 2. Substrate Scope of the Allenes
a,b
Scheme 3. Competitive Study between Various Allenes
a
Experimental conditions: 1 (0.15 mmol) and 2a (0.23 mmol) in
b
H2O/EtOH (1:1, 1 mL) at room temperature for 1 h. Conversions
and yields were determined by H NMR using CH2I2 as the internal
1
standard.
reactivity of the different allenic carbonyl species are as follows:
allenic ketones are the most reactive followed by allenic amides
and, finally, allenic esters. This is evident based on the longer
reaction time required for allenic esters as compared to allenic
ketones or amides (Scheme 3).
In order to demonstrate the versatility of this protocol, a
handful of synthetic transformations (Figure 3) of the obtained
a
Experimental conditions: 1 (0.15 mmol) and 2a (0.23 mmol) in
H2O/EtOH (1:1) (1 mL) at room temperature for 1 h. Isolated
b
c
yields. Reaction was stirred for 72 h. Reaction was stirred overnight.
and 3t) also worked well under this protocol. Even aliphatic
allenic ketones (3v−3z) reacted with ease to give the vinylic
sulfones in modest to good yields. Allenic esters and amides
(3aa−3ae), which are inherently less reactive than the ketone
variants, also provided the vinylic sulfones in excellent to near
quantitative yields. The menthol (3ac) allene derivative also
reacted smoothly under these conditions to afford the
corresponding vinylic sulfone in 68% yield.
Thereafter, we carried out a competitive study between the
three electron-deficient allene variants (i.e., allenic ketone/
amide/ester). The reactions were carried out under the same
conditions and stopped in 1 h. The yields were determined
using NMR analyses (based on CH2I2 as the internal
standard). Based on our initial investigation, it is conclusive
that the allenic ketone is the most reactive under the reaction
conditions; the starting material was fully converted to afford
Figure 3. Synthetic transformations and functionalization of vinylic
sulfones.
products was evaluated. Interestingly, benzyl amine displaced
the sulfonyl group under the optimized conditions to give
enaminone 4 in 80% yield. Functionalization of vinylic sulfone
3a by a Zn/CuI-mediated Michael reaction20 with tert-butyl
iodide gave the corresponding alkylated sulfone 5 in 66% yield.
Vinylic sulfone 3a can also undergo protection of the ketone
with 1,2-bis(trimethylsiloxy)ethane to afford the protected
vinylic sulfone 6 in 32% yield.21 Treating vinylic sulfone 3ab
1
the corresponding vinylic sulfone with a H NMR yield of
98%. Under the same conditions, the allenic amide provided a
conversion of 91% with an NMR yield of 88%, whereas the
allenic ester was found to be the least reactive under this
protocol; only 41% of the substrate was converted, obtaining a
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with benzylamine afforded γ-lactam 7 in 62% yield.22 Vinylic
sulfone 3r can conveniently participate in a click reaction23
with the antiviral drug, Zidovudine,24 affording the corre-
sponding compound 8 in 51% yield.
Experimental procedures, screening reaction conditions,
analytical data for all new compounds, and NMR spectra
of products (PDF)
The feasibility of this synthetic protocol can be demon-
strated by isolating solid products obtained after a reaction, in
some cases, by a simple filtration without the need for
extraction and column chromatography (Figure 4). It is
AUTHOR INFORMATION
Corresponding Author
■
Teck-Peng Loh − Institute of Advanced Synthesis (IAS) and
Yangtze River Delta Research Institute, Northwestern
Polytechnical University (NPU), Xi’an 710072, China;
Division of Chemistry and Biological Chemistry, School of
Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371; orcid.org/0000-0002-
2936-337X; Email: teckpeng@ntu.edu.sg
Authors
Jeffrey Goh − Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang
Technological University, Singapore 637371
Manikantha Maraswami − Division of Chemistry and
Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore
637371
Figure 4. Simplicity of reaction demonstrated by filtration to obtain
solid products.
noteworthy to highlight that the reaction also proceeds with
1.0 equiv of sulfinic acid (Table 1, entry 8). We postulated that
water plays two important roles in this reaction. First, water
enhances the rate of the reaction via the hydrophobic effect.25
In addition, water could also possibly activate13a the sulfinic
acid as described by Loh’s group.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04257
Notes
The authors declare no competing financial interest.
The proposed mechanism of the sulfination is depicted in
Scheme 4 below. Nucleophilic attack by the sulfinic acid
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the financial support from
the National Natural Science Foundation of China
(21702108), the Natural Science Foundation of Jiangsu
Province, China (BK20160977), the Six Talent Peaks Project
in Jiangsu Province (YY-033), and Tier 1 grant M4012045.110
(RG12/18-S) from the Ministry of Education of Singapore and
Distinguished University Professor grant, Nanyang Techno-
logical University, Singapore.
Scheme 4. Proposed Mechanism
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