Synthesis of Aryl(chalcogen-heteroaryl)methyl Sulfones via Sulfuric Acid-Promoted Three-Component Reaction in Water

Article abstract of DOI:10.1002/ejoc.202000547

A facile and efficient three-component reaction in the presence of Br?nsted acid in water was developed to synthesize aryl(chalcogen-heteroaryl)methyl sulfones in good to very high yields with broad substrate scope. Our protocol is eco-friendly, metal free, and atom economic. The sulfone products may be efficiently transformed into a bactericidal agent analogue and an aryl heteroaryl ketone.

Full text of DOI:10.1002/ejoc.202000547

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthesis of Aryl(chalcogen-heteroaryl)methyl Sulfones via
Sulfuric Acid-Promoted Three-Component Reaction in Water
Authors: Ratnakar Reddy Kuchukulla, Qinqin Tang, Youming Huang,
Ze He, Lihong Zhou, and Qingle Zeng
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000547
Link to VoR: https://doi.org/10.1002/ejoc.202000547
01/2020

10.1002/ejoc.202000547
European Journal of Organic Chemistry
COMMUNICATION
Synthesis of Aryl(chalcogen-heteroaryl)methyl Sulfones via
Sulfuric Acid-Promoted Three-Component Reaction in Water
Ratnakar Reddy Kuchukulla,[a,b] Qinqin Tang,[a] Youming Huang,[a] Ze He,[a] Lihong Zhou,[b] and Qingle
Zeng*[a]
Abstract: A facile and efficient three-component reaction in presence
of Brønsted acid in water was developed to synthesize
aryl(chalcogen-heteroaryl)methyl sulfones in good to very high yields
with broad substrate scope. Our protocol is eco-friendly, metal free,
and atom economic. The sulfone products may be efficiently
transformed into a bactericidal agent analogue and an aryl heteroaryl
ketone.
sensitive Grignard reaction and the other is Lewis acid-catalyzed
condensation. Crudden et. al.[23] synthesized phenyl
thiophenemethyl sulfone by second step intermediate alcohol
substitution with sodium benzenesulfinate under inert atmosphere
in 16 h in DCM solvent (Scheme 1d). However, in earlier reports
they used metal catalyst, organic solvents, dry conditions and two
step reaction to synthesize aryl(heteroaryl)methyl sulfones. The
usage of organic solvents may have diverse harmful characters
to environment, such as flammable and explosive, they may be
toxic and persistent, so there is a need to use environmentally
benign solvent such as water.[24]
Sulfones are extensively used as biologically active compounds,[1]
natural products,[2] agrochemicals, such as Syngenta’s popular
herbicide mesotrione[3] and pharmaceuticals, such as γ-secretase
inhibitor which is a drug to prevent Alzheimer’s disease.[4]
Sulfones are also mostly used as valuable intermediates in
organic synthesis.[5]
Scheme 1a (Ref. 13)
Ar(Het)
Pd2(dba)3, NaH
Ar(Het)X
+
Y
SO2Ph
Y
CHCl3, PPh3
SO2Ph
On the other hand, chalcogen heterocyclic scaffolds shows
biological activity such as antitumor[6] and antiproliferative.[7] In
that, thiophene, furan and selenium containing compounds are
well known to exhibit various biological activities, such as anti-
inflammatory agents,[8] anti-HIV PR inhibitors,[9] inhibitors of
NQO2[10] and anti-cancer agents.[11] Most recently the structure-
activity relationship (SAR) of α-branched heterocyclic benzyl
sulfones was set out to explore in medicinal chemistry projects.[12]
Based on this importance, our interest was grown to synthesize
aryl(chalcogen-heteroaryl)methyl sulfones.
Scheme 1b (Ref. 12)
R'
Pd(dba)2, XPhos
TMP, ZnCl, LiCl
O
+
S
O
Het
Het
R'
S
THF, 130 oC,
mw, 2 h, N2
R''
Br
R''
R'''
Mg
O
O
R'''
S
Scheme 1c (Ref. 14)
Br
O
TolSO2CH2CN
BF3.Et2O
S
O
+
CH3CN, 80oC
dry THF
1 h
Ph
S
S
Tol
Ph
OH
O
In traditional methods, several reports[13-20] available on synthesis
of sulfone and related sulfonamide arylations. Only few reports
available on aryl(het)methylsulfones. For example, Beletskaya et.
al.[21] synthesized by palladium catalyzed arylation of strongly CH-
acidic sulfones (scheme 1a).
Knauber et. al.[12] synthesized palladium catalyzed α-
heteroarylation of sulfones (scheme 1b) under inert atmosphere
at 130 oC. In recent reports Prapurna et al.[22] synthesized
sulfonated thiophenephenyl methane which is involved in low
atom-economic two-step reaction (scheme 1c): one is moisture-
Scheme 1d (Ref. 15)
S
S
SO2Na
O
PTSA
+
S
OH
DCM, 16h,
Inert atmosphere
O
Scheme 1e (This work)
R''
O
X
H2SO4 (0.5 equiv)
R''
+
R' SO2Na
+
O
Water, 60oC, 7h
R
H
X
S
R
R'
O
1
2
3
4
* Metal free
R = H, Alkyl, Aryl, Heteroaryl
R' = Alkyl, Aryl
R'' = H, alkyl, RS, benzo
X = O, S, Se.
[a]
Dr. R. R. Kuchukulla, Q. Tang, Y. Huang, Dr. Z. He, Prof. Q. Zeng
State Key Laboratory of Geohazard Prevention and
Geoenvironment Protection, College of Materials, Chemistry &
Chemical Engineering
* Water as solvent
* Byproduct is water
* 27 exampples, up to 89% yield
Chengdu University of Technology
Chengdu 610059, China
Scheme 1. Synthesis of aryl(chalcogen-heteroaryl)methyl sulfones.
E-mail: qinglezeng@hotmail.com
http://www.cmcc.cdut.edu.cn/info/1056/2061.htm
Dr. R. R. Kuchukulla, Dr. L. Zhou
College of Environment and Ecology
Chengdu University of Technology
[b]
On the other hand, the focus on metal-free transformations has
become one of the main research topics in organic synthesis and
green chemistry, because the metal-free catalytic process is
favorable to cost-saving, elimination of metal toxicity and
reduction of environmental pollution.[25-27]
Chengdu 610059, China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.202000547
European Journal of Organic Chemistry
COMMUNICATION
In view of this and as our ongoing research in organosulfur
chemistry,[28-31] here we report a Brønsted acid-catalyzed metal-
free three-component reaction in water to obtain aryl(chalcogen-
heteroaryl)methyl sulfones with broad substrate scope (Scheme
1-1e), and product transformation into other valuable molecules
such as bactericidal agent analogue via new reactions are also
demonstrated.
Initially we chose benzaldehyde (1a), sodium phenylsulfinate (2a)
and 2-methylthiophene (3a) as substrates to obtain product 4aaa
with 69% yield in DCM solvent in presence of H2SO4 at room
temperature (Table 1, entry 1).
Further we tried to improve yield of 4aaa with acids such as
NaHSO4, HCl, HBF4 and AcOH in water at various temperatures
(Table 1, entries 10~14), and poor yields were observed. In the
case of PTSA in DCM also observed poor yield (Table 1, entries
14). Next we also tried with Lewis acids such as FeCl3, ZnCl2
(Table 1, entries 14-15) in DCM solvent, but product 4aaa was not
observed. So finally based on the above screened reactions, 0.5
equivalent of H2SO4 at 60 oC in water to give 82% yield of 4aaa in
7 h time (Table 1, entry 8) was chosen as optimized reaction
condition, which was metal free and environmentally benign
solvent contained reaction condition.
With the optimized condition in hand, we explored the substrate
scope of aldehydes 1. Various aryl/heteroaryl/alkyl aldehydes
(1a-k) were individually examined by reacting with substrates 2a
and 3a via three-component reaction (Table 2).
Table 1. Optimization of reaction conditions.[a]
S
SO2Na
Acid
O
+
+
O
S
Table 2. Substrate scope of the aldehydes (1).[a]
solvent
S
O
3a
1a
2a
O
4aaa
O
S
SO2Na
H2SO4(0.5 eq)
+
+
Water, 60oC, 7h
S
R
H
S
O
Entry
1
Acid
H2SO4
Solvent
Temp. (oC)
Yield (%)
69%
10%
15%
19%
14%
76%
80%
82%
82%
31%
32%
35%
20%
21%
NA
R
1a-k
3a
2a
1
4aaa-kaa
Yield (%)
DCM
EtOH
Water
EtOH
water
water
water
water
water
water
water
water
Water
DCM
DCM
DCM
rt
Entry
1
R
4
2
Amberlyst-15
Amberlyst-15
IR-120(H) resin
IR-120(H) resin
H2SO4
60
60
60
60
rt
1a
Phenyl
4aaa
82
89
88
88
86
77
77
72
74
69
71
3
2
1b
1c
1d
1e
1f
4-Fluorophenyl
2-Chlorophenyl
4-Chlorophenyl
2-bromophenyl
2-Hydroxyphenyl
4-Methylphenyl
H
4baa
4caa
4daa
4eaa
4faa
4gaa
4haa
4iaa
4
3
5
4
6
5
7
H2SO4
60
60
80
60
60
60
80
40
40
40
6
8[b]
9b
10
11
12
13
14
15
16
H2SO4
7
1g
1h
1i
H2SO4
8
NaHSO4
HCl
9
Methyl
10
11
1j
2-Furan
4jaa
HBF4
1k
3-Thiophene
4kaa
AcOH
[a] Reaction conditions: H2SO4 (0.5 mmol), benzaldehyde 1 (1.3 mmol), 2a (1.0
mmol) and 3a (1.0 mmol), 7 h, water (4 mL) under air atmosphere.
PTSA
FeCl3
When the aromatic aldehyde substrates with electron-
withdrawing groups on phenyl ring, such as F (1b), Cl (1c, 1d),
and Br (1e), the yields of 4baa (89%), 4caa (88%), 4daa (88%)
and 4eaa (86%) were very good. When we used aromatic
aldehydes with electron-donating group such as hydroxyl (1f),
methyl (1g) and alkyl aldehydes (1h and 1i) as substrates, the
yields of 4faa-4jaa were reduced to 77%, 77%, 72% and 74%,
respectively, when compared to aromatic aldehyde substrates
with electron-withdrawing group afforded product (4baa-4eaa).
When we used heterocyclic substrates (1j and 1k) in this three
component reaction, the yields of 4jaa and 4kaa were decreased
to 69% and 71%, respectively (Table 2). In a word, it seems that
there is a rule that electron-withdrawing groups on aldehydes
afforded higher yields than electron-donating groups including
ZnCl2
NA
[a]
Reaction conditions: resin (100%, weight percentage according to 3a) or
Bronsted /Lewis acid (1 equivalent according to 3a), benzaldehyde 1a (1.3
mmol), 2a (1.0 mmol) and 3a (1.0 mmol), reaction time 12 h, under air, unless
otherwise noted. [b] Reaction time 7 h, H2SO4 (0.5 mmol).
To optimize reaction conditions, in this model reaction were
further screened different acid catalysts such as Amberlyst 15, IR-
120(H) acid resins in ethanol or water as solvent, respectively, but
poor yields were got (Table 1, entries 2~5). So investigation was
continued with H2SO4 as catalyst in water with different
temperatures and different equivalents of H2SO4 (Table 1, entries
6~9), and 82% yield of 4aaa was obtained with 0.5 equivalent of
o
H2SO4 at 60 C (Table 1, entry 8), which was a very good yield.
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10.1002/ejoc.202000547
European Journal of Organic Chemistry
COMMUNICATION
electron-rich heteroaryl groups, perhaps electron-withdrawing
groups on aldehydes benefit stability of reactive intermediates.
Next, we explored the substrate scope of 2. Various sodium
aryl/alkylsulfinates (2a-i) were examined by reacting with
substrates 1a and 3a under the optimized reaction condition
(Table 3). The aromatic sulfinate substrates 2 bearing electron
withdrawing groups, such as F (2b), CF3 (2c) and Cl (2d) on
phenyl ring at ortho- or para- position were tolerated, and afforded
the desired products (4aba-4aca) in very good yields and
aromatic sulfinate substrates 2e bearing electron withdrawing
group F, at meta-position was afforded product 4aea in less yield
when compared to yields of products 4aba-4aca which were
afforded by substrates (2b-d) with electron withdrawing groups,
on phenyl ring at ortho- or para- position. Also we observed that
decreasing yields in case of aromatic sulfinate 2 with electron-
donating group, such as tertiary-butyl (2f), methyl (2g) and alkyl
sulfinate (2h and 2i) substrates afforded products (4afa-4aia,
Table 3).
Table 4. Substrate scope of chalcogen heteroarenes (3)
R
O
X
O
SO2Na
R
H2SO4 (0.5 equiv)
Water, 60oC, 7h
+
+
H
S
X
O
X = O, S, Se.
3a-i
1a
2a
4aaa-aai
S
S
HO
S
S
S
O
O
S
O
S
O
S
S
O
O
O
O
4aaa (82%)
4aac (72%)
4aad (79%)
4aab (74%)
S
O
O
O
O
S
O
S
O
S
O
S
O
O
O
O
4aag (67%)
4aae (70%)
4aaf (69%)
4aah (66%)
Table 3. Substrate scope of sodium aryl/alkylsulfinates (2)
Se
R
O
O
S
O
S O
H2SO4 (0.5 equiv)
Water, 60oC, 7h
S
H
+
+
SO2Na
R
O
S
4aai (67%)
2a-i
1a
4aaa-aia
3a
a
Reaction conditions: H2SO4 (0.5 mmol), benzaldehyde 1a (1.3 mmol), 2a~2i
Entry
2
R
4
Yield (%)
(1.0 mmol) and 3a (1.0 mmol), 7 h, water (4 mL) under air atmosphere.
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
Phenyl
4aaa
82
84
87
86
80
75
76
71
72
To study the reaction mechanism, control experiments were
carried out under the optimized reaction condition. The results
were showed that reaction of 1a and 3a produced intermediates
2-Fluorophenyl
4-Trifluoromethylphenyl
4-Chlorophenyl
3-Fluorophenyl
4-tBu-phenyl
4-Methylphenyl
Methyl
4aba
4aca
4ada
4aea
4afa
4aga
4aha
4aia
A
(Identified by ESI-HRMS and available in supporting
information) and B[32] (NMR spectrum available in supporting
information) in 42% yield (Scheme 2, equation a). Reaction of 1a
and 2a did not (Scheme 2, equation b) produce intermediate C.
S
H
O
S
2g
2h
2i
H2SO4 (0.5 mmol)
a)
+
+
S
Water (2 mL)
60 oC, 7 h
S
1a
3a
Ethyl
B, 42% yield
A (Detected by
ESI-HRMS)
(0.94 mmol) (0.84 mmol)
[a] Reaction conditions: H2SO4 (0.5 mmol), benzaldehyde 1a (1.3 mmol), 2 (1.0
mmol) and 3a (1.0 mmol), 7 h, water (4 mL) under air atmosphere.
H
O
SO2Na
H2SO4 (0.5 mmol)
SO2
S
b)
+
Water (2 mL)
60 oC, 7 h
Finally, we explored the substrate scope of 3. Diverse
thiophene/furans and selenophene (3a-i) were examined
individually by reacting with substrates 1a and 2a via three-
component reaction under the optimized reaction condition (Table
4). The thiophene substrates 3 with electron donating groups such
as methyl, ethyl, hydroxyethyl and thiomethyl at ortho position,
were afforded products (4aaa-4aad) in very good yields, whereas
simple thiophene afforded product 4aae yield was a little less. It
is also observed that in the case of various substituted furan
substrates’ and selenophene’s products 4aaf-4aai were obtained
in less yields when compared to diverse thiophene substrate’s
products (Table 4). In overall, the electron-rich thiophene
substrates afforded desired product 4 in very good yield, and
various furans and selenophene afforded desired products 4 in
good yield.
O2
1a
(0.94 mmol)
2a
C, 0% yield
(0.82 mmol)
Scheme 2. Control experiments.
Based on the control experiments (Scheme 2), and earlier
reports[32-33] a reaction mechanism for one-pot three-component
reaction between 1a, 2a and 3a is proposed (Scheme 3). Initially,
the oxygen atom of aldehyde 1a grasps a proton of sulfuric acid
to form intermediate D. The electron-rich carbon of 3a attacks on
protonated aldehyde
subsequently forms intermediate A by losing a molecule of water.
Here one more 3a attacks on the intermediate C to form
D
to form intermediate E, which
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10.1002/ejoc.202000547
European Journal of Organic Chemistry
COMMUNICATION
intermediate B. However intermediate B will disappear after 50
minutes, which was observed by TLC, since the transformation
between A and B is a reversible reaction. Next the sulfur atom of
sodium phenylsulfinate 2a attacks on intermediate A and forms
the stable targeted product 4aaa.
Experimental Section
General procedure for the synthesis of compounds 4
To a 25 mL glass test tube equipped with a stir bar were added the
corresponding aldehyde 1 (1.5 mmol), heteroarene 3 (1 mmol), sulfuric
acid (0.5 equiv) and 2 mL water. The test tube was stirred in an oil bath
preheated at 60°C for 15 minutes, and then slowly added sodium sulfinate
2 (1 mmol). The reaction mixture was stirred at 60°C. After 6 h, the reaction
progress was checked by TLC and confirmed reaction was completed. The
reaction mixture was cooled to room temperature. Then water (10 mL) was
added to the reaction mixture, which was extracted with ethyl acetate (10
mL) for three times. The combined organic layer was dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel (Petroleum
ether : Ethyl acetate = 10 : 1 used as eluents), to give the desired product
4.
S
OH2
OH
O
3a
H2SO4
- HSO4
H
S
H
H
-
H
E
D
1a
O
2
H
,
+
H
-
S
2a
ONa
S
S
S
S
O
3a
S
O
- Na
O
S
A
B
4aaa
Typical procedure for synthesis of compound 5
Scheme 3. A plausible reaction mechanism.
The compounds 4baa (0.28 mmol) was taken into CH3CN (2 mL) which
was already added in 25mL dried glass reaction tube, then added sodium
tertiary butoxide (1.2 equiv) and stirred the reaction mixture for 4 h at room
temperature. By using the TLC, we confirmed that the reaction was
completed after 4 h. Then the reaction mixture was concentrated by using
a rotary evaporator. And then water was added to the concentrated
reaction mixture, which was extracted with ethyl acetate (3× 5mL). The
combined organic layer was dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (Petroleum ether used as eluent) to
obtain pure product 5.
We also demonstrating application of one of the above products
4baa by C-SO2 bond activation, by synthesizing valuable ketone
compound 5 and bactericidal agent [34] analogue 6. Sulfone 4baa
to ketone compound 5 [35] was obtained in 71% yield in presence
of sodium t-butoxide base in acetonitrile at room temperature
(Scheme 4) by new and advanced route. The other transformation
is synthesis of bactericidal agent analogue 6 in 62% yield from
4baa in the presence of FeCl3 and DCM at room temperature
(Scheme 4).
Typical procedure for synthesis of compound 6
F
S
tBuONa (1.2 equiv)
To a 25 mL dried glass reaction tube equipped with a stir bar were added
compounds 4baa (0.28 mmol), 1,3,5-trimethoxybenzene (0.3 mmol), DCM
(2 mL), FeCl3 (10 mol%). The reaction mixture was stirred for 8 h at room
temperature. By using TLC, we confirmed that the reaction was completed
after 8h. Then the reaction mixture was concentrated with a rotary
evaporator. Water (10 mL) was added to the concentrated reaction mixture.
The resulting mixture was extracted with ethyl acetate (3  5 mL). The
combined organic layer was dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (Petroleum ether : Ethyl acetate =
20 : 1 used as eluents) to obtain pure product 6.
CH3CN, rt, 4 h
O
S
5, 71% yield
OMe
O
S
O
O
F
MeO
OMe
4baa
(1.2 equiv)
O
O
S
FeCl3 (10 mol%)
DCM, rt, 8 h
F
S
6, 62% yield
bactericidal agent analogue
Acknowledgements
N
F
O
7 (bactericidal agent)
This work was financially supported by the State Key Laboratory
of Geohazard Prevention and Geoenvironment Protection (No.
SKLGP2018Z002) and National Natural Science Foundation of
China (No. 21372034) for their financial support.
Scheme 4. Further transformation of product 4baa to 5 and 6, an analogue to
a bactericidal agent 7.
In summary, we have developed a facile and efficient Brønsted
acid-catalyzed three-component reaction in water to synthesize
aryl(chalcogen-heteroaryl)methyl sulfones in good to very good
Keywords: Sulfones • Sulfuric acid • Three component reaction
• Chalcogen heteroaryl • Bactericidal agent
yields
with
broad
substrate
scope.
Aryl(chalcogen-
heteroaryl)methyl sulfones were synthesized in single step by C-
C and C-S bond formation. We also demonstrated product
transformation to synthesize valuable bactericidal agent analogue
and ketone.
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10.1002/ejoc.202000547
European Journal of Organic Chemistry
COMMUNICATION
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000547
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Ratnakar Reddy Kuchukulla, Qinqin
Tang, Youming Huang, Ze He, Lihong
Zhou, Qingle Zeng*
R'
O
O
S
H2SO4 (0.5 eq.)
Water, 60oC, 7h
R''
O
R''
+
R' SO2Na
+
R
H
X
X
R
Page No. – Page No.
R = H, Alkyl, Aryl, Heteroaryl
R' = Alkyl, Aryl
R'' = H, alkyl, RS, benzo
X = O, S, Se.
* Metal free
* Water as solvent
* Byproduct is water
Synthesis of Aryl(chalcogen-
heteroaryl)methyl Sulfones via
Sulfuric Acid-Promoted Three-
Component Reaction in Water
* 27 exampples, up to 89% yield
A straitforward sulfuric acid-promoted three-component reaction in water for
synthesis of synthesis of aryl(chalcogen-heteroaryl)methyl sulfones was developed.
This article is protected by copyright. All rights reserved.