K2S2O8-mediated decarboxylative oxysulfonylation of cinnamic acids: A transition-metal-free synthesis of β-keto sulfones

Article abstract of DOI:10.1016/j.tetlet.2019.150964

A new paradigm of the oxidative decarboxylative sulfono functionalization of cinnamic acids with sulfinate salts mediated by K₂S₂O₈ under aerobic conditions to afford synthetically and biologically relevant β-keto sulfones has been described. It is the first report on the transition-metal-free synthesis of β-keto sulfones from cinnamic acids, which employs environmentally benign, readily available and inexpensive starting materials and oxidants, viz. air and K₂S₂O₈.

Full text of DOI:10.1016/j.tetlet.2019.150964

Accepted Manuscript
K2S2O8-mediated decarboxylative oxysulfonylation of cinnamic acids: A tran-
sition-metal-free synthesis of β-keto sulfones
Ruchi Chawla, Ritu Kapoor, Lal Dhar S. Yadav
PII:
S0040-4039(19)30715-4
https://doi.org/10.1016/j.tetlet.2019.150964
150964
DOI:
Article Number:
Reference:
TETL 150964
Tetrahedron Letters
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Accepted Date:
7 June 2019
17 July 2019
19 July 2019
Please cite this article as: Chawla, R., Kapoor, R., Yadav, L.D.S., K2S2O8-mediated decarboxylative
oxysulfonylation of cinnamic acids: A transition-metal-free synthesis of β-keto sulfones, Tetrahedron Letters
(2019), doi: https://doi.org/10.1016/j.tetlet.2019.150964
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Graphical Abstract
K2S2O8-mediated decarboxylative oxysulfonylation
of cinnamic acids: A transition-metal-free
synthesis of β-keto sulfones
Leave this area blank for abstract info.
Ruchi Chawla, Ritu Kapoor, Lal Dhar S. Yadav
COOH
O
O
S
O
R1
K2S2O8
R2
S
R2
Na
O2
(air)
O
DMF, 100 oC
-CO2
O
R1
17 examples
up to 93% yield

1
Tetrahedron Letters
journal homepage: www.elsevier.com
K2S2O8-mediated decarboxylative oxysulfonylation of cinnamic acids: A transition-
metal-free synthesis of β-keto sulfones
Ruchi Chawla, Ritu Kapoor, Lal Dhar S. Yadav*
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
*Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533; E-mail: ldsyadav@hotmail.com (L.D.S. Yadav).
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new paradigm of the oxidative decarboxylative sulfono functionalization of cinnamic acids
with sulfinate salts mediated by K2S2O8 under aerobic conditions to afford synthetically and
biologically relevant β-keto sulfones has been described. It is the first report on the transition-
metal-free synthesis of β-keto sulfones from cinnamic acids, which employs environmentally
benign, readily available and inexpensive starting materials and oxidants, viz. air and K2S2O8.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Cinnamic acids
Decarboxylative
β-Keto sulfones
Aerobic oxidation
Oxidative coupling, the coupling of two nucleophilic
reagents with the help of oxidants, is a rapidly thriving field [1].
Particularly, the decarboxylative coupling reactions of α,β-
unsaturated carboxylic acids have drawn significant attention
over the last few years [1e,2].Their straightforward preparation
using Perkin reaction, simple handling, non-toxicity, cost-
effectiveness and stability to air and moisture, in general, make
cinnamic acids attractive starting materials in organic synthesis.
Moreover, the credibility of the decarboxylative coupling
reactions is also leveraged by the ease of their operation and
formation of relatively less toxic by-products.
sulfonylation/cyclization cascade (Scheme 1b) [4a]. To the best
of our knowledge, there is no report in the literature on the
transition-metal-free oxidative coupling of α,β-unsaturated
carboxylic acids with sulfinate salts, which can lead to the
synthesis of valuable β-keto sulfones.
elimination
R'
R
R'
olefination product
CO2
COOH
COOA
R
R
addition
O
OH, O2
R'
R'
R
oxidation-
elimination
R' = Alkyl, nitro, sulfonyl etc.
oxyfunctionalized
product
A = Metal catalyst, stoichiometric
hypervalent iodine reagent (HIR) etc.
The C=C bond in α,β-unsaturated carboxylic acids is an
extra reactive site, which is highly susceptible to attack by
radicals. Under suitable conditions, radical attack followed by
decarboxylation or oxidation and decarboxylation lead to
olefination or oxyfunctionalized products, respectively (Fig. 1)
[1e]. However, reports on the synthesis of the latter products via
oxidative decarboxylative coupling are relatively scarce. In
addition, extensive work has been done in the field of
decarboxylative coupling reactions for the formation of C-C
bonds but the number of reports on the C-S bond formation is
limited [3]. All the previous reports on the decarboxylative
coupling reaction of α,β-unsaturated carboxylic acids leading
to C-S bond formation employ the coupling of these acids with
sulfonyl radical precursors to obtain vinyl sulfones via the
olefinic route under transition-metal [4] as well as transition-
metal-free conditions [5] (Scheme 1a). Based on this strategy,
Liu et al. reported a synthesis of 2-sulfonylbenzo[b]furans from
trans-2-hydroxycinnamic acids and sodium sulfinates mediated
by the CuCl2.2H2O/AgTFA system via a protodecarboxylation/
Fig. 1 Radical functionalizations of α,β-unsaturated carboxylic acids.
β-Keto sulfones, as a class of organosulfur compounds, are
well-recognized for their synthetic and biological importance
[6]. As building blocks, they are used for the synthesis of γ-
sulfonyl δ-lactones, β-sulfonyl styrenes, polyfunctionalized 4H-
pyrans,
quinolines,
sulfonyl
phenanthrenes
and
vinylcyclopropanes [7]. As regards their biological significance,
they are bestowed with exceptional pharmaceutical properties
such as anti-fungal, anti-bacterial, inhibitors of LpxC, MMP
and CES1 [8]. Accordingly, a number of methods have been
developed for the synthesis of β-keto sulfones [9]. However, the
decarboxylative sulfonylation approach for their synthesis is
only limited to the use of arylpropiolic acids [9b,d] and β-keto
acids [9f] as their precursors. α,β-Unsaturated carboxylic acids
have never been used to synthesize β-keto sulfones under
transition-metal-free conditions. Nevertheless,
a
CuBr2-

2
catalyzed decarboxylative oxysulfonylation of arylacrylic acids
using sulfinic acids has been reported for their synthesis by Lei
et al. in 2015 [10].Transition-metal-free conditions are highly
desirable in the pharmaceutical industry because it makes any
protocol free from the adverse traits of transition-metals, viz.
toxicity, sensitivity to air or moisture and need of additional co-
catalysts/ligands. All the above facts and our previous work on
the synthesis of sulfones [11] inspired us to develop a
transition-metal-free protocol for the synthesis of β-keto
sulfones from α,β-unsaturated carboxylic acids and sodium
sulfinates mediated by K2S2O8 under aerobic conditions
(Scheme 1d).
establishing DMF as the best solvent for our developed
protocol. When the temperature of the reaction was increased to
100 C, the yield of the product improved to 83% (entry 13).
o
Increasing the reaction time to 14 hours produced no significant
change in the yield of 3a (entry 14) but decreasing the reaction
time to 10 hours was detrimental to the yield (entry 15). On
dilution, the yield of the product decreased (entry 16), whereas
when 3 mL of DMF was used, the reaction became more
complex (entry 17).
Table 1
Optimization of experimental conditionsa
a) Synthesis of vinyl sulfones
COOH
O
O
S
O
R
O
O
oxidant
COOH
O
O
S
S
O2
(air)
Na
Ref. 4 & 5
O
solvent, temp.
S
R
O
Ar
1a
2a
3a
Ar
(Sodium sulfinates,
sulfonyl hydrazides etc.)
b) Liu's work4a
Entry
Oxidant
Solvent
Temper
Time
(h)
Yield
(%)b
-ature
(oC)
80
80
80
80
80
80
80
80
80
80
80
CuCl2.2H2O
AgOCOCF3
COOH
R
SO2R'
R
R'SO2Na
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16d
17e
K2S2O8 (1.5 mmol)
Na2S2O8 (1.5 mmol)
(NH4)2S2O8 (1.5 mmol)
KHSO5 (1.5 mmol)
DTBP (1.5 mmol)
-
K2S2O8 (2.0 mmol)
K2S2O8 (1.0 mmol)
K2S2O8 (1.5 mmol)
K2S2O8 (1.5 mmol)
K2S2O8 (1.5 mmol)
K2S2O8 (1.5 mmol)
K2S2O8 (1.5 mmol)
K2S2O8 (1.5 mmol)
K2S2O8 (1.5 mmol)
K2S2O8 (1.5 mmol)
K2S2O8 (1.5 mmol)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
H2O
Toluene
MeCN
DMF
DMF
DMF
DMF
DMF
12
12
12
12
12
12
12
12
12
12
12
12
12
14
10
12
12
68
32
30
O
Cs2CO3, DMF
OH
c) Lie's work10
61
18c
n.d.
70
O
O
HOOC
Ar
O
R
CuBr2 (10 mol %)
rt, DMF
S
O2
(air)
S
R'
O
Ar
R'
O
HO
R
47
65
traces
25
32
88
89
71
66
d) Present work
COOH
O
O
R1
S
K2S2O8
S
R2
R2
O
Na
O2
(air)
80
DMF, 100 o
C
O
R1
100
100
100
100
100
Scheme 1. Decarboxylative sulfonylation of α,β-unsaturated
carboxylic acids.
59
At the outset of our investigation, a model reaction was set
up between cinnamic acid 1a (1.0 mmol) and sodium benzene
sulfinate 2a (1.5 mmol) using K2S2O8 (1.5 mmol) as an oxidant
a
Reaction conditions: 1a (1.0 mmol), 2a (1.5 equiv.), oxidant,
solvent 5 mL, in an open-flask.
b Isolated yield, n.d. = not detected.
c Corresponding vinyl sulfone was obtained in 57% yield.
d Solvent 7 mL.
o
in DMF (5 mL) at 80 C in an open flask. To our satisfaction,
the desired β-keto sulfone 3a was formed in 68% yield in 12
hours (Table 1, entry 1). Encouraged by this preliminary
success, we next focused our efforts towards the optimization of
the reaction conditions. Since the external oxidant was the
cornerstone of our strategy, we first scrutinized other oxidants
for our protocol which included Na2S2O8, (NH4)2S2O8, KHSO5
and DTBP but none of them was found to be more effective
than K2S2O8 (entries 2-5 versus entry 1). In fact, in the
presence of DTBP, vinyl sulfone was obtained as the major
product (entry 5). The product formation could not be detected
in the absence of any oxidant (entry 6). Therefore, K2S2O8, an
inexpensive, readily available and versatile inorganic oxidant
[12], remained our choice for the role of an oxidant in the
reaction. Any further increase in the amount of the oxidant did
not affect the yield of 3a much (entry 7) but a decrease in the
amount of K2S2O8 to 1.0 mmol led to a substantial decrease in
the yield (entry 8).
e Solvent 3 mL.
After deciding the optimal reaction conditions, our next goal
was to examine the substrate scope of the reaction with respect
to both the starting materials (Table 2). Cinnamic acids with
both electron-donating or -withdrawing group and halogens on
the phenyl ring reacted with sodium benzene sulfinate to
produce the desired sulfones 3a-h in good to excellent yields
(74-93%). The developed protocol could be successfully
applied irrespective of the position of the methoxy group at the
ortho-, meta- or para- position of the aryl ring in cinnamic
acids with not much difference in the efficiency of the
transformation (3c-e). The heterocyclic derivative, 3-(pyridin-2-
yl)acrylic acid and the corresponding alkyl derivative (hex-2-
enoic acid) of cinnamic acid were not amenable to our oxidative
decarboxylative protocol (compounds 3i and j). Similarly, in
the case of sulfinate salts, a broad range of substituents on the
aromatic ring were well tolerated (3k-o). In general, the
sulfinate salts with electron-donating groups on the aryl ring
gave better yield of the products (3k and 3l) than those with
electron-withdrawing groups on the ring (3m-o). The
methodology could be extended successfully to naphthyl (3p)
and alkyl sulfinates (3q) as well.
In order to decide the best solvent, the model reaction was
also performed using different solvents (entries 9-12). Decent
yield of the product was obtained in DMSO (entry 9) but the
aqueous environment was not conducive to the formation of
product (entry 10) which is in accordance with earlier
observations [13]. Low yield of the product in toluene (entry
11) and MeCN (entry 12) can be attributed to the low solubility
of the model substrate/reagent in these solvents, thus

3
In view of gaining insight into the mechanism of the
reaction, a number of control experiments were performed
(Scheme 2). In the presence of 2 equivalents of TEMPO
basis of literature precedents [13], a tentative mechanism has
been proposed in Scheme 3. Initially, K2S2O8 oxidizes sulfinate
salt to sulfone radical I. The attack of radical I on cinnamic acid
with ensuing addition of atmospheric oxygen would produce
the peroxide radical II. The decomposition of II could form the
radical intermediate III, which is subsequently transformed into
IV by K2S2O8. Then, the compound IV undergoes
decarboxylation via the cyclization process under the standard
conditions to give V, which finally ketonises to the product 3.
(2,2,6,6-tetramethyl-1-piperidinyloxyl)
under
standard
conditions, the product was formed in traces which suggested
a radical pathway (Scheme 2a). In the absence of oxygen (N2
atmosphere), no product formation could be detected (Scheme
2b). On the basis of this result, we concluded that the source of
keto oxygen atom in the synthesized sulfones was atmospheric
oxygen. This was further confirmed by isotopic labeling
experiments (Scheme 2c). With these results in hand and on the
Table 2
Scope of α,β-unsaturated carboxylic acids and sulfinate saltsa
COOH
O
O
S
O
R1
K2S2O8
R2
S
R2
Na
O2
(air)
O
DMF, 100 o
C
O
3b,c
R1
1
2
O
O
S
O
O
S
O
O
S
O
O
O
MeO
3c, 83%
3a, 88%
3b, 85%
O
O
OMe O
O
S
O
O
S
MeO
S
O
O
O
F
3e, 74%
3f, 90%
3d, 85%
O
O
O
O
S
O
O
S
S
O
O
O
N
Cl
Br
3g, 93%
3i, trace
3h, 84%
O
O
S
O
O
S
O
O
S
O
O
O
OMe
3j, 0%
O
3k, 86%
3l, 83%
O
S
O
O
S
O
O
S
O
O
O
F
Cl
Br
3n, 79%
3o, 82%
3m, 76%
O
O
O
O
S
S
O
O
3q, 46%
3p, 68%
a For experimental procedure, see Supplementary data.
b Isolated yield of the purified products 3.
c All compounds gave satisfactory spectral (1H NMR, 13C NMR and HRMS) data [9c,10].
a) Evidence in support of radical pathway
COOH
Scheme 2. Control experiments.
In conclusion, we have developed the first transition-
metal-free route to β-keto sulfones from cinnamic acids and
sulfinate salts mediated by K2S2O8. Experimental evidences
suggest that atmospheric oxygen is the source of keto oxygen
atom in the synthesized sulfones and the developed method
O
O
S
O
Standard reaction
conditions
TEMPO (2.0 equiv.)
S
Na
O
O
traces
b) Role of air as the oxidant
COOH
O
O
O
S
Standard reaction
conditions
N2 atmosphere
S
Na
O
O
follows
a
radical pathway. The aerobic oxidative
n.d.
18O
c) 18O-labeling experiment
decarboxylative approach for the synthesis β-keto sulfones
capitalizes on the use of inexpensive, easily accessible and
environmentally benign substrates/oxidant. The use of cinnamic
acids as the precursors to β-keto sulfones under transition-
metal-free conditions is the highlight of the developed protocol.
COOH
O
S
O
Standard reaction
conditions
S
Na
O
O
18O2/N2
70% yield

4
COOH
O
1/2K2S2O8
KNaSO4
R2
1
O
II
O
III
R1
O
S
COOH
SO2R2
COOH
SO2R2
R2SO2Na
2
O
O2
R1
I
R1
1/2O2
1/2K2S2O8
heat
KHSO4
H
O
3
O
O
O
OH
V
SO2R2
COOH
SO2R2
SO2R2
K2S2O8
heat
OH
SO2R2
IV
R1
R1
R1
R1
CO2
Scheme 3. Plausible mechanism for the formation of β-keto sulfones.
(c) C.-K. Chan, Y.-H. Chen, R.-T. Hsu, M.-Y. Chang, Tetrahedron
73 (2017) 46;
(d) J.L. Marco, J. Org. Chem. 62 (1997) 6575;
(e) J.-L. Marco, L. Fernández, N. Khiar, P. Fernández, A. Romeros,
J. Org. Chem. 60 (1995) 6678;
Acknowledgements
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9182.
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing spectra.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/xxxxxxxxxxxxxxxxxxx.
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Highlights
 Metal-free one-pot approach to β-keto sulfones.

5
 Use of air and K2S2O8 as eco-friendly and
inexpensive oxidants.
 Decarboxylative oxysulfonylation of cinnamic
acids.
 A synthetically useful radical pathway is
developed.