Metal-Free Synthesis of Sulfones and Sulfoxides through Aldehyde-Promoted Aerobic Oxidation of Sulfides

Article abstract of DOI:10.1007/s10562-021-03706-5

Metal-free aerobic oxidation of aryl sulfides to sulfoxides and sulfones has been developed in the presence of aliphatic aldehydes with excellent selectivity and yields. The reaction proceeded under mild conditions with the catalysis of N-hydroxyphthalimide (NHPI). Control experiments indicated that the reaction underwent a free radical pathway with the acylperoxyl radicals generated from aldehydes in situ as the key intermediates. The aromatic aldehydes were less efficient in the sulfide oxidation, which might be explained by the fact that the aromatic ring dispersed the electrons of free radicals and thus weakened the attacking ability of peroxy free radicals. Graphic Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-021-03706-5

Catalysis Letters
https://doi.org/10.1007/s10562-021-03706-5
Metal‑Free Synthesis of Sulfones and Sulfoxides
through Aldehyde‑Promoted Aerobic Oxidation of Sulfdes
Lingyao Wang1 · Yuanbin Zhang2 · Jia Yao1 · Haoran Li1,2
Received: 29 March 2021 / Accepted: 6 June 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
Abstract
Metal-free aerobic oxidation of aryl sulfdes to sulfoxides and sulfones has been developed in the presence of aliphatic alde-
hydes with excellent selectivity and yields. The reaction proceeded under mild conditions with the catalysis of N-hydroxyph-
thalimide (NHPI). Control experiments indicated that the reaction underwent a free radical pathway with the acylperoxyl
radicals generated from aldehydes in situ as the key intermediates. The aromatic aldehydes were less efcient in the sulfde
oxidation, which might be explained by the fact that the aromatic ring dispersed the electrons of free radicals and thus weak-
ened the attacking ability of peroxy free radicals.
Graphic Abstract
Keywords Sulfde · Aerobic oxidation · N-hydroxyphthalimide · Aldehyde · Radical
1 Introduction
industry [7–13]. Therefore, it is enticing and necessary to
explore green and mild catalytic system for the controllable
oxidation of sulfdes, particularly under sustainable metal-
free conditions with air or oxygen as the oxidant.
Organic sulfones and sulfoxides are important oxygen-con-
taining compounds that widely exist in natural products,
pharmaceuticals, and favors [1–3]. While many organic
methodologies have been developed for the synthesis of
sulfones and sulfoxide [4–6], the direct and selective oxi-
dation of sulfde to sulfone and sulfoxide remains the most
useful and practical method in biology and pharmaceutical
To date, the direct oxidation of organic substrates by
the combined use of molecular oxygen and aldehyde has
attracted a lot of attention [14–19]. The O2/aldehyde/N-
hydroxyphthalimide (NHPI) system has been developed by
us and other groups for the efcient epoxidation of alkene
(Scheme 1a), C–H oxidation of alkane, and Baeyer–Vil-
liger oxidation of ketone (Scheme 1b) [20–22]. The oxi-
dation of sulfdes to sulfoxides and sulfones has also been
achieved by the aldehyde–O2 system. However, much exces-
sive aldehydes (4 ~ 64 equiv.) were required to completely
consume the sulfdes as well as to provide reasonable yield
and selectivity. For example, Venkateshwar Rao et al. [23,
24] reported the co-oxidation of acyclic sulfdes with the
* Haoran Li
lihr@zju.edu.cn
1
Department of Chemistry, ZJU-NHU United R&D
Center, Zhejiang University, Hangzhou 310027,
People’s Republic of China
2
State Key Laboratory of Chemical Engineering, Department
of Chemical and Biological Engineering, Zhejiang
University, Hangzhou 310027, People’s Republic of China
Vol.:(0123456789)
1 3

L. Wang et al.
Scheme 1 Oxidation promoted by NHPI/RCHO system
aldehyde/O2 system, where 8–64 equiv. of aldehydes were
necessary. Murata et al. [25] found that the aerobic oxida-
tion of dibenzothiophene into sulfone could be achieved
under the catalysis of Co(OAc)2 or CoCl2 using 4 equiv. of
n-octanal. Tada et al. [26] studied the sulfoxidation reac-
tion using a SiO2-supported Ru complex in the presence of
O2 and aldehydes. Our group [27] developed a recoverable
photocatalytic system for the selective oxidation of sulfdes
to sulfoxides by utilizing O2/isopropyl aldehyde/mpg-C3N4
without transition metals. Herein, we would like to report
our consequent study on the mild oxidation of sulfdes to sul-
foxides and sulfones adopting the O2/aldehyde/NHPI system
in the absence of metal catalysts (Scheme 1c).
(EtOAc) were analytical grade and purchased from J & K
Scientifc Ltd.
2.2 General Methods
The reaction was monitored by taking samples at vari-
ous intervals using gas chromatography (GC) (Agilent
7820 A) equipped with a DB-35/ZB-35/HP-35 column
(30 m×0.32 mm×0.25 mm) and a fame ionization detector
(FID) for analysis. The conversion and yield were calculated
on the basis of the peak area ratio of sulfde, sulfone and
sulfoxide against the internal standard, biphenyl.
2.3 General Procedure for Sulfde Oxidation
2 Experiments
In a typical reaction, sulfdes (2 mmol), n-butylaldehyde
(6 mmol), NHPI (5 mol%) and DCE (3 g) were placed into
a three-necked round bottom fask (10 mL) ftted with an
oxygen balloon and a magnetic stir bar. The reaction mixture
was stirred at 40 °C for 24–36 h and monitored by GC.
2.1 Materials
Diphenyl sulfide (DPS) (> 99.0%), diphenyl sulfoxide
(> 99.0%), diphenyl sulfone (> 99.0%), n-butyraldehyde
(99.5%), acetaldehyde (98%), propionaldehyde (98%), isobu-
tyraldehyde (99%), valeraldehyde (99%), 3-methyl butanal
(> 99.0%) and were purchased from TCI without further
purifcation unless indicated. 1,1,1,3,3,3-Hexafuoro-2-pro-
panol (HFIP) (99%), trifuoroethanol (TFE) (99%), 4-phe-
nylacetaldehyde (PhCH2CHO) (98%), biphenyl (99.5%),
benzaldehyde (PhCHO) (98%), 4-nitrobenzaldehyde (98%),
NHPI (98%), and 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) (98%), were purchased from Energy Chemical
without further purifcation unless indicated. 1,2-Dichloro-
ethane (DCE), dichloromethane (DCM), carbon tetrachlo-
ride (CCl4), acetonitrile (MeCN), toluene and ethyl acetate
2.4 General EPR Experiments
To a 50 mL three-necked round bottom glass fask equipped
with a water-cooled refux condenser, a magnetic stir bar
and an oxygen balloon was added 6 mmol of n-butylalde-
hyde, 0.1 mmol NHPI and 20 mL of DCE. The mixture was
stirred at 40 °C for 30 min at atmospheric pressure. The
EPR spectra of the reaction solution (Fig. 2a, black) were
recorded using a computer-controlled X-band (9.5 GHz)
EPR spectrometer (Bruker A300). Then, 2 mmol of DPS
was added into the mixture and the mixture was stirred for
another 30 min. Thereafter, EPR signals were measured
1 3

Metal-Free Synthesis of Sulfones and Sulfoxides through Aldehyde-Promoted Aerobic Oxidation…
immediately upon addition of 2 mmol of DPS into the reac-
tion system (Fig. 2b, black). The reaction was continued for
30 min before measuring GC (Fig. 2d, black).
The efects of diferent aldehydes on the NHPI-promoted
oxidation of DPS were investigated. (Table 2). Among the
aldehydes studied, n-butyraldehyde and propionaldehyde
were found with the most positive efect, leading to the
complete oxidation to sulfone DPSO2 at 40 °C within 24 h
(entries 1 and 4). Acetaldehyde was less efcient. Only
DPSO was detected in the presence of acetaldehyde under
the same catalytic conditions with a conversion of 3% for
24 h and 15% for 52 h (entries 2, 3). Branched aliphatic
aldehydes, such as isobutyraldehyde and 3-methyl butanal,
were more favorable for the formation of DPSO (entries 5,
7) while linear aliphatic aldehyde valeraldehyde ofered the
DPSO2 as the major product (entry 6). It is interesting to
note that aromatic aldehydes were inactive in the sulfde oxi-
dation reaction system (entries 8–11). This result was oppo-
site to the trend in the Baeyer–Villiger oxidation reaction
with the O2/aldehyde/NHPI system [20]. To verify whether
the carbonyl group conjugated with an aromatic ring had
a negative efect on the reaction, we took PhCH2CHO as
a sacrifce to carry out same the experiment. The results
suggested that PhCH2CHO was efective for sulfoxidation
and even better than acetaldehyde (entries 12, 13). This indi-
cated that only aromatic ring directly conjugated with the
carbonyl group weakened the activity of aldehyde. Notably,
n-butyraldehyde is a highly cost-efective aldehyde and the
conversion of n-butyraldehyde into the corresponding acid
is a value increasing process. Considering the economic ef-
ciency, it is very promising to use n-butyraldehyde as a can-
didate of the sacrifcial materials in the practical application.
To a 50 mL three-necked round bottom glass flask
equipped with a water-cooled refux condenser, a magnetic
stir bar and an oxygen balloon was added 2 mmol of DPS,
6 mmol of n-butylaldehyde, 0.1 mmol NHPI and 20 mL of
DCE. The mixture was stirred at 40 °C for 30 min at atmos-
pheric pressure. The EPR spectra of the reaction solution
(Fig. 2c, black) were obtained immediately. n-Butylaldehyde
was replaced by t-butylaldehyde (red) and PhCHO (blue),
respectively.
A 20 μL of reaction solutions was adopted at certain time
and mixed with 5,5-dimethyl-1-pyrroline N-oxide (DMPO)
solution (0.1 M in phosphate bufer saline) of equivalent
volume. After shaking for 3 min, the mixture was injected
into a capillary and tested at room temperature in the pres-
ence of n-butylaldehyde (Fig. 3, black) and t-butylaldehyde
(Fig. 3, red), respectively.
3 Results and Discussion
3.1 Oxidation of DPS
DPS, 2 mmol, was initially used as a model substrate for
study. The results were summarized in Table 1. The aerobic
oxidation reaction was frst performed with NHPI (5 mol%)
and n-butyraldehyde (3 equiv.) in MeCN (3 g) at 40 °C.
The conversion of DPS was 71% with a 98% selectivity of
diphenyl sulfoxide (DPSO) and a 2% selectivity of diphe-
nyl sulfone (DPSO2) (entry 1, Table 1). It was found the
reaction medium had a signifcant efect on the reaction
efciency. Among the solvents of MeCN, toluene, EtOAc,
TFE, HFIP, CCl4, DCM and DCE, DCE was the most efec-
tive for the reaction (entries 1–7, 10). Reducing the DCE
amount to 1 or 2 g, the yield of DPSO2 decreased to 23%
and 34%, respectively (entries 8, 9). The yield of DPSO2
remained unchanged when the DCE amount increased to
4 or 5 g (entries 11, 12). The dual decrease of temperature
to 25 °C and reaction time to 6 h resulted in the increase of
DPSO (91% yield) but the decrease of DPSO2 (9% yield)
(entry 13). Prolonging the reaction time to 24 h, the yield of
DPSO decreased to 61% while the yield of DPSO2 increased
to 39% (entry 14). When a blank reaction was carried out
without NHPI or n-butyraldehyde, the reaction hardly pro-
ceeded (entry 15). Thus, it is likely that NHPI/n-butyralde-
hyde system had a great impact on the oxidation of sulfde.
n-Butyraldehyde as the sacrifce was vital to the reaction.
Reducing the amount of n-butyraldehyde led to a decrease
of DPSO2 yield but an increase of DPSO selectivity in the
presence or absence of NHPI (entries 16–19).
3.2 Substrate Scope of Sulfone and Sulfoxide
With the optimal reaction conditions in hand, the scope of
sulfde oxidation was investigated. A plenty of substituted
sulfdes were tested using the standardized reaction condi-
tions. The results were summarized in Table 3. Both ali-
phatic and aromatic sulfdes were efciently converted into
sulfones with nearly quantitative yield in 24–36 h.
3.3 Mechanistic Studies
The time-course experiments of the diphenyl sulfde oxi-
dation at diferent temperatures were conducted with the
results shown in Fig. 1.
The results at 40 °C indicated that formation of the oxida-
tion products increased with time (Fig. 1a). With the conver-
sion of diphenyl sulfde, the selectivity of sulfoxide gradu-
ally decreased, while the selectivity of sulfone gradually
increased. Almost all of the diphenyl sulfde was consumed
after 2.5 h with similar selectivity of sulfoxide and sulfone.
After 24 h, all the sulfoxide and aldehyde were converted to
sulfone and acid, respectively. The reaction was much more
slowly at 25 °C (Fig. 1b). After 24 h of the reaction, the fnal
1 3

L. Wang et al.
Table 1 Optimization of conditions
O
S
O
O
S
Catalyst
Solvent
S
O2
+
+
1a
2a
3a
Entry
Solvent (g)
Temp. (°C)
Time (h)
Conv.a
Select.a
2a (%)
Aldehyde (%)
1a (%)
3a (%)
1
2
3
4
5
6
7
8
MeCN (3)
Toluene (3)
EtOAc (3)
TFE (3)
40
40
40
40
40
40
40
40
40
40
40
40
25
25
25
40
40
40
40
24
24
24
24
24
24
24
24
24
24
24
24
6
24
24
24
24
24
24
42
76
81
20
Trace
26
66
62
74
100
100
100
55
71
94
100
12
Trace
17
100
100
100
100
100
100
100
100
Trace
100
66
98
94
27
98
N.D
52
73
77
66
0
2
4
70
0
N.D
6
27
23
34
100
100
100
9
39
N.D
25
9
HFIP (3)
CCl4 (3)
DCM (3)
DCE (1)
DCE (2)
DCE (3)
DCE (4)
DCE (5)
DCE (3)
DCE (3)
DCE (3)
DCE (3)
DCE (3)
DCE (3)
DCE (3)
9
10
11
12
13
14
15b
16c
17d
18e
19f
0
0
91
61
N.D
73
91
95
99
76
Trace
100
100
30
59
18
4
1
27
Conditions: diphenyl sulfde (1a) (2 mmol), NHPI (5 mol%), n-butyraldehyde (3 equiv.), solvent, O2 balloon
aDetermined by GC chromatography
bWithout NHPI and n-butyraldehyde
cn-butyraldehyde (2 equiv.)
dn-butyraldehyde (1 equiv.)
eWithout NHPI, n-butyraldehyde (2 equiv.)
fWithout NHPI, n-butyraldehyde (1 equiv.)
yields of sulfoxide and sulfone were 61% and 39%, respec-
tively. And the conversion of aldehyde was 76%.
oxidative products 2a and 3a. And the conversion of reac-
tant was 100% with the selectivities of corresponding
18O-labeled oxidative products in 52% and 48%, respectively
(Scheme 2b). This indicated that the oxygen atom of the
products originated from molecular oxygen. Under stand-
ard conditions, DPSO could be transformed into DPSO2
in > 99% yield, suggesting that the generation of sulfones
underwent the sulfoxide intermediate (Scheme 2c).
3.3.1 Control Experiments
To give some insight into the reaction mechanism of the
oxidation procedure, several control experiments were con-
ducted. The addition of 10 mol% of the generally used radi-
cal scavenger, TEMPO, nearly completely suppressed the
model reaction, which supported the free radical reaction
pathway [8, 28] (Scheme 2a). To track the oxygen source,
the model reaction was conducted under an 18O2 atmos-
phere. All the products were the corresponding 18O-labeled
3.3.2 EPR Evidence
A series of EPR experiments were conducted to reveal the
radicals involved in the reaction. As benzoylperoxyl radical
1 3

Metal-Free Synthesis of Sulfones and Sulfoxides through Aldehyde-Promoted Aerobic Oxidation…
Table 2 Efect of diferent
aldehydes in the oxidation of
diphenyl sulfde
Entry
Aldehyde
Temp. (°C)
Time (h)
Conv.a (%)
Select.a
2a (%)
3a (%)
1
2
3
4
5
6
7
8
n-Butyraldehyde
Acetaldehyde
Acetaldehyde
Propionaldehyde
Isobutyraldehyde
Valeraldehyde
3-Methyl butanal
Benzaldehyde
4-Chlorbenzaldehyde
4-Nitrobenzaldehyde
4-Hydroxybenzaldehyde
Phenylacetaldehyde
Phenylacetaldehyde
40
40
40
40
40
40
40
40
40
40
40
40
40
24
24
52
24
24
24
24
24
24
24
24
24
48
100
3
15
100
99
100
100
Trace
Trace
Trace
Trace
85
0
>99
0
0
>99
10
96
>99
>99
0
88
4
56
44
N.D
N.D
N.D
N.D
>99
87
N.D
N.D
N.D
N.D
0
9
10
11
12
13
100
13
Conditions: diphenyl sulfde (1a) (2 mmol), NHPI (5 mol%), aldehyde (3 equiv.), Solvent, O2 balloon
aDetermined by GC chromatography
Table 3 Oxidation of organic sulfdes
Entry
Substrates
Time
Conv. (%)
Select. (%)
Sulfone
S
1
2
3
24
24
36
100
100
100
>99
>99
>99
S
S
Cl
S
4
36
100
>99
could oxidize NHPI to PINO, there was a strong radical sig-
nal from PINO (A = 4.72 G, g = 2.0069) when combining
PhCHO and NHPI. Without DPS, the signal intensity of
PINO under the reaction conditions of diferent aldehydes
was in the order of PhCHO>n-butyraldehyde>isobutyral-
dehyde (Fig. 2a). After adding DPS into the solution, the
PINO signal immediately vanished (Fig. 2b). By the pre-
heating method, the conversion of DPS at t=30 min with
n-butyraldehyde, isobutyraldehyde and PhCHO was 45%,
31% and 41%, respectively (Fig. 2d). This result was dif-
ferent from that obtained from the typical procedure used
for sulfde oxidation, where PhCHO was not efective at all.
Such phenomenon suggested that the oxidation of aromatic
aldehyde was hampered by sulfdes while preheating aro-
matic aldehyde for some time could initiate the aromatic
acyl radicals, which can be used for promoting the oxida-
tion of sulfde. When sulfde was added at the beginning of
the reaction, the PINO signal could not be detected by EPR
after the reactant was heated and stirred for 30 min (Fig. 2c).
Fig. 1 Time-course of the diphenyl sulfde oxidation with NHPI in
DCE. a 40 °C; b 25 °C
To gain more direct evidences of the existence of radi-
cal intermediates, the EPR experiments with the assistance
of spin trap technique using DMPO as the spin trap agent
were conducted [29]. As shown in Fig. 3, a clear signal
1 3

L. Wang et al.
Scheme 2 Control experiments
a Radical trapping experiments under O
2
O
S
TEMPO/NHPI/
O
O
S
S
BuCHO
O2
+
+
DCE
40 °C, 24h
1a (2.4%)
2a (98.2%.)
3a (0%.)
O
S
O
O
TEMPO
S
S
BuCHO
O2
+
+
DCE
40 °C, 24h
1a (0%)
2a (0%)
3a (0%)
b Isotope labeling experiment with 18O2
18O
18O 18O
NHPI
S
S
S
BuCHO
18O2
+
+
DCE
40 °C, 2h
18O2-2a (52%)
18O2-3a (48%)
1a (100%)
GCMS of 18O2-2a calcd for 18C12H9OS [M] 204.28, found 204.10
GCMS of 18O2-2a calcd for 18C12H9O2S [M] 222.28, found 222.10
c Intermediate probe experiment
O
O
O
NHPI
S
S
BuCHO
O2
+
DCE
40 °C, 18h
3a(> 99%)
2a (100%)
of DMPOX [g = 2.007, aN = 6.8 G, aH = 3.9 G (2H)] that
was oxidized by the peroxy radical in the presence of
n-butyraldehyde was observed. Meanwhile, a weak tri-
plet signal (g = 2.005, aN = 14.4 G, aHγ = 1.5 G) was found
when the addition of DMPO was performed in the pres-
ence of t-butyraldehyde (Fig. 3, red line).
sulfoxide and acylacid. And the sulfoxide would be further
oxidized to the sulfone with oxygen.
4 Conclusions
We speculated that this radical species may be the
double adducts of DMPO and isobutyryl radical. It was
inferred that the linear fatty aldehyde was more active than
the branched.
In conclusion, we have developed a facile and green meth-
odology for the selective synthesis of sulfones and sul-
foxide by aerobic oxidation of sulfde in the presence of
NHPI and n-butyraldehyde. The simplicity in operation,
mild conditions, applicability make this procedure highly
attractive. Moreover, n-butyraldehyde is very cost efec-
tive and the conversion into the corresponding acid is also
a value increasing process. Therefore, it is promising to
use n-butyraldehyde as a potential sacrifcial material for
practical applications in organic synthesis and chemical
industry.
Based on the above experimental results as well as the
previous literature, a possible radical chain mechanism
pathway was proposed in Fig. 4. First of all, the aldehyde
was initiated by the PINO hydrogen abstraction to form an
acyl radical (I), which readily reacted with O2 to produce an
acylperoxyl radical (II). The acylperoxyl radical (II) formed
in situ acylperoxyacid (III) that attacked the sulfde with
NHPI to generate the adduct intermediate (IV). Through the
rearrangement, the intermediate (IV) converted to intermedi-
ate (V) which undergo O–O bond dissociation to produce the
1 3

Metal-Free Synthesis of Sulfones and Sulfoxides through Aldehyde-Promoted Aerobic Oxidation…
Fig. 2 EPR spectra of the mixture of NHPI and n-BuCHO (black), t-BuCHO (red) and PhCHO (blue): a in the absence of DPS for 30 min; b
adding DPS after 30 min; c in the presence of DPS for 30 min. d DPS oxidation results after (b) for 30 min
Fig. 3 EPR spectrum of the DMPOX species (black) and the DMPO-
double adduct (red)
1 3

L. Wang et al.
Fig. 4 Proposed mechanism
O
N
δ−
O
H
H
N
O
O
H
O
O
Alkyl
δ−
O
H
O
δ−
O
Alkyl
Alkyl
OH
(IV)
S
S
R1
R2
R1
R2
δ+
(V)
O
S
NHPI
S
R1
R2
R1
R2
O
O
OH
(III)
O
Alkyl
O
Alkyl
OH
O
O2
O2
N
N
O
O
O
NHPI
PINO
S
O
R1
R2
O
(II)
Alkyl
initiation
Alkyl
H
(I)
Supplementary Information The online version contains supplemen-
atom: applications in asymmetric synthesis. Chem Rev 117:4147–
4181. https://doi.org/10.1021/acs.chemrev.6b00517
tary material available at https://doi.org/10.1007/s10562-021-03706-5.
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Acknowledgements This work was supported by the National Natural
Science Foundation of China (Grant No. 22073081), and the Funda-
mental Research Funds for the Central Universities. L. Wang gratefully
acknowledge the fnancial support for this research by the Zhejiang
Province Postdoctoral Science Foundation (Grant No. ZJ2020159).
Declarations
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(2017) Efective utilization of in situ generated hydroperoxide by
a Co–SiO2@Ti–Si core-shell catalyst in the oxidation reactions.
ACS Catal 8:683–691. https://doi.org/10.1021/acscatal.7b03259
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Conflict of interest The authors declare that they have no confict of
interest.
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