Modulation of photochemical oxidation of thioethers to sulfoxides or sulfones using an aromatic ketone as the photocatalyst

Article abstract of DOI:10.1016/j.tetlet.2021.153376

We have developed an eco-friendly and chemo-selective photocatalytic synthesis of sulfoxides or sulfones via oxidation of sulfides (thioethers) at ambient temperature using air or O₂ as the oxidant. An inexpensive thioxanthone was used as the photocatalyst. Our method offers excellent chemical yields and good functional group tolerance. The hydrogen bonding between hexafluoro-2-propanol (HFIP) and sulfoxides may play an important role in minimizing the over-oxidization of sulfoxides.

Full text of DOI:10.1016/j.tetlet.2021.153376

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Modulation of photochemical oxidation of thioethers to sulfoxides or
sulfones using an aromatic ketone as the photocatalyst
Bin Zhao a, Gerald B. Hammond b, Bo Xu a
a Key Laboratory of Science and Technology of Eco-Textiles, Ministry of Education, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University,
Shanghai 201620, China
b Department of Chemistry, University of Louisville, Louisville, KY 40292, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an eco-friendly and chemo-selective photocatalytic synthesis of sulfoxides or sul-
fones via oxidation of sulfides (thioethers) at ambient temperature using air or O2 as the oxidant. An inex-
pensive thioxanthone was used as the photocatalyst. Our method offers excellent chemical yields and
good functional group tolerance. The hydrogen bonding between hexafluoro-2-propanol (HFIP) and sul-
foxides may play an important role in minimizing the over-oxidization of sulfoxides.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 23 July 2021
Revised 20 August 2021
Accepted 25 August 2021
Available online xxxx
Keywords:
Oxidation of thioethers
Aromatic ketone
Visible-light-catalysis
Oxygen
Sulfur-containing molecules are important fragments in natural
products [1–5] and valuable building blocks in organic synthesis
[6–11]. More specifically, sulfoxides (R1SOR2) and sulfones
(R1SO2R2) are essential intermediates in drugs [12–16] and biolog-
ically active molecules [17–19]. Consequently, the synthesis of sul-
foxides [20,21] and sulfones [22–26] has generated significant
attention. The oxidation of sulfides or thioethers (R1SR2) is one of
the most straightforward pathways for the synthesis of sulfoxides.
Common oxidants for sulfide oxidation include hypervalent iodine
reagents [27,28], hydrogen peroxide(H2O2) [29], peroxycarboxylic
acid [30], O3 [31], NaClO [21], K2S2O8 [32], Oxone [33]. Most of
these oxidants are not eco-friendly. In addition, a common issue
is the overoxidation of sulfoxides to sulfones if the conditions are
not well controlled. Developing a tunable and eco-friendly synthe-
sis of sulfoxides and sulfones through chemo-selective oxidation of
the abundant and readily available sulfides is highly desired.
Among chemical oxidants, molecular oxygen is the most abundant
and sustainable oxidant [34]. In 2019, the Liu group [35] proposed
the temperature-controlled selective oxidation of sulfides using
molecular oxygen in ether solvent under heating conditions (Sche-
me 1a). In 2020, He’s group [36] disclosed the oxidation of sulfides
to sulfoxide or sulfones by molecular oxygen; the selectivity was
modulated by different solvents (Scheme 1b). However, these reac-
tions needed high temperatures and flammable organic solvents,
which may create safety issues.
Visible light has served as a clean and renewable chemical
energy source in chemical transformations at ambient tempera-
tures. In 2019, the Jiang group [37] described a uranyl photocat-
alyzed selective oxygenation of sulfides (thioethers) in the
presence of O2 with H3PO4 as the product-dependent additives
(Scheme 1c). In 2020, Suzuki and Yamaguchi [38] reported the vis-
ible-light-responsive switchable oxygenation of sulfides using
tetraphenylphosphonium decavanadate (TPPV10) as the photocat-
alyst in methyl ethyl ketone by simply adding water to control the
product selectivity (Scheme 1d). Very recently, He’s group [39] dis-
closed that time controlled visible-light-induced oxidation that
synergistically catalyzed by CF3SO2Na and 2-butoxyethyl ether
for the switchable preparation of sulfoxides and sulfones
(Scheme 1e).
Recently, our group [40] developed electrochemical selective
oxidation of sulfides using a hydrogen-bonding donor HFIP (hex-
afluoro-2-propanol) as the solvent. The formation of a strong
hydrogen bond between HFIP and sulfoxides prevented the over
oxidation of sulfoxides to sulfones. Based on published reports
and our previous work, we were aware that a cheap and readily
available aromatic ketone could be used as a photocatalyst to acti-
vate molecular oxygen. Herein, we disclose an eco-friendly and
tunable protocol for the preparation of sulfoxides and sulfones
via the oxidation of thioethers (Scheme 1f). The hydrogen bonding
between HFIP and sulfoxides may play an essential role in mini-
mizing the over-oxidization of sulfoxides.
https://doi.org/10.1016/j.tetlet.2021.153376
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: B. Zhao, G.B. Hammond and B. Xu, Modulation of photochemical oxidation of thioethers to sulfoxides or sulfones using an aro-
matic ketone as the photocatalyst, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153376

B. Zhao, G.B. Hammond and B. Xu
Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Literature background.
We selected the oxygenation of sulfide 1r as our model reaction
(Table 1). When the model reaction was carried out under the stan-
dard conditions, the reaction gave a good yield of sulfoxide 2r
(99%) with little over-oxidation (1%) (Table 1, entry 1). As the pho-
tocatalyst was changed from a to other aromatic ketone photocat-
alysts b-d, the conversions were comparable, but the selectivity
was slightly reduced (Table 1, entry 2). Moreover, the reaction
using photocatalyst e only gave a 4% conversion (Table 1, entry
2). Besides, some other commonly used photocatalysts, including
Ir or Ru-based catalysts, organic dyes (Eosin Y, 4CzIPN), show less
efficacy or selectivity (Table 1, entry 3). DMSO, acetone, dioxane, t-
BuOH, MeOH, and THF were not suitable solvents as they gave
lower yields (0% to 55%) (Table 1, entry 4). Reactions in both ACN
and DCM gave 100% conversions, but over-oxidation was observed
(21% and 13%, respectively) (Table 1, entry 5). We also investigated
the effects of catalyst loading (see Table S2 in SI). Notably, the pho-
tocatalyst could be reduced to a very low level (0.01 mol% loading)
(Table 1, entry 6). When longer wavelength light sources were
employed, a compatible yield was found in the reaction under
425 nm LEDs (Table 1, entry 7). As expected, both photocatalyst
and light are essential for the reaction (Table 1, entries 8–9). More
detailed optimization attempts are shown in Tables S1-2 in the
supporting information.
cient or rich) had little effect on this transformation. Functional
groups such as alkyl (2b), halogens (2c, 2d, 2 l), ether (2e, 2 s, 2v,
2w), ester (2 h, 2 m, 2o), amide (2n), –NO2 (2 g, 2 t), –CN (2f), –
CHO (2u), amine (2y) and ketone (2aa) were all well tolerated,
affording good to excellent isolated yields. It should be noted that
the active hydrogens (–OH, –COOH, –NH2) were well tolerated (2i,
2j, and 2p). Heterocycle compounds, such as quinoline (2q), 1H-
indazole (2x), pyridine (2z), and thiophene (2an) worked well
under the standard conditions. Sulfides containing various func-
tional groups, such as primary, secondary, or tertiary alkyl groups
bonded to the sulfur atom directly (2ab – 2ag) were suitable sub-
strates, except a trifluoromethyl containing sulfide (2ag, 30%
yield). Additionally, our protocol also tolerated carbon chains
(2ah, 2aj) or ring (2ai) dialkyl sulfides and sulfides containing nat-
ural product skeletons (2ak). It should be noted that the benzyl
group led to poor yields (2ad and 2aj). Finally, the chemo-selectiv-
ity of this method was investigated in the oxidation of sulfides con-
taining two different sulfur moieties (2an). The oxidation
selectively occurred at the S-1 site, which may be due to this sulfur
having high electron density and being more prone to oxidation.
On the other hand, benzo[b]thiophene, in which the sulfur was
located in the conjugated ring system, could not be oxidized in
our conditions (2am, 0% conversion).
With the optimized conditions in hand, the scope of the model
reaction was evaluated (Table 2). Firstly, diverse thioanisole
derivatives (2a-2q) could be selectively oxidized to sulfoxides in
good to excellent yields. Besides, various diaryl sulfides (2r-2z)
also were suitable substrates and gave good yields in all cases. It
should be noted that the substitution pattern (ortho, meta, para)
and electronic properties of aromatic substituents (electron-defi-
We speculated that sulfoxides could be further converted to
sulfones using our protocol. Thus, we screened the photocatalyst
loading in the sulfone-promoted formation solvent ACN (Table 1,
entry 5) under higher oxygen concentration (oxygen balloon was
utilized) with sulfoxide 2r. The conversion was increased when
more photocatalyst was added (conversion was up from 5% on
0.1 mol% loadings to 73% on 10 mol% loading) (Table S3 in SI).
2

B. Zhao, G.B. Hammond and B. Xu
Tetrahedron Letters xxx (xxxx) xxx
Table 1
c (5 mol%)/O2 balloon/acetonitrile combination. Several sulfoxides
were successfully oxidated to sulfones in satisfactory yields
(Table 3).
Optimization of reaction conditions for sulfoxide formation.
Because sulfoxides could be oxidized to sulfones, we conjec-
tured that sulfides could also be oxidized to sulfones directly.
Indeed, sulfides successfully produced sulfones, albeit in slightly
lower yields (Table 4, 3a – 3z). Similarly, the conditions worked
well for diverse thioanisoles, diaryl sulfides, and dialkyl sulfides
with functional groups. The substitution pattern (ortho, meta, para)
and electronic property of substituents (electron-deficient or elec-
tron-rich) on aromatics had little effect on chemical yields.
Our methodology could be used in larger-scale synthesis with-
out complications. 1r was selectively oxidized to 2r in 94% yield or
3 m in 65% yield on a gram scale (Table 5).
Guo and coworkers [41] had suggested that the oxygenation of
sulfoxides from sulfides catalyzed by a ketone might occur via both
singlet oxygen involved energy transfer pathway and a superoxide
radical anion involved electron transfer pathway. To gain insights
into the reaction mechanism, we conducted several control exper-
iments. The radical trapping experiment (Scheme 2A-a and Sche-
me 2A-b) with excess TEMPO or BHT dramatically inhibited the
formation of sulfoxides and sulfones. These results suggested a
radical pathway. Then, a well-known sulfide cation radical scav-
enger, 1,4-dimethoxybenzene, was added into the reaction under
standard conditions. The reaction was depressed revealing that
the sulfide cation radical might be a key intermediate for the trans-
formation of sulfoxides (Scheme 2A-c). Next, the formation of a
superoxide anion radical was confirmed by adding benzoquinone
as a superoxide radical scavenger (Scheme 2A-d). Furthermore,
the addition of five equivalents of a singlet oxygen quencher
(1,4-diazabicyclo[2.2.2]octane, DABCO) did not inhibit the reaction
(Scheme 2A-e), and even large excess of DABCO (100 equiv) could
not inhibit the reaction completely (Scheme 2A-f). These combined
results suggested to us that singlet oxygen may not play an essen-
tial role in our reaction.
All the above control experiments indicated a superoxide radi-
cal anion-involved electron transfer pathway (Scheme 2B). The
excited ketone photocatalyst is a relatively strong oxidant; there-
fore, it should be able to transfer the sulfide 1 to the corresponding
radical cation A, together with the formation of a ketyl radical
anion. The ketyl radical anion reacts with oxygen to reproduce
the ground state photocatalyst and generate the superoxide radical
anion [42]. Next, the sulfide radical cation A reacts with the super-
oxide radical anion, and another molecule of sulfide to furnish the
final product 2 [41]. In the process of sulfoxidation, the strong
hydrogen bond between hydrogen donor solvent HFIP and hydro-
gen acceptor sulfoxide will deprive some electron density to the
sulfoxide and make it less prone to be further oxidized. However,
in the process of sulfonation, the formed 2 undergoes a second-
round single electron transfer (SET) trapped by the excited photo-
catalyst to generate intermediate C, which reacts with the superox-
ide radical anion, delivering the persulfone intermediate D. Finally,
D reacts with another sulfide or sulfoxide and produces sulfones 3.
However, the singlet oxygen-involved energy transfer pathway
cannot be ruled out.
No. Variations from standard
conditions
Yieldsa (2r/3m)%
1
2
none
99% (99/1)
b
b - e as photocatalyst
67% (99/1), 94% (97/3), 94% (96/4),
4%c (100/0)
b
3
4
f - j as photocatalyst
36%c (86/14), 96% (98/2), 94% (97/
3), 80%c (98/2), 82% (99/1)
c
DMSO, Acetone, Dioxane, t-BuOH, 0–55%
MeOH, THF as solvents
b
b
5
6
7
8
9
ACN and DCM as solvents
0.01 mol% photocatalyst loading
425 nm 18 W LEDs
No photocatalyst
56% (79/21), 84% (87/13)
99% (99/1)
99% (100/0)
0%
Dark
0%
Standard conditions: 1r (0.1 mmol), a (0.1 mol%), HFIP (0.1 M), air balloon, 18 W
a
405 nm LEDs, rt, 12 h. Yields determined by GC–MS with using 9H-fluorene as
internal standard. b 5 mol% photocatalyst loading. c Conversions determined by GC–
MS.
Then, the other photocatalysts were screened. The results showed
that aromatic ketone photocatalyst c gave the highest conversion
but with a low yield (91% conversion and 64% GC yield) (Table S4
in SI). Next, we investigated solvent effects, but no improvement
was observed (Table S5 in SI). On the other hand, the reaction con-
centration seemed to affect the conversion, and 0.2 M was the opti-
mal concentration (Table S6 in SI). Adding an additional portion of
photocatalyst several hours after the start of the reaction slightly
speeded up the reaction (Table S7 in SI). The formation of 2aa from
9H-thioxanthen-9-one indicated that the aromatic ketone photo-
catalyst could be oxidated. The optimal conditions were catalyst
3

B. Zhao, G.B. Hammond and B. Xu
Tetrahedron Letters xxx (xxxx) xxx
Table 2
Selective photochemical oxidation of thioethers to sulfoxides.
Conditions: 1 (0.2 mmol), a (0.1 mol%), HFIP (0.1 M), air balloon, 18 W 405 nm LEDs, rt,
12–24 h.
Table 3
Photochemical oxidation of sulfoxides to sulfones.
Conditions: 2 (0.2 mmol), c (5 mol%), ACN (0.2 M), O2 balloon, 18 W 405 nm LEDs,
rt, 16–40 h.
4

B. Zhao, G.B. Hammond and B. Xu
Tetrahedron Letters xxx (xxxx) xxx
Table 4
Selective photochemical oxidation of thioethers to sulfones.
Conditions: 1 (0.2 mmol), c (5 mol%), ACN (0.2 M), O2 balloon, 18 W 405 nm LEDs, rt,
24–40 h.
Table 5
Gram scale reaction.
5

B. Zhao, G.B. Hammond and B. Xu
Tetrahedron Letters xxx (xxxx) xxx
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153376.
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
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Acknowledgments
We are grateful to the National Science Foundation of China
(NSFC-21871046). G.B.H. is grateful to the National Science Foun-
dation for financial support (CHE-1855972).
6