Mechanistic Study of a Photocatalyzed C-S Bond Formation Involving Alkyl/Aryl Thiosulfate

Article abstract of DOI:10.1002/chem.201502951

This study presents thioether construction involving alkyl/aryl thiosulfates and diazonium salt catalyzed by visible-light-excited [Ru(bpy)₃Cl₂] at room temperature in 44-86 % yield. Electron paramagnetic resonance studies found that thiosulfate radical formation was promoted by K₂CO₃. Conversely, radicals generated from BnSH or BnSSBn (Bn=benzyl) were clearly suppressed, demonstrating the special property of thiosulfate in this system. Transient absorption spectra confirmed the electron-transfer process between [Ru(bpy)₃Cl₂] and 4-MeO-phenyl diazonium salt, which occurred with a rate constant of 1.69×10⁹ M^-1 s^-1. The corresponding radical trapping product was confirmed by X-ray diffraction. The full reaction mechanism was determined together with emission quenching data. Furthermore, this system efficiently avoided the over-oxidation of sulfide caused by H₂O in the photoexcited system containing Ru²⁺. Both aryl and heteroaryl diazonium salts with various electronic properties were investigated for synthetic compatibility. Both alkyl- and aryl-substituted thiosulfates could be used as substrates. Notably, pharmaceutical derivatives afforded late-stage sulfuration smoothly under mild conditions.

Full text of DOI:10.1002/chem.201502951

DOI: 10.1002/chem.201502951
Full Paper
&
Photocatalysis
Mechanistic Study of a Photocatalyzed CÀS Bond Formation
Involving Alkyl/Aryl Thiosulfate
Yiming Li,[a] Weisi Xie,[a] and Xuefeng Jiang*[a, b]
Abstract: This study presents thioether construction involv-
ing alkyl/aryl thiosulfates and diazonium salt catalyzed by
visible-light-excited [Ru(bpy)3Cl2] at room temperature in 44–
86% yield. Electron paramagnetic resonance studies found
that thiosulfate radical formation was promoted by K2CO3.
Conversely, radicals generated from BnSH or BnSSBn (Bn=
benzyl) were clearly suppressed, demonstrating the special
property of thiosulfate in this system. Transient absorption
spectra confirmed the electron-transfer process between
[Ru(bpy)3Cl2] and 4-MeO-phenyl diazonium salt, which oc-
sponding radical trapping product was confirmed by X-ray
diffraction. The full reaction mechanism was determined to-
gether with emission quenching data. Furthermore, this
system efficiently avoided the over-oxidation of sulfide
caused by H2O in the photoexcited system containing Ru2+
.
Both aryl and heteroaryl diazonium salts with various elec-
tronic properties were investigated for synthetic compatibili-
ty. Both alkyl- and aryl-substituted thiosulfates could be
used as substrates. Notably, pharmaceutical derivatives af-
forded late-stage sulfuration smoothly under mild condi-
tions.
curred with a rate constant of 1.69”109 mÀ1 À1. The corre-
s
Introduction
Aiming to conserve energy and
reduce emissions, chemists have
been trying to mimic the com-
plex photosynthetic processes of
plants in relatively simple chemi-
cal ways, such as the photocata-
lyzed reduction of carbon diox-
ide[1] and solar-driven splitting of
water into molecular hydrogen[2]
and oxygen.[3] In fact, the origi-
nal photosynthetic procedure
was probably achieved through
a
reductive sulfur source.[4]
During the process of evolution,
sulfur bacteria came to play the
key role in the relevant transfor-
mation,[5] which used various re-
duced inorganic sulfur com-
pounds, such as thiosulfate, as
electron donors for photoauto-
Scheme 1. Strategies for constructing sulfides.
trophic growth.[6] However, chemical routes to the photocata-
lyzed transformation of thiosulfate have never been studied.
Our group has been focusing on the sulfur atom transfer re-
action,[7] which introduces sulfur atoms into organic com-
pounds from inorganic sulfur sources, in particular, Na2S2O3
(Scheme 1). During our research, lower temperatures and
cheaper catalysts have gradually been employed. To further
enable the transformation under milder and more “natural”
conditions, aqueous photocatalyzed transformations of thiosul-
fate were investigated, which was inspired by the photoauto-
[a] Y. Li, W. Xie, Prof. Dr. X. Jiang
Shanghai Key Laboratory of Green Chemistry and Chemical Process
East China Normal University
3663 North Zhongshan Rd., Shanghai 200062 (P. R. China)
E-mail: xfjiang@chem.ecnu.edu.cn
[b] Prof. Dr. X. Jiang
State Key Laboratory of Elemento-organic Chemistry
Nankai University (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502951.
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2À
trophic transformation of S2O3 in sulfur bacteria.[6a] Finally,
Table 2. Specificity of thiosulfate.[a]
the photocatalyzed[8] cross-coupling reaction between aryl di-
azonium salt[9] and alkyl/aryl thiosulfate salt[10] was established
for constructing sulfides, which are widely found in the
body,[11] natural products,[12] pharmaceuticals,[13] and foods.[14]
Furthermore, despite the sulfide construction involving thiosul-
fate being realized through a radical process,[7b,d] the detection
of the corresponding thiosulfate radical signal and the study of
the detailed mechanism have not been conducted. Herein, we
take advantage of this photocatalyzed system to investigate
the properties of the thiosulfate radical and possible pathways
of the relevant CÀS bond construction.
Entry
Sulfur source
Yield[b]
1
2
3
4
5
6
BnSSO3Na (2)
BnSH
BnSSBn
BnSCN
BnSAc
BnSSO2tol
76%
trace
trace
ND
trace
ND
7
trace
Results and Discussion
[a] Reaction conditions: 1 (0.2 mmol), sulfur source (1.0 mmol), [Ru(b-
py)3Cl2] (0.004 mmol), K2CO3 (0.4 mmol), DMSO/H2O=0.82:0.18 mL, 8 W
CFL, N2, rt, 5 h. [b] Isolated yields.
Our study commenced by examining the reaction between 4-
methoxybenzenediazonium tetrafluoroborate, 1, and benzyl
thiosulfate salt, 2. The desired product could be obtained in
76% yield under visible-light-mediated conditions, which was
catalyzed by [Ru(bpy)3Cl2] and promoted by K2CO3 in DMSO/
H2O at room temperature (Table 1). Under these standard con-
ditions, BnSH, BnSSBn, and some other sulfur sources (Table 2;
Special role of the thiosulfate radical
To understand the special role of thiosulfate in this system,
which is different from thiol[16] or disulfide,[17] electron para-
magnetic resonance (EPR) experiments were conducted. As
shown in Figure 1(I), when benzyl thiosulfate was subjected to
base in solvent, the intensity of the sulfur radical signal was
slightly enhanced. In contrast, the signals of other two tradi-
tional sulfurating reagents (BnSH and BnSSBn) sharply de-
creased when subjected to base (Figure 1(II) and (III)), which
Table 1. Optimization of reaction conditions.[a]
Entry Catalyst
Base
Solvent
Yield[b] [%]
1
2
3
4
5
6
7
8
[Ru(bpy)3Cl2]·6H2O
–
–
–
MeOH
MeCN
DMSO
Trace
<10
45
30
47
43
72
64
61
[Ru(bpy)3Cl2]·6H2O
[Ru(bpy)3Cl2]·6H2O
[Ru(bpy)3Cl2]·6H2O
[Ru(bpy)3Cl2]·6H2O
[Ru(bpy)3Cl2]·6H2O
[Ru(bpy)3Cl2]·6H2O
[Ru(bpy)3Cl2]·6H2O
DIPEA[c] DMSO
NaHCO3 DMSO
K3PO4
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
9
10
Anthracene-9,10-dicarbonitrile K2CO3
[Ru(bpy)3Cl2]·6H2O K2CO3
DMSO/H2O[d] 76
[a] Reaction conditions:
1
(0.2 mmol),
2
(1.0 mmol), [Ru(bpy)3Cl2]
(0.004 mmol), K2CO3 (0.4 mmol), solvent (1 mL), 8 W CFL, N2, rt, 5 h.
[b] Isolated yields. [c] DIPEA=N,N-diisopropylethylamine. [d] DMSO/H2O=
0.82:0.18 mL.
Bn=benzyl) were not effective. Control experiments (Table S1
in the Supporting Information) showed that sulfide 3 could be
obtained with a relatively low yield (33%) in the absence of
visible light and Ru. However, the same conditions with BnSH
or BnSSBn did not afford compound 3 (Table S2 in the Sup-
porting Information), demonstrating the unusual property of
R-S-SO3Na. In addition, the sulfides are likely to be further oxi-
2+
dized by Ru(bpy)3 species in the presence of water and an
electron acceptor.[15] The stability of the organic thiosulfate
compound[7a] and thiosulfate radical intermediate (see below
for mechanistic evidence) decreased the probability of further
oxidation and other side reactions. This phenomenon further
indicated the critical need to identify its underlying mecha-
nism.
Figure 1. Sulfur radicals from different sources observed by electron para-
magnetic resonance experiments. All of the experiments were conducted
under irradiation by visible light and executed under the standard concen-
tration with radical trapping reagent DMPO (DMPO=5,5-dimethyl-1-pyrro-
line-1-oxide).
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indicated that the corresponding sulfur radical was inhibited.
These results were consistent with the control experiments
(Table 2) and further explained the higher reactivity of benzyl
thiosulfate in this system. However, when BnSH and BnSSBn
were applied in the standard conditions without K2CO3, the
sulfide 3 could be obtained, albeit in relatively lower yields
(Table S3 in the Supporting Information). These data verified
that K2CO3 exhibits a negative effect on BnSH and BnSSBn in
this system. For the different phenomena in Figure 1, a ration-
ale is given: a new intermediate was formed by the combina-
tion of benzyl thiosulfate and K2CO3 and a resonance effect
might help produce a relatively stable radical species. Con-
versely, K2CO3 might destroy the stability of the BnSH and
BnSSBn radicals.
could deliver an electron to the excited triplet Ru, which gen-
erates benzyl thiosulfate cationic radical B and Ru+. Then, Ru+
is oxidized by the phenyl diazonium salt and regenerates the
Ru2+ species. Simultaneously, one electron is delivered to com-
pound 1, which produces the phenyl diazonium radical that
can then react with the thiosulfate cationic radical to afford
the desired product. Furthermore, the thiosulfate 2 interacts
with K2CO3 and could generate a new species C, which could
undergo transition-metal-free electron exchange[20] and yield
the intermediates A and B (path III). The final product is ach-
ieved through radical coupling between A and B.
For a mechanistic study of a photocatalyzed reaction, first, it
is critical to identify what initiated the reaction. Emission
quenching experiments were performed (Figure 2), which
3
CÀ
showed that the emission intensity of *[Ru(bpy)2(bpy )Cl2] di-
minished with increasing concentration of diazonium salt.
Comparatively, benzyl thiosulfate salt and K2CO3 did not exhibit
this ability. This evidence indicated that the diazonium salt,
Mechanistic study
After investigating the special role of the thiosulfate radical,
mechanistic studies of the corresponding sulfuration process
instead of the benzyl thiosulfate salt, interacts with
3
CÀ
were conducted.
A
proposed mechanism is shown in
*[Ru(bpy)2(bpy )Cl2] directly through electron or energy trans-
Scheme 2. Firstly, [Ru(bpy)3Cl2] is activated by visible light to
generate a singlet excited state, which goes through a fast in-
tersystem crossing to the key excited triplet species
fer.
To verify whether the diazonium compound interacts with
the catalyst through an electron- or energy-transfer pattern,
transient absorption spectrum studies were conducted. As
shown in Figure 3(I), a strong negative bleach of the ground
state absorption of [Ru(bpy)3Cl2] was observed at 450 nm
3
[18]
CÀ
*[Ru(bpy)2(bpy )Cl2]. Subsequently, there are two different
possible interactions between substrates and excited triplet
Ru. Path I is an oxidative quenching process, in which diazoni-
3
CÀ
um salt 1 obtains an electron from *[Ru(bpy)2(bpy )Cl2] and
after excitation by 440 nm laser. Additionally, the characteristic
3
CÀ
generates the phenyl diazonium radical A (lifetime about
10À7 s).[19] Then, radical A couples with the thiosulfate electro-
philic radical B, which originated from 2. On the other hand,
path II is a reductive quenching process. Benzyl thiosulfate
absorption assigned to *[Ru(bpy)2(bpy )Cl2] at 370 nm was
observed (Figure 3(I)). Subsequently, K2CO3 was introduced
into the solution of [Ru(bpy)3Cl2], an addition that did not
result in absorption decay at 370 nm and 450 nm (Figure 3(II)).
When diazonium salt 1 was in-
troduced into the system, the
excited state difference spectra
showed apparent decay both at
370 nm and 450 nm (Fig-
ure 3(III)). In contrast, when thio-
sulfate 2 was added to the solu-
tion of [Ru(bpy)3Cl2]/K2CO3, there
was no obvious change in the
transient absorption spectra (Fig-
ure 3(IV)). Furthermore, kinetic
studies of the decay at 370 nm
(Figure 4) demonstrated that
the lifetime of the active triplet
Ru2+ species diminished only
when compound 1 was added.
These results confirmed the elec-
tron transfer mode between
3
CÀ
*[Ru(bpy)2(bpy )Cl2] and diazo-
nium compounds. As the life-
3
CÀ
time of *[Ru(bpy)2(bpy )Cl2] de-
creased from 1014 ns (Fig-
ure 4(II)) to 866 ns (Figure 4(III)),
the electron transfer rate con-
stant was calculated to be about
Scheme 2. Plausible mechanism for photocatalyzed sulfuration.
1.69”109 mÀ1 sÀ1
(Figure 4),
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which is consistent with the kinetic results of the Stern–Volmer
technique by Deronzier’s group.[21] These results detailed the
3
CÀ
oxidative quenching of *[Ru(bpy)2(bpy )Cl2] by a diazonium
compound in the reaction system in a photophysical manner.
Radical trapping tests were conducted and the presence of
a phenyl radical trapping species was confirmed by X-ray dif-
fraction (Scheme 3).[22]
Figure 2. Emission quenching of [Ru(bpy)3Cl2].
Scheme 3. Radical trapping experiment. Standard conditions with added
TEMPO (2 equiv).
After the initial electron-transfer process was proved, the in-
teraction manner between the phenyl diazonium radical and
the new sulfur cationic radical was further investigated. To ex-
amine the radical properties, electron paramagnetic resonance
(EPR) experiments were conducted (Figure 5(I)). There are clear
radical signals in the standard system. Control experiments re-
vealed that the radical species labeled B (aN=14.08, aH=
15.25) was from the benzyl thiosulfate (Figure 5(II)). From EPR
experiments under standard conditions without compound 2,
the phenyl radical was identified as well (aN=14.76, aH=
21.51) (Figure S6 in the Supporting Information), in which the
signal was labeled A. The above EPR results showed the pres-
ence of the phenyl and thiosulfate radical, with a peak area
ratio of 1:7. Moreover, the results indicated the desired sulfide
might be generated through the radical coupling[23] between
the two.
Figure 3. Transient absorption spectrum studies. The concentration ratio for
all experiments is identical to that in the reaction, c[Ru(bpy)3Cl2]=1”10À4 m.
The electron-transfer process from Ru3+ to Ru2+ still needs
to be elucidated (Scheme 2, path I). Emission quenching ex-
periments have shown that there is no direct interaction be-
tween [Ru(bpy)3Cl2] and benzyl thiosulfate (Figure 2). Accord-
ing to EPR studies (Figure 5), compared with the system with
only the benzyl thiosulfate in H2O under visible light (Fig-
ure 5(II)), an additional series of signals (labeled C) could be
observed when the standard solvent system (DMSO/H2O) was
used, which indicated that the solvent might be involved in
the electron-exchange process. Thus, the electron released
from the organic thiosulfate is captured and further transferred
to the photocatalyst by the solvent, which realizes the oxida-
tion process from Ru3+ to Ru2+. In addition to the above pro-
cess, a radical chain propagation pathway[24] might be possible
as well. The phenyl radical might add to the thiosulfate species
and form a new radical complex. The newly formed radical fur-
Figure 4. Kinetic study of the decay at 370 nm. The concentration ratio for
all experiments is identical to that in the reaction, c[Ru(bpy)3Cl2]=1”10À4 m.
t1 (1014 ns) is the lifetime of Ru2+* in condition II, t2 (886 ns) is the lifetime
of Ru2+* in condition III.
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ed benzyl thiosulfates (15–16), but also alkyl ones with diverse
functional groups (17–18) could afford the desired products. In
addition, the sp2-thiosulfates (19–20) could also be utilized to
synthesize diphenyl sulfide structures. A free combination of
both parts was investigated as well (21–31). The correspond-
ing experiments mainly focused on the fluoro- and cyano-con-
taining substrates (21–26). Finally, pyridine diazonium salts,
which are not frequently studied, were purposely investigated
here.[9a,b] It was found that both sp2- and sp3-substituted thio-
sulfates (27–31) were transformed in good to excellent yields,
a reaction type that is usually a challenge in coupling reac-
tions.[25] Taking pyridine-3-diazonium tetrafluoroborate as an
example, the standard conditions with [Ru(bpy)Cl2] and K2CO3
could only produce 27 in 26% yield; however, when methyl-
ene blue (MB) was used as the photocatalyst instead of Ru,
66% yield could be obtained (Table S5 in the Supporting Infor-
mation). Possible reasons for this are: 1) coordination from the
N atom on pyridine to Ru decreases the yield; 2) pyridine di-
azonium salts are more electron-deficient and less stable. Com-
pared with MB, the more energetic absorption wavelength of
[Ru(bpy)3Cl2] might cause the decomposition of unstable pyri-
dine substrates. The maximum absorption wavelength in visi-
ble light is 663 nm for MB[26] and 452 nm for [Ru(bpy)3Cl2].[8d]
Figure 5. Characteristic signal comparison in electron paramagnetic reso-
nance experiments. All the experiments were conducted under irradiation
by visible light and executed under the standard concentration with radical
trapping reagent DMPO (DMPO=5,5-dimethyl-1-pyrroline-1-oxide).
Pharmaceutical derivatives late-stage sulfuration
To implement our late-stage sulfuration strategy,[7a–e,g] several
crucial medicinal compounds were utilized (Table 4). Sulfona-
mides[27] are typical antimicrobial medicinal compounds, which
could efficiently defeat Gram-positive and Gram-negative bac-
teria. The p-sulfide sulfonamides exhibit important bioactivity
as well.[28] Therefore, we explored late-stage sulfuration on sul-
fonamide pharmaceuticals. Different representative substituted
compounds were evaluated, such as primidyl (32--33), pyridyl
(34), and oxazolinyl (35–36), of which the structure of 32 was
confirmed by X-ray crystallography analysis.[29] In these exam-
ples, the active hydrogen and complicated heterocycle substi-
tutions did not adversely affect the efficiency of this protocol.
In addition to alkyl thiosulfate, the aryl thiosulfate 36 could
also be used in this modification procedure for medically rele-
vant derivatives. The transformations were achieved under
mild conditions and might be potentially applicable in medici-
nal and biological studies.
ther experiences loss of an electron and cleavage of the SÀS
bond, which finally produces the sulfide.
Considering these results, a detailed mechanism is depicted
(Scheme 2, path I). Initially, [Ru(bpy)3Cl2] is activated by visible
3
CÀ
light to form *[Ru(bpy)2(bpy )Cl2], which goes through an oxi-
dative quenching process with diazonium salt 1 to generate
the Ru3+ and phenyl diazonium radical A. Organic thiosulfate
salt 2 releases an electron to the solvent and affords the thio-
sulfate radical cationic species B. The newly generated phenyl
diazonium and thiosulfate electrophilic radical are coupled to
afford the desired products. The solvent shuttles an electron to
Ru3+ and regenerates the catalyst. The transition-metal-free
electron-exchange process might generate the product as well.
Synthetic compatibility investigation
After the above mechanistic studies, the compatibility and ap-
plicability of this transformation were further investigated. As
shown in Table 3, various aryl diazonium tetrafluoroborates
were applied in our reaction conditions and it was found that
substitutions at the para- (3, 6–11), ortho- (12), and meta- (13)
positions were all compatible. Both electron-withdrawing and
electron-donating groups afforded moderate to excellent
yields. It is worth noting that chloro- (8, 13) and bromo-substi-
tutions (9) could be well tolerated in this system, thus, the cor-
responding products could be further transformed in cross-
coupling reactions. In addition, the reactivity of the multi-sub-
stituted aryl diazonium salt (14) could work as well. Next, dif-
ferent organic thiosulfates were examined. Not only substitut-
Conclusion
2À
To mimic the photosynthetic application of S2O3 in sulfur
bacteria, alkyl/aryl thiosulfates were introduced into an aque-
ous photocatalyzed sulfurating system. This method success-
fully overcame the over-oxidation of sulfide by Ru2+ in water.
Detailed mechanistic studies were performed to identify the
underlying mechanism. Electron paramagnetic studies detect-
ed a new thiosulfate radical species and explained the reason
for the specificity of thiosulfate radicals in this system. Transi-
ent absorption spectra investigation confirmed the electron
transfer between excited triplet Ru2+ and the diazonium com-
pound. Moreover, this mild sulfurating strategy is compatible
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with diverse substrates and could be successfully
applied to the modification of complex medicinal
compounds.
Table 3. Substrates scope.[a]
Experimental Section
Typical reaction procedure
3 (76%)
9 (59%)
6 (81%)
7 (53%)
8 (62%)
A Schlenk tube was filled with nitrogen, then diazo-
nium tetrafluoroborate (0.2 mmol), thiosulfate salt
(1 mmol), [Ru(bpy)3Cl2]·6H2O (4”10À3 mmol), K2CO3
(0.4 mmol), DMSO (0.82 mL)/H2O (0.18 mL) were
added. The reaction mixture was stirred for 5 h at
room temperature under the irradiation of 8 W Com-
pact Fluorescent Lamp (CFL). When the reaction was
finished, ethyl acetate (EA; 5 mL) was added to the
mixture, which was dried over MgSO4. Then, the mix-
ture was filtered through Celite, concentrated, and
purified by column chromatography on silica gel to
afford the desired product.
10 (71%)
11 (58%)
12 (50%)
13 (50%)
17 (76%)
14 (58%)
18 (67%)
15 (68%)
19 (62%)
16 (60%)
20 (55%)
Acknowledgements
21 (82%)
22 (64%)
23 (60%)
24 (66%)
We would like to thank Prof. Dr. Lizhu Wu for the
transient absorption spectra studies and sugges-
tions. We are also grateful to Ms. Yanhong Liu for
the electron paramagnetic resonance studies and
essential advice. Financial support was provided
by NBRPC (973 Program, 2015CB856600), NSFC
(21472050, 21272075), NCET (120178), DFMEC
(20130076110023), Fok Ying Tung Education
Foundation (141011), the program for Shanghai
Rising Star (15A1401800), Profes-
25 (56%)
26 (67%)
27 (66%)[b]
31 (80%)[b]
28 (86%)[b]
29 (83%)[b]
30 (55%)[b]
[a] Standard conditions, isolated yields. [b] Methylene blue and Li2CO3 were used instead
of [Ru(bpy)3Cl2] and K2CO3.
sor of Special Appointment
(Eastern Scholar) at Shanghai In-
Table 4. Late-stage modification of pharmaceuticals.[a]
stitutions of Higher Learning,
and the Changjiang Scholar and
Innovative Research Team in Uni-
versity.
Keywords: bond formation
mechanistic study organic
thiosulfates pharmaceuticals
·
·
sulfamethazine
32 (59%)
sulfapyridine
34 (44%)
·
sulfuration · photocatalysis
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clinic, space group P1, final R indices [I>2s(I)], R1 =0.0448, wR2 =
0.1165, R indices (all data), R1 =0.0678, wR2 =0.1328, a=9.6494 (4) Š,
b=9.7383 (4) Š, c=21.3124 (8) Š, a=97.991(1)o, b=102.561(1)8, g=
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22430/6676 (R(int) =0.0376).
Received: July 27, 2015
Published online on September 25, 2015
Chem. Eur. J. 2015, 21, 16059 – 16065
www.chemeurj.org
16065
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim