Metal- And oxidant-free electrochemical synthesis of sulfinic esters from thiols and alcohols

Article abstract of DOI:10.1039/c9gc02125f

An efficient and eco-friendly electrochemical synthesis of various sulfinic esters from thiols and alcohols via sequential S-H/S bond cleavage and double S-O bond formation under mild reaction conditions has been developed. Stoichiometric oxidants, metal catalysts, activating agents and even added bases were avoided in this method, and the only by-product generated from this reaction was dihydrogen gas which could serve as a green source of energy. Various functional groups are compatible with this green protocol which can be easily conducted on a gram-scale.

Full text of DOI:10.1039/c9gc02125f

Green Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Metal- and oxidant-free electrochemical synthesis
of sulfinic esters from thiols and alcohols†
Cite this: Green Chem., 2019, 21,
5528
Chongren Ai,‡ Haiwei Shen,‡ Dingguo Song, Yujin Li, Xiao Yi, Ze Wang,
Received 25th June 2019,
Accepted 22nd September 2019
Fei Ling * and Weihui Zhong
*
DOI: 10.1039/c9gc02125f
rsc.li/greenchem
An efficient and eco-friendly electrochemical synthesis of various hols with sulfonyl hydrazides7 or thiols8 in the presence of
sulfinic esters from thiols and alcohols via sequential S–H/S bond copper salts for the preparation of sulfinic ester derivatives.
cleavage and double S–O bond formation under mild reaction Very recently, Zhang’s group has also developed an efficient
conditions has been developed. Stoichiometric oxidants, metal route to access sulfinic esters via the Co/N-SiO2-AC-mediated
catalysts, activating agents and even added bases were avoided in cross-dehydrogenative coupling reaction of thiols and alco-
this method, and the only by-product generated from this reaction hols.9 Despite these great advances, the use of metal catalysts
was dihydrogen gas which could serve as a green source of and excess oxidants has limited their further applications.
energy. Various functional groups are compatible with this green Thus, there is a high demand for new, efficient and envir-
protocol which can be easily conducted on a gram-scale.
onmentally benign methods for the synthesis of sulfinic esters
from readily available starting materials under catalyst-,
oxidant- and additive-free conditions.
Organic electrosynthesis has been demonstrated to be an
eco-friendly synthetic tool since it can avoid the use of oxi-
dants, reducing agents, toxic bases or even catalysts, thus
decreasing waste and pollution.10 Under constant current
conditions, thiols will lose one electron to generate thiol
Development of practical methodologies for the preparation of
sulfinic esters is an important issue in organic synthesis
because these compounds not only exhibit diverse biological
and therapeutic activities,1 but also act as valuable synthons
for the preparation of functional sulfone-containing products.2
To date, numerous synthetic methods have been successfully
developed to produce these skeletons. The nucleophilic substi-
tution reactions of sulfur compounds (sulfinic acids,3 sulfinyl
chlorides,4 and sodium sulfinates5) with alcohols offered con-
venient ways to synthesize sulfinic esters (Scheme 1a).
However, the employment of stoichiometric amounts of con-
densation agents or activating agents resulted in a lot of unde-
sired waste, which is environmentally unfriendly. In this
context, the oxidative coupling reactions provided useful alterna-
tives for the synthesis of these compounds, since these
methods avoided the use of activating or condensation agents
(Scheme 1b). The early representative protocols are mainly
based on the oxidation of diaryl disulfides in the presence of
alcohols using excess N-bromosuccinimide (NBS),6a Br2 or
2b
6b
PhI(OCOCF3)2 as oxidants. In 2016, the groups of Pan and
Jang independently developed the coupling reaction of alco-
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of
Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, People’s Republic of China.
E-mail: lingfei@zjut.edu.cn, weihuizhong@zjut.edu.cn
†Electronic supplementary information (ESI) available: Experimental details and
copies of 1H NMR and 13C NMR spectra. See DOI: 10.1039/c9gc02125f
‡These authors contributed equally.
Scheme 1 Methods for the synthesis of sulfinic esters.
5528 | Green Chem., 2019, 21, 5528–5531
This journal is © The Royal Society of Chemistry 2019

View Article Online
Green Chemistry
Communication
radical species, which could undergo radical–radical coup- reaction dramatically; either increasing or decreasing the con-
ling,11 metal-catalyzed thiolation with aryl halides12 or stant current led to a lower yield (Table 1, entries 10 and 11).
ketones,13 difunctionalization of alkenes,14 and oxidation reac- Furthermore, changing the reaction temperatures did not
tions,15 leading to a variety of useful sulfur-containing com- improve the product yield (Table 1, entries 12 and 13). It was
pounds, such as disulfides, sulfides, methyl sulfoxides and sul- noteworthy that the reaction with air instead of N2 under the
fonamides. To the best of our knowledge, the synthesis of sulfi- standard conditions also afforded the desired product 3aa in
nic esters (R1SO-OR2) from thiols using electricity has not been 84% yield (Table 1, entry 14). In contrast, no desired product
reported yet, since it is difficult to avoid the overoxidation to sul- was obtained without an electric current (Table 1, entry 15).
fonate esters. Herein, we describe a versatile and efficient Interestingly, this protocol could be easily conducted at the
electrochemical oxidative reaction of thiols with alcohols to 12 mmol scale to produce 3aa in 1.67 g, 82% yield (Table 1,
afford sulfinate esters as products under metal catalyst- and entry 16).
oxidant-free undivided electrosynthetic conditions (Scheme 1c).
After identifying the optimum reaction conditions, we next
At the outset of this study, 4-methylthiophenol (1a) and set out to determine the versatility of this reaction system in
methanol (2a) were chosen as the starting materials (Table 1). the electrochemical oxidative coupling of various thiophenols
The initial reaction was performed in an undivided cell with and alcohols. The scope of this reaction was initially explored
platinum plates as electrodes under 6 mA constant current at with a range of thiophenols 1 and methanol (2a). As depicted
room temperature using nBu4NBF4 as the electrolyte and in Scheme 2, various sulfinic esters could be synthesized with
CH2Cl2 as the solvent. Fortunately, the desired product 3aa satisfactory yields (58–90%). The substituents on the aryl ring
was obtained in 87% yield (Table 1, entry 1). Subsequently, a of aryl thiols affected the desired product yields to some
series of solvents were investigated, and replacement of extent. para-Substituted substrates with electron-donating
CH2Cl2 with CH3CN or THF gave a slightly decreased yield, groups on the thiols, such as –Me (1a), –tBu (1c) and –OMe
while only a trace amount of the product was observed when (1d), gave better yields than those with electron-withdrawing
using DMF as the reaction solvent (Table 1, entries 2–4). Next, groups (1e–h). Moreover, the substitution patterns on the aryl
various supporting electrolytes such as LiClO4, nBu4NBF4, rings of thiols had a slight effect on this reaction, forming 3ia–
nBu4NPF6, and nBu4NI were explored (Table 1, entries 5 and 6). ka from ortho- and meta-substituted substrates in relatively
nBu4NBF4 was found to be the most efficient electrolyte for lower yields. In addition, disubstituted thiols also underwent
this reaction. In addition, using graphite rod as an anode elec- this reaction smoothly to provide 3la in 68% yield. Notably,
trode resulted in a much poorer yield, while nickel turned out other aromatic skeletons were also tolerated, such as naphtha-
to be an unsuccessful cathode in this transformation (Table 1,
entries 8 and 9). Notably, the constant current affected the
Table 1 Optimization of the reaction conditionsa
Entry
Variation from the standard conditions
Yieldb (%)
1
2
3
4
5
6
7
8
None
87
74
71
Trace
72
78
70
68
NR
64
83
75
58
84
0
CH3CN instead of CH2Cl2
THF instead of CH2Cl2
DMF instead of CH2Cl2
LiClO4 instead of nBu4NBF4
Bu4NPF6 instead of nBu4NBF4
nBu4NI instead of nBu4NBF4
Graphite rod as an anode
Nickel as a cathode
3 mA instead of 6 mA
10 mA instead of 6 mA
40 °C
9
10
11
12
13
14
15
16
10 °C
Air instead of N2
No electric current
12.0 mmol instead of 1.0 mmol
82
Scheme 2 Substrate scope of thiols. Reaction conditions: Undivided
cell, Pt anode (1 cm × 1 cm), Pt cathode (1 cm × 1 cm), 1 (1.0 mmol),
2a (1.0 mL), n-Bu4NBF4 (1.0 mmol), CH2Cl2 (4.0 mL), N2, 20 h. Isolated
yields.
a Reaction conditions: Undivided cell, Pt anode (1 cm × 1 cm), Pt
cathode (1 cm × 1 cm), 1a (1.0 mmol), 2a (1.0 mL), n-Bu4NBF4
(1.0 mmol), CH2Cl2 (4.0 mL), N2, 20 h. b Isolated yields.
This journal is © The Royal Society of Chemistry 2019
Green Chem., 2019, 21, 5528–5531 | 5529

View Article Online
Communication
Green Chemistry
lene and pyridine, leading to the corresponding products 3ma
and 3na being obtained in 65% and 71% yields, respectively.
Delightfully, the less-reactive cyclohexanethiol (1o) was still
compatible with this transformation to produce the targeted
product 3oa in a moderate yield.
Next, the scope of this reaction with respect to various alco-
hols was studied, furnishing the sulfinic esters in 61–89%
yields (Scheme 3). High yields (73–89%) were obtained when
using primary aliphatic alcohols as substrates, such as ethanol
(2b), n-propanol (2c), n-butanol (2e), n-hexanol (2g), etc.
Furthermore, the reactions were also conducted efficiently
with secondary aliphatic alcohols (2d and 2i), delivering the
sulfinic ester derivatives 3bd and 3bi in 78% and 67% yields,
respectively. It is noteworthy that benzyl alcohol turned out to
be an efficient substrate, affording the corresponding product
3bj in 61% yield. Delightfully, functionalized alcohols contain-
ing heteroatoms such as 3-Cl (2k) and 2-OEt (2l) were also tol-
erated in this reaction with moderate yields, thereby providing
an opportunity for further manipulations.
Scheme 4 Control experiments.
To gain mechanistic insight into this transformation, some
control experiments were performed (Scheme 4, see the ESI†
for more details). We observed that the thiol was first con-
verted into disulfane 4, and then 4a reacted with 2a smoothly
to give 3aa in 89% yield under the standard conditions
(Scheme 4, eqn (1)). In addition, reducing the reaction time to
10 h led to 3aa in 54% yield accompanied by 6a in 5% yield
(Scheme 4, eqn (2)). Subjecting 6a to the standard conditions
led to the formation of the desired product 3aa in 78% yield
within 4 h (Scheme 4, eqn (3)). The experimental results
strongly suggested that disulfane 4a and thiosulfinate 6a were
the key intermediates in this transformation. Furthermore,
this reaction still proceeded smoothly when dry methanol was
used as the solvent under a N2 atmosphere (Scheme 4, eqn
(4)), which indicated that the alcohols may act not only as reac-
tants but also as oxidants to oxidize the S(II) to S(IV) species.
More importantly, an isotopic labelling reaction was carried
out by the treatment of 1a and 2a in the presence of H218O
(Scheme 4, eqn (5)) under the standard conditions, leading to
a mixture of 3aa and [18O]-3aa (1 : 1.25) in 85% yield. The isoto-
pic labelling experimental results indicated that oxygen in
sulphur could also come from water.
On the basis of the control experiments and literature
reports,11–15 a plausible mechanism is depicted in Scheme 5.
Initially, thiol 1 is oxidized to a thiol radical I in the anode.
Subsequently, the homo-coupling of thiol radical I forms the
disulfide 4 in situ, followed by the oxidation of 4, leading to
the generation of thiosulfinates 6. Finally, the nucleophilic
attack of 6 by methanol gives the desired product 3, with the
release of 1. On the other hand, the hydrogen ion was reduced
to dihydrogen gas in the cathode.
Scheme 3 Substrate scope of alcohols 2. Reaction conditions: Undivided
cell, Pt anode (1 cm × 1 cm), Pt cathode (1 cm × 1 cm), 1a or 1b
(1.0 mmol), 2 (1.0 ml), n-Bu4NBF4 (1.0 mmol), CH2Cl2 (4.0 mL), N2, 20 h.
Isolated yields. a CH3CN as the solvent.
Scheme 5 Proposed reaction mechanism.
5530 | Green Chem., 2019, 21, 5528–5531
This journal is © The Royal Society of Chemistry 2019

View Article Online
Green Chemistry
Communication
5 A. Tranquilino, S. R. C. P. Andrade, A. P. M. da Silva,
P. H. Menezes and R. A. Oliveira, Tetrahedron Lett., 2017,
58, 1265.
6 (a) P. Brownbridge and I. C. Jowett, Synthesis, 1988, 252;
(b) M. Xia and Z. C. Chen, Synth. Commun., 1997, 27, 1321.
7 B. Du, Z. Li, P. Qian, J. Han and Y. Pan, Chem. – Asian J.,
2016, 11, 478.
8 P. K. Shyam, Y. K. Kim, C. Lee and H. Y. Jang, Adv. Synth.
Catal., 2016, 358, 56.
9 C. Zhou, Z. Tan, H. Jiang and M. Zhang, Green Chem.,
2018, 20, 1992.
Conclusions
In summary, we have developed an eco-friendly electron
induced oxidative S–O coupling reaction which avoids the use
of metals, oxidants and additives. Readily available alcohols
and thiols could be used as substrates under constant con-
ditions in an undivided electrochemical cell equipped with a
platinum anode and a platinum cathode, providing versatile
sulfinic esters in good yields. Furthermore, this reaction could
be conducted on a gram scale easily. We anticipate that this
novel and efficient synthetic protocol used to prepare sulfinic
esters will find applications in both academic research and 10 For selected reviews, see: (a) J.-I. Yoshida, K. Kataoka,
industrial development settings.
R. Horcajada and A. Nagaki, Chem. Rev., 2008, 108, 2265;
(b) B. A. Frontana-Uribe, R. D. Little, J. G. Ibanez, A. Palma
and R. Vasquez-Medrano, Green Chem., 2010, 12, 2099;
(c) R. Francke and R. D. Little, Chem. Soc. Rev., 2014, 43,
2492; (d) M. Yan, Y. Kawamata and P. S. Baran, Chem. Rev.,
2017, 117, 13230; (e) Y. Jiang, K. Xu and C. Zeng, Chem.
Rev., 2018, 118, 4485; (f) S. Liang, K. Xu, C.-C. Zeng,
H.-Y. Tian and B.-G. Sun, Adv. Synth. Catal., 2018, 360,
4266; (g) N. Sauermann, T. H. Meyer, Y. Qiu and
L. Ackermann, ACS Catal., 2018, 8, 7086; (h) Z.-W. Hou,
Z.-Y. Mao and H.-C. Xu, Synlett, 2017, 28, 1867;
(i) Q.-L. Yang, P. Fang and T.-S. Mei, Chin. J. Chem., 2018,
36, 338.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the National Natural Science Foundation of China
(No. 21676253 and 21706234) and the Natural Science
Foundation of Zhejiang Province of China (No. LY19B060011)
for financial support.
11 (a) P. Huang, P. Wang, S. Tang, Z. Fu and A. Lei, Angew.
Chem., Int. Ed., 2018, 57, 8115; (b) Y. Li, Q. Yang, L. Yang,
N. Lei and K. Zheng, Chem. Commun., 2019, 55, 4981;
(c) Z.-Y. Mo, T. R. Swaroop, W. Tong, Y.-Z. Zhang,
H.-T. Tang, Y.-M. Pan, H.-B. Sun and Z.-F. Chen, Green
Chem., 2018, 20, 4428; (d) S. Tang, Y. Liu, L. Li, X. Ren,
J. Li, G. Yang, H. Li and B. Yuan, Org. Biomol. Chem., 2019,
17, 1370; (e) D. Li, S. Li, C. Peng, L. Lu, S. Wang, P. Wang,
Y.-H. Chen, H. Cong and A. Lei, Chem. Sci., 2019, 10, 2791;
(f) Y. Yuan, Y. Cao, J. Qiao, Y. Lin, X. Jiang, Y. Weng,
S. Tang and A. Lei, Chin. J. Chem., 2019, 37, 49; (g) F. Lu,
Z. Yang, T. Wang, T. Wang, Y. Zhang, Y. Yuan and A. Lei,
Chin. J. Chem., 2019, 37, 547.
Notes and references
1 (a) J. H. Kim, J. O. Lee, S. K. Lee, J. W. Moon, G. Y. You,
S. J. Kim, S. H. Park, J. M. Park, S. Y. Lim, P. G. Suh,
K. O. Uhm, M. S. Song and H. S. Kim, J. Biol. Chem., 2011,
286, 7567; (b) J. Blackinton, M. Lakshminarasimhan,
K. J. Thomas, R. Ahmad, E. Greggio, A. S. Raza,
M. R. Cookson and M. A. Wilson, J. Biol. Chem., 2009, 284,
6476.
2 (a) J. A. Lujan-Montelongo, A. O. Estevez and F. F. Fleming, 12 S. Liang, C.-C. Zeng, H.-Y. Tian, B.-G. Sun, X.-G. Luo and
Eur. J. Org. Chem., 2015, 1602; (b) J. E. Resek and F.-Z. Ren, Adv. Synth. Catal., 2018, 360, 1444.
A. I. Meyers, Tetrahedron Lett., 1995, 36, 7051; (c) F. Yuste, 13 (a) D. Liu, H.-X. Ma, P. Fang and T.-S. Mei, Angew. Chem.,
J. García Ruano, A. Parra and V. Mastranzo, Synthesis, 2008,
311; (d) M. Funes Maldonado, F. Sehgelmeble,
2019, 58, 5033; (b) Y. Wang, L. Deng, X. Wang, Z. Wu,
Yi Wang and Y. Pan, ACS Catal., 2019, 9, 1630.
F. Bjarnemark, M. Svensson, J. Åhman and P. I. Arvidsson, 14 For
a review, see: (a) G. M. Martins, B. Shirinfar,
Tetrahedron, 2012, 68, 7456; (e) F. Yuste, A. H. Linares,
V. M. Mastranzo, B. Ortiz, R. Sanchez-Obregon, A. Fraile
and J. L. Ruano, J. Org. Chem., 2011, 76, 4635;
(f) N. T. Nguyen, H. T. Vo, F. Duus and T. X. T. Luu,
Molecules, 2017, 22, 1458; (g) R. R. Tata, C. S. Hampton and
M. Harmata, Adv. Synth. Catal., 2017, 359, 1232.
3 A. R. Hajipour, A. R. Falahati and A. E. Ruoho, Tetrahedron
Lett., 2006, 47, 2717.
T. Hardwick and N. Ahmed, ChemElectroChem, 2019, 6,
1300. For selected examples, see: (b) Y. Yuan, Y. Chen,
S. Tang, Z. Huan and A. Lei, Sci. Adv., 2018, 4, eaat5312;
(c) Y. Wang, L. Deng, H. Mei, B. Du, J. Han and Y. Pan,
Green Chem., 2018, 20, 3444.
15 (a) G. Laudadio, N. J. W. Straathof, M. D. Lanting,
B. Knoops, V. Hessel and T. Noël, Green Chem., 2017, 19,
4061; (b) K.-S. Du and J.-M. Huang, Green Chem., 2018, 20,
1405; (c) G. Laudadio, E. Barmpoutsis, C. Schotten,
L. Struik, S. Govaerts, D. L. Browne and T. Noël, J. Am.
Chem. Soc., 2019, 141, 5664.
4 I. Fernandez, N. Khiar, A. Roca, A. Benabra, A. Alcudia,
J. L. Espartero and F. Alcudia, Tetrahedron Lett., 1999, 40,
2029.
This journal is © The Royal Society of Chemistry 2019
Green Chem., 2019, 21, 5528–5531 | 5531