Sulfonylation from sodium dithionite or thiourea dioxide

Article abstract of DOI:10.1016/j.cclet.2020.04.043

The cheap and easily available sodium dithionite and thiourea dioxide have been used as the source of sulfonyl group in the synthesis of sulfones and sulfonamides recently. Compared with other methods for the sulfonylation reactions, the strategies using sodium dithionite or thiourea dioxide provide an alternative and complementary route to diverse sulfonyl compounds. During the reaction process, sulfur dioxide anion radical is the key intermediate, which is usually generated from a single electron transfer under suitable conditions. The advantages using sodium dithionite or thiourea dioxide in the sulfonylation reactions include mild conditions and broad substrate scope with excellent functional group compatibility. Further applications by using sodium dithionite and thiourea dioxide in organic transformations will be anticipated.

Full text of DOI:10.1016/j.cclet.2020.04.043

Journal Pre-proof
Sulfonylation from sodium dithionite or thiourea dioxide
Fu-Sheng He, Min Yang, Shengqing Ye, Jie Wu
PII:
S1001-8417(20)30261-8
https://doi.org/10.1016/j.cclet.2020.04.043
CCLET 5622
DOI:
Reference:
To appear in:
Chinese Chemical Letters
Accepted Date:
23 April 2020
Please cite this article as: He F-Sheng, Yang M, Ye S, Wu J, Sulfonylation from sodium
dithionite or thiourea dioxide, Chinese Chemical Letters (2020),
doi: https://doi.org/10.1016/j.cclet.2020.04.043
This is a PDF file of an article that has undergone enhancements after acceptance, such as
the addition of a cover page and metadata, and formatting for readability, but it is not yet the
definitive version of record. This version will undergo additional copyediting, typesetting and
review before it is published in its final form, but we are providing this version to give early
visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal
pertain.
© 2020 Published by Elsevier.

Chinese Chemical Letters
journal homepage: www.elsevier.com
Highlight
Sulfonylation from sodium dithionite or thiourea dioxide
Fu-Sheng Hea, Min Yangb, Shengqing Yea, JieWua,c

aSchool of Pharmaceutical and Materials Engineering &Institute for Advanced Studies, Taizhou University, Taizhou 318000, China
bSchool of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
cState Key Laboratory ofOrganometallic Chemistry, Shanghai Institute of OrganicChemistry, Chinese Academy of Sciences, Shanghai 200032, China
Corresponding author.
Email address:jie_wu@fudan.edu.cn
Graphical Abstract
The cheap and easily available sodium dithionite and thiourea dioxide have been used as the source of sulfonyl group in the
synthesis of sulfones and sulfonamides recently. Compared with other methods for the sulfonylation reactions, the strategies
using sodium dithionite or thiourea dioxide provide an alternative and complementary route to diverse sulfonyl compounds.
ARTICLE INFO
ABSTRACT
Article history:
The cheap and easily available sodium dithionite and thiourea dioxide have been used as the
source of sulfonyl group in the synthesis of sulfones and sulfonamides recently. Compared with
other methods for the sulfonylation reactions, the strategies using sodium dithionite or thiourea
dioxide provide an alternative and complementary route to diverse sulfonyl compounds. During
the reaction process, sulfur dioxide anion radical is the key intermediate, which is usually
generated from a single electron transfer under suitable conditions. The advantages using
sodium dithionite or thiourea dioxide in the sulfonylation reactions include mild conditions and
broad substrate scope with excellent functional group compatibility. Further applications by
using sodium dithionite and thiourea dioxide in organic transformations will be anticipated.
Received 31 March 2020
Received in revised form 21 April 2020
Accepted 23 April 2020
Available online
Keywords:
Sodium dithionite
Thioureadioxide
Sulfones
Sulfonamides
Sulfur dioxide anion radical
———

Since
the
reagent
of
DABCO·(SO2)2
(1,4-
and a broad substrate scope with excellent functional group
tolerance was observed. For instance, 2-sulfonated adenosine
with free hydroxyl and amino groups was obtained in 56% yield.
diazabicyclo[2.2.2]octane-sulfur dioxide) developed by Santos
and Mello [1] was firstly applied in 2010 by Willis [2] and
potassium metabisulfite as the source of sulfur dixoide was
reported in 2012 by Wu [3], the strategies with the insertion of
sulfur dioxide under transition metal catalysis or radical
processes have been developed rapidly [4]. Among the inorganic
sulfites screened in the palladium-catalyzed reaction of aryl
halides with hydrazines, potassium metabisulfite was
demonstrated as the most efficient one [3]. Later, the
development of radical process was boomed, and potassium or
sodium metabisulfite was effective as well in the radical reactions
[4a,5]. So far, significant progress has been witnessed in this
field of sulfur dioxide insertion. As a result, diverse sulfonyl-
containing (-SO2-) compounds including sulfones and
sulfonamides are generated easily by using DABCO·(SO2)2 and
inorganic sulfites as the sulfur dioxide surrogates [6]. Compared
with the classical synthesis of sulfonyl compounds from the
oxidation of sulfides and sulfonylation with the corresponding
sulfonyl chlorides, the incorporation of sulfonyl unit into small
molecules through the insertion of sulfur dioxide provides an
alternative and complementary route. Besides the reagent of
DABCO·(SO2)2 and inorganic sulfites (potassium or sodium
metabisulfite), other sources are also explored for the generation
of sulfonyl compounds. For example, Rongalite, commonly used
as a bleaching agent in the printing and dyeing industry, was used
as the source of sulfonyl group as well [7,8]. Luo and co-workers
described the iron-catalyzed reaction between rongalite and
diaryliodonium salts [8a]. In this transformation, rongalite was
used as the sulfoxylate anion radical precursor. Wu and co-
workers reported the synthesis of N-aminosulfonamide through a
metal-free reaction of rongalite with aryldiazonium
tetrafluoroborates [8b]. During the reaction process, rongalite
was found to serve as a radical initiator, a sulfur dioxide
surrogate and a reducing reagent simultaneously.
Scheme 1. Generation of sulfones and sulfonamides starting from
(hetero)aryl iodides and sodium dithionite under catalyst-free
conditions.
Later, Jiang and co-workers reported the construction of
sterically bulky sulfones through
a
multicomponent
decarboxylative reaction of N-hydroxyphthalimide esters, sodium
dithionite, and electrophiles (Scheme 2) [11]. In this
transformation, sodium dithionite served as the radical initiator
for the decarboxylation as well as the sulfonyl source. It was
noteworthy that the reactions of diverse naturally abundant
carboxylic acids and other carboxyl-containing drugs with
multiple heteroatoms and sensitive functional groups proceeded
smoothly with decarboxylative sulfonylation, leading to sterically
bulky tertiary sulfones in moderate to good yields. The
mechanistic studies were performed, which revealed that sulfur
dioxide radical anion generated from sodium dithionite would
undergo a single electron transfer (SET) process with carboxylic-
derived redox-active ester assisted by ZnCl2, giving rise to
sterically hindered carbon radical with the extrusion of CO2. This
sterically hindered carbon radical intermediate would react with
sulfur dioxide radical anion to produce sulfinate salt, which
would be trapped by electrophile leading to the corresponding
sulfone.
Recently, sodium dithionite and thiourea dioxide have
attracted our attention, which are cheap and easily available. It is
reported that sodium dithionite (Na2S2O4) can be used as a
reductant in various organic transformations [9]. Additionally, it
can be used as the sulfoxylate anion radical precursor as well. In
the iron-catalyzed reaction of rongalite and diaryliodonium salts
as mentioned above [8a], sodium dithionite was also employed as
a replacement of rongalite, although the yield was low. Since the
commercially available and cheap sodium dithionite as
sulfoxylate anion radical precursor could produce the SO2 anion
radical, the application of sodium dithionite in the sulfonylation
reactions could be expected.
In 2019, Wu and co-workers described the generation of
sulfones and sulfonamides starting from (hetero)aryl iodides and
sodium dithionite under catalyst-free conditions (Scheme 1) [10].
During the reaction process, sodium dithionite acted as a
reductant and reacted with (hetero)aryl iodide leading to
(hetero)aryl radical and sulfur dioxide. The (hetero)aryl radical
would further combine with SO2 anion radical to provide the
corresponding sodium sulfonate, which would be trapped by
electrophile to furnish sulfones or sulfonamides in one pot under
suitable conditions. The control experiments and several EPR
experiments confirmed that (hetero)aryl radical intermediate
would be produced from (hetero)aryl iodidein the presence of
sulfur dioxide radical anion. The reaction conditions were mild,

thiourea dioxide would be converted to sulfur dioxide anion and
urea in the presence of base [13]. Wu and co-workers disclosed
the generation of heteroaryl sulfones and sulfonamides from
heteroaryl halides and thiourea dioxide in the presence of sodium
hydroxide under visible light irradiation (Scheme 4) [14]. This
transformation also went through heteroaryl sulfinate
intermediates, which were trapped subsequently by various
electrophiles. The conditions were suitable for diverse substrates,
especially for the electron-deficient heteroaryl halides. Control
experiments showed that heteroaryl radical generated in situ
would couple with sulfur dioxide radical anion during the
reaction process with the assistance of photoredox catalyst, as
supported by EPR spectroscopy and DFT calculations.
Scheme 2. Multicomponent decarboxylative reaction of N-
hydroxyphthalimide esters, sodium dithionite, and electrophiles.
In Wu’s report [10], the three-component reaction of
iodobenzene, sodium dithionite, and alkyl bromide gave a low
yield (18%). Jiang and co-workers described an improved
procedure by using palladium catalyst in the reaction system
(Scheme 3) [12]. In this transformation, phosphate esters were
used as the electrophiles to capture the sulfinate intermediate.
The addition of palladium catalyst would be beneficial for the
final outcome. Initially, an oxidative addition of Pd(0) with aryl
iodide would take place leading to Pd(II) complex, which would
undergo a single electron transfer with sulfur dioxide radical
anion to provide another Pd(II) complex. Further reductive
elimination would occur to produce the corresponding sulfinate
intermediate.
Scheme 4. Synthesis of heteroaryl sulfones and sulfonamides from
heteroaryl halides and thiourea dioxide under visible light irradiation.
Wu and co-workers further developed the sulfonylation of
alkenes through photoredox-catalyzed functionalization of
alkenes with thiourea dioxide under visible-light irradiation
(Scheme 5) [15]. Alkyl sulfones and sulfonamides could be
easily accessed through a reaction of alkenes, thiourea dioxide
and electrophiles withbroad substrate scope.Good functional
group compatibility and excellent regioselectivity were observed.
A plausible mechanism supported by fluorescence quenching
experiments was proposed, involving a radical addition process
-
Scheme 3. Palladium-catalyzed reaction of (hetero)aryl iodides,
sodium dithionite and phosphate esters.
with sulfur dioxide radical anion (SO2 ) derived from the
2-
oxidation of sulfur dioxide anion (SO2 ) under visible-light
irradiation.
Thiourea dioxide is a good alternative as well for the
introduction of sulfonyl group into small molecules, since

using sodium dithionite and thiourea dioxide in organic
transformations will be anticipated.
Declaration of interests
The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
Financial support from the National Natural Science
Foundation of China (Nos. 21871053 and 21532001) and the
Leading Innovative and Entrepreneur Team Introduction
Program of Zhejiang (No. 2019R01005) is gratefully
acknowledged.
Scheme 5. Photoredox-catalyzed functionalization of alkenes
with thiourea dioxide under visible-light irradiation
References
Followed by Wu’s report [14,15], Jiang and co-workers
described the synthesis of sulfones from alkyl bromide, thiourea
dioxide and phosphate esters (Scheme 6) [12]. Again, thiourea
dioxide was used as a reductive sulfur dioxide surrogate, and the
alkylsulfones were obtained in moderate to good yields. A
similar reaction pathway was proposed, which showed that the
sulfur dioxide radical anion formed from thiourea dioxide in the
presence of caesium carbonate would initiate the reaction.The
resulting alkyl sulfinate salt would be captured by phosphate
ester, giving rise to the desired alkylsulfone.
[1] P.S. Santos, M.T.S. Mello, J. Mol. Struc.178 (1988) 121-133.
[2] B. Nguyen, E.J. Emmet, M.C. Willis, J. Am. Chem. Soc.132
(2010) 16372-16373.
[3] S. Ye, J. Wu, Chem. Commun. 48 (2012) 10037-10039.
[4] (a) G. Qiu, K. Zhou, L. Gao, J. Wu, Org. Chem. Front. 5 (2018)
691-705.
(b) K. Hofman, N. Liu, G. Manolikakes, Chem. -Eur. J. 24
(2018) 11852-11863.
(c) D. Zheng, J. Wu, Sulfur Dioxide Insertion Reactions for
Organic Synthesis, Nature Springer: Berlin, 2017.
(d) G. Liu, C. Fan, J. Wu,Org. Biomol. Chem.13 (2015) 1592-
1599.
(e) E.J. Emmett, M.C. Willis, Asian J. Org. Chem. 4 (2015) 602-
611.
(f) A.S. Deeming, E.J. Emmett, C.S. Richards-Taylor, M.C.
Willis, Synthesis 46 (2014) 2701-2710.
(g) P. Bisseret, N. Blanchard, Org. Biomol. Chem. 11 (2013)
5393-5398.
(h) G. Qiu, L. Lai, J. Cheng, J. Wu, Chem. Commun. 54 (2018)
10405-10414.
(i) G. Qiu, K. Zhou, J. Wu, Chem. Commun. 54 (2018) 12561-
12569.
(j) S. Ye, G. Qiu, J. Wu, Chem. Commun. 55 (2019) 1013-1019.
(k) S. Ye, M. Yang, J. Wu, Chem. Commun. 56 (2020) 4145-
4155.
(l) M. Wang, X. Jiang, Chin. Sci. Bull. 63 (2018) 2707-2716.
[5] (a) D. Zheng, Y. An, Z. Li, J. Wu, Angew. Chem., Int. Ed. 53
(2014) 2451-2454.
Scheme 6. Synthesis of sulfones from alkyl bromide, thiourea
dioxide and phosphate esters.
(b) D. Zheng, J. Yu, J. Wu, Angew. Chem., Int. Ed. 55 (2016)
11925-11929.
[6] (a) Z. Chen, N.W. Liu, M. Bolte, H. Ren, G. Manolikakes, Green
Chem. 20 (2018) 3059-3070.
(b) Q. Lin, Y. Liu, Z. Xiao, et al., Org. Chem. Front. 6 (2019)
447-450.
(c) X.Y. Qin, L. He, J. Li, et al., Chem. Commun. 55 (2019)
3227-3230.
(d) R.J. Reddy, A.H. Kumari, J.J. Kumar, J.B. Nanubolu, Adv.
Synth. Catal. 361 (2019) 1587-1591.
(e) L. Lu, C. Luo, H. Peng, et al., Org. Lett. 21 (2019)2602-2605.
(f) S. Ye, D. Zheng, J. Wu, G. Qiu, Chem. Commun. 55 (2019)
2214-2217.
In conclusion, the cheap and easily available sodium dithionite
and thiourea dioxide have been used as the source of sulfonyl
group in the synthesis of sulfones and sulfonamides recently.
Compared with other methods for the sulfonylation reactions, the
strategies using sodium dithionite or thiourea dioxide provide an
alternative and complementary route to diverse sulfonyl
compounds. During the reaction process, sulfur dioxide anion
radical is the key intermediate, which is usually generated from a
single electron transfer under suitable conditions. The advantages
using sodium dithionite or thiourea dioxide in the sulfonylation
reactions include mild conditions and broad substrate scope with
excellent functional group compatibility. Further applications by
(g) J. Zhang, W. Xie, S. Ye, J. Wu, Org. Chem. Front. 6 (2019)
2254-2259.

(h) Y. Chen, P.R.D. Murray, A.T. Davies, M.C. Willis, J. Am.
Chem. Soc. 140 (2018) 8781-8787.
(d) P. Cao, C.Y. Li, Y.B. Kang, et al., J. Org. Chem. 72 (2007)
6628-6630.
(i) B. Ni, B. Zhang, J. Han, et al., Org. Lett. 22 (2020) 670-674.
(j) K. Zhou, J.B. Liu, W. Xie, S. Ye, J. Wu, Chem. Commun. 56
(2020) 2554-2557.
(k) J. Zhang, M. Yang, J.B. Liu, F.S. He, J. Wu, Chem.
Commun. 56 (2020) 3225-3228.
(l) X. Gong, M. Yang, J.B. Liu, et al., Green Chem. 22 (2020)
1906-1910;
(m) S. Ye, K. Zhou, P. Rojsitthisak, J. Wu, Org. Chem. Front. 7
(2020)14-18.
(n) K. Chen, W. Chen, B. Han, et al., Org. Lett. 22 (2020) 1841-
1845.
[7] S. Kotha, P. Khedkar, Chem. Rev. 112 (2012) 1650-1680.
[8] (a) W. Zhang, M. Luo, Chem. Commun. 52 (2016) 2980-2983.
(b) M. Wang, B.C. Tang, J.G. Wang, et al., Chem. Commun.54
(2018) 7641-7644.
(e) S. Oda, H. Shimizu, Y. Aoyama, et al.,Org. Process Res. Dev.
16 (2012) 96-101.
(f) I.S. Kondratov, M.Y. Bugera, N.A. Tolmachova, et al., J. Org.
Chem. 80 (2015) 12258-12264.
[10] Y. Li, T. Liu, G. Qiu, J. Wu,Adv. Synth. Catal. 361 (2019)
1154-1159.
[11] Y.Li, S.Chen, M.Wang, X. Jiang, Angew. Chem. Int. Ed. (2020)
DOI: 10.1002/anie.202001589.
[12] S. Chen, Y. Li, M. Wang, X. Jiang, Green Chem. 22 (2020)
322-326.
[13] (a) E.B. Barnett,J. Chem. Soc. 97 (1910) 63-65.
(b) K. Nakagawa, K. Minami, Tetrahedron Lett. 13 (1972) 343-
346.
(c) R.C.L. Mangoni, G. Palumbo, L. Previtera,Tetrahedron Lett.
(1975) 1041-1042.
(c) A. Shavnya, S.B. Coffey, K.D. Hesp, S.C. Ross, A.S. Tsai,
Org. Lett. 18 (2016) 5848-5851.
(d) R.B. dos Santos, T.J. Brocksom, U. Brocksom, Tetrahedron
Lett. 38 (1997) 745-748.
[9] (a) Z.Y. Long, Q.Y. Chen, J. Org. Chem. 64 (1999) 4775-4782.
(b) M.O. Ratnikov, D.L. Lipilin, A.M. Churakov, Y.A.
Strelenko, V.A. Tartakovsky,Org. Lett. 4 (2002) 3227-3229.
(c) H.J. Xu, Y.C. Liu, Y. Fu, Y.D. Wu,Org. Lett. 8 (2006) 3449-
3451.
[14] S. Ye, Y. Li, J. Wu, Z. Li, Chem. Commun. 55 (2019) 2489-
2492.
[15] Y. Li, J.B. Liu, F.S. He, J. Wu, Chin. J. Chem. 38 (2020) 361-
366.