the renaissance of alkali metabisulfites as so2 surrogates
TRANSCRIPT
232
A. K. Sahoo et al. ReviewSynOpen
SYNOPEN2 5 0 9 - 9 3 9 6Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart2021, 5, 232–251
reviewen
The Renaissance of Alkali Metabisulfites as SO2 SurrogatesAshish Kumar Sahoo
Anjali Dahiya
Amitava Rakshit
Bhisma K. Patel* 0000-0002-4170-8166
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati-781039, [email protected]
Corresponding AuthorBhisma K. PatelDepartment of Chemistry, Indian Institute of Technology Guwahati, Guwahati-781039, IndiaeMail [email protected]
R + SO2
Smallmolecules
R SO
O
Sulfones&
SulfonamidesX = N2, Cl, Br, IB(OH)2 etc.
Cheap, abundant& safe SO2 source
Synthesis of bioactivesulfonyl compounds
Alkalimetabisulfites
TM
TM
R X
1–3
Received: 08.07.2021Accepted after revision: 03.08.2021Published online: 03.08.2021DOI: 10.1055/a-1577-9755; Art ID: so-2021-d0035-rvLicense terms:
© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
Abstract The upsurge of interest in the development of methodolo-gies for the construction of sulfur-containing compounds via the use ofexpedient reagents has established sustainable tools in organic chemis-try. This review focuses on sulfonylation reactions using inorganic sul-fites (Na2S2O5 or K2S2O5) as the sulfur dioxide surrogates. Compared tothe bis-adduct with DABCO, which is an excellent surrogate of gaseousSO2, the use of sodium or potassium metabisulfites as SO2 surrogatesare equally efficient. The objective of the current review is to exemplifyrecent sulfonylation reactions using inorganic sulfites. For better under-standing, the review is categorized according to the mode of reactions:transition-metal-catalyzed SO2 insertion, metal-free SO2 insertion, andvisible-light-mediated SO2 insertion. All the reactions in each of the sec-tions are illustrated with selected examples with a pertinent explana-tion of the proposed mechanism.1 Introduction2 Outlines of the Reactions Involving SO2 Insertion2.1 Transition-Metal-Catalyzed SO2 Insertion2.2 Transition-Metal-Free SO2 Insertion2.3 Visible-Light-Mediated SO2 Insertion3 Conclusion and Outlook
Key words DABCO·(SO2)2, sodium or potassium metabisulfite, SO2
surrogate, sulfonylation reaction, SO2 insertion
1 Introduction
In the past decades, the insertion of sulfone functional-
ity into organic molecules has garnered much attention be-
cause of the versatile reactivity and enhanced properties of
the generated moieties. Owing to their unique chemical
and biological activity, compounds possessing a sulfone
backbone are privileged structural motifs in many clinical
drugs, natural products and agrochemicals (Figure 1). In
pharmaceuticals, the sulfone moiety has been explored ex-
tensively because of the biological activities that it can im-
part, such as anti-inflammatory, antimicrobial, anticancer,
anti-HIV, and antimalarial action. In particular, Vismodeg-
ib® is an anti-cancer agent, Adociaquinone® is used for the
treatment of breast cancer, and Tinidazole® and Amisul-
pride® are used as anti-inflammatory and anti-psychotic
drugs, respectively (Figure 1).4 Besides their use in the me-
dicinal field, sulfone-containing compounds display a wide
range of reactivity in the field of synthetic organic chemis-
try and the moiety can act as a leaving group; therefore, it
has been designated as a ‘chemical chameleon’ by Trost.5
Figure 1 Representative active sulfone-containing molecules
Given the various applications of sulfones, synthetic
chemists have long attempted to find new pathways to in-
corporate this important structural motif. Traditional
methods used for the synthesis of such scaffold soften re-
quire multistep reactions and utilize pre-functionalized
sulfonyl compounds such as sulfonyl halides,6–9 sulfonyl
SMe
SMe
OONN
CONH2
OH
Me
SMe
OO
ON
O
N NMe
HO
Cl
SMe
OO
O
NHCl
N
S
HN
O
Me
O
O
O OO
SEt
OO
N
N
O2N
Me
SEt
OO
MeO NH2
NH
O
NEt
S
OO
NH
NMe
Cranloformin(Natural product)
Topramezone(Herbicides)
Vismodegib(Anti-cancer drug)
Amisulpride(Anti-psychotic)
Tinidazole(Anti-inflammatory drug)
Adociaquinone(Breast cancer)
Eletriptan(Anti-migraine)
© 2021. The Author(s). SynOpen 2021, 5, 232–251Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany
233
A. K. Sahoo et al. ReviewSynOpen
hydrazines,10–13 and sodium sulfinates.14–16 To overcome
these shortcomings, chemists started to explore various
sulfur dioxide surrogates as the source of sulfur dioxide in
the sulfonylation reactions. With the use of sulfur dioxide
surrogates, it is possible to avoid the problem of handling
toxic, gaseous sulfur dioxide. The reagent 1,4-diazabicyclo-
[2.2.2]octane-sulfur dioxide (DABSO or [DABCO·(SO2)2])
was reported by Willis et al. as the first sulfur dioxide
Biographical Sketches
Bhisma Kumar Patel (born inAugust 1965) received his B.Sc(Hons) and M.Sc degrees fromSambalpur University, Odisha,India. He was admitted to IITKanpur for his PhD in theresearch group of Prof. S.Ranganathan (FNA) (1988–1994). After three years of post-doctoral tenure with Prof. DrFritz Eckstein at the Max-PlanckInstitute for Experimental Medi-cine (1994–1997), he joined the
Department of Chemistry,Indian Institute of TechnologyGuwahati as an Assistant Profes-sor in April 1997, where he waselevated to the post of Full Pro-fessor in August 2005, and HAGProfessor in September 2011and continued as the Head ofthe Department. His current re-search interests include greenchemistry, C–H activation, crossdehydrogenative coupling,metal-catalyzed/metal-free oxi-
dative functionalization, multi-component reactions and hy-pervalent iodine mediatedorganic transformations. Alto-gether 25 students have beenawarded PhD degrees under hissupervision and his researchwork has resulted in the publi-cation of 162 research papers injournals of international repute,and three patents.
Ashish Kumar Sahoo wasborn in 1994 in Odisha, India.He received his BSc. from UtkalUniversity and M.Sc. and M.Phil.both from North Orissa Univer-sity, Odisha. He qualified for the
CSIR National Eligibility Test &GATE in 2016 and is currentlypursuing his doctoral researchunder the supervision of Prof.Bhisma K. Patel at the Indian In-stitute of Technology in Guwa-
hati (India). His researchprimarily focuses on photoredoxcatalysis and radical-based C–Hfunctionalization.
Anjali Dahiya was born in1993 in Haryana, India. She re-ceived her BSc (Hons.) and MSc.degrees from Hansraj College,Delhi University in 2013 and2016 respectively. She qualifiedfor the CSIR National Eligibility
Test & GATE in 2016 and is cur-rently pursuing her doctoral re-search under the supervision ofProf. Bhisma K. Patel at the Indi-an Institute of Technology inGuwahati (India). Her researchinterests focus on the develop-
ment of new sustainable meth-odologies for the constructionof C–C and C–Heteroatombonds in a one-pot cascademanner.
Amitava Rakshit was born in1993 in West Bengal, India. Hereceived his B.Sc. (Hons.) de-gree from Bankura ChristianCollege, The University of Burd-wan in 2014 and MSc. degree
from IIT Kharagpur in 2016. Hequalified for the CSIR NationalEligibility Test & GATE in 2016and is currently pursuing hisdoctoral research under the su-pervision of Prof. Bhisma K.
Patel at the Indian Institute ofTechnology in Guwahati (India).His research focuses primarilyon nitrile-triggered access of N-heterocycles via thermal andphotochemical processes.
SynOpen 2021, 5, 232–251
234
A. K. Sahoo et al. ReviewSynOpen
surrogate in a palladium-catalyzed amino sulfonylation re-
action.17 In 1988, Santos and Mello reported DABCO·(SO2)2
as a stable and innocuous reagent.18 However, the synthesis
of DABCO·(SO2)2 is performed at –78 °C using gaseous sulfur
dioxide. Moreover, the process is neither atom-economic
nor cost-effective as a large excess of 1,4-diazabicyclo-
[2.2.2]octane (DABCO) is used during the reaction. Al-
though the application of DABCO·(SO2)2 in sulfonylation re-
actions has developed rapidly in the past few years, chem-
ists still strive to find an alternative to DABSO, which can be
utilized as a better sulfur dioxide surrogate.19 In this per-
spective, the use of inorganic sulfites such as K2S2O5 or
Na2S2O5 is demonstrated to be attractive and to offer suit-
able alternative sulfur dioxide surrogates for the synthesis
of sulfonylated compounds. Such inorganic sulfites are in-
expensive, readily available, and environmentally benign,
providing an atom-economic route for the synthesis of an
array of sulfonyl compounds, including sulfones and sulfon-
amides. Indeed, more reports using inorganic sulfites as the
source of sulfur dioxide have started appearing.20 Sulfonyla-
tion reactions utilizing these alkali metabisulfites could be
performed under transition-metal catalysis or through a
radical process under metal or additive-free conditions. In
some cases, a photocatalyst is necessary to promote the re-
action under visible-light irradiation. Although some as-
pects of this fast-developing area has been covered in a few
reviews, the primary objective of the present review is to
bring the latest uses of alkali metabisulfites to the fore.21,22
For convenience, this review is divided into three categories
based on the SO2 insertion strategy during the sulfonylation
reaction: (i) transition-metal-catalyzed SO2 insertion; (ii)
transition-metal-free SO2 insertion; and (iii) visible-light-
mediated SO2 insertion.
2 Outlines of the Reactions Involving SO2 Insertion
2.1 Transition-Metal-Catalyzed SO2 Insertion
Although several methodologies have been developed
for SO2 insertions, the transition-metal-catalyzed SO2 inser-
tion is still in demand due to its remarkable catalytic activi-
ty and better selectivity.23
Sulfonamides are found in many pharmaceuticals and
biologically active compounds and hence the development
of new methodologies is deemed worthy.24 A three-compo-
nent reaction of an arylboronic acid, nitroarene (1), and po-
tassium metabisulfite under copper catalysis was estab-
lished by Wu et al. yielding a variety of sulfonamides. Vari-
ous functional groups including hydroxy-, cyano-, amino-
and carbonyl were well tolerated in this strategy (Scheme
1).25
Scheme 1 Synthesis of phenyl N-aryl sulfonamides using nitrobenzene and boronic acids
According to the mechanism (Scheme 2), the copper-
catalyzed addition of K2S2O5 with an aryl boronic acid gen-
erates an arylsulfinate intermediate (d). Further, a copper-
assisted nucleophilic interaction of intermediate (e) with
nitroarene (1) gives rise to intermediate (1e) followed by
protonation to afford intermediate (1f). The intermediate
(1f) undergoes reduction with isopropanol, producing a
sulfonyl hydroxylamine (1g), which, on further reduction,
affords the final product 2.
Scheme 2 Proposed mechanism for the formation of phenyl N-aryl sul-fonamide derivatives
A similar approach was reported by Wu et al. for the
synthesis of sulfonamides 4, which proceeds via a Pd-cata-
lyzed coupling of aryl halides 3, hydrazines, and potassium
metabisulfite. Both aryl iodides, as well as aryl bromides,
reacted smoothly under identical reaction conditions. How-
ever, aryl chlorides and alkyl halides were demonstrated
not to be substrates in this conversion (Scheme 3).26
Scheme 3 Synthesis of sulfonamides using aryl halides
NO2
70 °C, 48 h
SNH
O O
K2S2O5(1)(2)
R1
R2
(2a, 68%)
BHO OH
R2
R1
SNH
O O
(2b, 75%)
SNH
O O
(2c, 80%)
SNH
O O
(2e, 75%)
SNH
O O
MeO2C
(2f, 90%)
SNH
O O
NH
(2g, 92%)
Cu(MecCN)4PF6 (20 mol%)
1,10-phenanthroline (10 mol%)iPrOH (2.0 equiv), NMP
Cl
SNH
O O
Cl
Cl
NC Me(2d, 82%)
SNH
O O
Cl
LnCu Ar
ArBHO
HO
K2S
2O5 LnCu
SO2SO3
Ar
2
SO32
LnCu SO2Ar
CuLn SOAr
O
Cu
SO
ArO
CuN
Ar
OO
SO
ON
Ar O
OAr
Cu
–Cu+ SO
ON
Ar O
OHAr
iPrOH–H2O–Me2CO
ArS
N
O OAr
OH
iPrOH
–H2O–Me2CO
ArS
NH
O OAr
(a)
(b)
(c)
(d)
(1e) (1f)
(1g)
(2)
+
(e)
(1)
+H+
XH2N N
R2
R3
Pd(OAc)2 (5 mol%) PtBu3·HBF4
TBAB, 1,4-dioxane 80 °C
SNH
O ON
R2
R3
K2S2O5
X = I, Br(3) (4)
R1
R1
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235
A. K. Sahoo et al. ReviewSynOpen
In 2019, the Ramon group demonstrated a copper-cata-
lyzed synthesis of sulfonamides 6 from triaryl bismuthines
5, sodium metabisulfite, and nitro compounds as the amino
source in a deep eutectic solvent. It was found that sub-
strates containing neutral, electron-withdrawing, and elec-
tron-donating substituents all gave products in moderate to
good yields. The reaction was successful for the aliphatic
nitrocyclohexane, although a lower yield of the desired
product was obtained (Scheme 4).27
Scheme 4 Synthesis of phenyl N-aryl sulfonamide derivatives using nitrobenzene
Manabe et al. in 2017, demonstrated an elegant method
for the synthesis of sulfonamides 8 and sulfinamides 8′
from heteroarenes 7 bearing an amino group and K2S2O5 as
the SO2 surrogate. In this protocol, the selectivity is gov-
erned by the nature of the ligand and the equivalents of the
base used. The protocol covers a wide range of cyclic
amines with good functional group tolerance. From the
mechanistic investigations, the group confirmed the gener-
ation of sulfonamides, which are converted into sulfon-
amides in the presence of ≤1.0 equiv of the base. In the pro-
cess, sulfinamides are produced through an unprecedented
insertion of sulfur monoxide, and products were obtained
via oxidation using an iodide/DMSO combination. The pres-
ence of iodide and DMSO is vital for the successful conver-
sion of sulfinamides into sulfonamides (Scheme 5).28
Scheme 5 Synthesis of cyclic sulfonamides
Recently, Jiang and co-workers reported a similar multi-
component approach for the reductive coupling of sodium
metabisulfite (Na2S2O5), 4-iodotoluene (9), and n-butyl bro-
mide in the presence of a Pd-catalyst and potassium hydro-
gen phosphate. Important features of this protocol are the
broad substrate scope, tolerance of various functional
groups, simple and cheap coupling partner, and high yields
of the products (Scheme 6).29
Scheme 6 Synthesis of sulfonyl derivatives using alkyl bromides as the coupling partner
From the control experiments performed, a suitable
mechanism was proposed. Initially, the n-butyl radical is
generated via a single-electron transfer between alkyl ha-
lide and tin, which reacts with sodium metabisulfite to give
sulfonyl intermediate (a). The intermediate (a) undergoes
reduction with tin, giving sulfonyl anion intermediate (b).
Intermediate (b) then reacts with intermediate 9a (generat-
ed via the oxidative addition of Pd(0) and aryl halide) to
give intermediate 9c. Reductive elimination of intermediate
9c provides the sulfonylated product 10 (Scheme 7).
Scheme 7 Proposed mechanism for the formation of aryl alkyl sul-fones
Since methyl sulfones are privileged scaffolds in many
pharmaceuticals, synthesis of such molecules has attracted
considerable attention.21 For example, Vismodegib® (Figure
1) is a basal-cell carcinoma treatment that was first ex-
plored by Roche. Xiidra® (Figure 2) has been applied for dry
eye disease as an ophthalmic solution.30
An elegant synthesis of -methylsulfonylated N-hetero-
cycles (12 or 12′) via FeCl3-catalyzed C(sp3)–H dehydroge-
nation and C(sp2)–H methylsulfonylation of unactivated cy-
clic amines using sodium metabisulfite and dicumyl perox-
ide (DCP) has been demonstrated by the Fan group.
However, in this method, DCP serves as an oxidant as well
Ph3Bi
Na2S2O5NO2
O
ON Cl
O
NH2(1:2) 0.4 M
CuCl (1 mol%), 80 °C, 24 h PhS
OO
NH
RR
PhS
OO
NH
OMe
PhS
OO
NH
NH2
PhS
OO
NH
Cl PhS
OO
NH Cl
PhS
OO
NH
PhS
OO
NH
(6a, 69%) (6b, 87%) (6c, 79%)
(6d, 72%) (6f, 85%)(6e, 21%)
(5) (6)
+
I
K2S2O5
Bu3N, DMSO, 100 °C
Pd(OAc)2 (10 mol%)PCy3 (20 mol%)
Pd(OAc)2 (10 mol%)tBu3PHBF4 (20 mol%)
Bu3N, DMSO, 100 °C
NSO
R( ) n
NS
R( ) n
OO
R1
R1
(7)
(8)
(8')
+
NHR
Na2S2O5
R-Br
Pd(dppf)Cl2, dppfSn, K2HPO4.3H2O
TBAB, DMSO100 °C
SOO
R
NH
SnBu
OO
(9) (10)
(10a, 68%)
SO O
Ph
(10b, 60%)
SnBu
OO
S
(10c, 72%)
S SO
O
SO O O
OO O
(10f, 70%)(10d, 67%) (10e, 82%)
R1R1
I
+
nBuBrnBu
1/2 Sn 1/2 SnBr2
Na2S2O5
Na2SO3nBu
SO
O
nBu
SO
O
1/2 Sn
1/2 Sn2+
Pd0LnI PdII X2Ln
ArI
Ar Pd
Ln
S
O
O
nBu
Ar Pd IILn
I
ArS
nBu
O O
(10)
(a)
(b)
(9a)
(9c)
(9)
Pd catalytic cycle radical coupling
SynOpen 2021, 5, 232–251
236
A. K. Sahoo et al. ReviewSynOpen
as a methyl radical source to generate a methyl sulfonyl
radical. This protocol provided several -methylsulfonylat-
ed tetrahydropyridines, tetrahydroazepines, and pyrroles in
one-pot (Scheme 8).31
Scheme 8 Synthesis of -methylsulfonylated N-heterocycles
In the proposed mechanism, the methyl radical initially
generated from DCP is captured by sulfur dioxide to give a
methylsulfonyl radical (a) along with the formation of ace-
tone. Meanwhile, compound 11 is oxidized by Fe(III) to de-
liver a radical cation intermediate 11a, which undergoes
dehydrogenation to produce an iminium intermediate 11b
and PhC(Me)2OH. Subsequently, enamine intermediate 11c
is generated via -hydrogen abstraction by DABCO or
PhC(Me)2O–. Next, the methylsulfonyl radical intermediate
A undergoes addition with the enamine intermediate 11c
to provide intermediate 11d, which, upon Fe(III)-promoted
oxidation, gives cationic species 11e. The final product 12 is
obtained upon loss of a proton (Scheme 9).
Similarly, Jiang et al. demonstrated an efficient method
for the synthesis of methyl sulfones 14 involving a three-
component cross-coupling protocol of boronic acid 13,
sodium metabisulfite, and dimethyl carbonate. Important
features of the reaction include a wide range of substrate
scope, and good functional group tolerance Among the var-
ious ligands tested, it was found that electron-rich and ster-
ically hindered phosphine ligands are more suitable for the
desired conversion (Scheme 10).32
Scheme 10 Synthesis of sulfonyl derivatives using dimethyl carbonate as the methylating agent
Synthesis of o-substituted diaryl sulfones 16 via a multi-
component reaction of arylboronic acid 15, potassium met-
abisulfite, and diaryliodonium salt was demonstrated by Tu
et al. in 2019 using an acenaphthoimidazolylidene gold
complex as the catalyst (Scheme 11).33 The sterically hin-
dered aryl groups in diaryliodonium salts are preferentially
transformed over less bulky ones during the process, which
might be due to the better stability of the bulky Ar+ formed
from diaryliodonium salt. A wide variety of diaryl sulfones
could be obtained using various arylboronic acids and
aryldiazonium salts.
Scheme 11 Synthesis of diaryl sulfones using boronic acid and di-aryliodonium salts
Figure 2 Sulfone-containing drug Xiidra®
NH
N O
O
Cl
Cl
OO OH
xiidra (opthalmic solution)
SO OMe
NR1
R2
Na2S2O5
(11)(12')
(12)
(12a, 71%)
O OPh
MeMe
Me
Ph
Me FeCl3, DABCO
MeCN140 °C, 2 h
NR1
R2
S MeOO
n = 1, 2
n = 0
R2 = HNR1
SMe
O O
N
S MeOO
MeONPh
SMe
O
O
(12b, 71%)
N
SMe
O
O
(12c, 78%)
MeO
NS
MeO O
NC
(12'a, 41%)
NS
MeO O
MeO2C
(12'b, 43%)
n
n
Scheme 9 Proposed mechanism for the formation of aryl alkyl sul-fones
O OPh
MeMe
Me
Ph
Me heatO
Me
Ph
MeMe
OMe
Ph
Na2S2O5SMe
O
O
NR1
FeIII FeII
NR1
OMe
Ph
Me
OHMe
Ph
Me
NR1
OMe
Ph
Me
OMe
Ph
Me
NR1
OMe
Ph
Me
OHMe
Ph
Me
DABCO
NR1
S MeOO
FeIIIFeII
NR1
S MeOO
Me
Ph
MeOH
Me
Ph
MeO
DABCONR1
S MeOO
(11) (11a) (11b) (11c)
(11d)(11e)(12)
(a)
NR1
(11c)
Na2S2O5
O
OMeMeOPdCl2, tBuXPhos
TBAB, DMF120 °C
SMe
OO
R R
B(OH)2
SMe
OOO
O
(13) (14)
(14a, 61%)
SMe
OO
(14b, 59%)
SMe
OO
(14c, 73%)
SMe
OO
N
(14d, 74%)
OOO
MeMe
O
O
OMe
Me(14e, 85%)
SMe
OO
+
Ar B(OH)2
RI
Ar'
K2S2O5 5 mol% NHC-Au
ArS
Ar'
OO
(15) (16)
S
SMes
OOSOO
MeO
iPr
iPriPr
SMes
OO
(16b, 50%) (16c, 74%)(16a, 81%)
N N
AuCl
NHC-Au
+
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237
A. K. Sahoo et al. ReviewSynOpen
According to the proposed mechanism, initial trans-
metalation of NHC-Au(I) with arylboronic acid 15 provides
NHC-Au-Ar species 15a. This is then followed by the inser-
tion of SO2 to provide a sulfonyl Au(I) complex 15b. The
NHC-AuSO2-Ar (15b), furnishes an aryl sulfonyl radical in-
termediate 15c in the presence of base. The combination of
intermediate 15c with the more stable bulky Ar+ species
(a), generated from diaryliodonium salt, affords the steri-
cally hindered diaryl sulfone 16 (Scheme 12).
Scheme 12 Proposed mechanism for the formation of diaryl sulfones
By utilizing the same SO2 insertion strategy, the Jiang
group reported a method for the synthesis of diarylannulat-
ed sulfones 18 and 18′ using Na2S2O5 as SO2 surrogate. The
diarylannulated sulfones were synthesized via SO2/I ex-
change of iodonium (III) salts 17. By this protocol, a new
type of OLED material was synthesized on gram scale with
good functional group tolerance, permitting a broad range
of substrate scope (Scheme 13).34
Scheme 13 Synthesis of diaryl annulated sulfones
Often, compounds having a furan2(5H)-one backbone
have high biological activity.35a For example, Rofecoxib®
(Figure 3) is an anti-inflammatory drug launched by Merck
and approved by the US FDA.35b Several 4-aryl-3methyl-fu-
ran-2(5H)-ones are effective in controlling fungal diseases
in plants of agronomic importance.36 In this context, Wu et
al. in 2019 demonstrated a method in which 4-sulfonylated
furan-2(5H)-ones 20 are formed by a three-component re-
action of 2,3-allenoic acids 19, sulfur dioxide, and aryldi-
azonium tetrafluoroborates in the presence of a copper cat-
alyst. The method utilizes both DABSO and Na2S2O5 as the
SO2 source. Mild reaction conditions, as well as tolerance of
various functional groups, such as nitro groups and esters,
as well as broad substrate scope are the important features
of the protocol. However, steric effects in the aryl diazoni-
um salt greatly affect the outcome, giving a downward
trend in the yield of the product (Scheme 14).37
Figure 3 Rofecoxib® an anti-inflammatory drug
Scheme 14 Synthesis of 4-sulfonylated furan-2(5H)-ones
Based on literature precedent, the proposed mechanism
involves the generation of an aryl radical via single-electron
transfer of an aryl diazonium tetrafluoroborate with Cu(I).
This radical then reacts with SO2 obtained from Na2S2O5, af-
fording an aryl sulfonyl radical intermediate (a). The C-cen-
tral position of 2,3-allenoic acid 19 is then attacked by the
aryl sulfonyl radical (a) to give intermediate 19a, which is
transformed into intermediate 19b, assisted by the cop-
per(II) catalyst. Subsequently, the intermediate 19b under-
goes intramolecular nucleophilic attack by the carboxylate
anion in the presence of a base, leading to 4-sulfonylated
furan-2(5H)-one (20) (Scheme 15).
Scheme 15 Proposed mechanism for the formation of 4-sulfonylated furan-2(5H)-ones
Alkyl nitriles are present in various natural products
and pharmaceuticals.38 Moreover, cyanoalkyl groups can be
readily converted into other useful functional groups such
as esters, amides, carboxyls, and tetrazoles.39 Similarly, ox-
indoles are privileged scaffolds in many drugs and biologi-
cally active compounds.40 Liu’s group demonstrated an
Ar B(OH)2
K2S2O5
NHC-Au NHC-Au-Ar
NHC-Au-SO2ArbaseAr–SO2
RI
Ar
R–IAr'
Ar
SAr'
OO
(15)
(16)
(15a)
(15b)(15c)
(a)
SO2
Δ
I
–OTf
S
R R
SOO
OO( )nDMEDA (10 mol%)Na2S2O5, DIPEA, TBAB, DMSO
Na2S2O5, K3PO4, TBAB, DMSO
Cu(OTf)2, 1,10-Phen
(17)
(18')
(18)
(n = 0)
(n = 1)
O
O
rofecoxib
SO
OMe
R1
R2
R3
COOHSO2
Ar–N2BF4
Cu(OAc)2 (10 mol%)
1,4-dioxane, 60 °C O OR2
R1
ArO2S R3
O OPh
Me
SO
O
O OPh
S MeO
OMeO
(20a, 75%)O OPh
Me
SO
OF
(20b, 70%)O O
Ph
Me
SO
OF3C
(20c, 42%) (20d, 35%)
O2N
DABCO.(SO2)2
orNa2S2O5
(19) (20)
R1 R2
R3 COOH
Na2S2O5, Cu(I) Na2SO3, Cu(II)
Ar–SO2Ar–N2BF4
R2
COOH
R3
ArO2S
R1
R2
COOH
R3
ArO2S
R1
O OR2
R1
ArO2S R3
(20)
Cu(I)
Cu(II)
(19)
(19a)
(19b)
(a)
DABCO+
DABCO+
DABCO
DABCO·(SO2)2
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iron-catalyzed protocol for the synthesis of cyanoalkyl sul-
fonylated oxindoles 22 from activated olefins 21 and cyclic
keto oximes via C–C single-bond insertion of sulfur dioxide.
The method does not require any additional base or oxi-
dant, which is one of the main advantages of the protocol
(Scheme 16).41
Scheme 16 Synthesis of 3-cyanoalkyl sulfonylated oxindoles
Based on literature precedent and on experimental re-
sults, a mechanism for the iron-catalyzed radical cyano-
alkylsulfonylation/arylation of active olefins was proposed
(Scheme 17). Initially, the oxime ester (a) undergoes SET re-
duction by Fe(II) to give an iminyl radical intermediate (b),
which forms intermediate (c) via cleavage of the C–C bond.
Subsequently, the intermediate (c) is captured by the SO2
generated from K2S2O5, to provide another intermediate (d).
Next, the radical intermediate (d) attacks the C–C bond of
acrylamide (21) to provide intermediate 21d, which under-
goes intramolecular cyclization to give intermediate 21e.
Finally, SET oxidation of intermediate 21e by Fe(III) fol-
lowed by 4-(trifluoromethyl)benzoate ion assisted depro-
tonation gives the final product 22 and regenerates Fe(II)
for the next catalytic cycle.
Scheme 17 Proposed mechanism for the formation of 3-cyanoalkyl-sulfonylated oxindoles
In 2021 Yu et al. demonstrated an iron-catalyzed SO2 in-
sertion between 2,3-allenoic acids 23 and cyclobutanone
oxime esters using K2S2O5 as the SO2 surrogate (Scheme
18).42 During the reaction, ring-opening of the cyclobuta-
none oxime ester produces a cyanoalkyl radical, which is
followed by a radical tandem cyclization providing cyano-
alkylsulfonylated butenolides 24.
Scheme 18 Cyanoalkylsulfonylation of 2,3-allenoic acids
The suggested mechanism involves the reduction of the
cycloketone oxime ester by Fe(II) via SET, leading to the for-
mation of an iminyl radical (a) through N–O bond cleavage.
Subsequently, the C–C bond cleavage of intermediate (a)
gives an alkyl radical species (b), which, in combination
with sulfur dioxide from K2S2O5, provides a sulfonyl radical
intermediate (c). This is then followed by the addition to al-
lenoic acid 23 to form intermediate 23c. The intermediate
23c undergoes oxidation in the presence of the Fe(III) cata-
lyst to provide allylic cation 23d. Finally, the cyclized prod-
uct 24 is obtained via intramolecular nucleophilic attack
(Scheme 19).
Scheme 19 Proposed mechanism for the cyanoalkylsulfonylation of 2,3-allenoic acids
N
R2
OMe R5R4
NOR
MeCN, 80 °CAr, 12 h
N
R2S ONC
R4R5
O
R1
O
K2S2O5
N
MeS
OCN
O
Me
O
N
MeS
OO CN
O
Me
O
N
MeS
OCN
O
Me
O
Me
(22a, 62%) (22b, 55%)
(22c, 51%)
R3
(21) (22)
N
MeS
OCN
O
Me
OF3C
(22d, 50%)
2
+ FeCl2R3
NO –RCO2 N
Fe(II) Fe(III)
K2S2O5
K2SO3
(21)
N
Me
OMe
SO
OCN
N
SO
O
Me
OH
(22)
(21d)
(21e)
–H
(a)
(b) (c)
RO
CN CN S
O
O
R = p-CF3C6H4
CN
Fe(III)
Fe(II)
(d)
CR2 R3
COOH
R1 R4 R5
NO
O
Ph
FeCl2 (10 mol%)
K2S2O5DCE, 60 °C, 24 h
O
O
R2
SO
O
R5
R4NC
R3
R1
(24a, 78%)
O
O
SO
ONC
Me
Me (24b, 45%)
O
O
SO
ONC
Me
Br (24c, 61%)
O
O
SO
ONC
Me
Br
Ph
(24d, 60%)
O
O
PhSO
ONC
Me
tBu(24e, 51%)
O
O
PhSO
O
Me
N
NC
Boc (24f, 36%)
O
O
PhSO
ONC
Me
OO
Me
Me
Me
(23) (24)
NO
O
Ph PhCO2 N
Fe(II) Fe(III)
NC
(a)(b)
K2S2O5
SO O
NC
(c)Ph
CMe
COOH
NCO
OS
CHO2H
MeNCO
OS
CO2H
Me
(24)
(23)(23c)(23d)
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2.2 Transition-Metal-Free SO2 Insertion
Although transition-metal-catalyzed SO2 insertion has
gained considerable attention, the development of efficient
and practical protocols for the direct introduction of sulfo-
nyl group in the absence of a transition-metal catalyst is an
attractive approach. The introduction of a sulfonyl group
under transition-metal-free conditions is a challenging
task.43
A metal-free multi-component strategy was disclosed
by Wu et al. for the synthesis of nitrile-containing sulfones
26 using aryldiazonium tetrafluoroborates 25, and 3-azido-
2-methylbut-3-en-2-ol with sodium metabisulfite as the
sulfur dioxide surrogate (Scheme 20).44
Scheme 20 Synthesis of nitrile-containing sulfones
A plausible mechanism for this sulfonylation process is
described in Scheme 21. Initially, aryl sulfonyl radical 25a is
generated in situ by the reaction of aryldiazonium tetra-
fluoroborate 25 and sodium metabisulfite. Further, the ad-
dition of aryl sulfonyl radical 25a to 3-azido-2-methylbut-
3-en-2-ol gives the radical intermediate 25b, which subse-
quently releases N2, generating a nitrogen-centered radical
25c. The radical intermediate 25c provides arylsulfonylace-
tonitrile 26 via C–C bond cleavage, along with a ketyl radical
(a), which, upon loss of a proton, forms acetone as the sole
by-product.
Scheme 21 Proposed mechanism for the formation of nitrile-contain-ing sulfones
Vinyl sulfones are found in many natural products and
pharmaceuticals.45 The reactivity of ,-unsaturated sul-
fones leads to various organic transformations via nucleop-
hilic addition, radical addition, and cycloaddition. A metal-
free, three-component reaction protocol involving propar-
gyl alcohol 27, sodium metabisulfite, and aryldiazonium
tetrafluoroborates was demonstrated by Wu et al. in 2020
(Scheme 22).46 The reaction proceeds efficiently at room
temperature in the absence of catalyst, providing E-vinyl
sulfones 28 in moderate to good yields. The approach in-
volves a vinyl radical-induced 1,5-hydrogen atom transfer
and functional group migration, resulting in sequential
cleavage of inert C–H and C–C bonds, respectively. Aryldi-
azonium tetrafluoroborates bearing electron-donating or
electron-withdrawing groups on the aromatic ring worked
smoothly in this transformation, providing the desired
products 28 in moderate to good yields. Besides this, a wide
variety of propargyl alcohols was also successful (Scheme
22).
Scheme 22 Synthesis of vinyl sulfones
In the proposed mechanism, an aryl sulfonyl radical in-
termediate (a) is generated from the aryl diazonium salt
and Na2S2O5. Radical addition of intermediate (a) to alkyne
27 provides intermediate 27a, which, upon 1,5-[H] shift,
gives intermediate 27b. The intermediate 27b undergoes
radical cyclization followed by SET and deprotonation to
give product 28 (Scheme 23).
Scheme 23 A tentative mechanism for the formation of vinyl sulfones
N2BF4
Na2S2O5
DCE
rt, 8 h
SOO
CN
RR(25) (26)
SOO
CN
(26a, 72%)
MeMe OH
Me
SOO
CN
(26b, 78%)MeO
SOO
CN
(26c, 65%)MeO2C
N
SOO
CN
(26c, 40%)
SOO
CN
(26d, 40%)
O
O
SOO
CN
(26e, 61%)
N3
Ar
SOO
Ar N2BF4Na2S2O5
MeMe OH
N3
MeMe OH
N3SAr
O
O
–N2
Me
Me OH
NS
Ar
O
OAr
SOO
CN
Me Me
OH
Me Me
O
(25)
(26)
(25a) (25b)
(25c)
(a)
R1
OHR2
Na2S2O5
N2BF4
Na2HPO4
DCE, rt R2
SOO
OR1
R R
(27) (28)
Ts
OPh
SPh
OO
OPhMeMe
Ts
OPh
SOO
OPhMeMe O
MeMe
S
Ts
OPhMeMe
Ts
Me
(28a, 63%) (28b, 56%) (28c, 67%)
(28f, 77%)(28d, 37%) (28e, 21%)
Me
ArN2BF4SO2 Ar
SOO (27)
R1
SAr
OO
OH
R2H
R1
SAr
OO
OH
R2H
R2
R1OH
SAr
OO
R2
S O
OHO
R1
ArN2BF4R2
S O
OOH
R1
(28)
(a) (27a)(27b)
(27c)(27d)(27e)
1,5-[H] shift
Na2S2O5
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Recently, an elegant method for the synthesis of aryl
sulfones was reported by Wu et al. The method offers a
range of (arylsulfonyl)methylbenzenes 30 via a multicom-
ponent reaction of electron-rich arenes 29, potassium met-
abisulfite, aromatic aldehydes, and aryldiazonium tetraflu-
oroborates in the presence of formic acid (Scheme 24).47
The reaction proceeds very well under mild reaction condi-
tions with broad substrate scope tolerating various func-
tional groups.
Scheme 24 Synthesis of aryl sulfones using aromatic aldehydes and aryl diazonium salts
According to the proposed mechanism, condensation of
1,3,5-trimethoxybenzene (29) with an aldehyde in the
presence of formic acid generates cationic intermediate
29a. Aryldiazonium tetrafluoroborate reacts with potassi-
um metabisulfite, leading to an arylsulfonyl radical inter-
mediate (b) that attacks intermediate 29a to provide a radi-
cal cation 29c. Subsequently, deprotonation via SET affords
product 30 (Scheme 25).
Scheme 25 A plausible mechanism for the formation of aryl sulfones
Five-membered sulfur heterocycles have a major pres-
ence in medicinal chemistry and materials sciences.48 In
this regard, Larionov et al. in 2018 reported an efficient
method for the synthesis of 3-sulfolenes 32 or 32′ from 1,3-
dienes 31 or allylic alcohols 31′ with sodium metabisulfite
as the SO2 surrogate. Most of the sulfolenes were obtained
in good to excellent yields when carried out in HFIP or with
KHSO4 in methanol. Broad substrate scope, good product
yield, gram-scale synthesis, and metal-free conditions are
some noteworthy features of this protocol (Scheme 26).49
Scheme 26 Synthesis of 3-sulfolenes using 1,3-dienes
Sulfonyl fluorides have gained importance and attracted
attention due to their unique reactivity and stability. In ad-
dition, sulfonyl fluorides are also used in place of sulfonyl
chloride for the synthesis of sulfonylated compounds.50 In-
spired by this, Lu and co-workers established a method for
the formation of aryl sulfonyl fluorides 34 from arene dia-
zonium salts 33 using sodium metabisulfite as the SO2
source (Scheme 27).51 Aryl diazonium salts possessing elec-
tron-donating, as well as electron-withdrawing substitu-
ents, performed well in this transformation. Furthermore,
several heteroaromatic diazo compounds reacted smoothly
under identical reaction conditions to give the correspond-
ing sulfonyl fluorides. Using this protocol, a copper-free
Sandmeyer fluorosulfonylation was established.
Scheme 27 Synthesis of aryl sulfonyl fluorides
K2S2O5
EtOH/H2O = 4:1
(29) (30)
(30a, 64%)
OMe
OMeMeOR H
O HCOOH
60 °C, air
OMe
OMeMeO
S
RAr
O O
Ar N2BF4
OMe
OMe
Sp-Tol
O OMeO
N
CF3
(30b, 93%)
OMe
OMe
SO O
MeO
S O
(30c, 52%)
OMe
OMe
SO O
MeO
NO2
NEt
(30d, 65%)
OMe
OMe
Sp-Tol
O O
MeO
F
Br
R H
O
R H
OH+H+
OMe
OMeMeO
–H2O
OMe
OMeMeO
R
OMe
OMeMeO
R
SAr
O O
OMe
OMeMeO
S
RAr
O O
ArS
OO
Ar N2BF4
K2S2O5 SO3
HSO3
(29a)
(b)
(29c)
(29)
(30)
R4R3
R5R2
R1 Na2S2O5
KHSO4R3
R5R2
R1
OH S
R3 R4
R1R2
R5
OO
SOO
Me Me
SOO
Me Me
MeMeS
OO
S OO
SOO
MeMe
Me S OO
Me
(31)
(31')
(32 or 32')
(32a, 95%) (32b, 97%) (32c, 98%)
(32'a, 63%) (32'b, 87%) (32'c, 62%)
Me( )3 Me( )3
R4
N2BF4
Na2S2O5Selectfluor (2.0 equiv)
MeOH, 70 °C, 9 h
SF
OO
SF
OO
N
SF
OO
SF
OO
SF
OO
SF
OO
SF
OO
RR
MeO
N
S
N
OO
Me
(33) (34)
Me
Me
(34a, 63%) (34b, 50%)
(34f, 52%)
(34c, 62%)
(34d, 51%) (34e, 55%)
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According to the proposed mechanism, the aryl diazoni-
um salt undergoes SET to give an aryl radical 33a that then
captures SO2 from the sodium metabisulfite to give the aryl
sulfonyl radical intermediate 33b. The radical intermediate
33b then reacts with the fluoride radical obtained from
Selectfluor®, affording the desired product 34. In this proto-
col, sodium metabisulfite serves the dual role of reductant
and SO2 source, enabling this copper-free Sandmeyer-type
fluorosulfonylation (Scheme 28).
Scheme 28 Proposed mechanism for the formation of aryl sulfonyl flu-orides
Radical difunctionalization of alkenes and alkynes is an
interesting approach to introduce two functional groups si-
multaneously.52 Singh et al. in 2020 reported an efficient
method for the synthesis of -ketosulfones 36 and 36′ via a
multicomponent reaction of alkenes or alkynes, aryldiazo-
nium salts 35, and SO2 derived from K2S2O5 under transition-
metal-free conditions. The strategy is equally successful for
phenyl acetylenes and styrenes bearing electron-withdraw-
ing as well as electron-donating groups (Scheme 29).53
Scheme 29 Synthesis of -ketosulfones
Similarly, Wu et al. reported a four-component reaction
of aryldiazonium salts 37, sulfur dioxide, alkenes, and hy-
droxylamine. The methodology utilized both DABCO·(SO2)2
and K2S2O5 as the SO2 surrogate, which underwent a
smooth reaction both with aryl diazonium salts and sty-
renes (Scheme 30).54
Sulfonamide synthesis via a metal-free approach is
challenging for synthetic chemists. In this regard, Wu et al.
in 2021 developed a multicomponent reaction involving ni-
troarenes 39, arylboronic acids, and potassium metabisul-
fite, leading to the formation of sulfonamides 40. A note-
worthy feature of this protocol is that it is transition-metal-
free, and exhibits broad functional group tolerance. A range
of sulfonamides bearing different reactive functional
groups was obtained in good to excellent yields (Scheme
31).55
Scheme 31 Metal-free synthesis of sulfonamides
The mechanism shown in Scheme 32 involves decom-
position of K2S2O5, resulting in formation of SO2, which un-
dergoes nucleophilic addition with the arylboronic acid to
form benzenesulfinate (a). Subsequently, nucleophilic addi-
tion of (a) to nitroarene 39 generates intermediate 39a,
which couples with another molecule of SO2 to provide in-
termediate 39b. In the presence of K2CO3, intermediate 39b
eliminates SO42– to give intermediate 39c. Subsequently, ad-
dition of SO2 followed by elimination of SO42– provides the
desired sulfonamide 40 via the intermediacy of 39d.
Quinolines are an important class of heterocycles with
diverse biological and pharmacological properties.56 In this
context, quinoline N-oxides are valuable starting materials
for different transformations to provide functionalized
quinolines. Recently, Xia and co-workers developed a met-
al-free, three-component reaction of quinoline N-oxides 41,
sodium metabisulfite, and aryldiazonium tetrafluoro-
borates via a radical process to give 2-sulfonyl quinolones/
(33)
Na2S2O5
Na2S2O5
Na2SO3 N
N FS
F
OO
(34)(33a) (33b)
SO2N2BF4
N2BF4
K2S2O5
Air, MeCN
R2
SO O
R1
O
SO O
R2
O
SOO
O
MeO
(35)
(36')
(36)
Ph(36a, 69%)
SOO O
Br tBu(36c, 54%)
SO O O
O2N F(36b, 67%)
SOO
O
O2N COMe
SO O O
O2N
CF3
CF3SO O O
O2N
Me
Me
(36d, 42%)
(36'b, 34%)(36'a, 37%)
K2S2O5
Air, MeCN
R
R
R1R
Scheme 30 Vicinal difunctionalization of alkenes via SO2 insertion
N2BF4 R1
NR3
R2
OHK2S2O5 or
DABCO·(SO2)2
toluene25 °C
SOO
R1
ON
R3
R2
RR
(37) (38)
SOO
ON
COPh
Ph
SOO
ON
COPh
Ph
SOO
ON
COPh
Ph
SOO
ON
COPh
Ph
Me
SOO
ON
COPh
Ph
SOO
ON
COPh
Ph
N
Me CF3 Br
OMe
(38a, 87%) (38b, 68%)
(38d, 87%)(38e, 76%) (38f, 64%)
(38c, 77%)
SO2
NO2
MeCN, 130 °C
SNH
O O
K2S2O5(39) (40)
R1
R2
(40a, 73%)
BHO OH
R2
K2CO3, nBu4NClR1
SNH
O O
OMe
(40b, 78%)
SNH
O O
CN
(40c, 93%)
SNH
O O
O
O
O
Me
(40c, 75%)
SNH
O OPh
MeO
(40d, 66%)
SNH
O OPh
NH
(40e, 87%)
O SO
NH
O
Ph
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isoquinolines 42 (Scheme 33).57 In this approach, aryldiazo-
nium tetrafluoroborates bearing p-substituents were more
efficient than those bearing m- and o-substituents. This
might be due to steric effects. On the other hand, aryldiazo-
nium tetrafluoroborates bearing electron-donating groups
reacted better than those bearing electron-withdrawing
groups. Besides this, a variety of quinoline N-oxides and
isoquinoline N-oxides worked well in this methodology.
Scheme 33 Metal-free synthesis of 2-sulfonyl quinolones/isoquino-lines
In the proposed mechanism (Scheme 34), the aryldiazo-
nium tetrafluoroborate undergoes thermal decomposition
to give an aryl radical (a) that combines with SO2 obtained
from sodium metabisulfite to provide an aryl sulfonyl radi-
cal (b). Then addition of (b) to quinoline N-oxide 41 via a
Minisci-like radical transformation generates an O-radical
intermediate 41b that captures another aryl sulfonyl radical
to give intermediate 41c. Finally, elimination of aryl sulfon-
ic acid from intermediate 41c affords the corresponding 2-
sulfonyl quinolines 42.
Scheme 34 Proposed mechanism for the formation of 2-sulfonyl quinolones
In 2020, Ramon et al. developed a catalyst-free method-
ology for the multicomponent synthesis of sulfones, di-
sulfides, and sulfides using non-toxic triarylbismuthines
(Ar3Bi) (43) and sodium metabisulfite in a deep eutectic
solvent (DES) (Scheme 35).58 The use of DES helped to solu-
bilize all reagents, thereby, enhancing their reactivity. A va-
riety of electrophiles and nucleophiles in the synthesis of
sulfones and sulfide worked well.
Scheme 35 Synthesis of sulfones and sulfides in deep eutectic solvents
In 2018, Jiang et al. demonstrated a metal-free synthesis
of sulfonamides 46 via a three-component reaction involv-
ing sodium metabisulfite, sodium azide, and aryl diazoni-
um salts 45 (Scheme 36).59
Scheme 36 Synthesis of primary sulfonamides
The mechanism for the formation of the product 46 is
depicted in Scheme 37. The process involves the generation
of an aryl radical intermediate (a) via SET between the aryl
diazonium salt and triphenylphosphine. Then the SO2 com-
bines with the aryl radical intermediate (a) to give an aryl
sulfonyl intermediate 45a, which reacts with the phosphine
imine radical (b) and sodium azide to provide intermediate
45c. Subsequent hydrolysis of intermediate 45c affords the
product 46 along with the by-product triphenylphosphine
oxide.
Previously, the Pan group in 2013 demonstrated a cata-
lyst-free method for the synthesis of sulfonylhydrazides 48
from phenylhydrazines 47 as the aryl source and potassium
metabisulfite as the SO2 source. Metal-free, additive-free
conditions, readily available starting materials, and low
Scheme 32 Proposed mechanism for the formation of sulfonamides
ArB(OH)2
SO2
K2S2O5
heat
Ar SO
O
ArNO
O
S NO
OAr
O
O SO O
S NO
OAr
O
O SO
O
K2CO3
SO42
Ar Ar
S NO
OAr
O
ArS
O O
S NO
OAr
Ar
O SO
O
K2CO3 + H2OSO42
S NHO
OAr
Ar
(a) (39a)
(40)
(39)
(39b)
(39c)(39d)
NO
Na2S2O5 Ar-N2BF4DCE
N SO2Ar(41) (42)
R R
N
SO2PhN
F
N
Me
N
Me
SO2Ar
(42d, 61%)
+
Ar = 4-BrC6H4
(42b, 67%)
SO2Ar
Ar = 4-FC6H4
(42a, 47%)
SO2Ar
Ar = 4-MeC6H4
(42c, 75%)
50 °C+
N
O
Ar–N2BF4
N SO2Ar
(41)
(42)
R
R
Ar ArS
OO
SO2Ar
NOSO2Ar
RSO2Ar
ArSO3H
(a) (b) (41b)
(41c)
Ph3Bi
Na2S2O5
E+AcChCl:acetamide
SE
OO
(43) (44)80 °C, 5 h
Nu-HI2, 80 °C, 5 hAcChCl:acetamide
PhS
Nu(44')
S
OO
SOO OMe
MeO OMe
SPh
NH
SPh
(44a, 90%) (44b, 85%) (44'a, 79%) (44'b, 81%)
N
S
N2BF4
Na2S2O5
NaN3
PPh3, TBAB
MeCN/H2O
SNH2
OO
R R
SNH2
OO
SNH2
OOS
NH2
OO
SNH2
OO
O
O Me
H H
H
Me
Me Me
(46c, 71%)OMe
(46b, 92%)
EtO2C
(46a, 78%)
(46d, 65%)
(45) (46)
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reaction temperatures are the merits of this protocol, in
which phenylhydrazines bearing both electron-withdraw-
ing and electron-donating groups were well tolerated
(Scheme 38).60
Scheme 38 Synthesis of primary sulfonylhydrazides
In the suggested mechanism, in the presence of O2,
phenylhydrazines 47 undergoes two-step deprotonation to
give an aryl radical intermediate 47c via the intermediacy
of 47a and 47b. Then the intermediate 47c combines with
the sulfonyl anionic intermediate (e) (obtained from the re-
action of cyclic amine (d) and K2S2O5) to generate an anion-
ic intermediate 47f along with a radical cation 47h via SET.
Oxidation of intermediate 47f affords the aryl sulfone radi-
cal 47g, and deprotonation of the intermediate 47h pro-
vides intermediate 47i. Finally, radical coupling of interme-
diate 47g and 47i affords the desired product 48 (Scheme
39).
In 2018 Jiang et al. developed an efficient method for
the synthesis of sulfonamides 50 from readily available ni-
trobenzenes 49, boronic acids, and Na2S2O5 as the SO2 sur-
rogate. In this protocol sodium metabisulfite (Na2S2O5)
serves the role of both activator as well as reductant during
sulfonamidation (Scheme 40).61
In the proposed reaction, nitrobenzene (49) reacts with
sodium metabisulfite to give intermediate 49a, which is
converted into nitrosyl intermediate 49b with the release of
Na2SO3 and SO3 (Scheme 41). Simultaneously, sodium meta-
bisulfite acts as an anionic counterpart to activate the C–B
bond of boronic acid (a) to afford an SO2 conjugate interme-
diate (b). The sulfonyl radical intermediate (c) is generated
from (b) via 1,5-migration and SET. Subsequently, interme-
diate 49b and (c) combine to give the nitroso radical inter-
mediate 49d followed by hydrolysis to afford the desired
product 50.
Scheme 37 Proposed mechanism for the formation of primary sulfon-amides
N2BF4
(45)
Na2S2O5
Na2SO3 + SO2
SOO
PPh3 PPh3
PPh3
N2
NaN3 NaBF4
PPh3NNN
SOO
N N
NPh3P
H2OPPh3O + N2SNH2
OO
(46)
(a) (45a)
(45c)
(b)
NH NH2
K2S2O5
H2N NR1
R2
MeCN, air40 °C, 12 h
SNH
OON
R2
R1
SNH
OON
OS
NH
OON
O
SNH
OON
OS
NH
OON
O
MeO F3C
Me Br
R R
(47) (48)
(48a, 69%) (48b, 59%)
(48c, 65%) (48d, 58%)
+
Scheme 39 Proposed mechanism for the formation of sufonylhydra-zides
HN
NH2N
NH
O2 OOH O2 OOHN
N
N2
O
NNH2
O
N NH2
SOO
K2S2O5
O N NH2
SO
O
O2
SO
OH+
O N NH
SNH
OON
O
(47) (47a) (47b)
(47c)(47f)(47h
(47g)(47i)
(48)
(d)(e)
Scheme 40 Synthesis of sulfonamides using nitrobenzenes, boronic acids, and Na2S2O5
NO2
Na2S2O5
ChCl (1 equiv)
Li3PO4, DMF 130 °C, N2
HN
SOOR R
R1
HN
SOO
HN
SOO
N
HN
SOO
Me
O Me
Cl
O
PhHN
SOO
(50a, 41%)
(50c, 58%)
(50b, 83%)
(50d, 72%)Me
(49) (50)
B(OH)2
+
Scheme 41 Proposed mechanism for the formation of N-aryl sulfon-amides
NO
ONa2S2O5 N
O
OS
ONa
OSO3Na
Na2SO3 + SO3
R-B(OH)2
+ Na2S2O5
NaOS
OS
OO
OB
OHR
OHNa
1,5-migration & SET
RS
O
O
NO
SO RO
HSO
NaOO
B
OH
HO
NO
SO RO
SONaO
base
NaOB(OR)2
NHS
OO
(50)
(49) (49a) (49b)
(49d)(49e)
(a)
(b)
(d)
(c)
NO
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In 2020, the Shun-Jun Ji group reported an efficient TFA-
promoted, transition-metal-free, multicomponent reaction
of aryldiazonium salts 51 with sodium metabisulfite
(Na2S2O5) and thiols to construct thiosulfonates 52 (Scheme
42).62 The reaction proceeds smoothly with a broad toler-
ance of functional groups present in the aromatic rings of
both the aryldiazonium salts as well as in thiols. Moreover,
heteroaromatic and aliphatic thiols are also well tolerated
to afford the desired thiosulfonates.
Based on the proposed mechanism (Scheme 43) TFA re-
acts with diazonium salt 51 to generate the corresponding
aryl radical 51a. This aryl radical 51a then reacts with
Na2S2O5 to give an arylsulfonyl radical intermediate 51b
that combines with the sulfur anion to give radical anion
intermediate 51c. The radical anion 51c undergoes SET to
give the thiosulfonate 52.
Scheme 43 Proposed mechanism for the formation of thiosulfonates
2.3 Visible-Light-Mediated SO2 Insertion
Recently, visible-light-mediated functionalizations have
emerged as significant methodologies in contemporary or-
ganic chemistry.63,64 However, most organic compounds do
not absorb visible light efficiently, which limits the applica-
tion of light-mediated organic synthesis. To overcome this,
either a transition-metal complex (complexes of Rh, Ir, Ru)
or organic dyes such as eosin Y or rose Bengal are used as
sensitizers for the required photochemical transforma-
tion.65,66 As mentioned above, various methods used for SO2
insertion require high temperatures and harsh reaction
conditions; hence, there is a need for developing methods
for SO2 insertion under milder reaction conditions. In this
context, SO2 insertion reaction mediated by visible light
either in the presence of transition-metal complexes or
organic dyes as photoredox catalysts has gained a place in
organic synthesis.67,68
In 2020 Wu et al. reported a photocatalytic synthesis of
alkylalkynyl sulfones 54 through the insertion of sulfur di-
oxide between potassium alkyltrifluoroborates 53 and
alkynyl bromides using sodium metabisulfite (Na2S2O5) as
the SO2 source (Scheme 44).69 This photoinduced reaction
proceeded well at room temperature, had broad substrate
scope, and gave the products in moderate to good yields.
Scheme 44 Visible-light-mediated synthesis of alkylalkynyl sulfones
According to the proposed mechanism (Scheme 45) an
alkyl radical 53a is generated from potassium alkyltrifluo-
roborate 53 by the influence of the photocatalyst under vis-
ible-light irradiation. Subsequently, the sulfur dioxide gen-
erated from Na2S2O5 couples with radical 53a to provide al-
kylsulfonyl radical 53b that then attacks the C–C triple
bond of the alkynyl bromide to provide vinyl radical inter-
mediate 53c. Next, SET converts vinyl radical 53c into vinyl
anion 53d. Finally, elimination of bromide gives rise to al-
kylalkynyl sulfone 54.
Scheme 45 Proposed mechanism for the formation of alkylalkynyl sul-fones
Thiosulfonates are useful building blocks in organic syn-
thesis owing to their unusual reactivity and stability.70 A
visible-light-promoted synthesis of thiosulfonates 56 was
reported by He et al. using thiols, aryldiazonium salts 55,
and sodium metabisulfite under metal-free conditions
(Scheme 46).71 This mild, three-component reaction utiliz-
es rhodamine 6G as the photocatalyst to provide unsym-
metrical thiosulfonates.
Scheme 42 Synthesis of thiosulfonates
N2BF4
Na2S2O5DCE/MeCN
SS
OO
R1 R1
SS
OO
Me (52a, 73%)
(51) (52)
TFA
60 °C, 2.5 h
R2R2SH
OMe
SS
OO
Me (52b, 53%)
Br
SS
OO
Me (52c, 33%)
N
SS
OO
Me (52d, 75%)
SS
OO
Me (52e, 71%)
Me
Ar-N2BF4 ArNa2S2O5
ArS
OO
ArS
S
OOR2
ArS
S
OOR2
SET
TFA
R2SH
R2S
(51a) (51b)
(51c)
(51)
(52)
R BF3KNa2S2O5 Mes-Acr+ (2 mol%)
R
SOO
(53) (54)
(54a, 80%)
+
Ar BrNH4F, MeCN
36 W CFL Ar
SOO
Ph(54a, 80%)
tBu
SOO
Ph(54a, 81%)
SOO
Me
R BF3K R–BF3K+
Mes-Acr+* Mes-Acr+red
Na2S2O5
RS
OO
Ar Br
Ar
SO2R
Br
Mes-Acr+redMes-Acr+
Ar
SO2R
Br
–Br–
R
SOO
Ar
(53a) (53b)
(53c)(53d)
(53)
(54)
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Scheme 46 Visible-light-mediated synthesis of thiosulfonates
Following the proposed mechanism (Scheme 47),
rhodamine 6G (PC) is first excited to an excited species PC*
under visible-light irradiation. Then, aryl radical 55a is gen-
erated from the aryldiazonium salt 55 via SET with the re-
lease of N2 and BF4−. Subsequently, the interaction of aryl
radical 55a with Na2S2O5 generates arylsulfonyl radical 55b
and Na2SO3. The PC radical cation obtained from the SET
process oxidizes the thiol to produce a thiyl radical cation,
which is deprotonated by BF4− to produce a thiyl radical (c).
Finally, coupling of arylsulfonyl radical 55b with the thiyl
radical (c) gave the product 56; whereas homocoupling
provided the disulfide.
Scheme 47 Proposed mechanism for the formation of thiosulfonates
Subsequently, Wu and co-workers reported a photo-
induced three-component reaction of aryldiazonium tetra-
fluoroborates 57, sodium metabisulfite, and thiourea, lead-
ing to S-aryl thiosulfonates 58 (Scheme 48).72 A variety of
aryldiazonium tetrafluoroborates worked well in this trans-
formation. This method was unsuccessful for S-alkyl thio-
sulfonate preparation because of stability issues with the
alkyl diazonium tetrafluoroborates. Moreover, the reaction
was unsuccessful for 2-substituted aryldiazonium tetra-
fluoroborates. This might be due to the steric hindrance.
Scheme 48 Visible-light-mediated synthesis of S-aryl thiosulfonates
According to the suggested mechanism (Scheme 49),
initial reaction between thiourea and aryldiazonium tetra-
fluoroborate 57 generates a salt intermediate 57a, which
reacts with Na2S2O5 to give sodium thiophenolate (d), and
urea with the release of SO2. In the presence of visible light,
the photocatalyst is exited and produces aryl radical 57b
from another molecule of aryldiazonium tetrafluoroborate
57 via SET. Aryl radical 57b then reacts with SO2, generated
from sodium metabisulfite, giving aryl sulfonyl radical in-
termediate 57c. Subsequently, thiophenolate anion (d) af-
fords an aryl sulfur radical (e), regenerating the ground-
state photocatalyst. Finally, the combination of arylsulfonyl
radical 57c with the aryl sulfur radical (e) affords S-aryl
thiosulfonate 58.
Scheme 49 Proposed mechanism for the synthesis of S-aryl thiosul-fonates
A Ru(II) photoredox-catalyzed synthesis of ,-difluoro-
-ketosulfones 60 was reported by Wu et al. in 2020
(Scheme 50).73 The reaction involves a three-component
coupling of aryldiazonium tetrafluoroborates 59 with sodi-
um metabisulfite and 2,2-difluoroenol silyl ethers under
mild conditions. In this conversion, the difluoromethyl
group and sulfone moiety can be introduced in a single
step.
ArN2BF4
Na2S2O5
ArS
SAr
OO
SS
OO
SS
OO
Cl
SS
OO Me
MeO
SS
OO Me
MeO2C
(56b, 68%)
(56c, 70%) (56d, 64%)
(56a, 80%)
(55) (56)
Rhodamine 6G
MeCN, rt, 16 h+
Ar SH
3 W White LEDS
F
Me
Me
PC*
PC
PC
ArN2BF4
Ar
ArS
OO
ArS
SAr
OO
(55)
(55a)
(55b) (56)
hν
SET
Na2S2O5
ArSH
ArSH
ArS
BF4–+
HBF4
(c)
ArN2BF4
Na2S2O5
H2N NH2
SAr
SS
Ar
OO
SS
OO
F
F
SS
OO
Cl
Cl
SS
OO OMe
MeO
SS
OO OBn
BnO
(58b, 56%)
(58c, 60%) (58d, 47%)
(58a, 67%)
(57) (58)
Rhodamine 6G
MeCN, hν+
PC*
PC
PC+
H2N NH2
SArN2BF4
N2 HN NH2
SH
Ar BF4
Na2S2O5
SO2
UreaNaBF4
NaSAr
ArS
ArN2BF4
Ar
SO2
ArS
OO
ArS
SAr
OO
(57a)
(57)
(57b)
(57c)
(e)
(58)
hν
(d)
(57)
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Scheme 50 Visible-light-mediated synthesis of ,-difluoro--keto-sulfones
Based on the suggested mechanism as depicted in
Scheme 51, initially, aryl radical 59a is generated from the
aryldiazonium tetrafluoroborate 59 via SET. Intermediate
59a then reacts with SO2, giving rise to arylsulfonyl radical
59b. Intermediate 59b subsequently attacks the double
bond of the difluoroenoxysilane to provide a carbon-
centered radical intermediate 59c followed by SET with the
oxidized photocatalyst, to yield carbocationic intermediate
59d. Finally, the product 60 is formed through a fluoride-
mediated desilylation.
Scheme 51 Proposed mechanism for the formation of ,-difluoro--ketosulfones
In 2017, Manolikakes et al. established a method for the
formation of sulfonamides 62 by reacting diaryldiazonium
salts 61, Na2S2O5, and hydrazines under visible-light pho-
toredox catalysis. In this reaction, a combination of sodium
metabisulfite and acid TFA is used as the SO2 surrogate and
perylene (PDI) as the photoredox catalyst. Both aromatic as
well as aliphatic hydrazines worked well under identical re-
action conditions (Scheme 52).74
In the proposed mechanism, formation of a stable hy-
drazine-sulfur dioxide adduct (b) is suggested. Meanwhile
PDI* is produced by irradiation of photoredox catalyst PDI.
The radical quenching of PDI* with the hydrazine-sulfur di-
oxide complex (b) forms a radical cation (c), which under-
goes deprotonation to give a sulfonyl radical intermediate
(d). Simultaneously, aryl radical 61b, generated from the
aryl diazonium salt 61 via an electron transfer from PDI
radical anion, couples with the sulfonyl radical intermedi-
ate (d) to provide the final product 62 (Scheme 53).
Scheme 53 Proposed mechanism for the formation of sulfonamides
In 2019, Wu et al. demonstrated an efficient method for
the synthesis of 3-(methylsulfonyl)benzo[b]thiophenes 64
by reacting methyl(2-alkynyl phenyl)sulfonates 63 with so-
dium metabisulfite as the SO2 source in the presence of a Ru
complex as the photoredox catalyst and sodium methyl sul-
finate as the initiator for the reaction. Low catalyst loading,
room temperature reaction and broad substrate scope are
important features of the reaction. The protocol was suc-
cessfully applied using methyl(2-alkynyl phenyl)sulfonates
63, bearing electron-donating and electron-withdrawing
groups (Scheme 54).75
In the proposed mechanism, the excited state of the
photocatalyst oxidizes methylsulfinate to a methylsulfonyl
radical (a) as an initiator via SET. The triple bond of meth-
yl(2-alkynyl phenyl)sulfonate (63) is attacked by the meth-
ylsulfonyl radical (a), providing the cyclized product 64
with the release of a methyl radical. The released methyl
radical is subsequently captured by sulfur dioxide, to give
the methylsulfonyl radical (a). After this, the methylsulfonyl
radical (a) reacts with methyl(2-alkynyl phenyl)sulfonate
(63) to give product 64, with regeneration of the methyl
radical. In this process, the methyl radical relay combined
N2BF4
ArS
OO
R
O(59)
(60)
ArF
F
R
OTMS
Na2S2O5
Ru(bpy)3Cl2·6H2O (2 mol%)
15 W blue LEDsMeCN, rt F F
SOO
Ph
O
(60a, 80%)
F FMe
SOO
Ph
O
(60b, 79%)
F FCl
PhS
OOO
F FMe
(60c, 78%)
SOO
O
(60d, 80%)
F FCl Cl
PhS
OOO
F F
(60e, 57%)
S SOO
Ph
O
(60f, 41%)
F FS
MeO2C
Ru(II)Ru(II)*
Ru(III)
SET SET
hν
N2BF4Ar
ArNa2S2O5
ArS
O
O
F
F
R
OTMS
ArS
OO
R
OTMS
F F
ArS
OO
R
O
F F
TMS
ArS
OOR
O
F F
F
(59a)(59b)
(59c)
(59d) (60)
(59)
Scheme 52 Synthesis of sulfonamide using PDI as photoredox catalyst
NNMe
MeMe
Me
O
OO
O
PDI
Ar2I+X– S2O5
2– /TFA
PDIhν, rt Ar
SNH
OON
R1
R2
NR1
R2H2N
(61) (62)
PhS
NH
OON
Ph
Me
ArS
NH
OON
PhS
NH
OON
Ph
Ph
PhS
NH
OON Ph
Ph
PhS
NH
OON
Ph
Me
PhS
NH
OON
(62f, 70%)(62e, 59%)(62d, 70%)
(62a, 67%) (62b, 71%) (62c, 23%)
O
Ar = 4-MeC6H4
ArS
NH
OON
R1
R2
(62)
NR1
R2H2N
SO2N
R1
R2H2N
SO
O
NR1
R2H2N
SO
O
–H+
NR1
R2HNSOO
PDI* PHDI
PDIhνAr2I+
ArI
Ar
(a) (b) (c)
(d)
(61a)
(61b)
Ar2I
(61)
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with the insertion of sulfur dioxide provides a useful route
towards methylsulfonyl containing compounds (Scheme
55).
Scheme 55 Proposed mechanism for the formation of 3-(methylsulfo-nyl)benzo[b]thiophenes
Wu et al. reported a UV-irradiation mediated synthesis
of allylic sulfones 66 by reacting aryl/alkyl halides 65, po-
tassium metabisulfite, and allylic bromides. The desired
transformation was successful without any metal or pho-
toredox catalyst. A broad reaction scope covering alkyl and
aryl halides was demonstrated, and various sensitive func-
tional groups such as amino and ester groups were well tol-
erated (Scheme 56).76
Scheme 56 Visible-light-mediated synthesis of aryl/alkyl sulfonamides
Following the recent trends in C(sp3)–H functionaliza-
tion for sulfonylation, the Wu group demonstrated a visi-
ble-light-mediated sulfonylation of 2,4,6-trimethylphenol
(67) using sodium metabisulfite (Na2S2O5) as the SO2 surro-
gate. Although the result is interesting, the substrate scope
was limited and only 4-methyl phenols with a methyl or
tert-butyl group attached to the ortho-position are suitable
for this transformation. The reactions failed to provide the
desired products when 4-methylphenols with other groups
attached to the ortho-position were used. However, benzyl-
ic C(sp3)–H bond functionalization was achieved under
mild conditions and visible-light irradiation by using this
protocol (Scheme 57).77
Scheme 57 Visible-light-mediated benzylic C(sp3)–H sulfonylation of 2,4,6-trialkylphenols
According to the proposed mechanism, an aryl radical
(b) is generated from the aryl diazonium salt (a) by the ex-
cited Ir(bpy)3, which combines with the sulfonyl radical to
provide an arylsulfonyl radical intermediate (c). Meanwhile,
phenol 67 undergoes oxidation via a SET to give intermedi-
ate 67a, followed by intermolecular hydrogen atom abstrac-
tion to give the benzylic radical intermediate 67b. Finally,
combination of intermediate 67b and (c) affords the desired
product 68 (Scheme 58).
Scheme 58 Proposed mechanism for benzylic C(sp3)–H sulfonylation of 2,4,6-trialkylphenols
Alkylnitriles are privileged scaffolds in various natural
products and pharmaceuticals and can be readily converted
into other useful functional groups, including esters, am-
ides, carboxyls, and tetrazoles. In this context, in 2019, the
Wu group demonstrated a method for sulfonylation of
alkenes 69 using o-acyl oximes in the presence of Ir(bpy)3
as the photoredox catalyst under visible-light irradiation. A
wide range of substrates worked well with good functional
group tolerance (Scheme 59).78
Scheme 54 Synthesis of 3-(methylsulfonyl)benzo[b]thiophenes
R1
S
Me
Na2S2O5
Ru(bpy)3Cl2 MeSO2Na
35 W CFL, DCE12 h
SR1
SO2Me
(63) (64)
R R
S
SO2Me
S
SO2Me
Me
S
SO2Me
CF3
S
SO2MeS
(64a, 81%) (64b, 64%)
(64d, 75%)(64c, 96%)
R1
SMe
R
Na2S2O5
(64)
R
MeSO2–
hνInitiation
MeSO2
Me
SR1
SO2Me
(63) MeSO2
R1
S
Me
R
(63)
RSMe
R1
SO2Me
Radical initiation
(63a)
(a)
R X K2S2O5
R1
BrUV
Toluene RS
OO
R1
R = Aryl/Alkyl(65) (66)
HO
R1
R2
HNa2S2O5
ArN2BF4
R1
R2HO
SAr
OOIr(bpy)3, DCE
36 W CFL
Me
MeHO
SPh
OO
Me
MeHO
Sp-Tol
OO
tBu
MeHO
SPh
OO
tBu
tBuHO
Sp-Tol
OO
(67) (68)
(68a, 74%) (68b, <5%)
(68c, 53%) (68d, 77%)
+
HO
R1
R2
H
R1R2OH
ArN2BF4 Ar
Ir(III)*
Ir(III)
SO2
ArS
OO
R1
R2HO
CH2intramolecularH-atom transfer
(a) (b) (c)
(67a)
(67)
(67b)
O
R1
R2
H
S
Ar
O
O(68)
(67a)(c)
Ir(IV)
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Scheme 59 Visible-light-mediated sulfonylation of o-acyl oximes
Mechanistically, it was suggested that, in the presence
of a photocatalyst and visible light, N–O bond cleavage of
O-acyloxime (a) provides an iminyl radical intermediate
(b), which undergoes ring opening via C–C bond cleavage to
give a carbon-centered radical (c). The latter carbon radical
is captured by SO2, providing a sulfonyl radical (d), which,
on reaction with alkene 69, provides another carbon-cen-
tered radical 69d. Subsequently a cationic intermediate 69e
is generated from 69d via SET, and is attacked by the nucleo-
philic MeOH in the presence of a base to give the desired
product 70 (Scheme 60).
Scheme 60 Proposed mechanism for sulfonylation of O-acyl oximes
In 2020, Tang and co-workers described a similar proto-
col in which simultaneous cleavage of two C–C bonds of
methylenecyclopropane 71 and cycloketone oxime gave 2-
cyanoalkylsulfonylated 3,4-dihydronaphthalenes 72
(Scheme 61).79
In the suggested mechanism, cycloketone oxime (a) un-
dergoes reduction by the excited state photocatalyst
[Ru(bpy)3]2+* providing an iminyl radical (b), which under-
goes C–C bond cleavage to give a cyanoalkyl radical (c),
which is captured by the SO2 to give a cyanoalkyl sulfonyl
radical (d). Both the cyanoalkyl intermediate (c), and cya-
noalkylsulfonyl radical intermediate (d) are trapped by 1,1-
diphenylethylene (p) to give adducts (q) and (r), respective-
ly. The cyanoalkylsulfonyl radical (d) then adds to the C–C
double bond of the methylene cyclopropane 71, providing
intermediate 71d. The intermediate 71d undergoes ring-
opening via another C–C bond cleavage to provide carbon-
centered radical 71e. After this, intermediate 71f is generat-
ed by an intramolecular cyclization of intermediate 71e,
which undergoes SET from [Ru(bpy)3]3+. Deprotonation of
intermediate 71f in the presence of a base affords product
72 and, finally, [Ru(bpy)3]3+ reverts to the ground state
[Ru(bpy)3]2+ (Scheme 62).
Scheme 62 Mechanism for synthesis of 2-cyanoalkylsulfonylated 3,4-dihydronaphthalenes
Recently, N-functionalized pyridinium salts such as
Katritzky’s salt have been found to be effective alkylating
agents under photoredox catalytic process for various
transformations.80 In 2019, Wu and co-workers reported
the synthesis of -keto sulfone 74 using Katritzky’s salt as
an alkyl radical precursor and potassium metabisulfite as
the SO2 surrogate (Scheme 63).81 A broad reaction scope,
good functional group tolerance including amino, cyano,
hydroxy, trifluoromethyl groups and good product yields
are the merits of this methodology.
NO Ar
OR3
K2S2O5
R1
R2
Ir(bpy)3
ROH/MeCNrt, hν
CN
SOO
OR
R1R2
R3
CN
SOO
OMe
MeC6H4p-Ph
CN
SOO
OMe
MeC6H4p-F
CN
SOO
OMePh
O
O
OMeMe
SOO
CN
(70a, 80%) (70b, 68%)
(70c, 78%) (70d, 45%)
(69) (70)
NO Ar
OR3
CN
SOO
Nu
R1R2
R3
NR3
PC*
PC+PC
CN
SOO R1R2
R3
CN
SOO R1R2
R3
CNR3
CN
SOO
R3SO2
Nu
(a)
(b)
(c) (d)
(69)
(70)
(69d)
(69e)
OAr
O
R2
R1
Scheme 61 Visible-light-mediated synthesis of 2-cyanoalkylsulfonyl-ated 3,4-dihydronaphthalenes
R2
R1 R5
N
R4R3
ORRu(bpy)3Cl2, K2S2O5
2,6-lutidine
MeCN, 80 °C, 18 hAr, 5 W blue LED
SOO
R5
R3
R4
CN
R2
R1
(71) (72)
SOO
CN
(72a, 71%)
SOO
PhMe
CN
SOO
Bn
CN
SOO
CN
SOO
CN
SOO
CN
OBn OBn OBn
(72b, 79%) (72c, 69%)
BnO
(72d, 83%)
OBn
(72e, 83%)
MeO
MeO
(72f, 80%)
+
R2
R1(72)
NOR
NRCO2
Ru (bpy)3 2+* Ru (bpy)3
3+
Ru (bpy)3 2+
hν
K2S2O5NC
Ph
Ph
K2SO3
NC SO
O
(71)
S
O
O
CN
ring-opening
R2
R1
SOO
CN
Ph PhPh Ph
S
O
O
CN
SOO
CN
H
–H+
SET
intramolecular
cyclization
(a) (c)(b) (d)
(p)(q)
(r)
(p)
(71d)
(71e)
(71f)
SE
T
NC
R1
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A. K. Sahoo et al. ReviewSynOpen
Scheme 63 Visible-light-mediated synthesis of -keto sulfones
Following the suggested mechanism, a photoredox ex-
cited Ir(III) species generates an alkyl radical (c) through an
intermediate (b) from the Katritzky salt (a) via SET. Then
sulfur dioxide from potassium metabisulfite combines with
the alkyl radical intermediate (c) to give an alkylsulfonyl
radical intermediate (d) that is trapped by the silyl enol
ether 73, leading to a carbon radical intermediate 73d. In
the presence of Ir(IV), this carbon radical intermediate is
oxidized to a carbocation species 73e that then undergoes
desilylation in the presence of base to afford the corre-
sponding -keto sulfone 74 (Scheme 64).
Scheme 64 Mechanism for synthesis of -keto sulfones
Use of 4-substituted Hantzsch esters as alkyl radical
precursors has been demonstrated and these alkyl units
could be readily installed into various substrates.82 The al-
kyl radical is generated from the 4-alkyl Hantzsch ester un-
der visible-light irradiation in the presence of a photoredox
catalyst through SET. Thus, synthesis of alkynyl sulfones 76
involves the reaction of 4-alkyl Hantzsch esters 75, sodium
metabisulfite, and alkynyl bromides under metal-free pho-
toinduced conditions as reported by Wu et al. in 2020
(Scheme 65).83 This transformation proceeds smoothly un-
der visible-light irradiation at room temperature, giving
rise to the corresponding alkyl alkynyl sulfones 76 in mod-
erate to good yields. Besides this, a broad range of substrate
scope with good functional group tolerance are other mer-
its of the methodology.
Scheme 65 Visible-light-mediated synthesis of alkyl alkynyl sulfones
According to the proposed mechanism, alkyl radical 75b
is generated from the 4-alkyl Hantzsch ester 75 in the pres-
ence of the photocatalyst under irradiation. The alkyl sulfo-
nyl radical 75d is formed via trapping of sulfur dioxide by
the alkyl radical intermediate 75b. Subsequently, addition
of alkyl sulfonyl radical 75d to the alkynyl bromide produc-
es vinyl radical intermediate 75e. With the assistance of ex-
cited photocatalyst, vinyl anion 75f is formed, which af-
fords the corresponding alkylalkynyl sulfone 76 with the
release of bromide anion (Scheme 66).
Scheme 66 Mechanism for the synthesis of alkyl alkenyl sulfones
An elegant method for the synthesis of 2-sulfonyl-sub-
stituted 9H-pyrrolo[1,2-a]indoles 78 was reported by Xie et
al. in 2019 through reaction of aryldiazonium tetrafluorob-
orates, potassium metabisulfite, and N-propargylindoles 77
under visible-light irradiation (Scheme 67).84 The proposed
mechanism involves the generation of an aryl radical (a)
from the aryldiazonium tetrafluoroborate by the assistance
of [Ru(bpy)3]2+* via SET. The aryl radical (a) then reacts with
the potassium metabisulfite and captures SO2 to afford aryl
sulfonyl radical (b) that then attacks the triple bond of N-
propargylindole 77 giving rise to vinyl radical intermediate
77b. This is followed by intramolecular cyclization and gen-
eration of cyclic radical intermediate 77c. This cyclic radical
intermediate undergoes oxidative SET and generates cat-
N
Ph
PhPh
R K2S2O5
Ar
OTIPS Ir[dF(CF3)ppy]2(bpy)PF6
(1.5 mol%)
DMSO35 W Blue LED
RS
OO
Ar
O
(73) (74)
SOO O
OMe
SOO O
S OMe
SOO O
O OMe
(74a, 80%) (74b, 46%)
(74e, 97%)
(74d, 59%)
(74f, 75%)
SOO O
OMe(74c, 81%)
FF
SOO O
OMeO
SOO O
OMeHO
N
Ph
PhPh
R
N
Ph
PhPh
R
R
SO2
RS
OO(73)
RS
OO
Ar
OSiR3
RS
OO
Ar
OSiR3
Ir(III)* Ir(IV)
Ir(III)
RS
OO
Ar
O
hν
base
(d)(73d)
(73e)(74)
pyridine
(a)(b)
(c)
N
Alkyl
CO2EtEtO2C
Me MeNa2S2O5R
BrEosin B (2 mol%)
MeCN, blue LEDAlkyl
SOO
R
CyS
OO
Ph
SOO
Ph
SOO
Ph
SOO
Ph
CyS
OO
C6H4p-OMe
CyS
OO
C6H4p-F
(76a, 87%) (76b, 85%) (76c, 81%)
(76d, trace) (76e, 77%) (76f, 96%)
(75) (76)
PC
PC*
PCNH
EtO2C CO2Et
Me MeAlkyl
H
NMe Me
CO2EtEtO2CSO2
AlkylS
OOAlkylS
OO
BrR
AlkylS
OO
RBr
AlkylS
OO
R
(75b)
(75d)(75e)
(75f)(76)
(75)
(75a)
(75c)
R Br
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A. K. Sahoo et al. ReviewSynOpen
ionic intermediate 77d, which undergoes deprotonation
and isomerization to afford the desired cyclic product 78
(Scheme 67).
Scheme 67 Mechanism for synthesis of 2-sulfonyl-substituted 9H-pyr-rolo[1,2-a]indoles
3 Conclusion and Outlook
This review focuses on the recent advancement in sulfo-
nylation reactions using inorganic sulfites as the source of
the sulfonyl group. Inorganic sulfites are readily available,
easy to manipulate and inexpensive. The use of inorganic
sulfites as sulfur dioxide surrogates has proven to be a
transformative tool, leading to a diverse range of sulfonyl
compounds including sulfones and sulfonamides. The sulfo-
nylation protocols have been achieved under transition-
metal catalysis or through metal or additive-free condi-
tions. In some cases, a photocatalyst is utilized, which me-
diates the reaction in the presence of visible light. Using
K2S2O5 or Na2S2O5 as SO2 sources, many substrates were
well tolerated under mild conditions. The reactivities of in-
organic sulfites in organic reactions deserves to be explored
further. The present review shows that only potassium me-
tabisulfite or sodium metabisulfite have been found to be
efficient, but these strategies will surely find application in
the synthesis of natural products and pharmaceuticals in
the immediate future. Considering the great potential of in-
organic sulfites in organic synthesis, it is believed that new
methodologies involving insertion of sulfur dioxide using
inorganic sulfites will be developed.
Conflict of Interest
The authors declare no conflict of interest.
Funding Information
B.K.P. acknowledges the support of this research by the Department of
Science and Technology, Science and Engineering Research Board, In-
dia (DST/SERB; EMR/2016/007042) and the Council of Scientific and
Industrial Research, India (CSIR; 02(0365)/19/EMR-II). A.K.S., A.D.,
and A.R. thank IIT Guwahati for Fellowships and for providing neces-
sary facilities.Council of Scientific and Industrial Research, India (02(0365)/19/EMR-II)Science and Engineering Research Board, India (EMR/2016/007042)
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