The Renaissance of Alkali Metabisulfites as SO2 Surrogates

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-rv
License 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

http://orcid.org/0000-0002-4170-8166

233


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


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


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


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

+

SynOpen 2021, 5, 232–251

237


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

SynOpen 2021, 5, 232–251

238


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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239


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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240


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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241


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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242


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)

SynOpen 2021, 5, 232–251

243


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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244


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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247


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


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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248


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


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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249


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

SynOpen 2021, 5, 232–251

250


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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Documents

The Renaissance of Alkali Metabisulfites as SO2 Surrogates