Hydrosulfonylation of Alkenes with Sulfonyl Chlorides under Visible Light Activation

Article abstract of DOI:10.1002/anie.202004070

Sulfonyl chlorides are inexpensive reactants extensively explored for functionalization, but never considered for radical hydrosulfonylation of alkenes. Herein, we report that tris(trimethylsilyl)silane is an ideal hydrogen atom donor enabling highly effective photoredox-catalyzed hydrosulfonylation of electron-deficient alkenes with sulfonyl chlorides. To increase the generality of this transformation, polarity-reversal catalysis (PRC) was successfully implemented for alkenes bearing alkyl substituents. This late-stage functionalization method tolerates a remarkably wide range of functional groups, is operationally simple, scalable, and allows access to building blocks which are important for medicinal chemistry and drug discovery.

Full text of DOI:10.1002/anie.202004070

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Hydrosulfonylation of Alkenes with Sulfonyl Chlorides under
Visible Light Activation
Authors: Sandrine Monique Hell, Claudio Flavio Meyer, Antonio Misale,
Jeroen B. I. Sap, Kirsten K. Christensen, Michael C. Willis,
Andrés A. Trabanco, and Veronique Gouverneur
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202004070
Link to VoR: https://doi.org/10.1002/anie.202004070

Angewandte Chemie International Edition
10.1002/anie.202004070
RESEARCH ARTICLE
Hydrosulfonylation of Alkenes with Sulfonyl Chlorides under
Visible Light Activation
Sandrine M. Hell,§,[a] Claudio F. Meyer,§,[a],[b] Antonio Misale, Jeroen B. I. Sap, Kirsten E.
[b]
[a]
[a]
[a]
[b]
[a]
Christensen, Michael C. Willis, Andrés A. Trabanco, and Véronique Gouverneur*
Abstract: Sulfonyl chlorides are inexpensive reactants extensively
radical source, a class of reagents often synthesized from sulfonyl
chlorides.7b This transformation is best suited for alkenes bearing
alkyl groups; electron-deficient alkenes are less reactive and/or
give mixture of products (Scheme 1A).
explored for functionalization, but never considered for radical
hydrosulfonylation
of
alkenes.
Herein,
we
report
that
tris(trimethylsilyl)silane is an ideal hydrogen atom donor enabling
highly effective photoredox-catalyzed hydrosulfonylation of electron-
deficient alkenes with sulfonyl chlorides. To increase the generality of
this transformation, polarity-reversal catalysis was successfully
implemented for alkenes bearing alkyl substituents. This late stage
functionalization method tolerates a remarkably wide range of
functional groups, is operationally simple, scalable, and allows access
to building blocks which are important for medicinal chemistry and
drug discovery.
As part of our ongoing research on photoredox-catalyzed
8
hydrofunctionalization of alkenes, this state-of-play encouraged
us to develop an operationally simple and scalable protocol
enabling hydrosulfonylation of a broad range of substrates using
commercially and readily available sulfonyl chlorides (Scheme
1B). Sulfonyl chlorides are suitable for atom transfer radical
addition leading to net chlorosulfonylation, 5a,5c,5f.5j,6a,6b,6e,6h,6j but
re-routing this process towards hydrosulfonylation of alkenes has
not been accomplished. Mechanistically, this process would
require the addition of sulfonyl radical A to the alkene, generating
the C-centered radical B, followed by hydrogen atom transfer
Introduction
(
HAT) to afford the hydrosulfonylated product. For successful
HAT, a polarity match between radical B and the hydrogen atom
donor (HAD) is necessary. Therefore, fine-tuning of the reaction
conditions will be necessary for this protocol to be applicable to
alkenes of different electronic profiles. Electrophilic radicals would
require a nucleophilic HAD for a polarity matched HAT, while an
electrophilic HAD would be necessary for nucleophilic radicals.
Sulfones are prevalent motifs in marketed drugs and natural
products due to their unique electronic and structural properties.1
Today, sulfone-containing molecules are considered routinely in
medicinal chemistry programs searching for anti-inflammatory,
antimicrobial, anticancer, anti-HIV and antimalarial activities.1
Traditionally, sulfone derivatives are prepared by oxidation of a
sulfide or sulfoxide with strong oxidants such as peracids or
hydrogen peroxide (Scheme 1A).2 These conditions limit
applicability in the context of late stage functionalization of
complex molecules. Other methods include alkylation of sulfinate
salts, Friedel-Crafts type sulfonylation of arenes, and addition
A Previous work
Traditional approach
•
strong oxidants
O
O
[
Ox]
• low functional group tolerance
• limited substrate scope
• potentially explosive
S
R
R'
S
R
R'
3
reactions to alkenes and alkynes. Most of these methods focus
2
Vicinal sulfonylation of alkenes
on the construction of C(sp )-sulfones. In recent years, the
via
3
O
S
O O
S
X
development of radical processes for the formation of C(sp )-
O
O O
+
R
S
sulfonylated fragments has gained considerable interest.4 In
these transformations, sulfonyl chlorides, metal sulfinates,
sulfonyl selenides, sulfonyl azides and allyl sulfones have been
used as precursors to generate sulfonyl radicals for the
R'
Cl
R'
R
R'
R = Ar, EWG
X = OH, Cl
Hydrosulfonylation of alkenes, Yu (2019)
Ir
O
H
O O
functionalization of electron-rich olefins, styrene derivatives, and
unactivated alkenes.5,6 These procedures typically feature atom
+
R
S
S
R'
ONa
AcOH, H O
2
R
R'
For R = alkyl, > 45 examples
For R = EWG, 3 examples ( 50%)
Synthesized from R = alkyl, EWG
transfer radical addition (ATRA) leading to vicinal difunctionalized
motifs.6 Despite these advances, methods enabling direct
sulfonyl chlorides
7
B
This work: Hydrosulfonylation of alkenes using sulfonyl chlorides
hydrosulfonylation of alkenes remain underexplored . Very
recently, Yu and co-workers reported a photoredox catalyzed
hydrosulfonylation of unactivated alkenes using sulfinate salts as
O
S
O
H-atom donor Ir
MeCN, blue LEDs
H
O O
+
R
S
R'
Cl
R
R'
For R = EWG, > 35 examples
For R = alkyl, > 10 examples
R' = alkyl,
hetero)aryl
R = alkyl, EWG
(



Scalable (up to 10 g)
Late-stage functionalization
Operationally simple
[
a]
b]
S. M. Hell, C. F. Meyer, Dr. K. E. Christensen, Prof. Dr. M. C. Willis,
Prof. Dr. V. Gouverneur
University of Oxford, Chemistry Research Laboratory
Ir
O O
S
R
O
S
O
12 Mansfield Road, Oxford, OX1 3TA (UK).
E-mail: veronique.gouverneur@chem.ox.ac.uk
C. F. Meyer, Dr. A. Misale, Dr. A. A. Trabanco
Discovery Chemistry, Janssen Research and Development
Jarama 75A, 45007 Toledo (Spain).
R
R
R' Polarity-matched HAT
[
A
B
Scheme 1. A) Selected routes to functionalized sulfones. B) Photoredox-
catalyzed hydrosulfonylation of alkenes using sulfonyl chlorides (this work).
§
S. M. Hell and C. F. Meyer contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202004070
RESEARCH ARTICLE
As expected, the choice of HAD influences the outcome of
the reaction (Table 1, entries 1-9). In the absence of HAD, the
reaction did not proceed (entry 1). When tetrahydrofuran,
triphenylmethane, triethylsilane or triphenylsilane were used, only
Results and Discussion
Hydrosulfonylation of electron-deficient alkenes.
Processes other than hydrosulfonylation have demonstrated that
sulfonyl radical A can undergo regioselective Giese-addition to an
electron-deficient alkene affording electrophilic radical C (Table
traces of desired product 3a and sulfinic acid 4a were formed
8b,c.10,11
(
entries 2-5).
With its favorable Si-H bond dissociation
12
energy (BDE = 351.5 kJ/mol), tris(trimethylsilyl)silane enabled
access to the hydrosulfonylated product 3a in 90% yield along
with 11% yield of 4a (entry 6). The yield was not further improved
using tributyltin hydride, Hantzsch ester, or thiophenol as
alternative HAD (entries 7-9). Light irradiation is essential for the
reaction to proceed (entry 10). In the absence of photocatalyst,
6
h,7
1).
For such radical, a nucleophilic HAD is required for a
polarity matched HAT. Sulfonyl radical A could also undergo
direct H-atom abstraction to form sulfinic acid D, a competitive
HAT pathway prompting us to test a range of H-atom donors. We
chose 4-fluorobenzenesulfonyl chloride as sulfonyl radical source,
N-phenylacrylamide (2a) as the model alkene, and fac-Ir(ppy)
photocatalyst to test the viability of this transformation.
Acetonitrile was selected as the reaction solvent.9
3
as
13,14
the reaction proceeded with significantly lower yield (entry 11).
Further screening of reaction conditions showed that more than
9
one photocatalyst was suitable for this transformation. However,
early experimentation on representative starting materials
indicated that fac-Ir(ppy)3 gave higher yields with the
organophotocatalyst Eosin Y being more often second best.
The generality of this approach was investigated on a range
of sulfonyl chlorides and alkenes (Scheme 2). Methoxy,
trifluoromethyl, nitro, nitrile, halide, ketone, ether, amide and
carbamate substituted sulfonyl chlorides were all tolerated under
the reaction conditions, and the desired hydrosulfonylated
products were obtained in moderate to excellent yields (3a-o). A
broad variety of heteroarylsulfonyl chlorides containing thiophene,
thiazole and pyridine were suitable (3f-h). Alkyl sulfonyl chlorides
gave access to dialkyl sulfones in good yields (3i-o).
Heterocycloalkyl sulfonyl chlorides yielded the hydrosulfonylated
products in high yields (3m,n). Moreover, a camphor derivative
was isolated in excellent yield (3o). Linear terminal, gem-
disubstituted and 1,2-disubstituted alkenes gave the desired
products in good to excellent yields (3p-v). Alkenes substituted by
a heteroaryl group, such as a pyridyl or benzothiazyl were
converted to the hydrosulfonylated product in moderate to good
yield (3r,s). A series of cyclic alkenes including cyclohexene,
cyclopentene and cyclobutene provided highly desirable 1,2-
disubstituted building blocks in good yields and with excellent
Table 1. Reaction design and optimization of the reaction conditions for the
[
a]
hydrosulfonylation of N-phenylacrylamide.
Reaction design for the hydrosulfonylation of electron-deficient alkenes
Ir H
H-atom donor
O O
O
O
+
S
EWG
S
R
Cl
MeCN, blue LEDs
R
EWG
R = alkyl,
O
S
(
hetero)aryl
Ir
HAD
R
O
OH
D
EWG
O O
S
O
HAD
S
R
R
EWG
Giese
addition
A
C
yield[b](3a)
yield[b] (4a)
entry
H-donor
1
2
3
4
5
6
7
8
9
-
traces
traces
traces
traces
traces
90% (82%[c]
28%
2%
4%
THF (solvent)
diastereoselectivities
(3w-ac).
Furthermore,
the
Ph
3
CH
SiH
SiH
SiH
SnH
traces
traces
4%
hydrosulfonylation of a dehydroalanine derivative was achieved
in 61% yield (3ad). We also investigated the addition of sulfonyl
radicals onto alkynes. Both electron-deficient and unactivated
alkynes led to the corresponding hydrosulfonylated alkenes (3ae-
3ah) in good yields, and moderate to high Z-selectivity. Finally,
this procedure was validated on biologically active molecules.
Hydrosulfonylated analogues of an Estrone derivative, Ibrutinib
and Ethacrynic acid were isolated in moderate to good yields (3ai-
Et
3
Ph
3
(TMS)
3
)
11%
59%
3%
Bu
3
Hantzsch ester
PhSH
34%
3ak). The hydrosulfonylation of Exemestane afforded the desired
26%
3%
product (3al) in moderate yield, excellent diastereoselectivity and
regioselectivity for the exo-1,6-system.
1
0[d]
1[e]
(TMS)
3
SiH
SiH
0%
0%
1
(TMS)
3
23%
4%
[
a] Reaction conditions: 1a (0.25 mmol), 2a (0.1 mmol), fac-Ir(ppy)
3
(0.5
mol%),H-atom donor (0.2 mmol), MeCN (0.6 mL) under blue light (λmax = 450
19
nm) irradiation for
1
h. [b] Yield determined by
F NMR using α,α,α-
trifluorotoluene as internal standard. [c] Yields of isolated products. [d] Reaction
performed in the dark. [e] Reaction performed in the absence of photocatalyst.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202004070
RESEARCH ARTICLE
fac-Ir(ppy)
3
(0.5 mol%)
O
O
(
TMS) SiH (2.0 equiv)
3
38 examples
up to 97%
O
O
S
+
R
EWG
S
EWG
MeCN, rt, 1 h
blue LEDs
R
Cl
(2.5 equiv)
Sulfonyl chloride scope
1
2 (1.0 equiv)
3a-al
O
O
O
O
O
O
O
O
O
O
S
NHPh
S
NHPh
S
NHPh
S
NHPh
S
NHPh
O
O
O
O
O
F
MeO
F
3
C
O
2
N
NC
3a, 82%
3b, 86%
3c, 92%
3d, 90%
3e, 83%
O
O
O O
S
NHPh
O
S
O
N
S
NHPh
O
O
S
O
O
S
NHPh
NHPh
Me
Me
NHPh
NHPh
S
O
S
O
Me
O
Br
N
NH
3h, 76%
O
Me
O
O
3f, 85%
3g, 74%
3i, 78%
3j, 85%
O
O
S
O
O
S
O
O
O
O
Me
O
S
O
NHPh
Cl
NHPh
S
NHPh
S
NHPh
Me
CbzN
O
O
O
O
O
O
O
3k, 79%
3l, 62%
3m, 97%
3n, 81%
3o, 90%
From (S)-camphorsulfonyl chloride
Alkene scope
O
S
O
O
S
O
H
O
O
H
O
O
Ar =
N
N
N
S
PhO
Ar
S
Ar
N
O
Ar
Ar
S
O
O
F
O
O
3
p, 88%
3q, 95%
3r, 55%
3s, 87%
O
O
O
O
Me O
O
O
Ar
BnN
O
Ph
S
MeO
S
S O O
S
Ar
Ar
Ar
O
O
O
Ph
Ph
3v, 88%
S
O
S
Ar
S
Ar
O
O
O
O
O
3t, 68%
3u, 78%
3w, 71%
3x, 76%
3y, 75%
O
O
O
O
O
N
O
PhthN
N
H
O
OMe
Ar
S
Ar
S
Ar
S
S
Ar
S
Ar
O
O
O O
O
O
O
O
O
O
[a]
3
z, 36% (d.r.: 35/65)[a]
3aa, 62% (d.r.: 94/6)[b]
3ab, 59% (d.r.: 93/7)[b]
3ac, 54% (d.r.: 90/10)
3ad, 61%
Alkyne scope[c]
O
O
O
O
O
O S
O
O
Ar
Ar
Ar
O O
S
S
N
S Ar
EtO
ae, 70% (Z/E, 89/11)[a]
BzHN
PhO
O
3
3af, 77% (Z/E, 86/14)[a]
3ag, 80% (Z/E, 63/37)[a]
3ah, 73% (Z/E, 73/28)[a]
OPh
Biologically active molecules
O
Me
O
Me
H
O
Me
H
H
H
Me
Ar
NH2
H
H
O
N
N
HO
O
H
O
Cl
S
O
Ar
S
O
N
O O
O
Cl
Ar
N
S
O
O
Ar
N
S
O O
O
O
3ai, 78%
3aj, 73%
From Ibrutinib
3ak, 42 %
From Ethacrynic acid
3al, 50% (d.r. > 20/1)
From Exemestane
From Estrone
3 3
Scheme 2. Substrate scope. Reaction conditions: 1a-o (1.25 mmol), 2a-x (0.5 mmol), (TMS) SiH (1.0 mmol), fac-Ir(ppy) (0.5 mol%), MeCN (3.0 mL), blue LED
irradiation (λmax = 450 nm), room temperature, 1 h. Yields of isolated products. [a] The isomers were separated by silica flash column chromatography. [b] The minor
isomer was not isolated. [c] 16 h reaction time.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202004070
RESEARCH ARTICLE
With the aim of scaling-up this transformation to multigram, we
explored the synthesis of a precursor to a family of Transient
Receptor Potential (TRP) channel antagonists (Scheme 3A).2d
Hydrosulfonylation was accomplished on a 5 g scale, affording
Under the standard reaction conditions, alkene 1z led to a
cascade spirocyclization to afford cyclobutylspirooxindoles 5a-
b.15 Aryl and alkylsulfone containing spirocycles could be
accessed in good yields and moderate diastereomeric ratio (5a-
b). When 1,2-dichloroethane was used as solvent and no H-atom
donor was present, the atom-transfer radical addition (ATRA)
product was obtained in high yield and excellent
diastereoselectivity (6, Scheme 3C).6a,b,e,g,h
3am in good yield (10.7 g, 81%) and diastereoselectivity (89/11).
Considering the benefits of performing photochemical reactions
in continuous processing, we also optimized the conditions for a
continuous flow protocol. A 5 g reaction in a solvent mixture of
acetonitrile/N,N-dimethylformamide (3:1) was performed in flow
with a residence time of 4 min (10 mL reactor volume) allowing
access to the desired hydrosulfonylated product 3am in good
yield (9.5 g, 72%) and identical level of diastereocontrol with
increased productivity (2.7 g/h). Collectively, these results
suggest that this methodology could be applicable to large-scale
production in batch or under continuous flow conditions. We also
explored the possibility to increase structural complexity through
quaternization of the intermediate α-carbonyl radical derived from
an alkene substituted with an N-arylated tertiary amide (Scheme
Hydrosulfonylation of other alkenes
The hydrosulfonylation of alkenes other than those bearing an
electron-withdrawing group was studied next (Scheme 4).
Reaction design for the hydrosulfonylation of other alkenes
O O
S
Ir H-atom donors
MeCN, blue LEDs
O O
S
H
+
R
R'
Cl
R'
R
3B).
R' = alkyl,
R = alkyl
slow
fast
(
hetero)aryl
Multigram synthesis[a]
A
O
O
S
R3Si-H
O
O O
S
Ir
PRC
R
O
OH
Batch and Continuous flow
g scale
R
R'
R
OH
radical
addition
PM
A
E
5
S
F
R
SH
PM
R3Si-H
R S
O
O
2y
3am
R3Si
Batch:
O
Cl
PM Polarity match
PRC Polarity reversal catalysis
•
•
81% (d.r.: 89/11)
10.7 g isolated product
N
N
N
H
Scope of other alkenes
O
S
Ar =
O
Flow:
• 72 % (d.r.: 89/11)
Ar
Ar
BzNH
S
PhthN
S
F
O O
O O
F
CF
3
•
•
9.5 g isolated product
a, 82% (40%[a]
8
)
8b, 76%
Transient Receptor Potential (TRP)
channel antagonist
2.7 g/h (Flow rate = 2.5 mL/min)
O O
S
4-CN-Ph
O
Ar BzO
Ar
S
S
PhO
Cascade spirocyclization[b]
Ar
O
O O
Me O O
B
O
O
R
RSO
fac-Ir(ppy)
2
Cl (2.5 equiv)
(0.5 mol%)
8
c, 79%
8d, 82%
OBz
8e, 86%
S
O
3
N
(TMS) SiH (2.0 equiv)
MeCN, rt, 1 h, blue LEDs
3
O
Ar
O
Me
N
S
O
Me
O
Ar
Me
N
N
S
O O
O
2z
5a-b
Ar
S
O
O
O
NC
O
O
Cl
O
S
S
iPr
8f, 93% (d.r: 70/30)
8g, 75% (d.r: 20/1)
8h, 73%
O O
O
O
O
N
N
Me
O
O
Me
a, 74% (d.r.: 50/50)
F
Me
Ar
S
N
N
Cl
N
Ar
S
O O
Me
5
5b, 76% (d.r.: 71/29)
N
N
O
O
Chlorosulfonylation
Me
8
C
i, 41%
Cl
8j, 67%
From Vinclozolin
O
O
Cl
From N-Allyl Theobromine
4-F-PhSO
2
Cl (2.5 equiv)
(0.5 mol%)
NHPh
fac-Ir(ppy)
3
Scheme 4. Scope of other alkenes. Reaction conditions: 1a (1.25 mmol), 7a-j
0.5 mmol), (TMS) SiH (1.0 mmol), 4-mercaptophenol (0.1 mmol), fac-Ir(ppy)
3
(0.5 mol%), MeCN (3.0 mL), blue LED irradiation (λmax = 450 nm), room
temperature, 16 h. Yields of isolated products. [a] Without thiol catalyst.
NHPh
(
3
K
2
HPO
4
(0.2 equiv)
S
F
DCE, rt, 16 h, blue LEDs
O
O
[c]
2aa
6, 73% (d.r. > 20/1)
Scheme 3. Further applications of the hydrosulfonylation of cyclobutene
derivatives. Yields of isolated products. [a] Reaction conditions: see Supporting
Information. [b] The diastereoisomers were separated by silica flash column
chromatography. [c] Stereochemistry was assigned by single-crystal X-ray
diffraction analysis.
Preliminary results showed that under our standard reactions
conditions, alkene 7a afforded the hydrosulfonylated product in
only 40% (8a),16 a result possibly stemming from a poor polarity
match between the nucleophilic radical intermediate E and the
3
nucleophilic H-atom donor (TMS) SiH. We reasoned that a two-
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202004070
RESEARCH ARTICLE
step polarity-matched process using an H-atom transfer catalyst
could improve the outcome of this reaction (polarity-reversal
Cl
+
O
NHPh
TEMPO (4.0 equiv)
1
7
catalysis (PRC) ). When a catalytic amount of a thiol catalyst
electrophilic H-atom donor) was added to the standard reaction
F
S
NHPh
MeCN, rt, 1 h
blue LEDs
O
O
H
(
1
a (2.5 equiv)
2a (1.0 equiv)
3a, 0%
conditions, the yield of 8a increased to 82%. Under these modified
conditions, various alkenes (7a-j) were tolerated, affording the
desired products in high yields (8a-j). Terminal and gem-
disubstituted alkenes were suitable for this transformation,
leading to the desired products in good yields (8a-f). The
hydrosulfonylation of a cyclopentene derivative gave 8g in good
yield and excellent diastereomeric ratio. Finally, alkene-
containing biologically active molecules were also suitable
substrates, and afforded 8i and 8j in moderate to good yields.
B
Reduction of sulfonyl chloride
O
O
O
S
S
3
fac-Ir(ppy) (0.5 mol%)
Cl
+
(TMS)
3
SiH
HO
MeCN, rt, 1 h
blue LEDs
F
F
1a
(1.0 equiv)
4a, quantitative[a]
C
Photoredox-catalyzed hydrosulfonylation of alkenes using sulfinic acid
O
S
F
3
fac-Ir(ppy) (0.5 mol%)
O
O
(TMS) SiH (2.0 equiv)
3
HO
+
NHPh
S
O
NHPh
MeCN, rt, 1 h
blue LEDs
F
O
H
4a (2.5 equiv)
2a (1.0 equiv)
3a, 23%
Mechanistic considerations
D
Michael-addition of sulfinic acid
O
F
O
O
We next turned our attention to the reaction mechanism. Control
experiments showed that no hydrosulfonylated product 3a
derived from the electron-deficient alkene 2a was formed in the
presence of the radical scavenger TEMPO (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl; 2a was fully recovered (Scheme
S
HO
+
NHPh
S
O
NHPh
MeCN, rt, 24 h
F
O
H
4a (2.5 equiv)
2a (1.0 equiv)
3a, 58%
O
O
S
O
OPh
HO
OPh
A).18 When the reaction was performed in absence of alkene,
+
5
MeCN, rt, 24 h
S
F
F
O
quantitative reduction of sulfonyl chloride 1a to sulfinic acid 4a
was observed (Scheme 5B). The use of sulfinic acid 4a instead of
sulfonyl chloride under our standard reaction conditions afforded
O
4
a (2.5 equiv)
2o (1.0 equiv)
3ac, 0%
E
Deuteration experiment
3
a, albeit in significantly lower yield (Scheme 5C). Previous
fac-Ir(ppy)3 (0.5 mol%)
O
S
O
F
O
(TMS)
SiH (2.0 equiv)
O
3
reports showed that sulfinic acids readily undergo Michael
addition.19 However, the efficiency of this addition is highly
dependent on the alkene as illustrated with 2a and 2o (Scheme
Cl
+
NHPh
MeOD-d
4
, rt, 1 h
S
NHPh
F
blue LEDs
O
O
R
1a (2.5 equiv)
2a (1.0 equiv)
[D]3a, R = D, 0%
H]3a, R = H, 47%
[
5
4
D). Furthermore, the reaction of 2a in MeOD-d did not lead to
F
3
Formation of (TMS) SiCl
deuterium incorporation, an observation advocating against the
formation of an enol-type intermediate, and in favor of direct H-
O
O
O
fac-Ir(ppy)3 (0.5 mol%)
TMS
S
Cl
+
(TMS) SiH (2.0 equiv)
3a (82%)
TMS Si Cl
TMS
3
+
NHPh
2a (1.0 equiv)
atom transfer between (TMS)
3
SiH and a radical intermediate
F
MeCN, rt, 1 h
blue LEDs
(
Scheme 5E; selective formation of [H]3a over [D]3a). This
1
a (2.5 equiv)
9 (69%)
deuteration experiment demonstrates that an ionic pathway
involving the Michael-addition of a sulfinic acid can be ruled out
under these reaction conditions.11 This is further supported by the
Scheme 5. A-F. Mechanistic investigations. Yields of isolated products. [a] Yield
determined by F NMR using α,α,α-trifluorotoluene as internal standard.
19
nature of the spiro-cyclized product obtained from 2z (Scheme
3
3
B). Furthermore, (TMS) SiCl 13 was isolated as a side-product
Stern-Volmer fluorescence quenching experiments provide
of the reaction, which is consistent with the oxidation of the silyl
radical (Scheme 5F).
additional information (Scheme 6A). The excited state of fac-
3
Ir(ppy) is quenched by sulfonyl chloride 1a, implying that a direct
single electron reduction of the sulfonyl chloride, leading to the
formation of sulfonyl radical is plausible. This reactivity profile
contrasts with N,N-dimethylsulfamoyl chloride.8d Notably,
(
TMS)
3
SiH does not quench the excited state of fac-Ir(ppy)
3
,
III
advocating against an initiation scenario whereby [Ir *] could
undergo single-electron transfer with tris(trimethylsilyl)silane to
generate the Si-centered radical 12 upon loss of a proton.20
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202004070
RESEARCH ARTICLE
A
Stern-Volmer Fluorescence quenching
Conclusion
R2 = 0.9994
3
2
1
In summary, we have developed a general photoredox-catalyzed
hydrosulfonylation of alkenes using commercially and readily
available sulfonyl chlorides. This methodology allows access to
an extensive range of hydrosulfonylated products derived from
alkenes with a large spectrum of reactivity. Spirocyclic oxindoles
can be obtained in one step by a radical cascade cyclization. This
method was applied to the late stage sulfonylation of biologically
4
2
-F-PhSO Cl
(TMS)
3
SiH
2a
Me
2
2
NSO Cl
0.0
0.2
0.4
0.6
0.8
1.0
quencher [mM]
Proposed mechanism
B
active molecules, and the multigram synthesis of
pharmaceutically relevant building block was demonstrated.
a
O
O
O
O
S
(TMS)
3
SiH
O
S
S
-
12
R'
Cl
R'
R'
OH
SET,
1
then -Cl-
10
4
R
2
7
, R = EWG
, R = alkyl
Acknowledgements
III
N
IrIV
Ir
N
O
O
We gratefully acknowledge Robert Szpera for helpful discussions.
This project has received funding from the European Union’s
Horizon 2020 research and innovation programme under the
Marie Skłodowska-Curie grant agreement No 721902, and the
Engineering and Physical Sciences Research Council
(EP/N509711/1) (studentship to J. B. I. S.).
Ir
S
R'
R
11
h
N
If R = EWG
(TMS) SiH
If R = alkyl
IrIII
3
R-SH
3
(TMS) SiH
Path B
SET,
R-S
13
3
(TMS) Si
12
then + Cl-
12
(TMS)
3
SiCl
3
(TMS) Si
9
12
O
O
H
Keywords: sulfonyl chlorides • hydrosulfonylation • alkenes •
S
Path A
R'
R
1
0
1
radicals • photochemistry
3
8
, R = EWG
, R = alkyl
[1]
a) S. Patai, Z. Rappoport, C. J. M. Stirling, The Chemistry of Sulphones
and Sulfoxides; Wiley: New York, 1988. b) I. Ahmad, Shagufta, Int. J.
Pharm. Pharm. Sci. 2015, 7, 19–27; c) M. Feng, B. Tang, S. H. Liang, X.
Jiang, Curr. Top. Med. Chem. 2016, 16, 1200–1216; d) K. A. Scott and
J. T. Njardarson, Top. Curr. Chem. (Z) 2018, 376, 5.
Scheme 6. A. Stern-Volmer fluorescence quenching experiments. B. Proposed
mechanism for the hydrosulfonylation of alkenes.
Based on these observations, we suggest a plausible mechanism
for this transformation (Scheme 6B). Irradiation with light affords
the excited triplet state of the iridium photocatalyst. Single-
electron transfer to sulfonyl chloride 1 renders the sulfonyl radical
[2]
a) K. Bahrami, M. M. Khodaei, M. S. Arabi, J. Org. Chem. 2010, 75,
6208–6213;
b)
M.
Kirihara,
A.
Itou,
T.
Noguchi,
J.
Yamamoto, Synlett 2010, 10, 1557–1561; c) E. Voutyritsa, I. Triandafillidi,
C. G. Kokotos, Synthesis 2017, 49, 917–924; d) Hoffmann-La-Roche &
Genentech (2018), Sulfonyl cycloalkyl carboxamide compounds as
TRPA1 modulators, WO2016CN90637A, 2016.
1
0 along with a chloride anion after fragmentation of the initially
formed radical anion intermediate. In presence of a nucleophilic
HAD such as (TMS) SiH, 10 can react to form 4, a suitable but
[3]
N.-W. Liu, S. Liang, G. Manolikakes, Synthesis 2016, 48, 1939–1973.
a) C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013, 113,
[4]
3
5
322–5363; b) N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116,
0075–10166; c) M. K. Bogdos, E. Pinard, J. A. Murphy, Beilstein J. Org.
less efficient reagent for hydrosulfonylation under our reaction
conditions. Alternatively, addition of 10 to the alkene furnishes the
C-centered radical 11. For electron-deficient alkenes (R = EWG),
1
Chem. 2018, 14, 2035–2064; d) R. C. McAtee, E. J. McClain, C. R. J.
Stephenson, Trends Chem. 2019, 1, 111–125.
the electrophilic radical 11 is trapped by (TMS)
3
SiH to afford the
[5]
a) A. S. Gozdz, P. Maslak, J. Org. Chem. 1991, 56, 2179–2189; b) C.-P.
Chuang, Synth. Commun. 1993, 23, 2371–2380; c) J. E. Brumwell, N. S.
Simpkins, N. K. Terrett, Tetrahedron 1994, 50, 13533–13552; d) K.
Narasaka, T. Mochizuki, S. Hayakawa, Chem. Lett. 1994, 23, 1705–
desired hydrosulfonylated product 3 along with the silyl radical 12.
For other alkenes (R = alkyl), the nucleophilic radical 11 could
undergo H-atom transfer with the thiol polarity-reversal catalyst,
generating the desired product 8 and thiyl radical 13, which can
1708; e) I. W. Harvey, E. D. Phillips, G. H. Whitham, Tetrahedron 1997,
53, 6493–6508; f) S. Caddick, D. Hamza, S. N. Wadman, Tetrahedron
Lett. 1999, 40, 7285–7288; g) V. Nair, A. Augustine, S. B. Panicker, T. D.
Suja, S. Mathai, Res. Chem. Intermed. 2003, 29, 213–226; h) P. James,
F.-X. Felpin, Y. Landais, K. Schenk, J. Org. Chem. 2005, 70, 7985–7995;
i) L. Quebatte, K. Thommes, K. Severin, J. Am. Chem. Soc. 2006, 128,
undergo H-atom abstraction from (TMS)
3
SiH to afford silyl radical
12 along with the regenerated thiol catalyst. The observation that
the reaction is possible in the absence of photocatalyst although
more effective in its presence (Table 1, entry 11), favours a
photoinitiation-radical chain propagation pathway (Scheme 5,
Path A). The regeneration of the iridium photocatalyst in its
ground state by the oxidation of 12 is also viable (Path B).
7440–7441; j) A. A. Ermoshkin, A. N. Kasatochkin, V. P. Boyarskii, Russ.
J. Org. Chem. 2007, 43, 990–994; k) P. James, K. Schenk, Y. Landais,
J. Org. Chem. 2006, 71, 3630–3633; l) N. Mantrand, P. Renaud,
Tetrahedron 2008, 64, 11860–11864; m) T. Taniguchi, A. Idota, H.
Ishibashi, Org. Biomol. Chem. 2011, 9, 3151–3153; n) X. Li, X. Xu, C.
Zhou, Chem. Commun. 2012, 4, 12240–12242; o) J. Aziz, S. Messaoudi,
M. Alami, A. Hamze, Org. Biomol. Chem. 2014, 12, 9743–9759; p) X.-J.
Tang, Z. Zhang, W. R. Dolbier, Jr., Chem. Eur. J. 2015, 21, 18961–
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202004070
RESEARCH ARTICLE
1
8965; q) Y.-L. Zhu, B. Jiang, W.-J. Hao, A.-F. Wang, J.-K. Qiu, P. Wei,
[12] J. Lalevée, X. Allonas, J. P. Fouassier, J. Org. Chem. 2007, 72, 6434–
6439.
D.-C. Wang, G. Li, S.-J. Tu, Chem. Commun. 2016, 52, 1907–1910.
a) C.-J. Wallentin, J. D. Nguyen, P. Finkbeiner, C. R. J. Stephenson, J.
Am. Chem. Soc. 2012, 134, 8875–8884; b) X. Zeng, L. Ilies, E.
Nakamura, Org. Lett. 2012, 14, 954–956; c) H. Jiang, Y. Cheng, Y.
Zhang, S. Yu, Eur. J. Org. Chem. 2013, 24, 5485–5492; d) N. Taniguchi,
J. Org. Chem. 2015, 80, 7797–7802; e) X.-J. Tang, W. R. Dolbier,Jr.,
Angew. Chem. Int. Ed. 2015, 54, 4246–4249; f) X. Liu, T. Cong, P. Liu,
Org. Biomol. Chem. 2016, 14, 9416–9422; g) S. K. Pagire, S. Paria, O.
Reiser, Org. Lett. 2016, 18, 2106–2109; h) M. Alkan-Zambada, X. Hu, J.
Org. Chem. 2019, 84, 4525–4533; i) A. Hossain, S. Engl, E. Lutsker, O.
Reiser, ACS Catal. 2019, 9, 1103–1109.
[6]
[13] In absence of photocatalyst, photoinitiation-radical chain propagation is
likely.
[14] Applying the conditions from our recent hydrosulfamoylation (see ref 8d)
resulted in lower yield; see Supporting Information.
[15] a) H. Masu, T. Okamoto, T. Kato, K. Katagiri, M. Tominaga, H. Goda, H.
Takayanagi, I. Azumaya, Tetrahedron Lett. 2006, 47, 803–807; b) G. S.
Singh, Z. Y. Desta, Z. Y. Isatins, Chem. Rev. 2012, 112, 6104–6155; c)
J. Xie, P. Xu, H. Li, Q. Xue, H. Jin, Y. Cheng, C. Zhu, C, Chem. Commun.
2013, 49, 5672–5674; d) X.-J. Tang, C. S. Thomoson, W. R. Dolbier, Jr.,
Org. Lett. 2014, 16, 4594–4597; e) M. M. M. Santos, Tetrahedron 2014,
70, 9735–9757; f) E. M. Carreira, T. C. Fessard, Chem. Rev. 2014, 114,
8257–8322; g) Q. Tang, X. Liu, S. Liu, H. Xie, W. Liu, J. Zeng, P. Cheng,
RSC Adv. 2015, 5, 89009–89014; h) L. Huang, L. Ye, X.-H. Li, Z.-L. Li,
J.-S. Lin, X.-Y. Liu, Org. Lett. 2016, 18, 5284–5287; i) G. Zou, X. Wang,
Org. Biomol. Chem. 2017, 15, 8748–8754; j) Z. Yang, A. Tang, Synlett
2019, 30, 1061–1066.
[
7]
8]
a) X. Huang, S. Luo, O. Burghaus, R. D. Webster, K. Harmsa, E.
Meggers, Chem. Sci., 2017, 8, 7126–7131; b) During this study, a
hydrosulfonylation of alkenes using sulfinate salts has been reported: J.-
J. Wang, W. Yu, Org. Lett. 2019, 21, 9236–9240; c) X. Wang, M. Yang,
W. Xie, X. Fan, J. Wu, Chem. Comm. 2019, 55, 6010–6013.
[
a) S. Mizuta, S. Verhoog, K. M. Engle, T. Khotavivattana, M. O’Duill, K.
Wheelhouse, G. Rassias, M. Medebielle, V. Gouverneur, J. Am. Chem.
Soc. 2013, 135, 2505−2508; b) C. F. Meyer, S. M. Hell, A. Misale, A. A.
Trabanco, V. Gouverneur, Angew. Chem. Int. Ed. 2019, 58, 8829;
Angew. Chem. 2019,131, 8921–8925; c) C. F. Meyer, S. M. Hell, J. B. I.
Sap, A. Misale, A. Peschiulli, D. Oehlrich, A. A. Trabanco, V. Gouverneur,
Tetrahedron 2019. Article 130679. doi.org/10.1016/j.tet.2019.130679; d)
S. M. Hell, C. F. Meyer, G. Laudadio, A. Misale, M. C. Willis, T. Noël, A.
A. Trabanco, V. Gouverneur, J. Am. Chem. Soc. 2019, doi:
[16] This could be explained by the in-situ formation of traces of the
electrophilic sulfinic acid; see Ref 7b.
[17] a) B. P. Roberts, Chem. Soc. Rev. 1999, 28, 25–35; b) B. Chan, C. J.
Easton, L. Radom, J. Phys. Chem. A 2018, 122, 1741–1746.
[18] The cascade cyclization leading to spirooxindoles 5 (see Scheme 3)
further agrees with a radical pathway.
[19] L. Li, Y. Liu, Y. Peng, L. Yu, X. Wu, H. Yan, Angew. Chem. Int. Ed. 2016,
55, 331–335; Angew. Chem. 2016, 128, 339–343.
1
0.1021/jacs.9b13071.
[20] One cannot rule out such a scenario when Eosin Y is used instead of fac-
red
•-
ox
•+
[
9]
See Supporting Information.
3
Ir(ppy) (E1/2 (EosinY*/EosinY ) = + 0.83 V; E (TTMSS/TTMSS ) = +
[10] C. S. Gloor, F. Dénes and P. Renaud, Angew. Chem. Int. Ed., 2017, 56,
3329–13332; Angew. Chem. 2017, 129, 13514–13517;
0.73 V).4a,8d
1
[11] The Michael-addition of sulfinic acids can be ruled out; for more details,
see Supporting Information.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202004070
RESEARCH ARTICLE
Entry for the Table of Contents
RESEARCH ARTICLE
Sandrine M. Hell, Claudio F. Meyer,
Antonio Misale, Jeroen B. I. Sap, Kirsten
E. Christensen, Michael C. Willis,
Andrés A. Trabanco, and Véronique
Gouverneur*
Page No. – Page No.
Title
This article is protected by copyright. All rights reserved.