Thiosulfonylation of Unactivated Alkenes with Visible-Light Organic Photocatalysis

Article abstract of DOI:10.1021/acscatal.0c02159

A metal-free method for the vicinal thiosulfonylation of unactivated alkenes with thiosulfonates using 9-mesityl-10-methylacridinium perchlorate as the photo-organocatalyst with visible-light irradiation has been developed. The method can be performed in dimethyl carbonate under air at room temperature and features a broad functional group compatibility. Metrics indicate the green potential of the developed versus the state-of-the-art methodologies. Mechanistic studies revealed no single electron transfer but involvement of an energy transfer from the excited photo-organocatalyst to thiosulfonate reactant, subsequently providing a sulfenyl and a sulfonyl radical via homolytic cleavage.

Full text of DOI:10.1021/acscatal.0c02159

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Article
Thiosulfonylation of Unactivated Alkenes
with Visible-Light Organic Photocatalysis
Karthik Gadde, Pieter Mampuys, Andrea Guidetti, HongYue Vincent Ching, Wouter A.
Herrebout, Sabine Van Doorslaer, Kourosch Abbaspour Tehrani, and Bert U. W. Maes
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c02159 • Publication Date (Web): 23 Jun 2020
Downloaded from pubs.acs.org on June 23, 2020
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Page 1 of 59
1
ACS Catalysis
Thiosulfonylation of Unactivated Alkenes with
Visible-Light Organic Photocatalysis
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‡
‡
†
†
Karthik Gadde, Pieter Mampuys, Andrea Guidetti, H.Y. Vincent Ching, Wouter A.
£
†
‡
,‡
Herrebout, Sabine Van Doorslaer, Kourosch Abbaspour Tehrani, Bert U.W. Maes*
‡
Division of Organic Synthesis, Department of Chemistry, University of Antwerp,
Groenenborgerlaan 171, B-2020 Antwerp, Belgium
†
Biophysics and Biomedical Physics (BIMEF), Department of Chemistry, University of
Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium
£
Molecular Spectroscopy, Department of Chemistry, University of Antwerp,
Groenenborgerlaan 171, B-2020 Antwerp, Belgium
KEYWORDS: Visible-light photocatalysis, Organic photocatalyst, Thiosulfonates,
Difunctionalization, Energy Transfer.
ABSTRACT
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Page 2 of 59
A metal-free method for the vicinal thiosulfonylation of unactivated alkenes with
thiosulfonates using 9-mesityl-10-methylacridinium perchlorate as photo-organocatalyst with
visible-light irradiation has been developed. The method can be performed in dimethyl
carbonate under air at room temperature and features a broad functional group
compatibility. Metrics indicate the green potential of the developed versus the state-of-the-
art methodologies. Mechanistic studies revealed no single electron transfer but involvement
of an energy transfer from the excited photo-organocatalyst to thiosulfonate reactant,
subsequently providing a sulfenyl and a sulfonyl radical via homolytic cleavage.
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INTRODUCTION
Functionalization via an addition reaction on alkenes represents an attractive atom-
economic transformation for the construction of complex organic molecules. While 1,2-
hydrofunctionalization1 already received a lot of attention, the corresponding 1,2-
2
difunctionalization has in comparison been far less studied, and especially 1,2-bis-
heteroatom introduction.3 O,O- (dioxygenation),3a,
3b
N,N- (diamination),3c O,N-
3e
and X,N- (haloamination3f and haloazidation ) as well as S,S-
3g
(
oxyamination),3d,
difunctionalization3h-k have been reported. In the latter class, especially 1,2-thiosulfonylation
4
1
of olefins has only rarely been explored (Scheme 1). The installation of a sulfonyl (R SO -)
2
2
and sulfenyl (R S-) moiety is of synthetic interest as these functionalities appear in natural
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ACS Catalysis
5
products, bioactive molecules and pharmaceuticals (Figure 1). Besides, sulfenyl and
sulfonyl groups are attractive functionalities in organic synthesis as these are easily
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transformed into other functional groups, such as alkenes via Julia olefination, a Ramberg-
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Bäcklund reaction or alkenylative cross-coupling.
Figure 1: Examples of sulfonyl- (top) and sulfenyl-containing (bottom) active ingredients
AIs) of pharmaceuticals and agrochemicals.
(
Cl
Sulfonyl-containing AIs
F
H2N
Me
Me
Me
O
S
N
Me
O
O
O
Me
OH
O
S
O
S
O
O
O
O
S
S
Me
O
O
NH
O
N
S
OH
O
NO2
O
O
N
N
N
O
H
CF3
CN
N
N
O
NEt2
NH2
Me
O
NH
Eletriptan
migraine drug
Bicalutamide
antiandrogen
Cafenstrole
herbicide
Mesotrione
herbicide
Dapsone
antibiotic
Letaxaban
thromboembolism and
acute coronary syndromes
Me
OMe
Me
Me
Me
Cl
Me
O
O
S
S
O
O
S
O
S
O
O
O
OEt
O
O
S
O
S
N
N
N
O
O
O
N
N
O
S
O
O
O
Cl
N
N
Me
CF3
OCHF2
Me
F
F
Cl
O
CF3
Me
O
O
O
Me
NH
N
N
Cl
Me
F
OH
OEt
O
Pyroxasulfone
Fenoxasulfone
Fluensulfone
Tembotrione
Topramezone
herbicide
Apremilast
herbicide
herbicide
nematicide
herbicide
treatment of psoriasis
Sulfenyl-containing AIs
Cl
N
Me
O
O
O
H
Me
Me
S
S
S
N
OMe
S
S
Me
N
NH
HO
Me
HO
CF3
Me
S
MeS
N
N
NH2
NH2
Cl
S
Chlorbenside
Captodiamine
Thioridazine
Albendazole
Methionine
amino acid
Methionine analogue
pesticide
antihistamine, sedative and anxiolytic
antipsychotic
treatment of parasitic worm infections
Me
Me
N N
Cl
N
N
Me
OH
Me
N
CO2H
S
H
O
N
O
O
N
HO
S
O
N
N
S
OH
Cl
S
Me
CF3
SCF3
S
N
HO
O
S
N
S
OH
O
H
O
Et
Me
Cl
N
HN
N
Cl
O
N
SCF3
Thiethylperazine
antipsychotic
Butoconazole
antifungal
Toltrazuril
antiprotozaol agent
Montelukast
respiratory disorders
anti-malarial;
anti-pneumonia
Cefazaflur
antibiotic
1
2 10
Recently, thiosulfonates (R SO SR )
have been disclosed as 1,2-thiosulfonylating
2
reactants. Xu applied dual Au (IPrAuCl) and Ru (Ru(bpy) Cl ·6H O) visible-light photoredox
3
2
2
4c
catalysis for the thiosulfonylation of styrenes (Scheme 1a). In this process ArSO SR reacts
2
with the Au catalyst and is not involved in the photoredox cycle. Later on, they reversed the
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Page 4 of 59
regioselectivity by employing a Sc Lewis acid catalyst (Sc(OTf) /bpy), favoring an ionic
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3
4d
rather than a radical pathway (Scheme 1b). The first example of thiosulfonylation involving
unactivated alkenes was reported by Shen, employing a silver nitrate catalyst and potassium
persulfate as a stoichiometric oxidant (Scheme 1c).4a, 4b Unfortunately, the procedure only
involved perfluoroalkyl benzenethiosulfonate reactants. Though pioneering from a synthetic
organic chemistry point of view, these three procedures still show significant short comings
with respect to green chemistry. They at least feature three of the following aspects: use of a
(highly) hazardous solvent, a stoichiometric oxidant, a high loading of expensive and
limitedly available rare-earth or noble metal based catalyst, an inert atmosphere. In addition,
they are still limited in reactant scope, either to activated alkenes (e.g. styrenes) or
perfluoroalkyl thiosulfonates. A general, mild, cheap and efficient method for
thiosulfonylation of unactivated alkenes with a broad thiosulfonate scope using a cheap and
readily available catalyst which can be performed in a green solvent under air has not been
reported so far. In continuation of our interest in thiosulfonates11 and green synthetic
methodology development, we envisioned unprecedented alkyl and aryl thiosulfonylation of
unactivated alkenes via visible-light organic photocatalysis (Scheme 1d). Considering the
high oxidation potential of unactivated aliphatic alkenes this is a challenging goal [styrenes
(E < 2.0 V) < trisubstituted alkenes (2.0 < E < 2.2 V) < disubstituted alkenes (2.2 > E >
0
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ox
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ox
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ACS Catalysis
2
.4 V) mono substituted alkenes (E > 2.4 V); potentials vs. saturated calomel electrode
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ox
12
(SCE)]. Photocatalysis in organic synthesis is predominantly focused on the use of noble
13
metal complexes (mainly iridium and ruthenium) as catalyst. However, the use of organic
0
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chromophores as catalyst is still far less explored and beneficial in terms of cost and green
credentials and therefore our preferred option.
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Scheme 1. Thiosulfonylation of alkenes: state-of-the-art metal catalysis versus
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9
1
1
1
1
1
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organocatalysis.
(
a) Dual Au/Ru catalysis (Xu, 2017)
Noble metal catalysts
Highly hazardous solvent
Inert atmosphere
Ru(bpy) Cl ·6H O (2.5 mol%)
3
2
2
IPrAuCl (10 mol%)
SO Ar
2
Ar
AgSbF (15 mol%)
6
Limited to arenethiosulfonates
High power LED required
Limited to styrenes
Ar
+
ArSO SR
2
DCE, N2
rt, 3 h
SR
0
1
2
3
4
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0
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9
0
1
2
3
4
5
6
7
8
9
0
(2.0 equiv)
(1.0 equiv)
100 W blue LED (405 nm)
Visible light mediated
Room temperature
R = aryl or alkyl
(b) Sc-catalysis (Xu, 2019)
Rare-earth metal catalyst
Highly hazardous solvent
Inert atmosphere
Sc(OTf)3 (20 mol%)
bpy (20 mol%)
SR
Ar
PhSO2SR
Ar
+
Limited to benzenethiosulfonates
Limited to styrenes
CCl , N
4
2
SO Ph
2
80 °C, 12 h
(
1.0 equiv)
(2.0 equiv)
R = aryl or alkyl
Reverse regio-selectivity
Reflux
(
c) Ag-catalysis + K S O (Shen, 2016)
2 2 8
Noble metal catalyst
Hazardous solvent
Air atmosphere
AgNO3 (10-30 mol%)
K S O (1.0 equiv)
2
2
8
SRf
+
PhSO2SRf
R
R
SO Ph
Stoichiometric oxidant
2
NMP/H O (1:1), air
2
(1.0 equiv)
(1.0-1.2 equiv)
Limited to R benzenethiosulfonates
25 °C, 12 h
f
Unactivated alkenes
Room temperature
R = aryl or alkyl
(d) This work (Metal-free): photo-organocatalysis
Organocatalyst
SO2R1
+
-
Mes-Acr -Me ClO (0.5 mol%)
Green solvent
4
1
2
+
R SO SR
2
R
R
Air atmosphere
DMC, air
rt, 18 h
9 W blue LEDs (456 nm)
SR2
(1.0 equiv)
(2.0 equiv)
Alkyl and aryl thiosulfonates
Unactivated alkenes
Visible light mediated
Room temperature
1
1
2
R, R , R = aryl or alkyl
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ACS Catalysis
RESULTS AND DISCUSSION
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We started our optimization with the reaction of allylbenzene (1a) and S-(4-methylphenyl) 4-
methylbenzenethiosulfonate (2a) to give 1-methyl-4-([1-(4-methylbenzene-1-sulfonyl)-3-
phenylpropan-2-yl]sulfanyl)benzene (3a) under visible light irradiation at room temperature
0
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0
(Table 1 and Supporting Information (SI) for detailed optimization studies). When 1 mol% of
13
a frequently used noble metal-based photocatalyst, Ru(bpy) Cl ·6H O, was applied only
3
2
2
9% of the desired product (3a) was obtained (Table 1, entry 1). This photocatalyst was also
used for the thiosulfonylation of styrenes via dual catalysis applying a high power light-
emitting diode (LED) (Scheme 1a).4c Clearly, completely different reaction conditions are
required for efficient thiosulfonylation of unactivated alkenes under visible light. In
accordance with our goal, a series of organic dyes, such as fluorescein, rose bengal, eosin
Y, eosin B, rhodamine 6G, rhodamine B, and 9-mesityl-10-methylacridinium perchlorate
+
–
[
Mes-Acr -Me ClO ] were subsequently evaluated as organic photocatalyst for the
4
14
+
–
envisioned transformation (Table 1, entries 2–8). Among them, Mes-Acr -Me ClO proved
4
15
to be an efficient photocatalyst and 3a was obtained in 54% yield (entry 8). All other dyes
furnished diminished yields (entries 2–5) or failed to deliver 3a (entries 6 and 7).
Interestingly, even a photocatalyst loading of 0.5 mol% proved still sufficient to obtain 3a
(entry 9). Raising the concentration from 0.1 M to 0.5 M allowed to achieve full conversion of
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1
a and delivered 3a in 97% yield (entry 10). Pleasingly, the reaction could also be performed
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9
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6
in air without significant loss of yield of 3a (91%, entry 11). Next, solvents recommended
based on green solvent guides were evaluated as alternative for problematic acetonitrile
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9
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0
1
2
3
4
5
6
7
8
9
0
(
entries 12–14).16 Gratifyingly, preferred solvents isopropyl alcohol and dimethyl carbonate
DMC) furnished 3a in 92% and 91% yield, respectively. DMC was chosen as the optimal
(
16
solvent for the reaction and delivered 3a in 89% isolated yield. Omitting the photocatalyst
or performing the reaction in the dark lead to no reaction, indicating their crucial role (entries
15, 17-18). Lowering the amount of 2a to 1.5 equivalents was not beneficial for the yield of
3a (entry 16).
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ACS Catalysis
Table 1. Reaction optimization on the model reaction of allylbenzene (1a) with S-(4-
methylphenyl) 4-methylbenzenethiosulfonate (2a).[a]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Me
O
Me
S S
O
photocatalyst
O S O
+
Ph
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
solvent, atm., rt
light irradiation, 18 h
Ph
Me
S
Me
1a
2a
3a
Entry
Photocatalyst
mol%)
Ered*
(V)[b]
Eox*
(V)[b]
Solvent (M)
& Ranking[c]
Atm.
LED
Yield 3a
(
[%][d]
1
Ru(bpy) Cl ·6H O (1.0) +0.77 -0.81 CH CN (0.1)
Ar
Ar
Blue
Blue
Green
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
9
12
23
34
23
0
3
2
2
3
2
3
4
5
6
7
8
9
1
Fluorescein (1.0) +1.25 -1.55 CH CN (0.1)
3
Rose Bengal (1.0) +0.81 -0.96 CH CN (0.1)
Ar
3
Na -Eosin Y (1.0) +0.83 -1.15 CH CN (0.1)
Ar
2
3
Eosin B (1.0) +0.78 -1.37 CH CN (0.1)
Ar
3
Rhodamine 6G (1.0) +1.18 -1.09 CH CN (0.1)
Ar
3
Rhodamine B (1.0) +1.26 -1.31 CH CN (0.1)
Ar
0
3
+
–
Mes-Acr -Me ClO (1.0) +2.08
/
/
/
/
/
/
/
/
/
/
/
CH CN (0.1)
Ar
54
65
97
91
92
55
91 (89)[e]
0
4
3
+
–
Mes-Acr -Me ClO (0.5) +2.08
CH CN (0.1)
Ar
4
3
+
–
0
Mes-Acr -Me ClO (0.5) +2.08
CH CN (0.5)
Ar
4
3
+
–
11
Mes-Acr -Me ClO (0.5) +2.08
CH CN (0.5)
Air
Air
Air
Air
Air
Air
Air
Air
4
3
+
–
12
13
14
15
Mes-Acr -Me ClO (0.5) +2.08
i-PrOH (0.5)
EtOAc (0.5)
DMC (0.5)
DMC (0.5)
DMC (0.5)
DMC (0.5)
DMC (0.5)
4
+
–
Mes-Acr -Me ClO (0.5) +2.08
4
+
–
Mes-Acr -Me ClO (0.5) +2.08
Blue
No[f]
4
+
–
Mes-Acr -Me ClO (0.5) +2.08
4
16[g]
Mes-Acr -Me ClO (0.5) +2.08
+
–
Blue
No[f]
Blue
52
0
4
1
7
8
no photocatalyst /
no photocatalyst /
1
5
[
a]
Reaction conditions: 1a (0.25 mmol, 1.0 equiv), 2a (0.50 mmol, 2.0 equiv), photocatalyst,
solvent, atmosphere, rt, 18 h. Illumination by light-emitting diode (LED) strips (blue LED: λmax = 456
nm or green LED: λmax = 517 nm). [b] Excited state reduction potential (E *) and excited state
red
14b, 14c
oxidational potential (E *) vs. saturated calomel electrode (SCE).
More electrochemical data
ox
[c]
can be found in the Supporting Information. Ranking according to the Chem21 solvent selection
guide: amber denotes problematic, green denotes recommended/preferred solvent.16 [d] 1H NMR yield
with 1,3,5-trimethoxybenzene as internal standard. [e] Isolated yield. [f] Reaction was performed in the
dark. [g] 1.5 equiv of 2a was used. EtOAc = ethyl acetate. DMC = dimethyl carbonate.
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Page 10 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
With the optimized conditions in hand [1a (0.5 mmol), 2a (2.0 equiv), Mes-Acr -Me ClO4–
(0.5 mol%), dimethyl carbonate (0.5 M), air, room temperature, 18 h and blue LED
irradiation] the scope of the reaction was evaluated. First, S-(4-methylphenyl) 4-
methylbenzenethiosulfonate (2a) was coupled with a variety of unactivated alkenes (1)
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
Table 2). Homoallylbenzene (1b) and hex-1-ene (1c) easily underwent 1,2-thiosulfonylation
and the desired products (3b and 3c) were isolated in excellent yield. Various functional
groups on the alkene reactant, such as a halide (1d), alcohol (1e), ether (1f), imide (1g),
ketone (1h), ester (1i), carboxylic acid (1j and 1k) and nitrile (1l) did not effect this 1,2-
thiosulfonylation reaction and the corresponding products (3d–3l) were obtained in good to
excellent yield. Interestingly, acidic functional groups (alcohol (1e) and carboxylic acid (1j
and 1k)) were also tolerated. The substrates giving a low to moderate yield (1f, 1g, and 1j),
performed better in acetonitrile under otherwise standard conditions. Allyltrimethylsilane
(
1m) was also successfully employed and furnished the corresponding product 3m in
moderate yield (42%). However, under these conditions also a small amount of desilylated
product 3m (6%) was isolated. 1,4-Pentadiene (1n) was also smoothly converted into the
corresponding mono-1,2-thiosulfonylated product 3n in 49% yield and only a small amount
(
5%) of the bis-thiosulfonylated product 3n was isolated. Gratifyingly, 1,1-disubstituted
terminal alkene such as 2-methyl-1-butene (1o) also afforded the desired product (3o) in
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ACS Catalysis
71% yield. Unfortunately, alkenes with low oxidation potential such as styrene did not deliver
1
2
3
4
the desired 1,2-thiosulfonylation product. Oxidative sensitive electron-rich arenes, such as
present in methyl eugenol (1p), gave only 9% target product 3p. Extending the reaction time
or altering of the solvent to acetonitrile did not significantly improve the yield in these cases.
Interestingly, those substrates quench the excited acridinium photocatalyst, rationalizing the
inhibition of the desired transformation (see SI, section 6.3.2). On the other hand, internal
alkenes are surprisingly amenable to this reaction, as illustrated by 2-norbornene (1q),
cyclohexene (1r), cyclopentene (1s), and 2,3-dihydrofuran (1t), which furnished the
corresponding 1,2-thiosulfonylation products 3q–3t in respectively 64%, 23%, 92% and 21%
yield under standard reaction conditions. The yield of compounds 3r and 3t was improved to
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
65% and 51% by extending the reaction time to 48 h in dimethyl carbonate. Altering the
solvent to acetonitrile, did not improve the yield here.
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Page 12 of 59
Table 2. Unactivated alkene (1) scope.[a]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
-
Me
S
Mes-Acr -Me ClO
4
Me
O
Me
S
S
+
-
Mes-Acr -Me ClO (0.5 mol%)
4
R1
O
O
O
+
R1
Me
Me
DMC (0.5 M), air, rt
blue LEDs, 18 h
Me
S
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
ClO4
Me
Me
1
2a
3
Me
S
Me
Me
S
Me
O
S
O
O
S
S
O
O
S
O
O
S
S O
Ph
Br
Ph
Me
Me
Me
Me
Me
3a, 89%
3b, 89%
3c, 95%
3d, 64%
Me
Me
Me
Me
S
O
O
S
S
O
O
S
S
O
O
S
O
O
O
S
S O
HO
N
PhO
Me
O
Me
Me
)
Me
Me
3e, 94%
f, 15%[f] (64%[b]
3g, 68% (82%[b]
3h, 85%
Me
3
)
Me
Me
Me
O
O
S
S
O
O
S
S
O
O
S
S
O
O
S
S O
HO
HO
EtO
N
O
O
Me
Me
)
Me
Me
3i, 86%
j, 54%[f] (78%[b]
3k, 88%
3l, 72%
3
Me
Me
Me
S
Me
S
O
S
S
O
O
S
S
O
O
Me
O
O
S
O
Me
MeO
MeO
Si
Et
Me
Me
S
Me
Me
Me
Me
m, 42%[c]
3n, 49%[d]
3o, 71%[e]
% (15%[b]
Me
3
3p,
9
)
Me
Me
Me
O
O
O
O
S
S
S
S
O
O
O
O
S
S
S
S
O
Me
Me
Me
Me
3t, 21%[f] (51%[g]
)
3q, 64%
3r, 23%[f] (65%[g]
)
3s, 92%
[
a]
+
–
Reaction conditions: 1 (0.5 mmol, 1.0 equiv), 2a (1.0 mmol, 2.0 equiv), Mes-Acr -Me ClO
4
(0.5 mol%), dimethyl carbonate (1.0 mL, 0.5 M), air, room temperature, 18 h, blue LEDs.
Isolated yield unless indicated otherwise. [b] Reaction was conducted in acetonitrile (1.0 mL;
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ACS Catalysis
0
.5 M). [c] 6% of the desilylated product 3m was obtained. [d] 5% of the bis-thiosulfonylated
1
2
[
e]
[f]
1H NMR yield with 1,3,5-
product 3n was obtained.
Reaction time 24 h.
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
[g]
trimethoxybenzene as internal standard. Reaction time: 48 h.
Our methodology could also successfully be applied on terminal aromatic and aliphatic
alkynes (Scheme 2), without alteration of the reaction conditions.17 Phenylacetylene (5a)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and
1-ethynylcyclohexene
(5b)
reacted
with
S-(4-methylphenyl)
4-
methylbenzenethiosulfonate (2a) and S-phenyl benzenethiosulfonate (2d) yielding the
corresponding thiosulfonylation products 6a, 6b, 6c and 6d in 68%, 72%, 53% and 56%
yield, respectively. Interestingly, in 5b the acetylene reacted chemoselectively over the
alkene.
Scheme 2. Aromatic and aliphatic terminal alkynes (5a and 5b).
R
(a)
O
R
S S
O
+
-
Mes-Acr -Me ClO (0.5 mol%)
4
O S O
+
DMC (0.5 M), air, rt
blue LEDs, 18 h
R
S
R
5a (0.5 mmol)
2a or 2d (2.0 equiv)
6a, R = Me; 68%
6b, R = H; 72%
2
2
a, R = Me
d, R = H
(b)
R
O
R
S S
O
+
-
Mes-Acr -Me ClO (0.5 mol%)
4
O S O
+
DMC (0.5 M), air, rt
blue LEDs, 18 h
R
S
R
5b (0.5 mmol)
2a or 2d (2.0 equiv)
6c, R = Me; 53%
6d, R = H; 56%
2
2
a, R = Me
d, R = H
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Page 14 of 59
Next, the scope of the reaction with respect to the thiosulfonate (2) reactant was
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
2
investigated with allylbenzene (1a) as the substrate (Table 3). Symmetrical (R = R ) S-aryl
arenethiosulfonates, featuring substituents in different positions at the arene ring of the S-
aryl arenethiosulfonate (2b–2e) were well tolerated (3u–3x). Heteroaromatic reactants can
also be used as exemplified by S-thienyl thiophenethiosulfonate (2f), providing 3y in 76%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
yield. Unsymmetrical S-aryl arenethiosulfonates (R ≠ R ) (2g–2i) also generated the
difunctional products (3z–3ab) in good to excellent yield. The protocol is also applicable to
S-aryl alkanethiosulfonates and some S-alkyl arenethiosulfonates as exemplified by S-
phenyl methanethiosulfonate (2j) and S-(trifluoromethyl) benzenethiosulfonate (2k), affording
respectively 3ac in 72% and 3ad in 82% yield. Unfortunately, S-butyl benzenethiosulfonate
(2l) did not convert towards the desired 1,2-thiosulfonation product 3ae.
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ACS Catalysis
Table 3. Thiosulfonate (2) scope.[a]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R1
+
-
O
Mes-Acr -Me ClO (0.5 mol%)
O S O
4
1
+
R S
O
S
Ph
R2
Ph
DMC (0.5 M), air, rt
blue LEDs, 18 h
S
R2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1a
2
3
F
Cl
F3C
CF3
O S O
O S O
O S O
O S O
Ph
Ph
S
Ph
Ph
S
CF3
S
S
F
Cl
CF3
3x, 70%
3u, 70%
3v, 80%
3w, 71%
Me
S
O S O
O S O
O S O
O S O
Ph
S
Ph
Ph
Ph
Ph
S
S
S
O
S
MeO
N
H
O
F
3y, 76%
3z, 63%
3aa, 84%
3ab, 90%
Me
O S O
Ph
O S O
O S O
S
Ph
Ph
SCF3
S
Me
3
ac, 13%[c] (72%[b]
)
3ad, 82%
3ae, 0%
[
a]
Reaction conditions: 1a (0.5 mmol, 1.0 equiv), 2 (1.0 mmol, 2.0 equiv), Mes-Acr -Me ClO4–
+
(0.5 mol%), dimethyl carbonate (1.0 mL, 0.5 M), air, room temperature, 18 h, blue LEDs.
Isolated yield unless indicated otherwise. [b] Reaction was conducted in acetonitrile (1.0 mL,
.5 M). [c] 1H NMR yield with 1,3,5-trimethoxybenzene as internal standard.
0
This methodology could also be extended to selenosulfonates, without adaptation of the
reaction conditions, as exemplified by the reaction of Se-phenyl benzeneselenosulfonate
(2m) with 1a under standard conditions, giving the desired 7a in 94% yield (Scheme 3).
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Scheme 3. Application of Se-phenyl benzeneselenosulfonate (2m).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
+
-
S Se
O
Mes-Acr -Me ClO (0.5 mol%)
4
O S O
Se
+
Ph
Ph
DMC (0.5 M), air, rt
blue LEDs, 18 h
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1a (0.5 mmol)
2m (2.0 equiv)
7a, 94%
When diallylether (1u) and diethyl diallylmalonate (1v) were subjected to the standard
reaction conditions, cyclized products 8a and 8b were obtained in 95% and 84% yield,
respectively (Scheme 4). While this 5-exo-trig cyclization is selectively occurring in 1,6-
dienes, 1,2 addition is preferred over 3-exo-trig cyclization in 1,4-dienes (3n, Table 2).
Scheme 4. 5-Exo-trig cyclization in 1,6-dienes (1u and 1v).
Me
O
Me
S
S
+
-
Mes-Acr -Me ClO (0.5 mol%)
4
O
O
+
X
S
DMC (0.5 M), air, rt
blue LEDs, 18 h
O
Me
S
X
Me
1u or 1v (0.5 mmol)
2a (2.0 equiv)
1u, X = O
8a, X = O; 95% (d.r. = 76:24)
1
v, X = C(CO Et)
8b, X = C(CO Et) ; 84% (d.r. = 92:08)
2
2
2
2
The robustness of our reaction was further studied via a toolkit recently developed by
Glorius and co-workers.18 Via a small number of experiments (SI, section 4) the reaction-
condition-based sensitivity of our reaction was evaluated and the obtained results are
visualized in Figure 2 via a color-coded radar diagram.18 The studied parameters were
concentration, water level, oxygen level, temperature, light intensity and scale of the
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ACS Catalysis
reaction. The resulting graph remains almost undeflected around the ‘0% deviation from
standard yield line’, except for low light intensity and high oxygen content. This medium
sensitivity to light intensity is expected as the reaction is dependent on the excitation of the
photocatalyst enabling crucial substrate excitation. With respect to oxygen sensitivity a
negative effect (-17%) is observed when increasing oxygen concentration from air towards
pure oxygen atmosphere, which of course has no practical meaning. Overall, a robust
reaction has been developed.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. Sensitivity assessment of the developed reaction towards concentration, water
level, oxygen level, temperature, light intensity and scale, illustrated via a color-coded radar
18
diagram as proposed by Glorius et al. The deviation from standard reaction conditions is
indicated as a black solid line. A round shape around the ‘0% deviation from standard line’
indicates low sensitivity, any line deflecting from that to the red or green zones refer to high
sensitivity of the reaction towards that parameter.
In order to appraise the greenness of the developed 1,2-thiosulfonylation approach, the
19
CHEM21 Metrics Toolkit was employed. This assessment is a relative concept considering
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Page 18 of 59
both quantitative and qualitative parameters. By comparing reported carefully selected
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
examples of each methodology the green potential of the new vs. the state-of-the-art
20
methodologies (Scheme 1) can be evaluated. A detailed discussion of this evaluation can
be found in the Supporting Information (section 5). Pleasingly, the results in Table 4 illustrate
that the novel route has the largest green potential of the examined methodologies as it
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
generates the lowest amount of waste (Process Mass Intensity (PMI) = 7.8 g g ). Moreover,
for this route only green flags are obtained for important qualitative aspects of a reaction
such as health and safety of reagents, energy use, solvent selection, and use of critical
elements whereas multiple amber, red and brown flags are attributed to the three other
routes.
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ACS Catalysis
Table 4. Appraisal of the green credentials of the different 1,2-thiosulfonylation approaches
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
presented in Scheme 1.[a]
Method
Scheme 1 (g g ) Safety[b]
PMI
Health and
Flag Energy Flag Solvents Flag Critical
elements
Flag
-
1
A
22.2
DCE
rt
DCE
Au
Sb
Ag
Ru
Sc
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Xu)
AgSbF6
IPrAuCl
Ru(bpy) Cl
3
2
B
32.0
14.8
CCl4
reflux
rt
CCl4
(Xu)
2,2-bipyridine
Sc(OTf)3
NMP
C
NMP
Ag
(Shen)
AgNO3
water
K S O
2
2
8
water
DMC
D
7.8
rt
DMC
none
+
(this work)
Mes-Acr -Me
ClO4–
[
a]
Green flag denotes recommended (or preferred), amber flag denotes problematic,
substitution preferred and red flag denotes hazardous (substitution is a priority) and brown
flag denotes highly hazardous. [b] The health and safety flags from the reactants, i.e. 1 and
2, have been omitted as only the green potential from the methodologies irrespective from
the selected examples is appreciated. DCE = 1,2-dichloroethane. NMP = N-methyl-2-
pyrrolidone. DMC = dimethyl carbonate.
Several experiments were conducted on the model reaction of 1a and 2a to gain insight in
the reaction mechanism of our transformation (Schemes 5-6 & SI section 6). The radical
nature of the reaction was confirmed by the addition of radical inhibitors to the model
reaction. All tested radical inhibitors - TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl),
galvinoxyl, and BHT (butylated hydroxytoluene) - completely inhibited the formation of 1-
methyl-4-([1-(4-methylbenzene-1-sulfonyl)-3-phenylpropan-2-yl]sulfanyl)benzene
(3a)
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Page 20 of 59
(
Scheme 5a & SI section 6.5). Radical formation from thiosulfonate was further supported by
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
irradiation a 1:1 mixture of S-(4-methylphenyl) 4-methylbenzenethiosulfonate (2a) and S-(4-
fluorophenyl) 4-fluorobenzenethiosulfonate (2b) under optimal reaction conditions in the
absence of allylbenzene (1a). Scrambled thiosulfonates 2g and 2n were obtained in 28%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Scheme 6a). Omitting the light or photocatalyst did not lead to the formation of 2g and 2n
and both 2a and 2b were fully recovered (Scheme 6a). These results suggest the homolytic
cleavage of the SO -S thiosulfonate bond under visible light irradiation in the presence of
2
photocatalyst, thereby generating both a sulfonyl and a sulfenyl radical. Interestingly, when
1
,2-bis-(4-fluorophenyl)disulfide (4b) was added to the model reaction a scrambled product
3z was obtained in 37%, along with 50% of the desired product 3a (Scheme 6b). This points
to the involvement of a disulfide intermediate in the catalytic cycle. Also in this case no
reaction was observed in the dark (Scheme 6b). When S-(4-methylphenyl) 4-
methylbenzenethiosulfonate (2a) and 1,2-bis-(4-fluorophenyl)disulfide (4b) were brought
under the standard reaction conditions in the absence of allylbenzene all possible
thiosulfonates and disulfides were observed, fully in accordance with the thiosulfonate
scrambling experiment (Scheme 6c).
Scheme 5. Control reactions to support mechanism.
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Page 21 of 59
ACS Catalysis
Me
S
(
a) Radical inhibition experiment
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
S
Me
S
+
-
Mes-Acr -Me ClO4 (0.5 mol%)
Radical
scavenger
O
+
O
S
O
+
Ph
DMC (0.5 M), air, rt
blue LEDs, 18 h
Ph
Me
Me
1a (0.25 mmol)
2a (2.0 equiv)
(2.0 equiv)
3a
Me
t-Bu
t-Bu
Radical scavenger
N
O
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
t-Bu
t-Bu
t-Bu
t-Bu
OH
BHT
none
TEMPO
galvinoxyl
0
Yield of 3a [%][a]
91
0
0
(b) Light-dark cycle experiment
80
70
60
50
40
30
2
0
0
0
no light
no light
no light
1
0
2
4
6
8
10
12
Time (h)
Time (h)
Me
(c) UV LEDs experiment
O
Me
S
S
No photocatalyst
O
O
S
S O
+
Ph
DMC (0.5 M), air, rt, 18 h
Ph
365 nm UV LEDs
Me
Me
1a (0.25 mmol)
2a (2.0 equiv)
3a, 64%[a]
[a] 1H NMR yield with 1,3,5-trimethoxybenzene as internal standard
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Page 22 of 59
Scheme 6. Scrambling experiments to support the reaction mechanism.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(a) Scrambling experiment between thiosulfonates 2a and 2b
+
-
Mes-Acr -Me ClO
4
O
O
O
O
(
0.5 mol%)
Me
S S
O
F
S S
O
+
F
Me
S S
O
+ F
S S
O
DMC (0.5 M), air, rt
blue LEDs, 18 h
Me
Dark: no reaction
Without catalyst: no reaction
2g, 28%[a,d]
68% recoup 2a[b] and 70% recoup 2b[a]
2n, 28%[a,d]
2a (1.0 equiv) Me
2b (1.0 equiv)
F
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(b) Scrambling experiment on the model reaction with added disulfide 4b
Me
Me
O
Me
S S
O
Mes-Acr -Me ClO4-
+
O S O
O S O
+
(0.5 mol%)
2a (2.0 equiv)
+
Ph
Ph
Ph
Me
DMC (0.5 M), air, rt
blue LEDs, 18 h
S
S
S
F
1
a (1.0 equiv)
F
S
Dark: no reaction
Me
F
3
a, 50%[b,f]
3z, 37%[b,f]
4b (2.0 equiv)
(c) Scrambling experiment between thiosulfonate 2a and disulfide 4b
F
Me
F
+
-
Mes-Acr -Me ClO
4
O
O
(0.5 mol%)
Me
S S
O
+
S S
Me
S S
+
S S
+
S S
DMC (0.5 M), air, rt
blue LEDs, 18 h
O
Me
F
Me
4x, 40%[a,e]
40% recoup 2a[b] and 50% recoup 4b[a]
Me
F
2g, 60%[a,c]
4a, 10%[b,c]
2a (1.0 equiv)
4b (1.0 equiv)
Dark: no reaction
+
(d) Scrambling experiment between disulfides 4a and 4b
F
Me
F
50% recoup 4a[b]
+
+
S
S
+
S
S
S
S
DMC (0.5 M), air, rt
blue LEDs, 18 h
50% recoup 4b[a]
Me
Me
F
4x, 50%[a,e]
4a (1.0 equiv)
4b (1.0 equiv)
Dark: no reaction
(e) Scrambling experiment between thiosulfonates 2a and 2l
+
-
Mes-Acr -Me ClO
4
O
O
O
O
(0.5 mol%)
Me
S S
O
+
S S
O
Me
S S
O
+
S S
O
DMC (0.5 M), air, rt
Me blue LEDs, 18 h
Me
2al, 0%[b,c]
98% recoup 2a[b] and 97% recoup 2l[b]
2la, 0%[b,c]
2a (1.0 equiv)
2l (1.0 equiv)
Without catalyst: no reaction
Me
Me
+
(f) Scrambling experiment between thiosulfonate 2a and disulfide 4l
+
-
Me
Mes-Acr -Me ClO
Me
4
O
O
(
0.5 mol%)
Me
S S
O
+
S S
Me
S S
O
+
S S
DMC (0.5 M), air, rt
Me blue LEDs, 18 h
Me
2al, 0%[b,c]
+ 100% recoup 2a[b] and 100% recoup 4l[b]
4y, 0%[b,c] Me
2a (1.0 equiv)
Me
4l (1.0 equiv)
Without catalyst: no reaction
[
[
a] 19
c]
F NMR yield with hexafluorobenzene as internal standard [b] 1H NMR yield with 1,3,5-trimethoxybenzene as internal standard
Based on the amount of 2a [d] Based on the amount of 2b
[e]
[f]
Based on the amount of 4b
Based on the amount of 1a
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Page 23 of 59
ACS Catalysis
Both allylbenzene (1a) and S-(4-methylphenyl) 4-methylbenzenethiosulfonate (2a)
marginally absorb light above 400 nm as supported by UV-visible absorption spectra (SI,
Figures S7-S8) in accordance with the observation that both visible light and the
photocatalyst are essential for the reaction (Table 1, entries 15, 17–18). The acridinium salt
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
–
[
Mes-Acr -Me ClO ] is the species in the reaction mixture absorbing the visible light photons
4
efficiently (λmax1 = 359 nm, λmax2 = 420 nm, see SI Figure S6), hereby generating an excited
state able to deliver radicals from the reactants. A ‘light-dark cycle experiment’ was
subsequently conducted (Scheme 5b and SI section 6.8). The model reaction was
completely inhibited in the absence of light and restarted when the light was turned back on.
Although this intuitively points to no involvement of a radical chain - i.e. our transformation
needs continuous irradiation of visible light to produce radicals - this type of experiment is
21
not conclusive as reported by Yoon. Indeed, a quantum yield of Ф = 1.9 was determined
for the model reaction, employing the standard ferrioxalate actinometry (see SI section 6.4),
which points to a combination of a photocatalytic transformation and a radical chain
reaction.21 However, as this value is close to 1, the photocatalytic route is likely the
dominant pathway.
Subsequently, we looked into how radicals can be formed by reaction with the excited state
of the photocatalyst. The redox properties of the excited photocatalyst, allylbenzene (1a),
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ACS Catalysis
Page 24 of 59
and S-(4-methylphenyl) 4-methylbenzenethiosulfonate (2a) were therefore compared to
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
check involvement of a single electron transfer (SET) mechanism. The photocatalyst Mes-
+
–
Acr -Me ClO4 displays an excited state reduction potential (E *) of + 2.08 V (charge
red
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
14b
transfer singlet state) or + 2.18 V (locally excited singlet state) vs. SCE (in CH CN). The
3
one-electron oxidation potential (E ) of 1a was determined to be + 2.52 V vs. SCE (in
ox
CH CN; Figure S9) which is higher than the excited-state reduction potentials (E *) of the
3
red
photocatalyst, eliminating a reductive quenching process. More substituted aliphatic alkenes
and styrenes (conjugated) reduce the E value, rationalizing the high oxidation potential
ox
measured for the unactivated mono substituted alkene 1a.12 S-(4-methylphenyl) 4-
methylbenzenethiosulfonate (2a) can be easily reduced (-1.43 V vs. SCE in CH CN; Figure
3
22
S10), but not oxidized. SET from either 1a and 2a to the excited state of the photocatalyst
is therefore excluded. Fluorescence quenching studies and a Stern-Volmer plot revealed
that 2a interacts with the excited organo-photocatalyst (Figures S13 - S15). This points to
involvement of an energy transfer (EnT) mechanism.23,24,25 Visible light-mediated energy
transfer catalysis has remained a relatively underdeveloped field.23 Interestingly, reported
photocatalytic reactions with acridinium photocatalyst involving alkenes have only been
reported to occur via the formation of the corresponding radical cations, subsequently
trapped with suitable nucleophiles.26
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ACS Catalysis
Two energy transfer mechanisms are possible, i.e. Förster (via coulombic interaction) and
Dexter (via exchange interaction). As no spectral overlap is observed between the emission
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
–
spectrum of the donor (photocatalyst Mes-Acr -Me ClO ; λ > 430 nm) and the UV-visible
4
em
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
absorption spectrum of the acceptor 2a (λab < 350 nm); a Dexter rather than Förster EnT
+
seems to be occurring (Figure S8). TD-DFT calculations on photocatalyst Mes-Acr -Me and
S-(4-methylphenyl) 4-methylbenzenethiosulfonate (2a) support a triplet-triplet energy
transfer (Figure S33).24l To further support involvement of an EnT, concomitantly producing
two radicals, additional studies were performed. Electron paramagnetic resonance (EPR)
experiments were conducted. DMPO (5,5-dimethyl-1-pyrroline N-oxide) was added to the
model reaction in order to trap the radicals involved, which indeed revealed the presence of
both a sulfenyl and a sulfonyl radical (Figure 3 & SI, section 6.9 for detailed EPR study).
This is in accordance with the scrambling experiment of two thiosulfonates (Scheme 6a).
Moreover, when the reaction was performed under UV light irradiation without a
photocatalyst, the same reaction also occurred with the same regioselectivity (Scheme 5c).
1
To exclude singlet oxygen ( O ) as quencher of our catalyst under air atmosphere, the
2
1
production of O was monitored via EPR using 2,2,6,6-tetramethylpiperidine as a trap (SI,
2
section 6.10). However, no significant spectral changes to the blank reaction were observed,
1
which therefore rules out O involvement in our catalytic cycle.
2
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Page 26 of 59
Figure 3. DMPO spin-trapping experiment on the model reaction of 1a and 2a, continuous
wave (cw) X-band (~9.44 GHz) EPR recorded at room temperature using 5 mW microwave
power, 0.05 mT modulation amplitude and 100 kHz modulation frequency, and the individual
components used for the spectral simulations. The ratio of R1 : R2 : R3 : Mes-Acr˙-Me used
for simulation was 1 : 0.9 : 0.6 : 6 (see SI section 6.9 for more details). Exp. = experimental
spectrum. Sim. = simulated spectrum.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
1a (8.8 µmol)
Me
S
+
Me
O
+
-
Mes-Acr -Me ClO
4
Me
S
S
S
(
0.14 mol%)
O
H +
O
O
H
O
N
DMC (0.5 M), N2, rt
47 nm laser
(~200 mW) 80 s
O
N
4
Me
Me
Me
2
a (2.0 equiv)
Me
Me
R2
R1
+
Me
OMe
H
N
O
Me
O
+ Mes-Acr-Me
N
Me
Me
R3
DMPO (10.2 equiv)
On the basis of the control experiments, both a photocatalytic and radical chain mechanism
have been proposed for the model reaction, which are concomitantly occurring (Scheme 7).
+
–
Initially, under irradiation with visible light, the photocatalyst Mes-Acr -Me ClO reaches an
4
+
–
excited-state, i.e. [Mes-Acr -Me ClO ]*, which then undergoes an energy transfer to S-(4-
4
+
methylphenyl) 4-methylbenzenethiosulfonate (2a), regenerating ground state Mes-Acr -Me
–
ClO , and excited S-(4-methylphenyl) 4-methylbenzenethiosulfonate (2a*). Subsequently,
4
2a* undergoes homolytic cleavage of the SO –S bond to afford a sulfenyl radical A and a
2
sulfonyl radical B. Addition of radical B to allylbenzene (1a) generates intermediate C.
Radical C can then react with sulfenyl radical A yielding target compound 3a
(photocatalysis). Radical C can also be involved in a radical chain process via reaction with
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ACS Catalysis
reactant 2a generating product 3a and radical B, which by reaction with allylbenzene (1a)
can initiate another cycle. There is a second possible radical chain involving sulfenyl radical
A, which could also react with thiosulfonate 2a, hereby delivering 1,2-bis-(p-tolyl)disulfide
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(4a) and radical B. Addition of radical B to allylbenzene (1a) generates intermediate C,
which then reacts with 1,2-bis-(p-tolyl)disulfide (4a) to furnish the desired product 3a along
with radical A. There is a driving force to rapidly form disulfide 4a from A. Reported
coulometric experiments on PhSO SPh involving one electron reduction show the formation
2
-
18a
of PhSSPh and PhSO . In accordance with this, the calculated Bond Dissociation Energy
2
-1
(
BDE) of 4a is larger than the one of 2a (BDE 4a = 189.9 kJ mol vs. BDE 2a = 181.1 kJ
-1
mol ) (SI, Section 6.11). There is no driving force to form 1,2-bis-(p-tolyl)disulfone from
-1
sulfonyl radical B as the BDE is significantly lower (167.0 kJ mol ), rationalizing its reaction
with allylbenzene (1a). 4a does not need to react with radicals as blue light can split it into
two sulfenyl radicals A.26a,c-27 This is confirmed via a scrambling experiment of 1,2-bis-(p-
tolyl)disulfide (4a) and 1,2-bis-(4-fluorophenyl)disulfide (4b) (Scheme 6d). While
thiosulfonates need a photocatalyst to homolytically cleave with visible light, the
corresponding disulfides do not (Scheme 6a and d). In addition, thiosulfonate 2a does not
scramble with S-butyl benzenethiosulfonate (2l) and 1,2-bis-(n-butyl)disulfide (4l) indicating
their BDE is too high and the radicals A and B formed from 2a just recombine (Scheme 6e
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Page 28 of 59
and f). This is in line with the reaction scope where S-butyl 4-methylbenzenethiosulfonate
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(2l) did not give reaction product 3ae and no 1,2-bis-(n-butyl)disulfide (4l) formation was
observed (Table 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 7. Proposed reaction mechanism for the model reaction of 1a with 2a.
Me
Me
S
S
Me
4a
Me
O
S
*
Me
Me
S
S
A
Mes-Acr-Me ClO4
(Excited State)
O
S
O
Me
S
2a
Me
O
O
*
O
Dexter energy transfer
Me
Me
S
2a
homolytic
cleavage
O
S
O
O
Mes-Acr-Me ClO4
(Ground State)
+
S
Me
Me
S
O
O
S
A
B
2a*
Me
O
B
S
S
Ph
Me
Me
Me
4a
1a
Ph
S
S
A
S
1a
photo-
catalysis
radical
chain
Me
4a
A
Me
Me
O
O
Ph
S
Ph
S
O
O
Me
C
C
Me
S
Me
O
radical
chain
Me
S
S
Ph
O
2a
1a
O
S
O
O
S O
O
S
O
Ph
Me
Ph
S
B
3a
Me
3a
Me
In order to demonstrate the synthetic utility of our protocol, a gram-scale reaction was
carried out on our model system under standard reaction conditions (Scheme 8). Scaling up
the reaction tenfold to 5 mmol allylbenzene substrate with S-(4-methylphenyl) 4-
methylbenzenethiosulfonate (2a) reactant gave 1-methyl-4-([1-(4-methylbenzene-1-
sulfonyl)-3-phenylpropan-2-yl]sulfanyl)benzene (3a) in 80% yield, which is only slightly lower
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Page 29 of 59
ACS Catalysis
in comparison to the 0.5 mmol scale experiment (89%). The unreacted excess 2a (1.29 g,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0.93 equiv, 93%) was also easily recovered during purification.
Scheme 8. Gram-scale synthesis of 3a via thiosulfonylation of 1a with 2a.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
O
O
S
Me
S
S
Me
S
+
-
Mes-Acr -Me ClO (0.5 mol%)
4
O
O
S
S
O
+
O
+
Ph
DMC (0.5 M), air, rt
blue LEDs, 18 h
Ph
Me
Me
[gram scale]
Me
3a, 80% (4.0 mmol, 1.58 g)
1a (5.0 mmol, 0.59 g)
2a (2.0 equiv, 2.78 g)
Recoup 2a (0.92 equiv, 1.29 g)
As further illustration of the utility of our methodology, a direct diversification of an active
pharmaceutical ingredient (API) has been attempted. Apronal (1w, hypnotic/sedative drug)
was selected as model as it features NH /NH groups of ureas and imides. Reaction of 1w
2
with 2a provided target product 9a in 79% yield (Scheme 9). This is remarkable as
processes involving amidyl type radical formation in the N-acyl urea functionality were not
observed. This further illustrates the chemoselectivity of the radical addition protocol
developed.
Scheme 9. Synthetic Applications: thiosulfonylation of API Apronal (1w) with thiosulfonate
2a.
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