Site-Selective Thiolation of (Multi)halogenated Heteroarenes

Article abstract of DOI:10.1021/jacs.0c01630

A general and simple strategy for the site-selective thiolation of various pharmaceutically relevant electron-rich heteroarenes with thiols is reported. This mild and reliable photocatalytic protocol enables C-S coupling at the most electron-rich position of the (multi)halogenated substrates, complementing established methodologies. Experimental and computational studies suggest a radical chain mechanism with the key step being a homolytic aromatic substitution of the heteroaryl halide by an electrophilic thiyl radical, highlighting an underdeveloped reactivity mode.

Full text of DOI:10.1021/jacs.0c01630

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Communication
Site-selective Thiolation of (Multi-)halogenated Heteroarenes
Frederik Sandfort, Tobias Knecht, Tobias Pinkert, Constantin G. Daniliuc, and Frank Glorius
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c01630 • Publication Date (Web): 01 Apr 2020
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Journal of the American Chemical Society
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Site-selective Thiolation of (Multi-)halogenated Heteroarenes
Frederik Sandfort, Tobias Knecht, Tobias Pinkert, Constantin G. Daniliuc, and Frank Glorius*
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Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
ABSTRACT: A general and simple strategy for the site-selective thiolation of various pharmaceutically relevant electron-rich
heteroarenes with thiols is reported. This mild and reliable photocatalytic protocol enables C–S coupling at the most electron-rich
position of the (multi-)halogenated substrates, complementing established methodologies. Experimental and computational studies
suggest a radical chain mechanism with the key step being a homolytic aromatic substitution of the heteroaryl halide by an
electrophilic thiyl radical, highlighting an underdeveloped reactivity mode.
substitution of aromatic C–X bonds with thiyl radicals via a
homolytic aromatic substitution has not been reported to date.
motifs in pharmaceuticals, and their selective functionalization
Heteroarenes rank among the most prominent structural
is therefore of particular interest.1 Decoration with further
heteroatom substituents typically begins from the respective
Selective Thiolation of Heteroarenes
a) Electron-poor heteroarenes: nucleophilic aromatic substitution (SNAr)
halogenated precursors, since they are either readily available,
or can be prepared in a straightforward manner.2 The synthesis
R
via
S
SR
X
R
R
R
of aromatic thioethers, prevalent in various biologically active
molecules, is no exception.3 The most common synthetic route
is the direct reaction of a heteroaryl electrophile with a sulfur
nucleophile in a nucleophilic aromatic substitution (SNAr).4 A
wide variety of electron-poor heteroarenes show inherent
reactivity in this transformation owing to mesomeric
stabilization of the intermediary Meisenheimer complex
(Figure 1a).5 It is therefore not surprising that SNAr reactions
are one of the most common reaction classes in drug discovery.2
R
SNAr
N
X
N
S
N
 highly established, mild, reliable
Meisenheimer complex
b) Electron-rich heteroarenes: no generally applicable method
NO2
B
A
B
A
B
A
B
A
RLi
R2S2
X
Li
SR
X
 activated substrates: SNAr
 harsh conditions, limited scope
In contrast, only few reports of the selective thiolation of
meaningful five-membered electron-rich heteroarenes, such as
imidazoles, pyrroles or thiazoles,1 can be found in the literature
(Figure 1b). Examples of metal-catalyzed thiolations are rare on
these substrates,6 owing to the challenging oxidative addition
into the electron-rich C–X bond and catalyst poisoning by soft
sulfur species.7 Direct nucleophilic aromatic substitution with
thiolates can only be realized by placing strongly electron-
withdrawing substituents, such as nitro groups, on the aromatic
ring, to overcome their inherent nucleophilic reactivity.8
Alternative methods often involve lithiation via metal-halogen
exchange, followed by trapping with a disulfide electrophile.9
While such reactions do not require a specific substitution
pattern, they are limited by the strongly basic reaction
conditions. Owing to these substantial limitations, a generally
applicable methodology for the selective thiolation of electron-
rich heteroarenes has remained elusive.
c) This Work: Radical Thiolation of Electron-rich Heteroarenes
Y
X
Y
S
B
A
B
A
Concept: HAS
R
+
PC
HS
Y
R
B
A
SR
X = Br,Cl
X
 general
 simple
 robust
 site-selective
 mild conditions
 predictable
Y = Br,Cl,CR3
A = NR,S,O
B = N,CR
 reactivity switch:
R
electrophile
S
Figure 1. Strategies for the selective thiolation of heteroarenes.
In the last decades, photocatalysis has emerged as an
indispensable tool in laboratory synthesis, since it often allows
for complementary reactivity under mild conditions.15 Among
numerous valuable transformations, several photocatalytic C–S
bond formations have been developed including cross-coupling
reactions of aromatic halides.16 These approaches either rely on
a
Nickel-photoredox dual-catalytic system,17 or involve
reduction of the aryl halide by strongly reducing photocatalysts
followed by thiolation in a radical nucleophilic substitution-
type process.18,19 Similar to classical palladium-catalyzed
thiolations,6 these reactions preferably occur with electron-
deficient to electron-neutral substrates.17,18 Coupling of five-
membered electron-rich heteroarenes could not be realized,
probably due to challenging oxidative addition and low
reduction potentials of the respective compounds.20
Conceptually, switching from a thiolate nucleophile to a thiyl
radical could offer complementary reactivity in formal SNAr-
type processes (Figure 1c). Thiyl radicals are electrophilic and
would thus have the matching philicity to add to electron-rich
heteroaromatics and substitute the halogen atom in a redox-
neutral homolytic aromatic substitution (HAS).4c,10,11 These
radicals can easily be generated from the respective thiols and
have been widely applied in organic synthesis.12 A broad range
of transformations has been discovered, which mostly involve
radical addition to electron-rich π-systems, such as alkenes or
alkynes.13,14 However, to the best of our knowledge, the direct
Herein, we report a protocol for the selective thiolation of
(multi-)halogenated, electron-rich heteroarenes. The reaction is
performed under remarkably simple photocatalytic conditions
and shows perfect selectivity for the most electron-rich
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Page 2 of 8
position, while tolerating other halides present in the
molecule.21
Our studies N-methyl-4,5-
imidazole ring. A 4,5-dibromoimidazole underwent the reaction
as smoothly as the chlorinated standard substrate with perfect
reactivity and selectivity (3a, 3b). Simple C5-monochlorinated
and -brominated starting materials could be reacted with good
yields (3c, 3d). While substrates with halogens present solely in
the C4-position remained untouched,23 a C2-brominated
imidazole was reactive under the standard reaction conditions,
raising the question of C5- vs C2-selectivity. Pleasingly, a
single product was observed (3f), when starting from a
tribrominated imidazole and the transformation was confirmed
to be selective for the most electron-rich C5-position via X-ray
1
2
3
4
5
6
7
8
began
by
reacting
dichloroimidazole (1a, 1.0 equiv) and thiol 2a (2.0 equiv) in the
presence of photocatalyst [Ir(dF(CF3)ppy)2dtbbpy)][PF6] (PC-
1) in MeCN under irradiation with visible light (λmax = 450 nm)
for 16 h. To our delight, the desired C–S coupling product 3a
could be obtained in good yield (77%, Table 1, entry 1) with
complete selectivity for the C5-position, leaving the second
chlorine substituent untouched. While the reaction proceeded in
various solvents of different polarity, use of DMA improved the
reactivity to almost quantitative yield (Table 1, entry 2).
Furthermore, the quantity of thiol 2a could be reduced to
1.5 equivalents, and even when a 1:1 mixture of imidazole 1a
and thiol 2a was reacted, the respective product could be
isolated in excellent yield (Table 1, entries 3 and 4). Control
experiments proved the necessities of light and photocatalyst
(Table 1, entries 5 and 6). Pleasingly, if transition-metal-free
conditions are desired, the iridium-based photocatalyst can be
replaced by the organic dye 4CzIPN (PC-2) giving product 3a
in excellent yield (91%, Table 1, entry 7).
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analysis of product 3g. The use of
a 2-bromo-4,5-
dichloroimidazole also resulted in C5-substitution as the major
product, albeit with reduced selectivity (C5:C2 = 85:15),
rationalized by the higher reactivity of bromide vs chloride (3h).
Alkyl substitution in C4-position was well tolerated, as
demonstrated on mono- and dichlorinated histidine scaffolds
(3i, 3j). Interestingly, electron-neutral aryl chlorides and
bromides, as well as an electron-poor 2-chloropyridine did not
show any interference with the desired transformation, and the
respective products could be isolated in excellent yields (3k–
3m). Next, we turned our attention towards reacting other
classes of electron-rich heteroarenes. The coupling products of
2,3- and 2,5-dibromothiophene were isolated in moderate to
good yields with complete selectivity for the C2-position (3n,
3o). Similar reactivity was also observed for furan substrates
(3p, 3q) as well as for pyrroles (3r). Notably, 2,3,4-
trihalogenated pyrroles resulted in selective formation of a
single C2-substituted product (3s, 3t). For N-methyl-2,5-
dichloropyrrole, dithiolation of the equivalent chlorine
substituents was achieved (3u). Remarkably, unprotected 5-
bromo-2-aminothiazole gave the desired coupling product in
good yield (3v), further demonstrating the general applicability
of the thiolation protocol.
Table 1. Optimization of the thiolation of heteroarenesa
Cl
Cl
Cl
S
N
N
N
N
PC (2.0 mol%)
CO2Me
+
HS
CO2Me
solvent (0.10 M), rt, 16 h
blue LEDs (450 nm)
1a
2a
(1.02.0 equiv)
3a
(0.10 mmol)
High c
CF3
[PF6
]
F
Big Scale
Low c
tBu
N
N
N
High I
Low I
H2O
N
N
NC
N
CN
N
F
Ir
F
Low O2
N
tBu
High T
High O2
F
CF3
We then decided to further investigate the scope of the thiol
coupling partner. Primary, secondary and benzylic thiols were
compatible substrates (3w–3y). In contrast, tertiary thiols were
found to be unreactive possibly due to steric effects. A free
alcohol as well as an alkyl chloride were well tolerated (3z,
3aa), and a dithiol could be coupled with two imidazole
moieties (3ab). Protected L-cysteine gave the corresponding
product in excellent yield with complete conservation of the
stereochemistry (3ac). Aromatic thiols bearing electron-
withdrawing groups underwent the desired transformation in
excellent yields (3ad, 3ae), and ortho-substitution showed no
significant impact on the reaction outcome (3af). Lower
reactivity was observed when electron-neutral to electron-rich
aromatic thiols (3ag–3ai) were used, presumably caused by the
lower electrophilicity of the respective thiyl radical.
Low T
PC-1
PC-2
sensitivity assessment
entry
photocatalyst solvent
1a/2a
yield / %
1
PC-1
PC-1
PC-1
PC-1
–
MeCN
DMA
DMA
DMA
DMA
DMA
DMA
1.0/2.0
1.0/2.0
1.0/1.5
1.0/1.0
1.0/1.5
1.0/1.5
1.0/1.5
77
97
98
90
0
2
3
4
5
6b
7c
PC-1
PC-2
0
91
aPerformed on 0.10 mmol scale. Yields were determined by GC-
FID using mesitylene as internal standard. bIn the absence of light.
cUsing 5 mol% of PC-2. DMA = N,N-dimethylacetamide. rt =
room temperature. PC = photocatalyst.
Lastly, we explored more complex thiols to show the
applicability of the methodology to late stage functionalization.
A thiol containing the biotin scaffold as well as protected
thioglucose gave the respective products in good to excellent
yields (3aj, 3ak). The cholestanol scaffold was well-tolerated
and even di- and tripeptides, derived from aspartame and
glutathione, could be reacted (3al–3an). An additive-based
robustness screen24 was also applied, and generally good
functional group tolerance with few exceptions was observed
(Table 2, see the Supporting Information for further details).
To ensure high reproducibility of this thiolation protocol, a
sensitivity assessment towards operational variations of the
reaction conditions was performed.22 Interestingly, the
transformation was shown to be insensitive towards important
reaction parameters such as moisture, oxygen, light intensity,
temperature and scale, highlighting the robustness and
applicability of the developed protocol (Table 1).
With the optimized conditions in hand, we set out to explore
the scope of the thiolation (Table 2). We first investigated the
generality regarding various halide substitution patterns on the
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Table 2. Scope of the thiolation of heteroarenesa
1
2
Scoping Studies
Additive-based Robustness Screen
15
15
3
4
5
6
7
8
9
Y
X
Y
[Ir(dF(CF3)ppy)2(dtbbpy)][PF6] (2.0 mol%)
B
A
B
A
R
+
Z
Z
HS
R
DMA (0.10 M), rt, 16 h
blue LEDs (30 W, max = 450 nm)
S
N
N
0
0
yield
yield
100%
100%
1
2
3
from
Cl or
Br
(0.30 mmol)
(1.5 equiv)
product yield
remaining additive
Heteroarene Scope
N
Cl
N
Br
N
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
CO2Me
S
S
N
S
S
S
N
3a
3b
3c
3d
3e
, 75%
, 99%
, 95%
, 57%
, 78%
[1.4 g isolated]
MeO2C
NHBoc
Cl
S
N
N
Br
S
N
N
Br
N
N
Br
CO2Me
CO2Me
CO2Me
Ph
S
3i
b
b
3f
3g
3h
, 89%
, 69%
, 73% , C5:C2 = 81:19
, 99%
L-histidine
from
MeO2C
NHBoc
Cl
N
Cl
Cl
N
N
N
N
Cl
N
Cl
CO2Me
CO2Me
S
N
N
S
CO2Me
H
N
Cl
S
N
CO2Me
S
Br
O
3j
3k
3l
3m
, 88%
, 83%, C5:C2 = 91:9
, 99%
, 91%
L-histidine
from
Cl
Cl
Br
Br
Br
S
Ph
Br
CO2Me
Ph
Ph
CO2Me
N
CO2Me
S
S
CO2Me
CO2Me
S
S
N
N
S
S
c
c
d
d
3o
, 40%
3n
3r
3s
3t
, 90%
, 64%
, 47%
, 53%
Br
N
S
Ph
CO2Me
H2N
N
CO2Me
S
Ph
CO2Me
O
S
S
CO2Me
S
MeO2C
O
S
d
3p
3q
3u
3v
, 64%
, 40%
, 71%
, 63%
Thiol Scope
Cl
S
Cl
S
Cl
Cl
S
Cl
S
N
N
N
N
N
N
N
C12H25
OH
Cl
N
N
N
S
Ph
d
3w
3x
Cl
3y
Cl
3z
3aa
, 97%
, 99%
, 99%
, 60%
, 54%
Cl
N
N
N
Cl
Cl
CF3
N
N
N
N
N
CO2Me
N
S
S
N
S
S
S
CO2Me
, 77%
NHBoc
, 87%d,f, >99% ee
e
3ab
3ac
from
3ad
3ae
3af
, 93%
, 99%
, 98%
L-cysteine
Cl
H
N
Cl
S
Cl
H
S
N
N
N
Cl
S
N
CF3
N
N
H
N
NH
N
S
O
N
S
H
HN
O
O
d,f
3ag
3ah
3ai
3aj
from
, 85%
, 41%
, 61%
, 65%
biotin
NHBoc
CO2Me
OAc
OAc
OAc
Cl
O
N
Cl
S
Ph
CO2Me
N
O
H
Cl
NH
O
N
H
N
O
N
S
Cl
N
N
N
N
H
H
H
N
S
O
HN
HN
Boc
S
OAc
H
CO2Me
3an
g
3ak
3al
3am
, 96%
, 60%
, 90%
aspartame
, 57%
glutathione
thiocholestanol
from
from
from
from
-D-thioglucose
aStandard conditions: 1 (0.30 mmol, 1.0 equiv), 2 (1.5 equiv), [Ir(dF(CF3)ppy)2(dtbbpy)][PF6] (2.0 mol%), DMA (0.10 M), blue LEDs,
rt, 16 h. See the Supporting Information for full experimental details. 1 (1.5 equiv), 2 (1.0 equiv), K2HPO4 (1.2 equiv) added. Pyridine
b
c
d
e
f
(1.5 equiv) added. 2 (3.0 equiv). 1 (2.5 equiv), 2 (1.0 equiv), K2HPO4 (2.0 equiv) added. [Ir(dF(CF3)ppy)2(dtbbpy)][PF6] (4.0 mol%).
gUsing a DMA:toluene mixture (1:1) as solvent.
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Next, we compared the radical thiolation to an established
Page 4 of 8
(2.0 mol%) was added as an initial oxidant of the photocatalyst.
These results indicate a secondary quenching of the pre-
oxidized photocatalyst.15d Determination of the reaction
quantum yield (Φ > 8)29 suggests a radical chain mechanism
that was further supported by a thermal experiment utilizing
azobisisobutyronitrile (AIBN) as a radical initiator (Figure 3b).
The following reaction mechanism was proposed and was
Pd-catalyzed cross-coupling reaction.6d Remarkably, we found
that 4,5-dichloroimidazole 1l reacted exclusively at the
electron-neutral aryl bromide group under the metal-catalyzed
conditions while the electron-rich heteroarene remained
untouched (Figure 2a). In contrast, selective substitution at the
C5-position of the imidazole was observed using our protocol,
showcasing the complementary nature.
1
2
3
4
5
6
7
8
substantiated by density functional theory (DFT) studies:29
a
radical chain is initiated by photocatalytic oxidation and
deprotonation of thiol 2 (either stepwise or via oxidative proton-
coupled electron transfer (PCET)) to generate thiyl radical A.
Homolytic aromatic substitution10 at the most electron-rich C5-
position of heteroarene 1a would deliver radical cation C under
extrusion of a chloride anion (ΔG = −7.7 kcal/mol). This step is
proposed to proceed through a concerted transition state B (ΔG‡
= 15.3 kcal/mol), as obtained from DFT computations. Radical
attack in the C4-position was accompanied by a significantly
Given the high relevance of methylthiolation in biological
processes,26 we were wondering whether our protocol could be
applied for the synthesis of methylthioethers. Recently, our
group published on the photocatalytic disulfide–ene reaction for
simple hydromethylthiolation of alkenes without the need for
gaseous and toxic methanethiol.14d,27 Pleasingly, we found that
a similar strategy was applicable, and simply exchanging the
thiol coupling partner for dimethyl disulfide (5, 3.0 equiv)
could deliver the desired product for the standard substrate 1a
in very good yield (6a, 83%, Figure 2b).28 A tribromoimidazole
as well as a 5-chloro-2-aminothiazole were also viable reaction
partners, demonstrating the applicability of the methylthiolation
protocol to a variety of structural motifs (6b, 6c).
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higher barrier (ΔΔG‡
= 4.6 kcal/mol), rationalizing the
observed site-selectivity. Product formation and chain
propagation can then occur via oxidation of thiol 2 by radical
cation C, most likely in an oxidative PCET. The overall
transformation is exergonic (ΔG = −9.7 kcal/mol).
a) Comparison to Cross-Coupling
a) Thiol ene Competition Experiment

Pd-catalyzed cross
coupling (ref 6d)
Cl
Cl
This work
N
N
Cl
Cl
Cl
N
N
N
N
Pd2(dba)3 (2.5 mol%)
Xantphos (5 mol%)
DIPEA (2.0 equiv)
CO2Me
S
PC-1
(2.0 mol%)
2a
(1.0 equiv)
Br
PC-1
thiol
(2.0 mol%)
1a
3a
(1.0 equiv)
, 32%
1l
+
1,4-dioxane
reflux, 16 h
DMA, rt, 16 h
blue LEDs
DMA (0.10 M), rt, 16 h
blue LEDs (450 nm)
+
+
H13C6
CO2Me
H13C6
CO2Me
S
HS
Cl
N
Cl
7
8,
(1.0 equiv)
68%
2a
N
N
b) Investigation of Radical Initiators
N
Cl
SR
AIBN (10.0 mol%)
Cl
Cl
Cl
N
N
N
N
2a
thiol
(1.5 equiv)
RS
Br
CO2Me
, 29%
CO2Me
4
R =
3l
DMA (0.10 M), 85 °C, 16 h
S
, 97%
, 91%
b) Methylthiolation of Electron-rich Heteroarenes
1a
3a
(1.0 equiv)
Y
Y
c) Proposed Reaction Mechanism
PC-1
(4.0 mol%)
B
B
S
+
Z
Z
Cl
S
N
C
DMA (0.10 M), rt, 16 h
blue LEDs (450 nm)
A
1
A
X
S
*IrIII
N
Cl
5
6
, from
Cl or
3
1a
(0.30 mmol)
(3.0 equiv)
Br
Ba
radical
IrIII
IrIV
R
R
Cl
N
Br
N
N
Cl
HS
2
S
A
chain
Br
H
3
N
N
S
H2N
S
Cl
SR
Cl
S
N
N
N
N
S
H
6a
6b
6c
, 46%
, 83%
, 52%
SR
2
Figure 2. Comparison of Pd-catalyzed cross-coupling and the
radical thiolation protocol and methylthiolation of halogenated
electron-rich heteroarenes.29
C
Figure 3. Investigation of the reaction mechanism.29 aTransition
state geometry obtained from DFT calculations.
Finally, we conducted preliminary mechanistic studies. The
formation of thiyl radicals was demonstrated in a competition
experiment (Figure 3a) using a 1:1:1 mixture of heteroarene 1a,
thiol 2a and 1-octene (7). Applying the standard reaction
conditions, both the thiolated heteroarene 3a and
hydrothiolation product 8, derived from a radical thiol–ene
reaction, could be isolated in 32% and 68% yield, respectively.
This result suggests that a homolytic aromatic substitution with
thiyl radicals is most likely to be operative, rather than a cation
radical accelerated SNAr.30 Neither heteroarene 1a nor thiol 2a
could be identified as direct quenchers of the photocatalyst by
Stern-Volmer studies. Furthermore, a reaction time profile
showed an induction period which was not present if K2S2O8
In summary, we have developed a general and simple
methodology for the thiolation of electron-rich heteroaryl
halides via a formal SNAr-type process, enabled by a radical
substitution reaction. The mild photocatalytic protocol allows
for predictable C–S coupling at the most electron-rich position
of the molecule with perfect selectivity in mostly excellent
yields. A variety of heterocycles was found to be reactive and
the synthetic value was further demonstrated by
functionalization of complex molecules. Notably, the reaction
was found to be complementary to Pd-catalyzed C–S coupling.
Mechanistic studies suggest a radical chain mechanism to be
operative with the key step being a homolytic aromatic
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6. For examples of Pd-catalyzed C–S coupling reactions of aryl
substitution of the heteroaryl halide by a thiyl radical. This
discloses previously underexplored reactivity mode.
Ultimately, we believe that this finding will greatly influence
method development in the area of thiolation reactions and
selective functionalization of heteroarenes.
halides, see (only few examples of less electron-rich 5-
membered heteroaryl bromides, e.g. pyrazoles, have been
reported): (a) Xu, J.; Liu, R. Y.; Yeung, C. S.; Buchwald, S. L.
Monophosphine Ligands Promote Pd-Catalyzed C–S Cross-
Coupling Reactions at Room Temperature with Soluble Bases.
ACS Catal. 2019, 9, 6461–6466. (b) Scattolin, T.; Senol, E.;
Yin, G.; Guo, Q.; Schoenebeck, F. Site-Selective C–S Bond
Formation at C–Br over C–OTf and C–Cl Enabled by an Air-
Stable, Easily Recoverable, and Recyclable Palladium(I)
Catalyst. Angew. Chem., Int. Ed. 2018, 57, 12425–12429. (c)
Farmer, J. L.; Pompeo, M.; Lough, A. J.; Organ, M. G.
[(IPent)PdCl2(morpholine)]: A Readily Activated Precatalyst
for Room-Temperature, Additive-Free Carbon–Sulfur
Coupling. Chem. Eur. J. 2014, 20, 15790–15798. (d) Itoh, T.;
Mase, T. A General Palladium-Catalyzed Coupling of Aryl
Bromides/Tiflates and Thiols. Org. Lett. 2004, 6, 4587–4590.
7. (a) Crabtree, R. H. The Organometallic Chemistry of the
Transition Metals; John Wiley & Sons, Inc.: Hoboken, NJ,
2014. (b) Beletskaya, I. P.; Ananikov, V. P. Transition-Metal-
Catalyzed C–S, C–Se, and C–Te Bond Formation via Cross-
Coupling and Atom-Economic Addition Reactions. Chem.
Rev. 2011, 111, 1596–1636.
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a
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available
free of charge at http://pubs.acs.org.
9
Experimental and computational details (PDF)
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Xray crystallographic data for 3g and 3ad (also deposited as CCDC
No. 1981863 and 1981864, which can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif) (CIF)
AUTHOR INFORMATION
Corresponding Author
* Frank Glorius – Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität Münster, Münster 48149, Germany;
https://orcid.org/0000-0002-0648-956X; Email: glorius@uni-
muenster.de
8. (a) Bennett Jr., L. L.; Baker, H. T. Synthesis of Potential
Anticancer Agents. IV. 4-Nitro- and 4-Amino-5-imidazole
Sulfones. J. Am. Chem. Soc. 1957, 79, 2188–2191. (b) Heindel,
N. D.; Lacey, C. J.; Mease, B. A.; Woo, D. V. 1-Methyl-4-
nitro-5-imidazolyl sulfones. Org. Prep. Proced. Int. 1986, 18,
275–278.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
9. (a) Iddon, B.; Lim, B. L. Metal–Halogen Exchange Reactions
of Mono- and Poly-halogenoimidazoles. J. Chem. Soc., Perkin
Trans. 1 1983, 735–739. (b) Iddon, B.; Khan, N. Azoles. Part
5. Metal-halogen exchange reactions of polybromoimidazoles.
J. Chem. Soc., Perkin Trans. 1 1987, 1445–1451. (c) Deprez,
P.; Guillaume, J.; Corbier, A.; Fortin, M.; Vevert, J.-P.;
Heckmann, B. Balanced AT1 and AT2 Angiotensin II
Antagonists. II. Potent 5 α-Hydroxyacid Imidazolyl Biphenyl
Sulfonylureas. Bioorg. Med. Chem. Lett. 1995, 5, 2611–2616.
10. (a) Williams, G. H. Homolytic Aromatic Substituion;
Pergamon Press: Oxford, 1960. (b) Traynham, J. G. Ipso
Substitution in Free-Radical Aromatic Substitution Reactions.
Chem. Rev. 1979, 79, 323–330. (c) Studer, A.; Bossart, M.
Homolytic Aromatic Substitutions in Radicals in Organic
Synthesis; ed. Renaud, P.; Sibi, M. P.; Wiley-VCH: Weinheim,
2001, pp. 62–80. (d) Bowman, W. R.; Storey, J. M. D.
Synthesis using aromatic homolytic substitution–recent
advances. Chem. Soc. Rev. 2007, 36, 1803–1822. (e) Vaillard,
S. E.; Schulte, B.; Studer, A. Radical-Based Arylation Methods
in Modern Arylation Methods; ed. Ackermann, L.; Wiley-
VCH: Weinheim, 2009, pp. 475–511. (e) Gurry, M.;
Aldabbagh, F. A new era for homolytic aromatic substitution:
replacing Bu3SnH with efficient light-induced chain reactions.
Org. Biomol. Chem. 2016, 14, 3849–3862.
11. For selected examples of HAS employing photoredox
catalysis, see: (a) Furst, L.; Matsuura, B. S.; Narayanam, J. M.
R.; Tucker, J. W.; Stephenson, C. R. J. Visible Light-Mediated
Intermolecular C–H Functionalization of Electron-Rich
Heterocycles with Malonates. Org. Lett. 2010, 12, 3104–3107.
(b) Nagib, D. A.; MacMillan, D. W. C. Trifluoromethylation
of arenes and heteroarenes by means of photoredox catalysis.
Nature 2011, 480, 224–228. (c) Hari, D. P.; Schroll, P.; König,
B. Metal-Free, Visible-Light-Mediated Direct C–H Arylation
of Heteroarenes with Aryl Diazonium Salts. J. Am. Chem. Soc.
2012, 134, 2958–2961. (d) Prier, C. K.; MacMillan, D. W. C.
Amine α-heteroarylation via photoredox catalysis: a homolytic
aromatic substitution pathway. Chem. Sci. 2014, 5, 4173–4178.
(e) Ikeda, Y.; Ueno, R.; Akai, Y.; Shirakawa, E. α-Arylation of
alkylamines with sulfonylarenes through a radical chain
mechanism. Chem. Commun. 2018, 54, 10471–10474. (f)
Wang, Z.-J.; Zheng, S.; Matsui, J. K.; Lu, Z.; Molander, G. A.
Desulfonative photoredox alkylation of N-heteroaryl sulfones
We thank the Fonds der Chemischen Industrie (F.S.) and the
Deutsche Forschungsgemeinschaft (Leibniz Award) for generous
financial support. We also thank Felix Strieth-Kalthoff, J. Luca
Schwarz, Toryn Dalton and Philipp Pflüger (all WWU Münster)
for helpful discussions and experimental support.
REFERENCES
1. Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
Structural Diversity, Substitution Patterns, and Frequency of
Nitrogen Heterocycles among U.S. FDA Approved
Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274.
2. (a) Roughley, S. D.; Jordan, A. M. The Medicinal Chemist’s
Toolbox: An Analysis of Reactions Used in the Pursuit of Drug
Candidates. J. Med. Chem. 2011, 54, 3451–3479. (b) Brown,
D. B.; Boström, J. Analysis of Past and Present Synthetic
Methodologies on Medicinal Chemistry: Where Have All the
New Reactions Gone? J. Med. Chem. 2016, 59, 4443–4458. (c)
Boström, J.; Brown, D. G.; Young, R. J.; Keserü, G. M.
Expanding the medicinal chemistry synthetic toolbox. Nat.
Rev. Drug Discov. 2018, 17, 709–727.
3. (a) Feng, M.; Tang, B.; Liang, S. H.; Jiang, X. Sulfur
Containing Scaffolds in Drugs: Synthesis and Application in
Medicinal Chemistry. Curr. Top. Med. Chem. 2016, 16, 1200–
1216. (b) Scott, K. A.; Njardarson, J. T. Analysis of US FDA-
Approved Drugs Containing Sulfur Atoms. Top. Curr. Chem.
2018, 376, 5.
4. (a) Bunnett, J. F.; Zahler, R. E. Aromatic Nucleophilic
Substitution Reactions. Chem. Rev. 1951, 49, 273–412. (b)
Bunnett, J. F. The Remarkable Reactivity of Aryl Halides with
Nucleophiles. J. Chem. Educ. 1974, 51, 312–315. (c) Mortier,
J. Arene Chemistry: Reaction Mechanism and Methods for
Aromatic Compounds; John Wiley & Sons, Inc.: Hoboken, NJ,
2016.
5. (a) Meisenheimer, J. Ueber Reactionen aromatischer
Nitrokörper. Justus Liebigs Ann. Chem. 1902, 323, 205–246.
(b) Buncel, E.; Crampton, M. R.; Strauss, M. J.; Terrier, F.
Electron-Deficient Aromatic- and Heteroaromatic-Base
Interactions; Elsevier: Amsterdam, 1984.
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Page 6 of 8
– an acid-free approach for substituted heteroarene synthesis.
Chem. Sci. 2019, 10, 4389–4393.
Breakthrough with Aryl Chlorides. Angew. Chem., Int. Ed.
2017, 56, 874–879. For a catalyst-free C–S coupling, see: (e)
Liu, B.; Lim, C.-H.; Miyake, G. M. Visible-Light-Promoted C–
S Cross-Coupling via Intermolecular Charge Transfer. J. Am.
Chem. Soc. 2017, 139, 13616–13619.
1
2
3
4
5
6
7
8
12. Dénès, F.; Pichowicz, M.; Povie, G.; Renaud, P. Thiyl Radicals
in Organic Synthesis. Chem. Rev. 2014, 114, 2587–2693.
13. (a) Posner, T. Beiträge zur Kenntnis der ungesättigten
Verbindungen. II. Ueber die Addition von Mercaptanen an
ungesättigte Kohlenwasserstoffe. Ber. Dtsch. Chem. Ges.
1905, 38, 646–657. (b) Hoyle, C. E.; Bowman, C. N. Thiol–
Ene Click Chemistry. Angew. Chem., Int. Ed. 2010, 49, 1540–
1573.
14. For selected examples of photoredox-mediated thiol-ene
reactions, see: (a) Tyson, E. L.; Ament, M. S.; Yoon, T. P.
Transition Metal Photoredox Catalysis of Radical Thiol-Ene
Reactions. J. Org. Chem. 2013, 78, 2046–2050. (b) Tyson, E.
L.; Niemeyer, Z. L.; Yoon, T. P. Redox Mediators in Visible
light Photocatalysis: Photocatalytic Radical Thiol–Ene
Additions. J. Org. Chem. 2014, 79, 1427–1436. (c) Keylor, M.
H.; Park, J. E.; Wallentin, C.-J.; Stephenson, C. R. J.
Photocatalytic initiation of thiol–ene reactions: synthesis of
thiomorpholine-3-ones. Tetrahedron 2014, 70, 4264–4269. (d)
Teders, M.; Henkel, C.; Anhäuser, L.; Strieth-Kalthoff, F.;
Gómez-Suárez, A.; Kleinmans, R.; Kahnt, A.; Rentmeister, A.;
Guldi, D.; Glorius, F. The energy-transfer-enabled
biocompatible disulfide-ene reaction. Nat. Chem. 2018, 10,
981–988.
19. For
a review on radical-nucleophilic substitution (SRN)
reactions, see: Rossi, R. A.; Pierini, A. B.; Peñéñory, A. B.
Nucleophilic Substitution Reactions by Electron Transfer.
Chem. Rev. 2003, 103, 71–167.
20. See the supporting information for redox potentials of several
heteroarenes used in this study which were obtained by DFT
calculations. The potentials are generally E1/2 << −1.5 V which
does not account for a reduction by the photocatalyst employed
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21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
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56
57
58
59
60
in this study (E1/2(M+/M*)
−1.37 V)15c
= =
−0.89 V, E1/2(M/M−)
.
21. For reviews on site-selective cross-coupling reactions of multi-
halogenated heteroarenes, see: (a) Schröter, S.; Stock, C.;
Bach, T. Regioselective cross-coupling reactions of multiple
halogenated nitrogen-, oxygen-, and sulfur-containing
heterocycles. Tetrahedron 2005, 61, 2245–2267. (b) Fairlamb,
I. J. S. Regioselective (site-selective) functionalisation of
unsaturated halogenated nitrogen, oxygen and sulfur
heterocycles by Pd-catalysed cross-couplings and direct
arylation processes. Chem. Soc. Rev. 2007, 36, 1036–1045. (c)
Almond-Thynne, J.; Blakemore, D. C.; Pryde, D. C.; Spivey,
A. C. Site-selective Suzuki-Miyaura coupling of heteroaryl
halides – understanding the trends for pharmaceutically
important classes. Chem. Sci. 2017, 8, 40–62.
15. (a) Yoon, T. P.; Ischay, M. A.; Du, J. Visible light
photocatalysis as
a greener approach to photochemical
synthesis. Nat. Chem. 2010, 2, 527–532. (b) Narayanam, J. M.
R.; Stephenson, C. R. J. Visible light photoredox catalysis:
applications in organic synthesis. Chem. Soc. Rev. 2011, 40,
102–113. (c) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C.
Visible Light Photoredox Catalysis with Transition Metal
Complexes: Applications in Organic Synthesis. Chem. Rev.
2013, 113, 5322−5363. (d) Skubi, K. L.; Blum, T. R.; Yoon, T.
P. Dual Catalysis Strategies in Photochemical Synthesis.
Chem. Rev. 2016, 116, 10035−10074. (e) Romero, N. A.;
Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev.
2016, 116, 10075–10166. (f) Twilton, J.; Le, C.; Zhang, P.;
Shaw, M. H.; Evans, R. W.; MacMillan, D. W. C. The merger
of transition metal and photocatalysis. Nat. Rev. Chem. 2017,
1, 0052.
22. Pitzer, L.; Schäfers, F.; Glorius, F. Rapid Assessment of the
Reaction-Condition-Based
Sensitivity
of
Chemical
Transformations. Angew. Chem., Int. Ed. 2019, 58, 8572–8576.
23. For more detailed information regarding reactivity of C3/C4-
halogenated heteroarenes as well as further limitation studies,
see the supporting information.
24. (a) Collins, K. D.; Glorius, F. A robustness screen for the rapid
assessment of chemical reactions. Nat. Chem. 2013, 5, 597–
601. (b) Gensch, T.; Teders, M.; Glorius, F. Approach to
Comparing the Functional Group Tolerance of Reactions. J.
Org. Chem. 2017, 82, 9154–9159. (c) Gensch, T.; Glorius, F.
The straight dope on the scope of chemical reactions. Science
2016, 352, 294–295.
16. Wimmer, A.; König, B. Photocatalytic formation of carbon–
sulfur bonds. Beilstein J. Org. Chem. 2018, 14, 54–83.
25. See the supporting information for a more detailed study
including the comparison to a photoredox-nickel dual-catalytic
coupling reaction.
17. For examples of photoredox-nickel dual-catalytic C–S bond
formations, see: (a) Oderinde, M. S.; Frenette, M.; Robbins, D.
W.; Aquila, B.; Johannes, J. W. Photoredox Mediated Nickel
Catalyzed Cross-Coupling of Thiols With Aryl and Heteroaryl
Iodides via Thiyl Radicals. J. Am. Chem. Soc. 2016, 138, 1760–
1763. (b) Jouffroy, M.; Kelly, C. B.; Molander, G. A.
Thioetherification via Photoredox/Nickel Dual Catalysis. Org.
Lett. 2016, 18, 876–879. (c) Vara, B. A.; Li, X.; Berritt, S.;
Walters, C. R.; Petersson, E. J.; Molander, G. A. Scalable
thioarylation of unprotected peptides and biomolecules under
Ni/photoredox catalysis. Chem. Sci. 2018, 9, 336 – 344. (d) Du,
Y.; Pearson, R. M.; Lim C.-H.; Sartor, S. M.; Ryan, M. D.;
Yang, H.; Damrauer, N. H.; Miyake, G. M. Strongly Reducing,
Visible-Light Organic Photoredox Catalysts as Sustainable
Alternatives to Precious Metals. Chem. Eur. J. 2017, 23,
10962–10968. (e) Santandrea, J.; Minozzi, C.; Cruché, C.;
Collins, S. K. Photochemical Dual-Catalytic Synthesis of
Alkynyl Sulfides. Angew. Chem., Int. Ed. 2017, 56, 12255 –
12259.
18. For examples of photoredox-catalytic C–S bond formations
involving reduction of aryl halides or aryl diazonium salts, see:
(a) Majek, M.; von Wangelin, A. J. Organocatalytic visible
light mediated synthesis of aryl sulfides. Chem. Commun.
2013, 49, 5507–5509. (b) Bottecchia, C.; Rubens, M.; Gunnoo,
S. B.; Hessel, V.; Madder, A.; Noël, T. Visible-Light-Mediated
Selective Arylation of Cysteine in Batch and Flow. Angew.
Chem., Int. Ed. 2017, 56, 12702–12707. (c) Jiang, M.; Li, H.;
Yang, H.; Fu, H. Room-Temperature Arylation of Thiols:
26. (a) Forouhar, F.; Arragain, S.; Atta, M.; Gambarelli, S.;
Mouesca, J.-M.; Hussain, M.; Xiao, R.; Kieffer-Jaquinod, S.;
Seetharaman, J.; Acton, T. B.; Montelione, G. T.; Mulliez, E.;
Hunt, J. F.; Fontecave, M. Two Fe-S clusters catalyze sulfur
insertion by radical-SAM methylthiotransferases. Nat. Chem.
Biol. 2013, 9, 333–338. (b) Takahashi, N.; Wei, F.-Y.;
Watanabe, S.; Hirayama, M.; Ohuchi, Y.; Fujimura, A.;
Kaitsuka, T.; Ishii, I.; Sawa, T.; Nakayama, H.; Akaike, T.;
Tomizawa, K. Reactive sulfur species regulate tRNA
methylthiolation and contribute to insulin secretion. Nucleic
Acids Res. 2017, 45, 435–445. (c) Kowalak, J. A.; Walsh, K.
A. β-Methylthio-aspartic acid: Identification of a novel
posttranslational modification in ribosomal protein S12 from
Escherichia coli. Protein Sci. 1996, 5, 1625–1632.
27. In a previous study from our group, in-depth mechanistic
studies including transient absorption spectroscopy proved that
disulfides quench the photocatalyst PC-1 via an energy transfer
mechanism to generate thiyl radicals.14d This was used to
replace thiols in thiol-ene reactions. For a more detailed
mechanistic discussion, see the supporting information.
28. For an example of the photoredox-catalytic methylthiolation of
aryl iodides involving reduction of the aryl halide, see: Czyz,
M. L.; Weragoda, G. K.; Monaghan, R.; Connell, T. U.;
Brzozowski, M.; Scully, A. D.; Burton, J.; Lupton, D. W.;
Polyzos, A. A visible-light photocatalytic thiolation of aryl,
heteroaryl and vinyl iodides. Org. Biomol. Chem. 2018, 16,
1543–1551.
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29. See the supporting information for further details.
16100–16104. (b) Holmberg-Douglas, N.; Nicewicz, D. A.
Arene Cyanation via Cation-Radical Accelerated-Nucleophilic
Aromatic Substitution. Org. Lett. 2019, 21, 7114–7118.
30. For examples of cation radical accelerated SNAr of
methoxyarenes, see: (a) Tay, N. E. S.; Nicewicz, D. A. Cation
Radical Accelerated Nucleophilic Aromatic Substitution via
Organic Photoredox Catalysis. J. Am. Chem. Soc. 2017, 139,
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Site-selective Thiolation of (Multi-)halogenated Heteroarenes
via
Y
X
Y
S
B
A
B
R
+
PC
HS
R
A
Cl
NHBoc
Cl
S
+
general and simple
mild and robust
predictable
N
N
Cl
S
O
N
N
N
CO2Me
Br
CO2Me
H
+
+
+
NH
O
N
O
Br
S
N
S
HN
Ph
H2N
CO2Me
N
CO2Me
important motifs
S
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