Site-selective and versatile aromatic C?H functionalization by thianthrenation

Article abstract of DOI:10.1038/s41586-019-0982-0

Direct C–H functionalization can quickly increase useful structural and functional molecular complexity^1–3. Site selectivity can sometimes be achieved through appropriate directing groups or substitution patterns^1–4—in the absence of such functionality, most aromatic C–H functionalization reactions provide more than one product isomer for most substrates^1,4,5. Development of a C–H functionalization reaction that proceeds with high positional selectivity and installs a functional group that can serve as a synthetic linchpin for further functionalization would provide access to a large variety of well-defined arene derivatives. Here we report a highly selective aromatic C–H functionalization reaction that does not require a particular directing group or substitution pattern to achieve selectivity, and provides functionalized arenes that can participate in various transformations. We introduce a persistent sulfur-based radical to functionalize complex arenes with high selectivity and obtain thianthrenium salts that are ready to engage in different transformations, via both transition-metal and photoredox catalysis. This transformation differs fundamentally from all previous aromatic C–H functionalization reactions in that it provides direct access to a large number of derivatives of complex small molecules, quickly generating functional diversity with selectivity that is not achievable by other methods.

Full text of DOI:10.1038/s41586-019-0982-0

Letter
https://doi.org/10.1038/s41586-019-0982-0
Site-selective and versatile aromatic C−H
functionalization by thianthrenation
Florian Berger1, Matthew B. Plutschack1, Julian riegger1, Wanwan Yu1, Samira Speicher1, Matthew Ho1, Nils Frank1 &
tobias ritter1*
Direct C–H functionalization can quickly increase useful structural targeted a reaction with a large absolute Hammett value, which could
and functional molecular complexity1–3. Site selectivity can result from an endergonic radical reaction with a late transition state.
sometimes be achieved through appropriate directing groups or A large absolute Hammett value, by definition, would result in reaction
substitution patterns1–4—in the absence of such functionality, rates spanning several orders of magnitude for a broad spectrum of
most aromatic C–H functionalization reactions provide more electronically different arenes. A broad substrate scope, with resulting
than one product isomer for most substrates1,4,5. Development slow productive reaction rate for some arenes, requires that the reactive
of a C–H functionalization reaction that proceeds with high species not be consumed by other deleterious reaction pathways—such
positional selectivity and installs a functional group that can serve as hydrogen atom abstraction by a radical—even if the desired reaction
as a synthetic linchpin for further functionalization would provide with the substrate is slow. On the basis of this analysis, we evaluated
access to a large variety of well-defined arene derivatives. Here we electrophilic persistent sulfur-based radicals. A persistent radical does
report a highly selective aromatic C–H functionalization reaction not engage in deleterious side reactions to the extent that most radicals
that does not require a particular directing group or substitution do and could result in an endergonic radical reaction, and therefore a
pattern to achieve selectivity, and provides functionalized arenes late transition state.
that can participate in various transformations. We introduce a
Thianthrene radical cations can be accessed in situ from the new
persistent sulfur-based radical to functionalize complex arenes thianthrene sulfoxide 1 (Fig. 2), which can be prepared on scale in
with high selectivity and obtain thianthrenium salts that are ready to two steps from 1,2-difluorobenzene and disulfur dichloride via
engage in different transformations, via both transition-metal and tetrafluorothianthrene 2 (TFT). As part of an extended study on the
photoredox catalysis. This transformation differs fundamentally reactivity of thianthrene in the 1970s, the reaction of isolated thian-
from all previous aromatic C–H functionalization reactions in that threnium radical cations with simple electron-rich arenes—such as
it provides direct access to a large number of derivatives of complex anisole—was evaluated, and the formation of arylthianthrenium cations
small molecules, quickly generating functional diversity with was observed14–16. However, the selectivity of the reactions was not
selectivity that is not achievable by other methods.
investigated, and the synthetic utility of arylthianthreniums was
Bromo and boryl substituents are among the most useful linchpins not recognized, possibly owing to the reported incompatibility of
in organic chemistry, but introducing those substituents selectively can thianthrenium radical cations with many functional groups, such as
be problematic when molecules lack appropriate functional groups or pyridines17, amines18 and alcohols19. Instead of the moisture-sensitive,
substitution patterns. We evaluated two of the most selective transfor- explosive thianthrenium perchlorate radical salt prepared separately,
mations for bromination6 and borylation7 to show their selectivity for our new method uses the bench-stable, fluorinated sulfoxide-based
functionalization of ethylbenzene (Fig. 1). Electrophilic bromination is thianthrene reagent 1 which—together with the modified reaction
mostly controlled electronically and, although some substrates can be conditions—expands the substrate scope, probably owing to a higher
brominated selectively, even the most selective bromination reactions reduction potential and functional-group tolerance (see Supplementary
developed so far6,8–11 produce mixtures of isomers for most substrates Tables S2, S3). Moreover, we discovered that addition of thianthrene
(Fig. 1, Supplementary Table S6). Iridium-catalysed borylation reac- proceeds with excellent selectivity and that thianthreniums can func-
tions are mostly sterically controlled and can afford high selectivity tion as synthetically useful functional groups.
for certain substitution patterns, such as for 1,3-disubstituted arenes1.
The tetrafluorothianthrene radical cation generated in situ
Of the few highly selective aromatic C–H functionalization reactions by comproportionation of 1 and 2 reacts chemoselectively to func-
that do not require particular directing groups or substitution patterns, tionalize arenes in preference to undergoing deleterious side reactions.
including our para-selective TEDAylation reaction12, none can intro- The high degree of chemoselectivity enables a large substrate scope
duce synthetic linchpins, and they are therefore not broadly useful (Fig. 2). Thianthrenation can proceed on arenes as electron-rich as
for introducing a variety of substituents. The C–H functionalization aniline derivatives to those as electron-poor as 1,2-dichlorobenzene.
reaction reported herein can proceed in >99% selectivity—not only Arenes that are more electron-rich than anisole undergo unproductive
for complex small molecules, but also for simple monosubstituted oxidation with the TFT-reagent 1, presumably through single-electron
arenes such as ethylbenzene—to afford novel synthetically useful oxidation. Therefore, we used an analogous non-fluorinated thian-
aryltetrafluorothianthrenium salts (Ar–TFT+; Fig. 1).
threne reagent for all arenes more electron-rich than anisole, such as
Previously, we developed an aromatic C–H functionalization reac- meclofenamic acid (30) and famoxadone (31). Even more electron-rich
tion that gives access to a large variety of constitutional isomers to gen- arenes, such as indole, are not tolerated and undergo unproductive
erate structural diversity13. The design was based on achieving a highly oxidation; hence, they cannot be functionalized. However, once an
exergonic radical addition with an early transition state that, in accord electron-withdrawing group is installed, the desired reaction pathway
with Hammond’s postulate, would elicit little discrimination between proceeds (for example, 32). In addition, boronic acids are not tolerated
different positions of a given arene. Hammett analysis afforded a ρ in the reaction because they undergo ipso-substitution. The transforma-
value close to zero, as would be expected for a reaction with an early tion is highly tolerant of many other functional groups, such as amines,
transition state. To achieve highly selective arene functionalization, we amides, alcohols, ethers, esters, carboxylic acids and heterocycles.
1Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany. *e-mail: ritter@kofo.mpg.de
1 4 M A r C H 2 0 1 9
| V O L 5 6 7 | N A t U r e | 2 2 3

reSeArCH Letter
H
R
Versatile synthetic
linchpins
Highly selective C−H
functionalizations
Cl
Me Me
Me
F
F
S
F
F
Me
N+
Br
O
O
S+
N+
B
–
BF4
Et
p:o = 6:1
Et
F
Et
p:o > 500:1
p:m > 200:1
p:m = 1:2
p:o > 99:1
FG
R
Fig. 1 | Selectivity of thianthrenation. Comparison of thianthrenation
with halogenation6, borylation7 and TEDAylation12. FG, functional group
(for example, CO2Et, Cl, CN). Bromination6 and borylation7 produce
synthetically useful arylbromides and arylboronic acids (blue area) as a 6:1
mixture of isomers for the bromination of ethylbenzene and a 1:2 mixture
of isomers for the borylation of ethylbenzene. TEDAylation12 is highly site-
selective, giving a para:ortho ratio of p:o > 99:1 for fluorobenzene (yellow
area); however, aryl-TEDAs are of low synthetic value. Thianthrenation
produces synthetically versatile arylthianthrenium salts in high selectivity
(p:o > 500:1, para:meta ratio of p:m > 200:1 for ethylbenzene; green area).
Alcohols are trifluoroacetylated under the reaction conditions but bias for regioselective electrophilic substitution reactions; for example,
trifluoroacetate esters hydrolyse during aqueous workup. In the case bromination of 1,2-dimethoxybenzene (3) and 2-methoxypyridine (28)
of sufficiently electron-rich arenes, olefins can be tolerated (for exam- proceed regioselectively20,21. However, regioselectivity is not achieved
ple, strychnine, 22). Basic functional groups are protonated under generally in arene C–H functionalizations, as shown in Fig. 1. In no
acidic reaction conditions and are thus protected from oxidation (for instance out of 48 evaluated cases was bromination more selective
example, 12, 21 and 27). HBF4OEt2 must sometimes be replaced by for the position of thianthrenation, and in 46 of those cases bromina
-
Lewis acids—such as BF3OEt2 or TMSOTf—which enables success- tion was substantially less selective or afforded no product at all (see
ful functionalization of compounds that contain acid-sensitive func- Supplementary Table S6).
tionality, such as salicin pentaacetate (6), or of compounds that would
The thianthrenium salts can behave as versatile linchpin electrophiles
otherwise be protonated and therefore deactivated for functionaliza- in both palladium-catalysed cross-coupling chemistry and photoredox
tion, such as electron-rich pyridine derivatives (for example, 28). The catalysis. We developed an initial set of 13 reactions, exemplified by
reaction is not sensitive to dioxygen or traces of water and can thus be the derivatization of the insecticide pyriproxyfen (16; Fig. 3a). Unlike
carried out under an ambient atmosphere in most cases. The majority alkylaryl sulfonium salts—which can engage in some cross-coupling
of the arylthianthrenium salts are soluble in organic solvents such as reactions22,23 but are strong alkylating reagents23—aryl thianthre-
acetonitrile, dichloromethane, 1,4-dioxane, dimethylformamide and nium salts are more resistant to nucleophiles such as cyanide, tertiary
dimethyl sulfoxide, and can be stored as solids under ambient condi- amines and organo zinc reagents, although treatment with strong bases
tions for years (see Supplementary Table S4). Although these salts can can result in benzyne formation24,25. The increased stability of
usually be used without purification (see below), chromatography on thianthrenium salts compared to alkylarylsulfonium salts towards
silica gel provides analytically pure compounds, as shown in Fig. 2. side-reactions makes them useful cross-coupling partners in many
High regioselectivity was observed in all cases, even for compounds palladium-catalysed reactions, such as Heck26, Sonogashira27,
containing several reactive positions in different aromatic rings, such Negishi28, Suzuki29 and carbonylation30 reactions. The thianthre-
as in 2-fluorobiphenyl (5), meclofenamic acid (30), famoxadone (31) nium substituent can engage in faster oxidative addition reactivity
and bifonazole (7). The only substrate for which we could identify more than observed with bromide and triflate, which enables chemoselec-
than one isomer was mizolastine (27), which produced a mixture of tive cross-coupling (Fig. 3b). Palladium is inserted selectively into the
two products (ratio 16:1); the major isomer was obtained in pure form. desired of the three C–S bonds of the triarylsulfonium group of the
The selectivity of the reaction is assumed to be mostly dependent on thianthrenium salts—possibly a result of steric hindrance and rigidity
electronic effects, which can discriminate even between slightly dif- of the tricyclic thianthrene structure.
ferent positions (for example, 7) and can override steric biases (for
In addition to palladium-catalysed cross-coupling chemistry, pho-
example, 26). Although thianthrenium is a large functional group, toredox catalysis31 enables the coupling of thianthrenium salts with
sterically hindered positions can be accessed—as exemplified by the several different nucleophiles at ambient temperature. For example,
thianthrenation of mesitylene (13)—presumably owing to the long C–S with nucleophiles such as chloride, trifluoromethylthiolate and triphe-
bond. The high selectivity for the most electron-rich position, com- nylphosphite, various carbon–heteroatom bonds can be accessed.
bined with the positive charge of the sulfonium salt, enables selective Photoredox functionalization of arylthianthrenium salts is also tolerant
monosubstitution, as illustrated by the selective functionalization of of arylhalides (for example, 51 and 52) and can access reactivity that
compound 29. Some of the arenes shown in Fig. 2 have an intrinsic is not currently achievable with aryl bromides, such as a Minisci-type
2 2 4
| N A t U r e | V O L 5 6 7 | 1 4 M A r C H 2 0 1 9

Letter reSeArCH
F
F
S
F
F
1–3 mol% 2
1.0 equiv. 1
3.0 equiv. (CF3CO)2O
1.1–4.5ꢀequiv. HBF4OEt2
O
S
H
R
F
F
S
S
F
F
S+
F
F
F
F
S
MeCN, 0–25 °C, 1–24 h
R
1
2 (TFT)
H
O
F
H
OMe
OAc
S
OAc
OMe
N
Br
N
AcO
AcO
O
H
Br
H
OAc
3
4
68%
5
85%
Salicin pentaacetate (6)
H
( )-Bifonazole (7)
76%a
94%b
87%c
O
I
Me
H
O
H
N
O
O
N
O
O
Me
O
Et
Et
NEt2
H
I
Bu
Br
H
O
H
H
O
H
Amiodarone (12)
8
92%
9
86%
Atomoxetine (11)
10
87%
58%a,d
92%
O
H
N
S
O
Me
NH
N
O
Me
O
O
O
Me
I
N
F
H
N
H
H
O
H
NO2
Me
Me
O
H
Nimesulide (15)
( )-Pyriproxyphen (16)
Ketanserin (17)
14
59%
13
62%a
93%
92%
60%
N
N
N
Me
H
N
Me
H
O
H
NH
H
H
OTf
S
N
Cl
N
O
N
O
H
N
O
H
Cl
N
H
Me
N
H
OH
F
Me
O
H
18
86%c
19
66%
Strychnine (22)
Neꢀracetam (20)
Dasatinib (21)
63%b
80%c
64%
Cl
O
OEt
H
O
Cl
HN
N
Cl
O
H
N
H
N
O
N
N
N
H
Me
Me
N
O
H
O
Cl
Me
H
23
20%c
Boscalid (25)
Etofenprox (26)
Mizolastine (27)
24
64%
95%
84%a
62%g
OMe
O
OH
O
O
N
O
HO
O
MeO
Cl
H
N
Me
H
NH
Me
Me
N
H
O
N
OMe
H
Cl
O
Cl
H
H
28
87%e
Meclofenamic acid (30)
( )-Famoxadone (31)
Indometacin methylester (32)
29
76%f
87%a
81%a
85%a
Fig. 2 | Substrate scope of thianthrenation. aNonfluorinated thianthrene
S-oxide and nonfluorinated thianthrene were used instead of 1 and 2; no
additional acid was used. The reaction was initiated at −78 °C. bBF3OEt2
was used instead of HBF4OEt2. cTfOH was used instead of HBF4OEt2.
dThe amino group was trifluoroacetylated. eTMSOTf was used instead of
HBF4OEt2 and the reaction was carried out under an inert atmosphere
with dry MeCN. f0.90 equiv. 1 was used. gSelectivity 16:1, isolated yield of
major isomer. OTf, triflate; TMS, trimethylsilyl.
1 4 M A r C H 2 0 1 9
| V O L 5 6 7 | N A t U r e | 2 2 5

reSeArCH Letter
a
Transition-metal-catalysed
cross-couplings
Photoredox catalysis
Borylation
Me
O
Me
Me
Phosphonylation
Carbonylation
O
O
B
O
P
Me
OPh
OPh
OEt
R
R
33, 76%
R
Cyanation
45, 91%
Suzuki coupling
34, 58%
N
a
b
l
R
R
35, 69%
44, 90%
c
d
e
k
O
N
–
n-C4H9
BF4
SCF3
Me
Sonogashira coupling
Pseudohalogenation
j
O
TFT+
R
R
36, 53%
43, 95%
O
i
16a
Cl
Alk
f
h
R
I
g
R
37, 53%
Negishi coupling
41, Alk = c-Pr, 59%
42, Alk = Me, 78%
Chlorination
Ph
O
O
S
R
Ph
R
38, 66%
R
40, 86%
39, 78%m
Iodination
Heck reaction
Sulfonylation
b
Competition with (pseudo-) halides in Suzuki coupling
Minisci-type C–H arylation
OTf
OTf
O
O
–
q
n
BF4
N
N
–
BF4
Br
+TFT
Br
MeO
+TFT
9a
50, 86%
19a
46, 92%
Competition with aryliodides in photoredox catalysis
I
O
I
O
–
n
BF4
r
MeO
+TFT
Br
–
Br
BF4
9a
+TFT
NC
47, 96%
51, 83%
14a
NEt2
Functional-group tolerance
N
NEt2
I
N
I
O
O
O
O
O
H
H
H
H
H
o
EtO
s
I
O
N
I
O
N
Bu
Bu
H
H
O
Cl
O
H
O
O
Amiodarone (12)
52, 50%, two steps
Strychnine (22)
48, 48%, two steps
Scalability (25 g scale)
OMe
H
O
O
O
O
OAc
n
p
OAc
NH
N
O
NH
Me
N
Me
AcO
AcO
O
O
O
AcO
AcO
O
O
OAc
O
OAc
O
( )-Famoxadone (31)
OAc
OAc
CN
Salicin pentaacetate (6)
53, 75%, two steps, 2 (TFT) recovered: 76%
H
49, 62%, two steps
Fig. 3 | See next page for caption.
2 2 6
| N A t U r e | V O L 5 6 7 | 1 4 M A r C H 2 0 1 9

Letter reSeArCH
Fig. 3 | Application of thianthrenation for functionalizing complex
arenes. a, Reaction scope of thianthrenium salts. Functionalization of
the pyriproxyfen-derived thianthrenium salt 16a. b, Compatibility of
thianthrenium salt reactions with aryl electrophiles, functional-group
tolerance, Minisci-type reaction and scalability. aB2Pin2 (2.5 equiv.),
pyridine (5.0 equiv.), LED. bP(OPh)3 (5.0 equiv.), pyridine (4.9 equiv.),
NaI (20 mol%), LED. cNBu4CN (2.5 equiv.), Cu(MeCN)4BF4 (1.2 equiv.),
LED. dNMe4SCF3 (1.1 equiv.), Cu(MeCN)4BF4 (1.0 equiv.), LED. eCuCl
(2.0 equiv.), NBu4Cl (2.5 equiv.), LED. fLiI (10 equiv.), Cu(MeCN)4BF4
(1.0 equiv.), MeCN/DMSO (3/2), LED. gPhSO2Na (3.1 equiv.), Pd2(dba)3
(2.5 mol%), Xantphos (5 mol%), THF, 60 °C. hPd(OAc)2 (9.0 mol%), PPh3
(15 mol%), styrene (2.0 equiv.), NEt3 (3.0 equiv.), DMF, 100 °C. ic-PrZnBr
or MeZnCl (3.0 equiv.), Pd(PPh3)2Cl2, KOAc (6.0 equiv.), THF, 50 °C.
j1-hexyne (2.0 equiv.), CuI (20 mol%), Pd(dppf)Cl2, N-methylmorpholine
(2.0 equiv.), dioxane, 40 °C. kCyclohexylvinylboronic acid (2.0 equiv.),
K2CO3 (4.0 equiv.), Pd(dppf)Cl2, EtOH, 50 °C. lCO (1.0 bar),
50 °C. mNon-fluorinated thianthrenium salt used. nm-methoxyphenylboronic
acid (1.0–1.2 equiv.), K3PO4 (2.0–3.0 equiv.), Pd(dppf)Cl2, i-PrOH/dioxane
(1/1), 50 °C. o1) Thianthrenation, 2) CO (1.0 bar), N-methylmorpholine
(2.0 equiv.), Pd(dppf)Cl2, EtOH, 50 °C. p1) Thianthrenation (non-
fluorinated thianthrene), 2) NBu4CN (2.5 equiv.), Cu(MeCN)4BF4
(1.0 equiv.), MeCN/DMSO (2/1), LED. qK2CO3 (1.0 equiv.), [Ir{dF(CF3)
ppy}2(dtbpy)]PF6 (1 mol%), no Ru(bpy)3(PF6)2, DMSO/pyrazine (1/2),
LED. rNBu4CN (3.3 equiv.), CuCN (2.3 equiv.), MeCN/DMSO (10/7),
LED. s1) Thianthrenation, 2) Cu(MeCN)4BF4 (1.6 equiv.), LiCl (4.8
equiv.), CF3CO2H (1.2 equiv.), MeCN, LED. All photoredox processes:
LED (450 nm, 60 W), 22 °C, Ru(bpy)3(PF6)2 (2.0–4.0 mol%), MeCN,
3–18 h, unless stated otherwise. All Pd-catalysed reactions: Pd-source
(2.0–5.0 mol%), 16–48 h, unless stated otherwise. Alk, alkyl; dba,
dibenzylideneacetone; DMF, dimethylformamide; DMSO, dimethyl
sulfoxide; dppf, 1,1ʹ-bis(diphenylphosphino)ferrocene; dtbpy, 4,4′-
di-tert-butyl-2,2′-dipyridyl; pin, pinacolato; ppy, phenylpyridyl; THF,
tetrahydrofuran.
N-methylmorpholine (2.0 equiv.), Pd(dppf)Cl2, EtOH/dioxane (1/1),
pyrazine arylation reaction (Fig. 3b). We assume that the thianthrenium mostly by precipitation after the two-step reaction sequence to 53 on
salt is cleaved into thianthrene and aryl radicals after single-electron a 25-g scale.
reduction by a photosensitizer. The aryl radicals then abstract atoms
or groups, react with copper complexes or add to arenes.
Complex small molecules such as 49, 52 and 53 can be accessed irreversible deprotonation to form the product (Fig. 4a). The generation
directly from the parent C–H compounds in two steps, without puri- of radical cations by comproportionation of TFT S-oxide 1 and TFT
fication of the intermediate sulfonium salts, and TFT can be recovered 2 under the reaction conditions, observed by electron paramagnetic
after the reaction; for example, 76% of thianthrene 2 was recovered resonance spectroscopy (Fig. 4b), supports the proposed mechanism.
We propose that thianthrenation proceeds in three steps: generation
of radical cations (I), formation of a dicationic adduct (II) and finally
a
F
F
S
F
F
H
2
S
–
CF3CO2
R
I
F
O
TFT+
F
S
O
CF3
F
F
S+
F
F
–H+
S+
H
F
F
S
F
F
F
S
F
S
R
2
R
II
b
(CF3CO)2O,
HBF4OEt2
F
F
S
F
F
1 + 2
MeCN, 25 °C
S
3,393
3,413
3,433
3,453
B (G)
EPR
I
c
p:o ≈ 520:1
p:m ≈ 230:1
O
S
F
F
F
(CF3CO)2O,
HBF4OEt2
+
F
F
F
S
F
F
MeCN,
0 °C to 25 °C
S
Et
1
S+
Undivided cell
electrolysis
HBF4OEt2
F
S
F
F
Et
+
F
NBu4BF4,
MeCN, 0 °C
S
p:o ≈ 500:1
p:m ≈ 250:1
Et
2
Fig. 4 | Proposed reaction mechanism and mechanistic experiments.
a, Proposed mechanism involving chain transfer. b, Comproportionation
of TFT S-oxide and TFT under the reaction conditions (left); electron
paramagnetic resonance spectrum (right; B, magnetic flux density).
c, Comparison of chemical and electrochemical thianthrenation. The
photographs show the typical colour of the reaction mixture of TFT
S-oxide with arenes (reaction almost complete; top) and the purple
colour of TFT radical cations formed at the surface of the Pt anode
during electrolysis of TFT in the presence of HBF4OEt2, NBu4BF4 and
ethylbenzene in MeCN at 25 °C (bottom; the photograph was taken
approximately 10 s after turning the current on).
1 4 M A r C H 2 0 1 9
| V O L 5 6 7 | N A t U r e | 2 2 7

reSeArCH Letter
Moreover, TFT radicals could also be generated and observed by anodic 14. Shine, H. J. & Silber, J. J. Ion radical. XXII. Reaction of thianthrenium perchlorate
(C12H8S2•+ ClO4−) with aromatics. J. Org. Chem. 36, 2923–2926 (1971).
15. Kim, K., Hull, V. J. & Shine, H. J. Ion radicals. XXIX. Reaction of thianthrene cation
radical perchlorate with some benzene derivatives. J. Org. Chem. 39,
2534–2537 (1974).
16. Shin, S.-R. & Shine, H. J. Reactions of phenols with thianthrene cation radical.
J. Org. Chem. 57, 2706–2710 (1992).
17. Shine, H. J., Silber, J. J., Bussey, R. J. & Okuyama, T. Ion radicals. XXV. The
reactions of thianthrene and phenothiazine perchlorates with nitrite ion,
pyridine, and other nucleophiles. J. Org. Chem. 37, 2691–2697 (1972).
18. Kim, K. & Shine, H. J. Ion radicals. XXX. Reactions of thianthrene cation
radical perchlorate with amino compounds. J. Org. Chem. 39, 2537–2539
(1974).
19. Shine, H. J. & Yueh, W. Reaction of thianthrene cation radical with alcohols:
cyclohexanols. Tetrahedron Lett. 33, 6583–6586 (1992).
20. Hirano, M., Monobe, H., Yakabe, S. & Morimoto, T. Kaolin-assisted aromatic
chlorination and bromination. J. Chem. Res. (S), 662–663 (1998).
21. Windscheif, P.-M. & Vögtle, F. Substituted dipyridylethenes and -ethynes and
oxidation of TFT 2, and in the presence of arene the formation of TFT
salts was observed to have selectivities similar to those observed under
standard reaction conditions, providing evidence that both reactions
proceed via the same reactive species (Fig. 4c). Radical formation from
1 can also be induced by reductants other than 2—for example, solvents
or trace impurities—because radicals were also detected in the initial
absence of 2. Under typical reaction conditions, radical concentrations
of more than 20% of the total TFT concentration were detected about
one hour after combining the reagents, and the deep purple colour
of such mixtures, which is indicative of I, did not fade away within
one week at 25 °C. The inverse first-order dependence of the reac-
tion rate of thianthrene radical cations with anisole on the concentra-
tion of thianthrene15 rules out radical addition followed by hydrogen
key pyridine building blocks. Synthesis 1994, 87–92 (1994).
22. Srogl, J., Allred, G. D. & Liebeskind, L. S. Sulfonium salts. Participation par
atom abstraction. A small primary kinetic hydrogen isotope effect of
1.7 and 1.9 for intra- and intermolecular competition experiments,
excellence in metal-catalyzed carbon–carbon bond-forming reactions. J. Am.
Chem. Soc. 119, 12376–12377 (1997).
respectively, together with this inverse first-order dependence, rules
out radical addition followed by deprotonation and subsequent oxida-
tion. A Hammett analysis indicated that positive charge is accumulated
on the aromatic ring during the reaction, which supports a mecha-
nism proceeding via a cationic intermediate such as II. The unusually
steep slope of ρ = −11, obtained when using the σ+ values reported in
ref. 32, means that the rate of reaction varies by more than nine orders
of magnitude between anisole and chlorobenzene. Dication II could be
formed from arene and I by radical addition and subsequent oxidation,
by single-electron oxidation of arene followed by recombination with
radical I, or by addition of arene to a thianthrene dication, which could
result from disproportionation of I. Detailed additional mechanistic
investigations to distinguish between these three pathways for a better
appreciation of the source of selectivity are currently under investiga-
tion in our laboratory.
23. Minami, H., Otsuka, S., Nogi, K. & Yorimitsu, H. Palladium-catalyzed borylation
of aryl sulfoniums with diborons. ACS Catal. 8, 579–583 (2018).
24. Kim, K. S., Ha, S. M., Kim, J. Y. & Kim, K. 5-arylthianthreniumyl perchlorates as
benzyne precursor. J. Org. Chem. 64, 6483–6486 (1999).
25. Yoon, K. & Ha, S. M. Kim, K. A convenient route to diverse heterocycles through
an addition of β-amino carbonyl compounds to 3-halo-4-methoxybenzenes.
J. Org. Chem. 70, 5741–5744 (2005).
26. Heck, R. F. Palladium-catalyzed reactions of organic halides with olefns. Acc.
Chem. Res. 12, 146–151 (1979).
27. Sonogashira, K. Development of Pd–Cu catalyzed cross-coupling of terminal
acetylenes with sp2-carbon halides. J. Org. Chem. 653, 46–49 (2002).
28. Negishi, E.-I. Palladium- or nickel-catalyzed cross coupling. A new selective
method for carbon-carbon bond formation. Acc. Chem. Res. 15, 340–348
(1982).
29. Suzuki, A. Recent advances in the cross-coupling reactions of organoboron
derivatives with organic electrophiles, 1995–1998. J. Organomet. Chem. 576,
147–168 (1999).
30. Brennführer, A., Neumann, H. & Beller, M. Palladium-catalyzed carbonylation
reactions of aryl halides and related compounds. Angew. Chem. Int. Ed. 48,
4114–4133 (2009).
Online content
31. Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis
with transition metal complexes: applications in organic synthesis. Chem. Rev.
113, 5322–5363 (2013).
32. Brown, H. C. & Okamoto, Y. Electrophilic substituent constants. J. Am. Chem.
Soc. 80, 4979–4987 (1958).
Any methods, additional references, Nature Research reporting summaries, source
data, statements of data availability and associated accession codes are available at
https://doi.org/10.1038/s41586-019-0982-0.
Received: 13 July 2018;Accepted: 23 January 2019;
Published online 13 March 2019.
Acknowledgements We thank M. van Gastel (Max Planck Institute for
Chemical Energy Conversion) for the acquisition of electron paramagnetic
resonance spectra, as well as S. Marcus and D. Kampen (Max-Planck-Institut
für Kohlenforschung) for mass spectrometry analysis. We thank G. Berger for
assistance with the construction of a photoreactor. We thank UCB Biopharma
and the Max-Planck-Institut für Kohlenforschung for funding.
1. Mkhalid, I. A. I., Barnard, J. H., Marder, T. B., Murphy, J. M. & Hartwig, J. F. C–H
activation for the construction of C–B bonds. Chem. Rev. 110, 890–931 (2010).
2. Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H
functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).
3. Leow, D., Li, G., Mei, T.-S. & Yu, J.-Q. Activation of remote meta-C–H bonds
assisted by an end-on template. Nature 486, 518–522 (2012).
4. Cheng, C. & Hartwig, J. F. Rhodium-catalyzed intermolecular C–H silylation of
arenes with high steric regiocontrol. Science 343, 853–857 (2014).
5. Olah, G. A. Aromatic substitution. XXVIII. Mechanism of electrophilic aromatic
substitutions. Acc. Chem. Res. 4, 240–248 (1971).
6. Tang, R.-J., Milcent, T. & Crousse, B. Regioselective halogenation of arenes and
heterocycles in hexafuoroisopropanol. J. Org. Chem. 83, 930–938 (2018).
7. Saito, Y., Segawa, Y. & Itami, K. para-C–H borylation of benzene derivatives by a
bulky iridium catalyst. J. Am. Chem. Soc. 137, 5193–5198 (2015).
8. Mo, F. et al. Gold-catalyzed halogenation of aromatics by N-halosuccinimides.
Angew. Chem. Int. Ed. 49, 2028–2032 (2010).
Reviewer information Nature thanks Kuangbiao Liao and the other anonymous
reviewer(s) for their contribution to the peer review of this work.
Author Contributions F.B. designed reagent 1, developed the reaction chemistry
and investigated the mechanism. J.R., F.B. and M.H. explored the substrate
scope. F.B., M.B.P., W.Y. and J.R. optimized the cross-coupling and photoredox
reactions. M.B.P. investigated the selectivity of bromination. F.B., S.S., N.F. and
J.R. developed the synthesis of reagent 1. T.R. and F.B. wrote the manuscript. T.R.
directed the project.
Competing interests A patent application (number EP18204755.5, Germany),
dealing with the use of thianthrene and its derivatives for C–H functionalization
and with reagent 1, has been filed and F.B. and T.R. may benefit from royalty
payments.
9. Samanta, R. C. & Yamamoto, H. Selective halogenation using an aniline catalyst.
Chem. Eur. J. 21, 11976–11979 (2015).
10. Maddox, S. M., Nalbandian, C. J., Smith, D. E. & Gustafson, J. L. A practical Lewis
base catalyzed electrophilic chlorination of arenes and heterocycles. Org. Lett.
17, 1042–1045 (2015).
11. Xiong, X., Tan, F. & Yeung, Y.-Y. Zwitterionic-salt-catalyzed site-selective
monobromination of arenes. Org. Lett. 19, 4243–4246 (2017).
12. Boursalian, G. B., Ham, W. S., Mazzotti, A. R. & Ritter, T. Charge-transfer-directed
radical substitution enables para-selective C–H functionalization. Nat. Chem. 8,
810–815 (2016).
Additional information
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10.1038/s41586-019-0982-0.
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13. Ham, W.-S., Hillenbrand, J., Jacq, J., Genicot, C. & Ritter, T. Divergent late-stage
(hetero)aryl C–H amination by the pyridinium radical cation. Angew. Chem. Int.
Ed. 58, 532–536 (2019).
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