Direct Vicinal Difunctionalization of Thiophenes Enabled by the Palladium/Norbornene Cooperative Catalysis

Article abstract of DOI:10.1021/jacs.9b10857

Herein we report a direct vicinal difunctionalization of thiophenes via the palladium/norbornene (Pd/NBE) cooperative catalysis. A series of mono- and disubstituted thiophenes can be difunctionalized site-selectively and regioselectively at the C4 and C5 positions in good yields, enabled by an arsine ligand and a unique amide-based NBE. The synthetic utility has been shown in derivatizations of complex bioactive compounds and an open-flask gram-scale preparation. Preliminary results have been obtained in the difunctionalization of furans and a direct C4-selective arylation of 2-substituted thiophenes.

Full text of DOI:10.1021/jacs.9b10857

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Communication
Direct Vicinal Difunctionalization of Thiophenes Enabled
by the Palladium/Norbornene Cooperative Catalysis
Renhe Li, Yun Zhou, Xiaolong Xu, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10857 • Publication Date (Web): 19 Nov 2019
Downloaded from pubs.acs.org on November 20, 2019
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Page 1 of 6
Journal of the American Chemical Society
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Direct Vicinal Difunctionalization of Thiophenes Enabled by the
Palladium/Norbornene Cooperative Catalysis
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Renhe Li, Yun Zhou, Xiaolong Xu and Guangbin Dong*
Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States
Supporting Information Placeholder
Yu9a and our9b groups independently disclosed the direct meta
ABSTRACT: Herein we report
difunctionalization of thiophenes via the palladium/norbornene
Pd/NBE) cooperative catalysis. series of mono- and
disubstituted thiophenes can be difunctionalized site- and regio-
selectively at the C4 and C5 positions in good yields, enabled by
an arsine ligand and a unique amide-based NBE. The synthetic
utility has been shown in derivatizations of complex bioactive
compounds and an open-flask gram-scale preparation. Preliminary
results have been obtained in the difunctionalization of furans and
a direct C4-selective arylation of 2-substituted thiophenes.
a
direct vicinal
functionalizations of arenes initiated by a directed ortho C−H
palladation (Scheme 1b). Very recently, a meta arylation of
electron-rich alkoxyarenes was developed by Yu through a related
(
A
1
0
approach. However, to the best of our knowledge, vicinal
difunctionalization of arenes through the C−H-initiated Pd/NBE
catalysis (either directed or non-directed) has not been reported
yet. The primary challenge is associated with the fact that, for the
proposed difunctionalization, acidic conditions are often
1
1
beneficial for the C−H palladation step, which could result in an
9
ipso protonation process instead of further couplings. Additional
difficulties could be envisaged for using heteroarene substrates in
the Pd/NBE catalysis, as many aromatic heterocycles can behave
as good ligands for Pd and they are often less stable than arenes
under oxidative conditions. Herein, stimulated by these challenges
Polysubstituted aromatic heterocycles are commonly found in
pharmaceuticals, agrochemicals and organic materials (Figure 1).
1
12
and given the therapeutic importance of thiophene derivatives,
we describe the initial development of double C−H
Site-selective conversion of unactivated C−H bonds directly to
new functional groups (FGs) represents an important and
straightforward approach for efficient functionalization of
a
functionalization of thiophenes at the C4 and C5 positons via the
Pd/NBE catalysis using a unique catalytic system (Scheme 1c).
2
heteroarenes. To date, great success has been achieved for site-
selectively introducing one FG to heteroarenes without aids of
Scheme 1. Direct C−H Functionalization of Heterocycles
3
directing groups (DGs); it remains challenging to simultaneously
4
a) The typical Pd/NBE catalysis with aryl halide susbtrates
install two different FGs, particularly at vicinal positions in a
R
R
regioselective manner. However, such a transformation would
constitute significant interests because it could rapidly increase
molecular complexity, thereby facilitating streamlined synthesis
of polysubstituted heteroarenes.
X
H
Nu
E
Pd(0)/NBE
FG
+
E
+
Nu
FG
FG
base
or olefin
b) CH palladation-initiated meta functionalization
Me
Me
Me
DG
N
DG
Me
S
O
O
H
O
Pd(II)/NBE
N
O
N
+
E
N
FG
acid
E
F
H
O
O
Me
N
H
c) This work: direct regioselective difunctionalization of thiophenes
S
Me
prasugrel
S
S 5
olanzapine
()-kallolide B
Pd(II)/NBE
5
FG
H
+
E
+
Nu
FG
Nu
HO
S
oxidant/acid
4
4
R
OH
H
R
E
ArI
S
S
O
S
N
The C5 (or C2) position of thiophene is generally considered to
S
be most electron-rich, and a number of direct C−H metalation
n
O
R
1
3
PBTTT
raloxifene
methods have been successfully developed. However, directly
merging the C5-palladation with the Pd/NBE catalysis would still
be nontrivial because of (1) the lack of an ortho substituent to
Figure 1. Examples of Polysubstituted Thiophenes and Furans
14
promote the NBE extrusion (namely the “ortho constraint”) and
The palladium/norbornene (Pd/NBE) cooperative catalysis, also
known as Catellani-type reactions, has emerged as a versatile
(2) the coordinative ability of the sulfur that could retard the C4
palladation and NBE extrusion (Scheme 2). For example, the use
of α-halothiophenes as substrates for the Catellani-type reactions
5
approach for vicinal difunctionalization of arenes. Seminal
6
7
efforts led by Catellani and Lautens show that, using aryl halides
as substrates, an electrophile and a nucleophile could be coupled
simultaneously at arene ipso and ortho positions, respectively
1
5
has been elusive. We hypothesized that one key to address the
sulfur coordination problem is to use a weak and π-acidic ligand
that could facilitate dechelation from the sulfur on thiophene but
not inhibit the C−H palladation and the Catellani process. In
8
(Scheme 1a). Beyond using aryl halides as substrates, in 2015 the
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Page 2 of 6
addition, the use of a bulkier NBE was also anticipated to be
beneficial over simple NBE for assisting the NBE extrusion step
via β-carbon elimination.
and 72% yield was still obtained with 25 mol% N1 (entry 7).
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
Other substituted NBEs were less optimal. For example, tertiary
5
c
17
amide-derived NBEs (N2 and N3) showed significantly reduced
reactivity likely due to excessive steric hindrance. In addition, the
R
R
R
R
S
4
II
S
S
18
Pd X2
HX
NBE
C2 ester-substituted one (N4) was slightly less effective. While
5
II
S
Pd X
-
simple NBE (N7) gave almost no desired product, the bulkier
Pd
XPd
14
bridgehead-substituted NBEs (N5 and N6) or the remotely
R
X
S
??
18,19
goal
substituted NBEs (N8-10)
could indeed afford the desired
product in higher yields. The difunctionalization reaction requires
stoichiometric oxidants to regenerate the Pd(II) catalyst. Both BQ
and AgOAc were found necessary (entries 8 and 9); it is likely
that BQ could promote fast oxidation of Pd(0) to Pd(II) by acting
EX
Pd
R
R
E
S 5
R
R
S
5
-NBE
S
Nu
Nu
oxidant
PdII
X
S
4
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
4
??
Pd
2
0
E
as a redox active ligand, while AgOAc could assist activation of
the C−I bond through forming AgI. Adding HOAc was beneficial,
though 51% yield could still be achieved without HOAc (entry
E
E
Pd
X
X
Scheme 2. Potential Challenges for the Proposed Approach
1
0). The reaction was less efficient at a lower concentration (entry
11). Finally, when substrates 1a and 2a were used in an equal
molar ratio, the desired product 4a was afforded in a good yield
To test the hypothesis, 2-butylthiophene (1a) was used as the
model substrate, and ortho arylation/ipso Heck reaction was
(
entry 12). It is noteworthy that the reaction can be run directly in
examined at this initial stage (Table 1). Indeed, AsPh
3
, previously
o
air at a relatively low reaction temperature (65 C).
employed for dechelating the amine directing group in our meta
9
b
Table 2. Thiophene Derivatives Scopea
arylation reaction, was found to be superior over phosphine and
phosphite ligands (entries 1-4) and delivered the desired C4,5-
difunctionalized thiophene product (4a) in 82% yield after
systematic optimization. Unsurprisingly, no desired product was
observed in the absence of Pd or NBE (entries 5 and 6). The C2
I
CO2Me
+
standard condition
S 5
S 5
2
CO Me
R
E
R
+
O
4
4
Me
Ar
1
6
N
H
methyl amide-substituted NBE (N1) proved to be most efficient,
N1
1
a-n
2a
3a-b
4a-n
Table 1. Control Experiments
nBu
Me
Ar =
S
S
E =
2
CO Me
I
nBu
S
2
CO Me
E
E
Pd(OAc)2 (10 mol%)
5
CO2Me
nBu
CO2Me
+
S
2
CO Me
AsPh3, N1
4
Ar
Ar
4b, 78%
Ph
+
AgOAc, BQ, HOAc
ethyl acetate (0.2 M) MeO2C
4a, 81%
65 oC, air
standard condition
1a
2a
3a
MeO
4a
S
BnO
S
TBSO
S
S
E
E
E
E
yield of 4a (%)a
Entry
Change from the "standard condition"
Ar
Ar
Ar
Ar
1
none
82(81)
4c, 76%
4d
4f
, 80%
,
72%
4e, 76%
2
w/o AsPh3
2
3
4
5
PPh3 instead of AsPh3
(PhO)3P instead of AsPh3
w/o Pd(OAc)2
1
0
0
MeO
MeO2C
Cl
Br
S
S
E
E
S
S
E
E
Ar
Ar
6
7
w/o N1
0
Ar
Ar
4h, 58%
25 mol% N1
72
4i, 60%
4j, 40%
4
g, 86%
NBE Effect (15 mol% NBE used instead)b
Me
sp3
Me
O
O
O
O
O
Cy
Cl
Br
O
Br
S
S
sp2
BnO
S
CO2Me
O
2
Me
Me
2
E
E
1
S
N
N
N
OMe
H
Me
Me
Me
Ar
Me
O
Ar
Ar
sp Ar
sp2
N1
N2
N3
N4
N5
Ph
62
5
15
45
16
tBuO2C
4k, 51%
4l, 52%
4m, 53%
4n, 40%
C7H15
aThe reaction was run with 0.3 mmol 1, 0.2 mmol 2 and 0.36
mmol 3 in 1.0 mL ethyl acetate for 48 h.
CN
5
CO2Me
CO2Me
5
O
NHMe
N6
N7
2
N8
11
N9
20
N10
10
With the optimized reaction condition in hand, the scope with
respect to thiophenes was examined first (Table 2). A range of
thiophenes with various substituents at the C2 position were found
to be suitable substrates for vicinal difunctionalization. Besides
alkyl substitution (4a-4e), aryl-derived thiophenes (4f-4h) still
delivered the desired products in good to excellent yields; both
electron-rich (4g) and deficient (4h) aryl groups were tolerated.
Interestingly, for 4g, the C−H functionalization took place site-
selectively at the thiophene site instead of the electron-rich
alkoxyarenes. Many FGs were found compatible, including
methoxy group (4c), benzyl and silyl-protected primary alcohols
(4d and 4e) and esters (4h). Note that 2-chloro and bromo
thiophenes (4i and 4j) were also reactive; the halogen FGs could
potentially be used as a handle for further functionalization. The
C2 and C3 disubstituted thiophenes also proved to be competent
18
8
9
w/o BQ
11
w/o AgOAc
w/o HOAc
0.1 M
13
1
0
1
2
51
72b
1
1
1a/2a = 1 : 1 (1 equiv)
71c
aThe reaction was run with 0.15 mmol 1a, 0.1 mmol 2a, 0.18
mmol 3a, Pd(OAc) (0.01 mmol), N1 (0.15 mmol), AsPh (0.025
2
3
mmol), AgOAc (0.3 mmol), BQ (0.1 mmol) and HOAc (0.5
mmol) in 0.5 mL ethyl acetate for 48 h. Yields were determined
1
by H NMR analysis using dibromomethane as the internal
b
c
standard. 1 mL ethyl acetate was used. 0.1 mmol 1a was used.
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substrates, giving fully substituted products (4k-4n) that are
in moderate to good yields. Additional chemoselectivity could be
observed from the tolerance of electron-rich arenes (7a, 7c, 7d),
ketones (7d), tertiary amines (7b, 7e) and epimerizable
stereocenters (7b, 7e). In addition, this reaction is robust and
scalable: a high yield was obtained on a gram scale in an open-
flask operation (Eq. 1). The commercial ethyl acetate can be
directly used as solvent without further purification.
1
2
3
4
5
6
7
8
9
nontrivial to be prepared via conventional approaches. In
particular, the reaction can tolerate internal alkyne (4m) and
generate a tetrasubstituted thiophene bearing all carbon groups
with three different hybridizations.
The scope with respect to aryl iodides and olefins was next
explored (Table 3). Aryl iodides with an ortho electron-
withdrawing group (EWG) were found to be most efficient, which
is consistent with the preference in the standard Catellani ortho
Table 4. Functionalization of Complex Bioactive
a
Compounds
5
9b
arylation and our prior observation . Ester, amide, ketone and
nitro-substituted aryl iodides served as effective electrophiles.
Notably, a second iodide moiety (5d) not ortho to the EWG was
compatible. Use of other aryl iodides, particularly the less reactive
electron-rich ones, was challenging under the current conditions,
though 3,5-bistrifluoromethylphenyl iodide gave the desired
difunctionalization product in 37% yield. In addition to methyl
acrylate, other Michael acceptors, such as conjugated esters (6a-
c), amides (6d, 6e) and ketones (6f), are also excellent coupling
partners for the C5 functionalization. Encouragingly, the more
electron-neutral styrene could also be efficiently coupled in 81%
yield (6g).
I
standard condition
CO2Me
+
S
S
2
CO Me
R4
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
R4
O
E
+
Me
N1
(
Ar-I)
2a
(E-H)
3a
N
Ar
H
1
o-s
7a-e
E
S
Me
E
S
Me
Ar
O
O
O
H
H
Me
2
O
Ar
H
Me
3
Me
Me
iPr
3
derived from Vitamin E
a, 56%
derived from Estrone
7d, 65%
7
Table 3. Aryl Iodides and Olefin Scopea
Ar
E
O
Boc
N
I
Ar
CO2Me
N
S
nBu
standard condition
nBu
S 5
S
4
R
5
N
E
R2
E
E
Me
S
N
+
+
O
O
N
4
S
Cl
Boc
Me
N
Ar
Ar
H
N1
5a-5i
6a-6g
from Clopidogrel
7b, 48%b
from Duloxetine
c, 57%
from hexahydro-1,4-diazepine-
L-proline
1
a
2b-i
3b-h
7
7
e, 45%
Aryl iodides
a
CO2Me
Ar =
The reaction was run with 0.3 mmol 1, 0.2 mmol 2a and 0.36
mmol 3a in 1.0 mL ethyl acetate for 48 h. A pair of rotational
isomers was isolated in a 1:1 ratio.
E =
CO2Me
CO2Me
2
CO Me
b
MeO2C
F
Br
nBu
5a, 87%
5b, 72%
5c, 81%
I
S
CO2tBu
nBu
CO2Me CO tBu
S
O
2
standard condition
(1)
+
+
CO2Me
NO2
NO2
MeO2C
2
MeO C
Ph
except N1 (50 mol%)
CO Me
2
1
a
2b
3b
4o
.04 g, 89%
I
OMe
2
5d, 56%
5e, 62%
5f, 60%
5g, 57%
O
iPr
O
NEt2
O
Me
CF3
CF3
5h, 68%
5i, 73%
Olefin scope
CO2nBu
5j, 37%
open flask
solvent
Ar =
Beyond thiophenes, preliminary success was achieved using a
simple furan substrate. When 2-butylfuran 1t was subjected to the
standard conditions with 1.0 equiv of N1, the desired
trisubstituted product (8) was obtained in 30% yield (Eq. 2). In
addition, the direct C4 arylation with protonation at the C5
position was realized with excess HOAc in the absence of acrylate
E =
CO2Bn
CO2tBu
6b, 84%
CO2Me
6a, 78%
6c, 80%
O
CONMe2
Ph
CONHtBu
21
Me
3a (Eq. 3).
6d, 81%
6e, 73%
6f, 77%
6g, 81%
aThe reaction was run with 0.3 mmol 1a, 0.2 mmol 2 and 0.36
mmol 3 in 1.0 mL ethyl acetate for 48 h.
The synthetic utility of this method was first tested in the
derivatization of complex bioactive compounds that contain
thiophenes (Table 4). Reactions with derivatives from vitamin E
(
(
7a), estrone (7d) and hexahydro-1,4-diazepine-L-proline adduct
7e), clopidogrel (7b) and Boc-protected duloxetine (7c) all
worked smoothly to afford the desired difunctionalized products
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Journal of the American Chemical Society
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nBu
O
CO2Me
The Supporting Information is available free of charge on the
ACS Publications website.
I
nBu
CO Me
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
2
CO Me
standard condition
2
(2)
+
+
except
N1 (1.0 equiv)
ethyl acetate (0.4 M)
MeO2C
AUTHOR INFORMATION
1
t
2a
3a
8
, 30%
Corresponding Author
gbdong@uchicago.edu
nBu
I
S
5
nBu
CO Me
H
S
2
standard condition
5
+
4
(3)
except
HOAc (10.0 equiv)
Author Contributions
MeO2C
4
(Word Style "Section_Content").
‡These authors contributed
1a
2a
9a, 71%
equally. (match statement to author names with a symbol, if
applicable)
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
Regarding the mechanistic pathway, an intriguing question is
whether the reaction goes through a “coupled” difunctionalization
as a regular Catellani pathway (path a) or a sequential stepwise
C4/C5 functionalization (path b), i.e. C4 arylation followed by an
independent C5 C−H/Heck reaction. To address this question, the
kinetic profile of the model reaction was obtained (Fig. 2), which
indicates that the difunctionalization product (4a) was formed
immediately at the beginning of the reaction and there was no
accumulation of the C4-arylation intermediate (9a) during the
course of the reaction. A competition experiment further indicated
that direct difunctionalization is more favorable than the C5
alkenylation (C−H/Heck) of 9a (see Supporting Information).
Taken together, these results suggest that the Heck quench at the
C5 position is preferred compared to the protonation, thus
supporting the “coupled” difunctionalization pathway (path a).
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial supports from the University of Chicago and NIGMS
(1R01GM124414-01A1) are acknowledged. Z.Y. is supported by
a CSC fellowship. X.X. is supported by a fellowship from
ShanghaiTech University. We thank Mr. Jianchun Wang for
helpful discussions.
REFERENCES
1
. Joule, J. A.; Mills, K., Heterocyclic Chemistry; Wiley: Weinheim,
2013.
2. For recent reviews, see: (a) Mkhalid, I. A. I.; Barnard, J. H.; Marder,
path b
path a
R
R
R
S
R'
S
R
S
R'
ArI
C4-arylation
S
T. B.; Murphy, J. M.; Hartwig, J. F., C−H Activation for the Construction
of C−B Bonds. Chem. Rev. 2010, 110, 890-931. (b) Yeung, C. S.; Dong,
V. M., Catalytic Dehydrogenative Cross-Coupling: Forming
Carbon−Carbon Bonds by Oxidizing Two Carbon−Hydrogen Bonds.
Chem. Rev. 2011, 111, 1215-1292. (c) Lyons, T. W.; Sanford, M. S.,
Palladium-Catalyzed Ligand-Directed C−H Functionalization Reactions.
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Controlled Site-Selective Bond Activation. Accounts of Chemical
Research 2017, 50, 549-555. (e) Toste, F. D.; Sigman, M. S.; Miller, S. J.,
Pursuit of Noncovalent Interactions for Strategic Site-Selective Catalysis.
Acc. Chem. Res. 2017, 50, 609-615. (f) Rouquet, G.; Chatani, N., Catalytic
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C−H Bonds as Ubiquitous Functionality: A General Approach to Complex
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C−H Bonds and Regioselective N-Alkylation Enabled by SEM-Group
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Heteroarene Ring. J. Am. Chem. Soc. 2011, 133, 16338-16341. (c) Bae, S.;
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S.; Jang, J. H.; Kim, H. T.; Han, S. J.; Tsui, G. C.; Joo, J. M., Synthesis of
Fluorescent Indazoles by Palladium-Catalyzed Benzannulation of
Pyrazoles with Alkynes. Org. Lett. 2017, 19, 1450-1453. (e) Yamamoto,
K.; Li, J.; Garber, J. A. O.; Rolfes, J. D.; Boursalian, G. B.; Borghs, J. C.;
Genicot, C.; Jacq, J.; van Gastel, M.; Neese, F.; Ritter, T., Palladium-
catalysed electrophilic aromatic C–H fluorination. Nature 2018, 554, 511.
R'
ArI
R'
Ar
Ar
Ar
stepwise functionalization
simultaneous difunctionalization
nBu
S
CO2Me
4a
MeO2C
nBu
S
MeO2C
9a
Figure 2. Kinetic Profile of the Model Reaction
In summary, a direct method for vicinal difunctionalizations of
thiophenes has been developed through the Pd/NBE cooperative
catalysis. The reaction exhibits excellent FG tolerance and
complete site- and regio-selectivity. The mild and robust reaction
condition should make it attractive for preparing complex poly-
substituted thiophenes and late-stage functionalization of
bioactive compounds. Efforts on disclosing the detailed
mechanism, including the exact role of the amide-derived NBE
cofactor, and expanding the reaction scope to other types of
difunctionalizations and other electron-rich heterocycles (besides
thiophenes and furans) are ongoing.
(b) Berger, F.; Plutschack, M. B.; Riegger, J.; Yu, W.; Speicher, S.; Ho,
M.; Frank, N.; Ritter, T., Site-selective and versatile aromatic C−H
functionalization by thianthrenation. Nature 2019, 567, 223-228. (c)
Cheng, C.; Hartwig, J. F., Rhodium-Catalyzed Intermolecular C–H
Silylation of Arenes with High Steric Regiocontrol. Science 2014, 343,
853.
ASSOCIATED CONTENT
Supporting Information
4
. (a) Ghosh, I.; Khamrai, J.; Savateev, A.; Shlapakov, N.; Antonietti,
M.; König, B., Organic semiconductor photocatalyst can bifunctionalize
arenes and heteroarenes. Science 2019, 365, 360. (b) Kim, H. T.; Ha, H.;
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Kang, G.; Kim, O. S.; Ryu, H.; Biswas, A. K.; Lim, S. M.; Baik, M.-H.;
(hetero)aryl-substituted heteroarenes via transition metal-catalysed direct
(hetero)arylation of heteroarene C–H bonds with aryl halides or
Joo, J. M., Ligand-controlled Regiodivergent C−H Alkenylation of
Pyrazoles and its Application to the Synthesis of Indazoles. Angew. Chem.
Int. Ed. 2017, 56 , 16262-16266. (c) Goikhman, R.; Jacques, T. L.; Sames,
D., C−H Bonds as Ubiquitous Functionality: A General Approach to
Complex Arylated Pyrazoles via Sequential Regioselective C-Arylation
and N-Alkylation Enabled by SEM-Group Transposition. J. Am. Chem.
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1
2
3
4
5
6
7
8
9
pseudohalides,
diaryliodonium
salts,
and
potassium
aryltrifluoroborates. Tetrahedron 2009, 65, 10269-10310. For selected
works, see: (c) Liégault, B.; Lapointe, D.; Caron, L.; Vlassova, A.;
Fagnou, K., Establishment of Broadly Applicable Reaction Conditions for
the Palladium-Catalyzed Direct Arylation of Heteroatom-Containing
Aromatic Compounds. J. Org. Chem. 2009, 74, 1826-1834. (d) Gorsline,
B. J.; Wang, L.; Ren, P.; Carrow, B. P., C–H Alkenylation of
Heteroarenes: Mechanism, Rate, and Selectivity Changes Enabled by
Thioether Ligands. J. Am. Chem. Soc. 2017, 139, 9605-9614. (e) Colletto,
C.; Panigrahi, A.; Fernández-Casado, J.; Larrosa, I., Ag(I)–C–H
Activation Enables Near-Room-Temperature Direct α-Arylation of
Benzo[b]thiophenes. J. Am. Chem. Soc. 2018, 140, 9638-9643.(f) Doba,
T.; Matsubara, T.; Ilies, L.; Shang, R.; Nakamura, E., Homocoupling-free
Iron-catalysed Twofold C–H Activation/Cross-couplings of Aromatics via
Transient Connection of Reactants, Nat. Catal. 2019, 2, 400-406.
14. Wang, J.; Li, R.; Dong, Z.; Liu, P.; Dong, G., Complementary site-
selectivity in arene functionalization enabled by overcoming the ortho
constraint in palladium/norbornene catalysis. Nat. Chem. 2018, 10, 866-
872.
5
. (a) Ye, J.; Lautens, M., Palladium-catalysed norbornene-mediated
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N.; Fontana, M.; Motti, E.; Catellani, M., Pd/Norbornene: A Winning
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Activation. Acc. Chem. Res. 2016, 49, 1389-1400. (c) Wang, J.; Dong, G.,
Palladium/Norbornene Cooperative Catalysis. Chem. Rev. 2019, 119,
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
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5
5
5
5
5
5
5
5
6
0
1
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7
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9
0
1
2
3
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7
8
9
0
1
2
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4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
478-7528. (d) Cheng, H.-G.; Chen, S.; Chen, R.; Zhou, Q., Palladium(II)-
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a
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Alkylation and Arylation Using a Modified Norbornene. J. Am. Chem.
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8
. For the first Pd(II)-initated Pd/NBE catalysis, see: (a) Jiao, L.; Bach,
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2
011, 133, 12990-12993. For representative works on transmetallation-
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Arylboronic Acids as Substrates. ACS Catal. 2018, 8, 3775-3779. (c)
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a
Palladium(II)-Initiated Borono-Catellani
Reaction. Angew. Chem. Int. Ed. 2018, 57, 7161-7165. (d) Li, R.; Liu, F.;
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. (a) Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu, R.-Y.; Li, S.; Engle,
K. M.; Yu, J.-Q., Ligand-enabled meta-C–H activation using a transient
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1
0. Liu, L.-Y.; Qiao, J. X.; Yeung, K.-S.; Ewing, W. R.; Yu, J.-Q.,
meta C–H Arylation of Electron-Rich Arenes: Reversing the Conventional
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1
1. Gómez, M.; Granell, J.; Martinez, M., Mechanisms of
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Processes. Eur. J. Inorg. Chem. 2000, 2000, 217-224.
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996, 9, 1403-1413.
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Pd(OAc)2 (10 mol%)
S
S 5
R
5
R
AsPh3, N1
FG
H
FG
+
Ar-I
+
AgOAc, BQ, HOAc
ethyl acetate, 65 oC, air
4
4
H
Ar
*
site- and regio-selective
* open flask reaction
* broad functional group tolerance
access to fully substituted thiophenes
O
As
Me
N1
Ph
N
Ph
Ph
H
*
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