Journal of the American Chemical Society
Page 2 of 11
Unsymmetrical biaryls, especially biheteroarenes, are
reaction (Table 1).Under the optimized reaction conditions,
we obtained an exclusively C4 selective cross-coupled
product (3a) in 86% yield with mol% of
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
important structural motifs in a number of scientific fields
including pharmaceuticals, agrochemicals, and organic
5
3
6, 37
38-42
materials.
Although gold-catalyzed biaryl coupling
(dimethylsulfide)gold(I) chloride (DMSAuCl), 20 mol% of
AgOAc and 1.5 equivalent of phenyliodine diacetate (PIDA)
(Entry 1). Although the pyrazole unit has often been used as
has enjoyed many advances in conjunction with palladium
catalysis, there remains an increasing demand for the
synthesis of unsymmetrical biaryls by cross-
4
9, 50
a directing group,
no directed arylation by-product was
1
2
dehydrogenative Ar -H/Ar -H coupling which has
remarkable atom- and step-economy. The major challenge
to such reactions stems from untamed chemo- and
regioselectivity. In 2010, Larrosa’s group reported that
gold(I) could promote selective C-H activation of electron-
observed and no other homocoupling products were
formed. The reaction did not proceed in the absence of
either the gold catalyst or silver salt (Entry 2). Further
investigation of the reaction revealed that an excess amount
of the silver salt was essential for its success. Only a trace
amount of 3a were detected with just 5 mol% of AgOAc, but
increasing the loading of AgOAc led to a significant
improvement in the yield (Entries 3-5). The acetate anion
was usually thought to promote metal-mediated C-H bond
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
43
deficient arenes via σ-bond metathesis manner and one
elegant gold-catalyzed cross-dehydrogenative coupling
between protected indoles and polyfluoroarenes was
4
4
developed in 2015 based on this principle (Scheme 1a). In
both cases, the presence of silver salt was necessary.
Although the authors recently suggested the role of silver
3
0-32
activation via CMD process,
but the loss of catalytic
reactivity with other non-silver acetate salts would rule out
this possibility (Entry 6). Interestingly, the use of
4
4
salts might be beyond a halogen scavenger, elucidation of
its exact role and characterization of key arylsilver(I)
intermediate in gold catalysis, and evaluation of its
possibility for aryl-transfer via transmetlation step to gold
as well as the clear mechanistic picture have not been
described.
Ph
afford the desired product, but the addition of a further 15
mol% of silver acetate together with Ph PAuOAc resulted in
3
PAuOAc without the addition of silver acetate failed to
3
60% yield (Entries 7 and 8). These experiments further
suggest that the silver salt in this cross-dehydrogenative
coupling does not function simply as a halogen scavenger.
In this paper, we report a highly selective cross-
dehydrogenative arylation of pyrazoles through
cooperative Au/Ag dual catalysis by experimental and DFT
theoretical studies (Scheme 1b), which is different from
routinely proposed Au(I)/Au(III) catalytic cycle. Our
mechanistic investigation has revealed that silver(I) was
the actual species for activation C-H bond of electron-poor
arene to form arylsilver(I), which would go through a
transmetalation to gold center. An Au/Ag bimetallic
catalytic process involves Ag(I)-catalyzed C-H activation of
electron-poor arenes and Au(III)-catalyzed C-H activation
of electron-rich arenes. This reaction allows an efficient and
high-selective access to unsymmetrical biheteroarenes
from two different aromatic C-H bonds. Its high selectivity
origins from orthogonal C-H activation selectivity of Ag(I)
and Au(III) on arenes with different electronic properties.
The Ag(I) catalyst favors C-H activation of the most acidic C-
H bond of electron-poor arenes via a concerted metalation-
deprotonation (CMD) process. In contrast, Au(III) shows
specific selectivity for C-H auration of the most electron-
rich position of electron-rich arenes via electrophilic
Table 1. Optimization of Reaction Conditions
H
N
F
F
C4
N
N
F
F
F
F
DMSAuCl (5 mol%), AgOAc (20 mol%)
PIDA (1.5 eq.),1,4-dioxane (0.1 M)
N
N
Ph
N
+
N
ArF
N
Ph
00 o
F
1
C
F
1
a
2a
1.5 eq.
3a
no directed arylation
1 eq.
exclusively at C4 position
no homocoupling products
Entry
Variation from optimal conditions
-
Yield
86%a
-
1
2
3
4
5
6
7
8
no DMSAuCl or AgOAc
5 mol% AgOAc
trace
60%b
76%b
-
10 mol% AgOAc
15 mol% AgOAc
15 mol% NaOAc, KOAc, or CsOAc
5 mol% Ph
3
3
PAuOAc
-
5 mol% Ph
PAuOAc, 15 mol% AgOAc
60%b
See Supporting Information (SI) for standard conditions and optimization
a
b
details. isolated yield. GC-MS yield with biphenyl as an internal standard.
Mechanistic Studies
E
aromatic substitution (S Ar) mechanism.
To gain a better understanding of this interesting
experimental result, we first focused our attention on
elucidation of the mechanism, especially the role of silver
salts and the selectivity in this reaction. In 2018, Larrosa et
al. reported that silver salts could carry out highly selective
C-H arylation of electron-rich benzo[b]thiophene at C2
RESULTS AND DISCUSSION
Reaction Optimization
Pyrazole derivatives, have witnessed widespread
application in pharmacology and drug design due to their
45
vast biological activities. However, owing to the strong
5
1
position. This led us to question whether the high
selectivity of this reaction was parallel to that induced by
the silver-catalyzed selective C-H activation of N-
phenylpyrazole (1a). However, the failure to observe H/D
exchange of pyrazole with silver salts under various
conditions appears to exclude this possibility (see SI for
details). On the other hand, it has been reported that the
strong electrophilic feature of gold(III) species can facilitate
coordinative ability of the nitrogen atom in pyrazoles, it is
highly challenging to achieve site-selective C-C coupling
directly from C-H bond on pyrazole scaffolds using catalysts
4
6
47
48
containing for example, Pd, Rh or Mn . Given by the
unique reactivity and functional group tolerance of gold, our
experiments aimed at evaluating the possibility of gold-
catalyzed cross-dehydrogenative C-C coupling of pyrazole.
We choose C-H/C-H biaryl coupling of N-phenyl-pyrazole
5
2
C-H auration of electron-rich arenes. Accordingly, we
(
1a) and 2,3,5,6-tetrafluoropyridine (2a) as a model
conducted the reaction of N-phenylpyrazole with
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