Ortho arylation of acetanilides via Pd(II)-catalyzed C-H functionalization

Article abstract of DOI:10.1021/ja070767s

A remarkable transformation to realize ortho arylation of acetanilides via Pd(II)-catalyzed C-H functionalization with trialkoxyarylsinaes was demonstrated. Copyright

Full text of DOI:10.1021/ja070767s

Published on Web 04/25/2007
Ortho Arylation of Acetanilides via Pd(II)-Catalyzed C-H Functionalization
Shangdong Yang, Bijie Li, Xiaobing Wan, and Zhangjie Shi*
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education, College of Chemistry and Green Chemistry Center, Peking
UniVersity, Beijing 100871, and State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
Received February 2, 2007; E-mail: zshi@pku.edu.cn
Table 2. Ortho Arylation with Different Silyl Reagents via C-H
Palladium-catalyzed coupling with silyl reagents is a very useful
method to construct a C-C bond in organic synthesis.1 With much
effort in the past, these couplings could be conducted with different
substitutions, such as iodide, bromide, triflate, and even inexpensive
but hard chloride.2 As a potential green and efficient process to
construct complicated structures from simple and commercially
available chemicals, the sp2 C-H bond may be functionalized to
construct C-C via Pd-catalyzation.3 Direct arylation of aromatic
C-H has also been studied with or without directing groups.4 With
the acetamino group as a directing group, ortho C-H of acetanilide
could be highly regioselectively functionalized.5 Herein we first
demonstrate a new development to form the C-C bond through
aryl C-H activation by coupling with (trialkyoxyl)phenylsilane
directed by an acetamino group.
Activationa
In our recently reported ortho halogenation, the palladacycle
formed through acetyl group-assisted electrophilic attack by Pd-
(II) cation was proposed as a key intermediate.5i We envisioned
that the same intermediate might undergo coupling with silyl
reagents under proper conditions. We first tried Hiyama coupling
between acetanilide 1a and (trimethoxy)phenylsilane 2a in the
presence of a stoichiometric amount of Pd(OAc)2 with TBAF in
dioxane. Unfortunately, no desired product was observed. Gratify-
ingly, the desired coupling product 3aa was observed in a low yield
monitored by GC when AgF was used as a fluoride source (entry
2, Table 1). Further studies indicated that a catalytic amount of
Pd(OAc)2 also made this transformation happen, but the efficiency
was lower. We envisioned that AgF might play more roles than
a All the reactions were carried out in 0.2 mmol scale. b Isolated yields.
Table 1. Ortho Arylation via C-H Activation under Different
Conditionsa
just a simple fluoride source; it may also serve as an oxidant to
oxidize a Pd(0) species back to Pd(II) to fulfill the catalytic cycle.
Thus, we hypothesized that the key point for this transformation is
a proper oxidant. After many trials, we found that Cu(OTf)2 was
the best choice (entry 3, Table 1). Other organic and inorganic
oxidants were not helpful for this transformation. The amount of
Cu(OTf)2 could be decreased to 1.0 equiv (entry 4, Table 1);
however, the increase of Cu(OTf)2 is helpful to inhibit the
homocoupling of phenylsilane to produce diphenyl as a byproduct.
On the basis of this observation, different trialkyloxyarylsilanes
were surveyed (Table 2). The coupling occurred to produce the
desired products 3 in moderate to excellent yields with (trimethoxy)-
phenylsilanes, regardless electron withdrawing group or electron-
donating group was introduced on the phenyl ring of the phenyl-
silane. However, phenyl silanol was not a good reagent for this
transformation under the same condition and the product 3aa was
obtained in much lower efficiency (entry 8, Table 2). It was
important to note that C-Cl on phenylsilane was compatible with
this system, which could be further transformed into different
functionalities (entry 6, Table 2).2c
entry
Pd (mol %)
oxidant (equiv)
additive (equiv)
3aab
10
2
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
PdCl2 (5.0)
Pd(OTFA)2 (5.0)
Pd(PPh3)2Cl2(5.0)
Pd(PhCN)2Cl2 (5.0) Cu(OTf)2 (2.0) AgF (2.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Cu(OTf)2 (2.0)
37
AgF (2.0)
8
86 (74)
68
56
19
67
66
73
11
3c
4
Cu(OTf)2 (2.0) AgF (2.0)
Cu(OTf)2 (1.0) AgF (2.0)
Cu(OTf)2 (2.0) AgF (1.0)
Cu(OTf)2 (2.0) AgF (2.0)
Cu(OTf)2 (2.0) AgF (2.0)
Cu(OTf)2 (2.0) AgF (2.0)
5
6
7
8
9
10
11
12
13
14
Cu(OTf)2 (2.0) CsF (2.0)
Cu(OTf)2 (1.0) CuF2 (2.0)
Cu(OTf)2 (1.0) TBAF (2.0)
CuCl2 (2.0)
CuBr2 (2.0)
15
<5
<5
<5
AgF (2.0)
AgF (2.0)
a All the reactions were carried out in the presence of 0.2 mmol of 1a
and 0.4 mmol 2a in 5 mL of dioxane at 110 °C for 48 h. b GC yields with
n-decane as an internal standard. c Isolated yield in parentheses.
The scope of acetanilides was also investigated (Table 3). Other
than acetyl, benzoyl and formyl could be used as directing groups
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J. AM. CHEM. SOC. 2007, 129, 6066-6067
10.1021/ja070767s CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Ortho Arylation of Actanilides with 2a via C-H
Scheme 1. Proposed Mechnism of Ortho Arylation by Coupling
via Pd(II)-Catalyzed C-H Activation
Functionalizationa
4 to form diaryl palladium species 5, which underwent reductive
elimination to produce the coupling product. Pd(0) was oxidized
back to Pd(II) by either Ag(I) or Cu(II) or both to complete the
catalytic cycle. Thus, electron-donating groups on acetanilides were
helpful for this transformation. The prepared palladacycle 4 could
stoichiometrically transform to the coupling product, which offered
a further proof for this proposed mechanism.5c
In summary, we developed a novel transformation to realize ortho
arylation of acetanilides with trialkoxyarylsilanes through direct
C-H functionalization. Further investigation to clearly understand
this transformation and expand the application of this chemistry is
underway in our laboratory.
Acknowledgment. Support of this work by a starter grant from
Peking University and the grant from NSFC (Grant No. 20542001
and 20521202) is gratefully acknowledged.
Supporting Information Available: Brief experimental details and
other spectra data for products. This material is available free of charge
via the Internet at http://pubs.acs.org.
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a All the reactions were carried out in the presence of 0.2 mmol of 1,
0.4 mmol of 2a, 0.01 mmol of Pd(OAc)2, 0.4mmol of Cu(OTf)2, and 0.4
mmol of AgF in 5 mL of dioxane at 110 °C for 48 h. b Isolated yields.c GC
yields with n-decane as an internal standard. d Reaction run in the presence
of 10.0 mol % of Pd(OAc)2 in these reactions, and some starting materials
were recovered.
with lower efficiency (entries 2 and 3). The other groups, such as
tosyl, acetacetyl, and trifluoroacetyl were not beneficial for this
transformation (entries 4, 6, and 9). N-alkylated and free anilines
were not fit for this transformation. Either the electron-donating
groups or electron-withdrawing groups introduced to the phenyl
group of acetanilides could be applied to form desired products
(entries 10-16). However, the efficiency of this transformation was
decreased by electron-withdrawing groups, perhaps arising from
the decrease of electron density on the phenyl ring (entries 14-
15). Furthermore, benzoyl, acetyl, and methyl groups could serve
as a protecting group of phenol, and the regioselectivity was not
affected by these functionalities (entries 10-12). The polysubsti-
tuted acetanilides were also investigated, and the expected products
were obtained in good yields (entries 18-20). It is worthy pointing
out that the regioselectivity of this arylation was also controlled
by the steric effect with substituents at the meta position of
acetanilides (entries 16 and 20).
This coupling may go through the following catalytic process
(Scheme 1). After the ortho electrophilic attack by Pd(II) cation
with the assistance of the acetamino group, the aryl group from
silicate 2′ assisted by fluoride was transmetalated to palladacycle
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