Pd(OAc)2-catalyzed lactonization of arylacetamides involving oxidation of C-H bonds

Article abstract of DOI:10.1246/cl.150041

The reaction of arylacetamides that contain a quinolin-8-ylmethylamine as the directing group with PhI(OAc)₂, in the presence of Pd(OAc)₂ as the catalyst, results in lactonization to give γ-lactones, the formation of which involves activation of the ortho C-H bonds, with concomitant cleavage of the directing group.

Full text of DOI:10.1246/cl.150041

Received: January 17, 2015 | Accepted: February 5, 2015 | Web Released: February 17, 2015
CL-150041
Pd(OAc)2-catalyzed Lactonization of Arylacetamides Involving Oxidation of C-H Bonds
Takeshi Uemura, Takuya Igarashi, Moe Noguchi, Kaname Shibata, and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871
(E-mail: chatani@chem.eng.osaka-u.ac.jp)
The reaction of arylacetamides that contain a quinolin-8-
ylmethylamine as the directing group with PhI(OAc)2, in the
presence of Pd(OAc)2 as the catalyst, results in lactonization to
give γ-lactones, the formation of which involves activation of
the ortho C-H bonds, with concomitant cleavage of the directing
group.
by hydrolysis after the final coupling event.9 From the stand-
point of atom economy, this type of reaction represents an
ideal route to the functionalization of C-H bonds because the
directing group can be recycled. However, examples of this type
are rare. The design of new directing groups continues to be an
important issue in terms of the development of new types of
functionalizations that cannot be achieved using known direct-
ing groups. In this context, we report herein the first use of an
quinolin-8-ylmethylamine moiety in the Pd(II)-catalyzed lacto-
nization of arylacetamides with PhI(OAc)2 as the oxidant.
The focus of our recent research has been on the use of N,N-
bidentate directing groups, such as pyridinylmethylamine and
8-aminoquinoline in C-H functionalization reactions.10,11 The
reaction is significantly affected by the nature of the directing
group. This encouraged us to design a new type of N,N-bidentate
directing group.12-14 We found that the reaction of 1a, containing
an quinolin-8-ylmethylamine moiety as the directing group, with
PhI(OAc)2 in toluene as the solvent in the presence of a catalytic
amount of Pd(OAc)2 gave 4-methylbenzofuran-2(3H)-one (2a).
Chen recently reported the Pd(OAc)2-catalyzed oxidation of
arylacetamides containing 8-aminoquinoline as the directing
group with PhI(OAc)2 to give γ-lactam derivatives, in which
an intramolecular C-N bond is formed and the directing group
remains attached to the product.15 Surprisingly, however, the
expected lactam 3a was not formed in our chelation system. The
formation of 2a involves the elimination of the directing group,
which is recovered as acetamide 4. Among the oxidants
examined, PhI(OAc)2 was found to be superior; Cu(OAc)2
trace, AgOAc 0%, K2S2O8 0%, PhI(OCOCF3)2 32%. After
optimization of the reaction conditions, we determined that
the following conditions were optimal for the reaction: 1a
(0.5 mmol), PhI(OAc)2 (1.0 mmol), NaHCO3 (1.0 mmol),
Pd(OAc)2 (0.05 mmol), toluene (2 mL) at 140 °C for 16 h
(Scheme 1). Under the standard reaction conditions, lactone 2a
was obtained in 55% isolated yield, along with the directing
group being recovered as acetamide 4 in 65% yield.
Chelation-assisted functionalization of C-H bonds has
become one of the most reliable methods for the regioselective
functionalization of C-H bonds.1 A wide variety of functional
groups can be used as the directing group in this type of
transformation. In most cases, the directing groups promote
the functionalization of C-H bonds, but remain intact under the
reaction conditions employed. In some cases, they can be easily
elaborated to more synthetically useful functional groups after
the complete functionalization of the C-H bond. A majority of
such functionalizations can be included in this category. In
another iteration of this reaction, the directing group is
incorporated in the final product. In this case, the directing
group promotes the functionalization of C-H bonds, and then
reacts further with the introduced groups and is incorporated into
the final product as a component of the final compound. We
recently reported the Pd(II)-catalyzed synthesis of dibenzophos-
phole derivatives from diarylphosphines, in which the phospho-
rus atom promotes the activation of the C-H bond, followed by
C-PPh bond cleavage.2 In this type of reaction, the originally
installed directing group becomes a part of the product. Because
of this, the directing group cannot be recovered or be recycled.
There are many examples of directing groups in this category.3
Recently, considerable attention has been focused on
traceless removal directing groups in the catalytic functionaliza-
tion of C-H bonds because of the synthetic utility of this
procedure.1j,4 A carboxylate directing group is an attractive
and promising traceless directing group because of its ready
availability and unique character.5 It is known that a carboxylate
directing group promotes the decarboxylative Mizoroki-Heck-
type alkenylation of C-H bonds at the C2-position of indoles
with acrylic esters and styrenes, but a C3-selective reaction took
place when the indoles contained no carboxylate directing
group.6 The carboxylate group also promotes both ipso-
decarboxylative arylation in benzoic acid derivatives with aryl
halides7 and ortho-decarboxylative arylation of C-H bonds in
benzoic acid derivatives, depending on the catalytic system in
use.8
Me
Pd(OAc)2
PhI(OAc)2
NaHCO3
10 mol%
1.0 mmol
1.0 mmol
Me
O
HN
O
O
+
H
toluene 2 mL
140 °C, 16 h
O
N
2a 55%
Me
O
1a
0.5 mmol
HN
In another class of directing groups, the directing group
spontaneously cleaved after the activation of the C-H bond, and
could be recovered intact or as a derivative. Hirano and Miura
recently reported the Cu(II)-catalyzed synthesis of carbazoles
from 2-aminobiphenyl derivatives that contain a picolinamide-
based directing group, in which the picolinamide moiety
promotes C-H amination and is then spontaneously removed
N
N
Q'
3a not formed
4 65%
Scheme 1. Pd(OAc)2-catalyzed reaction of 1a with PhI(OAc)2.
© 2015 The Chemical Society of Japan | 621
Chem. Lett. 2015, 44, 621–623 | doi:10.1246/cl.150041

a
O
Table 1. Pd(OAc)2-catalyzed lactone synthesis of 1 with PhI(OAc)2
Pd(OAc)2
10 mol%
O
O
HN
PhI(OAc)2 1.0 mmol
O
+
NaHCO3
1.0 mmol
NHQ'
HN
toluene 2 mL
140 °C, 16 h
N
O
O
OAc
H
toluene 2 mL
140 °C, 16 h
R
O
N
R
5
2j trace
2
4 42%
1 0.5 mmol
O
O
HN
NaHCO3 2 equiv
Me
OMe
Ph
O
+
NHQ'
toluene 2 mL
140 °C, 16 h
N
O
O
NHQ'
O
O
OAc
NHQ'
H
NHQ'
5
2j
29%
H
H
4 74%
1b 50%
1c 53%
OMe
1a 55%
Scheme 3. Controlled experiments.
MeO
O
O
Me
O
_
cat. Pd(II)
O
O
NHQ'
O
NHQ'
NHQ'
NHQ'
PhI(OAc)2
ref 11
NaHCO3
H
MeO
H
H
NHQ'
OAc
NQ'
H
O
1e 47%
1f 51%
1d 53%
O
1i
6
MeO
MeO
O
O
NHQ'
NHQ'
O
H
H
O
_
O
Q'
N
1g 48%
- 4
O
1h 61%
O
7
aReaction conditions: 1 (0.5 mmol), PhI(OAc)2 (1.0 mmol), NaHCO3
(1.0 mmol), Pd(OAc)2 (0.05 mmol), toluene (2 mL) at 140 °C for 16 h.
Yields are isolated yields by column chromatography. Q¤ refers
quinolin-8-ylmethanamino group.
Scheme 4. Proposed mechanism.
A proposed mechanism for this transformation is shown in
Scheme 4. The Pd(II)-catalyzed acetoxylation of C-H bonds in
1i takes place by taking advantage of the use of a directing
group, similar to the case of known reactions using another type
of directing group, to afford 6.16 A base-promoted intramolec-
ular acyl transfer then occurs to give 7, which undergoes
intramolecular cyclization to give a lactone, with the concom-
itant generation of 4.
OAc
10 mol%
2.0 mmol
Pd(OAc)2
PhI(OAc)2
toluene 2 mL
160 °C, 16 h
O
O
NHQ'
O
H
2i
35%
1i 0.5 mmol
In summary, we report a new synthesis of benzofuran-
2(3H)-one derivatives from arylacetamide derivatives. The
reported synthesis of benzofuran-2(3H)-one derivatives through
the activation of C-H bonds involves the cyclative formation of
C-O bonds in arylacetic acids.17 However, the presence of
disubstituents at the α-carbon was required for the successful
transformation. In contrast, in our system, the presence of a
substituent is not required, which contradicts the previously
reported reactions. Most importantly, the expected formation
of C-N bonds with the cleavage of C-H bonds to lactams did
not take place in our chelation system, in sharp contrast to the
case of other similar N,N-chelation systems.15 This result is an
example of the importance of designing new directing groups for
exploring new types of functionalizations of C-H bonds, which
cannot be realized when using conventional directing groups.
We are currently investigating the use of this new directing
group in various functionalization reactions of C-H bonds.
Scheme 2. Pd(OAc)2-catalyzed reaction of 1i with PhI(OAc)2.
Some examples of this reaction are listed in Table 1. The
reaction was highly dependent on the electronic nature of the
substituent. Only electron-rich substrates gave the expected
products. In the case of meta-methyl substrates 1d, 1e, and 1g,
only the less hindered C-H bonds were oxidized to give 2d, 2e,
and 2g. The reaction was not greatly affected by the steric effects
of the substituents, as in 1c.
The reaction of 1i gave 2i, the formation of which involves
both lactonization and acetoxylation (Scheme 2). It is known
that acetoxylation of C-H bonds does not occur when no
directing group is present on the substrate, suggesting that
the acetoxylation product is the initially produced, which then
undergoes intramolecular cyclization under the reaction con-
ditions to give lactones. To confirm the reaction mechanism
involved in the formation of a lactone, some controlled experi-
ments using acetoxy substrate 5 were carried out (Scheme 3).
In the absence of NaHCO3, lactone 2j was not formed. However,
2j was formed when NaHCO3 was used. These results suggest
that the acetoxylation product is an initial product and that the
base promotes further intramolecular cyclization.
This work was supported, in part, by a Grant-in-Aid for
Scientific Research on Innovative Areas “Molecular Activation
Directed toward Straightforward Synthesis” from Monbusho
(The Ministry of Education, Culture, Sports, Science and
Technology).
622 | Chem. Lett. 2015, 44, 621–623 | doi:10.1246/cl.150041
© 2015 The Chemical Society of Japan

Supporting Information is available electronically on J-STAGE.
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Chem. Lett. 2015, 44, 621–623 | doi:10.1246/cl.150041
© 2015 The Chemical Society of Japan | 623