Pd-catalyzed arylation/oxidation of benzylic C-H bond

Article abstract of DOI:10.1021/ol300037p

A palladium-catalyzed benzylic C-H arylation/oxidation reaction leading to diaryl ketones has been accomplished. The indispensable role of the bidentate system is disclosed for this sequential process. This chemistry offers a direct new access to a range of diarylketones.

Full text of DOI:10.1021/ol300037p

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1238–1241
Pd-Catalyzed Arylation/Oxidation of
Benzylic CꢀH Bond
Yongju Xie,† Yuzhu Yang,† Lehao Huang,† Xunbin Zhang,† and Yuhong Zhang*,†,‡
Department of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of
China, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, People’s Republic of China
yhzhang@zju.edu.cn
Received January 9, 2012
ABSTRACT
A palladium-catalyzed benzylic CꢀH arylation/oxidation reaction leading to diaryl ketones has been accomplished. The indispensable role of the
bidentate system is disclosed for this sequential process. This chemistry offers a direct new access to a range of diarylketones.
Transition-metal-catalyzed selective CꢀH bond acti-
vation has attracted considerable attention because it
provides an unprecedented disconnection strategy for
constructing carbonꢀcarbon and carbonꢀheteroatom
bonds.1 Recently, significant progresses in the develop-
ment of metal-catalyzed sp2 CꢀH activations have been
approached.2 However, attempts to establish metal-
catalyzed direct functionalization of sp3 CꢀH bonds have
met with great difficulty for both kinetic and thermody-
namic reasons.3 The benzyl group is an important motif of
organic synthesis, and the benzylic CꢀH bond belongs to a
relatively active sp3 CꢀH bond due to the proximity of the
aromatic system. However, the relevant examples of such
direct functionalizations have thus far remained scarce. A
pioneering work by Daugulis and co-workers describes the
method by employing bidentate systems for the direct
arylation of aliphatic sp3 CꢀH bonds.4 Their strategy
has been utilized in the synthesis of natural product (þ)-
obafluorin.5 Recently, Chatani’s group presented impor-
tant studies by the use of ruthenium catalyst and bidentate
systems for the cyclocarbonylation of aromatic6a and
aliphatic amides.6b These breaking discoveries provide
promising routes for the activation of sp3 CꢀH bond.
Herein, we report our findings on palladium-catalyzed
benzylic CꢀH arylation/oxidation that offers the useful
diarylmethanones by employing aryl iodides as coupling
partners. Importantly, the presence of a bidentate system is
essential for this sequential arylation/oxidation process.
The monodentate directing groups failed to achieve the
transformation (Scheme 1).
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r
10.1021/ol300037p
Published on Web 02/22/2012
2012 American Chemical Society

Table 2. Scope of Aryl Iodidesa
Scheme 1. Control Experiments
Amides are potential directing groups in the reactions of
CꢀH activation. We initially employed acetamide and
benzamide as directing groups for the arylation of benzylic
CꢀH bond with iodobenzene in the presence of palladium
catalysts and AgOAc (Scheme 1). After extensive screening
of the reaction conditions, the arylation failed. In light
of the remarkable success of Daugulis and Chatani,4ꢀ6
we explored the bidentate systems. To our delight, we ob-
tained a new product, diarylmethanone 3a, resulting from
palladium-catalyzed arylation and oxidation. The reaction
took place under argon or air, but dioxygen atmosphere
was superior (Table 1, entries 1ꢀ3). Screening of the
additives indicated that AgOAc gave the best yield (see
the Supporting Information). Other palladium catalysts
such as PdCl2, Pd(CH3CN)2Cl2, and Pd(PPh3)2Cl2 also
worked in this transformation but delivered lower yields
(Table 1, entries 4ꢀ6). Control experiments confirmed that
the palladium catalyst and silver additive were necessary in
this process. No reaction was observed in the absence of
silver salts or palladium catalysts (Table 1, entries 7ꢀ8).
Table 1. Optimization of Reaction Conditionsa
entry
catalyst
Pd(OAc)2
additive
atm
yield (%)b
1
2
3
4
5
6
7
8
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
none
Ar
Air
O2
O2
O2
O2
O2
O2
38
Pd(OAc)2
Pd(OAc)2
PdCl2
51
88
83
Pd(CH3CN)2Cl2
Pd(PPh3)2Cl2
Pd(OAc)2
none
86
47
n. r.
n. r.
AgOAc
a Reaction conditions: 1a (0.3 mmol), 2a (1.2 mmol), Pd(OAc)2
(0.03 mmol), additive (1.2 mmol), xylene (2 mL), 130 °C, 24 h. b Isolated yields.
We next examined the scope of aryliodide as shown
in Table 2. Aryliodides with both electron-withdrawing
and electron-donating groups presented good compatibil-
ity with the reaction conditions (Table 2, entries 1ꢀ11).
a Reaction conditions: 1a (0.3 mmol), aryl iodides (1.2 mmol),
Pd(OAc)2 (0.03 mmol), AgOAc (1.2 mmol), xylene (2 mL), 24 h.
b Isolated yields. c 71% of 3a was obtained on 2 mmol scale.
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Chem. Soc. 2009, 131, 6898. (b) Hasegawa, N.; Charra, V.; Inoue, S.;
Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 8070.
Org. Lett., Vol. 14, No. 5, 2012
1239

Table 3. Scope of Substrate 1a
Scheme 2. Plausible Reaction Mechanism
2-Iodothiophene also participated in the reaction to give
the corresponding ketone product (Table 2, entry 13).
Various arenes were then evaluated as shown in Table 3.
The arenes with both electron-withdrawing substituents
(F, Cl, and Br) and electron-donating substituents (OMe
and Me) on the para-position of the phenyl ring underwent
this novel transformation to form the corresponding pro-
ducts in moderate to good yields (Table 3, entries 2ꢀ6).
The introduction of substituents on the meta-position of
arenes had a negligible effect on the reactions, offering the
desired products with minimal variation in yields com-
pared with their para-substituted analogues (Table 3,
entries 7ꢀ8). Moreover, by replacing the pyridine moiety
in the substrate with quinoline and isoquinoline, the reac-
tion worked well to give the expected products (Table 3,
entries 9ꢀ10).
GCꢀMS analysis of the reaction mixture after 1 h
revealed the formation of arylated product 3aa0 (see
the Supporting Information), suggesting that the reaction
proceeded through a sequential arylation/oxidation pro-
cess. A plausible mechanism was proposed as depicted in
Scheme 2. The coordination of the substrate 1a with
Pd(OAc)2 and subsequent CꢀH bond cleavage led to the
formation of intermediate A, which underwent oxidative
addition with aryliodide to produce intermediate B invol-
ving a Pd(IV) center.4 The subsequent reductive elimina-
tion gave the arylation product 3aa0 (detected by GCꢀMS,
see the Supporting Information), which can complex with
Pd(OAc)2 followed by ligand exchange with H2O to form
the intermediate C. The subsequent oxidation of 3aa0
generated the final ketone product.
a Reaction conditions: 1 (0.3 mmol), 2j (1.2 mmol), Pd(OAc)2
(0.03 mmol), AgOAc (1.2 mmol), xylene (2 mL), 24 h, isolated yield.
b Isolated yields.
A larger scale of the reaction afforded 71% yield for 3a
(Table 2, entry 1). Notably, introducing functional groups
such as F, Cl, Br, CN, and COOEt adds flexibility to
further elaborate the ketone products. As for substitution
pattern, meta-substituted aryliodide also worked in the
reaction to give the desired product in 62% (Table 2, entry
11), but an attempt to employ ortho-substituted aryliodide
failed to yield the expected product, showing that the steric
effect plays the role in the reaction (Table 2, entry 12).
The reaction of 1a with iodobenzene under 18O2 atmo-
sphere delivered 18O-labeled product 18O-3a (see the Sup-
porting Information), indicating that the oxygen in the
diaryl ketones originated from molecular oxygen (eq 1).
We subjected 1a under the reaction conditions in the
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Org. Lett., Vol. 14, No. 5, 2012

presence of H218O under argon, and the 18O-labeled prod-
uct 18O-3a was indeed isolated in 51% (eq 2). However, the
oxidation product 3a was also produced in good yield
when the arylated product 3aa0 was employed as substrate
under argon under the reaction conditions. Moreover,
18O-labeledproduct18O-3awas isolatedin81% yield when
thereaction proceededinthepresenceof H218O (eq3). This
result suggested that the oxygen in the ketone also possibly
came from water. No oxidation was observed prior to
arylation under the standard conditions (eq 4). The ketone
was not detected in the absence of palladium catalysts
(eq 5). One possible explanation for this result is that 18O2
may serve as the oxidant for Pd(0) to Pd(II) and generate
H218O, which would participate in the catalytic cycle
Further experiments showed that the directing group
can be removed by hydrolysis under basic conditions
to afford 2-aminobenzophenone derivatives (Scheme 3),
which are key starting materials for the synthesis of
bioactive agents, such as proquazone8 and amfenac.9
18
to yield the O-labeled product. The oxidation of 3aa0
possibly occurred by the reductive elimination of inter-
mediate C followed by ligand exchange with Pd(OAc)2 to
give intermediate D, which underwent β-hydrogen elim-
ination to liberate 3 product. The resulting Pd(0) was oxi-
dized by dioxygen or silver salt to Pd(II) to furnish the
cycle. Under the dioxygen atmosphere, the direct oxida-
tion of 3aa0 by oxygen in the presence of palladium catalyst
to form the ketones was also possible under the reaction
conditions.7
Scheme 3. Hydrolysis of Amide 3a
In conclusion, we have developed a new protocol for
Pd-catalyzed arylation/oxidation of benzylic CꢀH bonds
by employing a bidentate system. This new transforma-
tion tolerates a broad range of substrates, providing an
alternative for the synthesis of diarylketones. Further
efforts for direct functionalization of the benzylic CꢀH
bond by using bidentate systems are going on in our
laboratory.
Acknowledgment. Funding from NSFC (No. 21072169)
and National Basic Research Program of China (No.
2011CB936003) is acknowledged.
Supporting Information Available. The experimental
procedures and spectroscopic data (1H NMR, 13C NMR,
and HRMS) for the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(8) Coombs, R. V.; Danna, R. P.; Denzer, M.; Hardtmann, G. E.;
Huegi, B.; Koletar, G.; Koletar, J.; Ott, H.; Jukniewicz, E. J. Med.
Chem. 1973, 16, 1237.
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Sancilio, L. F. J. Med. Chem. 1979, 22, 1074.
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Zhang, J.; Khaskin, E.; Anderson, N. P.; Zavalij, P. Y.; Vedernikov,
A. N. Chem. Commun. 2008, 3625.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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