Palladium-catalyzed direct oxidative ortho-acylation of anilides with toluene derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.12.059

Direct oxidative ortho-acylation reaction of anilides with toluene derivatives in the presence of palladium acetate using tert-butyl hydroperoxide as an oxidant was developed. A broad range of diaryl ketones was obtained in good to excellent yields (up to 95%). The plausible mechanism was also proposed.

Full text of DOI:10.1016/j.tetlet.2012.12.059

Tetrahedron Letters 54 (2013) 1205–1207
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed direct oxidative ortho-acylation of anilides with
toluene derivatives
⇑
⇑
Jianquan Weng , Zhiqin Yu, Xinghai Liu, Guofu Zhang
College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct oxidative ortho-acylation reaction of anilides with toluene derivatives in the presence of palladium
acetate using tert-butyl hydroperoxide as an oxidant was developed. A broad range of diaryl ketones was
obtained in good to excellent yields (up to 95%). The plausible mechanism was also proposed.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 15 October 2012
Revised 5 December 2012
Accepted 14 December 2012
Available online 22 December 2012
Keywords:
Acylation
Anilide
Cross-coupling
Palladium-catalyzed
Toluene
Transition-metal-catalyzed C–H functionalization has attracted
much attention in recent years.1 Amongst transition-metal-
catalyzed cross-coupling reactions, the direct acylation has
emerged as an appealing alternative to the traditional Friedel–
Crafts acylation reaction.2–6 In this content, the aryl C–H bond
was coupled efficiently with a series of oxygen-containing acyla-
acetamide (3a) was isolated in 12 h (entry 1). Different palladium
source was then tested and the reaction catalyzed by Pd(TFA)2 gave
Table 1
Reaction optimizationa
O
O
tion reagents, such as aldehydes,2,4
a
-oxocarboxylic acids,5 and
CH3
NH O
NH
catalyst
oxidant
+
alcohols,6 to afford aryl ketone compounds which are significant
building blocks found in biologically active molecules, pharmaceu-
ticals, and organic functional materials.7 Recently, much attention
has been focused on the oxidation of sp3 C–H bond. Specially, the
oxidation of benzylic C–H bond catalyzed by metallic copper and
cobalt catalysts, or organocatalysis could efficiently generate aryl
aldehydes, ketones, and aryl carboxylic acids.8 We thus envisioned
that the direct benzoylation of aryl C–H bonds might be realized by
using toluene derivatives as acylation reagents, through in situ oxi-
dation and generation of benzaldehydes. Herein, we report a direct
benzoylation reaction of anilides to synthesize diaryl ketone com-
pounds by using Pd(OAc)2 as catalyst and tert-butyl hydroperoxide
(TBHP) as oxidant.
1a
Entry Cat. (mol %)
2a
3a
Oxidant (equiv) Solvent
Temp (°C) Yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(TFA)2 (5)
PdCl2 (10)
CuBr (10)
CuI (10)
FeCl2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (10) TBHP (12)
Pd(OAc)2 (15) TBHP (12)
Pd(OAc)2 (20) TBHP (12)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
DTBP (6)
(NH4)2S2O8 (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
Toluene
Toluene
Toluene 115
Toluene 135
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
95
75
37
12
34
13
30
Trace
0
0
0
95
95
95
95
95
95
95
95
95
95
95
95
95
95
9
10
11
12b
13b
14b
15b
16
17
18
0
0
Initially, acetanilide (1a) and toluene (2a) were selected as mod-
el substrates and the reaction was carried out in toluene at 95 °C
with 5 mol % Pd(OAc)2 as catalyst and tert-butyl hydroperoxide
(TBHP, 6 equiv, 70% solution in water) as oxidant (Table 1). To our
delight, 37% yield of the desired product N-(2-benzoylphenyl)
Trace
Trace
Trace
Trace
68
PhCl
tBuOH
CH3CN
Toluene
Toluene
Toluene
82
94
a
⇑
Corresponding authors. Tel./fax: +86 571 88320147.
E-mail addresses: jqweng@zjut.edu.cn (J. Weng), gfzhang@zjut.edu.cn (G.
Reactions and conditions: acetanilide (1a, 1.0 mmol), toluene (2a, 3 mL), 12 h,
isolated yields.
Solvent (3 mL), toluene (5.0 mmol).
b
Zhang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.059

1206
J. Weng et al. / Tetrahedron Letters 54 (2013) 1205–1207
Table 2
Table 3
Acylation of anilides with toluenea
Acylation of acetanilide with toluene derivativesa
O
O
O
20% Pd(OAc)2
TBHP
95 oC, 12 h
O
20% Pd(OAc)2
12 equiv TBHP
95 oC, 12 h
CH3
CH3
R1 NH
NH
R1 NH O
NH O
+
+
R2
R3
R2
R3
1a
2
3
1
2a
3
Entry
1
Tolune
Product
Yield (%)
93 (62b)
Entry
1
Anilide
Product
Yield (%)
90
O
H
O
N
NH O
O
NH
2b
O
O
1b
3k
O
NH O
3b
H
N
O
O
O
NH
NH
2
3
4
5
87
83
90
17
2
3
4
87
86
95
2c
2d
2e
1c
3l
O
NH O
3c
O
H
N
O
MeO
1d
3m
O
NH O
OMe
O
3d
H
MeO
N
Cl
NH O
O
1e
Cl
3n
O
NH O
MeO
O
3e
Br
H
N
NH O
Br
2f
O
Cl
5
6
15
24
1f
3o
3f
Cl
O
a
Reactions and conditions: acetanilide (1a, 1.0 mmol), toluene (2, 3.0 mL),
Pd(OAc)2 (20 mol %), TBHP (16.0 equiv), 95 °C, 12 h under aerobic condition,
isolated yields.
H
N
NH O
b
O
O
Oxidant: TBHP (12.0 equiv).
Br
Cl
1g
Br 3g
O
NH O
of anilides reacted smoothly to give diaryl ketones in good to excel-
lent yields (3b–e), while significant lower yields were observed for
the substrates possessing halides (3f–h). Unfortunately, when ani-
lides with ortho-substituent (such as methyl-, methoxyl-, and
chloro-) were employed as substrates, no corresponding com-
pounds were detected owing to the steric effect. Besides the acetyl
group, propionyl and benzoyl are suitable protecting groups and
the reactions of 1i and 1j gave considerable yields of the corre-
sponding products. In addition, other groups substituted anilides
(such as N-(naphthalen-1-yl)acetamide, N-(biphenyl-4-yl)acetam-
ide, N-(4-fluorophenyl)acetamide, N-(3,5-dichlorophenyl)acetam-
ide, and N-(4-nitrophenyl)acetamide) were also investigated, but
no corresponding compounds were detected.
H
N
7
8
9
27
83
78
1h
Cl
3h
NH O
3i
H
O
N
O
O
1i
O
H
N
NH O
1j
3j
a
Toluene derivatives were then investigated and the results were
shown in Table 3. When para-xylene was used, the desired product
(3k) was obtained in 62% yield under the optimal conditions. By
increasing the amount of oxidant to 16.0 equiv, the yield was im-
proved to 93%. Under the modified conditions, only mono-acylated
Reactions and conditions: anilide (1, 1.0 mmol), toluene (2a, 3.0 mL), Pd(OAc)2
(20 mol %), TBHP (12.0 equiv), 95 °C, 12 h under aerobic condition, isolated yields.
a comparable yield (entry 5), while PdCl2 was completely inefficient
(entry 6). No product was detected when CuBr, CuI, and FeCl2 were
used as catalysts (entries 7–9) and di-tert-butyl peroxide (DTBP),
(NH4)2S2O8 were used as oxidants instead of TBHP (entries 10–
11). The reaction was fully suppressed when using 5 equiv of tolu-
ene in 1,2-dichloroethane (DCE), chlorobenzene (PhCl), tBuOH, and
CH3CN solvent (entries 12–15). Finally, it was found that the yield
could be remarkably improved by increasing both the catalyst load-
ing and the amount of oxidant (entries 16–18), and 94% isolated
yield of the product was obtained in the presence of 12 equiv of
TBHP and 20 mol % Pd(OAc)2.
20% Pd(OAc)2
4.0 equiv TBHP
O
H
O
H
N
NH O
+
3 mL toluene
O
95oC, 12h
1.0 mmol
2.0 mmol
89%
NH O
O
H
O
H
N
20% Pd(OAc)2
+
4.0 equiv TBHP
O
95oC, 12h
With the optimized conditions in hand, the scope of anilides
was explored. As shown in Table 2, the substrates bearing elec-
tron-donating groups in the para- or meta-position of phenyl rings
3.0 mL
1.0 mmol
84%
Scheme 1. Palladium catalyzed ortho-acylation of anilide with benzaldehyde.

J. Weng et al. / Tetrahedron Letters 54 (2013) 1205–1207
1207
Team of Science and Technology in Zhejiang Province
(2010R50018-06).
HN
O
O
Pd(OAc)2
Supplementary data
NH O
AcOH
Cyclopalladation
Supplementary data associated with this article can be found, in
Ac
HN
O
O
2
the
online
version,
at
http://dx.doi.org/10.1016/
Pd
Reductive
elimination
j.tetlet.2012.12.059.
I
TBHP
AcOH
H
O
O
References and notes
HN
O
TBHP
Pd
Oxidation
OAc
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Acknowledgments
This work is supported by the National Natural Science Founda-
tion of China (No. 30900959, 20702051) and the Key Innovation