Pd/C-Catalyzed Homocoupling Reaction for the Synthesis of Symmetrical Biaryl Diamides

Article abstract of DOI:10.1055/s-0036-1588437

Pd/C was found to be an efficient and convenient metal catalyst in the homocoupling reaction for the synthesis of symmetrical biaryl diamides. The catalyst system Pd/C-KOAc showed high catalytic activity, and a variety of symmetrical biaryl diamides were conveniently synthesized from 2-halo- N -phenylbenzamides in moderate to good yields.

Full text of DOI:10.1055/s-0036-1588437

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
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Synlett
G. Shen et al.
Letter
Pd/C-Catalyzed Homocoupling Reaction for the Synthesis of
Symmetrical Biaryl Diamides
Guodong Shen*
R2
O
Yichen Wang
Xiliang Zhao
N
R1
H
O
X
R2
Xinlei Huangfu
Yanmeng Tian
Tongxin Zhang
Bingchuan Yang*
R1
1
0% Pd/C, KOAc
N
R1
O
H
DMA, 125 °C, N2
NH
R2
X = Br, I
R1 = H, Me, F, Br
School of Chemistry and Chemical Engineering, School of
Pharmacy, Liaocheng University, Liaocheng 252000,
Shandong, P. R. of China
1
9 examples
R2 = H, Me, t-Bu, F, Cl, Br, CF , OCF
3
3
up to 82% yield
shenguodong33@163.com
yangbingchuan@lcu.edu.cn
Received: 17.03.2017
Accepted after revision: 04.05.2017
Published online: 24.05.2017
sis of symmetrical biaryl diamides are rare. The classic
method for the synthesis of symmetrical biaryl diamides is
to use [1,1′-biphenyl]-2,2′-dicarbonyl dichloride and ani-
line.15 In 2005, Goswami et al. reported a convenient palla-
dium-catalyzed synthesis of symmetric biaryls, biheterocy-
cles, and biaryl chiral diamides by using Pd(PPh ) Cl /CuI as
DOI: 10.1055/s-0036-1588437; Art ID: st-2017-w0197-l
Abstract Pd/C was found to be an efficient and convenient metal cata-
lyst in the homocoupling reaction for the synthesis of symmetrical bi-
aryl diamides. The catalyst system Pd/C–KOAc showed high catalytic
activity, and a variety of symmetrical biaryl diamides were conveniently
synthesized from 2-halo-N-phenylbenzamides in moderate to good
yields.
3
2
2
catalyst.16 Recently, Wang, Kuninobu, and Kanai reported a
molybdenum-mediated desulfurization of disulfides reac-
17
tion to obtain symmetrical biaryl diamides. In continua-
tion of our ongoing efforts, we report an efficient and con-
venient 10% Pd/C-catalyzed homocoupling reaction for the
synthesis of symmetrical biaryl diamides, which might be
potentially applicable in the industrial area (Scheme 1).
Initially, 2-iodo-N-phenylbenzamide 1a was selected as
the model substrates to identify and optimize the reaction
parameters including reaction solvent, base, and tempera-
ture. When the reaction was carried out with 10% Pd/C
(10% wt% of 1a, 10 mg), 2-iodo-N-phenylbenzamide 1a (0.3
mmol), and KOAc (0.6 mmol) in toluene (2.0 mL) at 110 °C
Key words Pd/C, homocoupling reaction, symmetrical biaryl di-
amides, 2-halo-N-phenylbenzamides, recyclability
Palladium on carbon, often referred to as Pd/C, is one of
the most commonly used catalysts for its large surface area,
good pore structure, and good load performance and reduc-
1
tion properties. It is often used for catalytic hydrogena-
tions, hydrodechlorinations,3 and coupling reactions4 in
organic synthesis. Among the palladium catalysts, it is also
attractive for industrial applications due to its high catalytic
activity, easy removal, commercial availability, and reason-
2
under N atmosphere for 20 hours, the desired product
2
2
2′
N ,N -diphenyl-[1,1′-biphenyl]-2,2′-dicarboxamide
(1b)
5
able cost.
could be isolated in 31% yield (Table 1, entry 1). The reac-
tion was investigated in other solvents (DMSO, DMF, NMP,
and DMA), and DMA was found to be the best choice (Table
1, entries 2–5). To our delight, when the reaction tempera-
ture was raised to 125 °C, the product was obtained in 82%
yield (Table 1, entries 6–8). Other bases such as K CO ,
Symmetric biaryl subunits are an important class of
molecules in natural products, biological compounds, ma-
6
terials science, and pharmaceuticals,. Significant efforts
have been made toward the development of efficient meth-
7
ods for their preparation. The most convenient approach
2
3
for accessing symmetrical biaryls is the reductive homo-
coupling of arylhalides either by Ullmann synthesis or by
KOt-Bu were also used, but the yields decreased (Table 1,
entries 9 and 10). Without the 10% Pd/C catalyst or the
base, the reaction did not proceed (Table 1, entries 11 and
12). 2-Bromo-N-phenylbenzamide 1a′ was used to repeat
the reaction under the optimal conditions, and the desired
product 1b was obtained in 68% yield (Table 1, entry 13).
The yields were also not good when the reaction was re-
peated in toluene or DMSO using DMA as the ligand (Table
1, entries 14 and 15). The reaction was also conducted in
8
9
10
oxidative coupling of arylboronic acid, arylzinc, arylstan-
11
12
nane, and aryl mesylate. Recently, palladium-catalyzed
homocoupling reactions have drawn considerable attention
for their efficiency, but Pd/C-catalyzed homocoupling re-
13
14
actions are rare.
Although symmetric biaryl subunits play an important
role in these areas, efficient synthetic routes for the synthe-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
Synlett
G. Shen et al.
Letter
air, leading to a decrease in the yield (Table 1, entry 16). Fi-
nally, the amount of 1a was increased to 20 mmol to repeat
the reaction, and the yield was got in 83% (Table 1, entry 7).
From the above experiments we can conclude that entry 7
shows the best reaction conditions.
Table 1 Optimization of the Reaction Conditionsa
O
N
H
O
With the optimized reaction conditions in hand, the
scope of substrates was further investigated (Table 2). The
substrates of 2-halo-N-phenylbenzamides a could generat-
ed the desired products b in moderate to good yields (Table
1
0% Pd/C, base
N
O
H
solvent, N2, temp
I
NH
1a
1b
2, entries 1–18). From the results we could conclude that
the reaction yields were mainly influenced by the electron-
2
2
Entry
Base
Solvent
Temp (°C)
Yield (%)b
ic effect of the functional group of R . The group R were
electron-donating groups (Me and t-Bu) generated better
yields than electron-withdrawing-substituted groups (F, Cl,
Br, CF , and OCF ; Table 2, entries 2–11). The functional
1
2
3
4
5
6
7
8
9
KOAc
toluene
DMSO
DMF
110
110
110
110
110
120
125
130
125
125
125
125
125
125
125
125
31
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
25
3
3
56
1
group R did not influenced the yield obviously (Table 2, en-
tries12–15). 2-Bromo-N-phenylbenzamide 16a and 2-bro-
mo-N-(p-tolyl)benzamide 17a were used to repeat the re-
NMP
21
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
toluene
DMSO
DMA
62
80
Previous work
82 (83)c
81
O
N
O
Cl
H
K
2
CO
3
62
NH2
NaOH, H2O
4 h, r.t.
10
11
12
13
14
15
KOt-Bu
KOAc
–
15
O
eq 1
2
0d
O
Cl
NH
0
O
68e
KOAc
KOAc
KOAc
KOAc
R1
O
N
H
33f
20f
R1
Pd(OAc)2, CuI, PPh3, Et3N
MeCN, 6 h, 82 °C
N
H
eq 2
O
56g
I
16
HN
R1
N
a
Reaction conditions: 10% Pd/C (10% wt% of 1a, 10 mg), 2-iodo-N-phenyl-
O
benzamide 1a (0.3 mmol), base (0.6 mmol) in solvent (2.0 mL) under N
2
O
atmosphere for 20 h.
N
b
Isolated yield after flash chromatography based on 1a.
R1
c
S
R1
0
.02 mol 1a was used.
No 10% Pd/C was used.
-Bromo-N-phenylbenzamide 1a′ was used.
0 mol% of DMA was added as the ligand.
Mo(CO)6, acetone
6 h, 120 °C
S
d
e
f
eq 3
2
1
O
O
g
The reaction was conducted under the air atmosphere.
N
R1
N
R1
R1 = H, Me
action, and the products were obtained in moderate yields
(Table 2, entries 16 and 17). When 2-chloro-N-phenylben-
zamide 18a was used, the reaction could not proceed (Table
2, entry 18). At last, iodobenzene or bromobenzene was
used to repeat the reaction, and only 7% yield of diphenyl
Our work
R2
O
O
X
N
R2
R1
H
1
0% Pd/C, KOAc
N
R1
R1 eq 4
H
16b was isolated for the reaction of iodobenzene (Table 2,
DMA, N2, 20 h, 125 °C
O
entries 19 and 20). From the results above we can conclude
that the neighboring-group effect is significant for this re-
action.
NH
X = Br, I
R2
Scheme 1 Synthesis of symmetrical biaryl diamides
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G. Shen et al.
Letter
Table 2 Scope of the Pd/C-Catalyzed Homocoupling Reactiona
Entry
a
b
Yield
b
(
%)
R2
O
N
F
O
R1
H
O
R2
N
F
R1
O
I
H
1
0% Pd/C, KOAc
N
H
R1
O
DMA, 125 °C, N2
6
N
H
74
O
X
NH
R2
X = Br, I
NH
6
a
a
b
F
Entry
a
b
Yield
6b
b
(
%)
Br
O
O
Br
N
N
H
O
I
H
O
7
N
H
72
N
H
1
2
3
82
80
84
O
O
I
NH
NH
7a
1
a
Br
1
b
7b
CF3
O
O
N
H
O
I
CF3
N
O
I
H
N
H
O
8
N
H
66
O
NH
2
a
NH
8
a
2
b
F3C
8
b
O
OCF3
N
H
O
O
OCF3
N
N
H
O
I
H
O
I
9
N
H
60
NH
O
3
a
NH
9
a
3
b
F3CO
9
b
O
N
H
O
O
I
N
N
H
4
81
O
I
H
Br
O
N
H
10
O
51
4
a
NH
Br
NH
Br
1
0a
4
b
t-Bu
10b
O
t-Bu
N
H
O
5
N
H
80
O
I
NH
5
a
t-Bu
5
b
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G. Shen et al.
Letter
Table 2 (continued)
Entry
a
b
Yield
b
(
%)
Entry
a
b
Yield
b
(
%)
O
Cl
17
N
2b
1b
66
O
H
Br
Cl
N
1
1
7a
8a
O
I
H
Cl
1
1
N
62
O
H
O
Cl
N
1
8
9
0
NH
H
1
1a
Cl
I
Cl
Cl
O
1
1b
1
7
0
1
6b
Br
19a
N
H
O
Br
Br
N
12
13
14
65
68
60
20
H
O
Br
I
20a
16b
NH
1
2a
a
Reaction conditions: 10% Pd/C (10% wt% of a), 2-halo-N-phenylben-
zamides a (0.3 mmol), KOAc (0.6 mmol) in DMA (2.0 mL) at 125 °C under
1
2b
N atmosphere for 20 h.
2
b
Isolated yield after flash chromatography based on a.
O
N
From an economic and industrial point of view, the re-
cyclability of the Pd/C catalyst is very important. Taking ad-
vantage of the insolubility of Pd/C in H O, a simple filtration
O
I
H
Br
Br
N
H
O
2
Br
1
was sufficient to recover the catalyst. The recyclability of
the catalyst was then studied in the homocoupling reaction
of 2-iodo-N-phenylbenzamide 1a. The results of the recy-
cling experiment are shown in Table 3. The catalyst could
be reused under the same reaction conditions after separa-
tion, washing with water. It was notable that the Pd/C cata-
lyst still remained catalytically active after being reused
four times. The coupling reaction at the fourth run gave the
desired product 1b in 51% yield.
NH
3a
1
F
3b
4b
5b
O
N
O
H
F
N
H
O
F
I
NH
1
4a
Table 3 Pd/C-Recycling Experiments for the Homocoupling Reactiona
1
Cycle
1
2
3
4
O
Yield (%)b
83c
80
70
51
N
H
a
O
I
Reaction conditions: 10% Pd/C (10% wt% of 1a), 2-iodo-N-phenylbenzamide
a (5 mmol), KOAc (10 mmol) in DMA (20 mL) at 125 °C under N atmo-
1
2
N
sphere for 20 h.
15
65
H
O
b
Isolated yield after flash chromatography based on 1a.
c
0
.02 mol 1a was used.
NH
1
5a
1
On the basis of the above results and previous work,18
a
O
possible reaction mechanism for Pd/C-catalyzed homocou-
pling reactions was proposed (Scheme 2). Because of the
N
H
16
1b
68
19
neighboring-group effect, the intermediate c was generat-
Br
0
1
6a
ed in the presence of a and Pd via the oxidative addition
reaction, then two molecular c was transferred to the inter-
mediate d, finally a reductive elimination reaction proceed-
ed, and d was converted into the product b.
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G. Shen et al.
Letter
R2
O
H
R2
N
R1
N
O
X
R1
R2
R1
H
H
O
Pd0
N
N
R1
2
R1
2
R2
Pd
H
O
O
O
Pd0
Pd
R1
PdX2
KOAc/DMA
Pd0
NH
X
N
R2
R2
c
H
a
d
b
Scheme 2 Proposed mechanisms of the Pd/C-catalyzed homocoupling reactions
In summary, we have developed a Pd/C-catalyzed ho-
mocoupling reaction for the synthesis of symmetrical biaryl
(5) (a) Heidenreich, R. G.; Kohler, K.; Krauter, J. G. E.; Pietsch, J.
Synlett 2002, 1118. (b) Conlon, D. A.; Pipik, B.; Ferdinand, S.;
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Williams, J. M.; Shi, Y. J.; Sun, Y. Adv. Synth. Catal. 2003, 345,
20
diamides. The reactions exhibit some functional-group
tolerance and allow for the preparation of a number of sym-
metrical biaryl diamides in moderate to good yields. The
high catalytic activity, easy removal, commercial availabili-
ty, and reasonable cost of Pd/C would render this protocol
attractive for both synthetic and industrial applications.
9
31.
6) (a) Wilkins, C. K.; Bohn, B. A. Phytochemistry 1976, 15, 211.
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Funding Information
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This work was financially supported by the National Natural Science
Foundation of China (No. 21402079) and the Research Fund for the
Doctoral Program of Liaocheng University (No. 318051403 and
318051419).
N
oaitn
a
l
N
a
ut arl
Secince
F
o
u
n
d
oaitn
of
C
h
n
i
a
2(
1
4
0
2
0
7
9
R)esearch
F
u
n
d
o
f
r
hte
D
o
cotra
l
P
orgra
m
of
aLoi ch
e
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1
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588437.
1
76.
13) (a) Omori, H.; Hiroto, S.; Shinokubo, H. Org. Lett. 2016, 18, 2978.
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References and Notes
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2
(
(
(
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(
20) General Procedure for the Synthesis of Symmetrical Biaryl
(b) Dams, M.; Drijkoningen, L.; Pauwels, B.; Van Tendeloo, G.; De
Diamides
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An oven-dried Schlenk tube equipped with a Teflon valve was
charged with a magnetic stir bar, 10% Pd/C (10% wt% of a), 2-
halo-N-phenylbenzamides a (0.3 mmol) and KOAc (0.6 mmol).
The tube was placed under vacuum for 20 min and backfilled
2483. (d) Yu, K.; Sommer, W.; Weck, M.; Jones, C. W. J. Catal.
2004, 226, 101. (e) Yu, K.; Sommer, W.; Richardson, J. M.; Weck,
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Vasiliev, A. N.; Panarello, A. P.; Khinast, J. G. Appl. Catal., A 2007,
with N . Then DMA (2.0 mL) was added through a syringe. The
2
reaction mixture was stirred at 125 °C for 20 h. The reaction
325, 76.
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Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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Synlett
G. Shen et al.
Letter
2
2
was monitored by TLC. When 2-halo-N-phenylbenzamides a
consumed completely, the reaction was stopped and cooled to
r.t., EtOAc (40 mL) was added, and the mixture was washed with
brine (3 × 20 mL). The organic phase was dried over Na SO and
Typical Analytical Data of N ,N ′-Diphenyl-[1,1′-biphenyl]-
2,2′-dicarboxamide (1b)
1
H NMR (400 MHz, CDCl ): δ = 9.00 (s, 2 H), 7.69 (d, J = 7.2 Hz, 2
3
H), 7.45–7.58 (m, 8 H), 7.26 (t, J = 7.6 Hz, 4 H), 7.17 (d, J = 8.4 Hz,
2
4
13
concentrated. The residue was purified directly by column chro-
2 H), 7.07 (t, J = 7.2 Hz, 2 H). C NMR (100 MHz, CDCl ): δ =
3
matography on silica gel to give the pure products b (PE–EtOAc
168.46, 139.21, 138.03, 136.20, 130.34, 129.86, 129.04, 128.27,
127.33, 124.61, 120.08.
=
2:1, v/v).
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F