Recycled Pd/C-Catalyzed Heck Reaction of 2-Iodoanilines under Ligand-Free Conditions

Article abstract of DOI:10.1055/s-0036-1590895

Recyclable Pd/C-catalyzed Heck reaction of 2-iodoanilines with acrylate has been developed. The reaction occurred readily in 1,4-dioxane using Pd/C (10 wt%) as catalyst under ligand-free conditions, and the cross-coupling products were obtained with medium to high yield. Gram-scale reactions and recycling of the catalyst were also demonstrated.

Full text of DOI:10.1055/s-0036-1590895

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
paper
A
en
Synthesis
X.-Y. Zhou et al.
Paper
Recycled Pd/C-Catalyzed Heck Reaction of 2-Iodoanilines under
Ligand-Free Conditions
Xiao-Yu Zhou*a
Xia Chen*a
Liang-Guang Wangb
O
I
OR'
Recyclable
OR'
R
+
R
O
Pd/C Catalyst
NH2
NH2
Up to > 99% yield
a
College of Chemistry and Materials Engineering,
Liupanshui Normal University, Liupanshui, 553004,
P. R. of China
zhouxiaoyu20062006@126.com
College of Chemistry and Chemical Engineering,
Anshun University, Anshun, 561000,
P. R. of China
Δ Recyclable Pd/C catalyst
Δ Ligand-free
R = alkyl, CN, NO2, Cl, Br, etc.
R' = Me, Et, Bu
b
t
Δ Under air
Δ Substrates with amino group
Received: 27.06.2017
Accepted after revision: 07.08.2017
Published online: 28.08.2017
reaction.12 A great many achievements have been reported
for the application of Heck reaction in the synthesis of nu-
merous functionalized molecules.2
DOI: 10.1055/s-0036-1590895; Art ID: ss-2017-h0423-op
Among metal catalysts, palladium has often been used
to construct C–C bonds in Heck reactions. For economic
Abstract Recyclable Pd/C-catalyzed Heck reaction of 2-iodoanilines
with acrylate has been developed. The reaction occurred readily in 1,4-
dioxane using Pd/C (10 wt%) as catalyst under ligand-free conditions,
and the cross-coupling products were obtained with medium to high
yield. Gram-scale reactions and recycling of the catalyst were also
demonstrated.
13
and environmental reasons, the recovery and the recycling
of the expensive palladium catalyst is mandatory. The pre-
vious strategies involving Heck reactions mainly employed
homogeneous palladium catalysis systems. Unfortunately,
homogeneous catalysis suffers several drawbacks with re-
spect to production-practice, such as the low catalytic ac-
tivity due to the poisoning of active palladium catalyst with
the amino group. Furthermore, the necessary ligand used to
form the active catalyst may be expensive and the removal
of the catalyst from the product can be a challenge because
the level of residual palladium in the active pharmaceutical
ingredient (API) must be consistently less than 10 ppm. In
this context, the development of heterogeneous and ligand-
free catalysis is meaningful.
Key words palladium, heterogeneous catalysis, Heck reaction, ligand-
free, 2-iodoaniline
Over the past few decades, there has been a steady
growth in the number of palladium-catalyzed cross-
coupling reactions that have been used for the construction
of carbon–carbon bonds. Among the palladium-catalyzed
cross-coupling reactions, Heck, Suzuki, and Negishi cross-
coupling reactions are by far the most widely exploited.1
The Heck reaction is a key technology for converting halo-
genated aromatics and olefins into useful chemicals.2
Alkenyl-substituted anilines represent a key building block
in organic synthesis, and they are common and important
substructures in the synthesis of indoles and quinolines.3
The most simple and direct method to construct these com-
pounds is C–C coupling reaction of their precursors, be-
cause of the high selectivity and efficiency of palladium
catalysis systems in these reactions.
A solution to these problems could be the use of a het-
erogeneous palladium catalyst, which could be prepared by
simple methods and recycled conveniently.14 During recent
years, attention has also focused on the development of cat-
alytic reactions for the manufacture of fine chemicals.
Palladium–carbon (Pd/C) catalyst, which is commercially
available, has been employed in industries, including for the
oxidation of glucose and hydrogenation of nitro compounds
and olefins. However, there are few productive practices
that involve the Heck reaction with Pd/C catalyst, especially
Recently, new generations of homogeneous catalysts
4
5
6
7
14g
such as palladacycles, iridium, rhodium, nickel, and cop-
in air atmosphere and under ligand-free conditions.
8
per catalysts have extended the scope of the reaction to al-
The Pd/C catalyst is an interesting alternative for cataly-
sis of the Heck reaction under ligand-free conditions. Here-
in, we report an efficient process for the Pd/C catalyzed
Heck reaction of 2-iodoanilines and acrylate without a li-
gand, in air (Scheme 1), which takes place in the presence of
most all aromatic halides. Even the electrochemical Heck
reaction has been developed to enhance the efficiency of
9
catalyst. Most recently, a large number of reports have fo-
cused on palladium-catalyzed Heck reaction in green sol-
10
11
vents, asymmetric Heck reactions, and oxidative Heck
triethylamine (Et N).
3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
Synthesis
X.-Y. Zhou et al.
Paper
Table 1 Optimization of the Synthesis of 3aa
O
I
OR'
Pd/C (10 wt%)
Et3N (2.0 equiv)
OR'
O
R
+
R
O
I
NH2
NH2
OEt Catalyst (10 wt%)
OEt
1
,4-dioxane, 100 °C
+
O
Base (2.0 equiv)
Solvent, 100 °C
NH2
NH2
R = alkyl, CN, NO2, Cl, Br, etc.
t
R' = Me, Et, Bu
1a
2a
3a
Scheme 1 Pd/C-catalyzed Heck reaction of 2-iodoanilines
Entry
Catalyst
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Et
Et
Et
Et
Et
Et
Et
3
3
3
3
3
3
3
N
N
N
N
N
N
N
toluenec
59
53
63
61
71
56
88
>99
52
85
N/A
30
90
58
32
In the course of our continuing research on palladium-
catalyzed reactions of aryl halides, ethyl 3-(2-aminophe-
nyl)acrylate (3a) was identified as a cross-coupling product
of the Heck reaction. Initial experiments began with 2-io-
doaniline (1a) and ethyl acrylate (2a) as model starting ma-
terials, wet Pd/C (10 wt% palladium on activated carbon
paste and 50% moisture, 10 wt% wet Pd/C based on starting
MeCNc
EtOHc
1,4-dioxanec
toluene
MeCN
material 1a) as catalyst and Et N (2.0 equiv) as base in tolu-
EtOH
3
ene at 80 °C. The product 3a was isolated with 59% yield
Et N
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
3
(Table 1, entry 1). This result encouraged us to investigate
d
Pd(OAc)
2
Et
Et
3
N
N
further our hypothesis that heterogeneous Pd/C can be ap-
plied to Heck reaction of aryl halides substituted with an
amino group. Other solvents, catalysts and bases were then
evaluated to improve the efficiency of the reaction.
d
10
11
12
PdCl
2
3
e
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
K
2
CO
Na CO
DIPEA
3
e
2
3
Firstly, acetonitrile (MeCN; Table 1, Entry 2), ethanol
13
14
(EtOH; entry 3), and 1,4-dioxane (entry 4) were tested as
Et N
e
3
solvent to improve the yield of 3a (53 63, and 61%, respec-
15
–
tively) in Pd/C-catalyzed Heck reaction of 2-iodoaniline at
a
Reaction conditions (unless noted otherwise): 1a (0.5 mmol), 2a (1.0
80 °C. Unfortunately, the results were not satisfactory, and
mmol), palladium catalyst (10 wt% palladium on activated carbon paste
and 50% moisture, 10 wt% wet Pd/C based on starting material 1a), base
the higher yield was desired. When the reaction was per-
formed at 100 °C in toluene, MeCN and EtOH (entries 5–7),
higher yields were obtained (56–88%). Pleasingly, the yield
was improved to >99% when 1,4-dioxane was used as the
solvent and the reaction mixture was heated to 100 °C (en-
try 8). The results indicated that 1,4-dioxane (at 100 °C)
was the best solvent for Pd/C-catalyzed Heck reaction of 2-
iodoanilines. Homogeneous catalysts Pd(OAc)2 and PdCl2
were also tested in 1,4-dioxane, but no more positive re-
sults were obtained (52% and 85%; entries 9 and 10). The
results indicate that the Pd/C catalyst may be more compat-
ible with the amino group of substrates.
(
2.0 equiv), solvent (3.0 mL), air, 100 °C, 20 h.
Isolated yield.
Carried out at 80 °C.
Catalyst (5.0 mol%) was used.
Base (1.0 equiv) was used.
b
c
d
e
as the base (entry 14). Notably, the Pd/C-catalyzed Heck re-
action did occur without base, but only 32% yield of 3a was
isolated (entry 15).
By the optimization of solvents, catalysts, and bases, the
best reaction conditions of Pd/C-catalyzed Heck reaction of
2-iodoanilines were established as Pd/C (10 wt%) as catalyst
To test whether Et N is necessary for the reaction, other
and Et N (2.0 equiv) as base in 1,4-dioxane at 100 °C. Based
3
3
bases and amounts were investigated. The results showed
that the reaction was inhibited in the presence of K CO (1.0
on the optimized conditions, the substrate scope of the
Pd/C-catalyzed Heck reaction of 2-iodoanilines with olefins
was tested; the results are summarized in Table 2.
2
3
equiv) or Na CO (1.0 equiv) (Table 1, entries 11 and 12). We
2
3
suggest that the catalyst may be enveloped by the solid in-
organic base and the catalytic activity was lost. The phe-
nomenon was also detected in Pd/C catalyzed hydrogena-
tion of olefins. When N-ethyl-N-isopropylpropan-2-amine
Under the optimal conditions, a variety of 2-iodoani-
lines 1a–s were subjected to the Pd/C-catalyzed Heck reac-
tion, as shown in Table 2. The 2-iodoanilines 1a–m (entries
1–13), with different substituents (Me, CF , Cl, Br, F, NO
3
2
(
DIPEA; 2.0 equiv) was employed as the organic base, a bet-
and CN) on the 4- or 5-position of the 2-iodoanilnes, react-
ed with ethyl acrylate under the optimal reaction condi-
tions, to give moderate to high isolated yields of 3a–m (64%
to >99%). The results indicated that substrates with Me, Br
or Cl gave slightly lower yields and those with electron-
withdrawing substituents, such as F, CN, NO and CF , gave
ter result was achieved (90% yield; entry 13). To some ex-
tent, the speculation that the catalytic activity was lost in
the presence of the solid inorganic base was confirmed.
Subsequently, the amount of Et N was tested and the yield
decreased dramatically when less Et N (1.0 equiv) was used
3
3
2
3
higher yields. Substrate 3-chloro-2-iodoaniline (1k), with a
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

C
Synthesis
X.-Y. Zhou et al.
Paper
bulky substituent ortho to the iodine gave the product in
4% yield after 48 hours together with recovered starting
material. Furthermore, the starting material 3-iodoaniline
1n) reacted with ethyl acrylate under the optimal reaction
conditions to give the target product with >99% yield (entry
4). The results indicate that an ortho-amino group on the
Table 2 (continued)
6
Yield (%)b
Entry
Substrate
Product
O
(
O2N
I
O2N
OEt
7
93
1
NH2
NH2
1
g
substrate is not required for the reaction. In addition, the
reaction system also can be applied to the Heck reaction of
3g
O
NC
I
2
1
-iodophenol (1o), giving the product in 84% yield (entry
5). The starting material iodobenzene (1p) was also tested
NC
OEt
8
9
>99
88
NH2
in the catalysis system and ethyl cinnamate 3p was pre-
pared with 88% yield (entry 16). The result indicated that
the amino group is not necessary for the reaction.
NH2
1
h
3
h
O
I
OEt
OEt
Table 2 Scope of the Reaction with Respect to Starting Materials 1 and
Cl
NH2
a
Cl
NH2
2
1i
3
i
O
O
I
I
OR'
Pd/C (10 wt%)
OR'
R
+
R
10
86
Br
1j
NH2
O
Et3N (2.0 equiv)
,4-dioxane, 100 °C
NH2
NH2
Br
NH2
O
1
1
2
3
3j
Cl
Cl
Entry
1
Substrate
Product
Yield (%)b
>99
I
OEt
O
1
1c
64
O
I
NH2
NH2
OEt
O
1
k
3k
NH2
NH2
1
a
Cl
I
3
a
Cl
OEt
12
98
84
Me
I
NH2
NH2
Me
OEt
OEt
OEt
OEt
Cl
2
3
4
5
6
85
96
75
76
93
Cl
1
l
NH2
3
l
NH2
1
b
3
b
O
Me
I
Me
O
OEt
F3C
I
F3C
13
NH2
NH2
O
Me
NH2
Me
NH2
1m
1
c
3m
3
c
O
I
Cl
I
Cl
OEt
14
>99
NH2
NH2
NH2
1
d
NH2
3
d
1
n
3
3
n
O
Br
I
O
O
Br
I
OEt
OEt
NH2
15
84
88
NH2
OH
I
1
e
OH
3
e
f
1o
1p
o
O
F
I
F
OEt
16
NH2
NH2
1
f
3
3p
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
Synthesis
X.-Y. Zhou et al.
Paper
Table 2 (continued)
23). The results may be caused by the low catalytic activity
of heterogeneous Pd/C catalysis system and by the low re-
activity of this type of starting material.
To test the effect of Pd/C-catalyzed Heck reaction under
scale-up conditions, 2-iodoaniline (1a) (5.0 g) was input
into the reaction and 3a was attained with 94.0% yield
Yield (%)b
Entry
Substrate
Product
O
Br
OEt
OEt
1
7
8
N/A
1
1
q
3
p
a
(4.1 g; Table 3, entry 1). Recycling of the Pd/C catalyst was
O
also assessed under the standard reaction conditions. Pleas-
ingly, the catalytic activity of Pd/C catalyst decreased only
slightly in the second and third runs (89.6% and 90.6%; en-
tries 2 and 3). The results indicate that the recyclable Pd/C
catalyst may be appropriate for the scale-up and industrial
production.
Br
1
N/A
N/A
97
NH2
NH2
r
3
NH2
NH2
O
O
O
I
OEt
1
2
2
2
9
0
1
2
3
Table 3 Test of Scale-Up Conditions and Recycling of the Pd/C Catalysta
N
N
1
1
s
3s
O
I
I
OEt
Pd/C (10 wt%)
OEt
+
OMe
O
Et N (2.0 equiv)
,4-dioxane, 100 °C
3
NH2
NH2
NH2
1
NH2
NH2
a
a
a
a
3
3
3
3
t
1a
2a
3a
Recycling run m (Pd/C)
m (1a)
m (3a)
Yield (%)b
I
t
O Bu
98
1
st
0.50 g
0.46 g
0.43 g
5.0 g
4.6 g
4.3 g
4.1 g
3.6 g
3.4 g
94.0
89.6
90.6
NH2
1
1
1
2nd
u
3rd
O
I
a
Reaction conditions: 1a (1.0 equiv), 2a (2.0 equiv), Pd/C (10 wt% palladi-
OEt
OEt
um on activated carbon paste and 50% moisture, 10 wt% wet Pd/C based
on starting material 1a), Et N (2.0 equiv), 1,4-dioxane (50 mL), air, 100 °C,
N/A
N/A
NH2
Me
3
NH2
Me
2
0 h.
Isolated yield.
b
v
O
I
In summary, the recyclable Pd/C catalyzed Heck reac-
2
tion of 2-iodoanilines and acrylate without ligand was de-
veloped and afforded 2-alkenylanilines in up to >99% yield.
The catalysis system provide a powerful means to develop
new applications for heterogeneous palladium-catalyzed
C–C, C–N, and C–O cross-coupling reactions. The heteroge-
neous Pd/C can be recovered and recycled three times.
NH2
NH2
w
a
Reaction conditions (unless noted otherwise): 1 (0.5 mmol), 2 (1.0
mmol), Pd/C (10 wt% palladium on activated carbon paste and 50% mois-
ture, 10 wt% wet Pd/C based on starting material 1), Et N (2.0 equiv), 1,4-
3
dioxane (3.0 mL), air, 100 °C, 20 h.
b
Isolated yield.
The reaction time was 48 h.
c
Commercially available reagents were used throughout without fur-
ther purification, other than those detailed below. Solvents were pur-
chased and used without further purification. Chemical shifts for H
Notably, the above optimal conditions were not appro-
priate for the Heck reaction of bromobenzene (1q), 2-bro-
mobenzene (1r), or 3-iodopyridin-4-amine (1s) (Table 2,
entries 17–19), and almost all of the starting material was
recovered.
Other acrylates, namely methyl acrylate and tert-butyl
acrylate, were investigated under the optimal reaction con-
ditions, and the corresponding products 3t and 3u were
isolated in 97% and 98% yield, respectively (Table 2, entries
1
NMR spectra are presented in ppm downfield from tetramethylsilane
(
TMS) with the solvent resonance as the internal standard. Chemical
13
shifts for C NMR are presented in ppm downfield using the central
peak of chloroform-d (δ = 77.23 ppm) as the internal standard. Cou-
pling constants (J) are reported in Hz and refer to apparent peak mul-
tiplications. Flash column chromatography was performed on silica
gel (200–300 mesh). TLC analysis was performed using glass-backed
plates coated with 0.2 mm silica.
2
0 and 21). Other olefins, such as ethyl but-2-enoate and
Synthesis of Alkenylanilines; Typical Procedure
ethyl methacrylate, were tested, but no target products
were detected under the optimal conditions (entries 22 and
A mixture of 2-iodoaniline 1 (0.50 mmol) and Pd/C (10 wt% palladium
on activated carbon paste and 50% moisture, 10 wt% wet Pd/C based
on starting material 1) in 1,4-dioxane (3 mL) was added into a Schlenk
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

E
Synthesis
X.-Y. Zhou et al.
Paper
flask (25 mL) and stirred at r.t. Ethyl acrylate (100 mg, 1.0 mmol, 2.0
Ethyl 3-(2-Amino-5-fluorophenyl)acrylate (3f)
equiv) and Et N (101 mg, 1.0 mmol, 2.0 equiv) were added and the
3
Yield: 93% (97.1 mg); light-yellow solid; mp 79–81 °C.
mixture was stirred at 100 °C until the reaction was complete. The
solvent was evaporated under reduced pressure and the residue was
purified by column chromatography.
1
H NMR (400 MHz, CDCl ): δ = 1.33 (t, J = 7.1 Hz, 3 H), 4.26 (q, J =
.1 Hz, 2 H), 6.33 (d, J = 15.8 Hz, 1 H), 6.66–6.70 (m, 1 H), 6.88–6.93
3
7
(m, 1 H), 7.07–7.10 (m, 1 H), 7.77 (d, J = 15.8 Hz, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.6, 113.2, 113.5, 118.1, 118.2,
3
Ethyl 3-(2-Aminophenyl)acrylate (3a)
1
18.3, 119.4, 138.75, 138.78, 141.2, 155.2, 157.5, 166.9.
Yield: >99% (96.0 mg); light-yellow solid; mp 75–76 °C.
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.7, 116.2, 119.2, 120.0, 120.6,
3
1
H NMR (400 MHz, CDCl ): δ = 1.33 (t, J = 7.2 Hz, 3 H), 4.26 (q, J =
3
120.9, 125.3, 125.4, 127.8, 138.5, 147.8, 166.8.
7.2 Hz, 2 H), 6.35 (d, J = 15.8 Hz, 1 H), 6.70–6.79 (m, 2 H), 7.15–7.19
19
F NMR (470 MHz, CDCl ): δ = 125.7 (m, 1 F).
(m, 1 H), 7.37–7.39 (m, 1 H), 7.80–7.85 (m, 1 H).
3
HRMS (EI): m/z [M]+ calcd for
09.0850.
C H12FNO : 209.0852; found:
11 2
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.4, 116.8, 118.2, 119.0, 120.0,
3
2
128.1, 140.0, 145.3, 167.5.
+
HRMS (EI): m/z [M] calcd for C11H13NO : 191.0946; found: 191.0942.
2
Ethyl 3-(2-Amino-5-nitrophenyl)acrylate (3g)
Yield: 93% (109.5 mg); yellow solid; mp 136–138 °C.
Ethyl 3-(2-Amino-5-methylphenyl)acrylate (3b)
1
H NMR (400 MHz, CDCl ): δ = 1.35 (t, J = 7.2 Hz, 3 H), 4.28 (q, J =
Yield: 85% (86.9 mg); light-yellow solid; mp 88–90 °C.
3
7
1
.2 Hz, 2 H), 6.48 (d, 15.8 Hz, 1 H), 6.70 (d, J = 9.0 Hz, 1 H), 7.70 (d, J =
5.7 Hz, 1 H), 8.05 (dd, J = 2.5, 15.7 Hz, 1 H), 8.31 (d, J = 2.5 Hz, 1 H).
1
H NMR (400 MHz, CDCl ): δ = 1.33 (t, J = 7.1 Hz, 3 H), 2.24 (s, 3 H),
3
4
1
.25 (q, J = 7.1 Hz, 2 H), 6.35 (d, J = 15.8 Hz, 1 H), 6.64 (d, J = 8.1 Hz,
H), 6.98–7.00 (m, 1 H), 7.20 (s, 1 H), 7.82 (d, J = 15.8 Hz, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.9, 115.4, 118.6, 121.4, 124.5,
3
126.7, 137.4, 139.4, 150.5, 166.5.
13
C NMR (100 MHz, CDCl ): δ = 14.3, 20.4, 60.4, 117.1, 117.9, 120.1,
3
HRMS (EI): m/z [M]+ calcd for C11H12N O : 236.0797; found:
128.2, 140.1, 142.8, 167.3.
2
4
236.0793.
+
HRMS (EI): m/z [M] calcd for C12H15NO : 205.1103; found: 205.1107.
2
Ethyl 3-(2-Amino-5-cyanophenyl)acrylate (3h)
Ethyl 3-(2-Amino-5-(trifluoromethyl)phenyl)acrylate (3c)
Yield: >99% (107.8 mg); yellow solid; mp 109–111 °C.
Yield: 96% (124.1 mg); light-yellow solid; mp 65–67 °C.
1
H NMR (400 MHz, CDCl ): δ = 1.34 (t, J = 7.1 Hz, 3 H), 4.27 (q, J =
3
1
H NMR (400 MHz, CDCl ): δ = 1.34 (t, J = 7.1 Hz, 3 H), 4.27 (q, J =
3
7.1 Hz, 2 H), 6.36 (d, J = 15.8 Hz, 1 H), 6.71 (d, J = 8.4 Hz, 1 H), 7.38–
7.1 Hz, 2 H), 6.40 (d, J = 15.8 Hz, 1 H), 6.74 (d, J = 8.5 Hz, 1 H), 7.38 (dd,
7.41 (m, 1 H), 7.63–7.69 (m, 2 H).
J = 8.6, 15.7 Hz, 1 H), 7.61 (s, 1 H), 7.76 (d, J = 8.6 Hz, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.9, 115.4, 118.6, 121.4, 124.5,
3
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.7, 116.2, 119.2, 120.0, 120.6,
3
126.7, 137.4, 139.4, 150.5, 166.5.
120.9, 125.3, 125.4, 127.8, 138.5, 147.8, 166.8.
HRMS (EI): m/z [M]+ calcd for C12H12N O : 216.0899; found:
2
2
19
F NMR (470 MHz, CDCl ): δ = 61.6 (s, 3 F).
3
216.0901.
HRMS (EI): m/z [M]+ calcd for C12H12F NO : 259.0820; found:
3
2
259.0821.
Ethyl 3-(2-Amino-4-chlorophenyl)acrylate (3i)
Yield: 88% (107.5 mg); light-yellow solid; mp 79–81 °C.
Ethyl 3-(2-Amino-5-chlorophenyl)acrylate (3d)
1
H NMR (400 MHz, CDCl ): δ = 1.33 (t, J = 7.1 Hz, 3 H), 4.25 (q, J =
3
Yield: 75% (92.5 mg); light-yellow solid; mp 79–81 °C.
7.1 Hz, 2 H), 6.32 (d, J = 15.8 Hz, 1 H), 6.73–6.76 (m, 2 H), 7.30 (d, J =
1
H NMR (400 MHz, CDCl ): δ = 1.33 (t, J = 7.2 Hz, 3 H), 4.26 (q, J =
8.2 Hz, 1 H), 7.74 (d, J = 15.8 Hz, 1 H).
3
7
.2 Hz, 2 H), 6.34 (d, J = 15.8 Hz, 1 H), 6.66 (d, J = 8.6 Hz, 1 H), 7.12 (dd,
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.6, 116.5, 118.59, 118.63,
3
J = 2.4, 15.8 Hz, 1 H), 7.35 (d, J = 2.4 Hz, 1 H), 7.72 (d, J = 15.8 Hz, 1 H).
1
19.4, 129.2, 136.8, 138.8, 145.9, 167.1.
HRMS (EI): m/z [M]+ calcd for C11H12ClNO2: 225.0557; found:
25.0559.
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.6, 118.0, 119.4, 121.2, 123.8,
3
127.3, 130.9, 138.5, 143.7, 166.9.
2
HRMS (EI): m/z [M]+ calcd for C11H12ClNO2: 225.0557; found:
25.0559.
2
Ethyl 3-(2-Amino-4-bromophenyl)acrylate (3j)
Yield: 86% (116.5 mg); light-yellow solid; mp 80–82 °C.
Ethyl 3-(2-Amino-5-bromophenyl)acrylate (3e)
1
H NMR (400 MHz, CDCl ): δ = 1.33 (t, J = 7.1 Hz, 3 H), 4.26 (q, J =
3
Yield: 76% (102.4 mg); light-yellow solid; mp 80–82 °C.
7.1 Hz, 2 H), 6.33 (d, J = 15.8 Hz, 1 H), 6.87–6.89 (m, 2 H), 7.22 (d, J =
1
H NMR (400 MHz, CDCl ): δ = 1.33 (t, J = 7.2 Hz, 3 H), 4.26 (q, J =
8.9 Hz, 1 H), 7.71 (d, J = 15.8 Hz, 1 H).
3
7
.2 Hz, 2 H), 6.33 (d, J = 15.8 Hz, 1 H), 6.59 (d, J = 8.5 Hz, 1 H), 7.24 (d,
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.6, 118.7, 118.8, 119.2, 122.0,
3
J = 8.6 Hz, 1 H), 7.476–7.482 (m, 1 H), 7.68–7.82 (m, 1 H).
1
25.1, 129.3, 138.9, 146.4, 167.1.
HRMS (EI): m/z [M]+ calcd for C11H12BrNO2: 269.0051; found:
69.0049.
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.6, 110.6, 118.2, 119.4, 121.7,
3
130.2, 133.7, 138.4, 144.3, 166.9.
2
HRMS (EI): m/z [M]+ calcd for C11H12BrNO2: 269.0051; found:
69.0049.
2
Ethyl 3-(2-Amino-6-chlorophenyl)acrylate (3k)
Yield: 64% (71.7 mg); light-yellow solid; mp 108–111 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
Synthesis
X.-Y. Zhou et al.
Paper
1
H NMR (400 MHz, CDCl ): δ = 1.34 (t, J = 7.1 Hz, 3 H), 4.28 (q, J =
Methyl 3-(2-Aminophenyl)acrylate (3t)
3
7
.1 Hz, 2 H), 6.46 (d, J = 16.5 Hz, 1 H), 6.62 (d, J = 8.1 Hz, 1 H), 6.82 (dd,
Yield: 97% (85.9 mg); light-yellow solid; mp 55–57 °C.
J = 7.9, 0.8 Hz, 1 H), 7.03 (t, J = 8.0 Hz, 1 H), 7.87 (d, J = 16.5 Hz, 1 H).
1
H NMR (400 MHz, CDCl ): δ = 3.80 (s, 3 H), 6.36 (d, J = 15.8 Hz, 1 H),
3
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.7, 114.6, 118.5, 123.4, 130.3,
3
6.70 (dd, J = 8.1, 0.7 Hz, 1 H), 6.77 (t, J = 7.5 Hz, 1 H), 7.13–7.21 (m,
135.2, 139.6, 146.3, 166.8.
1
H), 7.38 (dd, J = 7.8, 1.2 Hz, 1 H), 7.83 (d, J = 15.8 Hz, 1 H).
HRMS (EI): m/z [M]+ calcd for C11H12ClNO2: 225.0557; found:
25.0556.
13
C NMR (100 MHz, CDCl ): δ = 51.7, 116.7, 117.6, 118.9, 119.8, 128.1,
3
2
131.3, 140.3, 145.5, 167.7.
+
HRMS (EI): m/z [M] calcd for C10H11NO : 177.0790; found: 177.0792.
2
Ethyl 3-(2-Amino-3,5-dichlorophenyl)acrylate (3l)
Yield: 98% (127.4 mg); light-yellow solid; mp 89–91 °C.
tert-Butyl 3-(2-Aminophenyl)acrylate(3u)
1
H NMR (400 MHz, CDCl ): δ = 1.34 (t, J = 7.1 Hz, 3 H), 4.27 (q, J =
3
Yield: 98% (107.7 mg); light-yellow solid; mp 68–71 °C.
7.1 Hz, 2 H), 6.35 (d, J = 15.7 Hz, 1 H), 7.27 (dd, J = 10.4, 2.3 Hz, 2 H),
1
H NMR (400 MHz, CDCl ): δ = 1.53 (s, 9 H), 6.28 (d, J = 15.8 Hz, 1 H),
3
7.69 (d, J = 15.7 Hz, 1 H).
6.69 (d, J = 8.1 Hz, 1 H), 6.75 (t, J = 7.5 Hz, 1 H), 7.15 (m, 1 H), 7.36 (dd,
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.8, 120.9, 121.9, 122.8, 126.0,
3
J = 7.8, 1.3 Hz, 1 H), 7.73 (d, J = 15.8 Hz, 1 H).
130.2, 138.1, 140.5, 166.5.
13
C NMR (100 MHz, CDCl ): δ = 28.2, 80.4, 116.6, 118.9, 120.13,
3
HRMS (EI): m/z [M]+ calcd for C11H11ClNO2: 259.0167; found:
59.0165.
120.19, 128.1, 130.9, 139.0, 145.3, 166.6.
2
+
HRMS (EI): m/z [M] calcd for C13H17NO : 219.1259; found: 219.1255.
2
Ethyl 3-(2-Amino-3,5-dimethylphenyl)acrylate (3m)
Yield: 84% (92.3 mg); light-yellow solid; mp 70–73 °C.
Funding Information
1
H NMR (400 MHz, CDCl ): δ = 1.33 (t, J = 7.1 Hz, 3 H), 2.16 (s, 3 H),
3
2
1
.22 (s, 3 H), 4.26 (q, J = 7.1 Hz, 2 H), 6.34 (d, J = 15.7 Hz, 1 H), 6.92 (s,
H), 7.09 (s, 1 H), 7.85 (d, J = 15.7 Hz, 1 H).
The work was supported by the Youth Science and Technology Talent
Development Project in the Education Department of Guizhou Prov-
ince (Grant No.qianjiaohe KY zi [2016] number 263) and by the Inno-
vation Team of Liupanshui Normal University (Grant No.
13
C NMR (100 MHz, CDCl ): δ = 14.3, 17.6, 20.3, 60.4, 118.0, 119.6,
3
123.4, 125.9, 127.4, 133.4, 140.4, 141.3, 167.4.
LPSSYKJTD201601).
E
d
u
coaitn
D
e
p
artm
e
nt
of
G
uzhi
o
u
P
orvn
i
ce
,
Y
o
u
ht
S
ecin
c
e
a
n
d
Tech
n
o
lg
y
Taelnt
D
e
v
oelp
m
e
nt
Porejct
q(anoi
j
h
e
K
Y
zi
2[
0
1
6]
n
u
m
b
er
2
6
3nI)
n
o
v
oaitn
Te
a
m
of
Lu
i
p
a
nsh
u
i
N
orm
a
l
Unveiytrsi
L(P
S
S
Y
K
T
J
D
2
0
1
6
0
1)
+
HRMS (EI): m/z [M] calcd for C13H17NO : 219.1259; found: 219.1262.
2
Ethyl 3-(3-Aminophenyl)acrylate (3n)
Supporting Information
Yield: >99% (97.2 mg); light-yellow oil.
Supporting information for this article is available online at
1
H NMR (400 MHz, CDCl ): δ = 1.33 (t, J = 7.1 Hz, 3 H), 4.25 (q, J =
3
https://doi.org/10.1055/s-0036-1590895.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
7.1 Hz, 2 H), 6.37 (d, J = 16.0 Hz, 1 H), 6.71 (m, 1 H), 6.82 (m, 1 H), 6.93
(d, J = 7.6 Hz, 1 H), 7.16 (t, J = 7.8 Hz, 1 H), 7.59 (d, J = 16.0 Hz, 1 H).
1
3
C NMR (100 MHz, CDCl ): δ = 14.3, 60.4, 114.1, 117.1, 118.0, 118.6,
References
3
1
29.7, 135.4, 144.8, 146.6, 167.1.
(1) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Chem. Rev. 2015,
15, 9587.
+
HRMS (EI): m/z [M] calcd for C11H13NO : 191.0946; found: 191.0947.
2
1
(
2) For the application of Heck reaction, see: (a) Tietze, L. F.; Nobel,
T.; Spescha, M. J. Am. Chem. Soc. 1998, 120, 8971. (b) Dounay, A.
B.; Overman, L. E. Chem. Rev. 2003, 103, 2945. (c) Kwok, T. J.;
Virgilio, J. A. Org. Process Res. Dev. 2005, 9, 694. (d) Nicolaou, K.
C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442.
Ethyl 3-(2-Hydroxyphenyl)acrylate (3o)
Yield: 84% (80.4 mg); light-yellow solid; mp 31–33 °C.
1
H NMR (400 MHz, CDCl ): δ = 1.35 (t, J = 7.1 Hz, 3 H), 4.30 (q, J =
3
7.1 Hz, 2 H), 6.64 (d, J = 16.2 Hz, 1 H), 6.85–6.93 (m, 2 H), 7.21–7.26
(e) Martins, A.; Marquardt, U.; Kasravi, N.; Alberico, D.; Lautens,
(m, 1 H), 7.46–7.48 (m, 1 H), 8.04 (d, J = 16.2 Hz, 1 H).
M. J. Org. Chem. 2006, 71, 4937. (f) Cvetovich, R. J.; Reamer, R. A.;
DiMichele, L.; Chung, J. Y. L.; Chilenski, J. R. J. Org. Chem. 2006,
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.7, 116.4, 118.4, 120.7, 121.7,
3
129.2, 131.4, 140.6, 155.4, 168.5.
71, 8610. (g) Guthrie, D. B.; Geib, S. J.; Curran, D. P. J. Am. Chem.
+
HRMS (EI): m/z [M] calcd for C11H12O : 192.0786; found: 192.0782.
Soc. 2009, 131, 15492. (h) Brovetto, M.; Gamenara, D.; Mendez,
P. S.; Seoane, G. A. Chem. Rev. 2011, 111, 4346. (i) Pires, M. J. D.;
Poeira, P. D. L.; Purificação, S. I.; Marques, M. M. B. Org. Lett.
3
Ethyl Cinnamate (3p)
2016, 18, 3250. (j) Azcargorta, A. R.; Coya, E.; Barbolla, I.; Lete,
Yield: 88% (77.1 mg); colorless oil.
E.; Sotomayor, N. Eur. J. Org. Chem. 2016, 2054. (k) Donatoni, M.
C.; Vieira, Y. W.; Brocksom, T. J.; Rabelo, A. C.; Leite, E. R.; de
Oliveira, K. T. Tetrahedron Lett. 2016, 57, 3016. (l) Debnath, S.;
Malakar, S.; Mondal, S. Synthesis 2016, 48, 3544.
1
H NMR (400 MHz, CDCl ): δ = 1.34 (t, J = 7.1 Hz, 3 H), 4.27 (q, J =
.1 Hz, 2 H), 6.44 (d, J = 15.8 Hz, 1 H), 7.37–7.40 (m, 3 H), 7.51–7.54
3
7
(m, 2 H), 7.69 (d, J = 16.1 Hz, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 14.3, 60.5, 118.2, 128.0, 128.8, 130.2,
(3) (a) Gimbert, C.; Vallribera, A. Org. Lett. 2009, 11, 269. (b) Omote,
M.; Tanaka, M.; Tanaka, M.; Ikeda, A.; Tarui, A.; Sato, K.; Ando, A.
J. Org. Chem. 2013, 78, 6196.
3
1
34.4, 144.6, 167.0.
+
HRMS (EI): m/z [M] calcd for C11H12O : 176.0837; found: 176.0835.
2
(
4) Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reisinger, C.-P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl.
1995, 34, 1844.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

G
Synthesis
X.-Y. Zhou et al.
Paper
(
(
5) Satyanarayana, G.; Helmchen, G. Eur. J. Org. Chem. 2014, 2242.
6) Martinez, R.; Voica, F.; Genet, J.-P.; Darses, S. Org. Lett. 2007, 9,
213.
(13) For the palladium catalysis system applied in Heck reactions,
see: (a) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
(b) Mino, T.; Shirae, Y.; Sasai, Y.; Sakamoto, M.; Fujita, T. J. Org.
Chem. 2006, 71, 6834. (c) Muthumari, S.; Mohan, N.; Ramesh, R.
Tetrahedron Lett. 2015, 56, 4170. (d) Sperger, T.; Stirner, C. K.;
Schoenebeck, F. Synthesis 2017, 49, 115.
3
(
(
(
7) Liu, C.; Tang, S.; Liu, D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A.
Angew. Chem. Int. Ed. 2012, 51, 3638.
8) Nacci, V. C. A.; Monopoli, A.; Ieva, E.; Cioffi, N. Org. Lett. 2005, 7,
617.
(14) For Heck reaction under heterogeneous catalysis, see:
(a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
(b) Hajiwara, H.; Shimizu, Y.; Hoshi, T.; Suzuki, T.; Ando, M.;
Ohkubo, K.; Yokoyama, C. Tetrahedron Lett. 2001, 42, 4349.
(c) Hamza, K.; Abu-Reziq, R.; Avnir, D.; Blum, J. Org. Lett. 2004, 6,
925. (d) Perosa, A.; Tundo, P.; Selva, M.; Zinovyev, S.; Testa, A.
Org. Biomol. Chem. 2004, 2, 2249. (e) Xie, X.; Lu, J.; Chen, B.; Han,
J.; She, X.; Pan, X. Tetrahedron Lett. 2004, 45, 809. (f) Dahan, A.;
Portnoy, M. Org. Lett. 2005, 5, 1197. (g) Yin, L.; Liebscher, J.
Chem. Rev. 2007, 107, 133. (h) Jiang, X.; Sclafani, J.; Prasad, K.;
Repic, O.; Blacklock, T. J. Org. Process Res. Dev. 2007, 11, 769.
(i) Lipshutz, B. H.; Taft, B. R. Org. Lett. 2008, 10, 1329. (j) Schils,
D.; Stappers, F.; Solberghe, G.; van Heck, R.; Coppens, M.; van
den Heuvel, D.; van der Donck, P.; Callewaert, T.; Meeussen, F.
Org. Process Res. Dev. 2008, 12, 530. (k) Niembro, S.; Shafir, A.;
Vallribera, A.; Alibes, R. Org. Lett. 2008, 10, 3215. (l) Borja, G.;
Monge-Marcet, A.; Pleixats, R.; Parella, T.; Cattoën, X.; Man, M.
W. C. Eur. J. Org. Chem. 2012, 3625. (m) Liu, W.; Wang, D.; Duan,
Y.; Zhang, Y.; Bian, F. Tetrahedron Lett. 2015, 56, 1784.
9) Tian, J.; Moeller, K. D. Org. Lett. 2005, 7, 5381.
(
10) For Heck reaction in green solvents, see: (a) Carmichael, A. J.;
Earle, M. J.; Holbrey, J. D.; McCormac, P. B.; Seddon, K. R. Org.
Lett. 1999, 1, 997. (b) Vallin, K. S. A.; Emilsson, P.; Larhed, M.;
Hallberg, A. J. Org. Chem. 2002, 67, 6243. (c) Selvakumar, K.;
Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031. (d) Chandrasekhar,
S.; Narsihmulu, C.; Sultana, S. S.; Reddy, N. R. Org. Lett. 2002, 4,
4
(
(
399. (e) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751.
f) Li, S.; Lin, Y.; Xie, H.; Zhang, S.; Xu, J. Org. Lett. 2006, 8, 391.
g) Xu, H.-J.; Zhao, Y.-Q.; Zhou, X.-F. J. Org. Chem. 2011, 76, 8036.
(
11) For asymmetric Heck reactions, see: (a) Lapierre, A. J. B.; Geib, S.
J.; Curran, D. P. J. Am. Chem. Soc. 2007, 129, 494. (b) Oestreich,
M. Angew. Chem. Int. Ed. 2014, 53, 2282. (c) Yue, G.; Lei, K.;
Hirao, H.; Zhou, J. S. Angew. Chem. Int. Ed. 2015, 54, 6531.
12) For oxidative Heck reactions, see: (a) Beccalli, E. M.; Broggini,
G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318.
(
(b) Lipshutz, B. H.; Taft, B. R. Org. Lett. 2008, 10, 1329. (c) Bras, J.
L.; Muzart, J. Chem. Rev. 2011, 111, 1170. (d) He, Z.; Kirchberg,
S.; Frçhlich, R.; Studer, A. Angew. Chem. Int. Ed. 2012, 51, 3699.
(e) Izawa, Y.; Zheng, C.; Stahl, S. S. Angew. Chem. Int. Ed. 2013,
52, 3672.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G