An efficient phosphine-free heck reaction in water using Pd(l -Proline)2 as the catalyst under microwave irradiation

Article abstract of DOI:10.1055/s-0030-1258452

The present report describes an efficient and simple protocol for phosphine-free Heck reactions in water using a Pd(l-proline)₂ complex as the catalyst under controlled microwave irradiation conditions. This methodology is versatile and provides excellent yields of products in short reaction times and minimizes costs, operational hazards and environmental pollution. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258452

PAPER
1125
An Efficient Phosphine-Free Heck Reaction in Water Using Pd(L-Proline) as
2
the Catalyst Under Microwave Irradiation
Bharat Kumar Allam, Krishna Nand Singh*
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-221005, India
Fax +91(542)2368127; E-mail: knsinghbhu@yahoo.co.in
Received 3 December 2010; revised 25 January 2011
However, despite all these developments on catalyst de-
Abstract: The present report describes an efficient and simple pro-
sign, polar aprotic solvents still remain the preferred me-
dium for carrying out Heck reactions. Driven by
tocol for phosphine-free Heck reactions in water using a Pd(L-pro-
line)2 complex as the catalyst under controlled microwave
irradiation conditions. This methodology is versatile and provides environmental concerns, much effort has been directed to-
excellent yields of products in short reaction times and minimizes wards using water as the solvent for organic reactions.1
6–19
costs, operational hazards and environmental pollution.
Water offers practical advantages over organic solvents as
Key words: Heck reaction, palladium, Pd(L-proline) , microwave it is cheap, readily available, nontoxic and nonflammable.
2
irradiation, phosphine-free
Rapid synthesis using microwave irradiation has attracted
a great deal of attention and is characterized by spectacu-
lar accelerations in reaction rates, milder conditions,
Palladium-catalyzed coupling of alkenes with aryl, benzyl
and vinyl halides, a procedure known as the Heck reac-
shorter reaction times, higher yields and selectivity, and
20–26
enhanced product purities.
1
,2
tion, has continued to attract a great deal of attention
from the chemical community because of its versatility
In view of the above, and as a part of our ongoing interest
on microwave-assisted organic synthesis (MAOS),27 we
3
and the range of products that can be formed. The Heck
describe herein the first use of the Pd(L-proline) complex
2
reaction has found widespread use in the synthesis of nat-
ural products, pharmaceuticals, polymers, dendrimers and
various conjugated architectures of interest in materials
as an air-stable, efficient and water-soluble catalyst for the
controlled microwave-assisted arylation and benzylation
of alkenes in the presence of tetrabutylammonium bro-
mide and sodium acetate in water. The procedure does not
require phosphorus ligands or toxic organic solvents
4
science. Unlike other C–C bond forming reactions that
involve a polar addition, the Heck reaction tolerates many
sensitive functionalities such as unprotected amino, hy-
droxy, aldehyde, ketone, carboxy, ester, cyano and nitro
(
Scheme 1).
1
groups. A major challenge in this area is the development
R2
R2
H
of new Heck reaction catalysts with higher efficiency and
enhanced reactivity. Significant advances have been made
to meet these goals, which include the use of phospho-
Pd(L-proline)2, TBAB
R1
a–e
X
+ HX
+
NaOAc (10 mol%), H O
MW (200–300 W)
2
1
R3
R3
R1
2
a–i
80–140 °C, 10–50 min
3a–p
5
,6
7
8
9,10
rus, nitrogen, sulfur and carbene-based ligands.
R1 = aryl, benzyl
All of these catalyst systems, however, suffer from draw-
backs of one kind or another. These include sensitivity to-
wards air and moisture, tedious multi-step syntheses, high
costs of the ligands, and the requirement to use various ad-
X = Cl, Br, I
2
R = COOMe, COOEt, CN, COOn-Bu,
COOt-Bu, n-Hex, Ph
3
R = H, Ph
2
3
R –R = -(CH ) -
2
4
1
1
ditives. As a result, much attention has been devoted to
develop milder and operationally simpler procedures for
the Heck reaction. Some important developments include
the use of ligand-free palladium catalysts in combination
with tetraalkylammonium salts, palladacycles, pincer and
supported palladium catalysts, bulky electron-rich phos-
phines and N-heterocyclic carbene (NHC) complexes of
Scheme 1 Heck reaction between aryl/benzyl halides and various
alkenes
The Pd(L-proline) complex was prepared in quantitative
2
yield by reacting palladium(II) acetate, L-proline and tri-
ethylamine in methanol, at room temperature, under a ni-
trogen atmosphere. The product was characterized from
spectral data.
1
2
palladium. Reetz et al. have shown that palladium(II) ac-
etate [Pd(OAc) ] in combination with tetrabutylammoni-
2
um bromide (TBAB) gives rise to nanometric palladium In order to optimize the conditions for the Heck reaction a
colloids which are the actual catalysts under the so-called detailed study was undertaken by varying different pa-
Jeffery conditions.1
3–15
rameters. Iodobenzene and methyl acrylate were em-
ployed as model substrates in water as the reaction
medium. The results are presented in Table 1. Initial at-
tempts using 0.5 mol% of Pd(L-proline)2 and a micro-
wave power of 160 W for five minutes at 80 °C or 120 °C
resulted in no observable conversion (Table 1, entries 1
SYNTHESIS 2011, No. 7, pp 1125–1131
Advanced online publication: 01.03.2011
DOI: 10.1055/s-0030-1258452; Art ID: T50910SS
Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1
©

1
126
B. K. Allam, K. N. Singh
PAPER
and 2). The addition of varying amounts of tetrabutylam- (94%, Table 1, entry 16) being obtained. Further variation
monium bromide and changing the temperature did not of the microwave power, temperature, and reaction time
bring about any change in the reaction profile (Table 1, did not improve the yield of the product. These results re-
entries 3–6). However, when the amounts of Pd(L-pro- veal the high activity of the catalytic system used in the
line) and tetrabutylammonium bromide were increased to present study.
2
1
mol% and 50 mol%, respectively, a 15% yield of alkene
a was obtained (Table 1, entry 7). With the aim of en-
Subsequently, aryl and benzyl halides 1a–e underwent the
Heck reaction with activated and unactivated olefins 2a–i
3
hancing the product yield further, the concentration of tet-
rabutylammonium bromide was increased to 100 mol%,
and this resulted in an improved 25% yield of the product
in a molar ratio of 1:2 using Pd(L-proline) (1.0 mol%),
2
tetrabutylammonium bromide (100 mol%) and sodium
acetate (10 mol%) in water, using a safe pressure regula-
tion pressurized vial with a ‘snap-on’ cap. The microwave
(
Table 1, entry 8).
The effects of varying the microwave power, temperature power, temperature and reaction time were all varied
and time were also studied. Irradiation at 200 W and 80 °C (Table 2). After completion of the reaction, the resulting
for 10 minutes afforded a 37% yield of alkene 3a (Table 1, products 3a–p were isolated and purified by column chro-
entry 9). Finally, varying the concentration of the base matography and then characterized based on their physi-
(
NaOAc) resulted in the optimum yield of the product cal and spectral data.
Table 1 Optimization of the Model Reaction Conditions under Microwave Irradiation in Water
Entry
Pd(L-Proline) (mol%)
TBAB (mol%) NaOAc (mol%) Power (W)
Temp (°C)
80
Time (min)
Yield (%)a
2
1
2
3
4
5
6
7
8
9
0.5
0.5
0.5
0.5
0.5
0.5
1
0
0
0
0
160
160
160
160
160
160
160
160
200
200
300
200
200
200
200
200
200
300
200
200
200
200
200
5
5
–
120
80
–
50
0
5
–
50
0
120
80
5
–
100
100
50
0
5
–
0
120
80
5
–
0
5
15
25
37
35
36
50
63
72
79
94
68
92
94
90
91
93
94
1
100
100
100
100
100
100
100
100
100
100
100
100
100
200
100
100
0
80
5
1
0
80
10
10
10
10
10
10
10
10
10
10
10
10
10
20
10
1
1
1
1
1
1
1
1
1
1
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
1
0
100
80
1
0
1
1
80
1
3
80
1
5
80
1
7
80
1
10
10
10
20
10
10
10
10
80
1
60
1
80
1
80
1
100
80
1
1
80
2
2
80
a
Yield based on iodobenzene.
Synthesis 2011, No. 7, 1125–1131 © Thieme Stuttgart · New York

PAPER
Pd(L-Proline) -Catalyzed Heck Reaction in Water
1127
2
a
Table 2 Pd(L-Proline) -Catalyzed Heck Reaction of Aryl and Benzyl Halides with Alkenes 2a–i
2
R2
Entry
1
R1
Power (W) Temp (°C) Time (min) Product
Yield (%)b
X
R3
O
I
COOMe
200
80
10
94
Me
O
2
a
1
a
3
a
O
I
I
I
2
3
4
COOEt
CN
200
200
200
110
110
120
20
25
20
90
92
91
Et
O
2
2
2
b
1
1
1
a
a
a
3
b
N
c
3c
O
O
COOn-Bu
n-Bu
d
3
d
O
I
5
6
COOt-Bu
COOMe
300
300
125
135
25
35
89
87
t-Bu
O
2
2
e
1
1
a
3
e
O
Br
Me
O
a
b
3
a
O
Br
Br
Br
7
8
9
COOEt
CN
300
300
300
140
135
135
50
30
35
83
85
86
Et
O
2
2
2
b
1
1
1
b
b
b
3
b
N
c
3c
O
O
COOn-Bu
n-Bu
d
3
d
O
Br
1
1
0
1
COOt-Bu
COOMe
300
300
140
130
40
20
85
88
t-Bu
O
2
2
e
1
b
3
e
O
OHC
Br
Me
O
CHO
a
1
c
3
f
O
OHC
Br
Br
1
1
2
3
COOEt
CN
300
300
130
130
35
30
87
85
Et
O
CHO
2
b
c
1
c
3
g
N
OHC
CHO
2
1
c
3h
Synthesis 2011, No. 7, 1125–1131 © Thieme Stuttgart · New York

1
128
B. K. Allam, K. N. Singh
PAPER
a
Table 2 Pd(L-Proline) -Catalyzed Heck Reaction of Aryl and Benzyl Halides with Alkenes 2a–i (continued)
2
R2
Entry
R1
Power (W) Temp (°C) Time (min) Product
Yield (%)b
X
R3
O
O
OHC
Br
1
4
COOn-Bu
300
125
20
86
n-Bu
CHO
2
d
1
c
3
i
I
79c
77c
1
1
5
6
300
300
135
135
25
25
1
1
a
3j
2
f
f
Br
b
3j
2
I
1
1
1
7
8
9
300
300
300
135
135
135
20
25
25
90
1
1
a
2g
2g
2g
3
3
3
k
Br
85c
87
b
k
l
OHC
Br
CHO
1
c
I
2
2
0
1
300
300
140
140
15
25
86
83
2
h
h
1
1
a
3m
Br
2
b
3
m
O
2
2
2
2
2
3
4
5
COOMe
COOEt
COOMe
COOEt
300
300
300
300
135
135
135
135
20
20
30
30
80c
84c
78c
81c
Me
Br
O
2a
2b
2a
2b
1
1
1
1
d
d
e
3
n
O
Et
Br
Cl
Cl
O
3o
O
Me
O
3
n
O
Et
O
e
3o
O
O
Et
I
Et
2
6
200
130
20
86
O
1
a
O
2
i
3
p
Synthesis 2011, No. 7, 1125–1131 © Thieme Stuttgart · New York

PAPER
Pd(L-Proline) -Catalyzed Heck Reaction in Water
1129
2
a
Table 2 Pd(L-Proline) -Catalyzed Heck Reaction of Aryl and Benzyl Halides with Alkenes 2a–i (continued)
2
R2
Entry
R1
Power (W) Temp (°C) Time (min) Product
Yield (%)b
X
R3
O
O
Et
Br
Et
2
7
200
130
25
84
O
1
b
O
2
i
3
p
a
b
c
Aryl/benzyl halide 1 (1 mmol), alkene 2 (2 mmol), Pd(L-proline) (0.01 mmol), TBAB (1 mmol), NaOAc (0.1 mmol).
Isolated yield after column chromatography based on aryl/benzyl halide 1.
Reaction conducted with 0.3 mmol of base.
Yield corresponds to E-isomers only.
2
d
In conclusion, we have demonstrated a novel application taining H
O (1 mL). The vial was sealed with a ‘snap-on’ cap and
irradiated in a single-mode CEM microwave reactor at 200–300 W
and 80–140 °C for 10–50 min. After the reaction was complete
2
of the Pd(L-proline) complex as an air-stable and water-
2
soluble catalyst for efficient phosphine-free Heck reac-
tions under controlled microwave irradiation in water.
This simple method offers advantages in terms of product
yield, versatility, low catalyst concentration and minimi-
zation of environmental pollution.
(
TLC monitoring), the mixture was allowed to cool to r.t. and then
extracted with EtOAc (3 × 10 mL). The combined organic phase
was dried over Na SO , filtered and the solvent removed under vac-
uum. The residue was purified by column chromatography to afford
the pure product.
2
4
2
8
Butyl (2E)-3-Phenylprop-2-enoate (3d)
All chemicals were obtained from Aldrich, USA, and E. Merck,
Germany and were purified prior to use. IR spectra were recorded
on a JASCO FT/IR-5300 spectrophotometer. NMR spectra were
run on a JEOL AL300 FTNMR spectrometer; chemical shifts are
given in ppm relative to TMS as the internal standard. Microwave
irradiation was carried out using a CEM Discover Bench Mate sin-
gle-mode microwave synthesis system in a safe pressure regulation
1
H NMR (300 MHz, CDCl ): d = 0.97 (t, J = 7.3 Hz, 3 H), 1.40–1.50
m, 2 H), 1.67–1.74 (m, 2 H), 4.21 (t, J = 6.6 Hz, 2 H), 6.44 (d,
3
(
J = 16.0 Hz, 1 H), 7.37–7.40 (m, 3 H), 7.51–7.54 (m, 2 H), 7.68 (d,
J = 16.0 Hz, 1 H).
1
3
C NMR (75 MHz, CDCl ): d = 13.7, 19.2, 30.8, 64.4, 118.3, 128.0,
3
1
28.8, 130.2, 134.5, 144.5, 167.0.
1
0 mL pressurized vial with a ‘snap-on’ cap. Thin-layer chromatog-
2
9
Cyclohex-1-enylbenzene (3j)
raphy (TLC) was performed using silica gel 60 [Kieselguhr F254 pre-
coated on aluminium sheets (thickness 0.2 mm)], commercially
available from Merck. The visualization of spots on TLC plates was
effected by UV illumination or exposure to iodine. Column chroma-
tography was performed using commercial (Merck) column chro-
matography grade silica gel (60–120 mesh) using mixtures of
EtOAc and hexane as eluting agent.
1
H NMR (300 MHz, CDCl ): d = 1.67–1.71 (m, 2 H), 1.76–1.82 (m,
H), 2.22–2.23 (m, 2 H), 2.44–2.47 (m, 2 H), 6.14 (br s, 1 H), 7.21–
.42 (m, 5 H).
3
2
7
1
3
C NMR (75 MHz, CDCl ): d = 22.1, 23.0, 26.0, 27.3, 124.7, 124.8,
3
126.6, 128.2, 136.6, 142.7.
4
-[(E)-2-Phenylethenyl]benzaldehyde (3l)30
H NMR (300 MHz, DMSO-d ): d = 7.26–7.50 (m, 5 H), 7.65 (d,
J = 7.3 Hz, 2 H), 7.80 (d, J = 8.3 Hz, 2 H), 7.91 (d, J = 8.3 Hz, 2 H),
1
Pd(L-Proline)2
6
Et N (0.6 mL, 600 mL) was added to a vigorously stirred soln of L-
proline (4.34 mmol, 499 mg) in MeOH (10 mL). After 30 min,
Pd(OAc) (2.17 mmol, 487 mg) was added and the mixture was
stirred under an N atm for 5 h at r.t. After the reaction was com-
3
10.01 (s, 1 H).
13
2
C NMR (75 MHz, DMSO-d ): d = 126.9, 127.2, 128.7, 130.0,
31.9, 135.0, 136.5, 142.9, 192.3.
6
2
1
plete, the precipitated complex was filtered, washed with MeOH (2
×
2 mL) and dried to afford Pd(L-proline) in quantitative yield.
2
1E)-Oct-1-enylbenzene (3m)31
(
1
IR (KBr): 3447, 3075, 2934, 2862, 2510, 1624, 1442, 1351, 1311,
H NMR (300 MHz, CDCl ): d = 0.86 (t, J = 6.0 Hz, 3 H), 1.20–
3
–
1
1
213, 1082, 929, 863, 777, 649, 545 cm .
1.37 (m, 8 H), 2.15–2.24 (m, 2 H), 6.23 (dt, J = 16.0, 6.6 Hz, 1 H),
6.40 (d, J = 16.0 Hz, 1 H), 7.21–7.37 (m, 5 H).
1
H NMR (300 MHz, D O): d = 1.61 (br s, 2 H), 1.75–2.01 (br m, 4
2
1
3
H), 2.09–2.12 (br m, 2 H), 3.03 (br s, 4 H), 3.70–3.88 (br m, 2 H).
C NMR (75 MHz, CDCl ): d = 14.0, 22.7, 28.8, 29.4, 31.8, 33.0,
3
1
3
125.9, 126.8, 128.0, 128.5, 128.9, 129.7, 131.2.
C NMR (75 MHz, D O): d = 25.6, 25.8, 30.4, 30.8, 52.1, 53.7,
2
6
4.5, 65.9, 187.5, 189.1.
3
2
Methyl (3E)-4-Phenylbut-3-enoate (3n)
1
H NMR (300 MHz, CDCl ): d = 3.24 (dd, J = 7.0, 1.4 Hz, 2 H),
Microwave-Assisted Heck Reaction; General Procedure
A mixture of aryl/benzyl halide 1 (1 mmol), alkene 2 (2 mmol),
Pd(L-proline) complex (0.01 mmol, 3 mg, 1 mol%), TBAB (1
mmol, 322 mg, 100 mol%) and NaOAc (0.1 mmol, 8 mg, 10 mol%)
was placed in a safe pressure regulation 10 mL pressurized vial con-
3
3
.71 (s, 3 H), 6.30 (dt, J = 16.0, 7.2 Hz, 1 H), 6.48 (dt, J = 16.0, 1.3
Hz, 1 H), 7.02–7.46 (m, 5 H).
2
1
3
C NMR (75 MHz, CDCl ): d = 38.1, 51.7, 121.5, 126.3, 127.4,
3
128.5, 133.5, 136.6, 172.0.
Synthesis 2011, No. 7, 1125–1131 © Thieme Stuttgart · New York

1
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B. K. Allam, K. N. Singh
PAPER
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122, 9058.
(
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