Tetramethylguanidine as an inexpensive and efficient ligand for the palladium-catalyzed Heck reaction

Article abstract of DOI:10.1055/s-2005-871581

An inexpensive and efficient Pd(OAc)₂/tetramethylguanidine (TMG) or PdCl/TMG catalytic system has been developed for the Heck reaction of an olefin with an aryl halide. The TONs were up to 1000000 when iodobenzene was used as the substrate with butyl acrylate as the reactant. In addition, [Pd(TMG)₄]Cl₂(H₂O)₈, an air-stable compound, effectively promoted the Heck reaction, which demonstrated that TMG acted as a ligand in this reaction system. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871581

LETTER
1885
Tetramethylguanidine as an Inexpensive and Efficient Ligand for the
Palladium-Catalyzed Heck Reaction
T
etramethylgu
h
anidine –A
e
L
igandfor
n
the
H
eck
R
ea
g
ction hai Li,b Haibo Xie,a Suobo Zhang,*a Yingjie Lin,b Jianing Xu,b Jungang Caob
a
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Graduate School of Chinese Academy of Sciences, Changchun 130022, P. R. China
b
College of Chemistry, Jilin University, Changchun 130023, P. R. China
E-mail: sbzhang@ciac.jl.cn
Received 6 May 2005
coordination complex [Pd(TMG)4]Cl2 was published by
Drago in 1965.10
Abstract: An inexpensive and efficient Pd(OAc)2/tetra-
methylguanidine (TMG) or PdCl2/TMG catalytic system has been
developed for the Heck reaction of an olefin with an aryl halide. The
TONs were up to 1000000 when iodobenzene was used as the
substrate with butyl acrylate as the reactant. In addition,
[Pd(TMG)4]Cl2(H2O)8, an air-stable compound, effectively pro-
moted the Heck reaction, which demonstrated that TMG acted as a
ligand in this reaction system.
We first tested the catalytic activity of Pd(OAc)2/TMG in
the Heck reaction between styrene and bromobenzene,
and the results are summarized in Table 1. No conversion
was observed when Et3N was used as the base (Table 1,
entry 1). However, when several inorganic bases were
used in place of Et3N, all the reactions examined led to
some conversion, and NaOAc gave the best result. Thus,
when using Pd(OAc)2 (0.1 mol%)/TMG (0.4 mol%) as
catalyst and NaOAc as base in N,N-dimethylacetamide
(DMA) at 140 °C for 20 hours, the coupling of bromo-
benzene with styrene gave the product in 99% yield as a
trans-stilbene (>95% selectivity). In the absence of TMG,
a 66% yield of the corresponding coupling product was
obtained (Table 1, entry 5). Decreasing the catalyst load-
ing to 0.01 mol% still resulted in quantitative conversion
and high selectivity, even though the reaction times were
prolonged to 40 hours. When the catalyst loading was re-
duced to 0.0004 mol%, the yield was poor even when the
reaction time was extended. Noteworthy is that PdCl2 (0.1
mol%)/TMG (0.4 mol%) gave the same result as
Pd(OAc)2/TMG (Table 1, entry 10).
Key words: tetramethylguanidine, Heck reaction, palladium, aryl
halides, ligand
The palladium-catalyzed coupling of olefins with aryl or
vinyl halides, known as the Heck reaction,1 is one of the
most versatile tools for carbon–carbon bond formation in
organic synthesis. This reaction has attracted considerable
attention because it presents one of the simplest ways to
obtain variously substituted olefins, dienes, and other un-
saturated compounds, many of which are useful as dyes,2
pharmaceuticals, etc. The Heck reaction is typically per-
formed with 1–5 mol% of a Pd catalyst along with
phosphine3 or phosphorus4 ligands in the presence of a
suitable base. Phosphine ligands are expensive, toxic, and
unrecoverable; therefore, the development of a phos-
phine-free Pd catalyst is a topic of enormous interest. To
date, there have been a number of reports on sulfur-based
palladacyles,5 selenium-based catalysts,6 nitrogen-based
catalysts,7 and nucleophilic carbene ligands8 as catalyst
systems in relation to the development of the Heck reac-
tion. However, most of these new ligands are not commer-
cially available and some are cumbersome to synthesize.
It is desirable to have simple, inexpensive, easily pre-
pared, and stable catalysts for these reactions.
A search for the most appropriate solvent for this reaction
led us to conclude that the reaction rates were solvent-de-
pendent. Though numerous solvents could be used, polar
solvents such as DMF and DMA proved to be most effec-
tive (Table 2), with DMA as the solvent of choice. It is
believed that the high solvent polarity of DMA helps
solubilize all catalytic components and this is the principal
influence of the solvent in the present reaction.
After establishing the high catalytic efficiency of the
PdCl2/TMG-system in the Heck reaction, we next exam-
ined the coupling of other representative aryl halides with
different olefins, and the results are summarized in
Table 3. As expected the activated substrates such as
iodobenzene or bromobenzene with electron-withdrawing
groups reacted very smoothly. When iodobenzene was
used as the substrate with butyl acrylate, a yield of 42%
was still achieved even when the Pd loading was reduced
to 0.00004 mol%; the TON could be up to 1000000
(Table 3, entry 4). For the reaction between activated aryl
bromides (Table 3, entry 11, 12) and styrene, quantitative
conversions were observed with a Pd loading of 0.1 mol%
and a reaction time of 20 hours. 3-Bromopyridine was
also efficiently coupled with styrene to afford the desired
Tetramethylguanidine HN=C[N(CH3)2]2 (TMG) is an or-
ganic base, this material has attracted much attention in
organic synthesis,9 due to the multiplicity of coordination
positions present and its strongly basic character. A com-
parison of the structure of TMG with phosphines led us to
test the effectiveness of TMG as a ligand in the Heck
reaction. To the best of our knowledge, TMG has not been
reported as ligand for the Heck reaction, although the
SYNLETT 2005, No. 12, pp 1885–1888
0
1
.0
8
.2
0
0
5
Advanced online publication: 07.07.2005
DOI: 10.1055/s-2005-871581; Art ID: U13605ST
© Georg Thieme Verlag Stuttgart · New York

1886
S. Li et al.
LETTER
Table 1 Pd-Catalyzed Heck Reaction of Bromobenzene and Styrenea
Ph
Ph
Pd(OAc)2/TMG
Ph
Ph
Ph
+
+
PhBr
Ph
+
Ph
Base, DMA, 140 °C
X
Y
Z
Entry
Catalyst (mol%)
Base
T (h)
20
20
20
20
20
20
40
24
72
20
Yield (%)b
TON
0
1
2
0.1
Et3N
0
39
51
99
66
75
99
67.8
15
99
0.1
K3PO4
K2CO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
390
3
0.1
510
4
0.1
990
5c
6
0.1
660
0.01
7500
9900
17000
40000
990
7
0.01
8
0.004
9
0.0004
10
PdCl2 (0.1)/TMG
a Unless otherwise indicated, the reaction conditions were as follows: Pd(OAc)2/TMG (1:4), bromobenzene (5 mmol), styrene (6 mmol), base
(6 mmol), DMA (5 mL), 140 °C.
b trans-Stilbene > 95%, [GC, diethyleneglycol–Bu2O as the internal standard].
c No TMG added.
product in 92% yield (0.1 mol% Pd). When the catalyst that the addition of TMG resulted in a highly efficient
loading was increased (0.5 mol%), a remarkably high Heck reaction.
yield (90%) in the reaction between 4-methyl-bromoben-
To figure out the precise function of TMG in the Heck
zene and styrene could be achieved although 4-methyl-
reaction, the compound [Pd(TMG)4]Cl2(H2O)8 was syn-
bromobenzene is a deactivated aryl bromide; this was the
thesized from one equivalent of PdCl2 and four equiva-
best result when compared with the reports in the litera-
lents of TMG in dichloromethane at room temperature,
ture on nitrogen-based catalysts.7b,k Aryl chlorides with
according to the literature method.10 Single crystals of
electron-withdrawing groups were also effective in these
[Pd(TMG)4]Cl2(H2O)812 were obtained by slow diffusion
system, we found that when 4-nitrochlorobenzene reacted
of hexane into a dichloromethane solution of PdCl2/TMG.
with butyl acrylate, the yield was up to 90% in the absence
Its molecular structure is shown in Figure 1. The complex
of additives [such as N(Bu)4Br11]. The results indicated
[Pd(TMG)4]Cl2(H2O)8 was used in the coupling of aryl
halide and olefin. We found that similar results were ob-
tained (Table 2, entry 20, 21, 22) when compared with
those of PdCl2/TMG. This implies that TMG might act as
a ligand to stabilize the Pd(0) species during the course of
Table 2 Effect of the Solvent on Pd-Catalyzed Heck Reaction of
Bromobenzene and Styrenea
Pd(OAc)2/TMG
Ph
PhBr
+
Ph
Ph
the reaction.
NaOAc, 140 °C
Entry
Solvent
Yields (%)b
1
2
3
4
5
6
DMSO
76
92
99
81
21
83
DMF
DMA
Dioxane
CH3CN
Ethylene glycol
a Reaction conditions: bromobenzene (5 mmol), styrene (6 mmol),
NaOAc (6 mmol), catalyst (0.1 mol%), Pd(OAc)2/TMG (1:4), solvent
(5 mL), 140 °C.
b GC yield [diethyleneglycol–(Bu)2O as GC standard]; average of two
runs.
Figure 1 The molecular structure of [Pd(TMG)4]Cl2(H2O)8.
Hydrogen atoms and H2O are omitted for clarity.
Synlett 2005, No. 12, 1885–1888 © Thieme Stuttgart · New York

LETTER
Tetramethylguanidine – A Ligand for the Heck Reaction
1887
Table 3 PdCl2/TMG-Catalyzed Heck Reaction of Aryl Halides and Olefinsa,13
PdCl2/TMG
Ar
Ar-X
+
R
R
DMA, NaOAc, 140 °C
Entry
1
Aryl halide
R
Catalyst (mol%)
0.1
T (h)
2
Yield (%)b
100
100
81
TON
1000
PhI
CO2Bu
CO2Bu
CO2Bu
CO2Bu
Ph
2
PhI
0.01
0.0004
0.00004
0.004
0.01
0.1
5
10000
200000
1000000
24000
9200
990
3
PhI
30
56
24
2
4
PhI
42
5c
PhI
96
6c
PhI
CO2Bu
Ph
92
7
PhBr
20
20
20
20
20
20
30
20
35
35
20
20
20
20
20
20
99
8
p-MeC6H4Br
p-MeC6H4Br
p-MeC6H4Br
p-(CHO)C6H4Br
p-NO2C6H4Br
p-NO2C6H4Br
p-NO2C6H4Br
p-NO2C6H4Cl
p-NO2C6H4Cl
PhCl
Ph
0.1
65
650
9
Ph
0.5
90
180
10
11
12
13
14
15
16
17
18
19
20d
21d
22d
CO2Bu
Ph
0.1
76
760
0.1
96
960
CO2Bu
CO2Bu
Ph
0.1
100
96
1000
24000
10000
8000
9000
360
0.004
0.01
0.01
0.01
0.1
100
80
Ph
CO2Bu
Ph
90
36
3-Br-Pyridine
3-Br-Pyridine
PhBr
CO2Bu
Ph
0.1
98
980
0.1
92
920
Ph
0.1
99
990
p-MeC6H4Br
p-NO2C6H4Cl
CO2Bu
Ph
0.1
82
820
0.1
92
920
a Unless otherwise indicated, the reaction conditions were as follows: aryl halide (5 mmol), olefin (6 mmol), NaOAc (7.5 mmol), PdCl2/TMG
(1:4), DMA (5 mL), 140 °C.
b Average of isolated yields of two runs.
c trans-Stilbene > 95%, trans-cinnamic acid butyl ester >99% (GC, diethyleneglycol–Bu2O as the internal standard).
d [Pd(TMG)4]Cl2(H2O)8 as catalyst.
In summary, an air-stable, inexpensive, and easily pre- a ligand to stabilize the Pd(0) species in the Heck reaction.
pared TMG/Pd catalyst has been developed for the Heck Further studies aimed at the utility of these catalysts in Pd-
reaction of aryl halide with terminal olefins. TONs could catalyzed reactions are in progress.
be up to 1000000 for the reaction of iodobenzene with
butyl acrylate. This nitrogen-based catalyst showed a high
activity when aryl bromides and actived aryl chlorides
Acknowledgment
We thank the National Science Foundation of China (No.
20474061) for financial support.
were used as substrates. Furthermore, TMG might act as
Synlett 2005, No. 12, 1885–1888 © Thieme Stuttgart · New York

1888
S. Li et al.
LETTER
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(13) Typical Procedure for the Heck Reaction: An oven-dried
Schlenk flask was charged under N2 with styrene (6.0
mmol), bromobenzene (5.0 mmol), and NaOAc (6.0 mmol).
A solution of catalyst Pd(OAc)2/TMG (1:4) or PdCl2/TMG
(1:4) in DMA (5.0 mL, 1.0 × 10–6 M) was then added via
syringe. The flask was sealed and placed in a 140 °C oil bath
and stirred for 20 h. The course of the reaction was
monitored by periodically taking samples and analyzing
them by gas chromatography [di(ethylene glycol)–Bu2O as
internal standard]. After cooling to r.t., the reaction mixture
was poured into H2O (50 mL) and extracted with EtOAc
(3 × 40 mL). The combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated. Purification
by flash chromatography on silica gel (hexanes–CH2Cl2,
1:1) gave trans-stilbene (859 mg, 95.5%), estimated to be
>99% pure by 1H NMR and GC.
Synlett 2005, No. 12, 1885–1888 © Thieme Stuttgart · New York