Microwave-assisted copper-catalyzed heck reaction in PEG solvent

Article abstract of DOI:10.1055/s-2006-951523

A catalytic system made of a copper salt, potassium carbonate and PEG 3400 was developed to perform a Heck arylation under microwave activation. Copper iodide gave the best results in a short reaction time (30 min) and various substituted tert-butyl cinna

Full text of DOI:10.1055/s-2006-951523

LETTER
3029
Microwave-Assisted Copper-Catalyzed Heck Reaction in PEG Solvent
M
V
icrowave-Assist
a
e
d
Copper-C
l
atalyz
é
e
d
H
eckRe
r
action ie Declerck, Jean Martinez, Frédéric Lamaty*
Laboratoire des Aminoacides, Peptides et Protéines (LAPP), CNRS-Universités Montpellier 1 et 2, Place Eugène Bataillon,
4095 Montpellier cedex 5, France
3
Fax +33(0)467144866; E-mail: frederic.lamaty@univ-montp2.fr
Received 17 April 2006
Dedicated to Professor Richard F. Heck for the fascinating reaction he developed
We report herein our preliminary results regarding the
Heck reaction performed with a copper catalyst under mi-
crowave in PEG.
Abstract: A catalytic system made of a copper salt, potassium car-
bonate and PEG 3400 was developed to perform a Heck arylation
under microwave activation. Copper iodide gave the best results in
a short reaction time (30 min) and various substituted tert-butyl cin-
namates could be synthesized. Better results were usually obtained
after recycling the catalyst/solvent system.
The Heck reaction in the presence of a catalytic amount of
copper salts was tested in the substitution reaction be-
tween tert-butyl acrylate and phenyl iodide (Scheme 1).
Key words: Heck reaction, microwave, arylation, copper,
poly(ethylene glycol)
26–30
Since the use of microwaves
is known as a practical
heating technique which can reduce reaction times, the
Heck reaction was tested in this study at a temperature be-
tween 130 °C and 180 °C but with a short reaction time of
Discovered in the early 1970s, the Heck reaction1–3 has
become one of the most powerful synthetic method for the
3
0 minutes. PhI, tert-butyl acrylate were mixed with a
copper salt, PEG 3400 and an ionic base. The reaction
mixture was heated under microwave. When a tempera-
ture above 40 °C was reached, PEG 3400 melted and be-
came solvent of the reaction. After 30 minutes of reaction,
the mixture was cooled down, dissolved in a small amount
of CH Cl , precipitated in diethyl ether and filtered. The
4
,5
formation of carbon–carbon bonds. Since then, it has
found tremendous developments in synthetic chemistry,
as a key step in the preparation of complex organic mole-
6
cules, for the high throughput preparation of small organ-
ic molecules which can be screened for their biological
2
2
7
,8
9
activity or for the synthesis of organic materials. The
Heck reaction is associated with palladium catalysis and
as such has also promoted the use of palladium as a cata-
lyst in many organic transformations especially in cascade
expected product was obtained from the filtrate after
1
evaporation and analyzed by H NMR using CH Br as an
2
2
internal standard. The precipitate, after filtration, con-
tained a mixture of the copper salt, the solvent, the inor-
ganic base, and inorganic by-products. Different salts in
amounts of 10 mol% each were tested in poly(ethylene
glycol) 3400 and the results are presented in Table 1.
1
0–12
reactions.
Despite its efficiency, palladium is an expensive metal
and the search for other metallic catalytic systems, which
could substitute or complement the palladium catalysts
toolbox, is a valuable task. One cheaper metal which has
proved to be useful in coupling reactions is copper.1
Copper catalysis has been mostly applied to the so-called
Ullmann coupling for the formation of carbon–nitrogen
bonds. Surprisingly, only few publications are reporting
Ph
copper salt Ph
CO -t-Bu
2
3,14
PhI +
CO2-t-Bu
2
CO -t-Bu +
base
PEG 3400
microwave
Ph
1
2
3
Scheme 1
1
5–18
the use of copper catalysts in the Heck reaction.
Usu-
ally the copper-catalyzed Heck reaction is performed at
high temperature and need a long reaction time. As an on-
going project related to the use of poly(ethylene glycol)s
The first salt that was employed, copper acetylacetonate,
did not give any reaction with carbonated bases (entries 1
and 2). Better results were obtained when we moved to ac-
etate bases. A small amount of tert-butyl cinnamate (2)
was formed along with the double substitution product 3
in the case of AcOCs at higher temperature (180 °C, entry
1
9–21
(
PEG’s) as organic solvents,
we have explored the use
of copper catalyst in the Heck reaction under microwave
2
2,23
24
activation
in these alternative solvents.
PEG’s are homopolymers, which can substitute volatile
organic solvents. They present some interesting char-
acteristics, including high polarity and high boiling points
and have been used to a certain extent in substitution,
oxidation, reduction and organometallic reactions.25
Furthermore they present low toxicity.
3
). A lower temperature could be used with the ammoni-
um counter ion (entry 4) and in this case a conversion of
0% of the starting material to 2 was obtained, demon-
5
strating that catalysis in these conditions could be viable.
But from a practical point of view, the precipitation–filtra-
tion process was more efficient with a carbonated base.
Consequently, we screened more copper salts in the pres-
ence of K CO and Cs CO as a base. Copper and copper
SYNLETT 2006, No. 18, pp 3029–3032
0
3
.1
1
.2
0
0
6
2
3
2
3
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951523; Art ID: S08606ST
oxide (entries 5 and 6) did not provide any expected prod-
uct. The first copper salts to give encouraging results was
©
Georg Thieme Verlag Stuttgart · New York

3
030
V. Declerck et al.
LETTER
Table 1 Reaction Conditions for the Copper-Catalyzed Heck Reaction
Entry
Copper salt
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu
Base
Amount of 1
Temp (°C)
130
130
180
130
130
150
150
150
150
150
130
150
150
150
150
150
150
150
150
150
Yield of 2 (%)a
Yield of 3 (%)a
1
2
3
4
5
6
7
8
9
K CO
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
3
0
0
0
0
2
0
0
0
0
0
0
7
0
4
5
0
0
0
0
0
0
0
2
3
Cs CO
2
3
AcOCs
23
50
0
AcONBu4
Cs CO
2
3
CuO
K CO
0
2
3
3
3
3
3
3
CuCl2
K CO
25
23
29
29
15
51
50
34
95
59
100
91
1
2
CuBr·Me2S
CuBr
K CO
2
K CO
2
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
0
CuI
K CO
2
CuI
K CO
2
CuI
Cs CO
2 3
CuI
AcOCs
K CO
CuI
2
3
3
3
3
3
3
3
CuI
K CO
5
2
CuI
K CO
5
2
2nd cycle
3rd cycle
Cu(acac)2
K CO
5
2
K CO
5
2
K CO
5
2
2
2nd cycle
K CO
5
53
2
a
1
Yields were calculated by H NMR using CH Br as an internal standard.
2
2
copper dichloride with 25% of conversion to 2 (entry 7). when we tested the reaction in a second cycle, by using
Very similar results were obtained with other copper ha- again the precipitate obtained from a first experiment and
lides (entries 8–10) at 150 °C. Dropping the temperature charging it with the base and starting materials, excellent
to 130 °C decreased the yield to 15% (entry 11) while yields were always reached (entry 17). A third cycle could
switching from K CO to Cs CO (entry 12) afforded 51% be performed and the catalytic activity was maintained
2
3
2
3
of 2 along with a small amount of 3. AcOCs gave a similar (entry 18) but the catalyst/solvent mixture became more
result (entry 13).
difficult to handle due to the increasing amount of the in-
organic base and the formation of other potassium salts,
such as potassium iodide, which linger in the reaction
mixture. Since increasing the reaction time did not in-
crease the conversion, we tried also to prepare and heat the
copper salt, base and PEG mixture prior to adding the two
starting materials together, or one after the other,3 but
the results were not improved. We tested also the recy-
cling effect on the Cu(acac) /K CO system at 150 °C.
Poor results at the first cycle were achieved (entry 19).
The second cycle brought better conversion (entry 20), al-
beit inferior to the one reached the case of CuI. Since CuI,
among the other copper salts, gave the best results, this be-
came the salt of choice for this project. Other solvents
were explored, such as DMF, NMP or liquid PEG 300 but
poor results were obtained, even after a second cycle.
Since we are performing the reaction under microwave in
a sealed tube, volatile tert-butyl acrylate would vaporize
and most probably a below-equimolarity amount of 1 was
effectively present in the reaction mixture. This would
then promote further reaction of phenyl iodide with the
formed and less volatile tert-butyl cinnamate 2 to give the
product of double substitution 3. So we decided to in-
crease the amount of olefin from 1.2 to 3 equivalents (en-
try 14) then to 5 equivalents (entry 15) with respect to
phenyl iodide. The yields of 2 increased, up to 95%, with-
out formation of 3. Nevertheless repeating the same ex-
periment did not always yield such a reproducible good
result (entry 16). It seemed as if the catalytic system need-
1,32
2
2
3
1
8
ed some induction period to be fully effective. Indeed,
Synlett 2006, No. 18, 3029–3032 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Copper-Catalyzed Heck Reaction
3031
Different aryl halides were tested in the copper-catalyzed First, PhBr and PhCl were tried (entries 1 and 3) but the
3
3
Heck reaction as described in Scheme 2. Various exam- catalytic system was not reactive enough and no product
ples are presented in Table 2.
was obtained even after a second cycle (entries 2 and 4).
We then focused on substituted aryl iodides. 4-Iodoani-
sole gave a good yield of the expected product (entry 5),
while in the case of the nitro group, an excellent yield was
obtained only after recycling the catalytic system (entries
10 mol% CuI
ArX
+
CO -t-Bu
Ar
2
CO2-t-Bu
K2CO3
PEG
microwave
6
and 7). The precipitate recovered after filtration in the
Scheme 2
previous experiment (entry 7) was charged with 4-
formylphenyliodide and tert-butyl acrylate and reacted
under microwave irradiation to give the expected arylated
olefin in a quantitative yield (entry 8). In the case of p-cy-
ano or p-bromo substituents (entries 9–12), 2 cycles were
necessary to obtain good conversions of the starting mate-
rials.
Table 2 Copper-Catalyzed Heck Reaction with Different Aryl Ha-
lides
Entry Aryl halide
Product
Yield (%)a
1
2
3
4
5
PhBr
–
0
0
In conclusion, we have presented preliminary results con-
cerning the development of a new inexpensive and phos-
phine-free catalytic/solvent system, which can promote
the Heck reaction of aryl iodides under microwave activa-
tion. Removal of the copper catalyst is facilitated by pre-
cipitation and filtration of the solvent. Reaction times are
2nd cycle
PhCl
–
–
0
2nd cycle
4-MeO-C H -I
–
0
MeO
94
6
4
dramatically reduced, from the many hours usually need-
ed for the copper-catalyzed reactions1
5–18
to the half hour
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
required in this study. Further investigation to improve the
reactivity of the catalytic system, enlarge the scope and
elucidate the mechanism of this reaction is currently un-
derway in our laboratory.
6
7
8
9
0
1
4-NO -C H -I
O N
9
92
100
2
2
6
4
2
2nd cycle
2
O N
Acknowledgment
4-CHO-C H -I
OHC
6
4
We thank the CNRS and the MENRT for financial support.
References and Notes
4-NC-C H -I
NC
NC
Br
6
4
(
1) Heck, R. F. Pure Appl. Chem. 1978, 50, 691.
(2) Heck, R. F. Org. React. (N.Y.) 1982, 27, 345.
3) Heck, R. F. Palladium Reagents in Organic Syntheses;
Academic Press: London, 1985.
4) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
(
1
1
1
2nd cycle
91
2
(
3009.
4-Br-C H -I
(5) Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-i., Ed.; Wiley: New-York, 2002.
6) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int.
Ed. 2005, 44, 4442.
7) Bräse, S.; Kobberling, J.; Griebenow, N. In Handbook of
Organopalladium Chemistry for Organic Synthesis, Vol. 2;
Negishi, E.-i., Ed.; Wiley: New-York, 2002, 3031.
(8) Frànzen, R. Can. J. Chem. 2000, 78, 957.
9) Schiedel, M.-S.; Briehn, C. A.; Bauerle, P. J. Organomet.
Chem. 2002, 653, 200.
10) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem.
003, 4101.
6
4
(
2
2nd cycle
Br
84
(
CO2-t-Bu
CO2-t-Bu
3b
1
1
3-F-C H -I
100
86
6
4
(
F
(
4b
2-Me-C H -I
6 4
2
(
(
11) Negishi, E. Pure Appl. Chem. 1992, 64, 323.
12) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76,
1967.
CO2-t-Bu
Me
(
(
(
13) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004,
a
1
Yields were calculated by H NMR using CH Br as an internal stan-
2
2
248, 2337.
dard.
14) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359.
15) Iyer, S.; Ramesh, C.; Sarkar, A.; Wadgaonkar, P. P.
Tetrahedron Lett. 1997, 38, 8113.
b
Yields are given for the second cycle.
Synlett 2006, No. 18, 3029–3032 © Thieme Stuttgart · New York

3
032
V. Declerck et al.
LETTER
(
(
(
(
(
(
16) Iyer, S.; Thakur, V. V. J. Mol. Catal. A: Chem. 2000, 157,
75.
17) Li, J.-H.; Wang, D.-P.; Xie, Y.-X. Tetrahedron Lett. 2005,
6, 4941.
18) Yang, Y.; Zhou, R.; Zhao, S.; Li, Q.; Zheng, X. J. Mol.
Catal. A: Chem. 2003, 192, 303.
19) Ribière, P.; Enjalbal, C.; Aubagnac, J.-L.; Yadav-Bhatnagar,
N.; Martinez, J.; Lamaty, F. J. Comb. Chem. 2004, 6, 464.
20) Ribière, P.; Yadav-Bhatnagar, N.; Martinez, J.; Lamaty, F.
QSAR Comb. Sci. 2004, 23, 911.
21) Sauvagnat, B.; Lamaty, F.; Lazaro, R.; Martinez, J.
Tetrahedron Lett. 2000, 41, 6371.
(30) Loupy, A. C. R. Chimie 2004, 7, 103.
(31) Le Bars, J.; Specht, U.; Bradley, J. S.; Blackmond, D. G.
Langmuir 1999, 15, 7621.
(32) Thathagar, M. B.; Kooyman, P. J.; Boerleider, R.; Jansen, E.;
Elsevier, C. J.; Rothenberg, G. Adv. Synth. Catal. 2005, 347,
1965.
(33) Copper-Catalyzed Heck Reaction of Phenyl Iodide with
tert-Butyl Acrylate.
2
4
To a mixture of CuI (1.9 mg, 0.01 mmol, 0.1 equiv), finely
powdered K CO (41 mg, 0.3 mmol, 3 equiv) and PEG
2
3
3400-OH (250 mg) were added phenyl iodide (20 mg, 0.1
mmol, 1 equiv) and tert-butyl acrylate (64 mg, 0.5 mmol, 5
equiv). The resulting mixture was heated by microwave
irradiation at 150 °C (initial power 300W) for 30 min. After
cooling, the reaction mixture was solubilized in CH Cl and
(
(
(
22) Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582.
23) Diaz-Ortiz, A.; Prieto, P.; Vazquez, E. Synlett 1997, 269.
24) Chandrasekhar, S.; Narsihmulu, C.; Sultana, S. S.; Reddy,
N. R. Org. Lett. 2002, 4, 4399.
2
2
precipitated in Et O. Filtration and evaporation afforded
2
1
(
25) Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers, R. D.
Green Chem. 2005, 7, 64.
tert-butyl cinnamate (2) in 59% yield (measured by H NMR
using CH Br as internal standard). The precipitate was
2
2
(
(
26) Caddick, S. Tetrahedron 1995, 51, 10403.
27) Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J. L.; Petit, A.
Tetrahedron 1999, 55, 10851.
28) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
29) Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-
VCH: Weinheim, 2002.
reused in a similar reaction with finely powdered K CO (41
mg, 0.3 mmol, 3 equiv), phenyl iodide (20 mg, 0.1 mmol, 1
2 3
equiv) and tert-butyl acrylate (64 mg, 0.5 mmol, 5 equiv) to
1
(
(
give tert-butyl cinnamate (2) in 100% yield (measured by H
NMR using CH Br as internal standard).
2
2
Synlett 2006, No. 18, 3029–3032 © Thieme Stuttgart · New York