Poly(ethylene glycol) (PEG) as a Reusable Solvent Medium for Organic Synthesis. Application in the Heck Reaction

Article abstract of DOI:10.1021/ol0266976

(Matrix Presented) PEG has been used as a solvent medium for regioselective Heck reactions with easy recyclability of solvent and Pd catalyst for the first time.

Full text of DOI:10.1021/ol0266976

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4399-4401
Poly(ethylene glycol) (PEG) as a
Reusable Solvent Medium for Organic
Synthesis. Application in the Heck
Reaction†
S. Chandrasekhar,* Ch. Narsihmulu, S. Shameem Sultana, and
N. Ramakrishna Reddy
Organic Chemistry DiVision-I, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
sriVaric@iict.ap.nic.in
Received August 8, 2002
ABSTRACT
PEG has been used as a solvent medium for regioselective Heck reactions with easy recyclability of solvent and Pd catalyst for the first time.
Solvents are widely used in organic synthesis and have been
a cause of major concern due to their associated environ-
mental hazards. The major disadvantages are their pyrophoric
nature, volatility, and poor recovery. To address some of
these issues, attempts have been made to develop solvent-
free chemistry, which to some extent has been successful
for a few transformations.1 However, in performing the
majority of organic transformations, solvents play a critical
role in making the reaction homogeneous and allowing
molecular interactions to be more efficient. In recent times
ionic liquids have been in the forefront of research, and
several publications and reviews have already appeared.2
Even though ionic liquids offer some advantages, the tedious
preparation of ionic liquids (and raw materials for ionic
liquids) and their environmental safety is still debated. To
address the concerns raised by volatile organic solvents, we
initiated a new program to identify whether any available
liquid polymers or low melting polymers can be used as
solvents.3 We herein report the application of poly(ethylene
glycol) (PEG) having molecular weight 2000 (or lower) as
an efficient reaction medium for Pd-catalyzed C-C bond
formation, namely, the Heck reaction.4,5 We have noticed
that this transformation is more rapid and high yielding, and
the catalyst is easily recycled with high efficiency. Interest-
ingly, the stereo- and regioselectivities are also different from
those with conventional solvents and ionic liquid media. The
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M.; Ohkubo, K.; Yokoyama, C. Tetrahedron Lett. 2001, 42, 4349. (e)
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† IICT communication 020702.
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2159. (b) Toda, F.; Tanaka, K. Chem. ReV. 2000, 100, 1025. (c) Cave, G.
W. V.; Raston, C. L. Chem. Commun. 2000, 2199. (d) Toda, F. Acc. Chem.
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10.1021/ol0266976 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/21/2002

Table 1. Pd-Catalyzed Heck Reaction of Electron-Deficient and Electron-Rich Olefins in Polyethylene Glycol
1
a Yields calculated after column chromatography and characterized by H NMR and mass spectrometry.
results are presented herein. We first tested the Heck coupling
between bromobenzene (1) and ethyl acrylate, wherein both
the substrates (1:1), Pd(OAc)2 (3 mol %), and TEA (1 equiv)
were taken in PEG (MW 2000) and subjected to heating at
80 °C for 8 h. The reaction mixture was allowed to cool to
room temperature, diluted with ether, and cooled to 0 °C to
precipitate out PEG. The ether layer was characterized after
workup to identify the clean formation of ethyl cinnamate
(1a) in 90% yield and 90% purity. To further explore the
effect of the reaction medium in the Heck coupling,
bromobenzene was reacted with less reactive electron-rich
vinyl butyl ether to observe the clean formation of butyl
styryl ether (1c) with exclusive attack of aryl palladium
species at the â-carbon of butyl vinyl ether. This is in sharp
contrast to results obtained when the reaction is performed
in ionic liquids.6 Interestingly, when the reaction is conducted
in conventional solvents (DMF, DMSO, CH3CN) mixtures
of products are obtained with varying ratios.7 Thus PEG is
unique in obtaining a single regioisomer with good diaste-
reoselection (80/20 E/Z). In the third instance, bromobenzene
was reacted with styrene to isolate trans-stilbene (1b)
exclusively in 93% isolated yield.
vinyl ether. In all three cases, once again excellent regio-
and stereoselectivities were obtained (2a, 2b, and 2c). When
4-chlorobromobenzene was reacted with butyl vinyl ether
(4c), exclusive formation of E-geometrical olefin was
achieved. These results indicate that electronic factors in the
aryl system control the geometry of the olefin to a certain
extent. The other olefinic partners, styrene and ethyl acrylate,
behaved normally. In the case of naphthyl bromide (5), the
products obtained have similar selectivities as in the case of
bromobenzene. 3,4-Methylenedioxybenzene reacted well
with butyl vinyl ether to yield a single regioisomer (â attack)
with 75% diastereoselectivity of the E-isomer. In all of the
cases studied, the coupling was performed in the absence of
any ligand. Additionally, no external PTC was added as was
required in the earlier reports.8 We envisage that PEG not
only acted as an efficient solvent medium but also as a PTC
for smooth C-C bond formation.
To understand the role of PEG as a reaction medium,
bromoanisole (2) was subjected to the Heck reaction with
all the three olefins, namely, ethyl acrylate, styrene, and butyl
To check the reusability of the solvent as well as the
catalyst, after initial experimentation the reaction mixture
was extracted with dry ether9,10 and the PEG and Pd(OAc)2
(6) Xu, L.; Chen, W.; Ross, J.; Xiao, J. Org. Lett. 2001, 3, 295.
(7) (a) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S. J. Org. Chem.
1992, 57, 1481. (b) Cabri, W.; Candiani, I.; Bedeschi, A. J. Org. Chem.
1993, 58, 7421. (c) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2.
(d) Larhed, M.; Hallberg, A. J. Org. Chem. 1997, 62, 7858.
(8) (a) Morales-Morales, D.; Redon, R.; Yung, C.; Jensen, C. M. Chem.
Commun. 2000, 1619. (b) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
2719.
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Org. Lett., Vol. 4, No. 25, 2002

were solidified and subjected to a second run of the Heck
reaction by charging with the same substrates (bromoben-
zene, ethyl acrylate, and triethylamine). The results of this
experiment and four subsequent experiments were almost
consistent in yields (88%, 82%, 80%, 74%, 73%, 70%). After
five runs, the PEG layer retained 90% of the palladium
(residual analysis, which is within limits of experimental
error). In conclusion, low molecular weight PEG has been
utilized for the first time as a new solution medium for the
Heck reaction, which required no additional PTC or ligands.
Also, the reaction works very well for electron-deficient and
electron-rich olefins, with equal ease and with high regio-
and stereoselectivities.
(9) Extraction with dry ether is essential to avoid loss of palladium species
in the organic layer. No attempt has been made to make PEG free of salts
as the salts have never hampered the rate of reaction.
(10) Typical Procedure. A mixture of aryl bromide (1 mmol), olefin (1
mmol), PEG-2000 (2 g), TEA (1 mmol), and Pd (OAc)2 (0.05 mmol) was
placed in a 10-mL round-bottomed flask and was stirred and heated at 80
°C. After completion of the reaction (monitored by TLC) the reaction
mixture was cooled, extracted with cold diethyl ether (3 × 10 mL), and
purified by column chromatography.
Acknowledgment. C.N., S.S.S., and N.R.K. thank CSIR
for fellowships and CEFIPRA (2305-1) for funding.We also
thank referees for useful recommendations in improving the
manuscript.
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