directed toward using aqueous solvents for chemical reactions,3
including the Heck reaction.4 However, high temperatures were
required in all of the latter cases.5 Moreover, although regiose-
lectivity is required for constructing complex molecules, to the
best of our knowledge, there has been no report about the
regioselectivity of aryl iodides in the Heck reaction, except for
the regioselective coupling of R-position of olefin double bond.6
In this study, we report a Heck reaction with excellent
regioselectivity of para- over ortho-substitution in phenyl
iodides that is catalytized in situ by palladium nanoparticles
under aqueous and ultrasonic condition at ambient temperature
(25 °C).
The Heck reaction of iodobenzene with methyl acrylate was
initially studied in the presence of PdCl2 in water. The reaction
mixture of 1 mmol of iodobenzene, 2 mmol of methyl acrylate,
0.02 mmol of PdCl2, Na2CO3 as base, and 1 mmol of
tetrabutylammonium bromide (TBAB) was stirred in 3 mL of
water at 25 °C for 4.5 h. (E)-Methyl cinnamate 1 was obtained
with a yield of only 10%. Inspired by the report that ultrasonic
irradiation may promote organic reactions,7,8 we performed the
same reaction under ultrasonic irradiation hoping to realize the
Heck reaction in water without heating. Indeed, the reaction
carried out under such conditions resulted in an enhancement
of the yield from 10% to 86%. The reaction conditions were
systematically optimized, and the results are presented in Table
Catalysis and Regioselectivity of the Aqueous
Heck Reaction by Pd(0) Nanoparticles under
Ultrasonic Irradiation
Zuhui Zhang,† Zhenggen Zha,† Changsheng Gan,†
Chongfeng Pan,† Yuqing Zhou,† Zhiyong Wang,*,† and
Ming-Ming Zhou*,‡
Hefei National Laboratory for Physical Science at Microscale
and Department of Chemistry, UniVersity of Science and
Technology of China, Hefei, Anhui, 230026 P. R. China,
and Structural Biology Program, Department of Physiology
and Biophysics, Mount Sinai School of Medicine,
New York UniVersity, One GustaVe L. LeVy Place,
New York, New York 10029-6574
zwang3@ustc.edu.cn; ming-ming.zhou@mssm.edu
ReceiVed February 22, 2006
(3) For a general introduction to organic reactions in water, see: (a) Li,
C. J. Chem. ReV. 2005, 105, 3095. (b) Organic Synthesis in Water; Grieco,
P. A., Ed.; Blackie Academic and Professional: London, 1998. (c) Li, C.
J.; Chan, T. H. Organic Reactions in Aqueous Media; Wiley: New York,
1997. (d) Li, C. J. Chem. ReV. 1993, 93, 2023. (e) Genet, J.-P.; Savignac,
M. J. Organomet. Chem. 1999, 576, 305.
(4) For recent examples, see: (a) Arvela, R. K.; Leadbeater, N. E. J.
Org. Chem. 2005, 70, 1786. (b) Hagiwara, H.; Sugawara, Y.; Hoshi, T.;
Suzuki, T. Chem. Commun. 2005, 2942. (c) Bhattacharya, S.; Srivastavaa,
A.; Sengupta, S. Tetrahedron Lett. 2005, 46, 3557. (d) Botella, L.; Na´jera,
C. Tetrahedron Lett. 2004, 45, 1833. (e) Solabannavar, S. B.; Desai, U.
V.; Mane, R. B. Green Chem. 2002, 4, 347. (f) Mukhopadhyay, S.;
Rothenberg, G.; Joshi, A.; Baidossi, M.; Sasson, Y. AdV. Synth. Catal. 2002,
344, 348. (g) Ansos, M. S.; Mirza, A. R.; Tonks, L.; William, J. M. J.
Tetrahedron Lett. 1999, 40, 7147. (h) Uozumi, Y.; Kimura, T. Synlett 2002,
2045. (i) Botella, L.; Na´jera, C. J. Org. Chem. 2005, 70, 4360. (j) Na´jera,
C.; Gil-molto´, J.; Karlstro¨m, S.; Falvello, L. R. Org. Lett. 2003, 5, 1451.
(k) Jeffery, T. Tetrahedron 1996, 52, 10113.
(5) Heck couplings proceeding in organic solvent at room temperature
in the presence of air-sensitive phosphine ligands or catalyzed by chloro-
palladated propargylamine were reported, see: (a) Littke, A. F.; Fu, G. C.
J. Am. Chem. Soc. 2001, 123, 6989. (b) Stambuli, J. P.; Stauffer, S. R.;
Shaughnessy, K. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 2677. (c)
Consorti, C. S.; Zanini, M. L.; Leal, S.; Ebeling. G.; Dupont, J. Org. Lett.
2003, 5, 983.
(6) Regioselective couplings at the R-position of an olefin double bond
were reported, see: (a) Mo, J.; Xu, L. J.; Xiao, J. L. J. Am. Chem. Soc.
2005, 127, 751. (b) Svennebring. A.; Nilsson, P.; Larhed, M. J. Org. Chem.
2004, 69, 3345. (c) Nilsson, P.; Larhed, M.; Hallberg. A. J. Am. Chem.
Soc. 2003, 125, 3430. (d) Glorius, F. Tetrahedron Lett. 2003, 44, 5751. (e)
Barcia, J. C.; Cruces, J.; Este´vez, J. C.; Este´vez, R. J.; Castedo, L.
Tetrahedron Lett. 2002, 43, 5141. (f) Ishiyama, T.; Hartwig. J. J. Am. Chem.
Soc. 2000, 122, 12043. (g) Huang, Y. C.; Majumdar, K. K.; Cheng. C. H.
J. Org. Chem. 2002, 67, 1682. (h) Ashimori, A.; Bachand, B.; Calter, M.
A.; Govek, S. P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998,
120, 6488.
An aqueous Heck reaction carried out under ultrasonic
irradiation at the ambient temperature (25 °C) has been
shown in this study to afford high yields of corresponding
products. It was found that as a catalyst for the reaction
palladium forms nanoparticles in-situ, characterized by
transmission electron microscopy (TEM) and X-ray powder
diffraction (XRD) analyses, and can be recycled. Further-
more, the Heck reaction under such mild and environmentally
friendly conditions offers excellent regioselectivity of para-
over ortho-substitution in phenyl iodides especially with
electron-donating groups.
The palladium-catalyzed Heck reaction1 between aryl halides
and alkenes is a versatile method for carbon-carbon bond
formation in organic synthesis.2To minimize adverse impact of
organic solvents on the environment, recent efforts have been
† University of Science and Technology of China.
‡ Mount Sinai School of Medicine, New York University.
(1) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971,
44, 581. (b) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320.
(2) For selected reviews of Heck reaction, see: (a) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442. (b) Dounay,
A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945. (c) Whitcombe, N. J.;
Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57, 7449. (d) Beletskaya, I.
P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009. (e) Shibasaki, M.; Vogl,
E. M. J. Organomet. Chem. 1999, 576, 1. (f) Crisp, G. T. Chem. Soc. ReV.
1998, 27, 427. (g) Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron
1997, 53, 7371. (h) Negishi, E.; Cope´ret, C.; Ma, S.; Liou, S.-Y.; Liu, F.
Chem. ReV. 1996, 96, 365. (i) De Meijere, A,; Meyer, F. E. Angew. Chem.,
Int. Ed, Engl. 1995, 33, 2379. (j) Cabri, W.; Candiani, I. Acc. Chem. Res.
1995, 28, 2.
(7) Ultrasound-promoted Heck reaction and Sonogashi reaction in room-
temperature ionic liquids were reported, see: (a) Deshmukh, R. R.;
Rajagopal, R.; Srinivasan, K. V. Chem. Commun. 2001, 1544. (b) Gholap,
A. R.; Venkatesan, K.; Pasricha, R.; Daniel, T.; Lahoti, R. J.; Srinivasan,
K. V. J. Org. Chem. 2005, 70, 4869.
(8) For a Heck coupling assisted by ultrasound in NMP using Pd/C,
see: Ambulgekar, G. V.; Bhanage, B. M.; Samant, S. D. Tetrahedron Lett.
2005, 46, 2483.
10.1021/jo060372b CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/04/2006
J. Org. Chem. 2006, 71, 4339-4342
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