9582
J . Org. Chem. 1996, 61, 9582-9584
hydrogenation, catalyzed by RaNi or Pd/C,9 hydrosilyla-
tion, in the presence of CuCl and TMEDA,10 and addition
of chlorinated hydrocarbons, catalyzed by a Cu(I) com-
plex.11 Furthermore, vinylic substitution by the Baylis-
Hillman reaction can be achieved with substantial re-
duction of reaction times.12 The present investigation has
been devoted to a study of the effect of microwave
irradiation on the Heck arylation and briefly on the
related Suzuki13 and Stille14 reactions, in which labile
organotransition metal intermediates play a pivotal role
in the catalytic cycle. We herein report that these
palladium-catalyzed coupling reactions can be accom-
plished with reaction times ranging from 2.8 to 7.0 min
and that good yields were observed in most cases.
Micr ow a ve-P r om oted P a lla d iu m -Ca ta lyzed
Cou p lin g Rea ction s
Mats Larhed and Anders Hallberg*
Department of Organic Pharmaceutical Chemistry,
Uppsala Biomedical Center, Uppsala University, Box 574,
S-751 23 Uppsala, Sweden
Received J uly 9, 1996
In tr od u ction
The intermolecular Heck reaction of aryl halides or aryl
triflates with olefins is of the utmost importance in
organic synthesis.1 With a few exceptions,2-4 most
substrates for coupling require reaction temperatures of
70-100 °C1e and reaction times ranging from hours to
days for full conversion. Attempts to reduce the reaction
time by enhancing the temperature are seldom effective
due to collapse of the catalytic system.1d,5,6 Therefore,
access to alternative and general synthetic procedures
that permit fast coupling reactions would be valuable,
in particular with respect to the obvious applications of
such procedures to combinatorial chemistry.7
Resu lts a n d Discu ssion
We have reacted aryl iodides, aryl bromides, and aryl
triflates with various olefins. These substrates were
chosen to permit comparison of microwave-assisted reac-
tions to conventionally heated reactions, with respect to
chemo- and regioselectivity, as well as double bond
isomerization. The reactions were conducted under
nitrogen in sealed Pyrex vessels, and a commercially
available batch reactor producing continuous irradiation
was used. The primary objective was the minimization
of reaction times, and the irradiation power was altered
to allow full conversion of the arylating agents in less
than 7.0 min. With the exception of reaction scale,
solvent, and heating procedure, the reactions were per-
formed under reaction conditions identical to the original
procedures as described in the references cited, in order
to enable an accurate comparison. Our initial screening
experiments revealed that the microwave-promoted Heck
coupling under classical conditions (without solvent or
with trialkylamine as solvent) did not proceed satisfac-
torily.15 The addition of DMF, a microwave-active sol-
vent,8,15 drastically expedited the reactions, and the
desired compounds were obtained within minutes in good
yield. In the Suzuki and Stille cross-couplings, the
combination of ethanol/water/DME and N-methyl-2-
pyrrolidone (NMP), respectively, was found to interact
sufficiently strongly with microwaves and generate the
heat required to promote the reactions.
Many examples of the benefits of microwave irradia-
tion, including reduction of reaction times and electricity
costs, have been reported.8 Among the transformations
performed are reactions of double bonds, including
(1) For reviews on the Heck reaction see: (a) Heck, R. F. Org. React.
1982, 27, 345. (b) Trost, B. M.; Verhoeven, T. R. Comprehensive
Organometallic Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W.,
Eds.; Pergamon Press: Oxford, 1982; Vol. 8, pp 854. (c) Heck, R. F.
Palladium Reagents in Organic Synthesis; Academic Press: London,
1985; pp 276. (d) Heck, R. F. Comprehensive Organic Synthesis; Trost,
B. M., Flemming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, pp
833. (e) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2379. (f) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. (g)
Tsuji, J . Palladium Reagents and Catalysts: Innovations in Organic
Chemistry; J ohn Wiley & Sons: Chichester, 1995; pp 125. For Heck
arylation of heteroatom-substituted double bonds see: (h) Daves, G.
D., J r.; Hallberg, A. Chem. Rev. 1989, 89, 1433.
(2) Addition of phase-transfer catalysts, such as Bu4NCl, may have
a favorable effect on the reaction temperature. (a) J effery, T. J . Chem.
Soc., Chem. Commun. 1984, 1287. (b) Larock, R. C. Pure Appl. Chem.
1990, 62, 653. (c) J effery, T. Tetrahedron 1996, 52, 10113.
(3) High pressure is known to accelerate the Heck reaction. (a) Voigt,
K.; Schick, U.; Meyer, F. E.; de Meijere, A. Synlett 1994, 189. (b)
Sugihara, T.; Takebayashi, M.; Kaneko, C. Tetrahedron Lett. 1995, 36,
5547.
(4) Arylation of electron-rich olefins employing bidentate nitrogen
ligands were performed at 40 °C. (a) Cabri, W.; Candiani, I.; Bedeschi,
A.; Santi, R. Synlett 1992, 871. (b) Cabri, W.; Candiani, I.; Bedeschi,
A. J . Org. Chem. 1993, 58, 7421.
(5) (a) Herrmann, W. A.; Brossmer, C.; O¨ fele, K.; Beller, M.; Fischer,
H. J . Mol. Catal. A: Chem. 1995, 103 133. (b) A palladacycle acting
as an efficient catalyst at up to 140 °C was recently prepared from
Pd(OAc)2 and (o-tol)3P. Herrmann, W. A.; Brossmer, C.; O¨ fele, K.;
Reisinger, C. P.; Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1844.
(6) Heck reactions can be carried out with aryl chlorides at 140-
160 °C when electron-rich chelating ligands are used. (a) Ben-David,
Y.; Portnoy, M.; Gozin, M.; Milstein, D. Organometallics 1992, 11, 1995,
(b) Portnoy, M.; Ben-David, Y.; Milstein, D. Organometallics 1993, 12,
4734, (c) Portnoy, M.; Ben-David, Y.; Rousso, I.; Milstein, D. Organo-
metallics 1994, 13, 3465.
(7) For recent reviews, see: (a) Hermkens, P. H. H.; Ottenheijm,
H. C. J .; Rees, D. Tetrahedron 1996, 52, 4527. (b) Fru¨chtel, J . S.; J ung,
G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17. (c) DeWitt, S. H.;
Czarnik, A. W. Acc. Chem. Res. 1996, 29, 114. (d) Armstrong, R. W.;
Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Ibid. 1996,
29, 123. (e) Ellman, J . A. Ibid. 1996, 29, 132. (f) Gordon, E. M.; Gallop,
M. A.; Patel, D. V. Ibid. 1996, 29, 144. (g) Thompson, L. A.; Ellman, J .
A. Chem. Rev. 1996, 96, 555.
The preparative results are summarized in Table 1.
Methyl acrylate was converted smoothly in 3.8 min at
60 watt (W) to the corresponding cinnamic acid ester in
the presence of DMF (Table 1, entries 1 and 2).16,17 The
same transformation could be conducted at a lower
(9) (a) Bose, A. K.; Banik, B. K.; Barakat, K. J .; Manhas, M. S.
Synlett 1993, 575. (b) Leskovsek, S.; Smidovnik, A.; Koloini, T. J . Org.
Chem. 1994, 59, 7433.
(10) Abramovitch, R. A.; Abramovitch, D. A.; Iyanar, K.; Tamare-
selvy, K. Tetrahedron Lett. 1991, 32, 5251.
(11) Ada´mek, F.; Ha´jek, M. Tetrahedron Lett. 1992, 33, 2039.
(12) Kundu, M. K.; Mukherjee, S. B.; Balu, N.; Padmakumar, R.;
Bhat, S. V. Synlett 1994, 444. See also ref 8d.
(13) For reviews on the Suzuki reaction see: (a) Martin, A. R.; Yang,
Y. Acta Chem., Scand. 1993, 47, 221. (b) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457.
(14) For reviews on the Stille reaction see; (a) Stille, J . K. Angew.
Chem., Int. Ed. Engl. 1986, 25, 508. (b) Michell, T. N. Synthesis 1992,
803. (c) Ritter, K. Synthesis 1993, 735. (d) Farina, V. Pure Appl. Chem.
1996, 68, 73.
(8) (a) Mingos, D. M. P.; Baghurst, D. R. Chem. Soc. Rev. 1991, 20,
1. (b) Abramovitch, R. A. Org. Prep. Proc. Int. 1991, 23, 683. (c) Loupy,
A.; Bram, G.; Sansoulet, J . New J . Chem. 1992, 16, 233. (d) Strauss,
C. R.; Trainor, R. W. Aust. J . Chem. 1995, 48, 1665. (e) Caddick, S.
Tetrahedron 1995, 51, 10403. For a theoretical background see also:
(f) Neas, E. D.; Collins, M. J . Introduction to Microwave Sample
Preparation; Kingston, H. M., J assie, L. B., Eds.; American Chemical
Society: Washington, DC, 1988; p 7.
(15) A solvent with a high dipole moment (more correctly; a high
dielectric loss tangent) is beneficial for efficient absorption of microwave
energy. Trialkylamines are known to couple less effectively with
microwave radiation than DMF. Gedye, R. N.; Smith, F. E.; Westaway,
K. C. Can. J . Chem. 1988, 66, 17. See also ref 8.
(16) Heck, R. F.; Nolley, J . P., J r. J . Org. Chem. 1972, 37, 2320.
(17) Patel, B. A.; Ziegler, C. B.; Cortese, N. A.; Plevyak, J . E.;
Zebovitz, T. C.; Terpko, M.; Heck, R. F. J . Org. Chem. 1977, 42, 3903.
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