1082
J . Org. Chem. 1999, 64, 1082-1083
Ra p id Micr ow a ve-In d u ced
P a lla d iu m -Ca ta lyzed Asym m etr ic Allylic
Alk yla tion
Ulf Bremberg,† Mats Larhed,‡ Christina Moberg,*,† and
Anders Hallberg*,‡
F igu r e 1.
Department of Chemistry, Organic Chemistry,
Royal Institute of Technology, SE-100 44 Stockholm, Sweden,
and Department of Organic Pharmaceutical Chemistry,
Uppsala Biomedical Centre, Uppsala University, Box 574,
SE-751 23 Uppsala, Sweden
the key intermediates in the catalytic cycle. We herein report
an example of an enantioselective and very rapid microwave-
induced palladium-catalyzed alkylation of an allylic acetate
that proceeds via a π-allylpalladium(II) intermediate.
Racemic 1,3-diphenyl-2-propenyl acetate (1), which is a
commonly used substrate in asymmetric palladium-cata-
lyzed allylic alkylations, reacts smoothly with dimethyl
malonate in catalytic systems where phosphine ligands are
employed, while very long reaction times are sometimes
needed with dinitrogen ligands.2,3 The transformation of 1
into 2 was therefore chosen as a suitable model reaction for
studies of microwave flash-heating. Two types of ligands
with diverse inherent properties were assessed. One of them,
(+)-BINAP (4) (Figure 1), constitutes an example of an often
used C2-symmetric bis-phosphine ligand.7 As an example of
an N,N-ligand, C1-symmetric (4′R)-2-(4′,5′-dihydro-4′-phenyl-
2′-oxazolyl)quinoline (3) (Figure 1) was chosen.8 The alky-
lations were conducted essentially following the procedure
by Trost et al.9 using N,O-bis(trimethylsilyl)acetamide (BSA)
as the base, with modifications by Leutenegger et al.10a for
the nitrogen ligands and by Brown et al.10b for BINAP. A
π-allylpalladium(II)-ligand complex was prepared in situ,
and a low concentration of the nucleophile was generated
from dimethyl malonate in the presence of BSA and a
catalytic amount of KOAc. The microwave heating was
performed with a single-mode cavity11 in sealed12 heavy-
walled Pyrex tubes.13 The experiments were conducted
without stirring in acetonitrile, which is known to possess
a sufficiently high dissipation factor (tan δ) to be efficiently
heated under microwave irradiation.14 The results are sum-
marized in Tables 1 and 2.
Experiments in acetonitrile at room temperature provided
high yields with both ligands (Table 1). Neither of them
induced extreme enantioselectivities in acetonitrile. The
reaction with 4 (entry 5) delivered a slightly higher enan-
tiomeric excess and was considerably faster than the reac-
tions with 3 as ligand (entry 1), which is in agreement with
previous findings in dichloromethane.8,10a Alkylation with
ligand 3 required 3 days for completion at room temperature,
a typical rate for N,N-ligands. In Table 2, the microwave
irradiation experiments with selected combinations of reac-
tion time and power that result in complete consumption of
the starting material are summarized. The microwave-
induced alkylations provided excellent yields and high
reaction rates, but somewhat lower enantioselectivities were
encountered, in particular with the quinolineoxazoline 3 as
Received September 18, 1998
Palladium-catalyzed asymmetric allylic substitution reac-
tions have attracted considerable interest primarily due to
their synthetic utility.1,2 The enantioselectivity is determined
either during complex formation or, with substrates yielding
meso-allyl ligands, during the nucleophilic attack on either
of the two diastereotopic π-allyl carbon atoms of the π-
allylpalladium(II) intermediate.2a The absolute configuration
of the starting material is not recognized in the intermediate
π-allylpalladium complex, and high asymmetric induction
can be achieved by the employment of chiral ligands. A
plethora of C1- and C2-symmetric chiral ligands are available
for this reaction,3 and among these, bidentate ligands with
phosphorus and/or nitrogen as coordinating elements have
been most extensively used.2
We were encouraged to exploit the potential of microwave
irradiation as a nonconventional energy source for promotion
of slow asymmetric alkylations. Flash-heating by micro-
waves for the acceleration of organic reactions is well
established,4 but only during the past few years has the
power of the heating methodology been demonstrated in
palladium-catalyzed coupling reactions, where the collapse
of the catalytic system can be avoided by proper selection of
conditions. Thus, selective Heck,5 Suzuki,6 and Stille6 reac-
tions, in solution or on solid phase, were accomplished in
1.5-12 min and in high yields with a variety of reactant
combinations.5a,e,f,6 However, no reports have appeared on
the impact of microwave irradiation on asymmetric transi-
tion metal catalysis in general or on the reaction rate in such
processes where π-allylpalladium(II) complexes constitute
† Royal Institute of Technology.
‡ Uppsala University.
(1) Trost, B. M.; Strege, P. E. J . Am. Chem. Soc. 1977, 99, 1649.
(2) For reviews, see: (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev.
1996, 96, 365. (b) Shibasaki, M. In Advances in Metal-Organic Chemistry;
Liebeskind, L. S., Ed.; J AI Press: Greenwich, 1996; Vol. 5, p 119. (c) Tsuji,
J . Palladium Reagents and Catalysts; J ohn Wiley: Chichester, 1995; p 290.
(3) (a) Achiwa, I.; Yamazaki, A.; Achiwa, K. Synlett 1998, 45. (b) Gla¨ser,
B.; Kunz, H. Synlett 1998, 53. (c) Ahn, K. H.; Cho, C.-W.; Park, J .; Lee, S.
Tetrahedron: Asymmetry 1997, 8, 1179. (d) Chelucci, G. Tetrahedron:
Asymmetry 1997, 8, 2667. (e) Nordstro¨m, K.; Macedo, E.; Moberg, C. J . Org.
Chem. 1997, 62, 1604. (f) Zhang, W.; Hirao, T.; Ikeda, I. Tetrahedron Lett.
1996, 37, 4545.
(4) For reviews, see: (a) Mingos, D. M. P.; Baghurst, D. R. Chem. Soc.
Rev. 1991, 20, 1. (b) Caddick, S. Tetrahedron 1995, 51, 10403. (e) Langa,
F.; de la Cruz, P.; de la Hoz, A.; D´ıaz-Ortiz, A.; D´ıez-Barra, E. Contemp.
Org. Synth. 1997, 373. (f) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead,
B. S. J .; Mingos, D. M. P. Chem. Soc. Rev. 1998, 27, 213. For www resources
wave.html.
(5) (a) Larhed, M.; Hallberg, A. J . Org. Chem. 1996, 61, 9582. (b) D´ıaz-
Ortiz, A.; Prieto, P.; Va´zquez, E. Synlett 1997, 269. (c) Li, J .; Mau, A. W.-
H.; Strauss, C. R. J . Chem. Soc., Chem. Commun. 1997, 1275. (d) Wali, A.;
Muthukumaru Pillai, S.; Satish, S. React. Kinet. Catal. Lett. 1997, 60, 189.
(e) Garg, N.; Larhed, M.; Hallberg, A. J . Org. Chem. 1998, 63, 4158. (f)
Olofsson, K.; Larhed, M.; Hallberg, A. J . Org. Chem., 1998, 63, 5076. (g)
Villemin, D. Presented at the International Conference on Microwave
Chemistry, Prague, Sep 1998; Paper PL 5.
(7) 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl. See: Noyori, R.; Takaya,
H. Acc. Chem. Res. 1990, 23, 345.
(8) Bremberg, U.; Rahm, F.; Moberg, C. Tetrahedron: Asymmetry, in
press.
(9) Trost, B. M.; Murphy, D. J . Organometallics 1985, 4, 1143.
(10) (a) Leutenegger, U.; Umbricht, G.; Fahrni, C.; von Matt, P.; Pfaltz,
A. Tetrahedron 1992, 48, 2143. (b) Brown, J . M.; Hulmes, D. I.; Guiry, P. J .
Tetrahedron 1994, 50, 4493.
(11) Stone-Elander, S.; Elander, N. Appl. Radiat. Isot. 1993, 44, 889.
(12) One often overlooked hazard that may become prevalent under
microwave irradiation is the formation of electrical arcs. Arcing could result
in vessel rupture if air and flammable compounds are involved. We believe
the possibility of running reactions in an inert gas atmosphere is a distinct
advantage with the sealed reaction vessel strategy.
(6) (a) Larhed, M.; Lindeberg, G.; Hallberg, A. Tetrahedron Lett. 1996,
37, 8219. (b) Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D. P.; Hallberg,
A. J . Org. Chem. 1997, 62, 5583. See also ref 5a.
(13) Baghurst, D. R.; Mingos, D. M. P. J . Chem. Soc., Dalton Trans. 1992,
1151.
10.1021/jo981896h CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/28/1999