Palladium-catalyzed intramolecular addition of 1,3-diones to unactivated olefins [1]

Full text of DOI:10.1021/ja011764x

11290
J. Am. Chem. Soc. 2001, 123, 11290-11291
Communications to the Editor
Table 1. Cyclization of Alkenyl 1,3-Diones and Alkenyl â-Keto
Esters Catalyzed by PdCl2(CH3CN)2 in Dioxane at Room
Temperature for 12-36 h
Palladium-Catalyzed Intramolecular Addition of
1,3-Diones to Unactivated Olefins
Tao Pei and Ross A. Widenhoefer*
P. M. Gross Chemical Laboratory, Duke UniVersity
Durham, North Carolina 27708-0346
ReceiVed July 20, 2001
The regioselective addition of a stabilized carbon nucleophile
to an olefin that bears an electron withdrawing group (Michael
addition) is one of the key C-C bond forming processes em-
ployed in organic synthesis.1 In contrast, the addition of a stabi-
lized carbon nucleophile to an unactivated olefin remains prob-
lematic and in this area, transition metal-based approaches have
received considerable attention.2 Despite this prolonged focus,
the efficient transition metal-catalyzed addition of a stabilized
carbon nucleophile to an unactivated olefin has not been demon-
strated. For example, zirconocene complexes catalyze the addition
of alkyl Grignard reagents to olefins, but these catalysts are not
compatible with stabilized carbon nucleophiles.3 Conversely,
Pd(0) complexes catalyze the addition of active methylene com-
pounds to allenes4 and conjugated dienes5 but these catalysts are
unreactive toward simple olefins. Although Pd(II) complexes
mediate the addition of both stabilized carbanions6 and silyl enol
ethers7 to unactivated olefins (eq 1), efficient catalysis has not
been realized.8 Here we report the regioselective, Pd(II)-catalyzed
intramolecular addition of 1,3-diones to unactivated olefins.
Coordination of an olefin to an electron deficient transition
metal complex greatly enhances the reactivity of the olefin toward
nucleophilic attack.9 In the presence of a suitable oxidant, Pd(II)
(1) Jung, M. E. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Semmelhack, M. F., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 4,
Chapter 1.1, pp 1-67.
complexes catalyze the intramolecular addition of alcohols10 and
protected amines11 to unactivated olefins with net oxidation of
the substrate (eq 2). Unfortunately, Pd(II)-catalyzed addition of
(2) (a) Free radical2b and Lewis acid-catalyzed approaches2c have also been
explored with limited success. (b) Snider, B. B. Chem. ReV. 1996, 96, 339.
(c) Reetz, M. T.; Chatziiosifidis, I.; Schwellnus, K. Angew. Chem., Int. Ed.
Engl. 1981, 20, 687.
(3) (a) Dzhemilev, U. M.; Vostrikova, O. S. J. Organomet. Chem. 1985,
285, 43. (b) Hoveyda, A. H.; Morken, J. P.; Houri, A. F.; Xu, Z. J. Am. Chem.
Soc. 1992, 114, 6692. (c) Knight, K. S.; Waymouth, R. M. J. Am. Chem. Soc.
1991, 113, 6268. (d) Takahashi, T.; Seki, T.; Nitto, Y.; Saburi, M.; Rousset,
C. J.; Negishi, E.-I. J. Am. Chem. Soc. 1991, 113, 6266.
(4) (a) Trost, B. M.; Gerusz, V. J. J. Am. Chem. Soc. 1995, 117, 5156. (b)
Yamamoto, Y.; Al-Masum, M.; Asao, N. J. Am. Chem. Soc. 1994, 116, 6019.
(5) (a) Goddard, R.; Hopp, G.; Jolly, P. W.; Kruger, C.; Mynott, R.; Wirtz,
C. J. Organomet. Chem. 1995, 486, 163. (b) Takahashi, K.; Miyake, A.; Hata,
G. Bull. Chem. Soc. Jpn. 1972, 45, 1183. (c) Jolly, P. W.; Kokel, N. Synthesis
1990, 771.
(6) (a) Hegedus, L. S.; Williams, R. E.; McGuire, M. A.; Hayashi, T. J.
Am. Chem. Soc. 1980, 102, 4973. (b) Hegedus, L. S.; Darlington, W. H. J.
Am. Chem. Soc. 1980, 102, 4980.
(7) (a) Kende, A. S.; Roth, B.; Sanfilippo, P. J.; Blacklock, T. J. J. Am.
Chem. Soc. 1982, 104, 5808. (b) Kende, A. S.; Roth, B.; Sanfilippo, P. J. J.
Am. Chem. Soc. 1982, 104, 1784. (c) Ito, Y.; Aoyama, H.; Hirao, T.;
Mochizuki, A.; Saegusa, T. J. Am. Chem. Soc. 1979, 101, 494. (d) Ito, Y.;
Aoyama, H.; Saegusa, T. J. Am. Chem. Soc. 1980, 102, 4519.
(8) A single example of the Pd-catalyzed addition of a carbon nucleophile
to an unactivated olefin employed 50 mol % of both Pd(OAc)2 and
benzoquinone to convert 2-trimethylsilyloxy-1,5-hexadiene to 3-methylcy-
clopent-2-enone in 70% yield.7c
carbon nucleophiles to olefins has been precluded by competitive
oxidation of the nucleophile by the stoichiometric oxidant and/
or by the Pd(II) complex.7-11 Because silyl enol ethers reacted
readily with olefins in the presence of Pd(II), we considered that
the enol tautomer of a 1,3-diketone might be sufficiently nucleo-
philic to attack a tethered olefin in the presence of Pd(II) and yet
(9) (a) Hegedus, L. S. Transition Metals in the Synthesis of Complex
Organic Molecules; University Science Books: Mill Valley, CA, 1999;
Chapter 7.2, pp 188-204. (b) Hegedus, L. S. In Organometallics in Synthesis;
Schlosser, M., Ed.; John Wiley & Sons: Chichester, UK, 1994; Chapter 5.3.1,
pp 388-397.
(10) Hosokawa, T.; Murahashi, S.-I. Acc. Chem. Res. 1990, 23, 49.
(11) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113.
10.1021/ja011764x CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/17/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 45, 2001 11291
be resistant toward oxidation. If these two conditions were met,
the Pd(II)-catalyzed addition of a 1,3-diketone to an unactivated
olefin could be achieved.
Our working mechanism for the palladium-catalyzed conver-
sion of 1 to 2 is based on the established reactivity of Pd(II) olefin
complexes toward nucleophiles,9 and involves intramolecular
attack of the pendant enol on the palladium-complexed olefin of
intermediate I to form the palladium cyclohexyl intermediate II
(eq 4). Although Pd(II) alkyl complexes are typically unstable
In an effort to probe the reactivity of a 1,3-diketone toward a
pendant olefin in the presence of Pd(II), an equimolar solution
of 7-octene-2,4-dione (1) and PdCl2(CH3CN)2 in THF was stirred
at room temperature. After 15 min, the dione had been completely
consumed to form 2-acetylcyclohexanone (2) as the exclusive
product that was isolated in 70% yield and identified by
comparison to an authentic sample. The endo regioselectivity of
ring closure was somewhat unexpected based on the predomi-
nant exo regioselectivity of related Pd(II)-mediated and -cata-
lyzed annulation processes.7-11 More surprising, however, was
that carbocycle 2 did not possess a double bond and was there-
fore not oxidized relative to dione 1. This observation sug-
gested that no reduction of Pd(II) had occurred and therefore
no oxidant should be required for the catalytic conversion of 1
to 2. In accord with this hypothesis, treatment of 1 (25 mM) with
a catalytic amount of PdCl2(CH3CN)2 (10 mol %) in dioxane at
room temperature for 16 h led to the isolation of cyclohexanone
2 in 81% yield as a single regioisomer (Table 1, entry 1).12
Dione 1 also cyclized in the presence of 5 mol % PdCl2-
(CH3CN)2 within 36 h at room temperature to form 2 in 72%
yield (Table 1, entry 2).
with respect to â-hydride elimination,9 no evidence for the
formation of cyclohexenones in the conversion of 1 to 2 was
obtained. Rather, proton transfer from the protonated carbonyl
group to the palladium-bound carbon atom of II presumably
releases carbocycle 2 and regenerates the Pd(II) catalyst prior to
â-hydride elimination. We have obtained no experimental evi-
dence which would distinguish between intra- and intermolecular
proton transfer, nor do we as yet understand the circumstances
which facilitate protonation of II relative to â-hydride elimination.
In summary, we have presented the first examples of the
transition metal-catalyzed addition of active methylene and
methine compounds to unactivated olefins employing a simple,
commercially available Pd(II) complex. We are currently working
toward expanding the scope of this process and toward the
elucidation of the mechanism of the conversion of 1 to 2.
The Pd-catalyzed cyclization of alkenyl-1,3-diones tolerated
substitution at the terminal methyl group and at the carbon located
between the two carbonyl groups (Table 1, entries 3-6). In
addition, the cyclization protocol tolerated terminal olefinic
substitution (Table 1, entries 7-11). For example, both cis- and
trans-7-nonene-2,4-dione cyclized in the presence of PdCl2-
(CH3CN)2 to form 2-acetyl-3-methylcyclohexanone in >70%
yield as a single regioisomer (Table 1, entries 7 and 8). In com-
parison, 8-methyl-7-nonene-2,4-dione, which possessed a trisub-
stituted olefin, cyclized in 38% yield (Table 1, entry 11). Al-
kenyl-â-keto esters cyclized in the presence of PdCl2(CH3CN)2
to form the corresponding 2-carboalkoxycyclohexanones with di-
minished yields relative to the cyclization of 1 (Table 1, entries
12 and 13).
Acknowledgment. R.W. thanks the Camille and Henry Dreyfus
foundation for New Faculty and Teacher-Scholar awards, DuPont for a
Young professor Award, and the Alfred P. Sloan Foundation for a Re-
search Fellowship. We thank Mr. Xiang Wang for synthesizing 3-methyl-
7-octene-2,4-dione, benzyl 3-oxo-6-heptenoate, and 7-dodecene-2,4-dione.
Note Added in Proof: The PdCl2(CH3CN)2-catalyzed addition of
alcohols and acetic acid to R,â-unsaturated ketones and acetals in the
absence of a stoichiometric oxidant has been reported and was proposed
to occur via protonolysis of the Pd-C bond of a palladium alkyl
intermediate with HCl: Hosokawa, T.; Shinohara, T.; Ooka, Y.;
Murahashi, S.-I. Chem. Lett. 1989, 2001.
Supporting Information Available: Experimental procedures and
spectroscopic data for new compounds and cyclohexanones (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
(12) Dioxane was a more effective solvent than was THF, CH2Cl2, DCE,
toluene, or benzene. Similarly, catalysts such as PdCl2, PdCl2(PhCN)2, and
Pd(OAc)2 were inferior to PdCl2(CH3CN)2. Substrate concentrations g25 mM
led to competitive olefin isomerization.
JA011764X