metal-catalyzed conversion of an alkenyl ketone, alcohol,
or epoxide to a substituted furan has not been demon-
strated.8 Although olefins are significantly less reactive
toward transition-metal complexes than are alkynes or
allenes, olefins are more readily accessible and more
easily manipulated than are alkynes or allenes. Further-
more, utilization of alkenyl substrates in the transition-
metal-catalyzed synthesis of functionalized furans would
significantly expand the scope of suitable starting ma-
terials for these transformations. Here, we report the
palladium-catalyzed oxidative alkoxylation of R-alkenyl
â-diketones to form 2,3,5-trisubstituted furans.
P a lla d iu m -Ca ta lyzed Oxid a tive
Alk oxyla tion of r-Alk en yl â-Dik eton es To
F or m F u n ction a lized F u r a n s
Xiaoqing Han and Ross A. Widenhoefer*
Duke University, P. M. Gross Chemical Laboratory,
Durham, North Carolina 27708-0346
rwidenho@chem.duke.edu
Received October 27, 2003
We have recently reported the palladium-catalyzed
intramolecular hydroalkylation of 3-butenyl â-diketones
to form 2-acylcyclohexanones.9,10 For example, treatment
of 7-octene-2,4-dione with a catalytic amount of PdCl2(CH3-
CN)2 (1) formed 2-acetylcyclohexanone in 81% isolated
yield (eq 1).9 Similarly, we have reported the palladium-
catalyzed intramolecular oxidative alkylation of 4-pen-
tenyl â-diketones to form 2-acyl-2-cyclohexenones.11 As
an example, reaction of 8-nonene-2,4-dione with a cata-
lytic amount of 1 and a stoichiometric amount of CuCl2
led to the isolation of 2-acetyl-3-methyl-2-cyclohexenone
in 80% yield (eq 2).11
Abstr a ct: Treatment of 4-allyl-2,6-dimethyl-3,5-heptane-
dione with a catalytic amount of PdCl2(CH3CN)2 (5 mol %)
and a stoichiometric amount of CuCl2 (2.2 equiv) in dioxane
at 60 °C for 12 h formed 3-isobutyryl-2-isopropyl-5-methyl-
furan in 77% isolated yield. A number of R-alkenyl â-dike-
tones underwent oxidative alkoxylation under these condi-
tions to form 2,3,5-trisubsituted furans in moderate to good
yield.
Functionalized furans are a common component of
naturally occurring and biologically active molecules,1
pharmaceuticals,1 and fragrance and flavoring com-
pounds2 and are useful building blocks for the synthesis
of complex organic molecules.3 For these reasons, the
development of new and efficient methods for the syn-
thesis of functionalized furans remains an area of current
interest.4 A particularly effective approach to the syn-
thesis of functionalized furans is through the transition-
metal-catalyzed cyclization of an alkynyl or allenyl
ketone,5 alcohol,6 or epoxide.7 In contrast, the transition-
In an effort to expand the scope of palladium-catalyzed
olefin alkylation, we studied the reaction of 1 with
alkenyl â-diketones in which the alkenyl group was
tethered to the R-carbon atom of the â-diketone moiety.
However, reaction of R-alkenyl â-diketones with 1 led not
to olefin alkylation, but rather to oxidative alkoxylation
to form substituted furans. For example, treatment of
4-allyl-2,6-dimethyl-3,5-heptanedione (2) with a catalytic
amount of 1 (5 mol %) and stoichiometric amount of
CuCl2 (2.2 equiv) in dioxane at 60 °C for 12 h led to the
isolation of 3-isobutyryl-2-isopropyl-5-methylfuran (3) in
77% yield (eq 3).
(1) (a) Greve, S.; Friedrichsen, W. In Progress in Heterocyclic
Chemistry; Gribble, G. W., Gilchrist, T. L. Eds.; Pergamon: New York,
1999; Vol. 11, pp 144-162. (b) Friedrichsen, W. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Pergamon: Elsevier Science Ltd.: Oxford, 1996; Vol. 2, pp
351-386. (c) Donnelly, D. M. X.; Meegan, M. J . In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Perga-
mon: New York, 1984; Vol. 4, pp 657-712.
(2) (a) The Chemistry of Heterocyclic Flavoring and Aroma
Compounds; Vernin, G.; Ed.; Ellis Horwood: Chichester, 1982. (b)
Levisalles, J . Perfumery Essent. Oil Record 1958, 49, 627. (c) Common
Fragrance and Flavor Materials; Bauer, K., Garbe, D., Eds.; VCH:
Weinheim, 1985. (d) Naim, M.; Zuker, I.; Zehavi, U.; Rouseff, R. L. J .
Agric. Food Chem. 1993, 41, 1359. (e) Bock, I.; Bornowski, H.; Ranft,
A.; Theis, H. Tetrahedron 1990, 46, 1199. (h) Mortensen, D. S.;
Rodriguez, A. L.; Carlson, K. E.; Sun, J .; Katzenellenbogen, B. S.;
Katzenellenbogen, J . A. J . Med. Chem. 2001, 44, 3838.
Palladium was required for furan formation; stirring
a suspension of 4-allyl-3,5-heptanedione (4) and CuCl2
(3) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Raczko, J .;
J urczak, J . Stud. Nat. Prod. Chem. 1995, 16, 639. (c) Wong, H. N. C.;
Yu, P.; Yick, C.-Y. Pure Appl. Chem. 1999, 71, 1041.
(4) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.;
Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955.
(7) Lo, C.-Y.; Guo, H.; Lian, J .-J .; Shen, F.-M.; Liu, R.-S. J . Org.
Chem. 2002, 67, 3930.
(5) (a) Sheng, H.; Lin, S.; Huang, Y. Tetrahedron Lett. 1986, 27,
4893. (b) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J . Org.
Chem. 1991, 56, 5816. (c) Kel′in, A. V.; Gevorgyan, V. J . Org. Chem.
2002, 67, 95. (d) Ma, S.; Zhang, J . Chem. Commun. 2000, 2, 117. (e)
Marshall, J . A.; Wang, X.-J . J . Org. Chem. 1992, 57, 3387. (f) Marshall,
J . A.; Wang, X.-J . J . Org. Chem. 1991, 56, 960. (g) Arcadi, A.; Cacchi,
S.; Larock, R. C.; Marinelli, F. Tetrahedron Lett. 1993, 34, 2813.
(6) (a) Wakabayashi, Y.; Fukuda, Y.; Shiragami, H.; Utimoto, K.;
Nozaki, H. Tetrahedron 1985, 41, 3655. (b) Gabriele, B.; Salerno, G.;
Lauria, E. J . Org. Chem. 1999, 64, 7687. (c) Seiller, B.; Bruneau, C.;
Dixneuf, P. H. J . Chem. Soc., Chem. Commun. 1994, 493. (d) Seiller,
B.; Bruneau, C.; Dixneuf, P. H. Tetrahedron 1995, 51, 13089. (e)
Ku¨cu¨kbay, H.; Cetinkaya, B.; Guesmi, S.; Dixneuf, P. H. Organome-
tallics 1996, 15, 2434.
(8) A related transformation involving the palladium-catalyzed
addition of an enolic oxygen atom to a pendant olefin terminated by
â-hydroxide elimination has been previously reported,8a as has the
synthesis of benzofurans via the palladium-catalyzed addition of a
phenolic oxygen atom to a pendant olefin.8b (a) Tenaglia, A.; Kammerer,
F. Synlett 1996, 576. (b) Hosokawa, T.; Murahashi, S.-I. Heterocycles
1992, 33, 1079.
(9) Pei, T.; Widenhoefer, R. A. J . Am. Chem. Soc. 2001, 123, 11290.
(10) For related transformations and mechanistic work see: (a)
Qian, H.; Widenhoefer, R. A. J . Am. Chem. Soc. 2003, 125, 2056. (b)
Pei, T.; Widenhoefer, R. A. Chem. Commun. 2002, 650. (c) Wang, X.;
Pei, T.; Han, X.; Widenhoefer, R. A. Org. Lett. 2003, 5, 2699.
(11) Pei, T.; Wang, X.; Widenhoefer, R. A. J . Am. Chem. Soc. 2003,
125, 648.
10.1021/jo035576w CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/31/2004
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J . Org. Chem. 2004, 69, 1738-1740