5682
J . Org. Chem. 1997, 62, 5682-5683
Sch em e 1
P a lla d iu m -Ca ta lyzed Allylic Su bstitu tion in
γ-Oxygen a ted Vin yl Su lfon es: On e-Step
Syn th esis of Tetr a su bstitu ted
Dih yd r ofu r a n s
Ine´s Alonso, J uan C. Carretero,* J ose L. Garrido,
Virginia Magro, and Concepcio´n Pedregal†
Departamento de Qu´ımica Orga´nica, Universidad
Auto´noma de Madrid, 28049-Madrid, Spain
Received May 15, 1997 (Revised Manuscript Received J uly 14,
1997 )
One of the most synthetically useful processes involv-
ing palladium-catalyzed reactions is the nucleophilic
substitution of allylic alcohols and derivatives via their
π-allylpalladium complexes. Both the regioselectivity
and stereoselectivity of the reaction as well as the nature
of the nucleophilic partners have been widely studied.1
However, unlike allylic alcohols substituted with alkyl,
aryl, or donating substituents, those substituted with
electron-withdrawing groups at the double bond have
been much less studied2 because of their lower reactivity
toward the palladium catalysts and their high tendency
to undergo conjugate addition of the nucleophile.
Earlier work in our laboratory showed that γ-oxygen-
ated vinyl sulfones are versatile intermediates in organic
synthesis, mainly because they undergo highly stereo-
selective conjugate additions of a variety of nucleophiles.3
We report here our preliminary results on their pal-
ladium-catalyzed allylic substitution with carbon nucleo-
philes, to give a new γ-substituted vinyl sulfone which
could be used in further stereoselective conjugate addi-
tions. To the best of our knowledge, the only previous
studies dealing with metal promoted allylic substitutions
in this type of vinyl sulfones have been recently reported
by Enders et al. who described the stoichiometric reaction
of their cationic tetracarbonyl(η3-allyl)iron derivatives
with nucleophiles.4
ducts, showing that the conjugate addition to the vinyl
sulfone was much faster than the formation of the
π-allylpalladium intermediate.
Taking into account the impossibility of forming the
π-allylpalladium complex when the malonate anion is
present, we focused our attention on the use of their
carbonates 2 (Tsuji’s method),7 which were readily pre-
pared in high yield by reaction 1 with ethyl chloroformate
(pyridine, DMAP, THF, rt).2a These substrates would
allow to carry out the reaction in the presence of diethyl
malonate instead of malonate anion, generating in situ
the required nucleophile only after oxidative addition of
Pd(0) to the allyl carbonate 2 with consequent formation
of the π-allylpalladium intermediate and release of the
alkoxide, which would then deprotonate the malonate.
We were pleased to find that the reaction of 2 with
diethyl malonate in the presence of Pd2(dba)3 (5 mol %),
dppe (20 mol %) as ligand,8 and molecular sieves (4 Å)9
in THF at reflux afforded exclusively the γ-substituted
products 4, which were isolated in good yields after
chromatography (64-79%). Hence, under these condi-
tions the nucleophile reacts with the intermediate π-al-
lylpalladium complex 3 rather than adds to another
molecule of 2. Furthermore, the reactions were com-
pletely regioselective, with the nucleophile attacking at
the γ-position of complexes 3 regardless of the steric size
of the R group (Scheme 1).
Next, we extend this reaction to other soft carbon
nucleophiles such as â-keto esters and 1,3-diketones
(Table 1). Surprisingly, instead of the expected γ-sub-
stituted acyclic compounds 5, tetrasubstituted dihydro-
furans 6-8 were obtained as the major products. These
results indicate that a tandem process, based on an initial
γ-allylic substitution followed by cyclization of 5 via an
intramolecular conjugate addition of its enol tautomer
(or enolate) to the vinyl sulfone moiety, had taken place.10
Dihydrofurans 6-8 were isolated in good yields (54-79%
after chromatographic purification) excepting the case of
The starting γ-hydroxy vinyl sulfones 1 were readily
prepared by our usual one-step procedure based on the
condensation of phenylsulfonyl arylsulfinyl methanes
with aldehydes, followed by in situ olefin migration and
sulfoxide-sulfenate [2,3] sigmatropic rearrangement.5
However the reaction of their allylic acetates or chloro-
acetates with sodium diethyl malonate in THF at rt or
reflux in the presence of Pd2(dba)3 (5 mol %) and a variety
of ligands6 afforded almost exclusively the Michael ad-
† Current address: Centro de Investigacio´n Lilly, S. A., Paraje de
la Cruz s/n. 28130 Valdeolmos, Madrid, Spain.
(1) For some recent reviews, see: (a) Trost, B. M.; Van Vranken, D.
L. Chem. Rev. 1996, 96, 395. (b) Williams, J . M. J . Synlett 1996, 705.
(c) Tsuji, J . Palladium Reagents and Catalysts; J ohn Wiley & Sons:
New York, 1995; p 290-422.
(2) For palladium-catalyzed allylic substitutions in γ-oxygenated-
R,â-unsaturated esters, see: (a) Tanikaga, R.; J un, T. X.; Kaji, A. J .
Chem. Soc., Perkin Trans. 1 1990, 1185. (b) Tsuda, T.; Horii, Y.;
Nakagawa, Y.; Ishida, T.; Saegusa, T. J . Org. Chem. 1989, 54, 977. (c)
Tanikaga, R.; Takeuchi, J .; Takyu, M.; Kaji, A. J . Chem. Soc., Chem.
Commun. 1987, 386. (d) Tsuji, J .; Ueno, H.; Kobayashi, Y.; Okumoto,
H. Tetrahedron Lett. 1981, 22, 2573.
(3) (a) Adrio, J .; Carretero, J . C.; Go´mez Arraya´s, R. Synlett 1996,
640. (b) Carretero, J . C.; Go´mez Arraya´s, R.; Storch, I. Tetrahedron
Lett. 1996, 37, 3379. (c) Carretero, J . C.; Go´mez Arraya´s, R. J . Org.
Chem. 1995, 60, 6000. (d) De Blas, J .; Carretero, J . C.; Dom´ınguez, E.
Tetrahedron Lett. 1994, 35, 4603. (e) Dom´ınguez, E.; Carretero, J . C.
Tetrahedron 1994, 50, 7557.
(6) PPh3, dppe, dppp and P(OEt)3 were used as ligands.
(7) (a) Tsuji, J .; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.;
Takahashi, K. J . Org. Chem. 1985, 50, 1523. (b) Tsuji, J .; Shimizu, I.;
Minami, I.; Ohashi, Y. Tetrahedron Lett. 1982, 23, 4809.
(8) Although other ligands, such as PPh3, dppp, dppf and neocu-
proine were also tested, the best yields were obtained in the presence
of dppe.
(9) A significant decrease in the yields of the γ-substituted products
was observed when the reactions were performed in the absence of
molecular sieves due to the competitive hydrolysis of the carbonates 2
to the corresponding alcohols 1.
(10) For other recent synthesis of dihydrofurans based on tandem
processes, see: (a) Lee, Y. R.; Kim, B. S. Tetrahedron Lett. 1997, 38,
2095. (b) Hagiwara, H.; Sato, K.; Suzuki, T.; Ando, M. Tetrahedron
Lett. 1997, 38, 2103. (c) Hayashi, T.; Yamane, M.; Ohno, A. J . Org.
Chem. 1997, 62, 204. (d) Hayashi, T.; Ohno, A.; Lu, S.-J .; Matsumoto,
Y.; Fukuyo, E.; Yanagi, K. J . Am. Chem. Soc. 1994, 116, 4221.
(4) (a) Enders, D.; J andeleit, B.; Raabe, G. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1949. (b) Enders, D.; Von Berg, S.; J andeleit, B. Synlett
1996, 18.
(5) (a) Dom´ınguez, E.; Carretero, J . C. Tetrahedron 1990, 46, 7197.
(b) Trost, B. M.; Grese, T. A. J . Org. Chem. 1991, 56, 3189.
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