J . Org. Chem. 1997, 62, 7565-7568
7565
Th e F ir st Ster eoselective P a lla d iu m -Ca ta lyzed Cycloca r bon yla tion
of â,γ-Su bstitu ted Allylic Alcoh ols
Melanie Brunner and Howard Alper*
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, K1N 6N5, Canada
Received February 12, 1997X
â,γ-Substituted allylic alcohols react with CO in the presence of catalytic quantities of palladium
acetate and 1,4-bis(diphenylphosphino)butane affording R,â-substituted-γ-butyrolactones in 42-
85% isolated yields. The complete stereoselectivity observed in some cases is a significant feature
of the lactonization reaction, with (E)-allylic alcohols affording trans-disubstituted lactones.
Depending on the structure of the allylic alcohol used in the cyclocarbonylation reaction, the
formation of the corresponding alkene or the â,γ-unsaturated carboxylic acid was observed as a
side or the principal reaction.
In tr od u ction
Resu lts a n d Discu ssion
Transition metal-catalyzed carbonylation of unsatur-
ated compounds has been a field of great interest, in
terms of both academic and industrial applications. The
intramolecular cyclization of unsaturated alcohols to
lactones, as a special class of carbonylation reaction,
represents an elegant route to heterocycles. It has been
the subject of several investigations in the last few
years.1-4
Treatment of allylic alcohols 1 with a 1/1 mixture of
carbon monoxide and hydrogen (800 psi) in the presence
of a catalytic amount of Pd(OAc)2 and dppb at 110 °C for
18 h resulted in the formation of lactones 2 in modest to
good yields (eq 1). The ratio of substrate to palladium
catalyst and added ligand was 25/1/1. The results of the
cyclocarbonylation of aliphatic and aromatic unsaturated
alcohols under these conditions are given in Table 1.
So far, only allylic alcohols with up to two substituents
on the CdC bond have been successfully subjected to the
cyclocarbonylation reaction. The Pd(dba)2-catalyzed lac-
tonization in the presence of 1,4-bis(diphenylphosphino)-
butane (dppb) at 190 °C in DME,5 and at 100 °C in
CH2Cl2,2 was applicable to allylic alcohols with a terminal
olefinic unit, but no reaction occurred for allylic alcohols
bearing an internal double bond. However, palladium-
(II) chloride could mediate the carbonylation of allylic
alcohols, even with internal CdC bonds, when acidic
conditions were employed in the presence of oxygen and
copper(II) chloride.6 Nevertheless, this reaction is re-
stricted to disubstituted double bonds.
There are no examples in the literature concerning the
cyclocarbonylation of â,γ-substituted allylic alcohols with
a 1,1,2-trisubstituted olefinic unit to form R,â-substituted-
γ-butyrolactones. Lactones with such a substitution
pattern are sometimes difficult to prepare using other
classical synthetic methods, and they are potentially
useful for the synthesis of biologically active molecules.
Bicyclic derivatives of this lactone type including hexahy-
dro-2(3H)-benzofuranones and tetrahydro-1H-cyclopenta-
[c]-furan-1,4(3H)-dione (cyclosarkomycin) have already
been proven to possess high activities as an insect
repellent or antitumor agent.7,8
Other palladium complexes like Pd(acac)2, Pd2(dba)3‚
CHCl3, or (PCy3)2Pd(H)(H2O)+BF4- in combination with
1 equiv of dppb gave similar results but slightly lower
isolated yields of the lactones. Pd(PPh3)4 with or without
dppb was almost inactive, with only 13% of the allylic
alcohol 1c being converted into 2c. As already demon-
strated, reducing the metal-chelate ring size lowers the
yield of the obtained lactone.2 In the case of 1c, the
lactone could be isolated in 63% yield with dppb as the
ligand, while dppp (1,3-bis(diphenylphosphino)propane)
gave the lactone in only 17% yield, and almost no
conversion occurred with dppe (1,2-bis(diphenylphosphi-
no)ethane). An increase of the dppb/metal ratio from 1/1
to 2/1 resulted in a lower yield of the lactone. No
carbonylation occurred when the palladium acetate cata-
lyzed reaction was carried out in THF, benzene, DME,
or DMF. A reaction temperature of 110 °C was found to
be optimal. Lowering the reaction temperature led to the
complete suppression of any reaction, while higher tem-
peratures resulted in lower yields of the lactone due to
several side reactions. The presence of hydrogen is
essential since without hydrogen no lactone was obtained
at all.
We now wish to report the synthesis of R,â-substituted-
γ-butyrolactones from â,γ-substituted allylic alcohols by
the use of appropriate palladium catalysts and phosphine
ligands.
The lactonization of the allylic alcohols 1a , 1c, 1d , 1e,
and 1g proceeded with complete stereoselectivity, with
(E)-allylic alcohols affording trans-lactones. The trans-
stereochemistry of the obtained lactones was established
on the basis of a crystallographic study of 2c (see
Supporting Information).
A mixture of five- and six-membered ring lactones was
formed as an inseparable mixture by the cyclocarbony-
lation reaction of 1b. Nevertheless, the 1H, 13C, and
COSY NMR spectral data indicated that the five- as well
as the six-membered rings exist as a mixture of cis- and
X Abstract published in Advance ACS Abstracts, September 15, 1997.
(1) Matsushita, K.; Komori, T.; Oi, S.; Inoue, Y. Tetrahedron Lett.
1994, 35, 5889.
(2) Yu, W.-Y.; Bensimon, C.; Alper, H. Chem.-A Eur. J . 1997, 3, 417.
(3) El Ali, B.; Okuro, K.; Vasapollo, G.; Alper, H. J . Am. Chem. Soc.
1996, 118, 4264.
(4) Tamaru, Y.; Hojo, M.; Ichi, Z.-I. J . Org. Chem. 1991, 56, 1099.
(5) El Ali, B.; Alper, H. J . Org. Chem. 1991, 56, 5357.
(6) Alper, H.; Leonard, D. Tetrahedron Lett. 1985, 26, 5639.
(7) Coulston, F.; Korte, F. W. A. G. K. U.S. Pat. Appl. 615 521, 1984,
Chem. Abstr. 104, P 83827q.
(8) (a) Ikeda, I.; Kanematsu, K. J . Chem. Soc., Chem. Commun.
1995, 453. (b) Linz, G.; Weetman, J .; Hady, A. F. A.; Helmchen, G.
Tetrahedron Lett. 1989, 30, 5599.
S0022-3263(97)00270-3 CCC: $14.00 © 1997 American Chemical Society