J . Org. Chem. 2002, 67, 3861-3865
3861
Sa m a r iu m (II) Iod id e-Med ia ted In tr a m olecu la r Con ju ga te
Ad d ition s of r,â-Un sa tu r a ted La cton es
Gary A. Molander* and David J . St. J ean, J r.
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323
gmolandr@sas.upenn.edu.
Received February 5, 2002
Samarium(II) iodide, in the presence of catalytic amounts of nickel(II) iodide, has been used to
promote intramolecular conjugate additions of alkyl halides onto R,â-unsaturated lactones. This
process has been shown to be applicable to a number of R,â-unsaturated lactones, including
tetrasubstituted olefins, and has been demonstrated to be quite general for the formation of
saturated bicyclic and tricyclic lactones. The method presented herein provides a mild, efficient
process to form structurally complex lactones from simple precursors.
In tr od u ction
conjunction with a catalytic amount of NiI2,6 was able to
effect conjugate additions of alkyl iodides onto a variety
of electron-deficient olefins.5d However, to the best of our
knowledge, only one example of cyclization onto an R,â-
unsaturated lactone with SmI2 has been reported.5d
Herein we report a general procedure for the SmI2-
mediated, nickel(II)-catalyzed cyclization of alkyl halides
onto R,â-unsaturated lactones. Under optimized condi-
tions, conjugate additions were achieved using a variety
of primary iodides and various lactones. This method was
expanded to include tri- and tetrasubstituted olefins,
which provided the desired cyclized lactones in high
yields under mild reaction conditions.
Only a handful of examples have been reported in
which an alkyl halide was a precursor in the intramo-
lecular conjugate addition onto R,â-unsaturated lactones.1
Although these cyclizations, promoted almost exclusively
by Bu3SnH, yielded the desired lactones in good overall
yield, they are burdened with several disadvantages. Tin-
mediated cyclizations typically require elevated temper-
atures, usually boiling ethyl acetate1a-c or benzene.1f The
difficulty of removal as well as the toxicity of the residual
tin species2 makes the use of these reagents undesirable,
especially when compared to the rather benign nature
of SmI2.3 Furthermore, to maintain a low radical con-
centration during the reaction, tin-mediated cyclizations
are often encumbered by the inconvenience of long
addition times, sometimes as long as 5 h.1a
Resu lts a n d Discu ssion
To determine the generality of the SmI2-mediated
cyclization, a number of suitable substrates were pre-
pared. Compounds 8-10 were prepared from the same
intermediate, bromo amide 1 (Scheme 1).
Since the initial report by Kagan and co-workers4 on
the convenient synthesis of SmI2 and its use in various
reductive transformations, this reagent has been used
in a variety of intramolecular conjugate addition reac-
tions.5 Molander and Harris reported that SmI2, in
Coates reported that bromo amide 1 could be lithiated
and trapped with various carbonyl electrophiles to form,
after acidic hydrolysis, bicyclic lactones.7 Under optimized
conditions, 1.3 equiv of t-BuLi cleanly effected the lithia-
tion. Addition of the appropriate chloro ketone [(5-
chloropentan-2-one (2), 6-chlorohexan-2-one (3), or 4′-
chlorobutyrophenone (4)] yielded, after hydrolysis, the
desired chloro lactones. Conversion to the iodo lactone
derivatives 8-10 was achieved using standard Finkel-
stein procedures. Unfortunately, the cyclopentene deriva-
tive 13 could not be made via the route described above.
However, reaction of bromo acid 11 with 3 equiv of t-BuLi
yielded, after benzenesulfonyl chloride-mediated ring
closure,8 the desired lactone 12, albeit in low yield
(Scheme 2). The resultant chloro lactone was converted
to the iodo derivative 13 in high yield by a Finkelstein
reaction.
(1) (a) Lundt, I.; Horneman, A. M. Tetrahedron 1997, 53, 6879. (b)
Lundt, I.; Horneman, A. M. J . Org. Chem. 1998, 63, 1919. (c) Lundt,
I.; Horneman, A. M. Synthesis 1999, 317. (d) Hsia, K. Y.; Ward, P.;
Lamont, R. B.; de Q. Lilley, P. M.; Watkin, D. J .; Fleet, G. W. J .
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K. P. Aust. J . Chem. 1983, 36, 2243. (d) Milstein, D.; Stille, J . K. J .
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1989, 54, 3140.
(3) Molander, G. A. In The Chemistry of the Metal-Carbon Bond;
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Vol. 5.
(4) Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
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To determine the effect of substitution on this intramo-
lecular conjugate addition, monocyclic lactones with and
(5) (a) Molander, G. A. Chem. Rev. 1996, 96, 307. (b) Molander, G.
A.; Harris, C. R. Tetrahedron 1998, 54, 3321. (c) Krief, A.; Laval, A.
M. Chem. Rev. 1999, 99, 745. (d) Molander, G. A.; Harris, C. R. J . Org.
Chem. 1997, 62, 7418 and references therein. (e) Salari, B. S. F.;
Biboutou, R. K.; Bennett, S. M. Tetrahedron 2000, 56, 6285.
(6) Machrouhi, F.; Hamann, B.; Namy, J . L.; Kagan, H. B. Synlett
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10.1021/jo0255936 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/01/2002