that the cyclization is promoted by neither acids such as HCl,
TFA, or TsOH nor bases (tBuOK in DMSO), even under
stoichiometric conditions.
Scheme 1
Substituted alkynes also cyclized, but in this case, we also
observed the formation of products arising from a 6-endo-
dig cyclization mode. Hence, treatment of 4-but-2-ynyl-
cyclohexane-1,3-dione (4b) with catalytic amounts of Pd-
(OAc)2 at room temperature produced the dihydrofuran
derivative 5b together with a small amount of the enolether
6b. Remarkably, this endo product predominates when PtCl2
or W(CO)5‚THF is used as a catalyst. The reaction with PtCl2
was completed in a few hours at room temperature, whereas
4 days were required with the tungsten catalyst. Thus, these
results show that by choosing the appropriate catalyst, it is
possible to control the formation of either the endo or the
exo regiosomer, when R ) Me. As far as we know, no such
regiochemical difference between Pd(II) and Pt(II) catalysts
has been reported hitherto in other cyclizations.
oxabicyclic products, prompted us to examine these cycliza-
tions further using related but synthetically straightforward
substrates such as the cyclohexanediones 4. These precursors
can be obtained in two simple steps and good yield from
commercially available 1,3-cyclohexanedione.6
Treatment of a THF solution of cyclohexanedione 4a with
5 mol % Pd(OAc)2, at room temperature, gave the expected
5-exo-dig oxacyclization product 5a in 85% yield. As
indicated in Table 1, the reaction also takes place with a
We were next curious about the performance of the
cyclopentanedione homologues, as a similar oxacyclization
would produce interesting fused cyclopenta[b]pyran or
cyclopenta[b]furan skeletons.8 The poor solubility of cyclo-
pentadione 7a in THF required the use of dioxane as a
cosolvent. Treatment of 7a6 with 10 mol % PtCl2 in 2:1 THF/
dioxane at room temperature produced exclusively the endo-
dig oxacyclization product 8a in 76% isolated yield. Use of
dioxane or acetone as the only solvent gave poorer results,
so THF seems to be necessary for the reaction to proceed
well. The reaction also works with substituted alkynes such
as 7b, again yielding exclusively the 6-endo product. As
shown in Table 2, with the cyclopentanedione precursors,
Table 1. Metal-Catalyzed Oxacyclization of 4a
products
entry
4
catalyst (mol %)
(ratio)b
yieldc
time
1
2
3
4
5
4a Pd(OAc)2 (5)
4a Pd(OAc)2 (2)
4a W(CO)5‚THF (10)
4a W(CO)5‚THF (10)d
4a PtCl2 (10)
5a
5a
5a
5a
5a
85%
78%
85%
90%
79%
80%
71%
75%
2 min
3 h
0.5 h
0.5 h
15 min
7 days
2 days
8 h
6
7
4a CpRuCl(PPh3)2 (10) 5a
4a PdCl2(CH3CN)2(10) 5a
Table 2. Metal-Catalyzed Oxacyclization of 7a
8
9
10
4b Pd(OAc)2 (5)
4b PtCl2 (5)
4b W(CO)5‚THF (10)
5b/6b (8:1)
5b/6b (1:14) 91%
5b/6b (1:11) 83%
9 h
5 days
a All reactions were carried out at room temperature, under an argon
atmosphere, by adding the catalyst to a solution of the substrate in THF
(0.1 M, or 1 M in the case of entry 4) and were stopped after apparent
consumption of the starting material. b Calculated by 1H NMR after workup.
c Isolated yield. d Prepared in situ by irradiating a THF suspension of
W(CO)6 and the substrate for 3-4 h with a high-pressure Hg lamp.
entry
7
catalyst (mol %)
product
yield
time
1
2
3
4
5
6
7a
7a
7a
7b
7b
7b
PtCl2 (10)
8a
8a
8a
8b
8b
8b
76%
74%
65%
85%
67%
78%
3 days
5 days
3 days
1 day
5 days
3 days
W(CO)5‚THF (20)
Pd(OAc)2 (10)
PtCl2 (10)
W(CO)5‚THF (20)
Pd(OAc)2 (10)
smaller amount of catalyst, although it takes longer (entry
2). Using either previously generated W(CO)5‚THF or
irradiating a THF solution of 4a in the presence of catalytic
amounts of W(CO)6 afforded the same bicycle, likewise in
good yield. Carrying out this latter experiment in the presence
of Et3N (4 equiv), conditions previously used in the cycliza-
tion of alkynols,7 also gave exclusively the exo product. The
transformation is also catalyzed by PtCl2 and even by
CpRuCl(PPh3)2, although with the latter it takes several days
for completion at room temperature. It should be remarked
a All reactions were carried out at room temperature under an argon
atmosphere by adding the catalyst to a 0.1 M solution of the substrate in
2:1 THF-dioxane, except for that of entry 5, which was carried out in
THF, and were stopped after apparent consumption of the starting material.
Pd(OAc)2 led to a regiochemical outcome similar to using
PtCl2 and W(CO)5‚THF.
(6) See Supporting Information and: Stork, G.; Danheiser, R. J. Org.
Chem. 1973, 38, 1775.
(7) Tungsten-catalyzed isomerization of several 4-alkyn-1-ols proceeds
in a endo-selective fashion: McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J.
Am. Chem. Soc. 2000, 122, 4304.
(8) These are important frameworks for the synthesis of prostaglandin
derivatives. See for instance: (a) Newton, R. F.; Wadsworth, A. H. J. Chem.
Soc., Perkin Trans. 1 1982, 823. (b) Skuballa, V. Tetrahedron Lett. 1980,
21, 3261. (c) Herndon, J. W.; Matasi, J. T. Tetrahedron Lett. 1992, 33,
5725.
1976
Org. Lett., Vol. 5, No. 11, 2003