α-hydroxy cyclopentenones from α-diketones

Article abstract of DOI:10.1021/ol050970x

(Chemical Equation Presented) Metalloenolates derived from α,β-unsaturated α-diketones undergo cyclization to α-hydroxy cyclopentenones. This is apparently the first reported Nazarov reaction that takes place in the presence of base.

Full text of DOI:10.1021/ol050970x

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2771-2774
r
r
-Hydroxy Cyclopentenones from
-Diketones
William A. Batson, Divakaramenon Sethumadhavan, and Marcus A. Tius*
Department of Chemistry, 2545 The Mall, UniVersity of Hawaii,
Honolulu, Hawaii 96822, and The Cancer Research Center of Hawaii,
1236 Lauhala Street, Honolulu, Hawaii 96813
tius@gold.chem.hawaii.edu
Received April 29, 2005
ABSTRACT
Metalloenolates derived from
r,â-unsaturated r-diketones undergo cyclization to r-hydroxy cyclopentenones. This is apparently the first
reported Nazarov reaction that takes place in the presence of base.
We recently described two related palladium(II)-catalyzed
cyclizations of R-alkoxy dienones that led to cyclopenten-
ones.1 The two processes are illustrated in Scheme 1.
one 2, but not dienone 3, could also have been formed
through a conventional cationic 4π electrocyclization,2 the
evidence suggested otherwise. The question we had was
whether there might be additional processes operating on
acyclic dienones or on closely related structures, such as
R-diketone 4, that lead to R-hydroxycyclopentenones. What
follows is a preliminary account of our findings.
Scheme 1
Scheme 2 summarizes our results. Exposure of R-diketone
4 to a small excess of lithium tetramethylpiperidide (LiTMP)
in THF at -78 °C led to R-hydroxycyclopentenone 2 in 71%
yield.3 The same product is formed in 63% yield through a
slower process that is catalyzed by Yb(OTf)3 and other Lewis
acids in the presence of an amine base.4,5 A very rapid ring
closure of 4 is catalyzed by triflic acid, leading to furanone
5 in 78% yield, whereas treatment of 4 with tert-butyldi-
methylsilyl triflate leads to silyloxyfuran 6 in 76% yield. It
is possible that all four reactions are mechanistically related.
Since we are most interested in carbocyclizations, these have
been examined first.6
Exposure of ketone 1 to PdCl2(MeCN)2 in wet acetone led
to R-hydroxycyclopentenone 2, whereas Pd(OAc)2 in DMSO
led to dienone 3 through an oxidative process. The occur-
rence of 2 in very small quantities in the Pd(OAc)2-catalyzed
reactions suggested a common mechanism involving the
intermediacy of a palladium enolate. Although cyclopenten-
(2) For a reviews of the Nazarov reaction, see: (a) Habermas, K. L.;
Denmark, S.; Jones, T. K. in Organic Reactions; Paquette, L. A., Ed.; John
Wiley & Sons: New York, 1994; Vol. 45, pp 1-158. (b) Harmata, M.
Chemtracts 2004, 17, 416-435. (c) Frontier, A.; Collison, C. Tetrahedron
2005, in press. For an example of an application of the Nazarov cyclization
in synthesis, see: Bender, J. A.; Arif, A. M.; West, F. G. J. Am. Chem.
Soc. 1999, 121, 7443-7444.
(1) Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 4927-4930.
10.1021/ol050970x CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/25/2005

Table 1. 2-Hydroxycyclopentenonesa
Scheme 2
Table 1 lists our results. The R-diketone starting materials
were conveniently prepared by combining the lithio anions
derived from the cyanohydrin trimethylsilyl ethers of R,â-
unsaturated aldehydes with saturated aldehydes.7,8 The ad-
dition reaction is accompanied by migration of the trimeth-
ylsilyl group, which is cleaved hydrolytically under mild
conditions to produce an R-hydroxyketone. Oxidation with
IBX leads to the R-diketone.9,10
Amide base-catalyzed cyclizations were performed with
LiTMP in THF. In the case of 4, cyclization also took place
when the R-diketone enolate was prepared with LHMDS
(40% yield) or with LDA (72% yield). In the case of diketone
7, exposure to LDA led to R-ketol 28, presumably as a result
of hydride transfer from the isopropyl group of LDA in a
surprisingly efficient process. Since hydride transfer from
LDA appeared to be faster than the desired cyclization in
some cases, all reactions were performed with LiTMP. The
cyclization generally proceeded in good yield; however, the
process failed in the case of tetrasubstituted alkenes. For
example, diketones 29 and 30 that lack a â olefinic hydrogen
atom failed to undergo cyclization when exposed to LiTMP.
Diketones 29 and 30 also failed to undergo cyclization under
Lewis acid catalysis.
The Yb(OTf)3-catalyzed reactions were performed in
DMSO in the presence of pyrrolidine.11 Although we were
(3) General Procedure for the LiTMP-Mediated Cyclization. A
solution of LiTMP (0.5 M, 1.1 equiv) was prepared by the addition of
n-BuLi to TMP in THF at 0 °C. The solution was kept at 0 °C for 0.5 h
and then was cooled to -78 °C. During this time, the R-diketone was
dissolved in THF (0.1 M) and allowed to stand over activated 4 Å molecular
sieves for 0.5 h under nitrogen. The dry R-diketone was quickly added to
the cold stirring solution of LiTMP via cannula at -78 °C. The reaction
mixture was allowed to warm to room temperature over 15 min and was
allowed to stir until the reaction was complete, as judged by TLC (ca. 2-24
h). The reaction mixture was cooled to 0 °C, 1 M HCl was added, and the
aqueous phase was extracted with Et2O. The organic phase was dried
(MgSO4), concentrated and purified by flash column chromatography over
silica gel (5% EtOAc/hexanes) to afford the R-hydroxycyclopentenone.
(4) Scandium triflate has been used for an asymmetric Nazarov cycliza-
tion of divinyl ketones: Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004,
126, 9544-9545.
a The first yield refers to the LiTMP-mediated process, whereas the
second refers to the process catalyzed by Yb(OTf)3 and pyrrolidine. b The
sole product of the LiTMP mediated reaction was 8. c A 4/1 mixture (not
separated) of 8 and 9 was formed from the Yb(OTf)3-mediated reaction.
d These reactions were not performed.
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Org. Lett., Vol. 7, No. 13, 2005

tempted to postulate an enamine intermediate, this is unlikely
to be the case, since the cyclization also took place when
N-methylpyrrolidine was used in place of pyrrolidine. The
Lewis acid catalyzed process appears to take place under
kinetic control. For example, diketone 7 (Table 1, entry 1)
leads to a ca. 4/1 mixture of products 8 and 9. The negligible
difference in stability between these two isomers suggests
that keto-enol equilibration is slow under the reaction
conditions. In the case of diketone 4 (Scheme 2), Yb(OTf)3
was the most effective of the Lewis acids that we screened
in promoting the desired cyclization. Inferior yields of 2 were
obtained from reactions catalyzed by Cu(OTf)2, Sc(OTf)3,
La(OTf)3, or InCl3 (31%, 32%, 36%, or 26% yield, respec-
tively). The same Lewis acids were screened for the
cyclizations of diketone 10 (Table 1, entry 2). The yield of
cyclopentenone 11 from the Cu(OTf)2-, Sc(OTf)3-, La-
(OTf)3-, and InCl3-catalyzed reactions was 96%, 48%, 90%,
and 91%, respectively. It appears that R branching in the
diketone facilitates the Lewis acid-catalyzed cyclizations.
The mechanism of the LiTMP-mediated process will be
considered first, using 4 as the example. It is reasonable to
assume that enolization of 4 precedes cyclization. The
intramolecular Michael addition of the enolate to the enone
is precluded by poor orbital overlap (this would represent a
5-endo-trig ring closure, which is disallowed by Baldwin’s
Rules).12 However, an electrocyclic process involving the
internally chelated lithium enolate 31 (M ) Li) cannot be
ruled out. The Lewis acid-catalyzed cyclizations of the
diketones may proceed through a related mechanism, whereby
bidentate complexation of the metal salt by the two carbonyl
oxygen atoms is followed by proton abstraction by the amine
base to give enolate 31 (M ) Yb(OTf)2), which subsequently
undergoes conrotatory ring closure. If this mechanistic
hypothesis is valid, these cyclizations represent the first
examples of Nazarov reactions of metalloenolates. Some
years ago, in the context of allene ether Nazarov reactions
we made the observation that polarization of one of the
alkenes flanking the ketone carbonyl group by means of an
electron-donating oxygen atom accelerates the cyclization.13
These enolate cyclizations may represent extreme examples
of the same phenomenon.14
If the cyclizations of R-diketones do indeed take place
through the intermediacy of enolates, it is reasonable to
postulate that R substitution by an electron-withdrawing
group is likely to facilitate the process. The result shown in
Scheme 3 lends some credence to this hypothesis. Mor-
Scheme 3
pholino enamide 3215 was treated with the R lithio anion
derived from tetrahydropyranyl vinyl ether16 to give dienone
33 in 94% yield. Exposure of an ethereal solution of 33
containing 1 mL of water to a small excess of NBS at room
temperature led to bromide 34 in 82% yield following
column chromatography as a labile pale yellow oil. This
material underwent slow decomposition upon storage at 4
°C neat; however, in chloroform solution at room temperature
over 2 days it underwent partial cyclization to bromocyclo-
pentenone 35 spontaneously. Exposure of 34 to LiTMP in
THF at -78 °C, followed by warming, led to 35 in 74%
yield as a single (trans) isomer. These results suggest that
the chemistry is likely to offer considerable opportunities
for the synthesis of multifunctional cyclopentenones.
In summary, mechanistically interesting cyclization reac-
tions that may be categorized as Nazarov reactions have been
described. If indeed these reactions represent conrotations,
they are apparently the first such reactions to be described
for enolates.17 The cyclizations that lead to heterocycles 5
and 6 are likely to be part of a much larger family of
heterocycle-forming electrocyclizations.
(5) General Procedure of the Yb(OTf)3-Mediated Cyclization. The
R-diketone and Yb(OTf)3 were dissolved in DMSO (0.04-0.1 M) at room
temperature under nitrogen. To this solution was added pyrrolidine (1 equiv),
and the reaction mixture was allowed to stir at room temperature until the
reaction was judged to be complete by TLC (ca. 6-24 h). The solution
was diluted with water and the aqueous phase was extracted with Et2O.
The organic phase was dried (MgSO4), concentrated, and purified by flash
column chromatography over silica gel (5% EtOAc/hexanes) to afford the
R-hydroxycyclopentenone.
(13) Tius, M. A.; Kwok, C.-K.; Gu, X-q.; Zhao, C. Synth. Commun.
1994, 24, 871-885.
(6) Tius, M. A. Acc. Chem. Res. 2003, 36, 284-290.
(7) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.; Prasad, A. R.
Tetrahedron Lett. 2002, 43, 9703-9706.
(14) Polarization of the alkene by electron withdrawal also accelerates
the Nazarov cyclization: He, W.; Sun, X.; Frontier, A. J. J. Am. Chem.
Soc. 2003, 125, 14278-14279.
(8) (a) Hertenstein, U.; Hu¨nig, S.; O¨ ller, M. Synthesis 1976, 416-417.
(b) Fischer, K.; Hu¨nig, S. Chem. Ber. 1986, 119, 3344-3362.
(9) Moore, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003.
(10) For an alternative approach to similar compounds, see: Williams,
D. R.; Robinson, L. A.; Amato, G. S.; Osterhout, M. H. J. Org. Chem.
1992, 57, 3740-3744.
(15) Harrington, P. E.; Murai, T.; Chu, C., Tius, M. A. J. Am. Chem
Soc. 2002, 124, 10091-10100.
(16) Tamao, K.; Nakagawa, Y.; Arai, H.; Higuchi, N.; Ito, Y. J. Am.
Chem. Soc. 1988, 110, 3712-3714; see footnote 9.
(17) Professor David R. Williams (Indiana University) has alerted us to
unpublished work from his research program that demonstrates the Nazarov
reaction of an R-diketone upon exposure to BF3‚Et2O in refluxing 1,2-
dichloroethane. The vigorous conditions for cyclization are consistent with
a process that proceeds through Lewis acid activation of the enol form of
the diketone rather than a process involving an enolate, as we have postulated
in this paper. Professor Williams’ unpublished work is discussed in the
following review article: Rodr´ıguez, A.; Gonza´lez, E.; Ram´ırez, C.
Tetrahedron 1998, 54, 11683-11729. See compound 164.
(11) The reaction worked best in DMSO that had not been scrupulously
dried.
(12) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-736.
(b) Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.;
Thomas, R. C. J. Chem. Soc., Chem. Commun. 1976, 736-738. (c) Baldwin,
J. E.; Kruse, L. I. J. Chem. Soc., Chem. Commun. 1977, 233-235. (d)
Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org. Chem.
1977, 42, 3846-3852.
Org. Lett., Vol. 7, No. 13, 2005
2773

Acknowledgment. We thank the National Institutes of
Health (GM57873) for generous support.
5-27 and 33-35; spectroscopic data and reproductions of
1H and 13C NMR spectra for 5-27 and 33-35. This material
is available free of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: Assignment of ster-
1
eochemistry for 8, 23, and 35. H and 13C NMR data for
OL050970X
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Org. Lett., Vol. 7, No. 13, 2005