Lithium naphthalenide induced reductive cleavage of a,b-epoxy ketones: an
efficient procedure for the preparation of b-hydroxy ketones
Renata Jankowska,a George L. Mheheb and Hsing-Jang Liu*a†
a Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada, T6G 2G2
b Department of Chemistry, University of Dar-Es-Salaam, PO Box 35061, Dar-Es-Salaam, Tanzania
Received (in Cambridge, UK) 10th June 1999, Accepted 6th July 1999
Lithium naphthalenide presents itself as a mild and efficient
reagent for the cleavage of a,b-epoxy ketones to give the
corresponding b-hydroxy ketones in good yields.
ml) at 278 °C. The resulting solution was stirred at 278 °C
under an atmosphere of argon for 10 min. Then water (1 ml) was
added, and the resulting solution was allowed to warm up to
room temperature, diluted with water (4 ml) and extracted with
Et2O (15 ml). Usual work-up of the ethereal solution gave the b-
hydroxy ketone 2 in 78% yield after flash chromatography on
silica gel (prewashed with a 1% solution of Et3N in hexanes),
eluting with a 15% solution of EtOAc in hexanes containing a
small amount of Et3N (5 drops in 100 ml of solution). The
generality of this procedure is evident from the results obtained
for a number of a,b-epoxy ketones examined (Table 1). In all
cases, products were obtained in synthetically useful yields,
many of which are superior to those obtained using other
reducing agents. For example, the reduction of epoxide 3
derived from (R)-carvone was found to be ineffective with
samarium diiodide.6 With lithium in liquid ammonia, it gave
only 35% yield of the desired product 4.4b In the present case
with LN, a considerably higher yield of 4 (62%) was realized.
As another example, many attempts previously made to
introduce the b-hydroxy ketone moiety to steroidal compounds
often met with undesirable results.4c,d,8 Again, by the use of LN
under the described conditions, two isomeric steroidal epoxy
ketones (entries 8 and 9) were readily reduced to the
corresponding b-hydroxy ketones.
b-Hydroxy ketones and the closely related 1,3-diol group are
important functionalities, which are found in prostaglandins,1
taxol and congeners,2 and many other interesting natural
products. b-Hydroxy ketones are commonly prepared by an
aldol condensation reaction3 or by reductive cleavage of an a,b-
epoxy ketone. The aldol process proved to be highly useful for
the preparation of ‘acyclic’ b-hydroxy ketones. For cyclic b-
hydroxy ketones, however, this method cannot be generally
applied efficiently due to the lack of stereo- and regio-control in
general, side reactions such as the intermolecular aldol, and
further reactions (e.g. dehydration) of the desired products.
Many reagents have been found to be effective for the reductive
cleavage of a,b-epoxy ketones, which are readily accessible
from conjugated enones and allylic alcohols with stereocontrol
and possible asymmetric induction, including alkali metal in
liquid ammonia,4 zinc in acetic acid,5 samarium diiodide,6
aluminium amalgam,7 chromous salts in alcohol,8 organoselen-
ium borate complex,9 sodium hydrogen telluride,10 sodium
iodide in conjunction with sodium acetate,11 and the combina-
tion of palladium, formic acid and triethylamine.12 It has also
been shown that the reductive cleavage can be carried out
electrochemically.13 The yields of the desired b-hydroxy
ketones, however, are often inconsistent by the use of many of
the existing procedures. This is mainly because of the intrinsic
instability of the b-hydroxy ketone system which may undergo
facile dehydration or retro-aldol reaction even under weakly
acidic or basic conditions at somewhat higher temperature over
somewhat longer reaction time. Herein we describe an efficient
and apparently general procedure for the reductive cleavage of
a,b-epoxy ketones to the corresponding b-hydroxy ketones
under very mild conditions, which minimize the side reac-
tions.
In light of its generality, operational simplicity, good yield in
product formation, and the mild reaction conditions under
which many functional groups are known to be unaffected
towards LN,14 the aforementioned procedure promises to be a
method of choice for the synthesis of b-hydroxy ketones via
reductive cleavage of the corresponding epoxy ketones. As
illustrated by the following experimental results, this procedure
can be extended to facilitate the preparation of a,a-disubstituted
b-hydroxy ketones via alkylation of the ensuing enolate
produced from the reductive cleavage of the epoxy ring and of
2,2-disubstituted 1,3-diones by subsequent oxidation. Treat-
ment of epoxy ketone 3 with LN in tetrahydrofuran under the
standard conditions (vide supra) for 30 min, followed by
addition of MeI (5 equiv.) and warming up to room temperature
resulted in the formation of b-hydroxy ketone 5 in 70% yield.
The new procedure, which is operationally simple, makes use
of lithium naphthalenide (LN) as the reducing agent. This
reagent, which can be easily prepared as a stable stock solution
by mixing equal parts of lithium metal and naphthalene in THF
at room temperature,14 was found to be highly effective for the
selective cleavage of the a,b-epoxy ketone system.‡ In a typical
experiment, a solution of epoxy ketone 1 (49 mg, 0.32 mmol) in
THF (2 ml) was added to a 0.34 M solution of LN in THF (2.8
When hydroxy ketone 5 was subjected to oxidation [PCC (5
equiv.), CH2Cl2, 20 °C, 8 h], diketone 6 was formed in 78%
yield.
We are grateful to the Natural Sciences and Engineering
Research Council of Canada and the University of Alberta for
financial support and to the University of Dar-Es-Salaam for
granting a sabbatical leave to G. L. M.
†
Present address: Department of Chemistry, National Tsing Hua
University, Hsinchu, Taiwan 30043, R.O.C. E-mail: hjliu@chem.nthu.
edu.tw
Chem. Commun., 1999, 1581–1582
1581
Jankowska, Renata
