SHORT PAPER
547
Enhanced Catalytic Activity and Selectivity in Oxidation of -Isophorone to
Ketoisophorone with Phosphomolybdic Acid
Eamonn F. Murphy,a Michael Schneider,b Tamas Mallat,a Alfons Baikera*
aLaboratory of Technical Chemistry, Swiss Federal Institute of Technology, ETH-Zentrum, 8092 Zurich, Switzerland
Fax +41(01)6321163; E-mail: baiker@tech.chem.ethz.ch
bF. Hoffmann-La Roche Ltd., Vitamins and Fine Chemicals Division, Research and Technology Development, 4070 Basel, Switzerland
Received 9 November 2000; revised 18 December 2000
Abstract: Aerobic allylic oxidation of -isophorone with phospho-
molybdic acid as catalyst in combination with DMSO and potassi-
um tert-butoxide provides ketoisophorone in unprecedented high
yield. This study suggests that the solvent can play a pivotal role in
directing selectivity in allylic oxidations of highly substituted cyclic
olefins.
Key words: isophorone, oxidations, catalysis, oxygen, DMSO
Selective aerobic allylic oxidation of cyclic olefins is a
synthetically useful and environment-friendly conversion
which currently attracts considerable attention.1 Catalytic
allylic oxidations are, however, characterized by the for-
mation of product mixtures containing allylic ketones, al-
cohols and competitive epoxidation products. The
Scheme Catalytic oxidation of isophorone to ketoisophorone with
dioxygen
compared to 45% in the solvent-free system.6 At low
difficulties encountered are highlighted in the allylic oxi-
-isophorone (1) conversion, the selectivity to ketoiso-
dation of the isophorone isomers (1 and 2), in particular,
phorone (3) is high (approx. 90%) and decreases to 70%
-isophorone (1) to ketoisophorone (3) (Scheme). Interest
as the reaction proceeds. Small amounts of formyliso-
in this conversion stems from the availability of isophor-
phorone (4) (entry 2), formed by competitive allylic oxi-
dation at the -methyl group, were detected at short
one as starting material and the fact that ketoisophorone
(3) is a versatile intermediate for the preparation of vari-
ous flavoring and fragrance fine chemicals.2 Ketoisophor-
one (3) is currently obtained in >90% yield via
homogeneous liquid phase oxidation of -isophorone
(2).3,4 On the other hand, investigations of the catalytic ox-
idation of -isophorone (1) using known allylic oxidation
catalysts provided ketoisophorone (3) in poor yields.5-10
Given the interest in ketoisophorone (3), an effective di-
rect oxidation of -isophorone (1) to this product, elimi-
nating the intermediate isomerization step (Scheme),11 is
intrinsically attractive. In the present contribution we re-
port that phosphomolybdic acid (PMA) in combination
with a highly polar aprotic solvent (DMSO) and a strong
base (KOBut) gives almost quantitative conversion of -
isophorone (1) under relatively mild reaction conditions
while providing ketoisophorone (3) in good yield.
reaction times and appeared to further react probably via
a pinacol cross-coupling of the aldehyde as the reaction
progressed.12 The reduction in selectivity on addition of
DMSO to the catalyst-free autoxidation of -isophorone
(1) (entries 4, 5) is compensated for by the introduction of
KOBut to the -IP/DMSO mixture (entry 3). Importantly,
addition of DMSO to catalytic oxidations with -IP/PMA
more than doubles conversion accompanied by a signifi-
cant increase in selectivity to ketoisophorone (3) (entries
6, 7). An extensive study of alternative solvents showed
that oxidation was not observed in low boiling point sol-
vents (< 90 °C). In benzonitrile, for example, conversion
and selectivity were significantly reduced (entry 9). Based
on the observations that only negligible amounts of ke-
toisophorone (3) (< 1.0%) were observed under catalytic
reaction conditions in the absence of oxygen, and that the
addition of DMSO did not influence conversion in the au-
toxidation of -isophorone (1) (entry 4), it seems unlikely
that DMSO is directly involved in oxygen transfer to -
isophorone (1). Small amounts of methyl sulfide detected
by GC-MS analysis during ketoisophorone (3) synthesis
may be a result of a reaction of DMSO with phosphomo-
lybdic acid. Therefore, the significant role of DMSO in
the -isophorone oxidation may be attributed to its high
proton solvating power.13 Following proton abstraction
from -isophorone (1), the oxidation of the enolate inter-
Results for the phosphomolybdic acid (PMA) catalyzed
allylic oxidation of -isophorone (1) ( -IP) to ketoiso-
phorone (3) in DMSO, based on GC-MS analysis of the
reaction mixtures, are summarized in Table 1. In all cases,
subsequent work-up of the reactions gave isolated yields
2 6% lower than those determined by GC-MS analysis.
With PMA/DMSO/KOBut almost quantitative conversion
of -isophorone (1) is achieved in remarkably short reac-
tion times (24 h versus 95 h) simultaneously providing ap-
prox. 70% yield of ketoisophorone (3) (entry 1) as
Synthesis 2001, No. 4, 547–549 ISSN 0039-7881 © Thieme Stuttgart · New York