Highly chemoselective, oxyvanadium-catalysed cleavage of á-hydroxy
ketones
Masayuki Kirihara, Shinobu Takizawa and Takefumi Momose*
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University,
Sugitani 2630, Toyama 930-01, Japan
á-Hydroxy ketones (á-ketols) can be cleaved chemoselec-
tively with a catalytic amount of dichloroethoxyoxyvana-
dium under an oxygen atmosphere.
OH
O
OH
or
X
1 mol% VO(OEt)Cl2,O2
EtOH, reflux
No reaction
(
)n
The oxidative cleavage of a carbon᎐carbon bond in α-hydroxy
ketones is one of the most important processes in organic syn-
3
4 n = 3, X = OAc
5
n = 3, X = SPh
1
–6
thesis, and several kinds of oxidants are used for this purpose.
6 n = 1, X = NH2
2
The most versatile reagents are periodic acid (and its salts),
O
3
4
CO2Et
calcium hypochlorite and lead tetraacetate. Although these
reagents cause bond fission effectively in α-hydroxy ketones,
a stoichiometric amount of the reagent is required in all cases.
We now report that α-hydroxy ketones can be cleaved effi-
ciently with a catalytic amount of dichloroethoxyoxyvanadium
OH
OH
1
mol% VO(OEt)Cl2,O2
CO Et
2
EtOH, rt, 15 min
OH
7
8 (74%)
[
VO(OEt)Cl ]† under an oxygen atmosphere in ethanol. The
2
Scheme 2
results are summarised in Table 1.
The oxidation of ketones bearing a secondary α-hydroxy
group (1b–h) gave diesters (2b–h) (entries 2–4), while those with
a tertiary hydroxy group (1i,j) resulted in the formation of keto
esters (2i,j) (entries 5 and 6) in moderate to high yields. With 1i,j
other reagents (lead tetraacetate, sodium periodate or calcium
hypochlorite) gave the products 2 in poor yields. Although a
similar reaction of 2-methylcyclohexanone has been reported
In the presence of a radical inhibitor [2,6-di(tert-butyl)-p-
cresol], the reaction of ketone 1d, bearing a secondary α-
hydroxy group, did not give a diester but the 1,2-diketone 9. The
same result was obtained when acetonitrile was used as solvent
instead of ethanol. The 1,2-diketone 9 was cleaved efficiently
with VO(OEt)Cl under an oxygen atmosphere. A ketone with a
2
tertiary α-hydroxy group, 1i, was inert under these reaction
conditions. Although the reaction mechanism is unknown,
these results suggest that this reaction involves radical inter-
mediates and that ethanol is essential to the cleavage. Molecular
oxygen acts as the co-oxidant and reoxidises the low valent
vanadium compound formed, thus a stoichiometric amount, or
7
to afford ethyl 6-oxoheptanoate, in the present case reaction of
2
-hydroxy-6-methylcyclohexanone 1k resulted in the regioselec-
tive bond-cleavage of C(1)᎐C(2) (α-cleavage) with complete
regioselectivity (Scheme 1).‡ The high chemoselectivity was
O
more, of VO(OEt)Cl reacted with 1d in the absence of oxygen
2
CO2Et
Me
OH
Me
to give 2d (Scheme 3). The result is in sharp contrast to that
1
mol% VO(OEt)Cl2,O2
EtOH, rt, 0.5 h
2
CO Et
O
1
k
1 mol% VO(OEt)Cl2
2
k (81%)
2
mol% 2,6-di(tert-butyl)-p-
O
cresol, O2, EtOH (56%)
EtO2C OH
O
or 1 mol% VO(OEt)Cl2
O2, MeCN (76%)
( )3
1
9
OH
Me
mol% VO(OEt)Cl2
O2, EtOH (90%)
CO2Et
CO2Et
O
( )3
2
k′
200 mol% VO(OEt)Cl2,
N2, EtOH (53%)
1
d
Scheme 1
(
)3
2
d
evidenced by the fact that α-acetoxy- (4), α-phenylthio- (5) and
α-amino-cyclohexanone (6) or cis- and trans-cyclohexane-1,2-
diol (3) were found to be inert under the conditions examined,
and was evidently illustrated by the reaction of an α,β-
dihydroxy ketone 7 where only α-cleavage was found to partici-
pate (Scheme 2).§ These results are in contrast to those with
other oxidants which cleave both α-hydroxy ketones and 1,2-
O
1
mol% VO(OEt)Cl2
OH
Me
2 mol% 2,6-di(tert-butyl)-p-
cresol, O2, EtOH
No reaction
or 1 mol% VO(OEt)Cl2
O2, MeCN
1
i
2–6
Scheme 3
diols.
seen in the reaction of 2-alkylcyclohexanone with VO(OEt)Cl2,
where only a trace amount of the product is obtained in the
absence of oxygen.
Further details of the reaction mechanisms are currently
under investigation.
†
Dichloroethoxyoxyvanadium was prepared by a known procedure:
see ref. 7.
Diethyl 2-methylhexanedioate 2k was the only product isolated.
Ethyl 2-hydroxy-6-oxoheptanoate 2kЈ was not obtained.
The sole product isolated was the hydroxy diester 8.
7
‡
§
J. Chem. Soc., Perkin Trans. 1, 1998
7