Efficient and selective catalytic oxidative cleavage of α-hydroxy ketones using vanadium-based HPA and dioxygen

Article abstract of DOI:10.1039/b106969a

The combination of H_{3 + n}[PMo_{12 - n}V_nO ₄₀]·aq (HPA-n, n = 3) and dioxygen provides a clean and regioselective reagent for the homolytic cleavage of various representative α-hydroxy ketones (primary to tertiary) and turns out to be as efficient for the catalytic ring opening of chiral natural products.

Full text of DOI:10.1039/b106969a

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Efficient and selective catalytic oxidative cleavage of a-hydroxy
ketones using vanadium-based HPA and dioxygen
Leïla El Aakel,ab Franck Launay,*a Ahmed Atlamsanib and Jean-Marie Brégeaulta
a Laboratoire des Systèmes Interfaciaux à l’Echelle Nanométrique, Université Pierre et Marie Curie,
unité CNRS 2312, case 196, 4 place Jussieu, 75252 Paris cedex 05, France.
E-mail: flaunay@ccr.jussieu.fr; Fax: 33 (0)1 44 27 55 36
b Laboratoire de Chimie Physique Appliquée, Département de Chimie, Faculté des Sciences, Université
Abdelmalek-Essaadi, BP2121, 93000 Tétouan, Morocco
Received (in Cambridge, UK) 2nd August 2001, Accepted 18th August 2001
First published as an Advance Article on the web 5th October 2001
The combination of H3 + n[PMo12 2 nVnO 40]·aq (HPA-n, n =
3) and dioxygen provides a clean and regioselective reagent
for the homolytic cleavage of various representative a-
hydroxy ketones (primary to tertiary) and turns out to be as
efficient for the catalytic ring opening of chiral natural
products.
The conversion of the 2-hydroxycyclohexanone dimer to the
monomer with accessible hydroxy and carbonyl groups proved
to be an important prerequesite for the exclusive scission of this
bond. Otherwise, significant amounts of 2-methoxybutane-
dioate were formed. In fact, the availability of both groups is not
necessary for the occurrence of the desired reaction in methanol,
as shown in Table 1 (runs 3 and 4). Comparison of the
conversion rates (not shown) of 2,2-dimethoxycyclohexanol, a
potential intermediate under acidic conditions, and 2-methoxy-
cyclohexanone showed clearly the negative effects of the OH
substituent. These results are consistent with a mechanism in
which there is substrate pre-coordination to [VO2]+ species.2,7
The use of ‘HPA-3’ as a catalyst for the aerobic C–C bond
cleavage of a-ketols was then applied successfully to a range of
representative substrates (Table 2). For all the benzoyl deriva-
tives (3a–d), the reactions could be carried out at room
temperature with completion of dioxygen uptake within 5 h.
Methyl benzoate and/or benzoic acid were formed with
90–100% selectivity. Quantitative yields of other benzoyl
derivatives or cyclohexanone are obtained with 3b or 3d
respectively. In accordance with published results,2,7 the
outcome with 2-hydroxy-2-phenylacetophenone (3b, benzoin)
was much more sensitive to the nature of the solvent.
Significant amounts of 1,2-diphenylethanedione (benzil) were
produced in AcOH–H2O, whereas only carbon–carbon bond
cleavage products (benzaldehyde and its dimethyl ketal) and
methyl benzoate were formed at room temperature in metha-
nol.
Keggin type mixed-addenda heteropolyanions such as
[PMo12 2 nVnO40](3 + n)2, denoted HPA-n (n = 1, 2, 3, etc.),
have found many applications in catalysis.1 Recently, their
variable redox and acid–base properties have been used for the
catalytic cleavage of different cycloalkanones by dioxygen.2,3
Carboxylic acids, including adipic acid were obtained with high
yields and selectivities. Early mechanistic studies showed
clearly that the a-ketol (a-hydroxy ketone) is not a major
intermediate during cyclohexanone oxidation. In fact, 2-hy-
droxycyclohexanone is converted to adipic acid with a better
yield.
The oxidative cleavage of carbon–carbon bonds in a-ketols is
widely used in organic synthesis. In many synthetic schemes,
including that of Taxol®, ring opening strategies are based on
prior formation of a-hydroxy ketones.4 Most of the published
procedures use stoichiometric reagents.5 Efforts have been
made to find dioxygen-based catalytic pathways running either
with Bi(0)/Bi(III) salts or moisture-sensitive dichloro(ethoxy)-
oxy vanadium complexes.6 In this communication, we report on
the synthetic utility of the reaction catalysed by robust
oxidation-resistant compounds like vanadium-based HPA and
present a general route for the selective homolytic carbon–
carbon bond cleavage of a-hydroxy ketones.
Table 1 Oxidation of 2-hydroxycyclohexanone (1a) or its derivatives with
dioxygen catalysed by ‘HPA-3’a
Using 2-hydroxycyclohexanone (1a) and H6[PV3Mo9O40]·aq
as the catalyst precursor, the reaction was carried out either in
methanol or in an acetic acid–water mixture at 65 °C. Dioxygen
consumption was monitored by a gas burette system. Colour
changes of the initial solutions from orange to blue-green and
finally orange-brown were observed in both cases. They are
consistent with the variation of the oxidation state of vanadium
Conv.
Run Substrate
Solvent
MeOH
t/h (%)b Yield (%)b
1
2
3
4
2-Hydroxycyclohexanone
2-Hydroxycyclohexanone
2,2-Dimethoxycyclohexanol MeOH
2-Methoxycyclohexanone MeOH
10 100 90 (2a + 2b)
AcOH–H2O 3.5 100 80 (2a)
100 83 (2a + 2b)
54 67 52 (2b)
7
[V( )/V(IV)] and the overall reaction can be interpreted in terms
V
of a vanadium-catalysed process assisted by dioxygen. Under
dinitrogen the solution remained blue and there was no
significant reaction. The results are summarized in Table 1.
Regioselective cleavage of 1a gave adipic acid or its dimethyl
ester (Scheme 1) as the major products in acetic acid or
methanol, respectively (runs 1 and 2). As shown in a blank
experiment, adipic acid (2a) conversion to dimethyl adipate
(2b) was also catalysed by ‘HPA-3’† in methanol (100% yield
in 1.5 h).
a Reaction conditions: substrate (7.7 mmol), ‘HPA-3’ (0.078 mmol), MeOH
(7 ml) or AcOH–H2O (6.3+0.7 ml), dioxygen pressure (0.1 MPa),
temperature (65 °C) stirred at 1000 rpm; b Conversions (% of substrate
consumed) and yields [(mmol of product per mmol substrate) 3 100] were
determined by GC analysis (OV1701) after the addition of an ethereal
solution of diazomethane to the crude mixture using methyl heptanoate as
internal standard. Products were identified by GC-MS (RTX5-MS).
The in situ esterification yield, as determined by comparison
of the diester (2b) amounts before and after addition of an
ethereal solution of diazomethane was about 85–90%. Very low
yields ( < 1%) of glutaric acid derivatives were obtained. In
methanol, the major by-products identified as methyl 6-oxohex-
anoate (2c) and methyl 6,6-dimethoxyhexanoate (2d) also arise
from the cleavage of the C(O)–CH(OH) bond.
Scheme 1
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Chem. Commun., 2001, 2218–2219
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106969a

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Table 2 ‘HPA-3’-catalysed oxidative cleavage of a-ketolsa
Conv.
(%)b
O2/Subst.
(molar ratio)
Run
a-Ketol
Solvent
Product(s) [Yield (%)]b
5
6
7
8
2-Hydroxyacetophenonec(3a)
MeOH
AcOH–H2O
MeOH
AcOH–H2O
MeOH
AcOH–H2O
MeOH
100
100
100
100
100
100
100
60
PhCO2Me (97)
PhCO2H (100)
PhCO2Me (110); PhCHO (45); PhCH(OMe)2 (45)
PhCO2H (81); PhCHO (1); PhCOCOPh (47)
PhCO2Me (97)
PhCO2H (100)
PhCO2Me (100); C6H10(†O) (100)
PhCO2H (54); C6H10(†O) (60)
1.2
2-Hydroxyacetophenonec(3a)
1.05
0.77
0.75
0.70
0.50
0.80
0.35
2-Hydroxy-2-phenylacetophenone (3b)
2-Hydroxy-2-phenylacetophenone (3b)
2-Hydroxy-2-methylpropiophenonec(3c)
2-Hydroxy-2-methylpropiophenonec(3c)
1-Hydroxycyclohexyl phenyl ketone (3d)
1-Hydroxycyclohexyl phenyl ketone (3d)
9
10
11
12
AcOH–H2O
a Reaction conditions: substrate (7.7 mmol), ‘HPA-3’ (0.078 mmol), MeOH (7 ml) or AcOH–H2O (6.3+0.7 ml), dioxygen pressure (0.1 MPa), room
temperature. b See Table 1. c Formaldehyde and acetone or their oxidized derivatives were not determined.
Notes and references
† The heteropolyacids ‘HPA-3’ were prepared according to described
procedures.10 Their elemental analysis gave P, 1.7, Mo, 45.5, V, 7.75%
which is consistent with the formula ‘H6[PV3Mo9O40]·11H2 O’. Solid
HPA-n and their aqueous solutions are multi-component systems: they
contain several polyanions, positional isomers of these, [VO2]+ and often
traces of V(IV).
‡ Methyl esters obtained from the oxidation of (1S,2S,5S) or (1R,2R,5R)-
2-hydroxypinan-3-one were characterized by their [MNH4]+ and [MH]+
signals at 216 and 199 Da, respectively, using GC-MS/CI+ (NH3). Complete
retention of configuration of both asymmetric carbon atoms in the 1S,3S and
1R,3R compounds was established by NOE 1H NMR studies. Specific
rotations of the diastereoisomeric mixtures isolated from the oxidation of
(1S,2S,5S)-2-hydroxypinan-3-one at 65 °C or its enantiomer (1R,2R,5R) at
RT were +65.1 deg cm2 g21(c 2.17, CHCl3) and 281.4 1021 deg cm2 g21(c
5.03, CHCl3), respectively, in accordance with data for the pure com-
pounds.11
§ The IUPAC name for pinonic acid is 3-acetyl-2,2-dimethylcyclobutane-
acetic acid.
Scheme 2
Clean oxidation of 3d to methyl benzoate or benzoic acid and
1 I. V. Kozhevnikov, Chem. Rev., 1998, 98, 171; M. Misono, Chem.
cyclohexanone was only possible at room temperature; other-
Commun., 2001, 1141.
wise subsequent cleavage of the cycloalkanone becomes
significant.3 The oxygen consumed–substrate molar ratio was in
good agreement with the stoichiometric values (Table 2). The
dioxygen uptake for primary a-ketols (3a) was roughly twice
that for tertiary ones (3c,d) as expected for pure C–C bond
cleavage (runs 6, 10 and 12).
The same experimental procedure was successfully applied
to natural compounds. For example, the oxidative cleavage of
(1S,2S,5S)-2-hydroxypinan-3-one(4a) or its enantiomer (4b)
led to the diastereoselective formation of methyl esters‡ of the
corresponding cis-pinonic acids§ with 100% conversion
(Scheme 2).
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The epimerization of the cyclobutane carbon atom (C3)
linked to the acyl group under acidic conditions is well-
documented8 but this competing reaction did not exceed 10% at
65 °C and did not occur at all at room temperature.
Cyclobutane-derived amino-acids and related peptides iso-
lated from natural sources display interesting biological proper-
ties, and methyl pinonates are very important chiral cyclobutane
synthons. However, stereoselective methodologies based usu-
ally on a-pinene oxidation are scant9 and our approach
corresponds to a convenient green alternative.
In conclusion, the present study has proved that the aerobic
oxidative cleavage of a-hydroxy ketones (or a-hydroxy ketals)
catalysed by ‘HPA-3’ could replace stoichiometric polluting
reagents either for large-scale products or for fine chemicals
synthesis. We are currently investigating the mechanism as well
as the supported counterpart of these catalysts.
Financial support by the Comité franco-marocain (AI
217/SM/00) is gratefully acknowledged.
Chem. Commun., 2001, 2218–2219
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