Chemoselective oxidation of secondary alcohols using a ruthenium phenylindenyl complex

Article abstract of DOI:10.1021/om301156v

A straightforward catalytic alcohol oxidation procedure using the recently reported complex [RuCl(PPh₃)₂(3-phenylindenyl)] (1) with KHMDS as cocatalyst, in acetone as the oxidant, is reported. Complex 1 shows remarkable chemoselectivity in oxidizing secondary alcohols to ketones.

Full text of DOI:10.1021/om301156v

Article
pubs.acs.org/Organometallics
Chemoselective Oxidation of Secondary Alcohols Using a Ruthenium
Phenylindenyl Complex
Simone Manzini, Cesar A. Urbina-Blanco, and Steven P. Nolan*
́
EaStCHEM School of Chemistry, University of St Andrews, St Andrews, U.K. KY16 9ST
*
S Supporting Information
ABSTRACT: A straightforward catalytic alcohol oxidation
procedure using the recently reported complex [RuCl-
(
PPh ) (3-phenylindenyl)] (1) with KHMDS as cocatalyst, in
3 2
acetone as the oxidant, is reported. Complex 1 shows
remarkable chemoselectivity in oxidizing secondary alcohols to
ketones.
3
4
he oxidation of primary and secondary alcohols to the
ruthenium. Indeed, the ruthenium-based complexes are
usually a good compromise between activity and price, as
already proven in a wide variety of reactions, such as olefin
T
corresponding aldehydes and ketones is a fundamental
1
reaction in organic synthesis. Traditionally, these trans-
3
5,36
37,38
25
formations have been performed using stoichiometric amounts
metathesis,
hydrogenation,
and oxidation, among
2
of oxidant, such as the Dess−Martin periodinane (DMP),
others.
3
4
Jones’s oxidant, and Swern’s methodology. However, these
methodologies often use toxic reagents or generate a significant
We proceeded to evaluate the catalytic activity of the recently
reported complex [RuCl(PPh ) (3-phenylindenyl)] (1). 1 can
be easily and inexpensively synthesized, starting from a suitable
propargylic alcohol and [RuCl (PPh ) ] (Scheme 2).
3
2
5
amount of waste.
39
In order to develop an efficient and greener alcohol oxidation
2 3 3
protocol, numerous catalytic systems have been reported in the
Complex 1 is extremely active in alcohol racemization
reactions, which are formally tandem hydrogenation/oxidation
processes. Additionally, as previously reported, 1 is remarkably
active in the hydrogenation of aldehydes, imines, and ketones,
6
−16
literature,
using a combination of organometallic complexes
and mild oxidants to regenerate the active species. Although
these procedures are a significant improvement, the co-oxidants
used are usually expensive reagents (for example TEMPO and
outperforming in activity the most commonly used ruthenium
8
,17
difficult to handle (such as using gaseous O2),18−21
39,40
Ag O),
catalysts.
For these reasons, we hypothesized that 1 could
2
or very reactive reagents, which are less compatible with
be an efficient catalyst for alcohol oxidation (Scheme 3).
Using the oxidation of benzhydrol as a benchmark reaction,
the reaction conditions were optimized (see Table 1). Complex
1 can catalyze alcohol oxidation at room temperature but
requires long reaction times to achieve complete conversions.
However, increasing the temperature significantly reduces the
reaction time (Table 1, entries 1 and 2). Using toluene as a co-
solvent has a beneficial effect on the reaction; in fact,
conversion reached 86% in 1 h at 56 °C, a 10% increase in
conversion in comparison to simply using acetone as solvent
(Table 1, entries 2 and 3). Moreover, this solvent combination
permits us to operate at higher temperatures, allowing
quantitative conversions in shorter reaction times. Indeed at
110 °C, the optimized condition, benzhydrol (2) is fully
oxidized to benzophenone (3) in just 0.5 h (Table 1, entry 6).
t
22−29
sensitive substrates (for example, H O and BuOOH).
2
2
Moreover, most of the complexes used contain expensive
metals, such as Pd or Ir, or costly ligands, making the systems
less suitable for large-scale reactions and for industrial
2
0,21,28,30−32
applications.
One of the best alternatives among the existing methods is
the Oppenauer oxidation, where the substrate is easily oxidized
via transfer of two hydrogen atoms by a metal complex into a
33
sacrificial ketone, such as acetone (Scheme 1).
In order to achieve an efficient oxidation system using a
relatively inexpensive metal complex, we focused on the use of
Scheme 1. Oppenauer Oxidation
Received: November 29, 2012
Published: January 15, 2013
©
2013 American Chemical Society
660
dx.doi.org/10.1021/om301156v | Organometallics 2013, 32, 660−664

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Article
Scheme 2. Synthesis of Complex 1
a
Scheme 3. Reactions Catalyzed by Complex 1
Table 2. Activity of Catalyst 1 with Different Bases
b
entry
base
conversn (%)
1
2
3
4
KHMDS
>99
97
t
KO Bu
KOH
94
K CO3
2
90
a
Reaction conditions: benzhydrol (0.25 mmol), base (2.5 mol %),
b
dissolved in 1/1 toluene/acetone (0.5 mL). Conversion determined
by H NMR from an average of at least two runs.
1
a
Table 1. Activity of Catalyst 1 under Various Conditions
perform alcohol oxidation in most “eco-friendly” solvents and
also, very interestingly, in water (Table 3, entry 5).
a
Table 3. Activity of Catalyst 1 under Different Conditions
cat. loading
(mol %)
conversn
b
entry solvent
T (°C)
t (h)
(%)
1
2
3
4
5
6
7
8
9
1
toluene room temp 16
0.5
0.5
0.5
0.5
0.5
0.5
0
45
72
86
79
90
>99
0
56
toluene 56
toluene 56
toluene 89
toluene 110
toluene 110
toluene 110
toluene 110
toluene 110
1
1
b
entry
solvent
conversn (%)
0.5
0.5
0.5
0.5
1
1
2
3
4
5
6
toluene
heptane
>99
96
80
79
96
77
cyclopentyl methyl ether
acetone
0.25
0.1
0.05
94
91
63
5
2-Me-THF
0
24
water
a
a
Reaction conditions: benzhydrol (0.25 mmol), KHMDS (2.5 mol %),
dissolved in 1/1 toluene/acetone (0.5 mL). Conversion determined
by H NMR from an average of at least two runs.
Reaction conditions: benzhydrol (0.25 mmol), KHMDS (2.5 mol %),
b
b
dissolved in 1/1 solvent/acetone (0.5 mL). Conversion determined
1
1
by H NMR from an average of at least two runs.
Taking further steps in the direction of a very green system,
we modified the co-oxidant used, in our case acetone, to a more
easily handled alternative. Indeed, the major issue with acetone
is its low flash point (−20 °C) that makes it very flammable and
less attractive for industrial-scale applications. To highlight
the utility of the system for industrial large-scale synthesis,
isobutyl methyl ketone, which has a higher flash point (14 °C),
was evaluated as the hydrogen acceptor (eq 1).
To test the limits of 1, a low catalyst loading screening was
performed (Table 1, entries 8−10). 1 shows a maximum
turnover number (TON) of 1250. This result demonstrates the
high activity of the catalysts and showcases 1 as one of the best
46
1
3,31,41−45
catalysts for the Oppenauer oxidation reaction.
Moreover, 1 also shows a remarkably high turnover frequency
TOF); for example, compound 2 is converted into the
(
−1
corresponding ketone with a TOF of 400 h .
Although KHMDS is one of the best bases for the catalytic
system used (as previously reported for the hydrogenation of
ketones), different bases were also screened (Table 2).
As shown above, it is possible to perform the oxidation with a
variety of bases, using cheaper bases such as KOH (Table 2,
entry 3) or milder conditions using, for example, K CO (Table
2
3
2
, entry 4).
This ketone shows good compatibility with the system,
although the conversion is lower than that with acetone (77%
conversion). However, as shown, the system is very versatile
A number of more industrially acceptable and “green”
46
solvents were next evaluated with this system. Complex 1 can
6
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Organometallics
Article
a
Table 4. Scope of the Oxidation Reaction
a
b
Reaction conditions: substrate (1 mmol), 1 (0.5 mol %), KHMDS (2.5 mol %), dissolved in 1/1 toluene/acetone (2 mL). Conversion determined
1
c
d
e
by H NMR from an average of at least two runs. Isolated yields are average of two runs. Presence of dimerized product (7%). Results in
parentheses are referred to the conversion into the desired product under the following reaction conditions: 5 mol % of 1 and 5 mol % of KHMDS
dissolved in 1/1 toluene/acetone (2 mL).
and leads to the possibility of using very mild conditions to
carry out the oxidation.
The tolerance of the catalytic system to different substrates
bearing various structural motifs was next examined, and the
6
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Organometallics
Article
results are presented in Table 4. Complex 1 exhibits high
activity in the oxidation of secondary alcohols, typically
achieving full conversions in 1 h. It is highly active with
aliphatic and aromatic substrates (Table 4). Alcohols bearing
electron-withdrawing substituents are less prone to be oxidized
than electron-rich analogues (Table 4, entries 4 and 5).
Substrates that are sterically hindered at the aromatic positions
are more difficult to oxidize; however, electronic effects appear
to have more impact than steric effects (Table 4, entries 5 and
underway to explore further applications of this easily accessible
complex.
49
EXPERIMENTAL SECTION
■
General Procedure for Oxidation Reactions. In a vial fitted
with a screw septum cap, benzhydrol (2; 0.25 mmol), 1 (0.00125
mmol), and base (0.005 mmol) were charged inside the glovebox and
dissolved in organic solvent (0.25 mL). To this mixture was added
acetone (or isobutyl methyl ketone) (0.25 mL). The solution was
stirred at a given temperature for 1 h (in the case of Table 1 the
reactions were analyzed at 0.5 and 1 h). The solvent was removed
6
). Moreover, this methodology is suitable for biologically
active molecules. In fact, catalyst 1 oxidizes cholesterol (22) in
h, surpassing the catalytic activity of the very efficient and
versatile Shvo catalyst under its optimized conditions (Table 4,
1
under vacuum, and the crude reaction mixture was analyzed by H
1
NMR spectroscopy.
General Procedure for Oxidation Reactions in Table 4. In a
10 mL J. Young type Schlenk flask, the substrate considered (1 mmol),
1 (0.005 mmol), and KHMDS (0.02 mmol) were charged inside the
glovebox and dissolved in toluene (1 mL). To this mixture was added
acetone (1 mL). The solution was stirred at 110 °C for the time
reported in Table 4. The solvent was removed under vacuum, and the
crude reaction mixture was purified by column chromatography using
as eluent a 95/5 mixture of pentane and ethyl acetate (with the
exception of entry 11, Table 4, where dichloromethane was used as
eluent).
4
1,47
entry 11).
Interestingly, the oxidized product of 22 is not
the 7β-cholest-5-en-3-one; instead, isomer 23, where the
double bond is rearranged to bring it into conjugation, is
obtained.
Complex 1 shows no activity in the oxidation of primary
alcohols to aldehydes (Table 4, entries 3 and 10). With
aromatic primary alcohols, there is formation of traces of the
corresponding ester, resulting from dimerization of the starting
material. Even when the catalyst loading was increased to 5 mol
Low Catalyst Loading Procedure. In a 10 mL J. Young type
Schlenk flask, inside the glovebox, an aliquot of 1 from a stock solution
of catalyst 1 in toluene (2.6 mg in 5 mL) was added and diluted with
toluene to a total volume of 0.25 mL. Benzhydrol (2; 0.25 mmol),
KHMDS (0.0625 mmol, 1.2 mg) and acetone (0.25 mL) were added.
The solution was stirred at 110 °C for a period of time indicated in
Table 1. The solvent was removed under vacuum, and the crude
%
, the conversion remained the same, suggesting that primary
alcohols can be dehydrogenated, but the mechanism is
thermodynamically not favored, as hydrogenation of the
produced aldehyde is favored over hydrogenation of acetone.
48
In order to showcase the high selectivity of catalyst 1, a
competition experiment was performed (eq 2).
In a 1/1 mixture of phenylethanol isomers, complex 1
oxidizes 1-phenylethanol (4) to acetophenone (5), without
oxidizing the other isomer. However, the presence of primary
alcohols in the reaction mixtures leads to longer reaction times
to reach complete conversion.
1
reaction mixture was analyzed by H NMR spectroscopy.
ASSOCIATED CONTENT
Supporting Information
■
*
S
Text and figures giving synthetic procedures and NMR spectra
of products. This material is available free of charge via the
Internet at http://pubs.acs.org.
To further evaluate this selectivity, a molecule containing
primary and secondary alcohols was tested with our system (eq
3
). Although the reaction required slightly higher loading and
AUTHOR INFORMATION
Corresponding Author
E-mail: snolan@st-andrews.ac.uk. Fax: +44 (0)1334 463808.
■
*
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The EC is gratefully acknowledged for funding through the
seventh framework program (CP-FP 211468-2-EUMET).
Umicore AG is gratefully thanked for gift of materials. S.P.N.
is a Royal Society Wolfson Research Merit Award holder.
longer reaction times, complex 1 is capable of oxidizing
selectively the secondary alcohol moiety in 25. In fact, as shown
in the previous experiments, primary alcohols have a
detrimental effect on the activity of 1. However, only the
secondary alcohol has been oxidized, proving the high selectivity of
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