The Effect of pH Control on the Selective Ruthenium-Catalyzed Oxidation of Ethers and Alcohols with Sodium Hypochlorite

Article abstract of DOI:10.1002/adsc.200303124

Highly selective oxidations of ethers to esters or lactones and of secondary alcohols to ketones were achieved using catalytic amounts of various Ru precursors and the theoretical amount of NaOCl. Reactions were carried out in biphasic solvent mixtures at constant pH 9-9.5 via either feed-on-demand addition of HCl and NaOH or in the presence of NaHCO₃/Na ₂CO₃ buffer. The catalyst could be easily recycled for at least 4 times with only minor loss in selectivity. Products were generally recovered by simple phase separation and evaporation of the organic solvent. The effects of catalyst precursor, additives and pH control method are also described.

Full text of DOI:10.1002/adsc.200303124

FULL PAPERS
The Effect of pH Control on the Selective Ruthenium-Catalyzed
Oxidation of Ethers and Alcohols with Sodium Hypochlorite
Luca Gonsalvi,a, b Isabel W. C. E. Arends,a Pasi Moilanen,a Roger A. Sheldona,*
a
Laboratory for Biocatalysis and Organic Chemistry, Delft University of Technology, Julianalaan 136, 2628 BL Delft,
The Netherlands
Fax: ( ‡ 31)-15-2781415, e-mail: r.a.sheldon@tnw.tudelft.nl
b
Current address: Istituto di Chimica dei Composti OrganoMetallici, Consiglio Nazionale delle Ricerche (ICCOM-CNR),
Area di Ricerca di Firenze, Via Madonna del Piano, 50019 Sesto Fiorentino, Firenze, Italy
Fax: ( ‡ 39)-55-5225203, e-mail: l.gonsalvi@iccom.cnr.it
Received: July 22, 2003; Accepted: October 8, 2003
Abstract: Highly selective oxidations ofethers to
esters or lactones and ofsecondary alcohols to
minor loss in selectivity. Products were generally
recovered by simple phase separation and evapora-
ketones were achieved using catalytic amounts of tion of the organic solvent. The effects of catalyst
various Ru precursors and the theoretical amount of precursor, additives and pH control method are also
NaOCl. Reactions were carried out in biphasic described.
solvent mixtures at constant pH 9 9.5 via either
feed-on-demand addition of HCl and NaOH or in the
presence ofNaHCO 3/Na2CO3 buffer. The catalyst Keywords: alcohols; esters; ethers; ketones; lactones;
could be easily recycled for at least 4 times with only oxidation; pH effect; ruthenium
Introduction
been successfully applied to the oxidation of many
different substrates, including linear and cyclic saturated
Oxidations are ubiquitous reactions in both inorganic hydrocarbons,[7] olefins and dienes,[8] alkynes,[9] alcohols
and organic chemistry. These transformations are of and diols,[10] carbohydrates,[11] amino compounds,[12] a-
great importance not only in the laboratory, but also in amino acids (to a-aminodicarboxylic acids),[13] and
industry, where they account for a majority of the steroids.[14]
applied processes in bulk and fine chemistry. Stoichio-
metric amounts ofoxidants are still applied, despite the
The Ru/NaIO4 method was substantially improved by
Sharpless and co-workers[15] by addition ofMeCN to the
fact that a wealth of research has focused on catalytic traditional CCl4/H2O system. The higher catalytic
systems for organic oxidations. Our group has a long- activity was explained by the coordinating properties
standing interest in the area ofcatalytic oxidations,
ofMeCN, thus preventing the formation ofinsoluble Ru
including radical processes, metal-mediated homoge- species which caused catalyst deactivation. This strategy
neous and heterogeneous catalysis for oxidation of has become a general procedure in oxidation protocols
organic substrates such as alkenes, alcohols, etc.[1]
described since then. In spite ofthe improvement,
Recently we have focused our attention on the however, literature methods still suffer from drawbacks:
selective a-oxidation ofethers to esters. This reaction the need for high ruthenium concentrations, and the use
can be applied in fine chemical industry for the ofexpensive or toxic oxidants (NaIO 4, NaBrO3), often
production ofcomplex natural products and, in princi- in large excess (NaOCl), which in turn generate copious
ple, to carbohydrate chemistry, where it may enable amounts ofwaste by-products giving high E-factors and
efficient oxidative deprotection of carboxyl groups. The poor atom efficiencies.[16] In addition, some substrates
most efficient oxidant for this transformation is RuO4.[2] were oxidized with medium to poor selectivity, as is the
Classical use involves stoichiometric amounts ofthis
reagent, but RuO4 can also be conveniently generated in
situ via a combination ofruthenium precursors, usually
case ofethers and acetals. [17]
We found that for ether oxidation these methods
could be dramatically improved both in activity and
RuCl3 ¥ H2O or RuO2 ¥ H2O, with an inorganic oxidant selectivity to esters by simple pH control.[18] This allows
such as NaIO4,[3] NaBrO3[4] or NaOCl.[5] In practice these for (a) low concentrations ofRu precursors; (b) use ofa
systems involve biphasic conditions, typically CCl4/ stoichiometric quantity (2 equivs.) ofoxidant, i.e.,
H2O,[6a] often in the presence of phase transfer agents NaOCl; (c) easy product recovery by simple phase
such as tetraalkylammonium salts.[6b] The method has separation and (d) efficient catalyst recycling. The
Adv. Synth. Catal. 2003, 345, 1321 1328
DOI:10.1002/adsc.200303124
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Luca Gonsalvi et al.
FULL PAPERS
protocol was also successfully applied to the oxidation of
alcohols, in particular giving spectacular results for the
otherwise difficult conversion of 1,2:4,5-di-O-isopropy-
lidene-b-d-fructopyranose (1) into 1,2:4,5-di-O-isopro-
pylidene-b-d-erythro-2,3-hexadiulo-2,6-pyranose (2).[19]
Hereby we describe the effect of catalyst precursor,
additives and pH control method on the oxidation of
aliphatic and aromatic ethers, together with mechanistic
considerations.
Results and Discussion
In order to optimize the existing ether oxidation
methods based on Ru/NaOCl, we reasoned that effi-
cient use ofNaOCl (i.e., 2:1 ratio vs. substrate for ethers,
1:1 for alcohols) could be achieved by optimizing the
reoxidation of the catalyst from its reduced form, thus
&
~
Figure 2. Conversion (^), yield ( ) and pH change ( ) in the
oxidation of( n-Bu)2O in the presence ofRuCl 2(dppp)2
(0.2 mol%), NaOCl (2 equiv.), pH-stat control, CH2Cl2, RT.
avoiding decomposition to inactive insoluble species. It to keep the pH constant in the range 8.5 9.5, using a
was previously shown that the nature ofhigh valent Ru
oxo species generated by addition ofan oxidant in
pH-stat device for the whole duration of the catalytic
run (see Experimental Section). In this way, the reaction
biphasic solvent systems strongly depends on pH.[20] In a could be carried out at room temperature from the
first catalytic experiment, n-butyl ether (5 mmol) was beginning with a stoichiometric amount ofNaOCl (2
added to a solution of[RuCl 2(dmso)4] (1 mol %) which equivs.), without the need for phase transfer agents.
was pre-activated by addition ofa few drops ofNaOCl,
Nearly complete conversion and highly selective ester
under vigorous stirring at 0 0C. To this solution (pH 8.5), formation was achieved for a series of symmetrical and
NaOCl (10 mmol) was added dropwise over 2 hours at unsymmetrical aliphatic, cyclic and benzylic ethers.
0 0C and pH was monitored. After this time, the Experimental data are summarized in Table 1, while
conversion stopped and a sharp decrease ofpH rfom
the reaction profile of a typical high-performance run
8.5 to 4.8 was observed (Figure 1) together with for ether oxidation is shown in Figure 2.
formation of a black precipitate.
The addition ofanother aliquot ofNaOCl (10 mmol)
The catalyst is entirely confined in the organic phase
upon addition ofNaOCl, as is evident from simple visual
caused the precipitate to dissolve and led to complete analysis, so that the reoxidation ofthe catalyst occurs at
conversion and a final selectivity of 74% to butyl the phase boundary and is facilitated by fast magnetic
butyrate, with the pH back at the original value of8.5.
stirring. In contrast with early observations by Sharpless
Our experimental setup was therefore modified in order and co-workers,[15] the presence ofa chlorinated solvent
is not mandatory. Replacement ofCH 2Cl2 with EtOAc
or methyl t-butyl ether (MTBE), without the need for
additional MeCN, showed comparable or better cata-
lytic activity and selectivity to the desired product under
the same conditions (Table 1, entries 6, 9). It can be
expected that these polar coordinating solvents act, in
the words ofSharpless, ™to disrupt the insoluble
carboxylate complexes and return the ruthenium to
the catalytic cycle∫, analogous to acetonitrile.
The results of catalyst screening using a series of
ruthenium complexes with different oxidation states of
the metal in the oxidationofdibutyl ether are summarized
in Table 2. The best catalyst precursors under the pH-stat
conditions were found to be cis-Ru(dmso)4Cl2, trans-
Ru(dppp)2Cl2 [dpppˆ1,3-(diphenylphosphino)propane]
and [n-Pr4N][RuO4] (TPAP). We attribute this to a higher
stability ofthe precursors under catalytic conditions, and
&
~
Figure 1. Conversion (^), yield ( ) and pH change ( ) in the
oxidation of( n-Bu)2O in the presence ofRuCl 2(dmso)4
(1 mol %), NaOCl (4 equivalents), CH2Cl2, 08C (2 h) RT.
The oxidant was added in two aliquots (2 equivs. each,
slow conversion to RuO4 by acting as a reservoir.
For lactones hydrolysis may occur at basic pH, thus in
the case oftetrahydropyran (entry 10) the reaction was
arrows) at t ˆ 0 and t ˆ 5 h, dropwise at ca. 0.1 cm3/min rate. performed at pH 7.5, which in turn gives a slower
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Ruthenium-Catalyzed Oxidation ofEthers and Alcohols
FULL PAPERS
[a]
Table 1. Oxidation ofaliphatic and aromatic ethers via TPAP/NaOCl, pH-stat control.
Entry
Substrate
Product
Catalyst[b] (mol %)
% C[c]
82
% Y[c]
80
1
1 (0.5)
2
1 (0.5)
85
70
3
4
5
6
2 (0.5)
99
88
77
98
93
77
59
95
3 (0.25)
4 (0.5);
1 (0.25)[d]
7
1 (0.5)
99
73
8
9
2 (0.25)
86
86
51
71
1 (0.25)[d]
10
1 (0.5)[e]
1 (0.5)
67[f]
44
11
60
42
12
1 (0.5)
41
22
[a]
Conditions: substrate (5 mmol), NaOCl (10 mmol), CH2Cl2 (2 cm3), RT, pH 9.5, 5 h.
1: [RuCl2(dmso)4], 2: [RuCl2(dppp)2], 3: TPAP, 4: RuO2 ¥ H2O.
Determined by GLC based on pure samples, isolated yields usually 2 3% lower.
[b]
[c]
[d]
[e]
[f]
EtOAc instead ofCH Cl2, 3 h.
2
At pH 7.5.
At 20 h.
reaction rate. Ethers containing aromatic moieties such addition ofacid and base. This was solved by replacing
as benzyl methyl ether and dibenzyl ether, were also the pH control either with adequate buffer solutions or
oxidized, albeit with moderate selectivity as RuO4 is by adding NaHCO3 to the NaOCl solution (pH 9 10).
known to degrade aromatic rings to carboxylic acids Control experiments were carried out and the results are
(Table 1, entries 11, 12). Oxidation ofdihydrobenzofur-
an (3) (81% conversion) using TPAP 0.5%, in the showed results comparable within the experimental
presence of2 equivalents ofNaOCl, yielded after 5 h a error, so we conclude that Dosimat control can be
summarized in Table 3. The three different methods
single product in 92% selectivity, which was identified as replaced with the buffer solution. For comparison,
the 1-chlorohydrobenzofuran by GC-MS (Scheme 1).
The blank reaction showed lower conversion (73%) and
selectivity (77%) to the same product again without
formation of coumaranone (4).
Apparently, chlorination ofthe benzylic position
takes place (elemental chlorine is always present in
solutions ofNaOCl).
A possible drawback ofour oxidation method could
be the cumbersome way to maintaining a constant pH
during the catalytic run through alternate Dosimat Scheme 1.
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Luca Gonsalvi et al.
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Table 2. Pre-catalyst screening for oxidation of Bu2O under
pH-stat control conditions.[a]
[Ru]
T [h] % C % Y % S
cis-Ru(dmso)4Cl2
5
20
97
97
83
83
86
86
trans-Ru(dppp)2Cl2
trans-Ru(PPh3)3Cl2
[n-Pr4N][RuO4]
5
20
5
20
5
20
99
99
72
73
92
94
93
93
57
57
80
82
93
93
79
79
87
87
Scheme 2.
cis-[Ru(dmp)2(MeCN)2](BF4)2
Ru/C (5% w/w)
5
20
5
20
5
20
78
87
52
64
79
81
58
68
42
48
59
59
74
77
81
75
75
73
perruthenate RuVIIO4 is the main species in biphasic
H2O/CCl4 solutions in the pH range 8 10. Although we
À
À
cannot rule out RuO4 as the active oxidant we favor
RuO2 ¥ H2O
RuO4 based on the following experimental evidence.
We performed the stoichiometric reaction of Bu2O with
TPAP under nitrogen and observed no substrate con-
version; moreover, the combination TPAP (10 mol %)/
O2, active for alcohol oxidation,[31b] is inactive for ether
oxidation. Oxidation ofacrolein dimethyl acetal gave
[a]
Conditions: Bu2O, 5 mmol; [Ru], 0.5 mol %; NaOCl 2
equivs., CH2Cl2 5 mL, TCB (standard) 1 mmol, RT,
pH 9.5.
ˆ
extensive decomposition, as expected for C C double
Table 3. Different methods to maintain constant pH during
bond cleavage by RuO4. Furthermore, a black precip-
itate, typical ofRuO 4, was often observed on the side of
the flask when the stirring rate was decreased during the
catalytic tests.
Ru/NaOCl oxidation ofBu O.[a]
2
Cat (mol %)
Method 1
Method 2
Method 3
% C % Y % C % Y % C % Y
Cyclic acetals such as 2-phenyl-1,3-dioxolane (5), 2-
hexyl-1,3-dioxolane (6) and 2-cyclohexyl-1,3-dioxolane
(7), synthesized according to known procedures,[23]
could be oxidized to the corresponding aryl- or alkyl
carboxylic acid carboxymethyl esters, albeit in modest
yields (Scheme 2). For example, the oxidation of 7, at
buffered pH 9.5 in the presence of Ru(dmso)4Cl2
(0.1 mol %) in EtOAc gave 67% conversion and 19%
yield ofthe acid, whereas 71% conversionand 10% yield
were observed at pH 6.5 (acid buffer, see Experimental
Section) using 0.5 mol % ofRu(dmso) 4Cl2. Lower yields
at pH 6.5 could be due to hydrolysis ofthe substrate,
hence leading to unidentified side products. The blank
reaction without Ru results in oxidation by NaOCl at the
Ru(dmso)4Cl2 (0.5) 85
70
77
59
81
83
75
65
74
58
82
81
73
64
78
58
TPAP (0.25)
RuO2 ¥ H2O (0.5)
88
77
[a]
Conditions: Bu2O, 5 mmol; TPAP, 0.5 mol %; NaOCl 2
equivs., CH2Cl2 5 mL, TCB (standard) 1 mmol, RT, 5 h.
Method 1: Dosimat addition ofHCl 2 M (during addition
ofNaOCl) then NaOH 2 M. Method 2: NaOCl 0.7 M
solution buffered to pH 10 by addition of NaHCO3 (s).
Method 3: NaHCO3/Na2CO3 buffer (pH 9.5), 1: 1 v/v ratio
to the solvent.
Morris and Kiely reported the use ofa small amount of
K2CO3 together with RuO2/NaIO4 in biphasic H2O/CCl4 tertiary carbon atom, giving almost quantitative forma-
media for the oxidation of the C-5 hydroxy group in a tion ofthe carboxylic acid 2-hydroxyethyl ester deriv-
series ofprotected carbohydrates, although the pres-
ence ofa phase transfer agent (benzyltriethylammoni-
um chloride) was necessary to bring about catalysis and
no rationale for the use of the base was given.[21]
atives under the same conditions both at pH 9.5 and 6.5
(Scheme 2).
Alcohol oxidations with Ru/NaOCl were also im-
proved using the pH control method, compared to
The mechanism ofether a-oxidation with RuO4 was reported data.[6b] Although ™greener∫ methods for
studied in detail by Bakke and Frohaug,[22] who pro- alcohol oxidation using O2 or H2O2 as terminal oxidants
posed two possible pathways to ester formation, namely are available nowadays[24,25] the modified Ru/NaOCl
(a) concerted reaction similar to SE2, involving a front- system is extremely efficient for recalcitrant substrates
side attack ofthe electrophile or (b) two-step reaction
consisting ofa reversible oxidative addition ofthe ether
such as 1,2:4,5-di-O-isopropylidene-b-d-fructopyra-
nose 1. For its conversion into 1,2:4,5-di-O-isopropyli-
to a RuO4 followed by a slow second step with a dene-b-d-erythro-2,3-hexadiulo-2,6-pyranose 2, other
concerted mechanism to eliminate the ester. The effect catalytic methods fail.[19] Oxidation ofthe sterically
ofpH on the nature ofRu oxo species in equilibrium was
hindered alcohol group in 1, is apparently highly favored
examined by Mills in a recent paper,[20a] showing that over oxidation ofthe C H bonds adjacent to the various
À
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Table 4. Oxidation ofsecondary alcohols via TPAP/NaOCl.[a]
Entry
Substrate
Product
% C[b]
% Y[b]
% S
92
‰cŠ
13
98
90
14
15
99
99
99
99
100
100
16
17
99
90
97
88
89
96
89
99
99
‰dŠ
18
[a]
Conditions: substrate (5 mmol), TPAP (0.25 mol %), EtOAc (5 cm3), NaHCO3/Na2CO3 buffer solution (pH 9.5, 5 cm3), 4 h,
RT, NaOCl 0.7 M, 1 equiv., dropwise over 2 h.
GC conversions and yields, based on pure samples.
TPAP 1 mol %, NaOCl 3 equivs., MTBE instead ofEtOAc.
TPAP 0.5 mol %, MTBE instead ofEtOAc.
[b]
[c]
[d]
ether and acetal O-atoms in this RuO4-based system. It
In order to decrease the amount ofRu without loss of
is a potentially interesting target reaction, as ketone 2 is activity, we examined the effect of promotors, in particular
a precursor for transition metal-free catalytic asymmet- pyridine oxide and bromide salts. Whilst the first type of
ric olefin epoxidation, developed by Shi and co-work- additive is expected to increase the solubility and stability
ers.[26] So far, this compound was obtained from fructose ofthe catalyst in the organic phase, bromide should be
diacetonide 1 in 93% yield by use ofan excess of
converted into hypobromite. The combination ofHOCl/
pyridinium chlorochromate (PCC) which is more ex- HOBr is known to be a more effective oxidant in organic
pensive and toxic. In a typical experiment 1 (5 mmol), solvents than hypochlorite alone.[27] The results ofoxida-
was oxidized to 2 (98% conversion, 90% isolated yield) tion ofdibutyl ether to butyl butyrate, with 2 equivalents
over 4 hours at RT in the presence ofTPAP (1 mol %),
MTBE (5 cm3), NaHCO3/Na2CO3 buffer solution buffer at different TPAP concentrations, with or without
(pH 9.5, 5 cm3), using 3 equivalents ofNaOCl 0.7 M.
additives, are summarized in Table 5. From these experi-
ofNaOCl in EtOAc at pH 9.5 using a NaHCO 3/Na2CO3
In a large-scale experiment under the same conditions, ments it can be concluded that efficient ether oxidation
oxidation of 1 (10.4 g, 40 mmol) afforded 2 as a NMR- can be achieved at high substrate to catalyst ratios (up to
pure white precipitate after solvent evaporation in 85% 1000:1) using TPAP and pyridine oxide, without the need
isolated yield (8.8 g, 34 mmol). For simple secondary ofan excess ofhypochlorite.
alcohols, the reactions proceed smoothly under opti-
mized conditions using a stoichiometric amount of simple series ofpH change and extractions (Experi-
NaOCl and 0.25 mol % ofTPAP, which is the precata- mental Section). For the oxidation of 1 to 2, the decrease
Efficient catalyst recycle could also be achieved by a
lyst giving the best performance (Table 4). For liquid in selectivity is moderate (from 83% to 72% after 4
substrates such as 2-octanol, organic solvent-free oxi- cycles) which we attribute to mechanical losses (starting
dation was also successfully carried out (conversion at TPAP, 0.02 mmol). The tests were repeated using
4 h, 99%, isolated yield of2-octanone 97%). Catalysis
dibutyl ether as substrate; in this case the decrease in
still occurs in the organic phase, in this case the substrate selectivity to butyl butyrate was negligible (from 99% to
itself.
96% after 5 cycles), as shown in Figure 3.
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Luca Gonsalvi et al.
FULL PAPERS
(TPAP),[31] cis-[Ru(dmp)2(MeCN)2](BF4)2 (dmp ˆ 1,10-dime-
thylphenanthroline)[32] were synthesized according to litera-
ture procedures. Ru/C (5% w/w) and RuO2 ¥ H2O were
purchased from Aldrich and used without further purification.
The commercially available substrates and products (used for
GC calibration purposes) were purchased from Acros and
Aldrich. All ethers were passed onto a short column ofbasic
alumina to remove stabilizers prior to use. 1,2:4,5-Di-O-
isopropylidene-b-d-fructopyranose (1) and 1,2:4,5-di-O-iso-
propylidene-b-d-erythro-2,3-hexadiulo-2,6-pyranose (2) were
supplied by Catalytica Ltd. (presently DSM pharmaceuticals)
as white crystalline solids at 97% purity.
Table 5. Effect of promotors on the oxidation of Bu2O at
different TPAP concentrations.[a]
Additive (mol %)
TPAP
% C
% Y
% S
(mol %)
none
KBr (1)
Pyridine oxide (1)
0.25
0.1
0.1
98
67
80
95
62
78
97
92
98
[a]
Conditions: Bu2O, 5 mmol; NaOCl 2 equivs., NaHCO3/
Na2CO3 buffer (pH 9.5), 5 mL; EtOAc 5 mL, TCB
(standard) 1 mmol, RT, 5 h.
Catalytic Tests
Feed-on-demand pHcontrol: In a typical experiment, a 2-
necked, pear-shaped flask was equipped with a magnetic
stirrer, an addition funnel and a pH electrode, the latter
connected to a Metrohm pH stat device, consisting ofa pH
meter, an Impulsomat and a Dosimat. The following reagents
were then added in the order stated: catalyst precursor
(prepared according to the literature), organic solvent (con-
taining the GC internal standard) and a few drops of aqueous
NaOCl. The biphasic mixture was stirred vigorously until the
organic phase assumed a yellow color and the aqueous phase
was colorless. The substrate was added rapidly dropwise with a
pipette while stirring, once dissolved in the remaining solvent.
The pH at this stage was typically in the range 12 13. The
oxidant, 0.7 M NaOCl, was then added dropwise via the
addition funnel, typically over 2 hours. During this phase, the
pH was maintained at 9.5 by addition ofHCl (2.0 M) via
Dosimat. After the addition of the oxidant was completed, the
pH was observed to drop and was therefore kept constant at
the chosen value by Dosimat addition ofNaOH 2.0 M for the
rest ofthe experiment (typically 5 hours overall). The reaction
was carried out at room temperature and was monitored by
taking samples ofthe organic phase regularly and analyzing the
mixture by GC after adsorption of the catalyst on a Celite pad
(retention times and response factors were determined by
calibration based on pure samples). When complete conver-
sion was reached (typically after 3 5 h) the final work-up
involved phase separation and evaporation ofthe organic
phase to yield the crude product (ca. 95% ofthe final amount).
The aqueous phase was extracted with CH2Cl2 after neutral-
ization with NaHCO3 followed by evaporation to yield a
second crop (ca. 5% ofthe final amount).
Figure 3. Catalyst recycling in the oxidation ofBu O in the
presence ofTPAP, 0.5 mol %; NaOCl 2 equivs., EtOAc,
buffer NaHCO3/Na2CO3 1 M (pH 9.5), RT, 3 h.
2
Conclusions
We have developed a convenient and selective Ru/
hypochlorite oxidation protocol for the selective trans-
formation of a series of ethers and alcohols. The catalytic
systems described in the literature, especially regarding
ether oxidation, have limited reproducibility and/or
require an excess ofterminal oxidant, i.e., NaOCl
solutions(householdbleach). WhenthepHismaintained
at 9 9.5 the reactions proceed smoothly, using the
theoretical amount ofhypochlorite, with fast, complete
conversion ofsubstrate and high selectivity to the target
molecules at low concentration ofRu precursor. A
variety ofRu precursors can be used, although we found
that [Pr4N][RuO4] (TPAP) gave the best results. The
catalyst can also be recycled with negligible loss of
selectivity and minimum loss ofactivity, which can be
Buffer solution pHcontrol: In a typical experiment, a 2-
necked, pear-shaped flask was equipped with a magnetic
stirrer, an addition funnel and a pH electrode, the latter
further optimized by scale-up. Lower selectivities were connected to a Metrohm pH meter. The following reagents
were then added in the order stated: buffer solution (NaHCO3/
Na2CO3, 1.0 M, pH 9.5; NaH2PO4/Na2HPO4, 1.0 M, pH 6.0),
catalyst precursor, organic solvent (containing the GC internal
standard) and a few drops of aqueous NaOCl. The biphasic
mixture was stirred vigorously until the organic phase assumed
a yellow color and the aqueous phase was colorless. The
substrate was added rapidly dropwise with a pipette while
stirring, once dissolved in the remaining solvent. The oxidant
was then added dropwise via the addition funnel, typically over
2 hours. The rest ofthe experiment was carried out as described
above.
observedwithetherscontainingaromatic moieties, which
are susceptible to non-selective oxidation by RuO4.
Experimental Section
Materials
The
Ru
complexes
trans-Ru(PPh3)3Cl2,[30]
cis-Ru(dmso)4Cl2,[28]
[n-Pr4N][RuO4]
trans-
Ru(dppp)2Cl2,[29]
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Ruthenium-Catalyzed Oxidation ofEthers and Alcohols
FULL PAPERS
[7] a) U. A. Spitzer, D. G. Lee, Can. J. Chem. 1975, 53, 2865;
b) U. A. Spitzer, D. G. Lee, J. Org. Chem. 1975, 40, 2539;
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Catalyst Recycling Tests
A series ofexperiments was carried out to test the activity of
the catalytic system after recycling. The procedure described in
a recent patent was used to recycle the catalyst from its low
valent state.[33] 1 was used as substrate for recycling tests.
Conditions: 1, 2 mmol; TPAP, 0.02 mmol; NaOCl (0.7 M)
6 mmol (8.6 mL) added over 3 h; MTBE 10 mL; TCB (1,3,5-
trichlorobenzene, GC internal standard) 1 mmol, RT, 4 h;
pH 9.50. After the run was completed, the organic phase
containing 1, 2 and TCB was separated after addition of NaOH
to pH 11, which forces the catalyst into the water phase. Then
the catalyst was back-extracted from the aqueous phase by
addition ofNaOCl (0.2 mmol) and MTBE (10 mL overall), at
pH 6. To the yellow solution so obtained, the substrate was
added as a solid. The oxidation protocol was then applied as
described above. The recycling tests were also carried out using
Bu2O as substrate for 5 cycles overall, under the following
conditions: Bu2O, 5 mmol; TPAP, 0.5 mol %; NaOCl 2 equivs.,
EtOAc 5 mL, buffer NaHCO3/Na2CO3 1 M (pH 9.5), 5 mL;
TCB (GC standard) 1 mmol; RT, 3 h.
Acknowledgements
This project was financed by the Dutch Ministry of Economic
Affairs under the Innovation Oriented Projects scheme (IOP
Catalysis) and the contribution is gratefully acknowledged. We
also thank Catalytica Ltd. (presently DSM pharmaceuticals) for
a generous gift of 1,2:4,5-di-O-isopropylidene-b-d-fructopyr-
anose. P. M. thanks IAESTE for funding.
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