RuCl3/CeCl3/NaIO4: A new bimetallic oxidation system for the mild and efficient dihydroxylation of unreactive olefins

Article abstract of DOI:10.1021/jo048020x

(Chemical Equation Presented) The catalytic dihydroxylation of olefins represents a unique synthetic tool for the generation of two C,O-bonds with defined relative configuration. Whereas OsO₄ has been established as a very general dihydroxylati

Full text of DOI:10.1021/jo048020x

Hence, the main goal in this area is the use of a powerful,
inexpensive and readily available catalyst and a stoichio-
metric reoxidant that is not hazardous and easy to
handle.3
RuCl3/CeCl3/NaIO4: A New Bimetallic
Oxidation System for the Mild and
Efficient Dihydroxylation of Unreactive
Olefins
The osmium-catalyzed dihydroxylation of C,C-double
bonds belongs to the most successful catalytic transfor-
mations developed so far. The early investigations of
Criegee4 on the chemistry of OsO4 and Sharpless’ sub-
sequent studies on the effect of ligands and reoxidants
on the course of the reaction5 finally led to a broadly
applicable asymmetric dihydroxylation for a variety of
different olefins with predictable absolute configuration
at the newly formed stereocenters. The use of OsO4,
however, has several drawbacks. It is very expensive,
volatile, and toxic. Hence, the search for a less expensive
and toxic albeit comparably selective oxidation catalyst
is still of current interest. In 1994, Shing reported the
dihydroxylation using catalytic amounts of RuO4.6 Due
to the high reactivity of the catalyst, dihydroxylations
using RuO4 are usually less selective and accompanied
by undesired fragmentation reactions. Furthermore, the
high catalyst loading of 7 mol % is economically prob-
lematic. Recently we found that simple Bro¨nsted acids
are able to accelerate the rate of this reaction.7 The new
procedure allowed a decrease of the catalyst loading from
the original 7 mol % down to only 0.5 mol % for the
oxidation of a wide variety of olefins. However, the
presence of protons led to problems with certain sub-
strates due to protolytic side reactions. To avoid these
undesired background reactions, we envisioned the use
of Lewis acids as appropriate substitutes for Bro¨nsted
acids. Our investigations led to the discovery of an
unprecedented bimetallic catalytic system of the bifunc-
tional redox active Lewis acid CeCl3 facilitating both the
reoxidation and the subsequent hydrolysis of the result-
ing ruthenium(VIII) ester.
Bernd Plietker* and Meike Niggemann
Organic Chemistry II, Chemistry Faculty, Dortmund
University, Otto-Hahn-Str. 6, D-44221 Dortmund, Germany
bernd.plietker@uni-dortmund.de
Received November 6, 2004
The catalytic dihydroxylation of olefins represents a unique
synthetic tool for the generation of two C,O-bonds with
defined relative configuration. Whereas OsO4 has been
established as a very general dihydroxylation catalyst within
the past 30 years, the less expensive and toxic isoelectronic
RuO4 has found only limited use for this type of oxygen-
transfer reaction. High catalyst loading and undesired side
reactions were severe drawbacks in RuO4-catalyzed oxida-
tions of C,C-double bonds. Recently, we were able to improve
the RuO4-catalyzed dihydroxylation by addition of Bro¨nsted
acids to the reaction mixture. This protocol proved to be of
general applicability, however, certain limitations were
observed. To address these problematic functional groups a
new Lewis acid accelerated oxidation was developed. The
use of only 10 mol % of CeCl3 allowed a further decrease in
the catalyst concentration down to 0.25 mol % while
broadening the scope of the reaction. Silyl ethers and
nitrogen containing functional groups are now tolerated in
this optimized protocol. Furthermore, competing scission
reactions are supressed in the presence of Lewis acid
allowing longer reaction times and the successful oxidation
of electron-deficient tetrasubstituted double bonds that
cannot be oxidized using known dihydroxylation protocols.
The search for an appropriate Lewis acid started with
an intense screening of a variety of metal chlorides
known to possess Lewis acidic properties and to be stable
in the presence of water (Table 1).8 Main group metal
salts showed a remarkable effect on reaction rate and
selectivity. Apparently, softer Lewis acids improve the
conversion rate while maintaining the selectivity (entries
Transition-metal-catalyzed reactions are among the
most powerful tools in modern organic synthesis. The
success of this type of transformation is a direct conse-
quence of the fruitful cooperation of organic and inorganic
chemists.1 Understanding the mode of action at the metal
center as well as on the organic substrate is a funda-
mental prerequisite for the successful development of a
broadly applicable catalytic system. Oxidation reactions
are an important subdivision among transition metal-
catalyzed transformations.2 Although this type of reaction
has been in the center of research for the past thirty
years, the development of economically attractive and
environmentally benign oxidation systems still remains
a challenging problem in oxygen transfer chemistry.
(3) Transition Metals for Organic Synthesis; Beller, M., Bolm, C.,
Ed.; Wiley-VCH: Weinheim, New York, 1998.
(4) (a) Criegee, R. Justus Liebigs Ann. Chem. 1936, 522, 75. (b)
Criegee, R.; Marchand, B.; Wannowius, H. Justus Liebigs Ann. Chem.
1942, 550, 99.
(5) (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, Weinheim,
2000; p 357. (b) Bolm, C.; Hildebrand, J. P.; Muniz, K. In Catalytic
Asymmetric Synthesis, 2nd.ed.; Ojima, I., Ed.; Wiley-VCH: New York,
Weinheim, 2000; p 399.
(6) (a) Shing, T. K. M.; Tai, V. W.-F.; Tam, E. K. W. Angew. Chem.
1994, 106, 2408; Angew. Chem., Int. Ed. Engl. 1994, 33, 2312. (b)
Shing, T. K. M.; Tam, E. K. W.; Tai, V. W. F.; Chung, I. H. F.; Jiang,
Q. Chem. Eur. J. 1996, 2, 50.
(7) (a) Plietker, B.; Niggemann, M. Org. Lett. 2003, 5, 3353. (b)
Plietker, B.; Niggemann, M. Org. Biomol. Chem. 2004, 2, 1116.
(8) Different anions were screened in order to exclude a possible
influence on the reaction course. Whereas bromide and iodide are
oxidized under the dihydroxylation conditions, chlorides and fluorides
are stable and have only a minor influence. Hydrogen sulfate, however,
increases both selectivity and conversion rate. Unfortunately, attempts
to combine the Lewis acid acceleration and the anion effect failed.
(1) Transition Metals in the Synthesis of Complex Organic Molecules,
2nd ed.; Hegedus, L. S., Ed.; University Science Books: Sausalito, 1999.
(2) Asymmetric Oxidation Reactions; Katsuki, T., Ed.; Oxford Uni-
versity Press: Oxford, 2001; p 128.
10.1021/jo048020x CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/16/2005
2402
J. Org. Chem. 2005, 70, 2402-2405

TABLE 1. Lewis Acid Effect in RuO4-Catalyzed
Dihydroxylation
SCHEME 1. CeCl3-Accelerated RuO4-Catalyzed
Dihydroxylation
entrya
Lewis acid
2/3b
conversionb (%)
1
2
2.0:1.0
1.0:1.7
1.6:1.0
2.1:1.0
2.5:1.0
1.0:1.8
1.7:1.0
1.8:1.0
1.8:1.0
2.3:1.0
1.3:1.0
1.4:1.0
1.2:1.0
2.2:1.0
4.0:1.0
61
32
51
57
67
26
71
74
98
99
70
72
66
97
92
LiCl
NaCl
KCl
3
Having in hand the optimized conditions, we turned
our interest to the dihydroxylation of olefins that proved
to be problematic in the Bro¨nsted acid accelerated
dihydroxylation. We were pleased to find that the new
CeCl3-accelerated dihydroxylation proceeded particularly
well in the oxidation of such olefins.7b The already
mentioned phenomenon of a reduced formation of scission
products at longer reaction times led to outstanding
selectivities with the amount of fragmentation product
usually being below 10%. Representative results are
listed in Table 2.
4
5
RbCl
MgCl2
CaCl2
SrCl2
FeCl3
FeCl2
CoCl2
NiCl2
CuCl2
ZnCl2
CeCl3
6
7
8
9
10
11
12
13
14
15
a All reactions were performed on a 2 mmol scale using 0.5 mol
% RuCl3 (as a 0.1 M stock solution in water), 20 mol % Lewis acid,
and 1.5 equiv of NaIO4 in a solvent mixture of EtOAc/CH3CN/
H2O (3 mL/3 mL/1 mL) at 0 °C and stopped after 3 min by addition
of aq Na2SO3 solution. b Determined by GC integration using
n-dodocane as internal standard.
Acid-labile silyl ethers or acetals are dihydroxylated
in good yields (entries 2 and 3, Table 2) using the milder
Lewis acidic conditions. Furthermore, cyclic olefins known
to undergo a rapid fragmentation7b were dihydroxylated
in excellent yield with only minor formation of scission
products. Competing allylic oxidations were not observed
in the dihydroxylation of electron-rich cyclohexene 10.
Diol 11 was observed as the only product (entry 4, Table
2). The competing acid-induced saponification of cou-
marin 12 or the corresponding diol 13 as observed upon
longer reaction times in the presence of Bro¨nsted acids
is disfavored in the presence of CeCl3. Diol 13 was
isolated in almost quantitative yield (entry 5, Table 2).
Importantly, amides (entry 7-9, Table 2) can be oxidized
to give interesting building blocks in excellent yields with
no formation of scission products.10 The efficiency of this
new protocol is underlined by the successful oxidation of
electron-poor tetrasubstituted olefin 20, which cannot be
dihydroxylated with OsO4 or RuO4 under the standard
conditions. In the presence of catalytic amounts of CeCl3
however a clean reaction to the corresponding vic-diol 21
was observed (entry 9, Table 2). As can be seen from
Table 2, the reaction times are longer compared to the
dihydroxylations under RuO4 catalysis published to
date.6,7 Although the RuO4-catalyzed dihydroxylation
reaction is slowed by catalytic amounts of CeCl3, the
undesired fragmentation pathway is almost inhibited
thus allowing for a better control of the reaction course.
5 and 8, Table 1). It is in line with these observations
that transition-metal chlorides such as FeCl3, FeCl2. and
ZnCl2 led to full conversions after only 3 min. The
selectivity, however, was not satisfying (entries 9, 10, and
14, Table 1). The use of lanthanides as Lewis acids has
received growing attention within the past 10 years due
to their unique ability to act as weak but efficient Lewis
acids even in aqueous reaction systems.9 Based upon the
results obtained in the screening of main group and
transition metal chlorides, we envisioned lanthanides to
be suitable for both a rate acceleration and an improve-
ment of the selectivity in dihydroxylations. Indeed, the
use of CeCl3 led to outstanding conversion rates and good
diol: aldehyde ratios (entry 15, Table 1).
After optimization, a further decrease in the catalyst
and Lewis acid loading was achieved while increasing
the overall substrate concentration by a factor of 2
(Scheme 1). Compared to Shing’s original protocol (7 mol
% RuCl3, 1.5 equiv of NaIO4, c ) 0.07 M)6 and the
Bro¨nsted acid-assisted protocol developed in our group
(0.5 mol % of RuCl3, 1.5 equiv of NaIO4, c ) 0.14 M),7
the new CeCl3-assisted procedure (0.25 mol % of RuCl3,
1.5 equiv of NaIO4, 10 mol % of CeCl3, c ) 0.28 M)
represents a significant improvement in the dihydroxy-
lation of olefins using RuO4. Interestingly, minor amounts
of scission products were only formed in the beginning
of the reaction. However, the initial amount did not
increase even at longer reaction times. Hence, the
selectivity for the formation of diol 2 increases with
ongoing conversion. This is an unusual and new behavior
for oxidations employing NaIO4 as a stoichiometric
reoxidant. Thus, the observed selectivities are the highest
obtained so far in RuO4-catalyzed dihydroxylations. The
optimized protocol is shown in Scheme 1.
A correlation of the pH value and redox potential for
the most powerful dihydroxylation systems (entries 9, 10,
14, and 15, Table 1) indicates the accelerating effect of
iron salts most likely to be a direct consequence of the
more acidic reaction medium. According to the Nernst
equation, the oxidation potential of NaIO4 is inversely
proportional to the pH value of the solution.11 This
behavior is found for the zinc and iron chlorides (Figure
(10) We found amides to be problematic to dihydroxylate employing
the original Upjohn-procedure (OsO4 (cat.), NMO, acetone/water) or
RuO4 under Shingss or our Bro¨nsted acid-accelerated conditions.
(11) The dependency of redox potential and pH value is reflected in
the simplified Nernst equation:
(9) Topics in Organometallic Chemistry 2: Lanthanides: Chemistry
and Use in Organic Synthesis; Kobayashi, S., Ed.; Springer-Verlag:
Berlin, Heidelberg, New York, 1999.
E ) E0 - 0.059pH
J. Org. Chem, Vol. 70, No. 6, 2005 2403

TABLE 2. CeCl3-Accelerated Dihydroxylation of Olefins
FIGURE 1. pH-E relation of a 0.25 M NaIO4 solution in the
presence of 20 mol % of additive at 6 °C. The potential and
pH value were measured vs Ag/AgCl after addition of 0.25
mmol of additive to 5 mL of a 0.25 M aqueous solution of NaIO4
at 6 °C. The data represent the average redox potentials out
of five independent measurements with the given error.
dihydroxylation process. A reactivity study on the CeCl3/
NaIO4 and the H[Ce(IO6)]/NaIO4 dihydroxylation system
in the oxidation of methyl cinnamate 1 showed a dra-
matic rate acceleration and almost identical conversion
rates for both cerium-assisted dihydroxylations compared
to the reaction in the absence of any additive. However,
the selectivity of the reaction in the presence of the
preformed Ce(IV)-periodato complex was not satisfying
(Table 3). The analysis of pH value and redox potential
of the CeCl3/NaIO4 and the H[Ce(IO6)]/NaIO4 system
indicated comparable potentials, the pH value, however,
was different (Table 3).
a All reactions were performed on a 2 mmol scale using 0.25
mol % of RuCl3 (as a 0.1 M solution in water), 10 mol %
CeCl3‚7H2O, and 1.5 equiv of NaIO4 at 0 °C in a solvent mixture
of ethyl acetate/acetonitrile/water (3 mL/3 mL/1 mL). b Isolated
yields. c Numbers in parentheses represent the yields obtained in
the dihydroxylation in the presence of H2SO4.
TABLE 3. pH Value and Redox Potential of
Reoxidation Systems
entrya
reoxidant
pH value
E (V)
2/3b
1
2
3
NaIO4
2.8
1.94
2.61
1.020
1.075
1.071
1.0:1.0
10.2:1.0
4.6:1.0
CeCl3/NaIO4
1).12 The redox potential of the CeCl3/NaIO4 system,
however, indicates that the effect of CeCl3 may not be a
simple pH-driven effect as found for other acids.
H[Ce(IO6)]/NaIO4
a The potential and pH value were measured vs Ag/AgCl after
addition of 0.25 mmol of Ce source to 5 mL of a 0.25 M aqueous
solution of NaIO4 at 6 °C. b The reactions were performed as
indicated in Table 2. Ratios were determined by GC integration.
The chemistry of periodate with various metal cations
is literature known. A variety of transition metal salts
form insoluble intensely colored periodato complexes.13
The observation that a yellow precipitate is formed upon
mixing CeCl3 with NaIO4 indicates an in situ oxidation
toward Ce(IV) which is known to form insoluble yellow
Ce(IV)-periodato complexes.14 We envisioned these com-
plexes to cause the increase in the redox potential at a
lower pH value. Hence, H[Ce(IO6)] was prepared accord-
ing to a literature procedure14 and subjected to the
The addition of CeCl3 to an aqueous solution of NaIO4
induces a slight decrease in the pH value and an increase
in the redox potential (entries 1 and 2, Table 3). The
latter effect might be caused by the in-situ formed Ce-
(IV)-periodato complex, which upon addition to a NaIO4
solution shows an almost identical oxidation potential
albeit at a higher pH value (entry 3, Table 3). At the
current state of research, however, it seems as if both
effects account for the observed high reactivity and
selectivity observed in the CeCl3-assisted RuO4-catalyzed
dihydroxylation. The latter aspects need to be investi-
(12) FeCl3 reacts with water with concomitant release of HCl
according to the equation:
FeCl3 + 6 H2O f [Fe(H2O)6]3+ + 3Cl- pH<28
[Fe(OH)(H2O)5]2+ + 2Cl- + HCl
(14) (a) Alimarin, I. P.; Pusdrenkowa, I. W.; Schiryajewa, O. A.
Nachr. Moskauer University Ser. II Chem. 1962, 17, 61. (b) Levason,
W.; Oldroyd, R. D. Polyhedron 1996, 15, 409. (c) Griffith, W. P.; Moreea,
R. G. H.; Nogueira, H. I. S. Polyhedron 1996, 15, 3493.
(13) For a review see: (a) Siebert, H. Fortschritte Chem. Forsch.
1967, 8, 470. (b) Dratovsky, M.; Pacesova, L. Russ. Chem. Rev. 1968,
243. (c) Levason, W. Coord. Chem. Rev. 1997, 161, 22.
2404 J. Org. Chem., Vol. 70, No. 6, 2005

gated in detail in order to get a deeper understanding
on the interplay between CeCl3, NaIO4, pH value, and
redox potential in the dihydroxylations. Hence, future
work will focus on these interesting results. However, to
the best of our knowledge this is the first successful
application of cerium-periodato complexes in organome-
tallic catalysis. The high oxidation potential and good
selectivity of these unexplored reagents might also be
beneficial in other oxygen transfer reaction employing
stoichiometric amounts of NaIO4.
Experimental Section
General Procedure for the Dihydroxylation. In a 50-mL
round-bottomed flask equipped with magnetic stirring bar and
overpressure valve were stirred NaIO4 (642 mg, 3 mmol) and
CeCl3‚7H2O (74.6 mg. 0.2 mmol, 10 mol %) in 0.9 mL of H2O
and gently heated until a bright yellow suspension was formed.
After cooling to 0 °C, ethyl acetate (2.5 mL) and acetonitrile (3
mL) were added, and the suspension was stirred for 2 min. A
0.1 M aqueous solution of RuCl3 (50 µL, 0.01 mmol) was added,
and the mixture was stirred for 2 min. A solution of the olefin
(2 mmol) in ethyl acetate (0.5 mL) was added in one portio,n
and the resulting slurry was stirred until all starting material
was consumed. Solid Na2SO4 (1 g) was added followed by ethyl
acetate (6 mL). The solid was filtered off, and the filter cake
was washed several times with ethyl acetate. The filtrate was
washed with satd Na2SO3 solution (3 mL), and the organic layer
was dried over Na2SO4 and concentrated in a vacuum. The crude
product was purified by flash chromatography.
In summary, a new CeCl3/NaIO4 reoxidation system
was developed for RuO4-catalyzed diyhdroxylation. This
new protocol possesses several advantages compared to
the previously published Bro¨nsted acid-accelerated di-
hydroxylation. Due to the milder conditions, protolytic
side reactions of the starting material are not observed.
Furthermore, the moderate pH value might account for
the result that neither a RuO4-catalyzed nor a NaIO4-
induced glycol cleavage of the final product becomes a
serious side reaction. These background processes, how-
ever, are known to be particularly problematic in RuO4-
catalyzed oxidations of C,C-double bonds at longer reac-
tion times. Hence, by disfavoring undesired reaction
pathways, the oxidation of unreactive tetrasubstituted
olefins was possible by a simple prolongation of the
reaction time. In addition, this new protocol allows a
further reduction in the catalyst concentration down to
only 0.25 mol % RuCl3. Thus, the new bimetallic oxida-
tion system of RuCl3/CeCl3/NaIO4 represents an improved
protocol for the preparation of racemic syn-diols from
unreactive or acid sensitive olefins in good to excellent
yields. Further studies toward the development of an
asymmetric version of this reaction and an environmen-
tally friendly reoxidation process are currently under
investigation in our laboratories.
(3R*,4S*)-1-Benzyl-3,4-dihydroxy-3,4-dimethylpyrroli-
dine-2,5-dione (15): (443 mg, 1.78 mmol, 89%); white solid;
mp 89 °C; Rf 0.12 (1:1 pentane/ethyl acetate); 1H NMR (400 MHz,
CDCl3) δ 7.27 (s, 5H), 4.61 (s, 2H), 4.23 (s, 2H), 1.33 (s, 6H); 13
C
NMR (100 MHz, CDCl3) δ 178.9, 136.5, 130.2, 129.6, 129.4, 76.9,
43.7, 20.1; IR (KBr) ν 3450 (s), 2991 (w), 1703 (s), 1404 (m), 1343
(m), 1134 (s), 1070 (m), 699 (s). Anal. Calcd for C13H15NO4
(249.26): C, 62.64; H, 6.07. Found: C, 62.65; H, 6.08.
Acknowledgment. We thank Prof. Dr. N. Krause
for generous support. B.P. thanks the Fonds der Che-
mischen Industrie (Liebig fellowship), the Otto-Ro¨hm-
Geda¨chtnisstiftung, and the Deutsche Forschungsge-
meinschaft (Emmy-Noether fellowship). Further
financial support by the Fonds zur Fo¨rderung des
wissenschaftlichen Nachwuchses im Fachbereich Che-
mie der Universita¨t Dortmund is gratefully acknowl-
edged.
1
Supporting Information Available: Copies of H NMR
spectra and spectral data for all diols. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO048020X
J. Org. Chem, Vol. 70, No. 6, 2005 2405