The RuO4-catalyzed ketohydroxylation. Part 1. Development, scope, and limitation

Article abstract of DOI:10.1021/jo048822s

A new straightforward oxidation of C,C-double bonds to unsymmetrical α-hydroxy ketones using catalytic amounts of RuCl₃ and stoichiometric amounts of Oxone under buffered conditions has been developed, a reaction for which we coined the expression "ketohydroxylation". The transformation allows the direct formation of α-hydroxy ketones (acyloins) from olefins without intermediate formation of syn-diols. The present paper will provide detailed information starting with the underlying concept and the subsequent development of the reaction. The effect of base, solvent stoichiometry, and temperature will be discussed resulting in an improved mechanistic model that might help to explain the influence of different reaction parameters on reactivity and selectivity in RuO₄-catalyzed oxidations of C,C-double bonds. Furthermore, an improved workup procedure allows the recovery of the ruthenium catalyst by precipitation while simplifying the overall product purification. The second part of the paper focuses on exploration of scope and limitation. A variety of substituted olefins are oxidized to α-hydroxy ketones in good to excellent regioselectivities and yield. Cyclic substrates proved to be problematic to oxidize; however, a careful analysis of temperature effects resulted in the development of a successful protocol for the ketohydroxylation of cyclic substrates by simply decreasing the reaction temperature.

Full text of DOI:10.1021/jo048822s

The RuO4-Catalyzed Ketohydroxylation. Part 1. Development,
Scope, and Limitation
Bernd Plietker*
Organic Chemistry II, Chemistry Faculty, Dortmund University, Otto-Hahn-Str. 6,
D-44221 Dortmund, Germany
plietker@pop.uni-dortmund.de
Received July 12, 2004
A new straightforward oxidation of C,C-double bonds to unsymmetrical R-hydroxy ketones using
catalytic amounts of RuCl3 and stoichiometric amounts of Oxone under buffered conditions has
been developed, a reaction for which we coined the expression “ketohydroxylation”. The transforma-
tion allows the direct formation of R-hydroxy ketones (acyloins) from olefins without intermediate
formation of syn-diols. The present paper will provide detailed information starting with the
underlying concept and the subsequent development of the reaction. The effect of base, solvent
stoichiometry, and temperature will be discussed resulting in an improved mechanistic model that
might help to explain the influence of different reaction parameters on reactivity and selectivity in
RuO4-catalyzed oxidations of C,C-double bonds. Furthermore, an improved workup procedure allows
the recovery of the ruthenium catalyst by precipitation while simplifying the overall product
purification. The second part of the paper focuses on exploration of scope and limitation. A variety
of substituted olefins are oxidized to R-hydroxy ketones in good to excellent regioselectivities and
yield. Cyclic substrates proved to be problematic to oxidize; however, a careful analysis of
temperature effects resulted in the development of a successful protocol for the ketohydroxylation
of cyclic substrates by simply decreasing the reaction temperature.
Introduction
Chiral R-oxygenated carbonyl compounds (acyloins) are
useful building blocks in organic synthesis and structural
motifs in a variety of biological active natural products.
The macrolides amphidinolides T1-T4, for example,
differ only in the regio- and stereochemical arrangement
of the R-hydroxy ketone (Figure 1).1
Given the importance of these macrocyclic compounds
with regard to their biological activity1d a both regio- and
stereoselective access toward R-hydroxy ketones is of high
synthetic interest. Different retrosynthetic approaches
have been investigated in the past. Consequently, asym-
metric protocols for the benzoin condensation2 and the
R-hydroxylation of carbonyl compounds3-5 have been
developed giving rise to a variety of enantiomerically
FIGURE 1. Acyloin substructure in amphidinolides T1-T4.
enriched acyloins. With regard to recent progress in the
field of olefin metathesis6 we envisioned the direct
asymmetric oxidation of olefins to R-hydroxy ketones to
(1) (a) Kobayashi, J.; Kubota, T.; Endo, T.; Tsuda, M. J. Org. Chem.
2001, 66, 134. (b) Tsuda, M.; Endo, T.; Kobayashi, J. J. Org. Chem.
2000, 65, 1349. (c) Kubota, T.; Endo, T.; Tsuda, M.; Shiro, M.;
Kobayashi, J. Tetrahedron 2001, 57, 6175. (d) For a current review on
amphidinolides, see: Chakraborty, T. K.; Das, D.; Curr. Med. Chem.:
Anti-Cancer Agents 2001, 1, 131.
(2) (a) Enders, D.; Kallfass, U. Angew. Chem. 2002, 114, 1822;
Angew. Chem., Int. Ed. 2002, 41, 1743. (b) Du¨nkelmann, P.; Kolter-
Jung, D.; Nitsche, A.; Demir, A. S.; Siegert, P.; Lingen, B.; Baumann,
M.; Pohl, M.; Mu¨ller, M. J. Am. Chem. Soc. 2002, 124, 12084. (c) Demir,
A. S.; Sesenoglu, O.; Eren, E.; Hosrik, B.; Pohl, M.; Janzen, E.; Kolter,
D.; Feldmann, R.; Duenkelmann, P.; Mu¨ller, M. Adv. Synth. Catal.
2002, 1, 96 (and references therein).
(5) (a) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. J.
Am. Chem. Soc. 2003, 125, 10808. (b) Zhoung, G. Angew. Chem. 2003,
115, 4379; Angew. Chem., Int. Ed. 2003, 42, 4247. (c) Bogevig, A.;
Sunde´n, H.; Co´rdova, A. Angew. Chem. 2004, 116, 1129; Angew. Chem.,
Int. Ed. 2004, 43, 1109. (d) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.;
Shoji, M. Angew. Chem. 2004, 116, 1132; Angew. Chem., Int. Ed. 2004,
43, 1112.
(6) (a) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42,
1900. (b) Fu¨rstner, A. Adv. Synth. Catal. 2002, 344, 567. (c) Trnka, T.
M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (d) Schrock, R. R. In
Topics in Organometallic Chemistry 1 - Alkene Metathesis in Organic
Synthesis; Fu¨rstner, A., Ed.; Springer-Verlag: Berlin, Heidelberg, 1998;
p 1. (e) Fu¨rstner, A. In Topics in Organometallic Chemistry 1 - Alkene
Metathesis in Organic Synthesis; Fu¨rstner, A., Ed.; Springer-Verlag:
Berlin, Heidelberg, 1998; p 37. (f). Nicolaou, K. C.; King, N. P.; He, Y.
In Topics in Organometallic Chemistry 1 - Alkene Metathesis in Organic
Synthesis; Fu¨rstner, A., Ed.; Springer-Verlag: Berlin, Heidelberg, 1998;
p 73.
(3) Zhou, P.; Chen, B. A.; Davies, F. A. In Asymmetric Oxidation
Reactions; Katsuki, T., Ed.; Oxford University Press: Oxford, 2001; p
128.
(4) Morikawa, K.; Park, J.; Andersson, P. G.; Hashiyama, T.;
Sharpless, K. B. J. Am. Chem. Soc. 1993, 115, 8463.
10.1021/jo048822s CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/27/2004
J. Org. Chem. 2004, 69, 8287-8296
8287

Plietker
be a synthetically interesting transformation. However,
whereas the dihydroxylation of alkenes has been in the
center of research for more than 30 years7 the direct
oxidation of a C,C-double bond to an R-hydroxy ketone
has almost been neglected.8-11 Based upon results ob-
tained during investigations in RuO4-catalyzed dihy-
droxylations,12 we recently reported a new RuO4-cata-
lyzed direct ketohydroxylation of olefins. This reaction,
although not enantioselective at the moment, represents
a first and important step toward the development of the
attempted asymmetric direct oxidation of olefins to
R-hydroxy ketones.13 The present paper gives a full
account on the basic ideas and the subsequent develop-
ment of this new direct oxidation reaction. Furthermore,
the workup procedure was significantly improved com-
pared to our original report. Whereas an aqueous workup
allows the removal of the catalyst, we were able to
reisolate different ruthenium-oxo compounds by simple
centrifugation or filtration during an anhydrous workup.
The reisolated catalyst was used in different runs during
the ketohydroxylation and proved to be catalytically
active. The second part will provide a full account of the
scope and limitations of this new catalytic process with
a special focus on functional group tolerance and tem-
perature effects in the oxidation of cyclic olefins.
nucleophilic attack furnishes the desired diol. In osmium-
catalyzed dihydroxylations the hydrolysis is the rate-
limiting step.15 Hence, different promoters for an accel-
erated hydrolysis have been identified. Akashi16 reported
on the beneficial influence of tetra-n-alkylammonium
acetates while Sharpless17 described the accelerated
dihydroxylation using stoichiometric amounts of sulfon-
amides. In either reaction, the promoter represents a
better nucleophile than water facilitating the initial
metal-oxygen bond cleavage in the osmate. As an
alternative to the addition of an external promoter a fine-
tuning of the pH value can lead to an accelerated
hydrolysis. Recently, we reported the acid-accelerated
ruthenium-catalyzed dihydroxylation.12 The addition of
catalytic amounts of H2SO4 resulted in a dramatic
increase in the rate of hydrolysis.18
Our concept for the development of a direct RuO4-
catalyzed ketohydroxylation is based upon the following
facts and ideas:
(i) RuO4 is less expensive and toxic compared to OsO4.
(ii) During the initial [3 + 2]-cycloaddition of RuO4 to
the C,C-double bond two stereocenters with defined
relative configuration are generated. This introduction
of stereoinformation differs significantly from the Mu-
rahashi protocol,11 in which the final stereocenter is
introduced via a nucleophilic addition of water to a planar
carbocation. Whereas a stereoselective addition of this
type is difficult to control, our protocol introduces the
center of chirality at an early stage of the catalytic cycle.
With regard to an asymmetric ketohydroxylation the
problem of stereoselectivity is finally reduced to an
enantioselective [3 + 2]-cycloaddition.
(iii) In analogy to the osmium-catalyzed dihydroxyla-
tion the nucleophilic addition of water, i.e., the hydrolysis,
should occur at the stage of an ruthenium(VIII)-ester
III (Figure 2). The results obtained for the ruthenium-
catalyzed dihydroxylation clearly indicated that an ac-
celerated nucleophilic addition might be achieved at pH
< 7.12
(iv) If the addition of an alternative nucleophile is
possible, the addition of a nucleophilic oxidant would
result in highly reactive ruthenium(VIII)-peroxo ester
VI (Figure 2) that could collapse to give the R-hydroxy
ketone VII without corrupting the stereocenter in the
final product. Figure 2 visualizes this mechanistic di-
chotomy.
Different problematic issues needed to be addressed
during the development of the ketohydroxylation:
(i) The nucleophile has to add to the metal center faster
than water.
Results and Discussion
Concept. RuO4 is isoelectronic to OsO4. Hence, both
cyclic ruthenates and osmates are primary intermediates
in the oxidation of C,C-double bonds.14 The hydrolysis of
these compounds furnishes vic-diols. From a mechanistic
point of view, the hydrolysis proceeds via a nucleophilic
addition of water to the metal center while cleaving one
of the two metal-oxygen bonds. A subsequent second
(7) (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.
(8) Acyloins are byproducts in dihydroxylation processes. (a) In
osmium-catalyzed oxidations, see ref 14a. (b) In ruthenium-catalyzed
oxidations: Zimmer, R.; Homann, K.; Angermann, J.; Reissig, H.-U.
Synthesis 1999, 1223. (c) In manganese-mediated oxidations: Carlson,
R. G.; Pierce, J. K. J. Org. Chem. 1971, 36, 2319.
(9) Enantiomerically enriched acyloins can be obtained via mono-
oxidation of enantiomerically enriched vic-diols: (a) D’Accolti, L.;
Detomaso, A.; Fusco, C.; Rosa, A.; Curci, R. J. Org. Chem. 1993, 58,
3600. (b) Curci, R.; D’Accolti, L.; Dinoi, A.; Fusco, C.; Rosa, A.
Tetrahedron Lett. 1996, 37, 115. (c) For a catalytic version of this
reaction, see: Plietker, B. Org. Lett. 2004, 6, 289. (d) The desym-
metrisation of meso-diols has been described: Adam, W.; Saha-Mo¨ller,
C. R.; Zhao, C.-G. J. Org. Chem. 1999, 64, 7492 (and references
therein).
(10) Fleming, S. A.; Carroll, S. M.; Hirschi, J.; Liu, R.; Pace, J. L.;
Redd, J. T. Tetrahedron Lett. 2004, 45, 3341.
(ii) The oxidation potential of the nucleophile has to
be high enough to oxidize ruthenium(VI) to ruthenium-
(VIII).
(11) For direct conversions of olefins to R-ketols see: (a) Murahashi,
S.-I.; Komiya, N. In Biomimetic Oxidations Catalyzed by Transition
Metal Complexes; Meunier, B, Ed.; Imperial College Press: London,
2000; p 563. (b) Murahashi, S.-I. Pure Appl. Chem. 1992, 64, 403. (c)
Ruthenium-catalyzed: Murahashi, S.-I.; Saito, T.; Hanaoka, H.; Mu-
rakami, Y.; Naota, T.; Kumobayashi, H.; Akutagawa, S. J. Org. Chem.
1993, 58, 2929. (d) Osmium-catalyzed: Murahashi, S.-I.; Naota, T.;
Hanaoka, H.; Chem. Lett. 1993, 1767. (e) OsO4-Ni-catalyzed: Takai,
T.; Yamada, T.; Mukaiyama, T. Chem. Lett. 1991, 1499. (f) CuSO4-
KMnO4-assisted: Baskaran, S.; Das, J.; Chandrasekaran, S. J. Org.
Chem. 1989, 54, 5182.
(15) (a) Becker, H.; Sharpless, K. B. In Asymmetric Oxidation
Reactions; Katsuki, T., Ed.; Oxford University Press: New York, 2001;
p 81. (b) Morikawa, K.; Park, J.; Andersson, P. G.; Hashiyama, T.;
Sharpless, K. B. J. Am. Chem. Soc. 1993, 115, 8463.
(16) (a) Sharpless, K. B.; Akashi, K. J. Am. Chem. Soc. 1976, 98,
1986. (b) Akashi, K.; Palermo, R. E.; Sharpless, K. B. J. Org. Chem.
1978, 43, 2063.
(12) (a) Plietker, B.; Niggemann, M. Org. Lett. 2003, 5, 3353. (b)
Plietker, B.; Niggemann, M.; Pollrich, A. Org. Biomol. Chem. 2004, 2,
1116.
(13) Plietker, B. J. Org. Chem. 2003, 68, 7123.
(14) Frunzke, J.; Loschen, C.; Frenking, G. J. Am. Chem. Soc. 2004,
126, 3642.
(17) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crsipino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;
Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
(18) Similar observations were published by Sharpless for osmium-
catalyzed dihydroxylation: Dupau, P.; Epple, R.; Thomas, A. A.; Fokin,
V. V.; Sharpless, K. B. Adv. Synth. Catal. 2002, 344, 421.
8288 J. Org. Chem., Vol. 69, No. 24, 2004

RuO4-Catalyzed Ketohydroxylation
TABLE 1. Influence of Reoxidant
(iii) Unsymmetrical substituted double bonds can lead
to complex mixtures of diols and regioisomeric acyloins.
Development. It is known that RuO4 tends to cleave
C,C-double bonds very fast.12,19 However, intense inves-
tigations on the related ruthenium-catalyzed dihydroxy-
lation carried out in our group indicated that the nucleo-
philic addition of water to the ruthenate is fast in a 3:3:1
mixture of ethyl acetate, acetonitrile, and water. Any
other solvent combination facilitated the scission reac-
tion.12 Hence, we chose this ternary solvent mixture as
a starting point. The development of the ketohydroxyla-
tion started with the search for an appropriate reoxida-
tion system matching our criteria of a nucleophilic and
oxidizing agent. To act as a nucleophile the oxygen part
of the oxidant has to add to the metal center in ruthenate
III (Figure 2). This process competes with the addition
of water present in the reaction mixture. To accelerate
the nucleophilic addition a 5-fold excess of the oxidizing
agent was used whereas the amount of water was
significantly lowered. Different reoxidation systems were
tested. The acidic Oxone in combination with NaHCO3
proved successful (Table 1).19
entry
reoxidanta
time
conversionb (%) 2/3/4c (%)
1
2
3
4
t-BuOOH, Et4NOH 1 d
30
12
60
80
17:5:78
n.d.
15:10:75
66:23:11
H2O2, Et4NOH
NaOCl
1 d
60 min
10 min
d
Oxone, NaHCO3
a All reactions were performed on a 2 mmol scale in a solvent
mixture of ethyl acetate (12 mL)/acetonitrile (12 mL)/water (2 mL)
at room temperature using 1 mol % RuCl3 (as a 0.1 M stock
solution in water) and 5 equiv of reoxidant. b Determined by GC
integration. c Percentage refers to the amount of product in the
mixture. d 1.5 equiv NaHCO3 was used.
TABLE 2. Influence of Solvent Stoichiometry
entry
EtOAc/CH3CN/H2Oa
conversionb (%)
2/3/4b (%)
1
2
3
4
5
6
1:1:2
1:1:1
2:2:1l
3:3:1
6:6:1
6:3:1
82
84
81
80
83
51
13:9:78
28:15:57
49:10:41
66:23:11
75:7:18
n.d.
a All reactions were performed on a 2 mmol scale in a solvent
mixture of ethyl acetate (12 mL)/acetonitrile (12 mL)/water (2 mL)
at room temperature using 1 mol % RuCl3 (as a 0.1 M stock
solution in water) and 5 equiv of reoxidant and stopped after 10
min. b Determined by GC integration.
TABLE 3. Influence of Base
entry
basea
conversionb (%)
2/3/4b (%)
1
2
3
4
5
6
7
8
NaHCO3
83
12
8
75:7:18
n.d.
c
Na2CO3
NaOH
CsCO3
n.d.
c
15
19
23
7
n.d.
Et4NOH
Et3N
pyridine
DMAP
n.d.
n.d.
n.d.
9
n.d.
a All reactions were performed on a 2 mmol scale in a solvent
mixture of ethyl acetate (12 mL)/acetonitrile (12 mL)/water (2 mL)
at room temperature using 1 mol % RuCl3 (as a 0.1 M stock
solution in water), 5 equiv of reoxidant, and 1.5 equiv of base and
stopped after 10 min. b Determined by GC integration. c 0.75 equiv
of base was used.
FIGURE 2. Nucleophilic addition of a reoxidant vs water.
These results are in line with our observations of a rate
acceleration in ruthenium-catalyzed dihydroxylation by
addition of Bro¨nstedt acids.12 Subsequently, we investi-
gated the influence of the solvent stoichiometry on
product distribution and reactivity. We envisioned the
amount of water to be crucial for the outcome of the
reaction. Water is needed in order to activate the Oxone;
however, it competes in the nucleophilic addition. Hence,
different solvent stoichiometries were tested. The results
are listed in Table 2.
The amount of water determines the product distribu-
tion. More water favors the formation of scission products
while less water pushes the selectivity toward the acyloin
formation. Knowing the optimum solvent stoichiometry
we investigated the influence of base on the reaction.
Different basic salts as well as organic nitrogen bases
were used under the standard reaction conditions. The
results are listed in Table 3.
A strong effect of the base on the reactivity of the
system was observed. Whereas carbonates or organic
nitrogen bases inhibit the reaction, NaHCO3 gave good
results. The influence of base is not clear at the moment;
however, it was noted that in cases with low reactivity
(entries 2-5, Table 3) the yellow color of the RuO4 was
not observed. Apparently, hydroxides or carbonates are
too basic leading to a preferred formation of perruthenate
- 20
RuO4
.
The inhibitory effect of the organic nitrogen
bases (entries 6 and 7, Table 3), however, is not fully
understood. Due to the known complexation ability of
these bases with RuCl3 the formation of catalytically
inactive low valent ruthenium-base adducts might be
possible.21
(20) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(21) Sliwa, W. Trans. Met. Chem. 1989, 14, 321.
(19) Yang, D.; Zhang, C. J. Org. Chem. 2001, 5, 3353;
J. Org. Chem, Vol. 69, No. 24, 2004 8289

Plietker
TABLE 4. Influence of the Amount of Base
TABLE 6. Solvent Effect
entry
NaHCO3a (equiv)
conversionb (%)
2/3/4b (%)
entry
solventa
conversionb (%)
2/3/4b (%)
1
2
3
4
5
6
7
0
58
38
79
96
81
73
86
48:15:37
61:23:16
81:12:7
98:0:2
1
2
3
4
5
6
7
8
EtOAc
96
98:0:2
87:5:8
13:16:71
n.d.
1
MTBEc
59
2
2.5
3
4
5
CH2Cl2
23
17
CHCl3
86:6:8
CCl4
n.d.
n.d.
89
n.d.
41:3:56
21:6:73
hexane
n.d.
0:27:73
65:18:17
tert-butyl alcohol
acetone
84
a All reactions were performed on a 2 mmol scale in a solvent
mixture of ethyl acetate (12 mL)/acetonitrile (12 mL)/water (2 mL)
at room temperature using 1 mol % RuCl3 (as a 0.1 M stock
solution in water), 5 equiv of Oxone, and the given amount of
NaHCO3 and stopped after 10 min. b Determined by GC integra-
tion.
a All reactions were performed on a 2 mmol scale in a solvent
mixture of ethyl acetate (12 mL)/acetonitrile (12 mL)/water (2 mL)
at room temperature using 1 mol % RuCl3 (as a 0.1 M stock
solution in water), 5 equiv of reoxidant, and 2.5 equiv of NaHCO3
and stopped after 10 min. b Determined by GC integration.
c Methyl tert-butyl ether.
TABLE 5. Temperature Effect
entry
Ta (°C)
conversionb (%)
2/3/4b (%)
1
2
3
4
5
0
10
20
40
60
59
67
96
75
67
96:0:4
94:0:6
98:0 8
58:15:27
5:27:68
a All reactions were performed on a 2 mmol scale in a solvent
mixture of ethyl acetate (12 mL)/acetonitrile (12 mL)/water (2 mL)
at room temperature using 1 mol % RuCl3 (as a 0.1 M stock
solution in water), 5 equiv of reoxidant, and 2.5 equiv of NaHCO3
and stopped after 10 min. b Determined by GC integration.
With regard to the pH-dependent oxidation rate in
RuO4-catalyzed dihydroxylations12 the influence of the
stoichiometry Oxone/NaHCO3 was investigated next
(Table 4).
The reaction course changes drastically within the
investigated pH range. There is an apparent maximum
at a stoichiometry of Oxone/NaHCO3 (2:1) (entry 4, Table
4). At higher base concentrations the hydrolysis of the
less activated ruthenate is slow compared to the electro-
cyclic ring cleavage.19 Hence, fission products such as 4
are formed predominantly. At lower pH values the
reaction rate is accelerated; however, at a certain point
the selectivity drops again. This observation might be
explained by the fact that both the nucleophilic attack
FIGURE 3. Optimization of catalyst concentration.
As in the dihydroxylation ethyl acetate proved to be
the solvent of choice. tert-Butyl alcohol speeds up the
addition of water rather than persulfate, whereas polar
aprotic solvents lower the conversion and selectivity.
Having in hand the optimized conditions for the
ketohydroxylation we finally investigated the amount of
catalyst needed for an efficient oxidation. As can be seen
in Figure 3 the conversion drops significantly at a
catalyst concentration below 1 mol % (Figure 3).
2-
of SO5 and of H2O is accelerated leading to a mixture
of diol, ketol, and aldehyde with the diol being cleaved
in a concomitant step.22 The influence of protons on the
rate of the reaction underlines the hypothesis of the
hydrolysis or any other nucleophilic addition being the
rate-limiting step in either RuO4-catalyzed oxidation.
In ruthenium-catalyzed dihydroxylations a strong in-
terplay between temperature and selectivity was ob-
served.12 In general, electrocyclic fragmentations are
faster at elevated temperature. Consequently, the influ-
ence of the temperature on the ketohydroxylation was
investigated. The results are listed in Table 5.
The temperature influences the selectivity of the
reaction. Whereas a temperature below 20 °C reduces the
conversion without changing the selectivity, higher tem-
peratures lead to a predominant formation of scission
products. Furthermore, black precipitates of catalytically
inactive ruthenium compounds responsible for the lower
conversion are formed. At this point we reinvestigated
the influence of solvent. The results are listed in Table
6.
In summary, the course of the reaction is influenced
by the nature of the reoxidant, the pH value of the
reaction medium, and the temperature.
Optimization of the Workup: Reisolation of the
Catalyst. In most RuO4-catalyzed oxidations the active
catalyst is destroyed during the workup procedure by
addition of reducing agents. However, due to the presence
of acetonitrile in the reaction mixture it is impossible to
remove the entire amount of catalyst during the workup.
Hence, we were seeking an optimized workup that would
allow the use of a minimum amount of solvent while
reisolating the ruthenium catalyst by precipitation. Dif-
ferent from other oxidation reactions, we did not observe
the formation of black ruthenium-oxo precipitates dur-
ing the ketohydroxylation reaction. The organic layer had
a yellow color even after complete conversion. This
observation inspired us to develop an “anhydrous” work-
(22) RuO4 catalyzes efficiently the cleavage of vic-diols: see ref 12b.
8290 J. Org. Chem., Vol. 69, No. 24, 2004

RuO4-Catalyzed Ketohydroxylation
to those obtained on a 2-mmol scale. Apart from this
important result the activity of the recycled catalyst was
analyzed. The amount of acyloin formed after four
reisolation cycles is lower indicating that the reisolated
catalyst might differ in the reactivity. However, the
concept of reisolating the catalyst by precipitation ap-
pears to be promising. We are currently trying to develop
a more selective “ruthenium scavenger” that allows the
separation of the ruthenium catalyst directly from the
product solution.
Mechanistic Proposal. The interplay of fragmenta-
tion, dihydroxylation, and ketohydroxylation is shown in
the preliminary mechanistic proposal in Figure 5. The
initial [3 + 2]-cycloaddition of ruthenium tetraoxide I to
the double bond in VIII leads to ruthenium(VI) com-
pound IX, which is oxidized to ruthenate XII. This
compound can react in different ways. Apart from an
electrocyclic fragmentation (path C) resulting in the
formation of scission products X and XI the competing
nucleophilic addition of water (path A) versus SO52- (path
B) determines the product composition. A low amount of
water in the reaction combined with the excess of Oxone
FIGURE 4. Activity of reisolated ruthenium compounds
(reactions were performed on a 100 mmol scale).
2-
favors the addition of SO5 to the metal center in XIV.
up with the goal of reisolating the catalyst (vide infra).
This new procedure allows the precipitation of ruthenium-
oxo compounds upon evaporation of the solvent. The
precipitates were removed by centrifugation and dried
in a vacuum. Treating the purple-black solid with Oxone
under the ketohydroxylation conditions resulted in a
yellow organic layer. Although the activity and chemose-
lectivity drops after two reaction cycles, this procedure
allows a partial recovery of an active ruthenium catalyst
while simplifying the overall workup and product puri-
fication. Preliminary results on the activity of the reiso-
lated ruthenium-oxo species in the oxidation of trans-
stilbene 1 are shown in Figure 4.
Upon addition of SO52- to the activated ruthenate XIV a
mixed peroxoruthenate XV is formed, which collapses to
give the desired R-hydroxy ketone XVI and RuO4 I.
Apart from these productive mechanistic pathways a
destructive background reaction is important in RuO4-
catalyzed oxidations as indicated in Figure 5: The
condensation (path D) between diol XIII and I results in
the formation of ruthenate XII, which can either be
attacked by HSO5- or undergo an electrocyclic fragmen-
tation (path C). Recently, we showed that the reaction
according to path is much slower compared to the direct
oxidation of olefins and is therefore most likely respon-
sible for the formation of scission products in RuO4-
catalyzed oxidations after longer reaction times. How-
The ketohydroxylation was performed on a 100-mmol
scale. The yields and product distributions were identical
FIGURE 5. Mechanistic relationship between the ruthenium-catalyzed dihydroxylation (path A), ketohydroxylation (path B),
fragmentation (path C), and mono oxidation (path D).
J. Org. Chem, Vol. 69, No. 24, 2004 8291

Plietker
TABLE 7. Ketohydroylation of Olefins: Functional
Group Tolerance
FIGURE 6. Ketohydroxylation (path A) vs fragmentation
(path B) in strained bicyclic ruthenates.
ever, this reaction allows the regioselective conversion
of enantiomerically enriched vic-diols to the correspond-
ing acyloins without loss of enantiopurity.9c The electro-
cyclic fragmentation of IX or XII results in the formation
of RuO2 or a ruthenium(VI)-oxo species which can be
reoxidized by Oxone to give catalytically active RuO4.
Scope and Limitations. Having in hand optimized
conditions for the transformation of olefins to acyloins
we turned our interest to an intense screening of scope
and limitation. Apart from the question of functional
group tolerance under acidic reaction conditions the
regioselectivity was expected to be a problematic issue.
However, we were pleased to find that the new developed
ketohydroxylation can be applied to the oxidation of a
wide variety of substrates. Depending on the electronic
character of the functional group good to excellent
regioselectivities were observed. Representative results
are listed in Table 7.
Functional groups such as chlorides, acetates, or imides
are tolerated. Surprisingly, even acetals can be oxidized
under the conditions indicating that the reaction times
are too short for the acetal hydrolysis to become a serious
side reaction. Whereas the conversion is not strongly
dependent on electronic properties of the C,C double bond
the regioselectivity is. Electron-withdrawing groups di-
rect the regioselectivity with the hydroxy group ending
up proximal to the electron-withdrawing substituent.
However, factors influencing the regioselectivity are
currently under investigation.
The oxidation of cyclic systems was explored next.
Whereas the reaction of acyclic substrates is a generally
high-yielding process with the formation of only minor
amounts of scission products, the fragmentation process
becomes dominant in the ketohydroxylation of cyclic
olefins. A possible explanation might be the ring strain
in the cis-annulated bicyclic ruthenates XVIII formed
upon [3 + 2]-cycloaddition between RuO4 and the cy-
cloalkene XVII (Figure 5). The tendency of cyclic ruth-
enates to undergo electrocyclic fragmentations is de-
scribed in the literature. Calculations indicated that in
contrast to the chemistry of the isoelectronic cyclic
osmates the fragmentation pathway of ruthenates is
thermodynamically favored.14 The energy difference be-
tween hydrolytic pathway and fragmentation amplifies
if strained bicyclic ruthenates are formed due to the
release of ring strain. Hence, the product distribution
reflects the competition between kinetic and thermody-
namic control. This mechanistic dichotomy is illustrated
in the simplified Figure 6.
a All reactions were performed on a 2 mmol scale in a solvent
mixture of ethyl acetate (12 mL)/acetonitrile (12 mL)/water (2 mL)
at room temperature using 1 mol % RuCl3 (as a 0.1 M stock
solution in water), 5.0 equiv of Oxone, and 2.5 equiv of NaHCO3.
b Percentage in parentheses refers to the relative amount of
regioisomer acccording to 1H NMR integration of the crude
product. c Combined isolated yield.
The observations we made in the related RuO4-
catalyzed dihydroxylation proved indeed the fragmenta-
tion to be the thermodynamically preferred mechanistic
pathway, thus decreasing the reaction temperature
8292 J. Org. Chem., Vol. 69, No. 24, 2004

RuO4-Catalyzed Ketohydroxylation
TABLE 8. Oxidation of Cyclohexene 35 at Different
Temperatures
SCHEME 1. Problematic Substrates
entrya
T (°C)
time (min)
conversionb (%)
yieldc (%)
1
2
3
4
5
20
10
30
30
45
60
90
97
97
95
95
96
23
54
67
72
78
0
-10
-20
reaction conditions. However, the influence of the ring
strain is reflected in the yield. Whereas cycloheptene 37
(entry 2, Table 9) is oxidized in good yield, cyclohexene
35 was converted less efficiently (entry 1, Table 9).
Cyclopentene reacted toward scission products. However,
an efficient oxidation might be obtained with problematic
cyclic substrates by lowering the reaction temperature.
In this context it is important to note that the reaction
even proceeds at temperature down to -20 °C albeit with
significant longer reaction times. This temperature effect
is exemplified in the oxidation of (1S)-(-)-R-pinene 45
(entry 6, Table 9). Due to the ring strain in the bicyclic
olefin an efficient ketohydroxylation is not possible at
room temperature. The fragmentation is the dominant
pathway, which can be suppressed by lowering the
temperature to 0 °C. Under these conditions, the desired
R-hydroxy ketone 46 was obtained in good yield and
excellent diastereomeric ratio. First results on the simple
diastereoselectivity indicate that the initial [3 + 2]-cy-
cloaddition between RuO4 and the C,C-bond follows the
Kishi rules developed for the related OsO4-catalyzed
dihydroxylation of olefins possessing a center of chirality
in the allylic position.23
a All reactions were performed at the given temperature under
the conditions listed in Table 7. b Determined by GC integration.
c Isolated yield of 36.
TABLE 9. Ketohydroxylation of Cyclic Compounds
Limitations. Although a variety of different olefins
are ketohydroxylated in good to excellent yields, certain
limitations do exist. Due to the acidic conditions some
acid-labile functional groups are not tolerated if the
oxidation is slow. Furthermore, oxidizable heteroatoms
can undergo competing side reactions. A survey of
problematic functional groups is given in Scheme 1. It
has to be emphasized that these functional groups were
incorporated proximal to the C,C-double bond. The
stability might vary in cases where the functional group
is distal to the olefin moiety. Moreover, strained cyclic
olefins tend to undergo electrocyclic fragmentations of the
intermediate bicyclic ruthenates (vide supra).
a All reactions were performed under the conditions listed in
Table 7. b Diastereomeric ratio (according to 1H NMR integration)
is given in parentheses. Only the major stereoisomer is shown.
c Isolated yield. The numbers in parentheses reflects the yield of
the reaction at ambient temperature.
These limitations indicate the need for further inves-
tigations directed toward the development of milder less
acidic conditions allowing the oxidation of these sub-
strates as well. However, decreasing the reaction tem-
perature or increasing the catalyst concentration might
lead to good results. Further work along these lines is
currently being carried out in our laboratory.
Conclusion. The first ruthenium(VIII)-catalyzed ke-
tohydroxylation has been developed. A careful analysis
of the influence of different reaction parameters led to a
protocol that allows the preparation of a variety of
unsymmetrical acyclic and cyclic acyloins with predict-
increased the rate of hydrolysis. We speculated that we
could discriminate the scission reaction in the ketohy-
droxylation by simply lowering the temperature. The
results are shown in Table 8.
Although the reaction times are longer the amount of
fragmentation products decreased at lower temperature.
Moreover, the reaction proceeds at temperatures below
0 °C, reflecting the fact that water is needed for the
formation of RuO4 from RuCl3 but not essential for the
ketohydroxylation. Different cyclic olefins were oxidized
at room temperature or below as indicated in Table 9.
Cyclic systems can be ketohydroxylated in good yields
and high regioselectivity. Six-, seven-, and eight-mem-
bered cyclic R-hydroxy ketones are stable under the
(23) (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40,
2247. (b) Cha, J. K.; Kim, N.-S. Chem. Rev. 1995, 95, 1761.
J. Org. Chem, Vol. 69, No. 24, 2004 8293

Plietker
General Procedure II. Ketohydroxylation: Waterfree
Workup and Reisolation of the Catalyst. The initial
procedure is the same as described above. After complete
conversion the mixture was diluted with ethyl acetate (20 mL).
The resulting suspension was filtered, and the filtrate was
neutralized by addition of solid NaHCO3. The solids were again
removed by filtration and washed with ethyl acetate. The
filtrate was concentrated in a vacuum. After reduction to ca.
20 mL of liquid the dissolved ruthenium catalyst precipitated
and was separated by centrifugation. The solution containing
the organic product was concentrated in a vacuum and purified
via flash column chromatography under the given conditions.
The reisolated dark ruthenium catalyst was dried under high
vacuum and reused for another reaction without any further
purification.
able and high regioselectivity starting from readily
available olefins. The detailed knowledge of the interac-
tion between temperature and chemoselectivity was used
in the oxidation of different cycloalkenes. Whereas the
oxidation of these substrates under the standard condi-
tions is less selective, a decrease in the reaction temper-
ature favors the kinetically preferred ketohydroxylation
pathway, thus leading to good isolated yields of different
cyclic R-hydroxy ketones. Furthermore, first results on
the simple diastereoselectivity indicate that the Kishi
rules known from OsO4-catalyzed dihydroxylation can be
applied to the ketohydroxylation reaction. However,
detailed investigations regarding selectivity issues are
of paramount importance in order to develop this new
oxidation reaction into a broad applicable method. Hence,
future work focuses on the development of general rules
allowing the prediction of regio-, chemo-, and diastereo-
selectivity of the ketohydroxylation process. This work
will be published in due course. With regard to the
experimental setup it is important to note that no special
precautions such as inert gas atmosphere or dry solvents
is necessary. First experiments indicate that a scale-up
of the procedure is possible. Furthermore, it is important
to note that depending on the workup procedure a simple
protocol for the reisolation of catalytically active ruthe-
nium compounds has been developed.
2-Hydroxy-1,2-diphenyl-ethanone (2).31 Following the
general procedure at room temperature, acyloin 2 (398 mg,
1.88 mmol, 94%) was obtained as a white solid within 10 min:
mp 137 °C; Rf 0.57 (pentane/ethyl acetate, 3:1); IR (KBr) ν 3379
(br), 2932 (w), 1679 (s), 1206 (m), 1092 (m), 755 (s), 704 (s),
511 (s) cm-1; 1H NMR δ 7.92 (d, 2H, Harom), 7.27-7.56 (m, 8H,
H
arom), 5.92 (s, 1H, 2-H), 4.56 (s, 1H, OH); 13C NMR δ 200.4,
140.5, 135.4, 130.6, 130.5, 130.3, 130.2, 130.0, 129.2, 77.6.
6-Hydroxydecan-5-one (6).32 Following the general pro-
cedure at room temperature, acyloin 6 (299 mg, 1.74 mmol,
87%) was obtained as a colorless oil within 10 min: Rf 0.52
(pentane/ethyl acetate, 5:1); IR (film) ν 3480 (br), 2958 (s), 2873
1
(m), 1712 (s), 1466 (m), 1045 (m) cm-1; H NMR δ 4.16 (dd, J
) 5.6, 2.8 Hz, 1H, 6-H), 3.42 (s, 1H, OH), 2.45 (m, 2H, CH2),
1.81 (m, 2H, CH2), 1.26-1.66 (m, 8H, CH2), 0.91 (m, 6H, CH3);
13C NMR δ 214.0, 77.8, 39.0, 34.9, 28.4, 17.2, 23.9, 15.3.
2-Hydroxy-1-phenylethanone (8a).33 Following the gen-
eral procedure at room temperature, acyloin 8a (180 mg, 1.32
mmol, 66%) was obtained as a white solid within 10 min: mp
88 °C; Rf 0.31 (pentane/ethyl acetate, 5:1); IR (KBr) ν 3430
(s), 3390 (s), 1683 (s), 1236 (m), 688 (m) cm-1; 1H NMR δ 7.92
(d, 2H, Harom), 7.62 (dd, 1H, Harom), 7.52 (dd, 2H, Harom), 4.88
(s, 2H, 2-H), 3.52 (s, 1H, OH); 13C NMR δ 199.8, 135.8, 134.8,
130.4, 129.2, 66.9.
Experimental Section
General Remarks. RuCl3 was obtained from Aldrich. A
stock solution was prepared by calculating with RuCl3(H2O)2
and dissolving the catalyst (2.44 g, 10 mmol) in 100 mL water
(0.1 M). The deep brown solution can be stored on the bench
for weeks without loss of activity. Olefins 17,24 21,25 23,26 25,27
27,28 29,29 and 3330 were prepared according to literature
procedures. All other starting materials were purchased from
commercial suppliers and used without further purification.
In cases where the regioselectivity of the oxidation was better
than 90:10 only the spectral data of the major isomer are
reported. Regioselectivities were determined by GC or NMR
integration of the crude product mixture.
General Procedure I. Ketohydroxylation: Aqueous
Workup. A 100-mL round-bottomed flask equipped with
magnetic stirring bar and overpressure valve was charged with
NaHCO3 (420 mg, 5 mmol). A 0.1 M aqueous solution of RuCl3
(200 µL, 0.02 mmol) was added, and the suspension was
diluted with H2O (1.8 mL), CH3CN (12 mL), and ethyl acetate
(12 mL). Oxone (6.1 g, 10 mmol) was added in one portion to
the resulting brownish suspension (gas evolution!) resulting
in the formation of a bright yellow suspension. At this point
the reaction mixture was cooled to the desired temperature.
The olefin (2 mmol) was added in one portion. The course of
the reaction was followed by TLC. After complete conversion
the mixture was diluted with ethyl acetate (20 mL). The
resulting suspension was filtered, and the filtrate was washed
with 10 mL of satd Na2SO3 solution and dried over Na2SO4.
Filtration and evaporation under reduced pressure gave the
crude product, which was purified by flash column chroma-
tography under the given conditions.
1-Hydroxyoctan-2-one (10a).34 Following the general
procedure at room temperature, acyloin 10a (184 mg, 1.28
mmol, 64%) was obtained as a colorless oil within 10 min: Rf
0.36 (pentane/ethyl acetate, 5:1); IR (film) ν 3426 (br), 2957
(s), 2930 (s), 2859 (s), 1722 (s), 1059 (m) cm-1; 1H NMR δ 4.21
(s, 2H, 1-H), 3.14 (s, 1H, OH), 2.37 (t, J ) 7.6 Hz, 2H, CH2),
1.61 (m, 2H, CH2), 1.21-1.38 (m, 6H, CH2), 0.85 (t, J ) 6.8
Hz, 3H, CH3); 13C NMR δ 210.0, 68.2, 38.5, 31.5, 28.9, 23.8,
22.5, 14.1.
2-Hydroxy-3-oxo-3-phenylpropionic Acid Methyl Ester
(12a).35 Following the general procedure at room temperature,
acyloin 12a (295 mg, 1.52 mmol, 76%) was obtained as a yellow
oil within 30 min: Rf 0.43 (pentane/ethyl acetate, 4:1); IR (film)
ν 3445 (br), 2956 (m), 2856 (s), 1749 (s), 1687 (s), 1449 (m),
1235 (s) cm-1; 1H NMR δ 8.08 (d, 2H, Harom), 7.64 (t, 1H, Harom),
7.51 (t, 2H, Harom), 5.62 (s, 1H, 2-H), 4.31 (s, 1H, OH), 3.72 (s,
3H, OCH3); 13C NMR δ 195.1, 170.5, 136.2, 134.4, 131.5, 130.3,
77.8, 54.5.
2-Hydroxy-3-oxo-3-cyclohexylpropionic Acid Methyl
Ester (14a).13 Following the general procedure at room
temperature, acyloin 14a (328 mg, 1.64 mmol, 82%) was
obtained as a colorless oil within 20 min: Rf 0.45 (pentane/
ethyl acetate, 3:1); IR (film) ν 2933 (s), 2856 (s), 1749 (s), 1717
(s), 1450 (m), 1242 (m) cm-1; 1H NMR δ 4.86 (s, 1H, 3-H), 3.78
(24) Sarkar, A.; Yemul, O. S.; Bandgar, B. P.; Gaikwad, N. B.;
Prakash, P. P. Org. Prep. Proced. Int. 1996, 28, 613.
(25) Persson, E. S. M.; Ba¨ckvall, J.-E. Acta Chem. Scand. 1995, 49,
899.
(26) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974.
(27) Hurd, C. D.; Schmerling, L. J. Am. Chem. Soc. 1937, 59, 107.
(28) Manhart, E.; von Werner, K. Synthesis 1978, 705.
(29) Gensler, W. J.; Rockett, J. C. J. Am. Chem. Soc. 1955, 77, 3262.
(30) Pyne, S. G.; David, D. M.; Dong, Z. Tetrahedron Lett. 1998, 39,
8499.
(31) Ueyama, N.; Kamabuchi, K.; Nakamura, A. J. Chem. Soc.,
Dalton Trans. 1985, 635.
(32) Srinivasan, N. S.; Lee, D. G. Synthesis 1979, 520.
(33) Tamura, Y.; Yakura, T.; Haruta, J.-I.; Kita, Y. Tetrahedron Lett.
1985, 26, 3837.
(34) Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron 1993, 49,
11263.
(35) Bovicelli, P.; Sanetti, A.; Lupatelli, P. Tetrahedron 1996, 52,
10969.
8294 J. Org. Chem., Vol. 69, No. 24, 2004

RuO4-Catalyzed Ketohydroxylation
(s, 3H), 2.77 (m, 1H), 1.61-1.83 (m, 5H), 1.22-1.45 (m, 5H);
13C NMR δ 207.3, 169.0, 76.3, 53.2, 46.6, 29.3, 27.7, 25.6.
2-Hydroxy-1,3-diphenylpropan-1,3-dione (16a).36 Fol-
lowing the general procedure at room temperature, acyloin 16a
(259 mg, 1.08 mmol, 54%) was obtained as a white solid within
60 min: mp 110 °C; Rf 0.59 (pentane/ethyl acetate, 7:1); IR
(KBr) ν 3448 (br), 3064 (m), 1683 (s), 1597 (m), 1450 (m), 687
(dd, J ) 10.5, 4 Hz, 1H, CH2), 3.76 (dd, J ) 10.5, 4 Hz, 1H,
CH2); 13C NMR δ 199.7, 137.8, 134.1, 129.0, 128.8, 128.5, 128.2,
127.8, 127.7, 73.9, 73.7, 72.8.
Ketohydroxylation of (3-Phenoxypropenyl)benzene
(25). Following the general procedure at room temperature, a
mixture of acyloin 26a and 26b (3.2:1.0) was obtained (353
mg, 1.46 mmol, 73%) as a white solid within 10 min, which
was separated via HPLC (pentane/ethyl acetate). Regioiso-
mer 1: 3-Phenyloxy-2-hydroxy-1-phenylpropan-1-one
(26a): mp 162 °C; Rf 0.36 (pentane/ethyl acetate, 3:1); IR (KBr)
ν 3447 (br), 1684 (s), 1598 (s), 1496 (s), 1243 (s), 1121 (m), 754
1
(m) cm-1; H NMR δ 7.99 (d, 4H, Harom), 7.57 (dd, 2H, Harom),
7.46 (dd, 4H, Harom), 6.12 (s, 1H, 2-H), 4.68 (s, 1H, OH); 13C
NMR δ 197.1, 135.8, 135.5, 130.8, 130.3, 79.9.
2-(5,5-Dimethyl[1,3]dioxan-2-yl)-2-hydroxy-1-phenyl-
ethanone (18a). Following the general procedure at room
temperature, acyloin 18a (320 mg, 1.28 mmol, 64%) was
obtained as a colorless oil within 10 min: Rf 0.31 (pentane/
ethyl acetate, 3:1); IR (KBr) ν 3461 (br), 2956 (s), 2853 (s), 1685
(s), 1598 (m), 1471 (m), 1450 (m), 1270 (s), 1127 (s), 1119 (s),
1032 (s), 988 (s), 689 (m) cm-1; 1H NMR δ 7.98 (d, 2H, Harom),
7.56 (dd, 1H, Harom), 7.45 (dd, 2H, Harom), 5.11 (m, 1H, 2-H),
4.70 (d, 1H, OH), 3.91 (m, 1H, 1-H), 3.51 (d, 2H), 3.42 (d, 2H),
0.81 (s, 3H), 0.61 (d, 3H); 13C NMR δ 236.2, 133.9, 133.8, 129.5,
128.4, 101.9, 77.4, 76.8, 74.5, 37.1, 22.5, 21.7. Anal. Calcd for
C14H18O4 (250.29): C, 67.18; H, 7.25. Found: C, 67.18; H, 7.23.
Acetic Acid 2-Hydroxy-3-oxo-3-phenylpropyl Ester
(20a).37 Following the general procedure at room temperature,
acyloin 20a (283 mg, 1.36 mmol, 68%) was obtained as a
colorless oil within 15 min: Rf 0.52 (pentane/ethyl acetate, 3:1);
IR (film) ν 3463 (br), 3064 (w), 2957 (w), 2856 (w), 1742 (s),
1688 (s), 1378 (m), 1235 (s), 1047 (m), 702 (m); 1H NMR δ 7.94
(dd, 2H, Harom), 7.62 (ddd, 1H, Harom), 7.49 (dd, 2H, Harom), 5.28
(dd, J ) 5.9, 3.2 Hz, 1H, 2-H), 4.53 (dd, J ) 11.6, 3.2 Hz, 1H,
1-H), 4.09 (dd, J ) 11.6, 5.9 Hz, 1H, 1-H), 3.93 (s, 1H, OH),
1.99 (s, 3H, CH3); 13C NMR δ 198.5, 170.9, 134.6, 133.5, 129.2,
128.7, 72.1, 66.9.
1
(m), 690 (m) cm-1; H NMR δ 7.94 (dd, J ) 8.1, 1.3 Hz, 2H,
Harom), 7.60 (ddd, J ) 8.0, 1.4 Hz, 1H, Harom), 7.48 (dd, J ) 8.0
Hz, 2H, Harom), 7.21 (m, 2H, Harom), 6.90 (m, 1H, Harom), 6.78
(m, 2H, Harom), 5.39 (dd, J ) 4.0 Hz, 1H, 2-H), 4.29 (dd, J )
9.6, 3.9 Hz, 1H, 3-H), 4.21 (dd, J ) 9.6, 3.9 Hz, 1H, 3-H); 13C
NMR δ 199.1, 158.4, 134.3, 133.9, 129.5, 129.0, 128.7, 121.5,
114.8, 72.7, 70.6. Anal. Calcd for C15H14O3 (242.27): C, 74.36;
H, 5.82. Found: C, 74.33; H, 5.84. Regioisomer 2: 1-Hy-
droxy-3-phenoxy-1-phenylpropan-2-one (26b): mp 154 °C;
Rf 0.36 (pentane/ethyl acetate, 3:1); IR (KBr) ν 3419 (br), 1724
(s), 1496 (s), 1224 (m), 1008 (m), 752 (m) cm-1, 690 (m); 1H
NMR δ 7-31-7.39 (m, 5H, Harom), 7.24 (dd, J ) 8.0 Hz, 2H,
H
arom), 6.96 (dd, J ) 8 Hz, 1H, Harom), 6.73 (d, J ) 8.0 Hz, 2H,
H
arom), 5.46 (s, 1H, 1-H), 4.57 (s, 2H, 3-H), 4.06 (s, 1H, OH);
13C NMR δ 206.0, 157.4, 137.4, 129.8, 129.2, 129.1, 127.4,
122.1, 114.5, 77.5, 69.8. Anal. Calcd for C15H14O3 (242.27): C,
74.36; H, 5.82. Found: C, 74.39; H, 5.79.
Ketohydroxylation of (3-Azidopropenyl)benzene (27).
Following the general procedure at room temperature, a
mixture of acyloin 28a and 28b (6.2:1.0) was obtained (329
mg, 1.72 mmol, 86%) as a colorless oil within 10 min, which
was partially separated via HPLC (pentane/ethyl acetate, 3:1).
Regioisomer 1: 3-Azido-2-hydroxy-1-phenylpropan-1-one
(28a): Rf 0.32 (pentane/ethyl acetate, 3:1); IR (film) ν 3448 (br),
Ketohydroxylation of Acetic Acid 3-Cyclohexylallyl
Ester (21). Following the general procedure at room temper-
ature, a mixture of acyloin 22a and 22b (3.5:1.0) was obtained
(326 mg, 1.52 mmol, 76%) as a colorless oil within 15 min,
which was separated via HPLC (pentane/ethyl acetate). Re-
gioisomer 1: Acetic acid 2-hydroxy-3-oxo-3-cyclohexyl-
propyl ester (22a): Rf 0.50 (pentane/ethyl acetate, 3:1); IR
(film) ν 3463 (br), 2933 (s), 2856 (m), 1742 (s), 1736 (s), 1450
2108 (s), 1685 (s), 1267 (s), 1113 (m), 767 (m), 701 (m) cm-1
;
1H NMR δ 7.85 (m, 2H, Harom), 7.63 (m, 1H, Harom), 7.49 (m,
2H, Harom), 5.24 (dd, J ) 3.4 Hz, 1H, 2-H), 3.68 (dd, J ) 12.8,
3.4 Hz, 1H, Harom), 3.41 (dd, J ) 12.8, 3.4 Hz, 1H, Harom); 13C
NMR δ 200.1, 135.9, 134.6, 130.6, 129.9, 74.9, 56.4. Anal. Calcd
for C9H9N3O2 (191.19): C, 56.54; H, 4.74; N, 21.98. Found: C,
56.59; H, 4.71; N, 22.03. Regioisomer 2: 3-Azido-1-hydroxy-
1-phenylpropan-2-one (28b): Rf ) 0.31 (pentane/ethyl ac-
etate, 3:1); IR (film) ν 3439 (br), 2107 (s), 1684 (s), 1269 (s),
1
(m), 1378 (m), 1237 (s), 1060 (w) cm-1; H NMR δ 4.46 (dd, J
) 4.0, 2.9 Hz, 1H, 2-H), 4.42 (dd, J ) 12.0, 2.8 Hz, 1H, 1-H),
4.28 (dd, J ) 12.0, 4.0 Hz, 1H, 1-H), 3.70 (m, 1H, OH), 2.56
(m, 1H, CH), 2.03 (s, 3H, C(O)CH3), 1.71-1.90 (m, 3H, CH2),
1.62-1.71 (m, 2H, CH2), 1.41-1.52 (m, 1H, CH2), 1.17-1.32
(m, 4H, CH2); 13C NMR δ 211.8, 174.9, 134.6, 73.8, 65.2, 46.4,
29.8, 27.3, 25.9, 25.2, 20.8. Anal. Calcd for C11H18O4 (214.26):
C, 61.66; H, 8.47. Found: C, 61.69; H, 8.46. Regioisomer 2:
Acetic acid 3-cyclohexyl-3-hydroxy-2-oxopropyl ester
(22b): Rf 0.22 (pentane/ethyl acetate, 4:1); IR (film) ν 3481 (br),
2931 (s), 2856 (s), 1741 (s), 1734 (s), 1451 (m), 1375 (m), 1233
1
1112 (m), 701 (m) cm-1; H NMR δ 7.38-7.44 (m, 3H, Harom),
7.32-7.36 (m, 2H, Harom), 5.23 (s, 1H, 1-H), 3.98 (d, J ) 18.0
Hz, 1H, 3-H), 3.94 (d, J ) 18.0 Hz, 1H, 3-H), 3.93 (s, 1H, OH);
13C NMR δ 200.0, 138.3, 136.0, 130.8, 128.6, 79.8, 55.6. Anal.
Calcd for C9H9N3O2 (mixture of regioisomers, 191.19): C,
56.54; H, 4.74; N, 21.98. Found: C, 56.52; H, 4.77; N, 21.94.
Ketohydroxylation of 2-(3-Phenylallyl)isoindole-1,3-
dione (29). Following the general procedure at room temper-
ature, an inseparable mixture of acyloin 30a and 30b (2.4:
1.0) was obtained (496 mg, 1.68 mmol, 84%) as a white solid
within 20 min. Analytical data are given for the mixture of
30a and 30b. 2-(2-Hydroxy-3-oxo-3-phenylpropyl)isoin-
dole-1,3-dione (30a) and 2-(3-Hydroxy-2-oxo-3-phenyl-
propyl)isoindole-1,3-dione (30b): mp 262 °C dec; Rf 0.13
(pentane/ethyl acetate, 4:1); IR (KBr) ν 3476 (br), 1769 (m),
1721 (s), 1691 (m), 1413 (m), 1387 (m), 1273 (m), 1093 (m),
1
(s), 1065 (m) cm-1; H NMR δ 4.87 (d, J ) 17.2 Hz, 1H, 1-H),
4.74 (d, J ) 17.2 Hz, 1H, 1-H), 4.13 (m, 1H, 3-H), 2.87 (m, 1H,
CH), 2.16 (s, 3H, C(O)CH3), 1.63-1.81 (m, 4H, CH2), 1.08-
1.42 (m, 6H, CH2); 13C NMR δ 205.7, 171.2, 79.5, 66.2, 41.9,
29.8, 26.5, 26.0, 25.9, 25.4, 20.5Anal. Calcd for C11H18O4
(214.26): C, 61.66; H, 8.47. Found: C, 61.64; H, 8.49.
3-Benzyloxy-2-hydroxy-1-phenylpropan-1-one (24a).9c
Following the general procedure at room temperature, acyloin
2 (440 mg, 1.72 mmol, 86%) was obtained as a colorless oil
within 10 min: Rf 0.51 (pentane/ethyl acetate, 3:1); IR (KBr)
ν 3464 (br), 3062 (m), 3030 (m), 2864 (m), 1685 (s), 1452 (s),
970 (m), 718 (m), 698 (m) cm-1
;
1H NMR δ 8.11 (m, 1H,
H
arom,30a), 7.83 (m, 4H, Harom,30a), 7.71 (m, 4H, Harom,30a), 7.61
(m, 1H, Harom,30b), 7.52 (m, 4H, Harom,30b), 7.42 (m, 4H, Harom),
5.45 (m, 1H, 2-H30a), 5.29 (s, 1H, 3-H30b), 4.49 (d, J ) 18.0 Hz,
1H, 1-H30b), 4.37 (d, J ) 18.0 Hz, 1H, 1-H30b), 4.02 (dd, J )
14.0, 3.2 Hz, 1H, 1-H30a), 3.88 (s, 1H, OH30b), 3.84 (dd, J )
14.0, 3.2 Hz, 1H, 1-H30a), 3.76 (d, J ) 7.6 Hz, 1H, OH30a); 13C
NMR δ 202.4, 199.0, 168.3, 167.5, 137.0, 134.6, 134.3, 134.2,
133.5, 132.1, 132.0, 129.4, 129.3, 129.2, 129.0, 127.5, 123.7,
123.5, 78.8, 71.3, 43.3, 42.8. Anal. Calcd for C17H13NO4
(295.29): C, 69.15; H, 4.44; N, 4.74. Found: C, 69.11; H, 4.47;
N, 4.76.
1
1235 (s), 1104 (s), 740 (m), 699 (s) cm-1; H NMR δ 7.90 (d, J
) 7.5 Hz, 2H, Harom), 7.62 (t, J ) 7.5 Hz, 1H, Harom), 7.49 (t, J
) 7.5 Hz, 2H, Harom), 7.27-7.36 (m, 1H, Harom), 7.22 (m, 2H,
H
arom), 7.13 (m, 2H, Harom), 5.21 (t, J ) 4 Hz, 1H, 2-H), 4.51 (d,
J ) 12.5 Hz, 1H, CH2), 4.44 (d, J ) 12.5 Hz, 1H, CH2), 3.81
(36) Blatt, K.; Hawkins, W. L. J. Am. Chem. Soc. 1936, 58, 81.
(37) Shing, T. K. M.; Tam, E. K. W.; Tai, V. W. F.; Chung, I. H. F.;
Jiang, Q. Chem. Eur. J. 1996, 2, 50.
J. Org. Chem, Vol. 69, No. 24, 2004 8295

Plietker
3-Chloro-2-hydroxy-1-phenylpropan-1-one (32a).9c Fol-
lowing the general procedure at room temperature, acyloin 32a
(328 mg, 1.78 mmol, 89%) was obtained as a colorless oil within
20 min: Rf 0.59 (pentane/ethyl acetate, 3:1); IR (film) ν 3455
(br), 1680 (s), 1598 (m), 1450 (m), 1293 (s), 1098 (s), 705 (m)
(2S*,3R*)-Acetic Acid 2-Hydroxy-3-oxocyclohexyl Es-
ter (42).11c Following the general procedure, a diastereomeric
mixture (9.1:1.0, 1H NMR integration) of acyloin 42 was
obtained as a colorless oil within 10 min. Purification via flash-
column chromatography led to the isolation of the major isomer
in 79% yield: Rf 0.23 (pentane/ethyl acetate, 1:1); IR (film) ν
3460 (br w), 2951 (m), 2872 (m), 1733 (s), 1730 (s), 1376 (m),
1
cm-1; H NMR δ 7.91 (d, J ) 7.5 Hz, 2H, Harom), 7.67 (t, J )
7.5 Hz, 1H, Harom), 7.54 (t, J ) 7.5 Hz, 2H, Harom), 5.36 (t, J )
3.5 Hz, 1H, 2-H), 4.05 (s, 1H, OH), 3.94 (dd, J ) 11.5, 3.5 Hz,
1H, 3-H), 3.77 (dd, J ) 11.5, 3.5 Hz, 1H, 3-H); 13C NMR δ 197.9,
134.5, 133.4, 129.2, 128.5, 72.6, 47.4.
2-Hydroxy-1-phenyl-3-(phenylsulfonyl)propan-1-one
(34a).9c Following the general procedure at room temperature,
acyloin 34a (487 mg, 1.68 mmol, 84%) was obtained as a yellow
oil within 30 min: Rf 0.59 (pentane/ethyl acetate, 5:1); IR (film)
ν 3451 (br), 3064 (m), 1694 (s), 1692 (s), 1310 (s), 1151 (m),
1024 (m), 737 (m) cm-1; 1H NMR δ 7.95 (dd, 4H, Harom), 6.56-
1
1245 (s), 1109 (m), 1035 (m) cm-1; H NMR δ 4.70 (ddd, J )
14.8, 10.0, 4.8 Hz, 1H, 1-H), 4.13 (d, J ) 10.0 Hz, 1H, 2-H),
3.66 (s, 1H, OH), 2.55 (ddd, J ) 14.0, 4.8, 2.8 Hz, 1H, CH2),
2.33 (ddd, J ) 14.0, 5.6 Hz, 1H, CH2), 2.12-2.23 (m, 1H, CH2),
2.08 (s, 3H, C(O)CH3), 1.98-2.04 (m, 1H, CH2), 1.66-1.77 (m,
1H, CH2), 1.47-1.58 (m, 1H, CH2); 13C NMR δ 207.3, 170.4,
78.6, 77.2, 38.5, 29.1, 21.2, 20.7.
1-Hydroxy-2-oxocyclohexanecarboxylic Acid Methyl
Ester (44).40 Following the general procedure, acyloin 44 (268
mg, 1.56 mmol, 78%) was obtained as a colorless oil: Rf 0.23
(pentane/ethyl acetate, 3:1); IR (film) ν 3451 (br w), 2959 (s),
2930 (m), 1731 (s), 1458 (m), 1275 (s), 1123 (m) cm-1; 1H NMR
δ 3.76 (s, 1H, OH), 3.73 (s, 3H, OCH3), 2.38 (m, 1H, CH2), 2.15
(m, 1H, CH2), 1.94 (m, 1H, CH2), 1.79 (m, 1H, CH2), 1.57 (m,
4H, CH2); 13C NMR δ 170.3, 109.2, 86.8, 52.3, 36.2, 27.3, 22.3,
21.4.
(1S,2S,5S)-2-Hydroxy-2,6,6-trimethylbicyclo[3.3.1]-
heptan-3-one (46).41 Following the general procedure, acyloin
46 (215 mg, 1.28 mmol, 64%) was obtained as a colorless oil:
[R]D ) -39.6 (c ) 0.56/CHCl3); Rf 0.29 (pentane/ethyl acetate,
5:1); IR (film) ν 3445 (br), 2977 (s), 2923 (s), 1720 (s), 1371 (s),
1162 (s), 920 (m) cm-1; 1H NMR δ 2.58 (m, 2H, 4-H), 2.43 (m,
1H, 1-H), 2.30 (s, 1H, OH), 2.08 (m overlaid by d, J ) 10.9 Hz,
2H, 5-H and 7-H), 1.65 (d, J ) 10.8 Hz, 7-H), 1.35 (s, 3H, CH3),
1.33 (s, 3H, CH3), 0.86 (s, 3H, CH3); 13C NMR δ 214.2, 71.2,
49.7, 43.0, 39.1, 38.3, 28.5, 27.4, 25.4, 22.9.
7.67 (m, 6H, Harom), 5.60 (dd, 1H, 2-H), 3.57 (dd, 1H, 3-H) cm-1
;
13C NMR δ 236.3, 197.4, 139.6, 134.9, 134.2, 132.3, 129.4,
129.1, 128.5, 68.7, 61.2.
2-Hydroxycyclohexanone (36).38 Following the general
procedure at -10 °C, acyloin 36 (153 mg, 1.34 mmol, 67%) was
obtained as a colorless oil within 60 min: Rf 0.21 (pentane/
ethyl acetate, 4:1); IR (film) ν 3451 (br), 2969 (s), 1790 (s), 1761
(s), 1383 (m), 1097 (s) cm-1 1H NMR δ 4.36 (ddd, 1H, J )
;
8.65, 5.21, 1.09 Hz, 1H, 2-H), 2.79 (d, J ) 1.09 Hz, 1H, OH),
2.31-2.40 (m, 2H, CH2), 1.66-2.15 (m, 6H, CH2); 13C NMR δ
203.0, 62.9, 39.3, 37.6, 27.0, 23.2.
2-Hydroxycycloheptanone (38).39 Following the general
procedure at 0 °C, acyloin 38 (184 mg, 1.44 mmol, 72%) was
obtained as a colorless oil within 30 min: Rf 0.27 (pentane/
ethyl acetate, 5:1); IR (film) ν 3466 (br), 2931 (s), 2858 (m),
1701 (s), 1454 (m), 1404 (m), 1272 (m), 1079 (s) cm-1; 1H NMR
δ 4.26 (dd, J ) 9.6, 3.6 Hz, 1H, 2-H), 2.65 (ddd, J ) 17.6, 7.2,
1.2 Hz, 1H, CH2), 2.43 (ddd, J ) 17.6, 11.6, 4.0 Hz, 1H, CH2),
2.01 (m, 1H, CH2), 1.72-1.88 (m, 2H, CH2), 1.51-1.68 (m, 3H,
CH2), 1.28-1.36 (m, 2H, CH2); 13C NMR δ 213.9, 77.2, 40.2,
33.9, 29.7, 26.8, 23.6.
Acknowledgment. I thank Prof. Dr. N. Krause for
generous support and the Fonds der Chemischen In-
dustrie (Liebig fellowship) and the Deutsche For-
schungsgemeinschaft (Emmy-Noether fellowship). Fur-
ther financial support by the Fonds zur Fo¨rderung des
wissenschaftlichen Nachwuchses im Fachbereich Che-
mie der Universita¨t Dortmund is gratefully acknowl-
edged.
2-Hydroxycyclooctanone (40).39 Following the general
procedure at room temperature, acyloin 40 (238 mg, 1.68
mmol, 78%) was obtained as a colorless oil: Rf 0.39 (pentane/
1
ethyl acetate, 4:1); H NMR δ 4.14 (dd, J ) 6.4, 2.8 Hz, 1H,
2-H), 3.69 (s, 1H, OH), 2.66 (ddd, J ) 12.0, 4.0 Hz, 1H, CH2),
2.26-2.39 (m, 2H, CH2), 1.89-2.04 (m, 2H, CH2), 1.59-1.81
(m, 4H, CH2), 1.29-1.38 (m, 2H, CH2), 0.81-0.92 (m, 1H, CH2);
13C NMR δ 217.6, 76.3, 37.3, 29.4, 28.6, 25.5, 24.5, 22.2; IR
(film) ν 3477 (br), 2930 (s), 2859 (s), 1703 (s), 1466 (m), 1447
Supporting Information Available: 1H NMR spectra of
all acyloins. This material is available free of charge via the
Internet at http://pubs.acs.org.
(m), 1239 (m), 1110 (s), 947 (m) cm-1
.
JO048822S
(38) El-Qisairi, A. K.; Qaseer, H. A. J. Organomet. Chem. 2002, 659
(1-2), 50.
(40) Crout, D. H. G.; Rathbone, D. L. Synthesis 1989, 40.
(41) Su, G.; Dorizon, P.; Ollivier, J. J. Salaun, Synth. Commun.
1998, 28, 1351.
(39) Matsubara, S.; Takai, K.; Nozaki, H. Bull. Chem. Soc. Jpn.
1983, 56, 2029.
8296 J. Org. Chem., Vol. 69, No. 24, 2004