Ruthenium-catalyzed tandem olefin metathesis-oxidations

Article abstract of DOI:10.1021/ol061837n

(Chemical Equation Presented) The utility of Grubbs' 2nd generation metathesis catalyst has been expanded by the development of two tandem olefin metathesis/oxidation protocols. These ruthenium-catalyzed processes provide cis-diols or α-hydroxy ketones from simple olefinic starting materials.

Full text of DOI:10.1021/ol061837n

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4759-4762
Ruthenium-Catalyzed Tandem Olefin
Metathesis Oxidations
−
Andrew A. Scholte, Mi Hyun An, and Marc L. Snapper*
Department of Chemistry, Merkert Chemistry Center, Boston College,
2609 Beacon Street, Chestnut Hill, Massachusetts 02467-3860
marc.snapper@bc.edu
Received July 25, 2006
ABSTRACT
The utility of Grubbs’ 2nd generation metathesis catalyst has been expanded by the development of two tandem olefin metathesis/oxidation
protocols. These ruthenium-catalyzed processes provide cis-diols or
r-hydroxy ketones from simple olefinic starting materials.
The introduction of well-defined ruthenium complexes, such
as 1-5 (Figure 1), has helped to establish olefin metathesis
tion vessel.2 The net result can be unique functional group
transformations that previously required several independent
reactions to accomplish. In this regard, these tandem catalytic
processes offer new opportunities for the preparation of
complex molecules in a more cost-efficient and environ-
mentally friendly manner. Recent examples of tandem
catalysis by metathesis-active ruthenium complexes include
olefin metathesis combined with radical atom transfer,3 olefin
isomerization,4 hydrogenation,5 and cyclopropanation.6 Herein,
we will describe a tandem, ruthenium-catalyzed olefin
metathesis-oxidation sequence for the preparation of cis-
diols and R-hydroxy ketones from simple olefinic precur-
sors.7
Figure 1. Commercially available metathesis-active ruthenium
complexes.
(2) For recent reviews on tandem catalysis, see: (a) Fogg, D. E.; dos
Santos, E. N. Coord. Chem. ReV. 2004, 248, 2365. (b) Wasilke, J. C.; Obrey,
S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV. 2005, 105, 1001. (c) Schmidt,
B. Pure Appl. Chem. 2006, 78, 469.
(3) (a) Seigal, B. A.; Fajardo, C.; Snapper, M. L. J. Am. Chem. Soc.
2005, 127, 16329. (b) Schmidt, B.; Pohler, M. J. Organomet. Chem. 2005,
690, 5552.
(4) (a) Schmidt, B. Eur. J. Org. Chem. 2003, 816. (b) Schmidt, B. Chem.
Commun. 2004, 742. (c) Schmidt, B. J. Org. Chem. 2004, 69, 7672. (d)
Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem.
Soc. 2002, 124, 13390. (e) Finnegan, D.; Seigal, B. A.; Snapper, M. L.
Org. Lett. 2006, 8, 2603.
(5) (a) Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003, 42, 308.
(b) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 11312.
as a powerful tool for the construction of carbon-carbon
double bonds.1 These complexes can offer even greater
synthetic utility if the metathesis reaction is combined with
other ruthenium-catalyzed transformations in the same reac-
(1) For recent reviews on catalytic olefin metathesis, see: (a) Grubbs,
R. H. Tetrahedron 2004, 60, 7117. (b) Furstner, A. Angew. Chem., Int. Ed.
2000, 39, 3013. (c) Astruc, D. New. J. Chem. 2005, 29, 42. (d) Deiters, A.;
Martin, S. F. Chem. ReV. 2004, 104, 2199. (e) Diver, S. T.; Giessert, A. J.
Chem. ReV. 2004, 104, 1317. (e) Mori, M. J. Mol. Catal. A: Chem. 2004,
213, 73.
(6) Kim, B. G.; Snapper, M. L. J. Am. Chem. Soc. 2006, 128, 52.
10.1021/ol061837n CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/13/2006

Recently, Plietker and co-workers described RuCl3-
catalyzed oxidations of olefins to generate cis-diols or
R-hydroxy ketones depending on the reaction conditions
used. In situ formation of the oxidative species, RuO4, using
NaIO4 and a Lewis8 or Brønsted acid9 afforded diols in high
yield, whereas treatment with Oxone and NaHCO3 provided
R-hydroxy ketones.10 In light of this useful transformation,
we envisioned that it should be possible to modify a
ruthenium alkylidene in situ to effect similar oxidations after
completing a metathesis reaction.
Table 2. Tandem Ring-Closing Metathesis/
R-Ketohydroxylation
Initially, we examined the ability of ruthenium alkylidenes
1-5 to catalyze the tandem ring-closing metathesis (RCM)/
R-ketohydroxylation reaction sequence. On the basis of
Plietker’s observations, the ketohydroxylation was performed
in a 6:6:1 mixture of MeCN/EtOAc/H2O in the presence of
Oxone, NaHCO3, and 5 mol % of the ruthenium catalysts.
As indicated in Table 1, the best results were found when
Table 1. Ruthenium Catalysts for R-Ketohydroxylation
time
entry
catalyst
(RCM; oxidation)
yield
(1)
(2)
(3)
(4)
(5)
(6)
1a
2a
3a
4a
5a
2b
3 h; 2 h
22%
61%
40%
45%
45%
65%
1 h; 10 min
3 h; 10 min
1 h; 10 min
1 h; 10 min
1 h; 10 min
a Conditions: Ru catalyst (5 mol %), rt, [0.1-0.2 M in EtOAc]; NaHCO3,
Oxone, MeCN/H2O (6:1). b Conditions: Ru catalyst (10 mol %), rt, [0.1-
0.2 M in EtOAc]; NaHCO3, Oxone, MeCN/H2O (6:1).
alkylidene 2 was employed as the ruthenium source. Further
optimization showed that increasing the catalyst loading of
2 to 10 mol % improved the yield slightly to 65% for the
tandem process (Table 1, entry 6).
a Conditions: 2 (5 mol %), rt, [0.1-0.2 M in EtOAc]; NaHCO3, Oxone,
MeCN/H2O (6:1). b Conditions: 2 (10 mol %), rt, [0.1-0.2 M in EtOAc];
NaHCO3, Oxone, MeCN/H2O (6:1).
Following these observations, the RCM/R-ketohydroxy-
lation of other olefinic substrates was studied; these results
are reported in Table 2. When the dienes were treated with
5 mol % of Grubbs’ 2nd generation catalyst 2 in ethyl acetate,
the RCM was complete within 1 h. The reactions were then
diluted with MeCN/H2O and treated with NaHCO3 and
Oxone. The oxidation was rapid (∼10-20 min) and provided
the R-ketohydroxylated products in 42-61% overall yields.
It was observed that the oxidation of unsymmetrical sub-
strates led to a mixture of regioisomers; for example, the
R-ketohydroxylations shown in entries 3 and 8 of Table 2
occur with only 2:1 regioselectivity (major product shown).
As described in entry 8, however, the reaction can proceed
with high diastereoselectivity when a stereocenter is proximal
1
to the olefin (only one diastereomer observed by H NMR
for the major regioisomer). Finally, oxidations of trisubsti-
tuted olefins, such as in entries 5-7 (Table 2), lead
selectively to the corresponding tertiary alcohol-containing
products in 42-53% yields.
Given the success of the tandem RCM/R-ketohydroxyla-
tion sequence, the strategy was expanded to include cross-
metatheses (CM). Initial olefinic reaction partners were
chosen to afford the corresponding CM products in good
yield and E/Z selectivity.11 Screening of the CM conditions
indicated that performing the metathesis in CH2Cl2 with a
(7) For a similar contribution, see: Beligny, S.; Eibauer, S.; Maechling,
S.; Blechert, S. Angew. Chem., Int. Ed. 2006, 45, 1900.
(8) Plietker, B.; Niggemann, M. J. Org. Chem. 2005, 70, 2402.
(9) Plietker, B.; Niggemann, M. Org. Lett. 2003, 5, 3353.
(10) (a) Plietker, B. J. Org. Chem. 2003, 68, 7123. (b) Plietker, B. J.
Org. Chem. 2004, 69, 8287. (c) Plietker, B. Eur. J. Org. Chem. 2005, 1919.
4760
Org. Lett., Vol. 8, No. 21, 2006

1:2 mixture of olefins gave the desired CM products in
excellent yield. For the ketohydroxylation step, the excess
cross-metathesis partner and solvent were removed in vacuo
prior to addition of the oxidants. The results of this study
are summarized in Table 3. The yields for the tandem process
as a further extension of this methodology. Recently, Blechert
and co-workers reported a similar finding.7 In our case,
however, the method was made more practical by eliminating
the need to change solvents and, for several examples,
provided the diol products with improved yields.
On the basis of our results from the metathesis/R-
ketohydroxylation studies, optimization of the metathesis/
dihydroxylation conditions was performed with alkylidene
2. After completion of the RCM step, the EtOAc solution
containing the metathesis products was added to a stirred
suspension of the preformed Ce(IV)-periodato complex in
a 6:1 mixture of MeCN/H2O. This complex was formed by
the treatment of 1.5 equiv of NaIO4 with 10 mol % of CeCl3‚
7H2O. It was observed that the reaction was rapid (∼10-20
min) and provided the desired cis-dihydroxylated products
in 63-81% yields (Table 4). Control experiments showed
Table 3. Tandem Cross-Metathesis/R-Ketohydroxylationa
Table 4. Tandem Ring-Closing Metathesis/Dihydroxylationa
a Conditions: 2 (10 mol %), rt, [0.1-0.2 M in CH2Cl2]; NaHCO3, Oxone,
EtOAc/MeCN/H2O (6:6:1).
ranged from 49 to 76%, and like the RCM examples, the
regioselectivity of the oxidation was generally low. It was
proposed that the mixtures observed were due to a selective
oxidation followed by an isomerization of the resulting â-keto
esters under the reaction conditions. This supposition was
supported by a control experiment, where purified â-keto
ester 24 was shown to equilibrate to the corresponding
regioisomer under the basic oxidation conditions.12 On the
other hand, entries 4 and 5 of Table 3 indicate that cross-
metatheses with methyl methacrylate, which lead to a
trisubstituted olefin, afford the R-hydroxy ketone products
with high selectivity. Entry 6 illustrates that the tandem cross-
metathesis/oxidation of cis-1,4-dichloro-2-butene (32) with
styrene (27) provided selectively ketohydroxy isomer 33.
Plietker and co-workers have also recently described a
RuCl3-catalyzed dihydroxylation of olefins.8 In this report,
the treatment of an olefin with RuCl3 and NaIO4 in the
presence of either a Brønsted or Lewis acid provided the
desired cis-diols in good yield. Given this observation, a
tandem olefin-metathesis/dihydroxylation was investigated
a Conditions: 2 (5 mol %), rt, [0.1-0.2 M in EtOAc]; NaIO4,
CeCl3‚7H2O, MeCN/H2O (6:1).
Org. Lett., Vol. 8, No. 21, 2006
4761

represented by the results shown in entries 5 and 6, the
reaction also displays high diastereoselectivity when a nearby
stereocenter is present. With more remote stereogenic centers,
the diastereoselectivity of the dihydroxylation is reduced (3:2
for entry 7 and 7:1 for entry 8, Table 4). The relative
stereochemical assignments of the dihydroxylated compounds
were determined by nOe studies on the corresponding
acetonide derivatives.
Table 5. Tandem Cross-Metathesis/Dihydroxylation
The tandem olefin metathesis/dihydroxylation was also
extended to include cross-metatheses. The data in Table 5
demonstrate that a variety of functional groups including
aliphatic and aromatic olefins are viable substrates for the
tandem CM/dihydroxylation reaction sequence. The CM step
of the tandem process can be performed in a variety of
solvents. For example, reaction of vinylcyclohexane (22) and
methylacrylate (23) in EtOAc gives diol 47 in 49% isolated
yield; in CH2Cl2, the diol is isolated in 77% yield, and when
the reaction is run in the absence of solvent, the diol is
isolated in 19% yield. These reactions could be made even
more operationally simple, therefore, by performing the
metathesis reaction in EtOAc instead of in CH2Cl2.13 As was
the case with the ketohydroxylations, trisubstituted olefins
are acceptable in the dihydroxylation step. Entries 3 and 4
in Table 5, for example, indicate the formation of these more
hindered diols in 50% and 76% yields, respectively.
In summary, two new ruthenium-catalyzed tandem trans-
formations for the generation of R-hydroxy ketones and cis-
diols have been developed. Owing to its ease of use, this
methodology will allow access to important oxygenated
intermediates in a more cost-effective and environmentally
friendly manner. Additional studies to extend further the
scope and utility of these tandem transformations are
underway.
a Conditions: 2 (5 mol %), rt, [0.1-0.2 M in CH2Cl2]; NaIO4,
CeCl3‚7H2O, EtOAc/MeCN/H2O (6:6:1).
Acknowledgment. The authors would like to thank
Boston College, the National Science Foundation, and the
Natural Sciences and Engineering Research Council of
Canada (postdoctoral fellowship to A.A.S.) for financial
support. Benjamin Seigal (Ensemble Discovery) is gratefully
acknowledged for early experimental support. We are also
grateful to Materia for the gift of the metathesis catalyst.
that the oxidation does not proceed in the absence of the
ruthenium complex.
As the data presented in Table 4 indicate, a variety of
functional groups can be tolerated in this tandem sequence.
Entries 1-4 of Table 4 illustrate that five-, six-, and seven-
membered cyclic diols can be accessed in g63% yield. As
Supporting Information Available: Experimental pro-
cedures and data on new compounds are provided (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(12) See Supporting Information for experimental details.
(13) For an example of an olefin metathesis using EtOAc as solvent,
see: Evans, P.; Grigg, R.; Monteith, M. Tetrahedron Lett. 1999, 40, 5247.
OL061837N
4762
Org. Lett., Vol. 8, No. 21, 2006