Ytterbium triflate-promoted tandem one-pot oxidation-cannizzaro reaction of aryl methyl ketones

Article abstract of DOI:10.1021/ol050125e

(Chemical Equation Presented) Ytterbium triflate was shown to be an effective catalyst in promoting the synthesis of either isopropyl esters or free α-hydroxy-arylacetic acids from substituted aromatic glyoxals and aryl methyl ketones, respectively. The reaction to provide acids starting from differently substituted ketones was carried out by an environmentally friendly method using an aqueous medium as a solvent and giving the adducts in 78-99% yield without any further purification after the usual workup.

Full text of DOI:10.1021/ol050125e

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1331-1333
Ytterbium Triflate-Promoted Tandem
One-Pot Oxidation Cannizzaro Reaction
−
of Aryl Methyl Ketones
Massimo Curini,* Francesco Epifano, Salvatore Genovese,
M. Carla Marcotullio, and Ornelio Rosati
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica,
Via del Liceo, 06123 Perugia, Italy
curmax@unipg.it
Received January 20, 2005
ABSTRACT
Ytterbium triflate was shown to be an effective catalyst in promoting the synthesis of either isopropyl esters or free
r
-hydroxy-arylacetic acids
from substituted aromatic glyoxals and aryl methyl ketones, respectively. The reaction to provide acids starting from differently substituted
ketones was carried out by an environmentally friendly method using an aqueous medium as a solvent and giving the adducts in 78
yield without any further purification after the usual workup.
−99%
The Cannizzaro reaction is one of the oldest processes
described in synthetic organic chemistry.1 It is conventionally
promoted by strong bases such as stoichiometric amounts
of alkali metal hydroxides at high temperatures. Moreover,
requiring drastic conditions, the Cannizzaro reaction is of
limited use and scope, except when performed as an
intramolecular process. In particular, when carried out using
aryl glyoxals as starting materials, the intramolecular Can-
nizzaro reaction becomes one of the most efficient routes
for the synthesis of mandelic acid and other substituted
R-hydroxy-arylacetic acids that are important synthons of
many natural and semisynthetic biologically active com-
pounds such as prostaglandins,2 â-lactams,3,4 vanillic acid
metabolites,5 and homatropine.6 Recently, new methods have
been developed using Lewis acids as catalysts instead of
“traditional” Brønsted bases to promote the intramolecular
Cannizzaro reaction for the synthesis of mandelic acid
derivatives. The use of catalytic quantities of a Lewis acid
would in fact decrease competitive side reactions that
frequently occur when the process is carried out in a strong
basic medium. Until now, only one method has been reported
to efficiently promote the synthesis of R-hydroxy-arylacetic
esters from the corresponding glyoxals: recently Morken and
co-workers7 described the use of 10 mol % Cr(ClO4)2
hexahydrate as a catalyst in 2-propanol/dichloroethane as a
solvent for 24 h at room temperature to obtain isopropyl
R-hydroxy-aryl acetates in 40-84% yield. Notably, other
Lewis acids such as Cu(II), Fe(III), Li+, Mg2+, Al3+, Y3+
and other transition metal salts gave no reaction or their
catalyzed processes were limited by conditions requiring high
temperature and more than 20% loading and by the occur-
rence of several side reactions.8 Although the one reported
by Morken and co-workers represents an effective method
for converting glyoxals into mandelate ester derivatives, the
(1) For a review, see: Geissman, T. A. Org. React. 1944, 2, 94-113.
(2) Miersch, O.; Kramell, R.; Parthier, B.; Wasternack, C. Phytochemistry
1999, 50, 353-361.
(3) Hoover, J. R. E.; Dunn, G. L.; Jakas, D. R.; Lam, L. L., Taggart, J.
J.; Guarini, J. R.; Phillips, L. J. Med. Chem. 1974, 17, 34-41.
(4) Nishihata, T.; Takahagi, H.; Yamamoto, M.; Tomida, M.; Rytting,
J. H.; Higuchi, T. J. Pharm. Sci. 1984, 73, 109-113.
(5) Yoshioka, M.; Yoshida, A.; Ichihashi, Y.; Saito, H. Chem Pharm.
Bull. 1985, 33, 2145-2148.
(7) Russell, A. E.; Miller, S. P.; Morken, J. P. J. Org. Chem. 2000, 65,
8381-8383.
(8) (a) Maruyama, K.; Murakami, Y.; Yoda, K.; Mashino, T.; Nishinaga,
A. J. Chem. Soc., Chem. Commun. 1992, 1617-1618. (b) Jin, S. J.; Arora,
P. K. Sayre, L. M. J. Org. Chem. 1990, 55, 3011-3018. (c) Okuyama, T.;
Kimura, K.; Fueno, T. Bull. Chem. Soc. Jpn. 1982, 55, 2285-2286.
(6) El Nimr, A. E.; Salama, H. A.; Khalil, R. M.; Kassem, M. A.
Pharmazie 1983, 38, 728-730.
10.1021/ol050125e CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/01/2005

use of toxic and hazardous Cr(III) and perchlorate salts,9 the
use of toxic chlorinated solvents, the need for SiO2 gel
column chromatography for purification of adducts, and no
recycling of the catalyst renders this method environmentally
unsound, especially with regard to a potential application
on large-scale synthesis. So, although different methods are
available for the synthesis of the above cited compounds,10
development of another facile, high-yielding, nonpolluting
preparation is still of great importance.
are important as a novel class of Lewis acids because they
are water-tolerant, nontoxic, reusable catalysts and their use
in organic synthesis has been recently exhaustively re-
viewed.12 Herein, we wish to report that the intramolecular
Cannizzaro reaction can be effectively catalyzed by Yb(OTf)3
in good yield using aromatic glyoxals as starting materials
to give mandelate esters and more generally that Yb(OTf)3
is capable of producing R-hydroxy-arylacetic acids directly
from aryl methyl ketones.
Table 2. Yb(OTf)3-Catalyzed Synthesis of Mandelic Acid
Derivatives
Table 1. Yb(OTf)3-Catalyzed Cannizzaro Reaction of Aryl
Glyoxals
a Yields of pure isolated products, characterized by IR, GC-MS, 1H NMR,
and 13C NMR.
Recently, we began a research program to explore the
utility of lanthanide triflate-catalyzed processes in synthetic
organic chemistry, and in particular we studied the use of
Yb(OTf)3 as a catalyst to promote new carbon-carbon and
carbon-heteroatom bond formation.11 Lanthanide triflates
a Yields of pure isolated products, characterized by IR, GC-MS, 1H NMR,
and 13C NMR.
(9) Perchlorate salts pose an explosion hazard. See: Prudent Practices
for Handling Hazardous Chemicals in Laboratories; National Academy
Press: Washington, DC, 1981; p 65.
(10) Chung, Y. M.; Gong, J. H.; Kim, J. N. Bull. Kor. Chem. Soc. 2002,
23, 1363-1364 and references therein.
As a preliminary test reaction we studied the conversion
of commercially available phenyl glyoxal hydrate (1) to
isopropyl mandelate (2) in the presence of Yb(OTf)3. The
reaction was optimized by carrying it out in 2-propanol at
80 °C for 18 h with 10 mol % catalyst; under these
conditions, 2 was obtained in 80% yield after purification
by SiO2 gel column chromatography.7 Other aryl glyoxals,
(11) (a) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.
Tetrahedron Lett. 2001, 42, 3193-3195. (b) Curini, M.; Epifano, F.;
Marcotullio, M. C.; Rosati, O. Eur. J. Org. Chem. 2002, 1562-1565. (c)
Curini, M.; Epifano, F.; Maltese, F.; Rosati, O. Tetrahedron Lett. 2002,
43, 4895-4897. (d) Curini, M.; Epifano, F.; Maltese, F.; Rosati, O. Synlett
2003, 552-554. (e) Curini, M.; Epifano, F.; Maltese, F.; Marcotullio, M.
C. Eur. J. Org. Chem. 2003, 1631-1634. (f) Curini, M.; Epifano, F.;
Montanari, F.; Rosati, O.; Taccone, S. Synlett 2004, 1832-1834.
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Org. Lett., Vol. 7, No. 7, 2005

used as model compounds, were synthesized from the
corresponding methyl ketone by SeO2 oxidation as described
in the literature,13 and the results of their conversion into
isopropyl R-hydroxy esters, under the same reaction condi-
tions, are reported in Table 1.
Although yields of this reaction are very good, the low
yields (5-26%) obtained in the synthesis of aryl glyoxals
dramatically decrease the overall yield of the “ketone to
mandelate ester” process, and this inconvenience prompted
us to search for an alternative method to carry out this
transformation.
and filtration, and this was transformed again into the triflate
salt.15 Excess SeO2 and other selenium-containing byproducts
were removed by adsorption on Celite. The process reported
herein is selective in yielding R-hydroxy-arylacetic acids as
the only reaction products, and no side products such as
intermediate glyoxals or those deriving, for example, from
aldol-type condensations or further oxidation of the inter-
mediate aldehyde function to R-ketoacids were detected.
To propose a rational reaction mechanism, we hypothesize
that coordination of the carbonyl oxygen to Yb3+ greatly
enhanced the susceptibility of the methyl to be oxidized by
SeO2, not only by electronic effects but also because the
oxidation would provide a stable chelate between the metal
center and the hydrate form of glyoxal, from which an
internal 1,2-hydride shift would furnish the hydroxy acid,
in a mechanistic way similar to that described by Morken
and co-workers.7
In conclusion, we disclosed an easy and environmentally
sound method for the synthesis of R-hydroxy-arylacetic acids
directly from substituted aryl methyl ketones under the
catalysis of Yb(OTf)3. The simple workup procedure, mild
reaction conditions, and high yields (78-99%) make our
methodology a valid contribution to the existing processes
in the field of mandelic acid derivative synthesis. Moreover,
the reaction described herein represents, to the best of our
knowledge, the first example of a direct one-pot transforma-
tion of aryl methyl ketones into R-hydroxyacetic acids.
It is well known that, among lanthanide elements, Yb3+
is the “hardest” and thus most oxophilic, due to its smaller
ionic radius.14 So, coordination of an oxygen atom of a
carbonyl to Yb3+ would result in a great enhancement of
the reactivity of this functional group, as witnessed by several
high-yielding transformations of ketones and aldehydes
catalyzed by Yb(OTf)3.6 Because glyoxal formation and
Cannizzaro reactions involve carbonyl functions, it is
conceivable that Yb(OTf)3 could be an ideal catalyst for both
efficiently promoting the methyl oxidation to aldehyde by
SeO2 (thus increasing yields of this step) and subsequent
rearrangement of glyoxal to the R-hydroxy acid, and these
two reactions could be carried out in the same reaction vessel.
The possibility of employing Yb(OTf)3 as an efficient
catalyst in aqueous media suggested the use of H2O as a
solvent. Thus, when acetophenone was treated with a 2-fold
excess of SeO2 and 0.1 mmol of Yb(OTf)3 in a 3:1 dioxane/
H2O mixture at 90 °C for 18 h, mandelic acid (13) was
obtained in 90% yield without any further purification after
standard workup. The same protocol was applied to differ-
ently substituted acetophenones and to heteroaromatic and
condensed aromatic methyl ketones, affording in each case
very good yields, ranging from 78 to 99%, as reported in
Table 2.
Acknowledgment. Financial support from MIUR Na-
tional Project “Sviluppo di processi sintetici ecocompatibili
nella sintesi organica”, COFIN 2004, and from University
of Perugia is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization data, including spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
After each reaction, Yb3+ was recovered from the mother
liquors simply by precipitation as the hydroxide at pH 12
(12) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. L. Chem. ReV.
2002, 6, 2227-2302.
OL050125E
(13) Fuson, R. C.; Emerson, W. S.; Gray, H. W. J. Am. Chem. Soc. 1939,
61, 480-482.
(15) Fieser, M. Reagents for Organic Synthesis; Wiley-Interscience: New
York; Vol. 14, p 188.
(14) Pitzer, K. S. Acc. Chem. Res. 1974, 12, 271-276.
Org. Lett., Vol. 7, No. 7, 2005
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