Boric acid catalyzed chemoselective esterification of α- hydroxycarboxylic acids

Article abstract of DOI:10.1021/ol036123g

Boric acid catalyzes the selective esterification of α- hydroxycarboxylic acids without causing significant esterification to occur with other carboxylic acids. The procedure is simple, high-yielding, and applicable to the esterification of α-hydroxy carboxylates in the presence of other carboxylic acids including β-hydroxyacids within the same molecule.

Full text of DOI:10.1021/ol036123g

ORGANIC
LETTERS
2004
Vol. 6, No. 5
679-681
Boric Acid Catalyzed Chemoselective
Esterification of r-Hydroxycarboxylic
Acids
,†
Todd A. Houston,* Brendan L. Wilkinson,† and Joanne T. Blanchfield‡
School of Science, Griffith UniVersity, Nathan, QLD 4111, Australia and
School of Molecular and Microbial Sciences, UniVersity of Queensland,
St. Lucia QLD 4072, Australia
t.houston@griffith.edu.au
Received October 30, 2003 (Revised Manuscript Received January 29, 2004)
ABSTRACT
Boric acid catalyzes the selective esterification of r-hydroxycarboxylic acids without causing significant esterification to occur with other
carboxylic acids. The procedure is simple, high-yielding, and applicable to the esterification of r-hydroxy carboxylates in the presence of
other carboxylic acids including â-hydroxyacids within the same molecule.
Fischer esterification conditions, a strong protic acid in
alcohol solvent, have been used for over a century to convert
carboxylic acids to their corresponding carboxylate esters.
Boron acids (i.e., boric and boronic) are useful catalysts for
a number of synthetic transformations including manipulation
of carbonyl-based functional groups and offer milder condi-
tions relative to common mineral acids.1 On the basis of the
affinity of boronic acids for R-hydroxycarboxylic acids in
both protic2 and aprotic solvents3 and the ability of boronates
to catalyze amide formation,4 we explored the possibility of
using boric acid as a catalyst for selective ester formation.
An example using boric acid as an esterification catalyst
appeared as early as 1971,5 but this involved high temperature
and an additional protic acid. Here, we show that simply
using 10-20 mol % boric acid in alcohol solution catalyzes
the esterification of R-hydroxycarboxylates selectively at
ambient temperature and that other carboxylates are un-
reactive to these reaction conditions.
As the results in Table 1 show, R-hydroxycarboxylic acids
are converted to their methyl esters in excellent yields.
Although sodium tetraborate and phenylboronic acid also
catalyze this esterification, neither works as efficiently as
boric acid at similar concentrations. The procedure is quite
simple. In a typical reaction the carboxylic acid was dissolved
in methanol, boric acid was added, and the reaction was
stirred overnight at room temperature (18 h). When the
reaction mixture was then concentrated under vacuum with
mild heating (40-50 °C), the majority of the catalyst was
removed as its methyl ester (trimethyl borate bp <70 °C).6
If necessary, the product was further purified through a short
silica column, but in most cases it was of sufficient purity
for further synthetic manipulation. The reactions for tartrate
and mandelate were run on a 2-g scale in 30 mL of methanol.
Although fairly concentrated (ca. 0.45 M), this appeared to
be sufficient dilution to avoid potential dimer or higher
oligomer formation between hydroxyacids. With malic acid,
however, significant amounts of diester (>10%) and dimer
† School of Science.
‡ School of Molecular and Microbial Sciences.
(1) Duggan, P. J.; Tyndall, E. M. J. Chem. Soc., Perkin Trans. 1 2002,
1325.
(2) Gray, C. W., Jr.; Houston, T. A. J. Org. Chem. 2002, 67, 5426 and
references therein.
(3) Flores-Parra, A.; Paredes-Tepox, C.; Joseph-Nathan, P.; Contreras,
R. Tetrahedron 1990, 46, 4137.
(4) (a) Pelter, A.; Levitt, T. E.; Nelson, P. Tetrahedron 1970, 26, 1539.
(b) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1996, 61, 4196.
(c) Ishihara, K.; Kurihara, H.; Yamamoto, H. Macromolecules 2000, 33,
3511. (d) Latta, R.; Springsteen, G.; Wang, B. Synthesis 2001, 1611. (e)
Yang, W.; Gao, X.; Springsteen, G.; Wang, B. Tetrahedron Lett. 2002, 43,
6339.
(6) While the reactions were not necessarily complete at room temper-
ature, remaining conversion occurred during evaporation of the solvent under
vacuum with heating.
(5) Lawrence, W. W., Jr. Tetrahedron Lett. 1971, 12, 3453.
10.1021/ol036123g CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/11/2004

Because simple carboxylates do not react under the esteri-
fication conditions described here, it is unlikely that the same
mechanism of activation is occurring in these reactions. Both
the neutral ester 2 and anionic species 3 may be present in
alcohol solution, but once esterification occurs to produce
4, neither of these complexes can form. It is unclear at present
whether a free alcohol molecule attacks the carbonyl carbon
of either 2 or 3 to yield product or whether the alcohol is
transferred in an intramolecular manner through 3 to produce
4. In either case, an electrophilic boron species will then be
regenerated to catalyze another esterification (Scheme 1).7
It is interesting to note that this reaction did not occur to
any appreciable extent when equimolar amounts of R-
hydroxyacid, alcohol, and boric acid were mixed in aqueous
solution at room temperature. The amount of borate ester
will be greatly reduced under these conditions, and it is
apparently necessary that the alcohol be present in excess
to react with this species. Even in 2:1 water/methanol solvent
systems, no appreciable reaction occurred after 24 h. This
result was important to us because it ensured that undesired
esterification did not interfere with fluorescent sensing
measurements of R-hydroxyacid binding by boronates.2
Although rigorously dried alcohol solvents were not neces-
sary for the esterification reactions, reagent grade material
was used in all cases. The lower yield observed for lactic
acid is likely due to the fact that this acid contained ca. 12%
water in the commercial form used.
Table 1. Isolated Yields from Boric Acid Catalyzed (10 mol
%) Methyl Ester Synthesis (18 h, Room Temperature)
(>5%) formed when the reaction was run at 0.5 M
concentration. Diluting the reaction mixtures below 0.25 M
reduced the amounts of these biproducts and increased the
yield of the monoester product. It is important to note that
although diacids such as tartrate and malate can form esters
upon prolonged reflux in alcoholic solvents, no appreciable
amount (<5%) of ester formation occurred after several days
at room temperature in the absence of boric acid. Even in
the presence of the catalyst, benzoic acid and succinic acid
were quite unreactive. While N-protected R-amino acids have
the potential to serve as chelating ligands for boric and
boronic acids, neither N-tosylglycine nor N-BOC-alanine
underwent significant esterification under standard condi-
tions.
Two entries in Table 1 demonstrate that the reaction
conditions allow for selective methyl esterification of R-
hydroxycarboxylic acids in the presence of â-hydroxycar-
boxylates. Malic acid contains a hydroxy group that is in
the R-position relative to one carboxylic acid and in the
â-position relative to another. Citric acid contains two such
â-carboxylates in addition to the R-hydroxyacid. The car-
boxylate adjacent to the hydroxy group in both malic and
citric acid reacts more rapidly, providing their respective
monomethyl esters as the major products with very little
diester (<10%) formed in either case. The malate monoester
can also be synthesized by hydrolysis of malic acid anhy-
drides,8 but such selective ring-opening reactions are only
amenable to diacids that are capable of forming cyclic
anhydrides. The protocol described here is not limited in this
regard. The citrate sym-monomethyl ester has previously
been synthesized in two steps using formaldehyde to create
an acetal that reacts with methanol to create the methyl ester.9
This monoester can alternatively be synthesized through
selective saponification of trimethyl citrate.10 The procedure
described here requires only one step.
Yamamoto has used trifluorophenylboronic acid as a
catalyst for amide formation under anhydrous conditions.3b
In the absence of protic solvents, an OH from the boronate
can serve to activate the carbonyl through formation of a
mixed anhydride such as the boxed species in Scheme 1.
Scheme 1. Possible Mechanisms of Catalysis
Other alcohols can be used as solvents to create esters
using this method (Table 2). In these cases, reactions
proceeded more slowly at room temperature (the conversion
to diethyl L-tartrate was only 50% complete after 24 h at
(7) A number of exchanging boron species are likely to be present at
any one time in alcohol solution and these are simply represented here as
B(OR′)3 where R′ ) H and/or Me(Et/iPr).
(8) Miller, M. J.; Bajwa, J. S.; Mattingly, P. G.; Peterson, K. J. Org.
Chem. 1982, 47, 4928.
(9) Lee, B. H.; Miller, M. J. J. Org. Chem. 1983, 48, 24.
(10) Pearce, K. N.; Creamer, L. K. Aust. J. Chem. 1975, 28, 2409.
680
Org. Lett., Vol. 6, No. 5, 2004

Because of the simple and mild nature of this procedure,
it should be applicable to selective esterification of a wide
range of R-hydroxyacids. More efficient, cost-effective, and
environmentally friendly esterification reagents are continu-
ally being sought;12 thus, the chemoselective ability of boric
acid, an inexpensive, easily handled solid esterification
catalyst, should prove valuable.
Table 2. Yields of Ester (Diester for Tartrate) Using 20 mol %
Boric Acid, 18 h, Room Temperature or 10 mol % Boric Acid,
18 h, Reflux [*]
ROH
acid
ethanol
2-propanol
tert-butyl alcohol
mandelic
tartaric
malic
68%
97%*
65%
93%
92%*
59%a
nr
nr
nr
Acknowledgment. The authors are grateful for start-up
funds from Griffith University (to T.A.H.) and the University
of Queensland (to J.T.B.) that supported this work.
aThe isopropyl malate ester is a mixture of regioisomers (see text).
Supporting Information Available: Experimental details
for the synthesis of each of the methyl, ethyl, and isopropyl
1
esters of DL-mandelic acid and DL-malic acid and H NMR
room temperature and the diisopropyl L-tartrate was <20%)
so 20 mol % boric acid catalyst was used or the reactions
were refluxed. For the tartrate diesters and mandelate esters,
aqueous bicarbonate wash was used to remove the catalyst
and any unreacted carboxylic acid to provide the pure esters.
As before, selectivity was observed for the R-hydroxy acid
over the â-hydroxy acid in ethyl DL-malate; however,
significant amounts of esterification occurred at this position
when the reaction was run in 2-propanol (R-/â-ester 3:1).11
The major product was again accompanied by small amounts
(10%) of diester removed by flash column chromatography.
Interestingly, no significant conversion occurred in tert-butyl
alcohol at room temperature or with heating (65 °C).
spectra for products from all reactions including one biprod-
uct (dimethyl malate). This material is available free of
charge via the Internet at http://pubs.acs.org.
OL036123G
(11) It is known that less polar solvents can increase the association
constant of boric acid with 1,3-diols while decreasing the association
constant of borate and 1,2-diols relative to that in more polar solvents. The
increased hydrophobicity of 2-propanol must alter the coordination of boron
to malic acid. Wirth, T. M.; Miller, V. R. Abstracts of Papers, 215th ACS
National Meeting, Dallas, March 29-April 2, 1998; American Chemical
Society: Washington, DC, 1998; CHED-524.
(12) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. Science 2000, 290, 1140.
(b) Ishihara, K.; Nakayama, M.; Ohara, S.; Yamamoto, H. Tetrahedron
2002, 58, 8179, and references therein.
Org. Lett., Vol. 6, No. 5, 2004
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