Direct aldol reactions of glyoxylic acid monohydrate with ketones

Article abstract of DOI:10.1055/s-1999-2786

The direct aldol reaction of various ketones with glyoxylic acid afforded the β-hydroxy carbonyl compounds in good yields and high regioselectivities.

Full text of DOI:10.1055/s-1999-2786

LETTER
1059
Direct Aldol Reactions of Glyoxylic Acid Monohydrate with Ketones
Teck-Peng Loh,1 Lin-Li Wei, Li-Chun Feng
Department of Chemistry, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260
Fax (65) 779 1691 E-mail: chmlohtp@nus.edu.sg
Received 13 April 1999
Abstract: The direct aldol reaction of various ketones with glyox-
ylic acid afforded the b-hydroxy carbonyl compounds in good
yields and high regioselectivities.
Scheme 1
Key words: InCl3, glyoxylic acid, a-hydroxy acid, direct aldol re-
action, neat reaction
Table 1 Direct aldol reaction of glyoxylic acid with ketones
The aldol reaction is one of the most powerful tools for the
construction of carbon-carbon bond1. Nature itself has
made use of this reaction in the prebiotic biosynthesis of
saccharides. In principle, the most classical and conven-
tional aldol reactions which involve the mixed aldol reac-
tion between a ketone containing a-hydrogen with an
aldehyde in the presence of base or acid should be an use-
ful method for the synthesis of complex molecules.1 How-
ever, this type of aldol reaction has not been well
exploited in organic synthesis due to the following rea-
sons: 1) side-reactions such as self-condensation of the
ketone or/and dimerization of the aldehyde can be a prob-
lem; 2) the harsh reaction conditions employed which
usually require a strong base or acid make it unattractive
for complex molecule synthesis which usually contain
acid or base-labile functional groups; 3) byproducts such
as a,b-unsaturated carbonyl compounds, dimers and poly-
mers are usually formed together with the desired aldol
addition product; 4) low regioselectivity was observed in
most of these cases. Therefore, a new method which em-
ployed mild reaction conditions whilst able to overcome
some if not all of the above problems is much sought after.
Recently, it has been reported that Zn-catalyst
3
(Zn(NO3)2·6H2O and a-amino acid ester)2, BCl3 and
TiCl44,5 are useful catalysts to promote the direct aldol re-
action. However, these reactions catalyzed by the latter
two Lewis acids must be carried out under anhydrous con-
dition because of their moisture sensitivities.
On the other hand, of special synthetic value among the
many aldol reaction variants are the glyoxylic acid-aldol
reaction which provide a-hydroxy acids which are of bio-
logical and synthetic importance.6 However, in most of
the cases, the aldol products were obtained in poor yields
under very harsh reaction conditions.6b,7
In this article, we present the direct aldol reactions of gly-
oxylic acid monohydrate with aliphatic and aromatic ke-
tones separately in the presence of InCl3 under solvent-
free condition (Scheme 1).8
Synlett 1999, No. 07, 1059–1060 ISSN 0936-5214 © Thieme Stuttgart · New York

1060
T.-P. Loh et al.
LETTER
In our investigation, we found that InCl3 can efficiently ous ketones with the commercially available hydrates of
promote the direct aldol reaction of glyoxylic acid mono- glyoxylic acid in the presence of indium trichloride under
hydrate under sonication. The results are shown in Table 1 solvent-free conditions. Since the products of direct aldol
reaction of ketones with glyoxylic acid are important and
As shown in Table 1, InCl3 is essential for the success of
useful intermediates for natural products, we can expect
the reactions with propiophenone (Table 1, entries 1, 2
that this simple, highly efficient, safe and environmentally
and 3). In the presence of 20 mol% InCl3 under sonication
friendly methodology will find wide application in indus-
and neat condition, satisfactory yields were obtained in all
try.
cases. The diastereoselectivities were low to moderate and
the syn products were predominant regardless of the ge- A Typical Experimental Procedure:
ometry of the enols. The observed syn diastereoselectivi-
ties can be explained using an open-chain antiperiplanar
transition state (Scheme 2).
Glyoxylic acid monohydrate (46 mg, 0.5 mmol), ace-
tophenone (120 mg, 1mmol) and InCl3 (24 mg, 0.1 mmol)
were mixed and sonicated for 2-4 d (~ 30 °C). After nor-
mal acid-base workup, the pure aldol products were ob-
tained in good yields.1H NMR (Acetone-d6): d 8.03-7.99
(m, 2H), 7.65-7.49 (m, 3H), 4.75 (t, J = 5.4 Hz, 1H), 3.50
(d, J = 5.4 Hz, 2H); 13C NMR (Acetone-d6): d 198.60,
176.23, 138.61, 134.80, 130.24, 129.66, 68.42 44.06;
FTIR (thin film) 1731.0, 1678.1 cm-1; HRMS calcd. for
C10H10O4 194.0579, found 194.0579.
Scheme 2
References and Notes
(1) Nielsen, A. T.; Houlihan, W. J. Organic Reactions.,John
The regioselectivities of unsymmetrical ketones were
high and the thermodynamically controlled product was
obtained as the major product (Scheme 3).
Wiley &Sons, New York 1968, Vol. 16, 1; (b) Heathcock, C.
H. In Comprehensive Organic Synthesis, Vol.1 (Eds.: Trost,
B. M.; Fleming, I.), Pergamon Press, Oxford 1991, pp. 133.
(2) Nakagawa, M.; Nakao, H.; Watanabe, K. Chem. Lett. 1985,
391.
(3) Chow, H. F.; Seebach, D. Helv. Chim. Acta. 1986, 69, 604.
(4) Evans, D. A.; Rieger, D. A.; Bilodeau, M. T.; Urpi, F. J. Am.
Chem. Soc. 1991, 113, 1047 and references cited therein.
(5) a) Mahrwald, R. Chem. Ber. 1995, 128, 919; b) Mahrwald, R.;
Gundogan, B. J. Am. Chem. Soc. 1998, 120, 413 and
references cited therein.
(6) a) For review: Coppola, G. M.; Schuster, H. F. a-Hydroxy
Acids in Enantioselective Synthesis,VCH: Germany,1997;
b) For example: Bianchi, M.; Butti, A.; Christidis, Y.;
Perronnet, J.; Barzaghi, F.; Cesana, R.; Nencioni, A. Eu. J.
Med. Chem. 1988, 23, 45.
(7) For examples: a) Kurath, P.; Cole, W. J. Org. Chem. 1961, 26,
4592 and references cited therein.;b) Debono, M.; Molloy, R.
M.; Patterson, L. E. J. Org. Chem. 1968, 34, 3033 and
references cited therein.
Scheme 3
(8) For comprehensive review on solvent-free organic reactions:
Ditter, D. C. Chemistry & Industry,1997, 779.
(9) a) Loh, T. P.; Pei, J.; Cao, G. -Q. J. Chem. Soc., Chem.
Commun. 1996, 1819; b) Loh, T. P.; Pei, J.; Koh, K. S. -V.
Cao, G. -Q.; Li, X. -R.Tetrahedron Lett.1997,38, 3465,
Corrigendum, ibid 1997, 38, 3993.
(10) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem.
1982, 13, 1.
(11) The aldol product obtained was subjected to the same reaction
condition for 3 d and no retro-aldol reaction was observed.
Generally, the direct aldol reactions of various ketones
with glyoxylic acid are clean. The possible a,b-unsaturat-
ed acid resulted from the aldol condensation and double
aldol reaction were not detected in most cases. The reac-
tions proceeded smoothly under extremely mild condi-
tions to give the corresponding a-hydroxyl acids in high
yields with moderate diastereoselectivities and regiose-
lectivities.11 For unsymmetrical ketones, the thermody-
namically controlling products were major products.
Article Identifier:
1437-2096,E;1999,0,07,1059,1060,ftx,en;Y08299ST.pdf
In summary, we have developed an easy approach to var-
ious a-hydroxy acids by the direct aldol reactions of vari-
Synlett 1999, No. 07, 1059–1060 ISSN 0936-5214 © Thieme Stuttgart · New York