SCHEME 1. Oxidative Conversion of Aldehydes to
2-Oxazolines6
Metal-Free One-Pot Oxidative Amidation of
Aldoses with Functionalized Amines
Ludovic Colombeau, Te´nin Traore´, Philippe Compain,* and
Olivier R. Martin
Institut de Chimie Organique et Analytique, UniVersite´
d’Orle´ans, CNRS UMR 6005, BP 6759,
45067 Orle´ans, France
alcohols4 has recently attracted much attention. The main
advantage of this approach relies on the fact that oxidation and
C-N bond formation are performed in a single step. This
challenging one-pot process is thus environmentally and eco-
nomically attractive and makes use of readily available starting
materials. Despite these advantages, few direct oxidative ami-
dation methods have been reported in the literature.3,4 Most of
them suffer from limitations such as the use of an excess amount
of expensive transition-metal catalyst and poor substrate scope.
It is important to note that such oxidative amidation reactions
have been successfully performed almost exclusively on aryl
aldehydes to date.
philippe.compain@uniV-orleans.fr
ReceiVed July 23, 2008
In connection with our work on bicyclic iminosugars5 related
to nagstatin,5e we were interested in a method recently described
by Togo et al. concerning the direct oxidative conversion of
aldehydes to 2-oxazolines.6 In this process, aryl aldehydes react
with 2-aminoethanol in the presence of iodine and potassium
carbonate to provide the corresponding 2-oxazolines in 41-83%
yield, whereas enolizable aldehydes give much lower yields or
lead only to degradation products (Scheme 1).6 As this process
could significantly shorten the synthesis of polyhydroxylated
1-oxaindolizidine derivatives, we decided to apply it to tetra-
O-benzyl-D-glucopyranose (1).
In a first attempt, reaction of 1 with ethanolamine (2)
following Togo’s protocol6 did not lead to the formation of the
expected 2-oxazoline derivative but to gluconamide 3 in 45%
yield (Table 1, entry 1). To our knowledge, this reaction
constitutes a rare example of metal-free one-pot oxidative
amidation of aldehydes. Till very recently, no such process
without metal catalyst was reported in the literature.3a,b,7 In
addition, its application to aldoses is also of interest for the direct
synthesis of relevant complex glycoconjugates including calix-
sugars, synthetic carbohydrate polymers, neoglycopeptides, or
sugar-modified oligonucleotides.8
Metal-free one-pot oxidative amidation of aldoses with
functionalized amines using iodine provides a rapid access
to functionalized aldonamides. The main advantage of this
approach relies on the fact that aldehyde oxidation and C-N
bond formation are performed in a single synthetic operation.
The amide is one of the most fundamental functional groups
in organic chemistry and biochemistry, from natural products
to synthetic pharmaceuticals. It has been reported that more than
25% of known drugs present in the Comprehensive Medicinal
Chemistry (CMC) database contain an aminocarbonyl group.1
The amide function is the link between amino acids in peptides
and proteins and thus is key to the structure of many biological
systems. Most of the preparative methods for amide bond
formation are based on the reaction between an amine and an
activated carboxylic acid derivative without change in the
oxidation level.2 These methods often require the use of coupling
agents such as carbodiimides from free carboxylic acids or the
prior synthesis of acid chlorides or anhydride derivatives. In
this context, direct oxidative amidation of aldehydes3 and
(4) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790.
(5) (a) Godin, G.; Compain, P.; Masson, G.; Martin, O. R. J. Org. Chem.
2002, 67, 6960. (b) Godin, G.; Compain, P.; Martin, O. R. Org. Lett. 2003, 5,
3269. (c) Compain, P.; Martin, O. R.; Boucheron, C.; Godin, G.; Yu, L.; Ikeda,
K.; Asano, N. ChemBioChem 2006, 7, 1356. (d) Toumieux, S.; Compain, P.;
Martin, O. R. J. Org. Chem. 2008, 73, 2155. (e) Iminosugars: from Synthesis to
Therapeutic Applications; Compain, P., Martin, O. R., Eds.; Wiley-VCH:
Weinheim, 2007.
(1) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Comb. Chem.
1999, 1, 55.
(2) (a) Bailey, P. D.; Collier, I. D.; Morgan, K. M. In ComprehensiVe Organic
Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees,
C. W., Eds.; Elsevier Science Inc.: New York, 1995; Vol. 5, pp 258-391. (b)
Larock, R. C. ComprehensiVe Organic Transformations; Wiley-VCH: New York,
1999. (c) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry, 6th
ed.; Wiley: New York, 2007. (d) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron
2005, 61, 10827.
(3) (a) Gao, J.; Wang, G.-W. J. Org. Chem. 2008, 73, 2955. (b) Ekoue-
Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429. (c) Yoo, W.-J.; Li, C.-J. J. Am.
Chem. Soc. 2006, 128, 13064. (d) Tillack, A.; Rudloff, I.; Beller, M. Eur. J.
Org. Chem. 2001, 523. (e) Naota, T.; Murahashi, S.-I. Synlett 1991, 693. (f)
Tamaru, Y.; Yamada, Y.; Yoshida, Z.-I. Synthesis 1983, 474. (g) Fukuoka, S.;
Ryang, M.; Tsutsumi, S. J. Org. Chem. 1971, 36, 2721. (h) Nakagawa, K.; Onoue,
H.; Minami, K. Chem. Commun. 1966, 17.
(6) Ishihara, M.; Togo, H. Tetrahedron 2007, 63, 1474.
(7) Recently, Fang et al. reported the synthesis of aldonamide derivatives
by direct oxidation of aldoses by iodine in aqueous ammonia: Chen, M.-Y.;
Hsu, J.-L.; Shie, J.-J; Fang, J.-M. J. Chin. Chem. Soc. 2003, 50, 129.
(8) See for example: (a) Fujimoto, K.; Miyata, T.; Aoyama, Y. J. Am. Chem.
Soc. 2000, 122, 3558. (b) Budka, J.; Tkadlecova, M.; Lhotak, P.; Stibor, I.
Tetrahedron 2000, 56, 1883. (c) Narain, R.; Armes, S. P. Macromolecules 2003,
36, 4675. (d) Kim, K.; Matsuura, K.; Kimizuka, N. Bioorg. Med. Chem. 2007,
15, 4311. (e) Kida, T.; Tanaka, T.; Nakatsuji, Y.; Akashi, M. Chem. Lett. 2006,
35, 112.
10.1021/jo801626v CCC: $40.75
Published on Web 10/08/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8647–8650 8647