Metal-free one-pot oxidative amidation of aldoses with functionalized amines

Article abstract of DOI:10.1021/jo801626v

(Chemical Equation Presented) 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.

Full text of DOI:10.1021/jo801626v

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

TABLE 1. Optimization of the Oxidative Amidation of Aldoses.
TABLE 2. Oxidative Amidation of Aldoses with Aminesa
T1
yield
entry
oxidant
base
2 (equiv)
solvent
(h)a (%)b
1
2
3
4
5
6
7
8
9
I2
I2
I2
I2
I2
I2
I2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
1.1
1.1
1.1
1.1
2.2
3.3
1.1
1.1
1.1
1.1
t-BuOH
t-BuOHc
MeCN
t-BuOH
t-BuOH
t-BuOH
t-BuOH
MeCN
0.5
1
1
1
1
1
1
1
1
45
27
46
74
47
62
58
trace
trace
trace
d
e
d
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
MeCN
t-BuOH
10
1
a T1 refers to reaction time between 2 and 1 before addition of
oxidant and base to the reaction mixture. b Isolated yield. c Aqueous
t-BuOH containing 25% of water. d 1.1 equiv of PhI(OAc)2 was used.
e 2.2. equiv of PhI(OAc)2 was used.
In this paper, we wish to report our exploration of the
synthetic scope of this reaction and to provide some insights
into its mechanism for rationalizing the unexpected formation
of the amide product. The effect of various experimental
parameters was examined to improve the yield. The reaction
was first studied with the I2/K2CO3 system. It appeared that an
increase in the reaction time (T1) between the aldose 1 and
ethanolamine (2) before introduction of the oxidant and the base
was critical for the efficiency of the process (Table 1, entries 1
and 4); following these conditions, the desired gluconamide 3
was indeed obtained after 3 h in 74% yield. No improvement
was observed when the solvent was switched from t-BuOH to
MeCN or to aqueous t-BuOH, although 1 appeared to be more
soluble under both conditions (entries 2 and 3). The addition
of more equivalents of ethanolamine (2) was found to decrease
the yield in amide 3 (entries 4-6). Contrary to what was
observed by Togo et al.6 for the formation of 2-oxazoline
derivatives (Scheme 1), the use of Na2CO3 instead of K2CO3
did not improve the product yield (entry 7). PhI(OAc)2 was then
evaluated as a different source of electrophilic iodine. In a recent
report, it was shown that PhI(OAc)2 could be a better oxidizing
agent than the I2/K2CO3 system for the formation of 2-oxazoline
derivatives from enolizable aldehydes and 2-amino alcohols.9
However, PhI(OAc)2 was found to be unsuitable to produce
amide 3 in any acceptable yield (entries 8-10).
a Reaction conditions: t-BuOH, 90 °C, 2-6 h, aldose/amine/I2/K2CO3
1:1.1:2:3. b Isolated yield. c 3.3 equiv of amine substrate were used. d 2.2
equiv of amine substrate were used. e 4.4 equiv of amine substrate were
used.
We then tested the oxidative amidation reaction of various
aldoses and amines under the optimized reaction conditions to
evaluate its synthetic scope (Table 2). Ethanolamine (2) reacted
with tetra-O-benzyl-D-galactopyranose (8) or tetra-O-benzyl-
D-mannopyranose (10) to produce the desired amides, however,
in lower yields compared to substrate 1 (entries 1, 4, and 5).
Further screening revealed that our optimized amidation pro-
cedure tolerated a wide range of amino alcohol derivatives. The
amidation reaction proceeded smoothly to provide the expected
amides from 1 in reasonable to good yields using 3-amino-1-
propanol (4), 4-amino-1-butanol (6) (entries 2 and 3), or
substituted ethanolamine derivatives (entries 6-13). Interest-
ingly, the amidation reaction could be performed with unpro-
tected amino-diol derivatives (entries 11-13). As a general
feature, it should be noted that better yields were observed with
ethanolamine derivatives carrying a substitutent R to the
hydroxyl group rather than R to the amino group (entries 6-13).
When aldose 1 reacted with ethylenediamine derivative 20,
instead of amino alcohol substrates, the corresponding amide
21 was obtained in moderate yield (entry 14).10 Finally, we
explored the reactivity of simple amine derivatives to evaluate
if the absence of a hydroxyl group was detrimental to the
amidation reaction (entries 15 and 16). Remarkably, the reaction
(10) The amidation reaction performed with ethylenediamine afforded the
expected amide in low yields along with side products.
(9) Karade, N. N.; Tiwari, G. B.; Gampawar, S. V. Synlett 2007, 1921.
8648 J. Org. Chem. Vol. 73, No. 21, 2008

SCHEME 2. Tentative Mechanism for the Oxidative
Amidation of Aldoses with Amino Alcohol Substrates
SCHEME 4. Lactone 23 as Possible Intermediate in the
One-Pot Synthesis of Gluconamide 3
n-butylamine. Consequently, we envisioned two main pathways
depending on the presence or the absence of a hydroxyl group
on the amine substrate (Schemes 2 and 3). We believe that the
first step of the process is the favored formation13 of the
glycosylamine derivative A by way of the corresponding open-
chain imine and the release of 1 equiv of water (Scheme 2).
With amino alcohol derivatives, the corresponding glycosy-
lamine A is in equilibrium with oxazolidine B, which is oxidized
by iodine to afford the corresponding oxazoline C.6 Then, the
next step might involve an intramolecular nucleophilic addition
to yield the reactive spiranic orthoamide D, which is hydrolyzed
to afford E. This intermediate is expected to exist predominantly
in a 4C1 chair conformation in which the hydroxyl group is axial
because of the anomeric effect. Finally, stereoelectronic control
in the cleavage of hemiorthoamide E would lead to the amide
product.14 In the intermediate E, lone pair orbitals of the nitrogen
and exocyclic oxygen atoms can be properly oriented anti-
periplanar to the leaving OR group, promoting the formation
of the amide. The formation of the lactone is disfavored by the
ꢀ-orientation of the amino group: because of the resulting
nonantiperiplanar orientation of the endocyclic oxygen lone pairs
in E, the ejection of the amino group is not facilitated.
In the case of simple amine substrates with no hydroxyl
group, two pathways could be conceived. The first one involves
the oxidation of glycosylamine A′ by iodine to yield the
corresponding imidate intermediate F15 and, after nucleophilic
addition of water, the key intermediate E′. Alternatively, the
aldose may be directly oxidized to give the lactone G and then
the imidate intermediate F. This latter pathway was partly
experimentally verified. It was demonstrated that aldose 1 could
be oxidized to give lactone 2316 in 68% yield by treatment with
molecular iodine and potassium carbonate in refluxing t-BuOH
(Scheme 4). This process required relatively long reaction time
(10 h). Treatment of lactone 23 with ethanol amine (2) in
refluxing t-BuOH under our classical oxidation conditions
afforded the amide 3 in 33% yield. These qualitative results
argue in favor of the hypothetical mechanism described in
Scheme 3.
SCHEME 3. Tentative Mechanisms for the Oxidative
Amidation of Aldoses with Simple Amine Substrates
proceeded well with n-butylamine or benzylamine to give
compounds 22a and 22b,11 respectively, although longer reac-
tion time and a larger number of equivalents of amine were
required. However, arylamines including aniline, 4-nitroaniline,
and p-toluidine were found to be unsuitable substrates for this
amidation reaction as were also N-methyl- and N-benzyl
ethanolamine. First attempts to perform the reaction under our
typical amidation conditions with fully unprotected monosac-
charide substrates were found to be unsuccessful to date.
A tentative mechanism for the oxidative amidation of aldoses
is proposed in Schemes 2 and 3.
First it is important to note that the 5-O-benzyl analog of 112
was not a substrate of the amidation reaction, since only products
corresponding possibly to 2-oxazoline or imidate derivatives
were observed by IR (V ) 1646 cm-1) and MS on the crude
reaction mixture. In addition to the work described by Togo et
al.6 (Scheme 1), this result strongly suggested that the free
hydroxyl group at C-5 in the aldose substrate was crucial for
the process. On the other hand, the hydroxyl group in the amine
substrate seemed to facilitate the reaction but was not absolutely
required as indicated by results obtained with benzylamine and
In conclusion, we report a metal-free one-pot oxidative
amidation of aldoses with functionalized amines using molecular
iodine as the oxidant. Experimental data appear to indicate that
the hydroxyl group at C-5 in the aldose substrate is crucial for
(13) See for example: Pigman, W.; Cleveland, E. A.; Couch, D. H.; Cleveland,
J. H. J. Am. Chem. Soc. 1951, 73, 1976 and ref. cited.
(14) (a) Deslongchamps, P. Tetrahedron 1975, 31, 2463. (b) Deslongchamps,
P. Pure. Appl. Chem. 1975, 43, 351.
(15) For examples of related glycosylamine oxidation see: (a) Ferris, J. P.;
Devadas, B. J. Org. Chem. 1987, 52, 2355. (b) Somsak, L.; Praly, J. P.; Descotes,
G. Synlett 1992, 119.
(16) (a) Hoos, R.; Naughton, A. B.; Vasella, A. HelV. Chim. Acta 1993, 76,
1802. (b) Kuzuhara, H.; Flechter, H. G. J. Org. Chem. 1967, 32, 2531.
(11) Fleet, G. W. J.; Ramsden, N. G.; Carpenter, N. M.; Petursson, S.; Apli,
R. T. Tetrahedron Lett. 1990, 31, 405.
(12) (a) The 5-O-benzyl analog of 1 was prepared by deprotection of the
corresponding diethyl dithioketal according to the procedure described by
Doutheau et al.: Malanda, J.-C.; Doutheau, A. J. Carbohydr. Chem. 1993, 12,
999. (b) Pozsgay, V.; Jennings, H. J. J. Org. Chem. 1988, 53, 4042.
J. Org. Chem. Vol. 73, No. 21, 2008 8649

MHz) δ 42.1 (NH-CH2-CH2-OH), 62.0 (NH-CH2-CH2-OH), 71.1
(C-6), 71.4 (C-4), 73.4-75.1 (4 × -O-CH2-Ph), 77.4 (C-3), 80.1
(C-5), 80.7 (C-2), 127.6-128.6 (CH-Ar), 136.7-138.1 (Cq-Ar),
172.1 (C-1); MS [M + H]+ 600.5. Anal. Calcd for C36H41NO7: C,
72.10; H, 6.89; N, 2.34. Found: C, 71.80; H, 6.86; N, 2.40.
the process and may greatly facilitate the hydrolysis step
according to the proposed mechanistic rational. The hydroxyl
group in the amine substrate seems to accelerate the reaction
by facilitating the oxidation step via an oxazolidine intermediate.
The synthetic application of this reaction for the preparation of
complex glycoconjugates are currently under investigation in
our laboratory.
N-2-Hydroxy-1-(hydroxymethyl)ethyl-2,3,4,6-tetra-O-benzyl-
D-gluconamide (19). Aldose 1 (200 mg, 0.37 mmol) was treated
as described in the general procedure using aminoalcohol 18 (111
mg, 1.22 mmol, 3.3 equiv), K2CO3 (154 mg, 1.11 mmol, 3 equiv).
and I2 (184 mg, 0.74 mmol, 2 equiv). The resulting crude product
was purified by silica gel chromatography (PE/AcOEt gradient) to
Experimental Section
General Experimental Procedure for the Oxidative
Amidation of Aldoses. To a solution of aldose (200 mg, 0.37
mmol) in t-butyl alcohol (4 mL) was added the amine (1.1-3.3
equiv). The mixture was stirred at reflux under an argon atmosphere
for 1 h, and then K2CO3 (154 mg, 3 equiv) and I2 (188 mg, 2 equiv)
were added. The solution was stirred at reflux until TLC indicated
total conversion of starting material (2-6 h). The reaction mixture
was quenched with saturated aqueous Na2S2O3 and was extracted
with Et2O (2 × 10 mL). The organic layer was washed with brine
(7 mL) and dried over MgSO4. After filtration, the solvent was
removed in vacuo. The residue was purified by chromatography
on silica gel (PE/AcOEt) to give the amide.
provide 19 (107 mg, 46%) as a white solid: mp 72-73 °C; [R]20
D
+29.5 (c 1.2, CH2Cl2); IR (neat) 1661 cm-1; H NMR (CDCl3,
1
250 MHz) δ 2.84 (br t, 1H, NH-CH(CH2-OH)-CH2-OH), 2.95 (br
t, 1H, NH-CH(CH2-OH)-CH2-OH), 3.07 (d, 1H, J ) 5 Hz, OH-5),
3.50 (m, 4H, NH-CH(CH2-OH)-CH2-OH), 3.58 (dd, 1H, J ) 5.5
Hz, J ) 9.8 Hz, H-6b), 3.65 (dd, 1H, J ) 3 Hz, J ) 10 Hz, H-6a),
3.79 (m, 1H, NH-CH(CH2-OH)-CH2-OH), 3.84 (dd, 1H, J ) 5.8
Hz, J ) 7.5 Hz, H-4), 3.94 (m, 1H, H-5), 4.09 (dd, 1H, J ) 3.6
Hz, J ) 5.4 Hz, H-3), 4.28 (d, 1H, J ) 3.5 Hz, H-2), 4.45 - 4.61
(m, 6H, -O-CH2-Ph), 4.70 (2 d, 2H, J ) 11.2 Hz, -O-CH2-Ph),
7.20 (m, 1H, NH), 7.18-7.34 (m, 20H, H-Ar); 13C NMR (CDCl3,
62.5 MHz) δ 52.3 (NH-CH(CH2-OH)-CH2-OH), 62.87, 62.94 (NH-
CH(CH2-OH)-CH2-OH), 71.1 (C-6), 71.4 (C-4), 73.4-75.1 (4 ×
-O-CH2-Ph), 77.4 (C-3), 80.1 (C-5), 80.6 (C-2), 127.6-128.6 (CH-
Ar), 136.6-137.9 (Cq-Ar), 171.6 (C-1); MS [M + H]+ 631.0. Anal.
Calcd for C37H43NO8: C, 70.57; H, 6.88; N, 2.22. Found: C, 70.56;
H, 6.99; N, 2.22.
N-2-Hydroxyethyl-2,3,4,6-tetra-O-benzyl-D-gluconamide
(3). Aldose 1 (200 mg, 0.37 mmol) was treated as described in the
general procedure using 2-aminoethanol 2 (25 mg, 0.41 mmol, 1.1
equiv), K2CO3 (154 mg, 1.1 mmol, 3 equiv) and I2 (188 mg, 0.74
mmol, 2 equiv). The resulting crude product was purified by silica
gel chromatography (PE/AcOEt gradient) to provide 3 (163 mg,
74%) as a white solid: mp 102-103 °C; [R]20D +24.5 (c 1, CH2Cl2);
1
IR (neat) 1667 cm-1; H NMR (CDCl3, 250 MHz) δ 2.46 (br t,
Acknowledgment. Financial support of this study by grants
from ANR, CNRS and the French department of research is
gratefully acknowledged.
1H, J ) 4.9 Hz, NH-CH2-CH2-OH), 2.95 (d, 1H, J ) 3.8 Hz, OH-
5), 3.31 (m, 2H, NH-CH2-CH2-OH), 3.53 (m, 2H, NH-CH2-CH2-
OH), 3.58 (dd, 1H, J ) 5.3 Hz, J ) 9.8 Hz, H-6b), 3.66 (dd, 1H,
J ) 2.8 Hz, J ) 9.9 Hz, H-6a), 3.86 (dd, 1H, J ) 5.8 Hz, J ) 7.5
Hz, H-4), 3.93 (m, 1H, H-5), 4.08 (dd, 1H, J ) 3.5 Hz, J ) 5.5
Hz, H-3), 4.29 (d, 1H, J ) 3.3 Hz, H-2), 4.44-4.58 (m, 6H, -O-
CH2-Ph), 4.71 (d, 2H, J ) 11 Hz, -O-CH2-Ph), 7.00 (t, 1H, J )
5.9 Hz, NH), 7.24-7.33 (m, 20H, H-Ar); 13C NMR (CDCl3, 62.5
Supporting Information Available: Additional procedures
and characterization data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO801626V
8650 J. Org. Chem. Vol. 73, No. 21, 2008