Synthesis of 1,2,3-triazolylpyranosides through click chemistry reaction

Article abstract of DOI:10.1016/j.tetlet.2012.01.102

We have developed an efficient method for the synthesis of functionalized C-glycosyl 1,2,3-triazoles through a Cu(I)-promoted azide-alkyne 1,3-dipolar cycloaddition between a TMS-protected C-alkynyl-glycoside and organic azides. The reaction was accelerat

Full text of DOI:10.1016/j.tetlet.2012.01.102

Tetrahedron Letters 53 (2012) 1742–1747
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 1,2,3-triazolylpyranosides through click chemistry reaction
Hélio A. Stefani a, , Nathália C.S. Silva a, Flávia Manarin a, Diogo S. Lüdtke b, Julio Zukerman-Schpector c,
⇑
Lucas Sousa Madureira c, Edward R.T. Tiekink d
a Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, CEP 05508-000, Brazil
b Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
c Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, Brazil
d Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an efficient method for the synthesis of functionalized C-glycosyl 1,2,3-triazoles
through a Cu(I)-promoted azide–alkyne 1,3-dipolar cycloaddition between a TMS-protected C-alkynyl-
glycoside and organic azides. The reaction was accelerated by ultrasound irradiation and the addition
of a base was not necessary to obtain the 1,2,3-triazole product. Moreover, further manipulation of the
products led to chiral molecules with a C-glycoside linkage.
Received 16 December 2011
Revised 20 January 2012
Accepted 23 January 2012
Available online 31 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
D-Glucal
1,2,3-Triazole
Cycloaddition
Click chemistry
Selenosugars
1. Introduction
linker in the biological environment, which is resistant to hydroly-
sis, oxidation, and reduction, coupled with their ability to partici-
The chemistry and chemical biology of C-glycosides has experi-
enced increasing attention due to their potential to serve as carbo-
hydrate analogues resistant to metabolic processes, which might
lead to an improved biological profile compared to their O-ana-
logues.1 In addition, C-glycosides have also been found embedded
in the structure of several bioactive natural products2 and have
served as chiral building blocks for the stereoselective synthesis
of optically active compounds.3 The Huisgen 1,3-dipolar azide al-
kyne cycloaddition has been the subject of intense research since
the discovery by Sharpless4 and Meldal5 that the addition of a cop-
per(I) source increases the reaction rate and governs the regiose-
lectivity, favoring 1,4-disubstituted 1,2,3-triazoles. Since then,
Cu(I)-promoted azide–alkyne 1,3-dipolar cycloaddition has be-
come commonly used in several areas of science, such as material
science,6 polymer chemistry,7 nucleoside, nucleotide and DNA
modifications,8 medicinal chemistry,9 and biomolecular ligation,10
to cite just a few.11 In addition, 1,2,3-triazoles have been reported
to have important biological activities, including anti-HIV,12 anti-
tumor,13 anti-bacterial,14 and anti-tuberculosis,15 and can also act
as glycosidase,16 tyrosinase,17 and serine hydrolase18 inhibitors.
Not surprisingly, sugar-derived triazoles have also been the
subject of research in recent years. The robustness of the triazole
pate in hydrogen-bonding and dipole interactions, has attracted
the attention of synthetic carbohydrate chemists, medicinal chem-
ists, and material chemists.19
In this context, we now wish to disclose our results on the syn-
thesis of functionalized C-glycosides through a Cu(I)-promoted
R1
2 (1.2 equiv)
BF3K
R1
O
O
AcO
AcO
AcO
AcO
BF3•OEt2 (2 equiv), CH3CN,
0 oC, 10-30 min
OAc
α-3
R1 = aryl, vinyl, alkyl
1
ratio α:β: up to >98:2
45 - 89% yield
Scheme 1. Glycosidation reaction favoring the
a-stereoisomer.
SiMe3
O
O
KF3B
SiMe3
AcO
AcO
AcO
AcO
BF3•OEt2, CH3CN
0
80%
oC, 15 min
[gram-scale]
3a
1
OAc
⇑
Corresponding author. Tel.: +55 11 3091 3654.
E-mail address: hstefani@usp.br (H.A. Stefani).
Scheme 2. Synthesis of the glycosyl alkyne 3a.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.102

H. A. Stefani et al. / Tetrahedron Letters 53 (2012) 1742–1747
1743
SiMe3
N
O
O
N
AcO
AcO
AcO
N
N3-C6H13 (1.2 eq.)
AcO
CuI (1 eq.), TBAF (1.2 eq.)
3a
4a
THF, rt
42%
Scheme 3. Cu(I) promoted azide–alkyne cycloaddition.
Table 1
Scope of the cycloaddition reaction
R
N
SiMe3
N
R-N3
CuI (1 equiv.)
(1.2 equiv.)
O
O
N
AcO
AcO
AcO
AcO
TBAF (1.2 equiv.), THF
rt, ultrasound
Entry
Azide
Product/Time (h)
Yielda (%)
N
1
C6H13-N3
68
O
N
AcO
N
AcO
4a (4h)
N
2
3
4
c-C6H11-N3
63
75 (59)a
51 (48)a
N
O
AcO
N
AcO
4b (2h)
N
N
O
Bn-N3
AcO
N
AcO
4c (2h)
N
N
Ph-N3
O
AcO
N
AcO
4d
(2h)
NO2
N
5
4-NO2C6H4-N3
66
O
N
AcO
AcO
N
4e (4h)
(continued on next page)

1744
H. A. Stefani et al. / Tetrahedron Letters 53 (2012) 1742–1747
Table 1 (continued)
Entry
Azide
Product/Time (h)
Yielda (%)
I
N
6
4-IC6H4-N3
67
O
N
AcO
AcO
N
4f (1h)
CH3
O2N
O
75 (38)a
N
N
N
7
4-Me-2-NO2C6H3-N3
AcO
AcO
4g (6h)
Cl
N
N
N
8
3-ClC6H4-N3
67
O
AcO
AcO
4h (1h)
O
H
N
N
N
AcO
AcO
9
NaN3
NR
4i (2h)
OMe
N
10
4-OMeC6H4-N3
70
O
N
AcO
AcO
N
4j (0.5h)
a
Reactions were carried out with PMDETA as base.
azide–alkyne 1,3-dipolar cycloaddition between a TMS-protected
C-alkynyl-glycoside and organic azides through ‘click chemistry’.
Our approach was based on our recently developed mild and
efficient method for the stereoselective synthesis of C-alkynyl-gly-
cosides, by the reaction of tri-O-acetyl-D-glucal with alkynyltriflu-
oroborate salts, in the presence of boron trifluoride as the Lewis
acid.20 The glycosidation reaction was found to be very selective,
favoring the a-stereoisomer in up to >98:2 dr (Scheme 1).
Initially, the synthesis of the required glycosyl alkyne 3a was
accomplished by our protocol, in a very fast (15 min) and mild
reaction in an 80% yield (Scheme 2). The reaction was completely
diastereoselective in favor of the
a-isomer and could be carried
out on the gram-scale, without any noticeable decrease in yield
or stereoselectivity.
With the required alkyne in hand, we turned our attention to
examining Cu(I) promoted azide–alkyne cycloaddition, initially
using hexyl azide as the dipole (Scheme 3). In order to avoid depro-
tection of the silylated glycosyl alkyne, which would require an
Figure 1. Molecular structure of compound 4d, showing atom labeling and
displacement ellipsoids at the 50% probability level for non-H atoms.

H. A. Stefani et al. / Tetrahedron Letters 53 (2012) 1742–1747
1745
Figure 2. Reaction course followed by in situ IR spectroscopy.
After some experimentation, we found that better results were
achieved under ultrasound irradiation,22,23 leading to an improve-
ment in the yield of compound 4a to 68% (Table 1, entry 1). The
beneficial effect of sonication on the azide–alkyne cycloaddition
has already been observed in our laboratory24 and by others.25
The extension of these conditions to a broader range of azides al-
lowed the synthesis of a number of chiral 1,2,3-triazoles in good
yields under mild reaction conditions. When aliphatic azides were
employed as substrates, the corresponding products were obtained
in good yields (entries 1–3). Aromatic azides were also tested as
substrates for Cu(I)-promoted cycloaddition; when phenylazide
was employed, the corresponding triazolyl glucoside was obtained
in a moderate 51% yield (entry 4). Conversely, substituted aromatic
azides, particularly those with electron withdrawing groups, re-
sulted in better yields (entries 5–8). The best result was achieved
with a trisubstituted aryl azide possessing a nitro group ortho to
the azide functionality (entry 7). In contrast to these results, when
sodium azide was employed as the 1,3-dipole, the desired product
was not obtained and only deprotection of the silyl group was ob-
served, and ethynyl C-glucoside was partially recovered from the
reaction (30%) (entry 9). Attempts to improve the yield by the addi-
tion of an amine base were also pursued. Therefore, based on the
work of Fiandanese et al., we choose to use N,N,N0,N’,N00-penta-
methyldiethylenetriamine (PMDETA) as the amine. Unfortunately,
for the cases studied, the presence of the amine resulted in a dele-
terious effect on the reaction outcome and a decrease in the yield
was observed (see entries 3, 4, and 7) or the product was not
formed at all (entry 9).
Table 2
Removal of the acetyl protecting groups
R
N
N
R
N
N
K2CO3
MeOH, rt
O
O
N
AcO
AcO
N
HO
HO
4a-h
5a-h
Entry
R
Yield (%)
1
2
3
4
5
6
7
8
C6H13 (5a)
c-C6H11 (5b)
Bn (5c)
95
98
94
94
93
93
90
95
Ph (5d)
4-NO2C6H4 (5e)
4-IC6H4 (5f)
4-Me-2-NO2C6H3 (5g)
3-ClC6H4 (5h)
N
N
SiMe3
N3
O
O
N
AcO
AcO
AcO
AcO
CuI, TBAF
THF, rt
As suitable crystals of 4d were obtained, its absolute configura-
tion was confirmed by X-ray diffraction.26 As shown in Figure 1, the
chirality of C2, C3, and C6 was R, S, and S, respectively. In the crystal,
3a
4b
ultrasound
Scheme 4. In situ ReactIR spectroscopy to monitor the formation of the triazole.
the molecules were linked by C–Hꢀ ꢀ ꢀO, C–Hꢀ ꢀ ꢀN, and C–Hꢀ ꢀ ꢀ
p
interactions, the latter involving the triazole moiety. The compound
crystallizes in space group P21 with only one independent molecule
in the asymmetric unit. The diffraction measurements were carried
additional step, the cycloaddition reaction was performed using
the conditions developed by Fiandanese and co-workers, which
make use of tetrabutyl ammonium fluoride to promote the re-
moval of the silyl protecting group in situ.21 Moreover, the reaction
was carried out using copper iodide as the Cu(I) source and THF as
the solvent. Applying these conditions to our system resulted in
the formation of the C-glycosyl triazole in a moderate 42% yield.
out with Cu K
a radiation and the absolute structure was deter-
mined using 1591 Friedel pairs, obtaining a Flack parameter of
ꢁ0.09(15).27
In order to investigate the reaction outcome, in situ ReactIR
spectroscopy was employed to monitor the formation of the
Ph
N
N
Ph
Ph
N
N
(PhSe)2, NaBH4
N
MsCl, py
N
O
O
O
PhSe
HO
N
MsO
HO
N
HO
HO
N
CH2Cl2
THF, EtOH
rt, 24 h
-20 oC to rt, 12 h
77%
76%
5d
6
7a
Scheme 5. Synthesis of seleno-carbohydrate derivative.

1746
H. A. Stefani et al. / Tetrahedron Letters 53 (2012) 1742–1747
O
Se
MeO
Ph
N
N
Ph
N
N
O
O
Me
Me
2
O
O
O
8
Se
HO
N
MsO
HO
N
MeO
NaBH4, THF/EtOH (3:1)
O
reflux, 24 h
O
6
7b
Me
80%
Me
Scheme 6. Synthesis of seleno-(
D)-galactose pyranoside.
O
O
O
Me
Me
Se
Ph
N
N
O
Ph
N
N
O
Me
Me
9
O
2
O
O
MsO
HO
N
O
O
Me
Me
Se
HO
N
NaBH4, THF/EtOH (3:1)
reflux, 24 h
O
6
O
Me
60%
7c
Me
Scheme 7. Synthesis of seleno-(
D)-ribose pyranoside.
triazole product, which is a useful tool for monitoring and optimiz-
ing reaction processes.28 The reaction between 3a and cyclohexyl
azide was chosen for this investigation (Scheme 4).
During the experiment, it was found that the mCO2 of the car-
bonyl group could be easily observed. After the addition of TBAF,
there was a rapid increase in this band at 1748 cmꢁ1. The surface
at 1234 cmꢁ1 could be assigned to a vibrational stretching of car-
bon–nitrogen in the triazole ring, indicating the formation of the
product. It is important to point out that this formation reached
a maximum in 45 min (Fig. 2).
In order to obtain some insight into why the tosylation reaction
did not occur, a calculation of the reaction pathway and the struc-
ture of the transition states for TsCl and MsCl was performed (for
computational details, see the Supplementary data). The Intrinsic
Reaction Coordinate (IRC) calculations showed that the transition
states, for both tosyl and mesyl, had very similar structures (Figs.
S1 and S2), with the chlorine atom making a Sꢀ ꢀ ꢀCl and three C–
Hꢀ ꢀ ꢀCl interactions. As can be seen in Tables S1 and S2, according
to the NBO (Natural Bond Orbital) analysis, the Sꢀ ꢀ ꢀCl interaction
was stronger in the transition state of the tosylate than in the mes-
ylate, thus making it easier for the chlorine atom to leave. More-
over, the non-bonded Sꢀ ꢀ ꢀCl distance after attaining the threshold
gradient value in the IRC for the mesylate case was 5.02 Å while
for the tosylate this was 3.24 Å (Figs. S3 and S4), indicating that
there was still some interaction between these atoms, thus pre-
cluding the continuation of the reaction toward tosylation.
Our next step was directed toward the functional group manip-
ulation of the triazole-glucosides. Thus, the removal of the acetyl
protecting groups was achieved by treatment with potassium car-
bonate in methanol, under mild reaction conditions, leading to the
corresponding product possessing two free hydroxy groups (Table
2). For all cases studied, the reaction was very efficient and the
deprotected products were obtained in excellent yields. These
chiral carbohydrate-derived compounds were interesting poly-
functionalized molecules and were amenable to further transfor-
mations. Selective reactions could be performed at the diol
moiety, since one of the hydroxy groups was primary and the other
was a secondary allylic alcohol. Moreover, the internal allylic dou-
ble bond could be selectively functionalized with several reagents
leading to two new additional stereogenic centers and an even
more functionalized molecule.
In an effort to further explore the potential of the glucal deriv-
atives, we sought to activate the primary hydroxy group. Initial at-
tempts were directed toward tosylation using TsCl; however, the
desired product was not obtained despite several experiments
varying the solvent, base, and temperature. Gratifyingly, when
we changed the activating agent to MsCl, the selective mesylation
of the primary hydroxyl in 5d occurred and the corresponding
product was obtained in a 76% yield in a clean reaction (Scheme
5). Further, in connection with the growing importance of the syn-
thesis of small molecules containing an organoselenium moiety,
due to their biological and pharmacological properties,29 we
sought to replace the mesylate leaving group with a selenium
nucleophile. Therefore, the reaction of the mesylate 6 with a phe-
nylselenide nucleophile resulted in a substitution reaction, leading
to the corresponding seleno-carbohydrate 7a in a 77% isolated
yield.
With the success achieved in the introduction of an organosele-
nium moiety in the triazole-glucoside framework, we decided to
explore the same strategy using selenium nucleophiles of more
complex structure, such as those derived from other sugars.30
Therefore, reductive cleavage of diselenides 8 and 9, derived from
D
-galactose and D-ribose, followed by trapping with the glucal-de-
rived mesylate 6, resulted in clean substitution reactions and the
corresponding products were isolated in good yields (Schemes 6
and 7). The reaction worked with both pyranoside and furanoside
selenium nucleophiles. It is worth noting that a significant increase
in structural complexity could be achieved by a simple synthetic
strategy. The obtained products displayed a disaccharide-like
structure in which two different sugar units were connected by a
selenium atom.
2. Conclusion
In summary, we have developed an efficient method for the
synthesis of functionalized C-glycosyl 1,2,3-triazoles through a
Cu(I)-promoted azide–alkyne 1,3-dipolar cycloaddition between a
TMS-protected C-alkynyl-glycoside and organic azides. The
reaction was accelerated by ultrasound irradiation and the
addition of a base was not necessary to obtain the 1,2,3-triazole
product. Moreover, further manipulation of the products led to
chiral molecules with a C-glycoside linkage.

H. A. Stefani et al. / Tetrahedron Letters 53 (2012) 1742–1747
1747
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Acknowledgements
The authors would like to acknowledge CNPq (300.613/2007-5)
and FAPESP (07/59404-2, 2010/15677-8 and 09/51850-9) for their
financial support.
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A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.102.
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