Synthesis of 5-halogenated 1,2,3-triazoles under stoichiometric Cu(I)-mediated azide-alkyne cycloaddition (CuAAC or 'Click Chemistry')

Article abstract of DOI:10.1016/j.carres.2012.08.014

Glucosylated heterocycles have been identified as potent inhibitors of glycogen phosphorylase (GP), a biomolecular target for the treatment of hyperglycemia and therefore type 2 diabetes. Several glucosylated triazoles have been evaluated as GP inhibitors

Full text of DOI:10.1016/j.carres.2012.08.014

Carbohydrate Research 362 (2012) 79–83
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Carbohydrate Research
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Synthesis of 5-halogenated 1,2,3-triazoles under stoichiometric Cu(I)-mediated
azide–alkyne cycloaddition (CuAAC or ‘Click Chemistry’)
⇑
David Goyard, Jean-Pierre Praly, Sébastien Vidal
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2—Glycochimie, UMR 5246, CNRS, Université Claude Bernard Lyon 1,
43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 June 2012
Received in revised form 24 July 2012
Accepted 28 August 2012
Available online 11 September 2012
Glucosylated heterocycles have been identified as potent inhibitors of glycogen phosphorylase (GP), a
biomolecular target for the treatment of hyperglycemia and therefore type 2 diabetes. Several glucosylat-
ed triazoles have been evaluated as GP inhibitors and additional structures are being considered in the
present study with the introduction of a substituent at the 5-position of the triazole ring. The 1,3-dipolar
cycloaddition of azide and alkyne using stoichiometric amounts of Cu(I) halides favored the formation of
the 5-halogenated 1,2,3-triazoles. The influence of the copper halide introduced (CuI, CuBr, or CuCl) pro-
vided different results and more specifically for the CuCl system which afforded a dimeric 5,50-bistriazole
in good yield (56%) as evidenced by crystallographic data.
Keywords:
1,3-Dipolar cycloaddition
1,2,3-Triazole
Atropoisomer
Click Chemistry
Catalysis
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
N
OH
O
N
OH
O
H
N
HO
HO
HO
HO
Ar
N
Ar
The design of glycogen phosphorylase (GP) inhibitors has at-
tracted a large interest over the past few years since this enzyme
is a potential target for the treatment of hyperglycemia for type
2 diabetic patients.1 GP is a homodimeric enzyme responsible for
the depolymerization of glycogen, the main source of glucose,
therefore releasing glucose in the blood stream and consequently
increasing glycemia. Several classes of glucose-based inhibitors
have been designed binding at the catalytic site of GP for a better
control of glycemia.2–4
OH
A
OH
B
O
Ki = 10 - 144 µM
Ki = 16 - 625 µM
Inhibition
of GP ?
?
N
N
Recently, Somsák et al.5,6 have demonstrated the inhibition of
GP with a series of acylated glucopyranosylamines A or 1-gluco-
pyranosyl 1,2,3-triazoles B with Ki values in the micromolar range
(Fig. 1). The introduction of hydrophobic aromatic moieties (Ar)
either acylating the glucopyranosylamine (A) or at the 4-position
of the triazole ring (B) was usually beneficial for enhanced inhibi-
tion of GP. The introduction of a second moiety (R) at the 5-posi-
tion of the triazole ring (C) might improve inhibitory properties
through additional interactions with the catalytic site of the
enzyme.
N
N
OH
O
OH
O
HO
HO
HO
HO
N
N
Ar
Ar
OH
Pd-catalyzed
OH
R
X
C-C couplings
C
D
X = I, Br, Cl
Figure 1. Strategy toward 5-halogenated 1,2,3-triazoles (D) for the design of
glucose-based GP inhibitors (C).
of these coupling reactions will provide a rapid access to a family
of potential GP inhibitors with a rather large variety of substituents
at the 5-position of the triazole moiety (aromatics, alkynes, or al-
kenes, respectively). The introduction of either an iodine, bromine,
or chlorine atom will be studied in order to analyze the scope of
the subsequent C–C coupling reactions, but also to evaluate the
influence of the halide ion associated to Cu(I) on the catalytic
1,3-dipolar cycloaddition process.
A general strategy toward such 1,4,5-trisubstituted triazoles C
involves the synthesis of the 5-halogenated triazole D as a precur-
sor for the subsequent C–C couplings under Pd-catalysis such as
Suzuki–Miyaura, Sonogashira, or Heck conditions. The diversity
⇑
Corresponding author. Tel.: +33 472 448 349; fax: +33 472 448 109.
E-mail address: sebastien.vidal@univ-lyon1.fr (S. Vidal).
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.08.014

80
D. Goyard et al. / Carbohydrate Research 362 (2012) 79–83
CH
N3
+
R1
C
R2
X
N
N
R2
N
R2
R1
R2
R1
R2
R1
R2
R1
E
R1
N
N
N
+
+
+
+
R2
R2
N
N
N
N
N
N
N
N
R1
A
B
C
D
N
N
N
N
Δ (not selective) Δ (not selective)
or
or
CuI cat.
RuI cat.
CuX stoichiometric
Figure 2. Azide–alkyne 1,3-dipolar cycloadditions under various conditions and their corresponding 1,2,3-triazoles.
Recently, the introduction of Cu(I) catalysts allowed for the reg-
structures D but also a 5-alkynylated derivative E resulting from
the coupling to a second alkyne moiety (Fig. 2).
ioselective synthesis of the 1,4-disubstituted 1,2,3-triazoles A in
high yields, in water and under catalytic conditions (Fig. 2).7–10
Consequently, these cycloadditions are certainly the most popular
reactions for the rapid and efficient access to a variety of heterocy-
clic structures.11,8 However, besides the triazoles expected from
Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC), different
types of byproducts have been identified (Fig. 2). This observation
has inspired a number of recent works aiming at a better
understanding of such an ‘apparently’ simple and popular reaction.
For example, the introduction of stoichiometric amounts of
Cu(I)–halides can lead to the formation of additional triazole
derivatives halogenated at the 5-position C or even dimeric
The cycloaddition of iodinated alkynes with azides afforded the
desired 5-iodinated triazoles C in good yields under Cu(I) catalysis
conditions12–17 while one report used a post-cycloaddition iodin-
ation methodology.18 Only three examples have been reported
for the synthesis of such 5-iodinated 1,2,3-triazoles from terminal
alkynes.19–21 Wu et al.21 have studied the cycloaddition of alkyl
and perfluoroalkyl azides with terminal alkynes and observed the
formation of the 5-iodinated derivative as the major product
of the reaction using stoichiometric amounts of CuI with sub-
stoichiometric amounts of ICl or I2 used as a source of electrophilic
iodine. More recently, Malnuit et al.19 reported a similar result and
N
N
OAc
O
AcO
AcO
N
Ph
OAc
2
X = I, Br
+
N
N
OAc
O
3a X = I
AcO
AcO
N
Ph
Ph
3b X = Br
3c X = Cl
Ph
OAc
CuX
OAc
O
X
DMAP
AcO
AcO
N3
MeCN
16h
rt
N
N
OAc
O
OAc
AcO
AcO
N
1
OAc
4 + 2 + 3c
X = Cl
+
Ph
N
N
OAc
O
AcO
AcO
N
Ph
AcO
OAc
O
AcO
OAc
Ph
N
OAc
5
N
N
Scheme 1. Azide–alkyne 1,3-dipolar cycloadditions using stoichiometric amounts of Cu(I)–halides and their corresponding 1,2,3-triazoles.

D. Goyard et al. / Carbohydrate Research 362 (2012) 79–83
81
Table 1
CuI, CuBr, and CuCl). Interestingly, the outcome of the 1,3-dipolar
cycloaddition and halogenation ‘one-pot’reactionswas not identical
for all three halogenated systems (Scheme 1), as compounds 4 (16%
yield) and 5 (56% yield) were only formed in the presence of CuCl.
The influence of the stoichiometry versus catalytic systems in
CuI was studied in a model reaction between phenyl acetylene
Influence of the CuI stoichiometry on the 1,3-dipolar cycloadditiona
CuI (equiv)
Conversionb (%)
Ratiob 2:3a
0.1
0.3
0.5
1.0
2.0
75
80
100
100
100
100:0
64:36
55:45
20:80
12:88
and 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl azide 1 in the pres-
ence of DMAP. Complete conversion was obtained when using at
least 0.5 equiv of CuI (Table 1, entry 3). Diluted alkyne solutions
(ꢀ25 mM final concentration in acetonitrile) were used thus
highlighting the critical role of concentration. Slow addition of
the alkynes was therefore required using a syringe pump over
16 h in order to maintain the highest dilution possible for the
alkyne species and to optimize the yield in 5-halogenated triazoles.
Formation of the 5-proto-triazole 2, as a single product without
any 5-iodinated triazole 3a was only possible when using 0.1 equiv
of CuI (Table 1). However, the presence of the iodinated derivative
3a could be detected using larger amounts of CuI (Tables 1 and 2,
entry 1) and reached a maximum for 2 equiv of CuI. The 1,3-dipolar
cycloaddition of phenyl acetylene and glycosyl azide 1 in the pres-
ence of an excess of Cu(I)–halide (2 equiv) and sub-stoichiometric
a
Conditions: RN3 1 (200 mg, 1 equiv), PhC„CH (2 equiv), DMAP (0.3 equiv).
b
Determined from 1H NMR analyses (see Supplementary data).
Table 2
Synthesis of halogenated triazoles and their derivativesa
CuX
Yieldb of 3 (%)
Yieldb of 4 (%)
Yieldb of 5 (%)
CuI
CuBr
CuCl
82
74
9d
0c
0c
0c
56
0c
16d
a
Conditions: RN3
(0.3 equiv).
1 (1 equiv), PhC„CH (2 equiv), CuX (2 equiv), DMAP
b
Isolated yields and the remaining were mainly composed of the 5-proto-tria-
zole 2.
c
Not detected.
(a)
d
Rf values were almost identical and a few fractions of pure compound 4 were
isolated by chromatography while the 5-chloro triazole 3c was always isolated as a
mixture with 4. Yields indicated were calculated from the isolated fractions and
proportions of 3c/4 were determined by 1H NMR to obtain the yield for 3c and a
cumulative yield for 4.
identified N-iodosuccinimide (NIS) as another source of electro-
philic iodine. Finally, a detailed study was reported in 2010 by
Smith et al.20 to identify the key parameters for the introduction
of an iodine atom at the 5-position of a 1,2,3-triazole ring. The con-
centration of alkyne was critical to reach high yields of the 5-iodin-
ated triazoles and N,N-dimethylaminopyridine (DMAP) was also
identified as the catalytic base (0.3 equiv) providing the best
results.
(b)
Alkynylation at the 5-position of the triazole ring was also re-
ported under Cu(I) catalysis to afford compounds E.22,23,13 Never-
theless, this outcome of the cycloaddition process was usually
marginal and did not afford the 5-alkynylated triazoles E as the
major compounds. The formation of bistriazoles D in which the
heteroaromatic rings are connected through their 5-position
carbon atom was also observed in recent reports24,25,22,26,23,27
and dimeric 5,50-bistriazoles D could be obtained as major com-
pounds24,26 and the pure diastereoisomers could also be readily
separated from the reaction mixture.24 The formation of such di-
meric species was dependent on the inorganic base used but also
temperature.24,26 Nevertheless, the 5,50-bistriazoles
D can be
converted into the corresponding 1,2,3-triazoles A in high yields
under basic and Cu(I) catalysis.26 Such atropoisomeric heteroaro-
matic 5,50-bistriazoles D can be of particular interest for funda-
mental studies28 as well as for the design and study of ligands
with applications in enantioselective transition metal catalyzed
reactions.29
(c)
N
N
OAc
O
AcO
AcO
N
Ph
2. Results and discussion
AcO
OAc
Ph
OAc
OAc
These reports have highlighted additional features of the CuAAC
process by mostly focusing on iodinated species while brominated
or chlorinated derivatives were not studied.23 In our ongoing pro-
gram on glycogen phosphorylase inhibitors,3 we have designed a
large series of glucosylated heterocyclic derivatives displaying
inhibitory properties toward this enzyme. We have observed the
selective formation of 5-halogenated 1,2,3-triazoles under smooth
conditions and using stoichiometric amounts of Cu(I)–halides (i.e.,
N
O
AcO
N
N
Figure 3. Crystallographic structure obtained for compound 5 (CCDC 867415). (a)
View from the axis following the C–C bond between the C-5 carbon atoms of the
1,2,3-triazoles. (b) Alternative view displaying the triazole rings in a different
rotation around the z axis. (c) Schematic representation of the stereochemistry for
the aR atropoisomer.

82
D. Goyard et al. / Carbohydrate Research 362 (2012) 79–83
DMAP (0.3 equiv) was also performed to prepare the 5-brominated
1,2,3,-triazoles 3b in good yields from the corresponding glucopyran-
osyl azide 1 with a portion of the 5-proto-1,2,3-triazole 2 (Table 2,
ꢀ20% yield). The introduction of a chlorine atom at the 5-position
of the 1,2,3-triazole ring proved more difficult and provided a differ-
ent set of cycloadducts (Table 2). Besides the expected 5-chlorinated
triazole 3c isolated in only 9% yield, the other compounds isolated
were the 5-alkynylated 1,2,3-triazole 4 (16%) and the dimeric bis-
triazole derivative 5 obtained as the major product (56%).
(0.027–0.54 mmol, 0.1–2 equiv), DMAP (58 mg, 0.80 mmol,
0.3 equiv), and CH3CN (50 mL). A solution of alkyne (5.36 mmol)
in CH3CN (10 mL) was added dropwise with a syringe pump over
16 h. The mixture was then concentrated under reduced pressure,
suspended in EtOAc, and filtered through celite. The 2/3a ratio and
conversion rate of azide 1 were determined according to 1H NMR
(CDCl3, 300 MHz) of the crude mixture (see Fig. S1).
4.3. 1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-4-phenyl-
The 1H and 13C NMR data recorded for compound 5 obtained
after silica gel column chromatography provided a single set of
signals for each proton and carbon of the molecule (see Supple-
mentary data), therefore indicating the presence of a single species
in the solution state. A molecular ion of m/z = 949.3057 was
observed for [M+H]+ by high resolution electrospray mass
spectrometry (ESI) therefore confirming the dimeric structure of
compound 5. The crystalline derivative 5 could be further analyzed
through X-ray crystallography (Fig. 3). A single atropoisomer
could be identified in the crystal structure with the aR
stereochemistry at the C-5–C-5 bond between the triazole rings.
1,2,3-triazole (2)
1H NMR (CDCl3, 400 MHz) d 8.00 (s, 1H, H-50), 7.82–7.85 (m, 2H,
H-Ar), 7.41–7.45 (m, 2H, H-Ar), 7.33–7.37 (m, 1H, H-Ar), 5.94 (d,
1H, J = 9.3 Hz, H-1), 5.53 (pdd, 1H, J = 9.4 Hz, H-2), 5.44 (pdd, 1H,
J = 9.4 Hz, H-3), 5.27 (pdd, 1H, J = 8.9 Hz, H-4), 4.33 (dd, 1H,
J = 12.6, 5.1 Hz, H-6a), 4.16 (dd, 1H, J = 12.6, 1.9 Hz, H-6b), 4.03
(ddd, 1H, J = 10.1, 5.0, 2.0 Hz, H-5), 2.08, 2.07, 2.04, 1.88 (4s, 12H,
acetyl); 13C NMR (CDCl3, 100 MHz) d 170.6, 170.1, 169.5, 169.1
(4C, C@O), 130.0 (C-40), 129.0 (2CH-Ar), 128.7 (CH-Ar), 126.0
(2CH-Ar), 117.8 (C-50), 85.9 (C-1), 75.3 (C-5), 72.9 (C-3), 70.3 (C-2),
67.9 (C-4), 61.7 (C-6), 20.8, 20.7, 20.7, 20.3 (4CH3, acetyl).
3. Conclusion
4.4. 1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-5-iodo-4-
phenyl-1,2,3-triazole 3a
As a conclusion, ‘Click Chemistry’ between alkynes and azides
(CuAAC) appears to be more than an efficient and reliable conjuga-
tion technique to provide 1,2,3-triazoles. While catalytic amounts
of copper halides provide specifically the 5-proto 1,2,3-triazoles,
the introduction of excess of CuX must be carefully controlled.
More specifically, a dimeric 5,50-bistriazole could be isolated as
the major compound (56% isolated yield) when using CuCl in ex-
cess (2 equiv) and DMAP and clearly identified by crystallography.
Applications of this synthetic methodology for the formation of 5-
halogenated 1,2,3-triazoles in high yields (>74%) and under smooth
conditions will be reported in due course for the design of potential
glycogen phosphorylase inhibitors through Pd-catalyzed C–C cou-
plings. The methodology reported herein appears as a valuable
(due to the class of molecules obtained), simple (no additives
required such as sources of iodine or Cu(I)–ligands), and efficient
(high yields and straightforward separation) one-step synthesis
of 5-halogenated 1,2,3-triazoles. The present study has revealed
that ‘Click Chemistry’ has not yet unveiled its complete potential.
A 500 mL round bottom flask was loaded with 2,3,4,6-tetra-O-b-
-glucopyranosyl azide 1 (1.00 g, 2.68 mmol, 1 equiv), CuI (1.020 g,
D
5.36 mmol, 2 equiv), DMAP (58 mg, 0.80 mmol, 0.3 equiv), and
CH3CN (200 mL). solution of phenylacetylene (587 L,
A
l
5.36 mmol, 2 equiv) in CH3CN (20 mL) was added dropwise with
a syringe pump over 16 h. The mixture was then concentrated un-
der reduced pressure, suspended in EtOAc, and filtered through
celite. The filtrate was concentrated under reduced pressure and
purified by silica gel chromatography (EtOAc/PE 3:7) to afford 3a
as a white powder (1.321 g, 2.20 mmol, 82%); Rf = 0.57 (EtOAc/PE
3:7); mp = 170–171 °C (CH2Cl2/PE); ½a D20
ꢂ
ꢁ27 (c 1.11, CH2Cl2); 1H
NMR (CDCl3, 400 MHz) d 7.93–7.95 (m, 2H, H-Ar), 7.45–7.49 (m,
2H, H-Ar), 7.40–7.43 (m, 1H, H-Ar), 6.13 (pdd, 1H, J = 9.4 Hz, H-2),
5.87 (d, 1H, J = 9.4 Hz, H-1), 5.46 (pdd, 1H, J = 9.5 Hz, H-3), 5.32
(pdd, 1H, J = 9.8 Hz, H-4), 4.29 (dd, 1H, J = 12.6, 5.0 Hz, H-6a),
4.22 (dd, 1H, J = 12.5, 2.3 Hz, H-6b), 4.04 (ddd, 1H, J = 10.1, 4.9,
2.3 Hz, H-5), 2.06, 2.06, 1.89 (4s, 12H, acetyl); 13C NMR (CDCl3,
100 MHz) d 170.7, 170.5, 169.4, 168.6 (4C, C@O), 150.6 (C-40),
129.6 (C-Ar), 129.1 (CH-Ar), 128.7 (2CH-Ar), 127.9 (2CH-Ar), 85.9
(C-1), 76.6 (C-50), 75.0 (C-5), 73.5 (C-3), 69.5 (C-2), 67.8 (C-4),
61.7 (C-6), 20.9, 20.7, 20.7, 20.5 (4CH3, acetyl); HRMS [ESI+] m/z
[M+Na]+ calcd for C22H24IN3NaO9 624.0449; found 624.0479.
4. Experimental section
4.1. General methods
All reagents and solvents used for syntheses were commercial
and used without further purification. NMR spectra were
recorded at 293 K using a 300 MHz, a 400 MHz, or a 500 MHz
spectrometer. Shifts are referenced relative to deuterated solvent
residual peaks. Low and high resolutions mass spectra were
recorded in the positive mode using a Bruker MicrOTOF-Q II XL
spectrometer. Thin-layer chromatography (TLC) was carried out
on aluminum sheets coated with silica gel 60 F254 (Merck).
TLC plates were inspected by UV light (k = 254 nm) and devel-
oped by treatment with a solution of 10% H2SO4 in EtOH/H2O
(1:1 v/v). Silica gel column chromatography was performed
4.5. 1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-5-bromo-4-
phenyl-1,2,3-triazole 3b
A 500 mL round bottom flask was loaded with 2,3,4,6-tetra-O-b-
-glucopyranosyl azide (1.00 g, 2.68 mmol, 1 equiv), CuBr
D
1
(769 mg, 5.36 mmol, 2 equiv), DMAP (58 mg, 0.80 mmol,
0.3 equiv), and CH3CN (200 mL). A solution of phenylacetylene
(587 lL, 5.36 mmol, 2 equiv) in CH3CN (20 mL) was added drop-
with silica gel Si 60 (40–63
measured using a Perkin Elmer polarimeter and values are given
in 10ꢁ1 deg cm2 gꢁ1
lm). Optical rotations were
wise with a syringe pump over 16 h. The mixture was then concen-
trated under reduced pressure, suspended in EtOAc, and filtered
through celite. The filtrate was concentrated under reduced pres-
sure and purified by silica gel chromatography (EtOAc/PE 3:7) to
afford 3b as a white powder (1.096 g, 1.98 mmol, 74%); Rf = 0.46
.
4.2. General procedure for the synthesis of 5-iodo triazole (3a)
and determination of 2/3a ratio
(EtOAc/PE 3:7); mp = 182–183 °C (CH2Cl2/PE); ½a D20
ꢁ34 (c 1,
ꢂ
CH2Cl2); 1H NMR (CDCl3, 400 MHz) d 7.97–7.99 (m, 2H, H-Ar),
7.45–7.49 (m, 2H, H-Ar), 7.39–7.43 (m, 1H, H-Ar), 6.07 (pdd, 1H,
J = 9.4 Hz, H-2), 5.86 (d, 1H, J = 9.5 Hz, H-1), 5.45 (pdd, 1H,
A 100 mL round bottom flask was loaded with 2,3,4,6-tetra-O-b-
D-glucopyranosyl azide 1 (100 mg, 0.27 mmol, 1 equiv), CuI

D. Goyard et al. / Carbohydrate Research 362 (2012) 79–83
83
J = 9.5 Hz, H-3), 5.31 (pdd, 1H, J = 9.8 Hz, H-4), 4.28 (dd, 1H, J = 12.6,
4.9 Hz, H-6a), 4.21 (dd, 1H, J = 12.6, 2.3 Hz, H-6b), 4.02 (ddd, 1H,
J = 10.0, 4.8, 2.4 Hz, H-5), 2.08, 2.08, 2.06, 1.89 (4s, 12H, acetyl);
13C NMR (CDCl3, 100 MHz) d 170.7, 170.4, 169.4, 168.6 (4C, C@O),
145.6 (C-40), 129.1 (CH-Ar), 129.0 (C-Ar), 128.8 (2CH-Ar), 127.2
(2CH-Ar), 108.6 (C-50), 84.8 (C-1), 75.1 (C-5), 73.4 (C-3), 69.2
(C-2), 67.7 (C-4), 61.7 (C-6), 20.8, 20.7, 20.7, 20.5 (4CH3, acetyl);
HRMS [ESI+] m/z [M+Na]+ calcd for C22H24BrN3NaO9 576.0588;
found 576.0578.
J = 9.4 Hz, H-1), 3.88 (dd, 1H, J = 12.7, 3.7 Hz, H-6a), 3.32 (ddd,
1H, J = 9.7, 3.5, 2.3 Hz, H-5), 3.14 (dd, 1H, J = 12.7, 2.0 Hz, H-6b),
1.97, 1.97, 1.95, 1.92 (4s, 12H, acetyl); 13C NMR (CDCl3, 100 MHz)
d 170.4, 170.3, 170.0, 168.3 (4C, C@O), 148.9 (C-40), 129.8 (CH-Ar),
129.1 (2CH-Ar), 128.2 (C-Ar), 126.8 (2CH-Ar), 120.0 (C-50), 83.8
(C-1), 75.1 (C-5), 73.6 (C-3), 69.2 (C-2), 66.8 (C-4), 60.4 (C-6);
HRMS [ESI+] m/z [M+H]+ calcd for C44H49N6O18 949.3098; found
949.3057.
Acknowledgments
4.6. Reaction of 2,3,4,6-tetra-O-b-D-glucopyranosyl azide 1 and
phenylacetylene using CuCl
Financial supports from CNRS, University Claude-Bernard Lyon
1 and the French Agence Nationale de la Recherche (ANR project
GPdia N° ANR-08-BLAN-0305) are gratefully acknowledged. Dr. F.
Albrieux, C. Duchamp, and N. Henriques are gratefully acknowl-
edged for mass spectrometry analyses. Dr. E. Jeanneau is gratefully
acknowledged for crystallographic studies.
A 500 mL round bottom flask was loaded with 2,3,4,6-tetra-O-b-
-glucopyranosyl azide (1.00 g, 2.68 mmol, 1 equiv), CuCl
D
1
(531 mg, 5.36 mmol, 2 equiv), DMAP (58 mg, 0.80 mmol,
0.3 equiv), and CH3CN (200 mL). A solution of phenylacetylene
(587 lL, 5.36 mmol, 2 equiv) in CH3CN (20 mL) was added drop-
wise with a syringe pump over 16 h. The mixture was then concen-
trated under reduced pressure, suspended in EtOAc, and filtered
through celite. The filtrate was concentrated under reduced pres-
sure and purified over silica gel chromatography using mixtures
of PE and EtOAc. TLC analysis (CH2Cl2/EtOAc 9:1) of the crude mix-
ture showed the formation of four different products which were
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2012.
08.014.
identified as 1-(2,3,4,6-tetra-O-acetyl-b-
phenylethynyl)-4-phenyl-1,2,3-triazole 4 (Rf = 0.49), 1-(2,3,4,6-tet-
ra-O-acetyl-b- -glucopyranosyl)-5-chloro-4-phenyl-1,2,3-triazole
3c (Rf = 0.49), 1-(2,3,4,6-tetra-O-acetyl-b- -glucopyranosyl)-4-
phenyl-1,2,3-triazole
(Rf = 0.27), and 1,10-di-(2,3,4,6-tetra-O-
acetyl-b-
-glucopyranosyl)-4,40-diphenyl-5,50-bis(1,2,3-triazole) 5
(Rf = 0.06). Product 3c could not be separated from compound 4
by silica gel chromatography and could only be characterized by
mass spectroscopy (m/z [M+Na]+ = 532.1). Yield for compound 3c
was determined according to 1H NMR (CDCl3, 300 MHz) of its
mixture with 4.
D-glucopyranosyl)-5-(2-
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D
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D
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phenylethynyl)-4-phenyl-1,2,3-triazole 4
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White foam (333 mg, 0.43 mmol, 16%); Rf = 0.24 (PE/EtOAc 7:3);
½
a 2D0
ꢂ
ꢁ21 (c 1, CH2Cl2); 1H NMR (CDCl3, 400 MHz) d 8.20 (d, 1H,
J = 7.6 Hz, H-Ar), 7.63–7.66 (m, 2H, H-Ar), 7.46–7.49 (m, 5H, H-Ar),
7.39 (t, 1H, J = 7.3 Hz, H-Ar), 6.12 (pdd, 1H, J = 9.4 Hz, H-2), 5.99
(d, 1H, J = 9.4 Hz, H-1), 5.47 (pdd, 1H, J = 9.5 Hz, H-3), 5.32
(pdd, 1H, J = 9.8 Hz, H-4), 4.30 (dd, 1H, J = 12.6, 4.8 Hz, H-6a), 4.19
(dd, 1H, J = 12.5, 1.7 Hz, H-6b), 4.04 (ddd, 1H, J = 9.9, 4.6, 1.8 Hz,
H-5), 2.07, 2.05, 1.90, 1.89 (4s, 12H, acetyl); 13C NMR (CDCl3,
100 MHz) d 170.7, 170.4, 169.4, 168.7 (4C, C@O), 131.8 (2CH-Ar),
130.2 (C-Ar), 129.8 (C-Ar), 129.1 (CH-Ar), 129.0 (2CH-Ar), 128.8
(2CH-Ar), 126.5 (2CH-Ar), 121.3 (CH-Ar), 103.4 (Csp), 85.1 (C-1),
75.1 (C-5), 74.8 (Csp), 73.4 (C-3), 69.4 (C-2), 67.7 (C-4), 61.7 (C-6),
20.7, 20.7, 20.6, 20.4 (4CH3, acetyl); HRMS [ESI+] m/z [M+Na]+ calcd
for C30H29N3NaO9 598.1796; found 598.1776.
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D
diphenyl-5,50-bis(1,2,3-triazole) 5
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White powder (712 mg, 0.75 mmol, 56%); Rf = 0.06 (EtOAc/PE
3:7); mp = 150–151 °C (CH2Cl2/PE); ½a D20
ꢂ
ꢁ54 (c 1.02, CH2Cl2); 1H
NMR (CDCl3, 400 MHz) d 7.59–7.61 (m, 2H, H-Ar), 7.27–7.32 (m,
3H, H-Ar), 6.00 (pdd, 1H, J = 9.3 Hz, H-2), 5.16 (pdd, 1H,
J = 9.6 Hz, H-4), 5.09 (pdd, 1H, J = 9.3 Hz, H-3), 5.07 (d, 1H,