Synthesis of variously coupled conjugates of d-glucose, 1,3,4-oxadiazole, and 1,2,3-triazole for inhibition of glycogen phosphorylase

Article abstract of DOI:10.1016/j.carres.2011.03.004

5-(O-Perbenzoylated-β-d-glucopyranosyl)tetrazole was obtained from O-perbenzoylated-β-d-glucopyranosyl cyanide by Bu₃SnN ₃ or Me₃SiN₃-Bu₂SnO. This tetrazole was transformed into 5-ethynyl- as well as 5-chloromethyl-2-(O-perbenzoylated- β-d-glucopyranosyl)-1,3,4-oxadiazoles by acylation with propiolic acid-DCC or chloroacetyl chloride, respectively. The chloromethyl oxadiazole gave the corresponding azidomethyl derivative on treatment with NaN₃. These compounds were reacted with several alkynes and azides under Cu(I) catalysed cycloaddition conditions to give, after removal of the protecting groups by the Zemple?n protocol, β-d-glucopyranosyl-1,3,4-oxadiazolyl-1,2,3- triazole, β-d-glucopyranosyl-1,2,3-triazolyl-1,3,4-oxadiazole, and β-d-glucopyranosyl-1,3,4-oxadiazolylmethyl-1,2,3-triazole type compounds. 5-Phenyltetrazole was also transformed under the above conditions into a series of aryl-1,3,4-oxadiazolyl-1,2,3-triazoles, aryl-1,2,3-triazolyl-1,3,4- oxadiazoles, and aryl-1,3,4-oxadiazolylmethyl-1,2,3-triazoles. The new compounds were assayed against rabbit muscle glycogen phosphorylase b and the best inhibitors had inhibition constants in the upper micromolar range (2-phenyl-5-[1-(β-d-glucopyranosyl)-1,2,3-triazol-4-yl]-1,3,4-oxadiazole 36: K_i = 854 μM, 2-(β-d-glucopyranosyl)-5-[1-(naphthalen-2- yl)-1,2,3-triazol-4-yl]-1,3,4-oxadiazole 47: K_i = 745 μM).

Full text of DOI:10.1016/j.carres.2011.03.004

Carbohydrate Research 346 (2011) 1427–1438
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of variously coupled conjugates of D-glucose, 1,3,4-oxadiazole,
and 1,2,3-triazole for inhibition of glycogen phosphorylase
a
a
a
a
a,
}
Sándor Kun , Gergo Z. Nagy , Marietta Tóth , Laura Czecze , Albert Nguyen Van Nhien
,
Tibor Docsa b, Pál Gergely c, Maria-Despoina Charavgi d, Paraskevi V. Skourti d,
Evangelia D. Chrysina d, Tamás Patonay a, , László Somsák
a,
⇑
⇑
a Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary
b Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences at the Department of Medical Chemistry, Medical and Health Science Centre,
University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
c Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
d The National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, 48 Vassileos Constantinou Avenue, 116 35 Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
5-(O-Perbenzoylated-b-D-glucopyranosyl)tetrazole was obtained from O-perbenzoylated-b-D-glucopyr-
Received 24 January 2011
Received in revised form 24 February 2011
Accepted 3 March 2011
anosyl cyanide by Bu3SnN3 or Me3SiN3–Bu2SnO. This tetrazole was transformed into 5-ethynyl- as well
as 5-chloromethyl-2-(O-perbenzoylated-b- -glucopyranosyl)-1,3,4-oxadiazoles by acylation with propi-
D
olic acid–DCC or chloroacetyl chloride, respectively. The chloromethyl oxadiazole gave the corresponding
azidomethyl derivative on treatment with NaN3. These compounds were reacted with several alkynes
and azides under Cu(I) catalysed cycloaddition conditions to give, after removal of the protecting
Available online 8 March 2011
Dedicated to Professor Dr. András Lipták on
the occasion of his 75th birthday
groups by the Zemplén protocol, b-
D-glucopyranosyl-1,3,4-oxadiazolyl-1,2,3-triazole, b-
D-glucopyrano-
syl-1,2,3-triazolyl-1,3,4-oxadiazole, and b-
D
-glucopyranosyl-1,3,4-oxadiazolylmethyl-1,2,3-triazole type
compounds. 5-Phenyltetrazole was also transformed under the above conditions into a series of aryl-
1,3,4-oxadiazolyl-1,2,3-triazoles, aryl-1,2,3-triazolyl-1,3,4-oxadiazoles, and aryl-1,3,4-oxadiazolylmeth-
yl-1,2,3-triazoles. The new compounds were assayed against rabbit muscle glycogen phosphorylase b
Keywords:
Azide–alkyne cycloaddition
Tetrazole
1,2,3-Triazole
1,3,4-Oxadiazole
b-D-Glucopyranosyl derivatives
Glycogen phosphorylase inhibitor
and the best inhibitors had inhibition constants in the upper micromolar range (2-phenyl-5-[1-(b-
copyranosyl)-1,2,3-triazol-4-yl]-1,3,4-oxadiazole 36: Ki = 854 M, 2-(b- -glucopyranosyl)-5-[1-(naph-
thalen-2-yl)-1,2,3-triazol-4-yl]-1,3,4-oxadiazole 47: Ki = 745 M).
Ó 2011 Elsevier Ltd. All rights reserved.
D-glu-
l
D
l
1. Introduction
aromatic compounds of various ring size and annelation type; clas-
sification of inhibitors binding to other sites such as the allosteric,
the new allosteric, and the storage sites is more complex and can
be found in the review literature.5,9
Glycogen phosphorylase (GP) has been a validated target in
combatting type 2 diabetes mellitus1 (for a detailed foundation of
inhibiting liver GP as an investigational concept for lowering blood
glucose levels, please consult recent review articles2–6). GP is a
well-known enzyme that has been investigated by various meth-
ods as to its structural features and kinetic behaviour.7,8 By X-ray
crystallographic studies on enzyme–inhibitor complexes several
binding sites of GP have been discovered and are exploited for
the design of new antidiabetic agents: the catalytic centre accom-
modates mainly glucose derivatives and the inhibitor site binds
Among the glucose-based10 inhibitors of GP, the first successful
series was that of the glucosylamides11–14 (Chart 1a, A). Consider-
ing the NHCO moiety as a linker (i) between the sugar and the aro-
matic part of these compounds several molecules with bioisosteric
replacements of the NHCO (see heterocyclic linkers ii–v) were de-
signed and synthesized. Kinetic and crystallographic studies
showed a very high resemblance both in strength and structural
features of binding between amides 1 and 2 and 1,2,3-triazolesà
3 and 4, respectively.16,17 Constitutional isomeric C-glucopyranosyl
oxadiazoles18,19 5–10 showed a strong preference for the 3-aryl-5-
b-D-glucopyranosyl-1,2,4-oxadiazoles 9 and 10 to exhibit the highest
affinity to GP. N-Acyl-N0-b-D-glucopyranosyl urea derivatives
⇑
Corresponding authors. Tel.: +36 52512900/22464; fax: +36 52512744 (T.P.);
tel.: +36 52512900/22348; fax: +36 52512744 (L.S.).
E-mail addresses: tpatonay@puma.unideb.hu (T. Patonay), somsak@tigris.uni-
deb.hu (L. Somsák).
à
Visiting scientist. Permanent address: Laboratoire des Glucides-UMR 6219,
Université de Picardie Jules Verne, Ilot des poulies, 10 rue Baudelocque, 80039
Amiens, France.
A very recent report15 indicated weak inhibition of GP by 1-b-D-glucopyranosyl-
1,2,3-triazole derivatives with coumarinyloxymethyl and other substituents in the 4-
position.
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.03.004

1428
S. Kun et al. / Carbohydrate Research 346 (2011) 1427–1438
a) Selected glucose analogue inhibitors of glycogen phosphorylase (GP) (Ki [μM] determined against rabbit
muscle GPb)
linker 1
linker
OH
linker 2
OH
H
N
O
H
N
H
N
HO
HO
O
R
HO
HO
R
R
HO
HO
O
O
O
A
B
R
linker
linker 1-2
i
– NHCO–
1
3
5
8111
2
4
6
1013
1316
NHCONHCO– 11 4.65
–
12 0.355
14412
ii
iii
15116
1616
N N
N
b) Target compounds
16217
3617
N
N
OH
10%
10%
at 625 μM19
at 625 μM19
O
HO
HO
linker 1 linker 2
R
O
HO
iv
v
7
9
10%
8
3818
N O
N
OH
at 625 μM18
O
HO
HO
linker 1 CH2 linker 2
R
HO
6419
10 2.419
O
N
where linker 1 and linker 2 = 1,2,3-triazole (linker ii) or
1,3,4-oxadiazole (linker iii)
N
Chart 1.
(Chart 1a, B) proved significantly better inhibitors than amides A
with the same aromatic part in the aglycon5,9 (compare inhibitor
constants for 1 and 11 as well as 2 and 12, respectively). Based on
the successful bioisosteric modification of amides A we have started
a program to synthesize a series of glucosyl heterocyclic compounds
(Chart 1b) which can be derived from acyl ureas B by substituting
each NHCO moiety by a heterocycle (linkers 1 and 2). In addition,
compounds with a methylene group between linkers 1 and 2 lending
higher flexibility to the molecules were also designed. In this paper
we present our results in synthesizing 1,2,3-triazole and 1,2,4-oxadi-
azole linked derivatives of D-glucose. With the aim of targeting the
inhibitor site of GP, compounds with aromatic rings in place of the
glucosyl groups were also synthesized.
glucopyranosyl tetrazole 17 was first prepared from 13 by the lit-
erature protocol20 using in situ obtained ammonium azide in DMF
at reflux (conditions a). To avoid chromatographic purification in
larger scale preparations, two other methods were investigated,
as well. Thus, reaction of 13 with Bu3SnN3 in 1,2-dimethoxyethane
at reflux (DME, conditions b) followed by acidic workup21 gave 17
in essentially quantitative yield. Another method, applying
Me3SiN3 and Bu2SnO (conditions c) for in situ generation of dibutyl
trimethylsilyloxytin azide22 was similarly efficient. Conditions a
afforded tetrazoles 18 and 20 from the corresponding nitriles 14
and 16 in good and excellent yields, respectively; however, reac-
tion of 15 to give the 1-naphthyl derivative 19 failed. The reaction
of 15 with Bu3SnN3 in boiling DME (conditions b) needed three
days to give 19, but using diglyme as a solvent of higher boiling
temperature diminished the reaction time to two hours with a con-
comitant increase of the yield.
2. Results and discussion
5-Substituted tetrazoles can be transformed into 1,3,4-oxadiaz-
oles by acylation.23,24 Although acid chlorides are generally used in
such acylations,25 the chloride of propiolic acid is rather difficult
to prepare and extremely sensitive to air. Therefore, the specific
2.1. Syntheses
Access to suitable precursors to assemble the target oxadiazoles
and triazoles is shown in Scheme 1. The O-perbenzoylated 5-b-D-
e
N
N
N
N
N
N
N N
f or g
NH
N
a or b or c
d
R
CN
R
Cl
N3
R
R
R
O
O
O
R
13
17
21
25
26
(f, 90%)
Bz4-β-D-Glcp
(a, 3.5 h, 94%)
(59%)
(96%)
(b, DME, 24 h, 99%)
(c, 19 h, 95%)
14 Ph
15 1-naphthyl
18 (a, 2 h, 69%)
22 (47%)
23 (58%)
27 (87%)
28 (g, 94%)
19 (a, 72 h, traces)
(b, DME, 72 h, 73%)
(b, diglyme, 2 h, 86%)
16
20
24
(51%)
2-naphthyl
(a, 2 h, 94%)
Scheme 1. Reaction conditions: (a) NaN3 (3 equiv), NH4Cl (3 equiv), dry DMF, reflux; (b) Bu3SnN3 (3 equiv), solvent, reflux; (c) Me3SiN3 (2 equiv), Bu2SnO (0.2 equiv), PhCH3,
80 °C; (d) HC„C–COOH (2 equiv), DCC (1 equiv), toluene, 80 °C, 2 h (reflux, 4 h in case of 21); (e) ClCH2COCl (1.1 equiv), PhCH3, reflux, 24 h; (f) NaN3 (1 equiv), dry DMF, 50 °C,
24 h; (g) NaN3 (3 equiv), 18-crown-6 (0.1 equiv), acetone, rt, 2 h.

S. Kun et al. / Carbohydrate Research 346 (2011) 1427–1438
1429
ethynyl-oxadiazoles 21–24 were prepared by DCC mediated reac-
tion19,26 of propiolic acid with the corresponding tetrazoles 17–
20 (conditions d) to give the target compounds in satisfactory
yields. Chloroacetyl chloride under conditions e, on the other hand,
furnished the chloromethyl-oxadiazoles 25 and 27 in excellent
yields. Replacement of the chloride by azide was effected by
NaN3 in DMF (conditions f) to give 26 or NaN3–18-crown-6 in ace-
tone (conditions g) to produce 28 in very high yields.
pyranosyl azide,31,32 respectively, and reactions of latter azide
with 22–24 gave very good yields of the respective 35, 39, and
43, too. In the absence of easily available 2-azidonaphthalene,
31 was obtained from 21 in a one pot, two-step reaction from
naphthalene-2-boronic acid under conditions b. O-Acyl protecting
groups were removed by the Zemplén protocol (conditions d) to
give test compounds 36, 40, 44, and 45–48 in very good to excel-
lent yields.
Ethynyl-oxadiazoles 21–24 were cyclized with several azides
under variants of the copper(I) catalysed azide–alkyne cycloaddi-
tion (CuAAC) conditions27–29 (Scheme 2). The triazole ring forma-
tion from 21 was similarly efficient by using phenyl azide
(conditions a) or by in situ generation of this reagent from the
corresponding commercial boronic acid30 (conditions b) to give
29. The reaction of 21 under conditions a gave high yields of 30
For the transformations of 2-aryl-5-ethynyl-1,3,4-oxadiazoles
22–24 to the corresponding triazoles (33, 37, 41 with phenyl azide,
34, 38, 42 with 2-azido-ethanol) addition of TMEDA to the reaction
mixtures (conditions c) proved advantageous and the compounds
were isolated in medium to good yields.
CuAAC reaction of 26 with phenylacetylene to give 49
(Scheme 3) was tried with the Cu(OTf)2–Cu system33 (conditions
a); however, conversion of the starting material was not complete
and 32 from 1-azidonaphthalene and O-peracetylated b-
D
-gluco-
OH
N
N
N
N
N
N
N
N
N
OH
N
N
O
HO
HO
HO
OH
OH
R1
N
O
R
R
O
O
O
HO
36 (99%), 40 (98%), 44 (98%)
21-24
45 (85%), 46 (91%), 47 (79%)
d
R1 N3
d
a or b or c
OH
N
N
N
N
N
N
R
N
N
N
N
OH
O
d
HO
HO
HO
OH
OH
R1
O
O
O
HO
29 (a 73%, b 68%)
30 (a 82%)
48 (93%)
R1
31 (b 77%)
32 (a 91%)
33 (c 81%)
34 (c 76%)
R
Ph
CH2CH2OH 1-naphthyl
2-naphthyl
Ac4 -β-D-Glcp
β
21 Bz4 - -D-Glcp
22 Ph
23 1-naphthyl
24 2-naphthyl
29
33
37
41
45
30
31
32
35
39
43
35 (a 87%)
37 (c 48%)
38 (c 75%)
39 (a 77%)
41 (c 45%)
42 (c 75%)
43 (a 74%)
34
38
42
46
36
40
44
47
Scheme 2. Reaction conditions: (a) R1N3 (1 equiv), CuSO4ꢀ5H2O (0.05 equiv), -ascorbic acid (0.15 equiv), CH2Cl2/water 1:1, 50 °C, 2 h; (b) (1) R1B(OH)2 (3 equiv), NaN3
L
(3 equiv), CuSO4ꢀ5H2O (0.3 equiv), MeOH, rt, 16 h; (2)
L
-ascorbic acid (1.5 equiv), 21 (1 equiv), CH2Cl2/water 1:1, 50 °C, 2 h; (c) R1N3 (1.2 equiv), CuSO4ꢀ5H2O (0.04 equiv), Na-
L
-ascorbate (0.16 equiv), TMEDA (0.08 equiv), tBuOH–water 1:2; (d) NaOMe (cat.), MeOH, rt.
Scheme 3. Reaction conditions: (a) R–C„CH (1 equiv), Cu(OTf)2 (0.03 equiv), Cu dust (0.03 equiv), CH2Cl2/water 1:1, 40 °C, 1 d; (b) R–C„CH (1 equiv), CuSO4ꢀ5H2O
(0.05 equiv), -ascorbate (0.04 equiv), TMEDA (0.08 equiv),
-ascorbate (0.16 equiv), tBuOH–water 1:2, rt 3 h (⁄ with 0.08 equiv TMEDA); (e) NaOMe
L
-ascorbic acid (0.15 equiv), CH2Cl2/water 1:1, 50 °C, 1 d; (c) R–C„CH (1.2 equiv), CuSO4ꢀ5H2O (0.01 equiv), Na-
L
tBuOH–water 1:2, rt 2 h; (d) R–C„CH (1.2 equiv), CuSO4ꢀ5H2O (0.04 equiv), Na-
(cat.), MeOH, rt; (f) NH3, MeOH, rt; (g) TBAF (0.6 equiv), dry THF, 70 °C, 5 h.
L

1430
S. Kun et al. / Carbohydrate Research 346 (2011) 1427–1438
in one day. Incomplete conversion was also observed in reactions
of 26 with ethyl propiolate and propargyl alcohol to give 50 and
51, respectively, when the more conventional CuSO4–L-ascorbic
respectively, were performed with higher catalyst loading
(conditions d) in some cases with added TMEDA. Removal of the
trimethylsilyl group from 56 was achieved by TBAF (conditions f)
to give 57 in quantitative yield.
acid reagent was used (conditions b). Triazoles 49–50 and azido-
methyl-oxadiazole 26 were deprotected by the Zemplén method
(conditions e) to give test compounds 59, 60, 62, and 63, respec-
tively, while carboxamido triazole 61 was obtained from 50 by
NH3 in MeOH (conditions f).
2-Azidomethyl-5-phenyl-1,3,4-oxadiazole 28 was reacted with
phenylacetylene to give triazole 52 with as few as 0.01 equiv of
Cu(I) in the presence of TMEDA (conditions c). Similar reactions
of 28 with ethyl propiolate, propargyl alcohol, 1,1-dimethyl-
prop-2-ynol, trimethylsilylacetylene, and 3-amino-phenylacety-
lene leading to the corresponding triazoles 52–56 and 58,
Each azide–alkyne cycloaddition was carried out under Cu(I)
catalyzed conditions for which formation of 1,4-disubstituted
1,2,3-triazoles with practically exclusive regioselectivity was
reported.27–29 The 1,4-substitution pattern was confirmed by the
carbon NMR spectra of the compounds exhibiting characteristic
resonances for C-4 (132–136 ppm in the sugar derivatives,
132–148 ppm for the aromatic compounds) and C-5 (120–
128 ppm for each type) in accordance with literature precedents
reporting significantly higher chemical shift values for the quater-
nary C-4 as compared to that of C-5.34–37
Table 1
Evaluation of the new compounds as inhibitors of rabbit muscle glycogen phosphorylase b (RMGPb) (Ki [
leads
l
M] unless otherwise stated) and comparison of inhibition to that of the
R
Entry
Others
11
OH
12
0.355
H
N
H
N
O
HO
HO
R
4.65
155
1
2
HO
O
O
36a
40b
44b
48a
OH
N
N
N
N N
O
OH
HO
HO
N
R
O
HO
O
854 17c
No inh.d
No inh.d
HO
HO
OH
19% at 1 mM
3
4
–CH2OH
1416
OH
N
15116
13616
1616
O
HO
HO
3
4
16217
3617
2617
N
R
HO
45a
31% at 1 mM
46a
47a
OH
N
N
N
N N
1318 86c
745 36c
O
HO
HO
N
R
O
O
HO
5
6
–CH3
21220
OH
N
10% at 625
l
V19
10% at 625
l
V19
10% at 625
l
V19
O
HO
HO
14540
R
5
6
63aꢁCH2N3
HO
40% at 1 mM
59b
60b –COOMe
OH
N
N
N N
N
No inh.e
No inh.e
O
HO
HO
61b
CH2
R
O
HO
–CONH2
No inh.d
62a –CH2OH
60% at 1 mM
33b
37b
41b
N
N
N
N
N
No inh.d
No inh.d
No inh.d
7
8
R
O
N
34b
38b
42b
N
N
N
N
No inh.d
No inh.d
No inh.d
R
HO
O
52b
53 –COOEt
54 –CH2OH
55 –CMe2OH
56 –SiMe3
N
N N
N
N
No inh.d
CH2
R
O
9
57 –H
b
each: No inh.d
a
b
c
Determined by the protocol described in Ref. 38.
Determined by the protocol in described in Ref. 12.
Calculated from the IC50 value by the Cheng–Prusoff equation:41 Ki = IC50/(1 + [S]/Km).
d
e
Tested concentration: 625
lM.
Tested concentration: 312.5
lM.

S. Kun et al. / Carbohydrate Research 346 (2011) 1427–1438
1431
2.2. Enzyme inhibition studies
for 1H/13C) and Varian UNITYINOVA 400 WB (400/100 MHz for
1H/13C) spectrometers. Chemical shifts are referenced to Me4Si as
the internal reference (1H) or the residual solvent signal (13C).
Thin-layer chromatography (TLC) was carried out on aluminium
sheets coated with Silica Gel 60 F254 (Merck). TLC plates were in-
spected by UV light (k = 254 nm) and after gentle heating for the
carbohydrate derivatives. Silica gel column chromatography was
The kinetic parameters of the synthesized molecules were
determined according to previously described enzymatic proto-
cols12,38 and the results are summarized in Table 1 showing also
the inhibitory efficiency of some reference compounds. Based on
the verified bioisosteric replacement of NHCO by 1,2,3-triazole
for the glycogen phosphorylase case by enzyme kinetic and X-
ray crystallographic investigations16 (cf. Chart 1a, 1–4), the pres-
ent study aimed at double replacement of the NHCONHCO moi-
eties in acyl urea derivatives (compounds in entry 1) by two five
membered heterocycles. Glucosyl-triazolyl-oxadiazoles (entry 2)
proved significantly weaker inhibitors both in comparison to
the acyl ureas (entry 1) and the glucosyl-triazoles in entry 3. This
might be partially attributed to the increased space required for
these molecules to get accommodated in the b-channel, a subsite
of the active site: while the phenyl derivative 36 showed weak
inhibition, compounds 40 and 44 with the naphthyl moieties
were no more active. The polar endgroup of 48 was also not
favourable for the binding as it was similarly experienced in a
series of glucosyl biuret derivatives.39 Glucosyl-oxadiazolyl-tria-
zoles (entry 4) with a reversed order of the heterocycles proved
similarly weak inhibitors as their counterparts in entry 2 and
also glucosyl-oxadiazoles in entry 5. In this latter series19 (entry
5) only the methyl derivative showed moderate inhibition,20,40
and any increase in the size of the side chain either by azide sub-
stitution in the methyl group as in 63 or appending a cycle to the
oxadiazole as in 5 and 6 proved detrimental for the binding.
Enhancing the flexibility of the aglycon (entry 6) by insertion
of a methylene bridge in between the oxadiazole and the triazole
as in compounds 59–62 did not strengthen binding to the en-
zyme. The heterocyclic compounds 33, 34, 37, 38, 41, 42, and
52–57 (entries 7–9) targeting the inhibitor site of GP proved also
inactive.
performed with silica gel Si 60 (40–63 lm) purchased from
Merck (Darmstadt, Germany). Organic solutions were dried over
anhydrous MgSO4, and concentrated at diminished pressure at
40–50 °C (water bath). 2-Azidoethanol was prepared according
to the literature.42 5-Substituted-tetrazoles 17,20 18,43 and 2043
were prepared by the Finnegan procedure44 from the correspond-
ing nitriles 13,45 15,46 and 16,47 respectively. 2-Chloromethyl-5-
phenyl-1,3,4-oxadiazole 27 was obtained by the literature
protocol.26
4.2. General procedure for the Zemplén deacylation
An O-peracylated compound (100 mg) was dissolved in dry
MeOH (1 mL) and a solution of NaOMe (1 M in MeOH) was added
to the solution in a catalytic amount. The reaction mixture was
kept at rt. When the reaction was complete (TLC, 7:3 CHCl3–MeOH)
the solution was neutralized with a cation exchange resin Amber-
lyst 15 (H+ form). Filtration and removal of the solvent resulted in
the corresponding deacylated sugar derivative, which, if necessary,
was purified by column chromatography.
4.3. General procedure for the synthesis of 5-substituted-
tetrazoles by using Bu3SnN3
A nitrile was dissolved in DME or diglyme and 3 equiv of
Bu3SnN3 were added. The mixture was stirred and heated at reflux
for the given time while the reaction was monitored by TLC (4:1
PhCH3–EtOAc) to indicate completion of the transformation. Then
it was cooled to rt and toluene and aq HCl (4 M solution) were
added and the mixture was stirred for 2 h. The precipitated product
was filtered, washed with water, and dried. The two phase filtrate
was separated, the organic phase was diluted by hexane to
precipitate a further crop of the product which was filtered and
dried.
3. Conclusion
Synthetic methods using tin azide derivatives adapted for the
synthesis of O-perbenzoylated 5-b-D-glucopyranosyl tetrazole
(17) gave the target compounds in almost quantitative yield. Acy-
lations of tetrazole 17 gave ethynyl- and azidomethyl-1,3,4-oxadi-
azoles (the latter via the chloromethyl compound) whose further
transformations under CuAAC conditions gave several variants of
4.3.1. 5-(20,30,40,60-Tetra-O-benzoyl-b-
D-glucopyranosyl)tetrazole
(17)
compounds containing a b-
1,3,4-oxadiazole and 1,2,3-triazole. By using similar chemistry a
series of compounds with aromatic rings replacing the b- -gluco-
D-glucopyranosyl moiety attached to
(i) Prepared by general procedure 4.3 from 1345 (4.0 g,
6.6 mmol) in diglyme (50 mL), reaction time 26 h. After the workup
the precipitate was washed with hot hexane to give 17 (4.24 g,
99%) as a white solid.
D
pyranosyl part was also prepared. Enzyme kinetic measurements
showed the new compounds to have weak or no inhibition towards
rabbit muscle glycogen phosphorylase b, with inhibition constants
for the best inhibitors in the upper micromolar range (36:
(ii) A solution of 1345 (1.00 g, 1.65 mmol), Me3SiN3 (434
lL,
3.3 mmol) and Bu2SnO (41 mg, 0.16 mmol) in dry toluene
(30 mL) was heated for 19 h at 80 °C. Toluene was removed under
reduced pressure, the residue was dissolved in MeOH and concen-
trated again. The residue was dissolved in EtOAc (15 mL), extracted
with satd aq NaHCO3 soln (2 ꢂ 15 mL). The combined organic
phases were dried, and then concentrated to a syrup that was trit-
urated in hexane to give 17 (1.02 g, 95%) as an amorphous white
solid.
Ki = 854 lM, 47: Ki = 745 lM). This might be attributed to the size
of the aglycon in these compounds that exceeds the otherwise
rather flexible space in the b-channel next to the catalytic site
of the enzyme in cases of the sugar derivatives, while the aromatic
compounds fit neither in the inhibitor nor in any other binding
site.
The material obtained by both methods had spectral character-
istics identical with the reported ones.20
4. Experimental
4.1. General methods
4.3.2. 5-(Naphthalen-1-yl)-tetrazole (19)
Prepared by general procedure 4.3 from compound 15 (3.68 g,
24 mmol) and Bu3SnN3 (19.8 mL, 24 g, 72 mmol) in diglyme
(70 mL). Reaction time 2 h. Product 19 (1.30 g, 86%) was obtained
as white crystals. Mp: 216–218 °C (lit.48 mp 165 °C). 1H NMR
(Me2SO-d6, 360 MHz) d (ppm): 7.65–7.75 (3H, m, H-30, H-70,
Melting points were measured in open capillary tubes or on a
Kofler hot-stage and are uncorrected. Optical rotations were deter-
mined on a Perkin–Elmer 241 polarimeter at room temperature.
NMR spectra were recorded with Bruker WP 360 SY (360/90 MHz

1432
S. Kun et al. / Carbohydrate Research 346 (2011) 1427–1438
H-80), 8.02 (1H, d, J = 7.1 Hz, H-20), 8.10 (1H, d, J = 7.7 Hz, H-40), 8.21
(1H, d, J = 8.2 Hz, H-60), 8.6 (1H, d, J = 8.1 Hz, H-90), 17.0 (1H, s, NH-
1). 13C NMR (DMSO-d6, 90 MHz) d (ppm): 121.9 (C-10), 125.6 (C-40),
125.8 (C-60), 127.2 (C-20), 128.2 (C-30), 128.9 (C-70), 129.1 (C-80),
130.4 (C-50), 131.9 (C-90), 133.8 (C-100), 165.3 (C-1). Anal. Calcd
for C11H8N4 (196.07): C, 67.34; H, 4.11; N, 28.55. Found: C,
67.16; H, 4.19; N, 28.48.
129.7 (C-50), 133.2 (C-90), 133.7 (C-10), 149.1 (C-2), 165.0 (C-5).
Anal. Calcd for C14H8N2O (220.06): C, 76.35; H, 3.66; N, 12.72.
Found: C, 76.43; H, 3.71; N, 12.79.
4.4.4. 2-Ethynyl-5-(naphthalen-2-yl)-1,3,4-oxadiazole (24)
Prepared by general procedure 4.4 from propiolic acid (3.57 g,
51 mmol), DCC (5.25 g, 25.5 mmol) in toluene (50 mL, then wash-
ing with 30 mL) and 20 (0.68 g, 3.4 mmol) in toluene (50 mL). Stir-
ring at 80 °C for 2 h. Column chromatography gave 24 (2.87 g, 51%)
as white crystals. Mp: 168.5–170.5 °C; 1H NMR (Me2SO-d6,
360 MHz) d (ppm): 5.4 (1H, s, C„CH), 7.67 (2H, m, H-70, H-80),
8.02–8.07 (4H, m, H-30, H-40, H-60, H-90), 8.64 (1H, s, H-10). 13C
NMR (Me2SO-d6 90 MHz) d (ppm): 67.4 C„CH), 90.3 (C„CH),
119.8 (C-20), 122.7 (C-30), 127.3 (C-40), 127.6 (C-60), 127.8 (C-90),
128.4 (C-10), 128.9 (C-70), 129.1 (C-80), 133.3 (C-50), 124.3 (C-100),
149.2 (C-2), 164.4 (C-5). Anal. Calcd for C14H8N2O (220.06): C,
76.35; H, 3.66; N, 12.72; Found: C, 76.45; H, 3.69; N, 12.80.
4.4. General procedure for the synthesis of 2-ethynyl-5-
substituted-1,3,4-oxadiazoles
Propiolic acid was dissolved in dry toluene and DCC was added.
The precipitated dicyclohexylurea (DCU) was filtered off and
washed with dry toluene. The combined filtrate was added to a
solution of a tetrazole 17–20 in dry toluene. This mixture was stir-
red at the given temperature. When the reaction was complete
(TLC 1:1 EtOAc–hexane for 21, 10:1 PhCH3–MeOH for 22–24) the
solvent was evaporated and the residue was purified by column
chromatography (eluent PhCH3 unless stated otherwise).
4.4.5. 2-(20,30,40,60-Tetra-O-benzoyl-b-
D-glucopyranosyl)-5-
chloromethyl-1,3,4-oxadiazole (25)
4.4.1. 2-(20,30,40,60-Tetra-O-benzoyl-b-
D-glucopyranosyl)-5-
Tetrazole 17 (15.00 g, 23.13 mmol) was dissolved in dry toluene
(300 mL), and chloroacetyl chloride (7.4 mL, 69.39 mmol) was
added. The reaction mixture was heated at reflux. After 2 h TLC
(1:1 EtOAc–hexane) indicated completion of the transformation.
The solvent was evaporated under reduced pressure and the resi-
due was dissolved in CH2Cl2 (50 mL) then washed with cold satd
NaHCO3 solution (3 ꢂ 15 mL), brine (20 mL), and water (20 mL).
The combined organic phase was dried, filtered, and evaporated
under reduced pressure to give 25 (15.54 g, 96%) as a yellow syrup.
The chromatographically uniform crude product was used for fur-
ther transformations. Rf = 0.82 (1:1 EtOAc–hexane); 1H NMR
(CDCl3, 360 MHz) d (ppm): 8.08–7.80 (10H, m, Ph), 7.54–7.20
(10H, m, Ph), 6.18 (1H, pt, J = 9.6, 9.5 Hz, H-20 or H-30 or H-40),
5.93 (1H, pt, J = 9.7 Hz, H-20 or H-30 or H-40), 5.90 (1H, pt,
ethynyl-1,3,4-oxadiazole (21)
Prepared by general procedure 4.4 from 17 (1 g, 1.57 mmol),
propiolic acid (220 mg, 3.14 mmol) and DCC (320 mg, 1.57 mmol)
in 14 mL abs toluene at reflux for 4 h. Column chromatography
(3:7 EtOAc–hexane) and crystallization from EtOH gave 21
(615 mg, 59%) as white crystals. Rf = 0.75 (1:1 EtOAc–hexane),
mp: 132–135 °C, [
a
]
D = ꢁ151 (c 0.18, CHCl3), 1H NMR (CDCl3,
360 MHz) d (ppm): 8.05–7.81 (8H, m Ar), 7.57–7.25 (12H, m, Ar),
6.09 (1H, t, J = 9.3, Hz, H-20 or H-30 or H-40), 5.87–5.81 (2H, m,
J = 9.3, 10.6 Hz, 2 of H-20 or H-30 or H-40), 5.22 (1H, d, J1 ,2 = 10.6 Hz,
0
0
H-10), 4.67 (1H, dd, J5 ,6 a = 2.6 Hz, J6 a,6 b = 11.9 Hz, H-60a), 4.52 (1H,
0
0
0
0
dd, J5 ,6 b = 5.3, J6 a,6 b = 11.9 Hz, H-60b), 4.35 (1H, ddd, J5 ,4 = 9.3 Hz,
0
0
0
0
0
0
J5 ,6 a = 2.6 Hz, J5 ,6 b = 5.3 Hz, H-50), 3.57 (1H, s, ethynyl-H). 13C
NMR (CDCl3, 90 MHz) d (ppm): 165.3, 165.1, 164.6, 164.4 (CO),
162.0, 150.0 (oxadiazole), 133.9–128.0 (Ar), 90.9 (C„CH), 75.1,
73.2, 70.4, 69.6, 68.6 (C-10–C-50), 66.7 (C„CH), 62.6 (C-60). Anal.
Calcd for C38H28N2O10 (672.65): C, 67.85; H, 4.20; N, 4.16; O,
23.79. Found: C, 67.78; H, 4.15; N, 4.10.
0
0
0
0
J = 9.7 Hz, H-20 or H-30 or H-40), 5.30 (1H, d, J1 ,2 = 10.0 Hz, H-10),
0
0
4.72–4.65 (3H, m, H-60a, CH2), 4.56 (1H, dd, J6 a, 6 b = 12.4 Hz, H-
0
0
60b), 4.43 (1H, m, J5 ,6 a = 2.9 Hz, J5 ,6 b = 5.2 Hz, J4 ,5 = 10.0 Hz, H-
50). 13C NMR (CDCl3, 90 MHz) d (ppm): 165.9, 165.5, 164.9, 164.7
(CO), 163.5, 162.4 (oxadiazole), 133.4–127.9 (Ar), 76.8, 73.2, 71.5,
70.3, 68.7 (C-10–C-50), 62.7 (C-60), 32.4 (CH2).
0
0
0
0
0
0
4.4.2. 2-Ethynyl-5-phenyl-1,3,4-oxadiazole (22)
Prepared by general procedure 4.4 from propiolic acid (3.81 g,
55 mmol), DCC (5.62 g, 27 mmol) in toluene (25 mL, then washing
with 25 mL) and 18 (4.00 g, 27 mmol) in toluene (100 mL). Stirring
at 80 °C for 1.5 h. Column chromatography gave 22 (2.50 g, 47%) as
white crystals. The compound is light sensitive therefore it must be
stored in a dark and cold place. Mp: 106–110 °C; 1H NMR (Me2SO-
d6, 360 MHz) d (ppm): 3.62 (1H, s, C„CH), 7.47–7.57 (3H, m, H-30,
H-40, H-50), 8.04 (2H, dd, J = 7.0 Hz, 1.6 Hz, H-20, H-60). 13C NMR
(Me2SO-d6, 90 MHz) d (ppm): 67.6 C„CH), 85.9 (C„CH), 122.9
(C-10), 127.1 (C-20, C-60), 129.1 (C-30, C-50), 132.3 (C-40), 149.4 (C-
2), 164.7 (C-5). Anal. Calcd for C10H6N2O (170.05): C, 70.58; H,
3.55; N, 16.46; Found: C, 70.46; H, 3.61; N, 16.51.
4.4.6. 2-(20,30,40,60-Tetra-O-benzoyl-b-
D-glucopyranosyl)-5-
azidomethyl-1,3,4-oxadiazole (26)
Oxadiazole 25 (15.54 g, 22.29 mmol) was dissolved in dry DMF
(40 mL), then NaN3 (5.80 g, 89.17 mmol) was added. The suspen-
sion was heated and stirred at 50 °C. After 2 h, TLC (1:3 EtOAc–
hexane) indicated completion of the transformation. The solvent
was evaporated under reduced pressure. The residue was diluted
with water (400 mL) and extracted with Et2O (3 ꢂ 70 mL), the
combined organic phase was washed with water (50 mL), dried,
filtered, and concentrated under reduced pressure to give 26
(13.60 g, 90%) as a yellow syrup. The chromatographically uniform
crude product was used for further transformations. Rf = 0.81 (1:1
EtOAc–hexane); 1H NMR (CDCl3, 360 MHz) d (ppm): 8.04–7.81
(10H, m, Ar), 7.58–7.25 (10H, m, Ar), 6.10 (1H, pt, J = 10.7, 9.3 Hz,
H-20 or H-30 or H-40), 5.84 (1H, pt, J = 10.5 Hz, H-20 or H-30 or
H-40), 5.81 (1H, pt, J = 9.4 Hz, H-20 or H-30 or H-40), 5.20 (1H, d,
4.4.3. 2-Ethynyl-5-(naphthalen-1-yl)-1,3,4-oxadiazole (23)
Prepared by general procedure 4.4 from propiolic acid (0.24 g,
3.4 mmol), DCC (0.72 g, 3.4 mmol) in toluene (10 mL, then washing
with 10 mL) and 19 (0.68 g, 3.4 mmol) in toluene (50 mL). Stirring
at 80 °C for 2 h. Column chromatography gave 23 (445 mg, 58%) as
yellow crystals. Mp: 168.5–170.5 °C; 1H NMR (Me2SO-d6,
360 MHz) d (ppm): 3.64 (1H, s, C„CH), 7.53–7.61 (2H, m, H-70,
H-80), 7.69 (1H, t, J = 7.2 Hz, J = 7.9, H-30), 7.91 (1H, d, J = 8.3 Hz,
H-20), 8.03 (1H, d, J = 8.3 Hz, H-40), 8.17 (1H, d, J = 7.2 Hz, H-60),
9.20 (1H, d, J = 8.6 Hz, H-90). 13C NMR (Me2SO-d6 90 MHz) d
(ppm): 67.7 C„CH), 86.1 (C„CH), 119.4 (C-100), 124.7 (C-20),
125.7 (C-70), 126.8 (C-80), 128.4 (C-30), 128.7 (C-40), 128.8 (C-60),
J1 ,2 = 10.7 Hz, H-10), 4.67 (1H, dd, J6 a,6 b = 12.2 Hz, J5 ,6 b = 2.8 Hz,
H-60b), 4.63–4.50 (3H, m, H-60a, CH2), 4.38–4.33 (1H, m, H-50).
13C NMR (CDCl3, 90 MHz) d (ppm): 166.0, 165.6, 165.1, 164.9
(CO), 163.1, 162.3 (oxadiazole), 133.6–128.1 (Ar), 77.1, 73.2, 71.8,
70.5, 68.8 (C-10–C-50), 62.8 (C-60), 44.1 (CH2).
0
0
0
0
0
0
4.4.7. 2-(Azidomethyl)-5-phenyl-1,3,4-oxadiazole (28)
A mixture of 2726 (6.00 g, 31 mmol), NaN3 (4.00 g, 93 mmol),
and 18-crown-6 (0.82 g, 10 mol %) in acetone (50 mL) was stirred

S. Kun et al. / Carbohydrate Research 346 (2011) 1427–1438
1433
at rt for 2 h. When the reaction was complete (TLC, 4:1 PhCH3–
EtOAc) the solids were filtered off. The solvent was evaporated
and the residue was purified by flash chromatography on alumin-
ium oxide (CH2Cl2) to give 28 (5.72 g, 94%) as white crystals. Mp:
66–68 °C (lit.49 mp: 72–73 °C); 1H NMR (Me2SO-d6, 360 MHz) d
(ppm): 3.91 (2H, s, CH2), 6.58–6.66 (3H, m, H-30, H-40, H-50), 6.99
(2H, dd, J = 8.6 Hz, 2.1 Hz, H-20, H-60). 13C NMR (Me2SO-d6
90 MHz) d (ppm): 43.5 CH2), 122.9 (C-10), 125.5 (C-20, C-60), 129.4
(C-30, C-50), 132.1 (C-40), 162.3 (C-2), 164.6 (C-5). Anal. Calcd for
C9H7N5O (201.07): C, 53.73; H, 3.51; N, 34.81. Found: C, 53.78; H,
3.62; N, 34.85.
(CO), 161.3, 159.2 (oxadiazole), 136.1–120.8 (Ar, triazole-C, tria-
zole-CH), 77.1, 73.5, 71.8, 70.5, 69.00 (C-10–C-50), 63.1 (C-60). Anal.
Calcd for C44H35N5O10 (791.76): C, 66.75; H, 4.20; N, 8.85; O, 20.21.
Found: C, 66.82; H, 4.15; N, 8.91.
(ii) Prepared by general procedure 4.5.2 from PhN3 (prepared
in situ from phenylboronic acid (27 mg, 0.22 mmol)) and 21 for
2 h. Column chromatography (3:7 EtOAc–hexane) and crystalliza-
tion from ethanol gave 29 (40 mg, 68%) as white crystals.
4.5.5. 2-(20,30,40,60-Tetra-O-benzoyl-b-
D-glucopyranosyl)-5-(1-
phenyl-1,2,3-triazol-4-yl)-1,3,4-oxadiazole (29)
(i) Prepared by general procedure 4.5.1 from 21 (150 mg,
0.22 mmol) and PhN3 for 2 h. Column chromatography (3:7
EtOAc–hexane) and crystallization from ethanol gave 29 (128 mg,
73%) as white crystals. Rf = 0.58 (1:1 EtOAc–hexane), mp: 137–
4.5. General procedures for the synthesis of 1,4-disubstituted-
1H-1,2,3-triazoles
4.5.1. In CH2Cl2–water mixtures with organic azides
Equimolar amounts of an alkyne and an azide were dissolved in
CH2Cl2 (7 mL/mmol alkyne). Water (the same volume as that of
140 °C, [
a]
D = ꢁ194 (c 0.16, CHCl3), 1H NMR (CDCl3, 360 MHz) d
(ppm): 8.65 (1H, s, triazole-H), 8.04–7.77 (10H, m, Ar), 7.58–7.28
(15H, m, Ar), 6.14 (1H, t, J = 9.3 Hz, H-20 or H-30 or H-40), 6.02
(1H, pt, J = 9.3, 10.5 Hz, H-20 or H-30 or H-40), 5.89 (1H, pt, J = 9.3,
CH2Cl2), CuSO4ꢀ5H2O (5 mol %),
L-ascorbic-acid (15 mol %) were
0
0
added and the mixture was stirred at 50 °C and monitored by
TLC (1:1 EtOAc–hexane). After disappearance of the starting mate-
rials (aromatic azide: 2–3 h, glucosyl azide: overnight) the reaction
mixture was diluted with water and CH2Cl2, the phases were sep-
arated, and the aqueous layer was washed with CH2Cl2 (2 ꢂ 10 mL/
mmol). The combined organic layer was dried, the solvent evapo-
rated, and the residue purified by column chromatography.
10.5 Hz, H-20 or H-30 or H-40), 5.33 (1H, d, J1 ,2 = 9.3 Hz, H-10),
4.69 (1H, dd, J6 a,6 b = 11.9 Hz, J5 ,6 a <1 Hz H-60a), 4.56 (1H, dd,
0
0
0
0
J6 a,6 b = 11.9 Hz, J5 ,6 b = 5.3 Hz, H-60b), 4.42 (1H, ddd, J <1 Hz, H-
50). 13C NMR (CDCl3, 90 MHz) d (ppm): 166.1, 165.7, 165.1, 164.9
(CO), 161.3, 159.2 (oxadiazole), 136.1–120.8 (Ar, triazole-C, tria-
zole-CH), 77.1, 73.5, 71.8, 70.5, 69.00 (C-10–C-50), 63.1 (C-60). Anal.
Calcd for C44H35N5O10 (791.76): C, 66.75; H, 4.20; N, 8.85; O, 20.21.
Found: C, 66.82; H, 4.15; N, 8.91.
0
0
0
0
4.5.2. In CH2Cl2–water mixtures with organic azides prepared
in situ from boronic acids
A boronic acid (1 equiv) and NaN3 (1.2 equiv) were dissolved in
MeOH (5 mL/mmol of boronic acid). CuSO4ꢀ5H2O (0.1 equiv) was
added and the mixture was stirred overnight at rt. CH2Cl2 and
water (10 mL of each/mmol of boronic acid), an alkyne (0.3 equiv)
4.5.6. 2-Phenyl-5-(1-phenyl-1H-1,2,3-triazol-4-yl)-1,3,4-
oxadiazole (33)
Prepared by general procedure 4.5.3 from 22 (171 mg, 1 mmol)
and PhN3 (100 mg, 0.84 mmol) in the presence of CuSO4ꢀ5H2O
(8 mg, 0.034 mmol), Na-L-ascorbate (27 mg, 0.13 mmol), and
and
L
-ascorbic acid (0.5 equiv) were added and the reaction mix-
TMEDA (10
to give 33 (197 mg, 81%) as pale yellow crystals. Mp: 201–202 °C;
1H NMR (Me2SO-d6, 360 MHz)
(ppm): 7.56–7.63 (6H, m,
lL, 0.07 mmol) in 6 mL solvent mixture at rt for 24 h
ture was heated to 50 °C. After consumption of the alkyne (TLC
1:1 EtOAc–hexane) the reaction mixture was diluted with water
and CH2Cl2, the phases were separated and the aqueous layer
was washed with CH2Cl2 (2 ꢂ 10 mL/mmol). The combined organic
layer was dried, the solvent evaporated, and the residue purified by
column chromatography.
d
H-300-500, H-3000-5000), 7.84 (2H, d, J = 7.7 Hz, H-200, H-600), 8.22 (2H, d,
J = 7.9 H-2000, H-6000), 8.76 (1H, s, H-50). 13C NMR (Me2SO-d6,
90 MHz) d (ppm): 119.1 (C-3000, C-5000), 121.6 (C-1000), 125.3 C-2000,
C-6000), 128.0 (C-50), 128.1 (C-300, C-500), 128.6 (C-200, C-600, C-4000),
130.8 (C-400), 132.2 (C-100), 134.6 (C-40), 156.3 (C-5), 162.4 (C-2).
Anal. Calcd for C16H11N5O (289.10): C, 66.43; H, 3.83; N, 24.21.
Found: C, 66.51; H, 3.91; N, 24.29.
4.5.3. In t-BuOH–water mixtures
Near equimolar amounts of an alkyne and an azide, catalytic
amount (1–4 mol %) of CuSO4ꢀ5H2O, Na-
L-ascorbate, and TMEDA
were placed in a 1:2 mixture of t-BuOH and water. The reaction
mixture was stirred at the given temperature for the indicated
time. When TLC (4:1 PhCH3–EtOAc) indicated complete transfor-
mation of the starting materials the precipitate was filtered off
and washed with water and then with hexane. Further purification,
if necessary, was performed by flash chromatography (4:1 PhCH3–
EtOAc).
4.5.7. 2-(4-(5-Phenyl-1,3,4-oxadiazol-2-yl)-1H-1,2,3-triazol-1-
yl)ethanol (34)
Prepared by general procedure 4.5.3 from 22 (235 mg,
1.38 mmol) and 2-azidoethanol (100 mg, 1.15 mmol) in the pres-
ence of CuSO4ꢀ5H2O (12 mg, 0.046 mmol), Na-
L-ascorbate (36 mg,
0.18 mmol), and TMEDA (14 L, 0.10 mmol) in 10 mL solvent mix-
l
ture at rt for 24 h to give 34 (270 mg, 76%) as pale yellow crystals.
Mp: 176–178 °C; 1H NMR (Me2SO-d6, 360 MHz) d (ppm): 3.88 (2H,
d, J = 4.0 Hz, N-CH2), 4.57 (2H, br s, CH2–OH), 5.13 (1H, s, OH), 7.66
(3H, br s, H-300, H-400, H-500), 8.11 (2H, d, J = 4.7 Hz, H-200, H-600), 9.00
(1H, s, H-50). 13C NMR (Me2SO-d6, 90 MHz) d (ppm): 52.7 N-CH2),
59.5 (CH2–OH), 123.0 (C-100), 126.5 (C-200, C-600), 126.8 (C-50),
129.4 (C-300, C-500), 132.1 (C-100), 132.3 (C-40), 158.1 (C-5), 163.6
(C-2). Anal. Calcd for C12H11N5O2 (257.09): C, 56.03; H, 4.31; N,
27.22. Found: C, 56.12; H, 4.35; N, 27.28.
4.5.4. 2-(20,30,40,60-Tetra-O-benzoyl-b-
D-glucopyranosyl)-5-(1-
phenyl-1,2,3-triazol-4-yl)-1,3,4-oxadiazole (29)
(i) Prepared by general procedure 4.5.1 from 21 (150 mg,
0.22 mmol) and PhN3 for 2 h. Column chromatography (3:7
EtOAc–hexane) and crystallization from ethanol gave 29 (128 mg,
73%) as white crystals. Rf = 0.58 (1:1 EtOAc–hexane), mp: 137–
140 °C, [
a
]
D = ꢁ194 (c 0.16, CHCl3), 1H NMR (CDCl3, 360 MHz) d
(ppm): 8.65 (1H, s, triazole-H), 8.04–7.77 (10H, m, Ar), 7.58–7.28
(15H, m, Ar), 6.14 (1H, t, J = 9.3 Hz, H-20 or H-30 or H-40), 6.02
(1H, pt, J = 9.3, 10.5 Hz, H-20 or H-30 or H-40), 5.89 (1H, pt, J = 9.3,
4.5.8. 2-Phenyl-5-[1-(20,30,40,60-tetra-O-acetyl-b-
D-
glucopyranosyl)-1,2,3-triazol-4-yl]-1,3,4-oxadiazole (35)
10.5 Hz, H-20 or H-30 or H-40), 5.33 (1H, d, J1 ,2 = 9.3 Hz, H-10),
Prepared by general procedure 4.5.1 from 2,3,4,6-tetra-O-acet-
0
0
4.69 (1H, dd, J6 a,6 b = 11.9 Hz, J5 ,6 a <1 Hz H-60a), 4.56 (1H, dd,
yl-b-D
-glucopyranosyl-azide31,32 (300 mg, 0.80 mmol) and 22 for
0
0
0
0
J6 a,6 b = 11.9 Hz, J5 ,6 b = 5.3 Hz, H-60b), 4.42 (1H, ddd, J <1 Hz, H-
50). 13C NMR (CDCl3, 90 MHz) d (ppm): 166.1, 165.7, 165.1, 164.9
28 h. Column chromatography (1:1 EtOAc–hexane) gave 35 (360 mg,
87%) as a white amorphous solid. Rf = 0.24 (1:1 EtOAc–hexane),
0
0
0
0

1434
S. Kun et al. / Carbohydrate Research 346 (2011) 1427–1438
[
a
]
D = ꢁ139 (c 0.17, CHCl3); 1H NMR (CDCl3, 360 MHz) d (ppm):
4.5.12. 2-(Naphthalen-1-yl)-5-[1-(20,30,40,60-tetra-O-acetyl-b-
D-
glucopyranosyl)-1,2,3-triazol-4-yl]-1,3,4-oxadiazole (39)
8.68 (1H, s, triazole-H), 8.19 (2H, d, J = 6.6 Hz, Ar), 7.58–7.52 (3H,
m, Ar), 6.03 (1H, d, J1 ,2 = 8.8 Hz, H-10), 5.52–5.50 (2H, m, 2 of H-
Prepared by general procedure 4.5.1 from 2,3,4,6-tetra-O-acet-
0
0
20 or H-30 or H-40), 5.32 (1H, pt, J = 9.7, 9.5 Hz, H-20 or H-30 or H-
yl-b-
D
-glucopyranosyl-azide31,32 (300 mg, 0.80 mmol) and 23 for
40), 4.35 (1H, dd, J5 ,6 a = 4.9 Hz, J6 a,6 b = 12.6 Hz, H-60a), 4.21 (1H,
16 h. Crystallization from EtOH gave 39 (365 mg, 77%) as white
crystals. Rf = 0.38 (1:1 EtOAc–hexane), mp: 181–182 °C,
0
0
0
0
dd, J5 ,6 b 1.3 Hz, J6 a,6 b = 12.6 Hz, H-60b) 4.10 (1H, ddd, J5 ,6 b
0
0
0
0
0
0
1.3 Hz, J5 ,6 a = 4.9 Hz, J5 ,4 = 9.7 Hz, H-50), 2.11, 2.10, 2.05, 1.92
(12H, 4s, CH3). 13C NMR (CDCl3, 90 MHz) d (ppm): 170.4, 169.8,
169.3, 168.9 (CO), 164.8, 157.6 (oxadiazole), 134.6 (triazole-C),
132.0, 129.1, 127.2, 123.3 (Ar), 123.2 (triazole-CH), 86.0, 75.4,
72.3, 70.5, 67.5 (C-10–C-50), 61.4 (C-60), 20.6, 20.5, 20.4, 20.0
(CH3). Anal. Calcd for C24H25N5O10 (543.16): C, 53.04; H, 4.64; N,
12.89; O, 29.44. Found: C, 53.00; H, 4.61; N, 12.81.
[a]
D = ꢁ140 (c 0.21, CHCl3); 1H NMR (CDCl3, 360 MHz) d (ppm):
0
0
0
0
9.29 (1H, d, J = 8.6 Hz, Ar), 8.76 (1H, s, triazole-CH), 8.31 (1H, d,
J = 7.2 Hz, Ar), 8.02 (1H, d, J = 8.2 Hz, Ar), 7.91 (1H, d, J = 8.1 Hz,
Ar), 7.70 (1H, pt, J = 7.8, 7.5 Hz Ar), 7.58 (2H, m, Ar), 6.10 (1H, d,
J1 ,2 = 7.9 Hz, H-10), 5.59–5.50 (2H, m, 2 of H-20 or H-30 or H-40),
0
0
5.35 (1H, pt, J = 9.6, 9.4 Hz, H-20 or H-30 or H-40), 4.37 (1H, dd,
J5 ,6 a = 5.0 Hz, J6 a,6 b = 12.7 Hz, H-60a), 4.22 (1H, dd, J6 a,6 b = 12.6 Hz,
0
0
0
0
0
0
J5 ,6 b = 1.6 Hz, H-60b), 4.14 (1H, ddd, J5 ,6 b = 1.6 Hz, J5 ,6 a = 4.9 Hz,
0
0
0
0
0
0
4.5.9. 2-Phenyl-5-[1-(b-D-glucopyranosyl)-1,2,3-triazol-4-yl]-
J4 ,5 = 9.9 Hz, H-50), 2.11, 2.10, 2.06, 1.94 (12H, 4s, CH3). 13C NMR
(CDCl3, 90 MHz) d (ppm): 170.4, 169.8, 169.2, 168.8 (CO), 164.6,
157.1 (oxadiazole), 134.6, 133.7, 132.8, 129.9, 128.7, 128.6, 128.2,
126.3, 126.0, 124.8, 123.5, 119.7 (Ar, triazole-C, triazole-CH),
85.9, 75.2, 72.2, 70.5, 67.5 (C-10–C-50), 61.3 (C-60), 20.6, 20.5, 20.4,
20.0 (CH3). Anal. Calcd for C28H27N5O10 (593.18): C, 56.66; H,
4.59; N, 11.80; O, 26.96. Found: C, 56.58; H, 4.53; N, 11.77.
0
0
1,3,4-oxadiazole (36)
Prepared by general procedure 4.2 from 35 (146 mg,
0.27 mmol) for 17 h. Filtration of the reaction mixture gave 36
(100 mg, 99%) as a white solid. Rf = 0.60 (7:3 CHCl3–MeOH),
[
a
]
D = ꢁ23 (c 0.19, Me2SO); 1H NMR (Me2SO-d6, 360 MHz) d
(ppm): 9.32 (1H, s, triazole-CH), 8.09 (m, 2H, Ar), 7.64 (m, 3H,
Ar), 5.69 (1H, d, J1 ,2 = 7.9 Hz, H-10), 3.87 (1H, pt, J = 7.9, 9.3 Hz,
0
0
H-20 or H-30 or H-40), 3.72 (1H, dd, J6 a,6 b = 10.6, J5 ,6 a <1 Hz, H-
60a), 3.48 (3H, m, H-20 or H-30 or H-40, H-50, H-60b), 3.30 (1H, t,
J = 7.9 Hz, H-20 or H-30 or H-40). 13C NMR (Me2SO-d6, 90 MHz) d
(ppm): 163.7, 157.9 (oxadiazole), 132.7 (triazole-C), 132.6, 132.1,
129.4, 126.6, 123.1 (Ar, triazole-CH), 88.11, 80.12, 76.83, 72.27,
69.50 (C-10–C-50), 60.73 (C-60). Anal. Calcd for C16H17N5O6
(375.12): C, 51.20; H, 4.57; N, 18.66; O, 25.58. Found: C, 51.25;
H, 4.55; N, 18.68.
4.5.13. 2-(Naphthalen-1-yl)-5-[1-(b-
D
-glucopyranosyl)-1,2,3-
0
0
0
0
triazol-4-yl]-1,3,4-oxadiazole (40)
Prepared by general procedure 4.2 from 39 (202 mg,
0.34 mmol) for 4 h. Filtration of the reaction mixture gave 40
(142 mg, 98%) as a white amorphous solid. Rf = 0.50 (7:3 CHCl3–
MeOH), [
a
]
D = ꢁ8 (c 0.18, Me2SO); 1H NMR (Me2SO-d6, 360 MHz)
d (ppm): 9.42 (1H, s, triazole-CH), 9.16 (1H, d, J = 8.6 Hz, Ar), 8.33
(1H, d, J = 7.3 Hz, Ar), 8.24 (1H, d, J = 8.2 Hz, Ar), 8.11 (1H, d,
0
0
J = 8.1 Hz, Ar), 7.80–7.67 (3H, m, Ar), 5.75 (1H, d, J1 ,2 = 9.2 Hz, H-
4.5.10. 2-(Naphthalen-1-yl)-5-(1-phenyl-1H-1,2,3-triazol-4-yl)-
1,3,4-oxadiazole (37)
Prepared by general procedure 4.5.3 from 23 (185 mg,
0.84 mmol) and PhN3 (100 mg, 0.84 mmol) in the presence of Cu-
10), 3.91 (1H, pt, J = 9.0, 9.1 Hz H-20 or H-30 or H-40), 3.75 (1H, dd,
J6 a,6 b = 10.7 Hz, J5 ,6 a <0 Hz, H-60a), 3.57–3.44 (3H, m, H-20 or H-
30 or H-40, H-50, H-60b), 3.32 (1H, pt, J = 9.0, 8.9 Hz, H-20 or H-30 or
H-40). 13C NMR (Me2SO-d6, 90 MHz) d (ppm): 163.6, 157.5 (oxadi-
azole), 133.4, 132.8, 132.7, 129.1, 128.9, 128.8, 128.3, 126.9,
126.0, 125.4, 125.3, 119.4 (Ar, triazole-C, triazole-CH), 87.9, 80.1,
76.6, 72.2, 69.4 (C-10–C-50), 60.7 (C-60). Anal. Calcd for
0
0
0
0
SO4ꢀ5H2O (8 mg, 0.034 mmol), Na-
L-ascorbate (27 mg, 0.13 mmol),
and TMEDA (10 L, 0.07 mmol) in 10 mL solvent mixture at 50 °C
l
for 168 h to give 37 (135 mg, 48%) as orange crystals. Mp: 186–
188 °C; 1H NMR (Me2SO-d6, 360 MHz) d (ppm): 7.50–7.61 (5H,
m, H-200–H-600), 7.69 (1H, t, J = 8.3 Hz, J = 7,2 Hz, H-3000), 7.82 (2H,
d, J = 7.9 Hz, H-7000, H-8000), 7.92 (1H, d, J = 7.9 Hz, H-2000), 8.04 (1H,
d, J = 8.3 Hz, H-4000), 8.37 (1H, d, J = 7.2 Hz, H-6000), 8.79 (1H, s, H-
50), 9.32 (1H, d, J = 8.6 Hz, H-9000-H). 13C NMR (Me2SO-d6, 90 MHz)
d (ppm): 119.8 C-100), 120.8 (C-300–C-500), 122.6 (C-50), 124.9 –
132.9 (C-200,C-600, C-2000–C-4000, C-6000–C-9000) 132.8 (C-5000, C-10000),
133.7(C-1000), 134.5 (C-100), 136.2 (C-40), 157.4 (C-2), 164.7 (C-5).
Anal. Calcd for C20H13N5O (339.11): C, 70.79; H, 3.86; N, 20.64.
Found: C, 70.85; H, 3.80; N.
C20H19N5O6 (425.13): C, 56.47; H, 4.50; N, 16.46; O, 22.57. Found:
C, 56.46; H, 4.54; N, 16.52.
4.5.14. 2-(Naphthalen-2-yl)-5-(1-phenyl-1H-1,2,3-triazol-4-yl)-
1,3,4-oxadiazole (41)
Prepared by general procedure 4.5.3 from 24 (185 mg,
0.84 mmol) and PhN3 (100 mg, 0.84 mmol) in the presence of Cu-
SO4ꢀ5H2O (8 mg, 0.034 mmol), Na-
L-ascorbate (27 mg, 0.13 mmol),
and TMEDA (10 L, 0.07 mmol) in 10 mL solvent mixture at 50 °C
l
for 168 h to give 41 (127 mg, 45%) as pale yellow crystals. Mp:
223–225 °C; 1H NMR (Me2SO-d6, 360 MHz) d (ppm): 7.59 (1H, t,
J = 6.5 Hz, J = 6,8 Hz, H-400), 7.60–7.71 (4H, m, H-300, H-500, H-6000, H-
7000), 8.06–8.08 (3H, m, H-2000, H-200, H-600), 8.18–8.21 (3H, m, H-3000,
H-7000, H-8000), 8.74 (1H, s, H-9000), 9.83 (1H, s, H-50). 13C NMR
(Me2SO-d6, 90 MHz) d (ppm): 120.5 C-100), 120.8 (C-200, C-600),
123.2 (C-50), 127.1–130.0 (C-300–C-500, C-2000, C-3000, C-5000–C-8000, C-
10000), 132.8 (C-1000), 134.6 (C-9000), 134.8 (C-4000), 136.2 (C-40), 157.9
(C-5), 165.0 (C-2). Anal. Calcd for C20H13N5O (339.11): C, 70.79;
H, 3.86; N, 20.64. Found: C, 70.87; H, 3.81; N, 20.65.
4.5.11. 2-{4-[5-(Naphthalen-1-yl)-1,3,4-oxadiazol-2-yl]-1H-
1,2,3-triazol-1-yl}ethanol (38)
Prepared by general procedure 4.5.3 from 23 (202 mg,
0.92 mmol) and 2-azidoethanol (80 mg, 0.92 mmol) in the pres-
ence of CuSO4ꢀ5H2O (9 mg, 0.037 mmol), Na-
L-ascorbate (29 mg,
0.15 mmol), and TMEDA (14 L, 0.10 mmol) in 10 mL solvent mix-
l
ture at rt for 29 h then then at 50 °C for 16 h to give 34 (243 mg,
76%) as white crystals. Mp: 198–199 °C; 1H NMR (Me2SO-d6,
360 MHz) d (ppm): 3.90 (2H, d, J = 4,7 Hz, N-CH2), 4.59 (2H, t,
J = 4,7 Hz, CH2–OH), 5.17 (1H, t, J = 5.0, OH), 7.68–7.81 (3H, m, H-
300, H-700, H-800), 8.13 (1H, d, J = 7.6 Hz, H-200), 8.26 (1H, d,
J = 8,3 Hz, H-400), 8.33 (1H, d, J = 7.2 Hz, H-600), 9.07 (1H, s, H-50),
9.16 (1H, d, J = 8.3 Hz, H-900). 13C NMR (Me2SO-d6, 90 MHz) d
(ppm): 52.7 N-CH2), 59.5 (CH2–OH), 119.3 (C-100), 125.3–132.7 (C-
50, C-200–C-400, C-600–C-800) 132.7 (C-1000), 133.1 (C-900), 133.8 (C-40),
157.6 (C-5), 163.4 (C-2). Anal. Calcd for C16H13N5O2 (307.11): C,
62.53; H, 4.26; N, 22.79. Found: C, 62.41; H, 4.24; N, 22.72.
4.5.15. 2-{4-[5-(Naphthalen-2-yl)-1,3,4-oxadiazol-2-yl]-1H-
1,2,3-triazol-1-yl}ethanol (42)
Prepared by general procedure 4.5.3 from 24 (303 mg,
1.38 mmol) and 2-azidoethanol (100 mg, 1.15 mmol) in the pres-
ence of CuSO4ꢀ5H2O (12 mg, 0.046 mmol), Na-
L-ascorbate (36 mg,
0.18 mmol), and TMEDA (14 L, 0.10 mmol) in 10 mL solvent mix-
l
ture at rt for 5 d then at 50 °C for 1 d to give 42 (423 mg, 76%) as
pale yellow crystals. Mp: 195–198 °C; 1H NMR (Me2SO-d6,

S. Kun et al. / Carbohydrate Research 346 (2011) 1427–1438
1435
360 MHz) d (ppm): 3.90 (2H, d, J = 4,0 Hz, N-CH2), 4.59 (2H, br s,
CH2–OH), 5.16 (1H, s, OH), 7.68 (2H, br s, H-600, H-700), 8.06 (1H,
d, J = 5.4 Hz, H-200), 8.17 (3H, br s, H-300, H-500, H-800), 8.72 (1H, s,
H-1000), 9.04 (1H, s, H-50). 13C NMR (Me2SO-d6, 90 MHz) d (ppm):
52.7 N-CH2), 59.5 (CH2–OH), 120.3 (C-100), 122.7 (C-50), 127.0–
129.2 (C-200, C-300, C-500–C-800, C-1000), 132.3 (C-400), 132.4 (C-900),
134.2 (C-40), 158.1 (C-5), 163.7 (C-2). Anal. Calcd for C16H13N5O2
(307.11): C, 62.53; H, 4.26; N, 22.79. Found: C, 62.45; H, 4.27; N,
22.82.
4.5.19. 2-(b-
triazol-4-yl]-1,3,4-oxadiazole (46)
Prepared by general procedure 4.2 from 30 (350 mg,
0.42 mmol) for 3 h. Column chromatography (9:1 CHCl3–MeOH)
gave 46 (161 mg, 91%) as
Rf = 0.35 (8:2 CHCl3–MeOH), [
(CD3OD, 360 MHz) d (ppm): 9.12 (1H, s, triazole-H), 8.12 (1H, d,
D-Glucopyranosyl)-5-[1-(naphthalen-1-yl)-1,2,3-
a
pale yellow amorphous solid.
a]
D = +19 (c 0.17, MeOH); 1H NMR
J = 8.0 Hz, Ar), 8.02 (1H, d, J = 7.8 Hz, Ar), 7.71–7.55 (5H, m, Ar),
4.72 (1H, d, J1 ,2 = 10.6 Hz, H-10), 3.94–3.85 (2H, m, H-60a, H-20 or
H-30 or H-40), 3.66–3.48 (4H, m, 2 of H-20 or H-30 or H-40, H-50, H-
60b). 13C NMR (CD3OD, 90 MHz) d (ppm): 165.6, 160.2 (oxadiazole),
135.6, 134.5, 133.9, 132.3, 129.5, 129.3, 128.5, 126.4, 126.2, 125.2,
123.1, 122.7 (Ar, triazole-C, triazole-CH), 82.5, 79.1, 74.5, 73.4, 71.3
(C10–C-50), 62.7 (C-60). Anal. Calcd for C20H19N5O6 (425.13): C,
56.47; H, 4.50; N, 16.46; O, 22.57. Found: C, 56.42; H, 4.48; N,
16.42.
0
0
4.5.16. 2-(Naphthalen-2-yl)-5-[1-(20,30,40,60-tetra-O-acetyl-b-
D-
glucopyranosyl)-1,2,3-triazol-4-yl]-1,3,4-oxadiazole (43)
Prepared by general procedure 4.5.1 from 2,3,4,6-tetra-O-
acetyl-b-
D
-glucopyranosyl-azide31,32 (300 mg, 0.80 mmol) and 24
for 16 h. Column chromatography (1:2 EtOAc–hexane) gave 43
(355 mg, 74%) as white crystals. Rf = 0.38 (6:4 EtOAc–hexane),
mp: 210–214 °C, [
360 MHz) d (ppm): 8.75 (1H, s, Ar), 8.68 (1H, s, Ar), 8.23 (1H, d,
a
]
D = ꢁ134 (c 0.22, CHCl3); 1H NMR (CDCl3,
4.5.20. 2-(b-D-Glucopyranosyl)-5-[1-(naphthalen-2-yl)-1,2,3-
triazol-4-yl]-1,3,4-oxadiazole (47)
J = 1.6, 8.6 Hz, Ar), 7.96 (2H, m, Ar), 7.90 (1H, m, Ar), 7.58 (2H,
Prepared by general procedure 4.2 from 31 (220 mg,
0.26 mmol) for 3 h. Column chromatography (9:1 CHCl3–MeOH)
gave 47 (88 mg, 79%) as a greenish amorphous solid. Rf = 0.32
m, Ar), 6.06 (1H, d, J1 ,2 = 7.9 Hz, H-10), 5.53 (2H, m, 2 of H-20 or
H-30 or H-40), 5.35 (1H, t, J = 9.3 Hz, H-20 or H-30 or H-40), 4.37
0
0
(1H, dd, J5 ,6 a = 5.3 Hz, J6 a,6 b = 13.2 Hz, H-60a), 4.22 (1H, dd,
0
0
0
0
(8:2 CHCl3–MeOH), [a]
D = +8 (c 0.14, Me2SO); 1H NMR (Me2SO-
J6 a,6 b = 13.2 Hz, J5 ,6 b = 1.9 Hz, H-60b), 4.12 (1H, ddd, J4 ,5 = 9.3 Hz,
0
0
0
0
0
0
d6, 360 MHz) d (ppm): 9.90 (1H, s, triazole-H), 8.68 (1H, s, Ar),
8.22 (2H, m, Ar) 8.09 (2H, t, J = 7.9 Hz, Ar), 7.66 (2H, m, Ar), 5.51
(1H, d, J = 6.6 Hz, OH), 5.29 (1H, d, J = 4.0 Hz, OH), 5.20 (1H, d,
J = 5.3 Hz, OH), 4.70 (1H, t, J = 5.3 Hz, OH), 4.65 (1H, d,
J5 ,6 a = 5.3 Hz5 6 b = 1.9 Hz, H-50), 2.11, 2.10, 2.05, 1.93 (12H, 4s,
CH3). 13C NMR (CDCl3, 90 MHz) d (ppm): 170.4, 169.8, 169.3,
168.9 (CO), 164.9, 157.6 (oxadiazole), 137.8, 134.6, 132.7, 129.0,
128.8, 128.0, 127.9, 127.8, 127.1, 123.5, 123.2, 120.5 (Ar, tria-
zole-C, triazole-CH), 86.0, 75.4, 72.3, 70.5, 67.5 (C-10–C-50), 61.4
(C-60), 20.6, 20.5, 20.4, 20.1 (CH3). Anal. Calcd for: C28H27N5O10
(593.18): C, 56.66; H, 4.59; N, 11.80; O, 26.96. Found: C, 56.61;
H, 4.50; N, 11.74.
0
0
0
0
J1 ,2 = 10.6 Hz, H-10), 3.79–3.66 (2H, m, H-60a, H-60b), 3.54–3.26
(4H, m, H-20, H-30, H-40, H-50). 13C NMR (Me2SO-d6, 90 MHz) d
(ppm): 163.8, 158.1 (oxadiazole), 133.5, 133.3, 132.7, 132.6,
129.9, 128.3, 127.8, 127.6, 127.3, 124.6, 118.6, 118.5 (Ar, triazole-
C, triazole-CH), 81.8, 77.3, 72.6, 71.8, 69.9 (C-10–C-50), 60.9 (C-60).
Anal. Calcd for C20H19N5O6 (425.13): C, 56.47; H, 4.50; N, 16.46;
O, 22.57. Found: C, 56.43; H, 4.50; N, 16.47.
0
0
4.5.17. 2-(Naphthalen-2-yl)-5-[(1-b-D-glucopyranosyl)-1,2,3-
triazol-4-yl]-1,3,4-oxadiazole (44)
Prepared by general procedure 4.2 from 43 (182 mg, 0.31 mmol)
for 2 h. Filtration of the reaction mixture gave 44 (128 mg, 98%) as a
4.5.21. 2-(b-
triazol-4-yl]-1,3,4-oxadiazole (48)
D-Glucopyranosyl)-5-[1-(b-D-glucopyranosyl)-1,2,3-
white amorphous solid. Rf = 0.60 (7:3 CHCl3–MeOH), [
a]
D = ꢁ11
Prepared by general procedure 4.2 from 32 (240 mg,
0.23 mmol) for 16 h. Column chromatography (6:4 CHCl3–MeOH)
gave 48 (98 mg, 93%) as a colourless oil. Rf = 0.31 (4:6 CHCl3–
(c 0.20, Me2SO); 1H NMR (Me2SO-d6, 360 MHz) d (ppm): 9.43 (1H,
s, triazole-H), 8.76 (1H, s, Ar), 8.23 (3H, m, Ar), 8.10 (1H, m, Ar),
7.11 (2H, m, Ar), 5.78 (1H, d, J1 ,2 = 9.3 Hz, H-10), 3.93 (1H, t,
0
0
MeOH), [a]
D = +24 (c 0.20, MeOH); 1H NMR (CD3OD, 360 MHz) d
J = 9.3 Hz, H-20 or H-30 or H-40), 3.79 (1H, dd, J6 a,6 b = 11.9, J5 ,6 a
<1 Hz), 3.60–3.47 (3H, m, H-20 or H-30 or H-40, H-50, H-60b), 3.35
(1H, t, J = 9.3 Hz, H-20 or H-30 or H-40). 13C NMR (Me2SO-d6,
90 MHz) d (ppm): 163.9, 157.9 (oxadiazole), 134.2, 132.7, 132.4,
129.3, 128.9, 128.3, 127.9, 127.4, 127.1, 125.9, 122.8, 120.4 (Ar,
triazole-C, triazole-CH), 87.9, 80.1, 76.6, 72.2, 69.4 (C-10–C-50),
60.7 (C-60). Anal. Calcd for C20H19N5O6 (425.13): C, 56.47; H, 4.50;
N, 16.46; O, 22.57. Found: C, 56.50; H, 4.54; N, 16.53.
0
0
0
0
(ppm): 9.04 (1H, s, triazole-H), 5.78 (1H, d, J1 ,2 = 7.9 Hz, H-10),
4.70 (1H, d, J = 9.3 Hz, H-100), 4.01–3.47 (12H, m, H-20, H-30, H-40,
H-50, H-60a, H-60b, H-200, H-300, H-400, H-500, H-600a, H-600b). 13C NMR
(CD3OD, 90 MHz) d (ppm): 165.5, 160.2 (oxadiazole), 134.3 (tria-
zole-C), 126.9 (triazole-CH), 89.8, 81.2, 78.7, 78.2, 74.4, 74.1, 73.4,
71.2, 70.7 (C-10–C-50, C-100-C-500), 62.7, 62.3 (C-60, C-600). Anal. Calcd
for C16H23N5O11 (461.14): C, 41.56; H, 5.02; N, 15.18; O, 38.14.
Found: C, 41.64; H, 5.01; N, 15.18.
0
0
4.5.22. 2-(200,300,400,600-Tetra-O-benzoyl-b- -glucopyranosyl)-5-(40-
D
4.5.18. 2-(b-D-Glucopyranosyl)-5-(1-phenyl-1,2,3-triazol-4-yl)-
1,3,4-oxadiazole (45)
phenyl-10,20,30-triazole-10-ylmethyl)-1,3,4-oxadiazole (49)
Prepared by general procedure 4.2 from 29 (249 mg, 0.31 mmol)
for 2 h. Column chromatography (9:1 CHCl3–MeOH) gave 45
(100 mg, 85%) as white crystals. Rf = 0.39 (8:2 CHCl3–MeOH), mp:
Oxadiazole 26 (100 mg, 0.14 mmol) was dissolved in CH2Cl2
(2 mL) and water (2 mL), phenylacetylene (14 lL, 0.14 mmol), cop-
per triflate (2 mg, 5.2 ꢂ 10ꢁ3 mmol) and copper dust (0.3 mg,
4.7 ꢂ 10ꢁ3 mmol) was added. The reaction mixture was heated at
40 °C. After 24 h TLC (1:1 EtOAc–hexane) indicated completion of
the transformation. The reaction mixture was diluted with CH2Cl2
(20 mL), the phases were separated, and the organic phase was
washed with cold satd NaHCO3 solution (3 ꢂ 10 mL), water
(10 mL), dried, filtered, and concentrated under reduced pressure.
The crude product was purified by column chromatography (1:1
EtOAc–hexane) to give 49 (56 mg, 70%, conversion 70%) as a col-
219–221 °C, [a]
D = +28 (c 0.22, Me2SO); 1H NMR (Me2SO-d6,
360 MHz) d (ppm): 9.78 (1H, s, triazole-H), 8.05 (2H, d, J = 7.9 Hz,
Ar), 7.66 (2H, pt, J = 7.9, 6.6 Hz, Ar), 7.57 (1H, pt, J = 6.6, 7.9 Hz,
Ar), 5.45 (1H, d, J = 5.3 Hz, OH), 5.22 (1H, d, J = 4.0 Hz, OH), 5.14
(1H, d, J = 4.0 Hz, OH), 4.66 (1H, d, J = 5.3 Hz, OH), 4.61 (1H, d,
J1 ,2 = 10.6 Hz, H-10), 3.73–3.18 (6H, m, H-20, H-30, H-40, H-50, H-
60a, H-60b). 13C NMR (Me2SO-d6, 90 MHz) d (ppm): 163.7, 158.1
(oxadiazole), 133.4 (triazole-C), 130.2, 129.9, 124.5 (Ar), 120.5 (tri-
azole-CH), 81.8, 77.2, 72.6, 71.8, 69.8 (C-10–C-60), 60.9 (C-60). Anal.
Calcd for C16H17N5O6 (375.12): C, 51.20; H, 4.57; N, 18.66; O,
25.58. Found: C, 51.15; H, 4.53; N, 18.59.
0
0
ourless syrup. Rf = 0.35 (1:1 EtOAc–hexane); [
a]
D = ꢁ50.4 (c 0.22,
CHCl3); 1H NMR (CDCl3, 360 MHz) d (ppm): 8.05 (1H, s, triazole-
CH), 8.02–7.72 (10H, m, Ar), 7.56–7.23 (15H, m, Ar), 6.06 (1H, pt,

1436
S. Kun et al. / Carbohydrate Research 346 (2011) 1427–1438
J = 9.6 Hz, H-200 or H-300 or H-400), 5.89 (2H, bs, CH2), 5.82 (1H, pt,
J = 9.9 Hz, H-200 or H-300 or H-400), 5.74 (1H, pt, J = 10.0, 9.8 Hz, H-
(303.11): C, 67.32; H, 4.32; N, 23.09. Found: C, 67.39; H, 4.40; N,
23.11.
200 or H-300 or H-400), 5.71 (1H, d, J1 ,2 = 10.1 Hz, H-100), 4.65 (1H,
00 00
dd, J6 a,6 b = 12.5 Hz, J5 ,6 a = 1.7 Hz, H-600a), 4.50 (1H, dd,
00 00
4.5.26. Ethyl 1-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1H-
1,2,3-triazole-4-carboxylate (53)
00
00
00 00
J5 ,6 b = 5.3 Hz, H-600b), 4.36–4.31 (1H, m, H-500). 13C NMR (CDCl3,
360 MHz) d (ppm): 166.0, 165.6, 165.1, 165.0 (CO), 162.9, 161.6
(oxadiazole), 148.7 (triazole-C), 133.7–125.8 (Ar), 120.1 (triazole-
CH), 77.2, 73.0, 71.8, 70.7, 68.7 (C-200-C-500), 62.8 (C-600), 44.1
(CH2). Anal. Calcd for C45H35N5O10 (805.79): C, 67.07; H, 4.38; N,
8.69. Found: C, 66.92; H, 4.27; N, 9.36.
Prepared by general procedure 4.5.3 from 28 (500 mg,
2.48 mmol) ethyl propiolate (293 mg, 2.96 mmol) in the presence
of CuSO4ꢀ5H2O (25 mg, 0.01 mmol), Na-L-ascorbate (79 mg,
0.40 mmol) in 12 mL solvent mixture at rt for 75 h to give 52
(567 mg, 76%) as white crystals. Mp: 116–117 °C; 1H NMR (CDCl3,
360 MHz) d (ppm): 1.39 (3H, t, J = 6.9 Hz, CH2–CH3), 4.42 (2H, q,
J = 7,0 Hz, CH2–CH3), 5.13 (2H, s, CH2), 7.48–7.57 (3H, m, H-300, H-
400, H-500), 8.02 (2H, d, J = 8.0 Hz, H-200, H-600), 8.40 (1H, s, H-50).
13C NMR (CDCl3, 360 MHz) d (ppm): 12.3 (CH2–CH3), 42.6 (CH2),
59.6 (CH2–CH3), 120.8 (C-100), 125.2 (C-200, C-600) 126.1 (C-50),
127.3 (C-300, C-500), 130.6 (C-400), 139.2 (C-40), 157.6 (C-2), 158.2
(C-5), 164.4 (C@O). Anal. Calcd for C14H13N5O3 (299.10): C, 56.18;
H, 4.38; N, 23.40. Found: C, 56.21; H, 4.39; N, 23.45.
4.5.23. 2-(200,300,400,600-Tetra-O-benzoyl-b- -glucopyranosyl)-5-(40-
D
ethoxycarbonyl-10,20,30-triazole-10-ylmethyl)-1,3,4-oxadiazole
(50)
Prepared by general procedure 4.5.1 from 26 (150 mg,
0.21 mmol). Column chromatography (1:1 EtOAc–hexane) gave
50 (107 mg, 82%, conversion 77%) as a colourless syrup. Rf = 0.22
(1:1 EtOAc–hexane); [a]
D = +57.1 (c 0.21, CHCl3); 1H NMR (CDCl3,
360 MHz) d (ppm): 8.42 (1H, s, triazole-CH), 8.03–7.78 (8H, m,
Ar), 7.58–7.25 (12H, m, Ar), 6.11 (1H, pt, J = 10.0, 9.5 Hz, H-200 or
H-300 or H-400), 5.91 (2H, br s, CH2), 5.82 (1H, pt, J = 9.8, 9.5 Hz, H-
200 or H-300 or H-400), 5.68 (1H, pt, J = 10.0, 9.9 Hz, H-200 or H-300 or
4.5.27. {1-[(5-Phenyl-1,3,4-oxadiazol-2-yl)methyl]-1H-1,2,3-
triazol-4-yl}methanol (54)
Prepared by general procedure 4.5.3 from 28 (201 mg,
1.00 mmol) prop-2-yn-1-ol (67 mg, 1.2 mmol) in the presence of
H-400), 5.20 (1H, d, J1 ,2 = 9.9 Hz, H-100), 4.67 (1H, dd, J5 ,6 a = 2.6 Hz,
00 00
00 00
H-600a), 4.51 (1H, dd, J6 a,6 b = 12.5, J5 ,6 b = 5.2 Hz, H-600b), 4.44–4.33
(3H, m, H-5’’, CH2CH3), 1.40 (3H, t, J = 7.2 Hz, CH2CH3). 13C NMR
(CDCl3, 90 MHz) d (ppm): 166.0, 165.6, 165.1, 165.0 (CO), 162.9,
161.0, 160.2 (oxadiazole, COOEt), 141.0 (triazole-C), 133.8–127.7
(Ar, triazole CH), 77.1, 72.9, 71.7, 70.7, 68.7 (C-100-C-500), 62.8,
61.3 (CH2, C-600), 44.2 (CH2), 14.2 (CH3). Anal. Calcd for
CuSO4ꢀ5H2O (10 mg, 0.04 mmol), Na-
mmol), and TMEDA (15 L, 0.11 mmol) in 9 mL solvent mixture
at rt for 3 h to give 54 (41 mg, 55%) as white crystals. Mp: 196–
197 °C; 1H NMR (CDCl3, 360 MHz)
(ppm): 4.56 (2H, d,
J = 5.3 Hz, CH2–OH), 5.27 (1H, t, J = 5.8 Hz, OH), 6.1 (2H, s, CH2),
7.60–7.63 (3H, m, H-300–H-500), 7.97 (2H, d, J = 6.8 Hz, H-200, H-600),
8.22 (1H, s, H-50). 13C NMR (CDCl3, 90 MHz) d (ppm): 42.2 (CH2–
OH), 53.5 (CH2), 121.4 (C-100), 122.3 (C-50), 125.1 (C-200, C-600),
128.0 (C-300, C-500), 130.8 (C-400), 147.1 (C-40), 160.1 (C-5), 163.3
(C-2). Anal. Calcd for C12H11N5O2 (257.09): C, 56.03; H, 4.31; N,
27.22. Found: C, 56.011; H, 4.38; N, 27.29.
L
-ascorbate (21 mg, 0.16
00
00
00 00
l
d
C
42H35N5O12 (801.75): C, 62.92; H, 4.40; N, 8.74. Found: C, 63.05;
H, 4.56; N, 8.86.
4.5.24. 2-(200,300,400,600-Tetra-O-benzoyl-b- -glucopyranosyl)-5-(40-
D
hydroxymethyl-10,20,30-triazole-10-ylmethyl)-1,3,4-oxadiazole
(51)
Prepared by general procedure 4.5.1 from 26 (224 mg,
0.32 mmol). Column chromatography (1:1 EtOAc–hexane) gave
51 (198 mg, 85%, conversion 96%) as a colourless syrup. Rf = 0.14
4.5.28. 2-{1-[(5-Phenyl-1,3,4-oxadiazol-2-yl)methyl]-1H-1,2,3-
triazol-4-yl}propan-2-ol (55)
Prepared by general procedure 4.5.3 from 28 (250 mg,
1.24 mmol) 2-methylbut-3-yn-2-ol (125 mg, 1.49 mmol) in the
(1:1 EtOAc–hexane); [
a]
D = ꢁ69 (c 0.20, CHCl3); 1H NMR (CDCl3,
360 MHz) d (ppm): 8.03–7.79 (9H, m, Ar, triazole CH), 7.77–7.25
(12H, m, Ar), 6.09 (1H, pt, J = 10.4, 9.2 Hz, H-200 or H-300 or H-400),
5.85–5.79 (3H, m, H-200 or H-300 or H-400, CH2), 5.73 (1H, pt,
presence of CuSO4ꢀ5H2O (12 mg, 0.049 mmol), Na-
L-ascorbate
(40 mg, 0.20 mmol) in 9 mL solvent mixture at rt for 1.5 h to give
55 (306 mg, 86%) as white crystals. Mp: 164–166 °C; 1H NMR
(CDCl3, 360 MHz) d (ppm): 1.45 (6H, s, 6H, CH3), 5.18 (1H, s, OH),
6.05 (2H, s, CH2), 7.57–7.59 (3H, m, H-300–H-500), 7.94 (2H, d,
J = 6.9 Hz, H-200, H-600), 8.08 (1H, s, H-50). 13C NMR (CDCl3,
J = 10.8, 9.1 Hz, H-200 or H-300 or H-400), 5.19 (1H, d, J1 ,2 = 10.7 Hz,
00 00
H-100), 4.79 (2H, br s, CH2) 4.66 (1H, dd, J5 ,6 a = 1.0 Hz, H-600a),
00 00
4.50 (1H, dd, J5 ,6 b = 5.6 Hz, J6 a,6 b = 12.5 Hz, H-600b), 4.37–4.33
(1H, m, H-500), 4.06 (1H, s, OH); 13C NMR (CDCl3, 90 MHz) d
(ppm): 166.1, 165.6, 165.1, 165.0 (CO), 162.8, 161.5 (oxadiazole),
148.6 (triazole-C), 133.8–127.8 (Ar), 122.6 (triazole-CH), 77.1,
73.1, 71.6, 70.6, 68.7 (C-100–C-500), 69.3 (CH2OH), 62.8 (C-600), 44.1
(CH2). Anal. Calcd for C40H33O10N5 (759.72): C, 63.24; H, 4.38; N,
9.22. Found: C, 63.36; H, 4.49; N, 9.15.
00 00
00
00
90 MHz)
d (ppm): 29.1 (–C(CH3)2OH), 42.1 (CH2), 65.6 (–
C(CH3)2OH), 120.1 (C-50), 121.4 (C-100), 125.1 (C-200, C-600), 128.0
(C-300, C-500), 130.8 (C-400), 154.9 (C-40), 160.1 (C-5), 163.3 (C-2).
Anal. Calcd for C14H15N5O2 (285.12): C, 58.94; H, 5.30; N, 24.55.
Found: C, 59.01; H, 5.38; N, 24.59.
4.5.29. 2-Phenyl-5-[(4-trimethylsilyl-1H-1,2,3-triazol-1-
yl)methyl]-1,3,4-oxadiazole (56)
Prepared by general procedure 4.5.3 from 28 (750 mg,
3.72 mmol) ethynyltrimethylsilane (439 mg, 4.47 mmol) in the
4.5.25. 2-Phenyl-5-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-
1,3,4-oxadiazole (52)
Prepared by general procedure 4.5.3 from 28 (250 mg,
1.24 mmol) and phenylacetylene (152 mg, 1.48 mmol) in the pres-
presence of CuSO4ꢀ5H2O (37 mg, 0.15 mmol), Na-
L-ascorbate
ence of CuSO4ꢀ5H2O (3 mg, 0.012 mmol), Na-
L
-ascorbate (10 mg,
(120 mg, 0.60 mmol) in 27 mL solvent mixture at rt for 60 h
to give 56 (1.090 g, 98%) as white crystals. Mp: 113–117 °C;
1H NMR (CDCl3, 360 MHz) d (ppm): 0.32 (9H, s, CH3), 5.92
(2H, s, CH2), 7.49–7.55 (3H, m, H-300, H-400, H-500), 7.77 (1H, s,
H-50), 8.02 (2H, d, J = 6.9 Hz, H-200, H-600). 13C NMR (CDCl3,
90 MHz) d (ppm): -3.1 (CH3), 41.5 (CH2), 121.0 (C-100), 125.2
(C-200,C-600), 127.2 (C-300, C-500), 127.4 (C-50), 130.4 (C-400), 146.0
(C-40), 158.4 (C-5), 164.2 (C-2). Anal. Calcd for C14H17N5OSi
(299.12): C, 56.16; H, 5.72; N, 23.39. Found: C, 56.04; H,
5.61; N, 23.29.
0.05 mmol), and TMEDA (15 L, 0.11 mmol) in 6 mL solvent mix-
l
ture at rt for 2 h to give 52 (256 mg, 68%) as white crystals. Mp:
180–181 °C; 1H NMR (CDCl3, 360 MHz) d (ppm): 5.93 (2H, s,
CH2), 7.26–7.55 (6H, m, H-300–H-500, H-3000–H-5000), 7.83 (2H, d,
J = 6.9 Hz, H-2000, H-6000), 7.99–8.03 (3H, m, H-50, H-200, H-600). 13C
NMR (CDCl3, 90 MHz) d (ppm): 42.3 (CH2), 118.0 (C-4000), 121.0
(C-1000), 123.9 (C-2000, C-6000), 125.2 (C-200, C-600), 125.9 (C-50), 126.6
(C-400), 127.0 (C-3000, C-5000), 127.2 (C-300, C-500), 127.9 (C-100), 134.4
(C-40), 146.9 (C-2), 158.2 (C-5). Anal. Calcd for C17H13N5O

S. Kun et al. / Carbohydrate Research 346 (2011) 1427–1438
1437
4.5.30. 5-Phenyl-2-[(1H-1,2,3-triazol-1-yl)methyl]-1,3,4-
oxadiazole (57)
176.9, 173.8 (oxadiazole), 167.9 (CO), 150.6 (triazole-C), 125.4
(triazole-CH), 81.7 (C-100), 79.6, 75.1, 74.6, 72.3 (C-200-C-500), 62.2
(C-600), 51.2 (CH2), 42.7 (CH3). Anal. Calcd for C13H17 N5O8
(371.30): C, 42.05; H, 4.61; N, 18.86. Found: C, 42.17; H, 4.75;
N, 18.92.
Compound 56 (226 mg, 0.75 mmol) was dissolved in dry THF
(7 mL) and
a solution of TBAF (80 mg, 0.25 mmol) in THF
(0.25 mL) was added. The mixture was stirred at 50 °C (bath
temp) for 1 h, and then TBAF (80 mg, 0.25 mmol) in THF
(0.25 mL) was added again. After 4 h TLC (2:1 PhCH3–EtOAc)
had indicated completion of the transformation, the solvent was
evaporated and the residue was purified by flash chromatography
(1:1 PhCH3–EtOAc) to give 57 (71 mg, 35%) as white crystals. Mp:
146–147 °C; 1H NMR (Me2SO-d6, 360 MHz) d (ppm): 5.92 (2H, s,
CH2), 7.48–7.56 (5H, m, H-200–H-600), 7.81 (1H, d, J = 6.5 Hz, H-
50), 8.01 (1H, d, J = 6.7, H-40). 13C NMR (Me2SO-d6, 90 MHz) d
(ppm): 43.5 CH2), 120.0 (C-40), 122.8 (C-1’’), 125.7–129.1 (C-200–
C-600), 133.8 (C-50), 161.4 (C-2), 164.7 (C-5). Anal. Calcd for
4.5.34. 2-(b-D
-Glucopyranosyl)-5-(40-carboxyamido-10,20,30-
triazole-10-ylmethyl)-1,3,4-oxadiazole (61)
Oxadiazole 50 (105 mg, 0.13 mmol) was dissolved in metha-
nolic ammonia solution (5 mL). After 48 h TLC (1:1 CHCl3–
MeOH) indicated completion of the transformation. The solvent
was evaporated under reduced pressure. The crude product
was purified by column chromatography (2:1 CHCl3–MeOH) to
give 61 (22 mg, 47%) as a colourless syrup. [a]D = +30.6 (c 0.20,
MeOH); Rf = 0.21 (1:1 CHCl3–MeOH); 1H NMR (CD3OD,
360 MHz) d (ppm): 8.51 (1H, s, triazole), 7.85 (2H, s, NH2),
C11H9N5O (227.08): C, 58.14; H, 3.99; N, 30.82. Found: C, 58.22;
3.80 (1H, d, J1 ,2 = 10.5 Hz, H-100), 3.85 (1H, dd, J6 a,6 b = 11.9 Hz,
00 00
00 00
00
00
H, 4.05; N, 30.90.
J5 ,6 a = 1.3 Hz, H-600a), 3.78 (1H, pt, J = 9.5, 8.7 Hz, H-200 or H-300
or H-400), 3.69 (1H, dd, 5 ,6 b = 5.2 Hz, H-600b), 3.51 (1H, pt,
J
00 00
4.5.31. 3-(1-((5-Phenyl-1,3,4-oxadiazol-2-yl)methyl)-1H-1,2,3-
triazol-4-yl)benzenamine (58)
Prepared by general procedure 4.5.3 from 28 (250 mg,
1.24 mmol) 3-ethynylbenzenamine (174 mg, 1.49 mmol) in the
J = 9.2, 7.9 Hz, H-200 or H-300 or H-400), 3.43–3.33 (2H, m, H-200 or
H-300 or H-400 and H-500), 3.25 (2H, s, CH2). 13C NMR (CD3OD,
90 MHz) d (ppm): 177.6, 174.7 (oxadiazole), 172.0 (CO), 151.8
(triazole-C), 128.5 (triazole-CH), 82.0 (C-100), 79.4, 79.2, 73.5,
70.9 (C-200–C-500), 62.2 (C-600), 43.0 (CH2). Anal. Calcd for
presence of CuSO4ꢀ5H2O (12.4 mg, 0.05 mmol), Na-
L-ascorbate
(40 mg, 0.20 mmol), and TMEDA (15 L, 0.11 mmol) in 10 mL sol-
l
vent mixture at rt for 28 h to give 58 (247 mg, 62%) as brown crys-
tals. Mp: 175–177 °C; 1H NMR (Me2SO-d6, 360 MHz) d (ppm): 5.20
(2H, vbr s, NH2), 6.17 (2H, s, CH2), 6.57 (1H, d, J = 4.7 Hz, H-6), 7.00–
7.16 (3H, m, H-2, H-4, H-5), 7.61–7.63 (3H, m, H-3000, H-4000, H-5000),
7.99–8.01 (2H, d, J = 5.4 Hz H-2000, H-6000), 8.65 (1H, s, H-50). 13C
NMR (Me2SO-d6, 90 MHz) d (ppm): 43.9 (CH2), 110.5 (C-2), 113.1
(C-4), 113.8 (C-6), 121.9 (C-5), 122.8 (C-100), 126.6 (C-200, C-600),
129.3 (C-50), 129.4 (C-300, C-500), 130.6 (C-1), 132.2 (C-400), 147.4
(C-40), 148.9 (C-3), 161.4 (C-500), 164.8 (C-200). Anal. Calcd for
C
12H16N6O7 (356.29): C, 40.45; H, 4.53; N, 23.59. Found: C,
40.39; H, 4.62; N, 23.69.
4.5.35. 2-(b-D
-Glucopyranosyl)-5-(40-hydroxymethyl-10,20,30-
triazol-10-ylmethyl)-1,3,4-oxadiazole (62)
Prepared by general procedure 4.2 from 51 (150 mg,
0.20 mmol). Column chromatography (1:1 CHCl3–MeOH) gave 62
(20 mg, 30%) as a colourless syrup. Rf = 0.58 (2:3 CHCl3–MeOH);
[a
]
D = +28 (c 0.18, MeOH); 1H NMR (CD3OD, 360 MHz) d (ppm):
4.70–4.66 (2H, m, CH2), 4.53 (1H, d, J1 ,2 = 10.6 Hz, H-100), 3.86
00 00
C17H14N6O (318.12): C, 64.14; H, 4.43; N, 26.40. Found: C, 64.25;
H, 4.51; N, 26.48.
(1H, dd, J6 a,6 b = 11.9 Hz, J5 ,6 a = 1.2 Hz, H-600a), 3.76–3.36 (5H, m,
H-200, H-300, H-400, H-500, H-600b). 13C NMR (CD3OD, 90 MHz) d
(ppm): 166.6, 165.4 (oxadiazole), 149.9 (triazole-C), 120.5 (tria-
zole-CH), 82.9, 79.1, 74.5, 73.4, 71.3 (C-100-C-500), 62.8 (C-600), 45.1
(CH2OH), 33.6 (CH2). Anal. Calcd for C12H17N5O7 (343.29): C,
41.98; H, 4.99; N, 20.40. Found: C, 42.08; H, 5.11; N, 20.49.
00
00
00 00
4.5.32. 2-(b-D
-Glucopyranosyl)-5-(40-phenyl-10,20,30-triazole-10-
ylmethyl)-1,3,4-oxadiazole (59)
Prepared by general procedure 4.2 from 49 (131 mg,
0.16 mmol). Column chromatography (2:1 CHCl3–MeOH) gave
59 (40 mg, 63%) as a colourless syrup. Rf = 0.58 (2:1 CHCl3–
MeOH); [
a]
D = +37 (c 0.19, MeOH); 1H NMR (CD3OD, 360 MHz)
4.5.36. 2-(b-D-Glucopyranosyl)-5-azidomethyl-1,3,4-oxadiazole
d (ppm): 8.35 (1H, s, triazole), 7.84–7.82 (5H, m, Ph), 3.83 (1H,
(63)
d, J1 ,2 = 10.4 Hz, H-100), 3.63 (1H, dd, J6 a,6 b = 11.8 Hz,
Prepared by general procedure 4.2 from 26 (150 mg,
0.21 mmol) for 2 h. Column chromatography (3:1 CHCl3–MeOH)
gave 63 (50 mg, 82%) as a colourless syrup. Rf = 0.48 (7:3 CHCl3–
00 00
00
00
J5 ,6 a = 1.4 Hz, H-600a), 3.62 (1H, pt, J = 9.7, 8.7 Hz, H-200 or H-300
00 00
or H-400), 3.55 (1H, dd, J5 ,6 a = 5.4 Hz H-600b), 3.48 (1H, pt,
00 00
J = 9.3, 7.9 Hz, H-200 or H-300 or H-400), 3.52–3.38 (2H, m, H-200 or
H-300 or H-400 and H-500), 3.36 (2H, s, CH2). 13C NMR (CD3OD,
90 MHz) d (ppm): 180.0, 175.4 (oxadiazole), 152.6 (triazole-C),
127.9 (triazole-CH) 133.2–127.5 (Ph), 82.3 (C-100), 80.4, 79.1,
73.4, 71.3 (C-200-C-500), 62.7 (C-600), 52.8 (CH2). Anal. Calcd for
MeOH); [
a]
D = +26.6 (c 0.20, MeOH); 1H NMR (CD3OD, 360 MHz)
d (ppm): 4.70 (2H, s, CH2), 4.57 (1H, d, J1 ,2 = 10.6, Hz, H-10), 3.87
0
0
(1H, dd, J6 a,6 b = 11.9 Hz, J5 ,6 a = 1.2 Hz, H-60a), 3.73 (1H, pst,
0
0
0
0
J = 9.4 Hz, H-20 or H-30 or H-40), 3.67 (1H, dd, J6 a,6 b = 11.9,
0
0
J5,6 b = 5.4 Hz, H-60b), 3.51–3.37 (3H, m, H-20 and/or H-30 and/or
0
C17H19N5O6 (389.36): C, 52.44; H, 4.92; N, 17.99. Found: C,
H-40, H-50). 13C NMR (CD3OD, 90 MHz) d (ppm): 166.8, 163.6 (oxa-
diazole), 149.8 (triazole C), 125.1 (triazole CH), 82.9, 79.0, 74.5,
73.4, 71.2 (C-10–C-50), 73.2 (CH2–N3), 62.7 (C-60), 56.5 (CH2). Anal.
Calcd for C9H13O6N5 (287.23): C, 37.63; H, 4.56; N, 24.38. Found:
C, 38.11; H, 4.74; N, 24.65.
52.37; H, 4.81; N, 17.87.
4.5.33. 2-(b-D
-Glucopyranosyl)-5-(40-methoxycarbonyl-10,20,30-
triazole-10-ylmethyl)-1,3,4 oxadiazole (60)
Prepared by general procedure 4.2 from 50 (150 mg,
0.19 mmol). Column chromatography (9:1 CHCl3–MeOH) gave
60 (68 mg, 96%) as a colourless syrup. Rf = 0.08 (9:1 CHCl3–
Acknowledgements
MeOH); [
a]
D = +29 (c 0.21, MeOH); 1H NMR (CD3OD, 360 MHz)
This work was supported by the Hungarian Scientific Research
Fund (OTKA CK77712, CNK80709), TÁMOP 4.2.1./B-09/1/KONV-
2010-0007 project implemented through the New Hungary
Development Plan, co-financed by the European Social Fund,
and FP7 capacities coordination and support actions REGPOT-
2008-1-No 230146 ‘EUROSTRUCT’ and REGPOT-2009-1-No
245866 ‘ARCADE’.
d (ppm): 8.49 (1H, s, triazole), 3.86 (1H, d, J1 ,2 = 10.5 Hz, H-100),
00 00
3.82 (1H, dd, J6a ,6 b = 11.6 Hz, J5 ,6 a = 1.3 Hz, H-600a), 3.52 (1H,
pt, J = 9.5, 8.5 Hz, H-200 or H-300 or H-400), 3.38 (s, 2H, CH2), 3.48
00 00
00 00
(1H, dd, J5 ,6 b = 5.2 Hz, H-600b), 3.33 (1H, pt, 8.2, 7.9 Hz, H-200 or
00 00
H-300 or H-400), 3.20–3.03 (2H, m, H-200 or H-300 or H-400 and H-
500), 3.01 (3H, s, CH3). 13C NMR (CD3OD, 90 MHz) d (ppm):

1438
S. Kun et al. / Carbohydrate Research 346 (2011) 1427–1438
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