Click Inspired Synthesis of 1,2,3-Triazole-linked 1,3,4-Oxadiazole Glycoconjugates

Article abstract of DOI:10.1002/jhet.2845

The glycoconjugation of biologically privileged 1,3,4-oxadiazole scaffold is described via Cu(I)-catalyzed azide–alkyne cycloaddition. A series of glycosyl alkynes 1b–i, obtained from various commercial sugars, were treated with azide functionalized 1,3,4-oxadiazole using click chemistry to access triazole-linked glycosylated 1,3,4-oxadiazoles 10b–i in good yields. The structure of the developed glycoconjugates has been ascertained by extensive spectroscopic analysis (¹H &¹³C NMR, IR, and MS).

Full text of DOI:10.1002/jhet.2845

Month 2017
Click Inspired Synthesis of 1,2,3-Triazole-linked
,3,4-Oxadiazole Glycoconjugates
1
Divya Kushwaha and Vinod K. Tiwari*
Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
*
E-mail: tiwari_chem@yahoo.co.in
Additional Supporting Information may be found in the online version of this article.
Received October 4, 2016
DOI 10.1002/jhet.2845
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
The glycoconjugation of biologically privileged 1,3,4-oxadiazole scaffold is described via Cu(I)-catalyzed
azide–alkyne cycloaddition. A series of glycosyl alkynes 1b–i, obtained from various commercial sugars,
were treated with azide functionalized 1,3,4-oxadiazole using click chemistry to access triazole-linked
glycosylated 1,3,4-oxadiazoles 10b–i in good yields. The structure of the developed glycoconjugates
1
13
has been ascertained by extensive spectroscopic analysis ( H & C NMR, IR, and MS).
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
process. Moreover, the product 1,4-disubstituted 1,2,3-
triazole skeleton, itself, is a well known pharmacophore [5].
On the other hand, 1,3,4-oxadiazole ring has been
recognized as an important construction motif for the
development of pharmacologically active compounds
with broad range of biological activities such as
antibacterial, anticancer, anti-fungal, anti-HIV, analgesic,
anti-inflammatory, anti-hypertension, and muscle-relaxing
activities [6–12]. The medicinal significance of 1,3,4-
oxadiazoles lies in its ability to isostere amide and ester
functionalities. The strong dipole moment of oxadiazoles
facilitates their hydrogen bonding interactions with
various receptors therefore contributes significantly
towards pharmacophoric activities [12,13]. Various
structural modifications have been carried out to alter the
inherent reactivity of this potent building block to create
novel lead compounds [5–13]. In fact, a number of potent
drugs composed of 1,3,4-oxadiazole skeleton are already
In recent years, Cu(I) catalyzed azide alkyne
cycloaddition (CuAAC) has emerged out as a powerful
conjugation strategy for the preparation of library of
simple to complex neoglycoconjugates of diverse
applications [1]. Instantly, after the discovery of click
chemistry by two independent research groups, Meldal [2]
and Sharpless [3], 1,2,3-triazole heterocycle, recognized
as the most popular and important scaffold because of
their wide applications in different fields. Since then, click
inspired heterocyclic system continuously employed to
find a potential drug candidate where a large number of
bioactive 1,2,3-triazoles with a good bioactivity profile are
reported in recent years [1,4,5]. The click chemistry,
being highly efficient, reliable and modular approach,
generates a plethora of novel compounds with apparent
ease thereby facilitates lead discovery and optimization
©
2017 Wiley Periodicals, Inc.

D. Kushwaha and V. K. Tiwari
Vol 000
available in the market, for example, Zibotentan
an anticancer drug) [14], Raltegravir or MK-0518 (an
anti-HIV drug) [15], and tiodazosin (an anti-hypertensive
drug) [16]. In addition, oxadiazole-based compound
RESULT AND DISCUSSION
Synthesis of glycosyl alkynes. The glycosyl alkynes,
(
precursor for synthesis of glycoconjugated oxadiazoles,
were prepared from the commercially available sugars
D-glucose, D-galactose, D-mannose, and D-fructose in
various high-yielding reaction sequences. For the
preparation of desired glycosyl alkynes 1b–i, the general
strategy followed was the partial protection of sugars
with protecting groups in a manner that generates a
product with one hydroxyl group free, accompanied by a
propargylation reaction of the free hydroxyl group.
Glycosyl alkynes 1b, 1c, 1d, and 1e were obtained
in a two-step process from D-glucose, D-mannose,
D-galactose, and D-fructose, respectively. Initially, a
classical acetonation of these sugars was carried out with
anhydrous acetone under acid catalysis, which lead to the
two vicinal protections of cis-diols locking the ring in
either furanose or pyranose form depending on their
stereochemistry and leaving one hydroxyl group free in
each case [46,47]. Further, the treatment of hydroxylated
sugars with propargyl bromide and NaH in DMF resulted
in corresponding glycosyl alkynes 1b, 1c, 1d, and 1e in
good yields (Scheme 1).
(
S)-9b has been identified as highly selective and potent
inhibitor against glycogen synthase kinase 3b [17].
MK-0633 p-toluenesulfonate is reported to exhibit
selective inhibition for 5-lipoxygenase, and 3(H) has
displayed human neutrophil elastase inhibitory activity
and currently is in clinical evaluation [18,19]. Besides
this, 1,3,4-oxadiazole skeleton also constitutes an integral
part of well known herbicide oxadiazon and widely used
household insecticide Metoxadiazone [10].
The glycoconjugation of biologically active heterocycles
has become a promising strategy in drug discovery because
sugar insertion may increases the hydrophilicity and
bioavailability of the compounds while lowers the
toxicity and side effects [20]. Also, considering the
involvement of carbohydrates in various interactions,
sugars are often incorporated in various simpler
molecules to deal with the targeting mechanism of action
and/or pharmacology [21,22]. 1,3,4-Oxadiazoles linked to
sugar skeleton such as a glucofuranose, glucopyranose,
xylopyranose,
psicopyranose,
thioglycosides
and
fructopyranose are documented in literature, and many of
these derivatives have showed potential antibacterial,
anticancer, antitumor, and antidiabetic activity [23–32].
Considering the aforementioned facts and our previous
5
-O-Benzyl-1,2-O-isopropylidine-3-O-propargyl-α-D-
xylofuranose 1f and 5-O-benzyl-2,3-O-isopropylidene-
1-O-propargyl-α-D-lyxosfuranose 1g were accessed
from 1b and 1c, respectively, by following a sequence
of standard high-yielding synthetic procedures (Scheme 2).
Initially, the selective cleavage of 5,6-O-isopropylidene
protection of 1b and 1c was performed with 80%
aqueous acetic acid that gave 2 and 4 respectively in
good yield. In the next step, cis-diol functionality of 2
experience
on
click-mediated
development
of
glycoconjugates of diverse application [1,33–45], we
intend to conjugate the orthogonally protected saccharide
residue with biologically privileged 1,3,4-oxadiazole
framework using Cu(I)-catalyzed click reaction to obtain
glycohybrids, which may exhibit the medicinal properties
of both the parent components. Herein, we report a
straightforward synthesis of 1,2,3-triazole linked 1,3,4-
oxadiazole-sugar derivatives by click reaction of an azide
armed 1,3,4-oxadiazole entity with diverse set of terminal
glycosyl alkynes under mild reaction condition.
and 4 was oxidized with NaIO in methanol to obtain
4
corresponding aldehydes, which were subsequently
reduced with NaBH4 in methanol that furnished
compounds 3 and 5 in 92% and 94% yield, respectively.
Final benzyl protection of the C-5 of each 3 and 5 with
benzyl bromide and NaH in DMF delivered desired
Scheme 1. Reagents and conditions: (i) Propargyl bromide, NaH, DMF, 0°C → r.t., 8 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Triazole-linked 1,3,4-Oxadiazole Glycoconjugates
4 4
Scheme 2. Reagents and conditions: (i) 80% aqueous AcOH, r.t., 8 h; (ii) NaIO , MeOH, 0°C → r.t., 4 h; (iii) NaBH , MeOH, 0°C → r.t., 8 h; (iv) BnBr,
NaH, THF 0°C → r.t., 8 h.
À1
glycosyl alkynes 1f and 1g in 69% and 71% yield,
respectively (overall in four steps).
acetylenic stretch ≡C-H in the range of 3268–3191 cm
À1
and C≡C stretch in between 2234 and 2180 cm
.
The synthesis of α/β propargyl glycosides 1h and 1i was
accomplished starting from D-glucose through the
procedure outlined in Scheme 3. A silica-H SO catalyzed
Fischer-type glycosylation of D-glucose with propargyl
alcohol was performed under heating conditions to afford
a mixture of α/β 1-O-propargyl glucopyranosides 6 in
Synthesis of azide armed 1,3,4-oxadiazole.
After
synthesizing diverse glycosyl alkynes, next, we focused
our attention towards the preparation of their click
counterpart, that is, azide armed 1,3,4-oxadiazole moiety,
which was synthesized according to the protocol
described in Scheme 4. An equimolar mixture of
4-chlorobenzohydrazide 7 and 3-chloropropionic acid was
refluxed in phosphorous oxychloride at 80°C for 6 h
that led to the formation of 2-(2-chloroethyl)-5-(4-
chlorophenyl)-1,3,4-oxadiazole 8. The formation of
2
4
7
2% yield [48], which was subsequently reacted with
benzyl bromide in the presence of NaH and TBAB in dry
DMF that delivered α/β per-O-benzylated 1-O-propargyl
glucopyranosides. Chromatographic separation of the
anomers revealed the formation of isomers 1h and 1i in
13
oxadiazole nucleus was primarily recognized by
C
5
:1 ratio.
NMR, where the characteristic carbon signals of the ring
were observed at δ 164.3 and 163.7 ppm, consistent with
the reported values [10]. The two carbons related to
The presence of acetylene functionality in all the
glycosyl alkynes 1b–i was ascertained on the basis of IR,
1
13
1
H, and C NMR. In H NMR of 1b–i, a signal typical
of ≡C-H proton was observed around δ 2.2–2.5 ppm as a
ethylene spacer appeared at δ 39.5 ppm (ÀCH Cl) and
2
1
at δ 29.2 ppm (ÀCH C═N). The H NMR spectrum of
2
1
3
singlet, whereas in
C NMR, two characteristic
8
exhibited two doublets at δ 7.98 and 7.49 ppm
acetylenic carbons resonated in the range of δ 77.0–79.0
for C≡CH and δ 75.0–76.0 for C≡CH ppm. The IR
spectra of sugar alkynes 1b–i displayed a distinct
corresponding to the presence of four phenyl protons. The
methylene protons linked to chloride and the one adjacent
to oxadiazole nucleus appeared as triplet at δ 3.96 and
2 2 4
Scheme 3. Reagents and conditions: (i) Propargyl alcohol, SiO -H SO , 75°C, 5 h; (ii) BnBr, NaH, DMF, TBAB, 0°C → r.t., 10 h.
3 3
Scheme 4. Reagents and conditions: (i) 3-chloropropionic acid, POCl , 80°C, 6 h; (ii) NaN , DMF, 65°C, 5 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Kushwaha and V. K. Tiwari
.42 ppm, respectively. In IR spectrum, the absorption
Vol 000
À1
3
peak corresponding to N═N═N stretch at 2112 cm
À1
13
bands appeared at 1590 and 1057 cm for C═N and C-O
verified the formation of 9. In C NMR spectrum of 9, a
stretch respectively, evidenced the presence of oxadiazole
ring in 8. An absorption peak at 3085 cm was also seen
due to the aromatic stretching.
A nucleophilic displacement of chloride by azide
nucleophile in compound 8 was carried out by its
downfield shift was observed for carbon signal of
ÀCH Cl upon ÀCH N conversion.
À1
2
2 3
Synthesis of 1,3,4-oxadiazole glycoconjugates. With both
click precursors in hand, we turned our attention towards
accessing the 1,3,4-oxadiazole glycoconjugates by
CuAAC. The first click reaction was attempted between
compound 9 and a commercially available terminal
alkyne phenylacetylene 1a in the presence of catalyst CuI
treatment with NaN in DMF at 65°C that furnished the
3
click precursor 2-(2-azidoethyl)-5-(4-chlorophenyl)-1,3,4-
oxadiazole 9. In IR spectrum, appearance of an intense
Scheme 5. Synthesis of 1,3,4-oxadiazole glycoconjugate 10i. [Color figure can be viewed at wileyonlinelibrary.com]
1
13
Figure 1. Representative H and C NMR spectrum of click derived 1,3,4-oxadiazole glycoconjugate 10i.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Triazole-linked 1,3,4-Oxadiazole Glycoconjugates
Table 1
Click derived 1,3,4-oxadiazole glycoconjugates.
a
Entry
1
Alkynes
1,3,4-Oxadiazole conjugates
Yield (%)
91
2
3
72
67
4
5
75
71
6
7
64
70
8
9
82
85
a
2
Isolated yield after flash column chromatography (SiO ).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Kushwaha and V. K. Tiwari
Vol 000
and DIPEA in dry DCM under inert atmosphere at room
temperature that gave expected triazole product 10a in
1% yield. The structural determination of 10a was
CONCLUSION
9
The glycoconjugation of the 1,3,4-oxadiazole skeleton
was achieved by a short, facile, and inexpensive coupling
reaction CuAAC to obtain the glycohybrid compounds.
Diverse glycosyl alkynes 1b–i were synthesized
using standard high-yielding reaction procedures and
were coupled with 2-(2-azidoethyl)-5-(4-chlorophenyl)-
1,3,4-oxadiazole 9 with the aid of CuAAC. All the
reactions preceded smoothly affording a good yield
(64–91%) of triazole liked 1,3,4-oxadiazole-sugar
conjugates 10b–i. The structural confirmation of
1
13
carried out on the basis of H, C NMR and mass
1
spectroscopy. H NMR of 10a showed a characteristic
proton of singlet for the 1,2,3-triazole ring at δ 7.88 ppm.
The four aromatic protons of aryl chloride ring appeared
as two doublets at δ 7.83 and 7.72 ppm, whereas the other
five aromatic protons related to phenyl acetylene appeared
as multiplet ranging between δ 7.39 and 7.19 ppm. The
four methylene protons of linker appeared as two triplets
at δ 4.91 (protons next to triazole ring) and δ 3.56 ppm
1
3
1
13
(
protons next to oxadiazole ring). In C NMR, the two
developed compound 10a–i was carried out by H,
C
triazole carbons C-4 and C-5 were identified at δ 144.6
and 121.8 ppm, respectively. The two carbons related to
oxadiazole ring were seen at δ 164.1 and 163.3 ppm. The
carbons corresponding to spacer were found at δ 46.3
NMR, mass, and IR analysis. These new compounds
composed of glycosides and 1,3,4-oxadiazole building
blocks could be biologically potent, and using the same
chemistry more such analogues of varying spacer length,
different sugar, and aryl frameworks can be easily prepared.
(carbon next to triazole) and at δ 26.8 ppm (carbon
adjacent to oxadiazole).
In an another experiment, click coupling of glycosyl
alkyne 1i with azide 9 under standard copper catalysis
EXPERIMENTAL
(CuI/DIPEA) in anhydrous dichloromethane afforded
1
,3,4-oxadiazole glycoconjugate 10i in 85% yield
General method. All the reactions were executed in
anhydrous solvents under an argon atmosphere in 1-h
oven-dried glassware at 100°C. All reagents and solvents
were of pure analytical grade. Thin layer chromatography
was performed on Merk 60 F254 silica gel, pre-coated
on aluminum plates, and revealed with either a UV
lamp (λmax = 254 nm) or a specific-color reagent
1
13
(Scheme 5).
H
and
C
NMR of resulting
glycoconjugate 10i is depicted in Figure 1, which
clearly confirm for the structure of regioselective
1
,4-disubstituted triazolyl glycoconjugate.
After testing the efficiency of CuAAC, the reaction of
2
-(2-azidoethyl)-5-(4-chlorophenyl)-1,3,4-oxadiazole
9
was explored with developed glycosyl alkynes 1b–i
under the similar reaction conditions. All the reactions
proceeded smoothly affording triazole linked sugar-
oxadiazole hybrid 10b–i in 64–85% yield, and their
structural identification was carried out on the basis of
IR, H, and C NMR (Table 1). IR spectral analysis
gave primary indication about completion of the
reactions, because characteristic peaks corresponding to
(
Draggendorff reagent or iodine vapors) or by spraying
with methanolic-H SO solution and subsequent charring
by heating at 100°C. NMR spectra were obtained on
JEOL AL300 FT-NMR spectrometer (300 MHz for H
NMR and 75 MHz for C NMR) in CDCl . Chemical
shifts are given in ppm downfield from internal TMS,
and J values are in Hz. Infrared spectra were recorded as
Nujol mulls in KBr plates by a Perkin-Elmer RX-1
2
4
1
13
3
1
13
À1
À1
azide functionality 2112 cm
were completely
(4000–450 cm ) spectrometer. The mass spectra of
1
disappeared. In H NMR spectra of 10b–i, the proton
peak typical of 1,2,3-triazoles appeared as a singlet in the
range of δ 7.80–7.51 ppm. The four aromatic protons of
phenyl ring in 10b–i were observed as two doublets, each
with two protons ranging from δ 7.93 to 7.85 and from
developed compounds were recorded on Jeol SX-102(EI/
CI/FAB) mass spectrometry. Column chromatography
was carried out on silica gel 234–400 mesh, E-Merck
using n-hexane and ethyl acetate as eluent.
2-(2-Chloroethyl)-5-(4-chlorophenyl)-1,3,4-oxadiazole (8).
7
.41 to 7.48 ppm. The chemical shift values
To a mixture of 4-chlorobenzohydrazide 7 (0.7 g, 4.1 mmol)
corresponding to the protons of sugar skeleton and linker
and 3-chloropropionic acid (0.44 g, 4.1 mmol), 20 mL
13
were noticed within the range of δ 5.84–3.42 ppm. In
C
of POCl was added, and the mixture was refluxed at 80–
3
NMR spectra of 10b–i, the triazole C-4 carbon signals
were assigned in the range of δ 147.0–144.0 ppm and
C-5 in the range of δ 121.9–124.0 ppm. The two carbons
of oxadiazole nucleus resonated around δ 164.6–163.2 ppm.
The methylene carbon next to triazole ring resonated at
approximately δ 46.1 ppm, while the other methylene
adjacent to oxadiazole ring was found at approximately
δ 26.6 ppm.
90°C for 5 h. The reaction mixture was cooled to room
temperature, the excess of POCl3 was concentrated
through high vacuum, the residue was quenched with
ice, and the solid separated was filtered, dried, and
further chromatographed (15% n-hexane/EtOAc) to
afford compound 8 as white solid (0.73 g, 72%). R 0.56
f
À1
1
(n-hexane/EtOAc, 1/1); IR (KBr) cm 3089 (Ar-H), 1590
(C═N), 1550 (C═C), 1057 (C-O); H NMR (CDCl3,
Journal of Heterocyclic Chemistry
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Month 2017
Synthesis of Triazole-linked 1,3,4-Oxadiazole Glycoconjugates
3
00 MHz): δ 7.98 (d, 2 H, J = 8.4 Hz, Ph-H), 7.49 (d, 2 H,
NCH ), 4.77 (s, 2 H, ÀOCH ), 4.59 (d, 1 H, J = 3.3 Hz),
2
2
J = 8.4 Hz, Ph-H), 3.96 (t, 2 H, J = 6.6 Hz, ÀCH Cl),
4.33–4.26 (m, 1 H), 4.13–3.96 (m, 4 H, overlapped), 3.60
2
1
3
3
7
1
.42 (t, 2 H, J = 6.6 Hz, ÀN═CCH ); C NMR (CDCl ,
(t, 2 H, J = 6.3 Hz, ÀN═CCH ), 1.48, 1.42, 1.36, 1.30
2
3
2
13
5 MHz): δ 164.3 (C═N), 163.7 (C═N), 138.1, 129.4,
(each s, each 3 H, 2 X > C (CH ) ); C NMR (CDCl ,
3 2 3
28.1, 122.1, 39.5, 29.2 ppm.
75 MHz): δ 164.6, 163.2, 144.9, 138.3, 129.5, 128.1,
2
-(2-Azidoethyl)-5-(4-chlorophenyl)-1,3,4-oxadiazole (9).
1
23.7, 121.8, 111.9, 109.1, 105.1, 82.6, 81.8, 81.0, 72.3,
A suspension of compound 8 (0.73 g, 2.96 mmol) and
NaN (0.77 g, 11.85 mmol) in dry DMF (8 mL) was stirred
at 65°C. After 4 h, the reaction mixture was concentrated,
and the residue was partitioned between CHCl (40 mL)
and water (3 × 100 mL). The organic phase was dried,
filtered, concentrated, and chromatographed to obtain
compound 9 (0.60 g, 80%) as yellow syrup. IR (KBr) cm
6
7.4, 64.0, 46.2, 26.8, 26.2, 25.5 ppm. HRMS: m/z Calcd
+
3
for C H N O ClNa [M + Na] : 570.1732; found:
25 30 5 7
5
70.1735.
3
1-[2-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)ethyl]-4-(2,3;5,
6-di-O-isopropylidene-1-O-methyl-α-D-mannofuranos-1-yl)-1H-
1,2,3]-triazole (10c). Compounds9(45mg,0.18mmol)and
[
À1
1
c (59 mg, 0.19 mmol) were treated with CuI (10 mg,
0
.05 mmol) and DIPEA (16 μL, 0.09 mmol) in DCM
3
1
096 (Ar-H), 2102 (N═N═N), 1588 (C═N), 1540 (C═C),
1
according to procedure A and chromatographed (n-hexane/
EtOAc 1/1) and afforded glycoconjugate 10c (66 mg, 67%)
046 (C-O); H NMR (CDCl , 300 MHz): δ 7.98 (d, 2 H,
3
J = 8.4 Hz, Ph-H), 7.49 (d, 2 H, J = 8.4 Hz, Ph-H), 3.83 (t, 2
H, J = 6.6 Hz, ÀCH N ), 3.21 (t, 2 H, J = 6.6 Hz,
as brown solid. R
cm 3008 (Ar-H), 2985, 1610 (C═N), 1510 (C═C), 1432,
1370, 1218, 1152 (C-O), 1020, 790; H NMR (CDCl
0.41 (n-hexane/EtOAc 1/1); IR (KBr)
2
3
f
13
À1
ÀN═CCH ); C NMR (CDCl , 75 MHz): δ 164.9 (C═N),
2
3
1
1
64.2 (C═N), 138.1, 129.4, 128.2, 122.1, 47.7, 25.8 ppm.
General experimental procedure for the synthesis of
,
3
3
00 MHz): δ 7.93 (d, 2 H, J = 8.1 Hz, Ar-H), 7.74 (s, 1 H,
1
,3,4-oxadiazole glycoconjugates via click reaction (10a–i).
triazolyl-H), 7.49 (d, 2 H, J = 8.1 Hz, Ar-H), 5.09 (m, 1 H),
4.93 (m, 1 H), 4.75–4.59 (m, 3 H, overlapped), 4.38 (m, 1
H), 4.13–3.89 (m, 4 H), 3.69–3.47 (m, 2 H), 3.18 (m, 1 H),
To a solution of compound 9 (1.0 equiv) and sugar alkyne
(1.1 equiv) in dry DCM, CuI (0.3 equiv) and DIPEA
0.5 equiv) were added, and the mixture was stirred at
1
(
13
1.45, 1.42, 1.37, 1.31 (each s, 12 H, >C (CH
) ) ppm;
3 2
C
room temperature under argon atmosphere for 8 h. After
confirming the completion of reaction on thin layer
chromatography, the mixture was concentrated and the
crude with purified by flash column chromatography.
NMR (CDCl , 75 MHz): δ 164.6, 147.2, 138.3, 129.5,
128.7, 128.4, 128.1, 127.9, 121.9, 112.7, 109.1, 105.7, 84.8,
80.4, 79.4, 73.1, 66.7, 60.5, 46.2, 26.9, 26.8, 25.8, 25.2,
3
24.5 ppm. HRMS: m/z Calcd for C25
[M + Na] : 570.1732; found: 570.1733.
H N O ClNa
30 5 7
+
1
-[2-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)ethyl]-4-(phenyl)-
H-[1,2,3]-triazole (10a). Compounds 9 (50 mg, 0.20 mmol)
and 1a (24.0 μL, 0.22 mmol) were treated with CuI (11.0 mg,
.06 mmol) and DIPEA (17 μL, 0.10 mmol) in DCM
according to procedure A and afforded conjugate 10a
63.6 mg, 91%) as white solid. R 0.48 (n-hexane/EtOAc
1
1-[2-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)ethyl]-4-(1,2;3,
4-di-O-isopropylidene-6-O-methyl-α-D-galactopyranos-6-yl)-
0
1H-[1,2,3]-triazole (10d).
Compound
9
(50 mg,
0.20 mmol) and glycosyl alkyne 1d (65 mg, 0.22 mmol)
were treated with CuI (11.0 mg, 0.06 mmol) and DIPEA
(17 μL, 0.10 mmol) in DCM following procedure A and
chromatographed (n-hexane/EtOAc 1/1) and afforded
(
1
f
1
/1); H NMR (CDCl , 300 MHz): δ 7.88 (s, overlapped,
3
triazolyl-H), 7.83 (d, overlapped, J 8.4 Hz, Ar-H), 7.72 (d,
overlapped, J 8.4 Hz, Ar-H), 7.39–7.19 (m, 5 H, Ph-H),
compound 10d (82 mg, 75%) as yellow brown solid. R
0.35 (n-hexane/EtOAc 1/1); IR (KBr) cm 3011, 2988,
f
À1
4
.91 (t, 2 H, J = 6.3 Hz, ÀN═CCH ), 3.56 (t, 2 H,
2
13
J = 6.3 Hz, ÀN-NCH ); C NMR (CDCl , 75 MHz): δ
1621 (C═N), 1522 (C═C), 1460, 1369, 1220, 1166
2
3
1
1
1
64.6, 163.3, 147.9, 138.3, 130.2, 129.5, 128.8, 128.3,
28.1, 125.7, 121.8, 120.8, 46.3, 26.8 ppm.
(C-O), 1075, 810; H NMR (CDCl
3
, 300 MHz): δ 7.86
(d, 2 H, J = 7.5 Hz, Ar-H), 7.67 (s, 1 H, triazolyl-H),
7.41 (d, 2 H, J = 7.8 Hz, Ar-H), 5.46 (m, 1 H, H-1),
1
-[2-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)ethyl]-4-(1,2;5,
-di-O-isopropylidene-3-O-methyl-α-D-glucofuranos-3-yl)-1H-
1,2,3]-triazole (10b).
4
[
4
4
4
.84 (m, 2 H), 4.62–4.53 (m, 3 H, overlapped), 4.24–
.15 (m, 2 H, overlapped), 3.92 (m, 1 H), 3.63–3.52 (m,
Compound 9 (50 mg, 0.2 mmol)
and glycosyl alkyne 1b (65 mg, 0.22 mmol) were treated
with CuI (11.0 mg, 0.06 mmol) and DIPEA (17 μL,
H, overlapped), 1.45, 1.36, 1.26, 1.18 (each s, 12 H, 2
13
X > C (CH ) ) ppm; C NMR (CDCl , 75 MHz): δ
3
2
3
0
.10 mmol) in DCM according to procedure A and
1
1
4
64.6, 163.3, 145.4, 138.3, 129.5, 128.2, 123.6, 121.9,
09.3, 108.6, 96.4, 96.2, 71.1, 70.6, 69.4, 66.7, 64.7,
chromatographed (n-hexane/EtOAc 1/1) and afforded
glycoconjugate 10b (78 mg, 72%) as yellow amorphous
6.2, 26.8, 26.0, 24.9, 24.4 ppm. HRMS: m/z Calcd for
À1
solid. R 0.38 (n-hexane/EtOAc 1/1); IR (KBr) cm
+
f
C H N O ClNa [M
+
Na] : 570.1732; found:
2
5
30
5
7
3
020 (Ar-H), 2992, 2940, 1602 (C═N), 1580 (C═C),
5
70.1733.
1
1
466, 1374, 1215, 1109, 1050 (C-O), 820; H NMR
1
-[2-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)ethyl]-4-(1,2;4,
(
CDCl , 300 MHz): δ 7.93 (d, 2 H, J = 8.7 Hz, Ar-H),
5-di-O-isopropylidene-3-O-methyl-β-D-fructopyranos-3-yl)-1H-
[1,2,3]-triazole (10e). Compound 9 (50 mg, 0.20 mmol)
3
7
.79 (s, 1 H, triazolyl-H), 7.48 (d, 2 H, J = 8.7 Hz,
Ar-H), 5.85 (s, 1 H, H-1), 4.92 (t, 2 H, J = 6.3 Hz, ÀN-
and glycosyl alkyne 1e (65 mg, 0.22 mmol) were treated
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Kushwaha and V. K. Tiwari
Vol 000
with CuI (11.0 mg, 0.06 mmol) and DIPEA (17 μL,
.10 mmol) in DCM following A and chromatographed
138.7, 138.5, 138.2, 129.5, 128.3, 128.1, 128.0, 127.6,
127.5, 123.9, 123.4, 121.8, 112.2, 105.6, 84.7, 79.8, 78.6,
0
(
(
n-hexane/EtOAc 1/1) and afforded glycoconjugate 10e
76.1, 73.5, 73.0, 70.8, 59.9, 46.1, 26.7, 26.0, 24.9 ppm.
+
78 mg, 71%) as brown amorphous solid. R 0.36 (n-
HRMS: m/z Calcd for C28H N O ClNa [M + Na] :
30 5 6
f
À1
hexane/EtOAc 1/1); IR (KBr) cm 3011, 2987, 1604
590.1783; found: 590.1785.
1
-[2-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)ethyl]-4-(2,3,4,
6-tetra-O-benzyl-1-O-methyl-α-D-glucopyranos-1-yl)-1H-[1,2,
]-triazole (10h).
(C═N), 1548 (C═C), 1463, 1377, 1230, 1170 (C-O),
1
1
088, 846; H NMR (CDCl , 300 MHz): δ 7.93 (d, 2 H,
3
3
Compound 9 (40 mg, 0.16 mmol),
alkyne 1h (102 mg, 0.18 mmol), CuI (9 mg,
.05 mmol), and DIPEA (14 μL, 0.08 mmol) were
reacted according to procedure A and chromatographed
n-hexane/EtOAc 1/1) and afforded glycoconjugate 10h
J = 8.4 Hz, Ar-H), 7.71 (s, 1 H, triazolyl-H), 7.49 (d, 2
H, J = 8.1 Hz, Ar-H), 5.06–4.77 (m, 4 H, ÀN-NCH ,
2
0
ÀOCH ), 4.32 (t, 1 H, J = 6.3 Hz), 4.20–3.97 (m, 5 H,
2
overlapped), 3.87 (d, 1 H, J = 8.4 Hz), 3.61–3.55 (m, 2
(
H, ÀN═CCH ), 1.55, 1.46, 1.37, 1.34 (each s, 12 H, 2
2
1
3
(108 mg, 82%) as brown solid. R 0.40 (n-hexane/
f
x > C (CH ) ) ppm; C NMR (CDCl , 150 MHz): δ
3
2
3
À1
EtOAc 1/1); IR (KBr) cm 3002, 2987, 2962, 1620
1
1
4
64.6, 164.1, 144.0, 138.2, 129.5, 128.1, 123.5, 121.8,
12.1, 109.1, 104.2, 76.6, 73.8, 71.7, 65.1, 60.4, 60.2,
(
1
C═N), 1591 (C═C), 1498, 1456, 1380, 1227, 1143,
1
121, 1062, 835; H NMR (CDCl , 300 MHz): δ 7.91
3
6.2, 28.2, 26.8, 26.2, 26.0 ppm. HRMS: m/z Calcd for
+
(d, 2 H, J = 7.2 Hz, Ar-H), 7.72 (s, 1 H, triazolyl-H),
.47 (d, 2 H, J = 6.9 Hz, Ar-H), 7.31–7.13 (m, 20 H,
Ph-H), 4.97–4.45 (m, 13 H, overlapped, ÀN-NCH
C H N O ClNa [M + Na] : 570.1732; found: 570.1730.
25 30 5 7
7
1
-[2-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)ethyl]-4-(1,2-O-
isopropylidene-3-O-methyl-α-D-xylofuranos-3-yl)-1H-[1,2,3]-
triazole (10f). Compounds 9 (40 mg, 0.16 mmol) and 1f
,
2
ÀOCH Ph), 4.12 (m, 1 H), 3.99–3.93 (m, 1 H), 3.84–
2
1
3
(
56 mg, 0.18 mmol) were treated with CuI (9 mg,
.05 mmol) and DIPEA (14 μL, 0.08 mmol) in
DCM according to procedure A and chromatographed
3.52 (m, 6 H, overlapped) ppm; C NMR (CDCl ,
3
0
75 MHz): δ 163.9, 163.1, 144.7, 138.8, 138.2, 137.9,
129.5, 128.4, 128.2, 128.1, 127.9, 127.7, 127.6, 123.8,
121.9, 96.6, 82.0, 79.8, 75.8, 75.5, 75.1, 74.9, 73.5,
73.2, 70.5, 68.5, 46.1, 26.7 ppm. HRMS: m/z Calcd for
(
(
1
n-hexane/EtOAc 1/1) and afforded glycoconjugate 10f
58 mg, 64%) as brown solid. R 0.34 (n-hexane/EtOAc
f
À1
+
/1); IR (KBr) cm 3020, 2977, 2935, 1615 (C═N),
572 (C═C), 1460, 1382, 1256, 1134 (C-O), 1080, 823;
C H N O Cl [M + H] : 828.3086; found: 828.3089.
4
7 46 5 7
1
1-[2-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)ethyl]-4-(2,3,4,
1
H NMR (CDCl , 300 MHz): δ 7.85 (d, 2 H, J = 7.8 Hz,
6-tetra-O-benzyl-1-O-methyl-β-D-glucopyranos-1-yl)-1H-[1,2,
3
3
]-triazole (10i). Compounds 9 (40 mg, 0.16 mmol) and
Ar-H), 7.51 (s, 1 H, triazolyl-H), 7.37 (d, 2 H, J = 7.8 Hz,
Ar-H), 7.33–7.25 (m, 5 H, Ph-H), 5.88 (d, 1 H, J = 3.6 Hz,
1
h (102 mg, 0.18 mmol), CuI (9 mg, 0.05 mmol) and
DIPEA (14 μL, 0.08 mmol) were reacted following
procedure A and chromatographed (n-hexane/EtOAc 1/1)
H-1), 4.92–4.55 (m, 6 H, overlapped, ÀOCH Ph), 4.76 (t,
2
J = 6.6 Hz, ÀNCH ), 4.23–3.90 (m, 4 H, overlapped),
2
and afforded glycoconjugate 10i (112 mg, 85%) as brown
3
1
.66 (m, 1 H), 3.53 (t, J = 6.6 Hz, 2 H, ÀN═CCH ), 1.46,
2
1
solid. R = 0.40 (n-hexane/EtOAc 1/1); H NMR (CDCl ,
.31 (each s, each 3 H, >C(CH ) ) ppm. HRMS: m/z
f
3
3
2
+
3
00 MHz): δ 7.90 (d, 2 H, J = 8.7 Hz, Ar-H), 7.65 (s, 1 H,
triazolyl-H), 7.45 (d, 2 H, J = 8.7 Hz, Ar-H), 7.33–7.15
(m, 20 H, Ph-H), 5.01–4.46 (m, 13 H, ÀN-NCH
ÀOCH Ph), 4.12 (dd, J = 14.1, 7.2 Hz, 1 H), 3.77–3.54
Calcd for C H N O ClNa [M + Na] : 590.1783; found:
5
2
8 30 5 6
90.1788.
1
-[2-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)ethyl]-4-(5-O-
benzyl-2,3-O-isopropylidene-1-O-methyl-α-D-lyxofuranos-1-yl)-
H-[1,2,3]-triazole (10g). (40 mg,
,
2
2
1
3
1
0
Compounds
.16 mmol) and alkyne 1g (56 mg, 0.18 mmol) were
treated with CuI (9 mg, 0.05 mmol) and DIPEA (14 μL,
.08 mmol) in DCM according to procedure A and
chromatographed (n-hexane/EtOAc 1/1) and delivered
9
(
m, 3 H), 3.46–3.44 (m, 4 H) ppm; C NMR (CDCl ,
3
7
1
1
7
5 MHz): δ 164.5, 163.1, 145.0, 138.5, 138.2, 138.0,
29.5, 128.4, 128.2, 128.1, 127.9, 127.8, 127.6, 124.1,
23.9, 121.9, 102.8, 102.7, 84.6, 82.2, 76.6, 75.6, 75.0,
0
4.7, 73.5, 69.0, 63.0, 46.1, 26.7 ppm. HRMS: m/z Calcd
+
glycoconjugate 10g (64 mg, 70%) as brown solid. R 0.34
f
for C H N O Cl [M + H] : 828.3086; found: 828.3084.
4
7 46 5 7
À1
(n-hexane/EtOAc 1/1); IR (KBr) cm 3005, 2970, 2933,
1
610 (C═N), 1560 (C═C), 1442, 1380, 1262, 1139 (C-
1
Acknowledgments. The authors thank Banaras Hindu
University, IIT Delhi, and CDRI Lucknow for spectroscopic
studies and Council of Scientific & Industrial Research, New
Delhi, for the funding (grant no. 02/(0173)/13/EMR-II). D. K.
acknowledges University Grants Comission for the fellowship.
O), 1066, 832; H NMR (CDCl , 300 MHz): δ 7.92 (d, 2
H, J = 8.1 Hz, Ar-H), 7.55 (s, overlapped, 1 H,
triazolyl-H), 7.46 (d, overlapped, J = 8.4 Hz, Ar-H),
3
7
.36–7.30 (m, 5 H, Ph-H), 5.05 (s, 1 H, H-1), 4.76 (m,
overlapped, 3 H, ÀN-NCH ), 4.69–4.54 (m, 4 H,
2
overlapped, ÀOCH Ph), 4.09 (m, 1 H), 3.98 (m, 1 H),
2
REFERENCES AND NOTES
3
.83 (m, 1 H), 3.70 (m, 1 H), 3.53 (t, 2 H, J = 6.3 Hz,
ÀN═CCH ), 1.42, 1.31 (each s, each 3 H, >C (CH ) )
2
3 2
[1] Tiwari, V. K.; Mishra, B. B.; Mishra, K. B.; Mishra, N.; Singh,
A. S.; Chen, X. Chem Rev 2016, 116, 3086.
13
ppm; C NMR (CDCl , 75 MHz): δ 164.5, 163.2, 147.5,
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Triazole-linked 1,3,4-Oxadiazole Glycoconjugates
[2] Tornoe, C. W.; Christensen, C.; Meldal, M. J Org Chem 2002,
[23] He, Y. W.; Cao, L. H.; Zhang, J. B.; Wang, D. Z.; Aisa, H. A.
6
7, 3057.
Carbohydr Res 2011, 346, 551.
[
3] Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew Chem Int Ed 2002, 41, 2596.
4] Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Chem Rev 2013,
13, 4905.
5] Gopalan, B.; Balasubramanian, K. K. Applications of click
[24] Yu, J.; Zhang, S.; Li, Z.; Lu, W.; Zhou, R.; Liu, Y.; Cai, M.
Carbohydr Res 2003, 338, 257.
[25] Han, D.; Meng, X. B.; Wang, L. N.; Liu, H.; Yao, Y.; Wang,
Z.; Yang, Z. J.; Liu, Z. M.; Li, Z. J. Tetrahedron: Asymmetry 2009, 20,
399.
[
1
[
chemistry in drug discovery and development; In Click Chemistry in
Organic SynthesisChandrasekaran, S. Ed.; Wiley-VCH Publication,
[26] Kun, S.; Nagy, G. Z.; Toth, M.; Czecze, L.; Van Nhien, A. N.;
Docsa, T.; Gergely, P.; Charavgi, M. D.; Skourti, P. V.; Chrysina, E. D.;
Patonay, T.; Somsak, L. Carbohydr Res 2011, 346, 1427.
[27] Szocs, B.; Toth, M.; Docsa, T.; Gergely, P.; Somsak, L.
Carbohydr Res 2013, 381, 187.
[28] Somsak, L.; Nagy, V.; Vidal, S.; Czifrak, K.; Berzsenyi, E.;
Praly, J. P. Bioorg Med Chem Lett 2008, 18, 5680.
[29] Nagy, V.; Benltifa, M.; Vidal, S.; Berzsenyi, E.; Teilhet, C.;
Czifrak, K.; Batta, G.; Docsa, T.; Gergely, P.; Somsak, L.; Praly, J. P.
Bioorg Med Chem 2009, 17, 5696.
2
016, pp. 25–76. chapter 2.
[6] Valente, S.; Trisciuoglio, D.; De Luca, T.; Nebbioso, A.;
Labella, D.; Lenoci, A.; Bigogno, C.; Dondio, G.; Miceli, M.;
Brosch, G.; Del Bufalo, D.; Altucci, L.; Mai, A. J Med Chem 2014, 57,
6
259.
[
[
[
7] Yale, H. L.; Losee, K. J Med Chem 1966, 9, 478.
8] Amir, M.; Shikha, K. Eur J Med Chem 2004, 39, 535.
9] Harfenist, M.; Heuser, D. J.; Joyner, C. T.; Batchelor, J. F.;
White, H. L. J Med Chem 1996, 39, 1857.
10] Zhang, M. Z.; Mulholland, N.; Beattie, D.; Irwin, D.; Gu, Y. C.;
Chen, Q.; Yang, G. F.; Clough, J. Eur J Med Chem 2013, 63, 22.
11] Chen, C.-Y.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. J Org Chem 1994, 59, 3738.
12] Guimaraes, C. R. W.; Boger, D. L.; Jorgensen, W. L. J Am
Chem Soc 2005, 127, 17377.
13] Bostrom, J.; Hogner, A.; Llinas, A.; Wellner, E.; Plowright,
A. T. J Med Chem 2012, 55, 1817.
[30] Abu-Zaied, M. A.; El-Telbani, E. M.; Elgemeie, G. H.;
Nawwar, G. A. M. Eur J Med Chem 2011, 46, 229.
[31] Polyak, M.; Varga, G.; Szilagyi, B.; Juhasz, L.; Docsa, T.;
Gergely, P.; Begum, J.; Hayes, J. M.; Somsak, L. Bioorg Med Chem
2013, 21, 5738.
[32] Wang, L.-N.; Han, D.; Xu, F.-F.; Meng, X.-B.; Li, Z.-J.
Carbohydr Res 2009, 344, 2113.
[33] Dwivedi, P.; Mishra, K. B.; Mishra, B. B.; Singh, N.; Singh,
R. K.; Tiwari, V. K. Glycoconj J 2015, 32, 127.
[34] Kushwaha, D.; Dwivedi, P.; Kuanar, S. K.; Tiwari, V. K. Curr
Org Synth 2013, 10, 90.
[
[
[
[
[
[
14] James, N. D.; Growcott, J. W. Drugs Future 2009, 34, 624.
15] Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi,
M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Gonzalez Paz, O.; Hazuda, D. J.;
Jones, P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi,
E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.;
Witmer, M. V.; Rowley, M. J Med Chem 2008, 51, 5843.
[35] Dwivedi, P.; Mishra, K. B.; Pritika Mishra, B. B.; Tiwari,
V. K. Glycoconj J 2017, 34, 61.
[36] Mishra, K. B.; Tiwari, V. K. J Org Chem 2014, 79, 5752.
[37] Kushwaha, D.; Tiwari, V. K. J Org Chem 2013, 78, 8184–8190.
[38] Mishra, A.; Tiwari, V. K. J Org Chem 2015, 80, 4869.
[39] Kushwaha, D.; Singh, R. S.; Tiwari, V. K. Tetrahedron Lett
2014, 55, 4532.
[
16] Vardan, S.; Smulyan, H.; Mookherjee, S.; Eich, R. Clin
Pharmacol Ther 1983, 34, 290.
17] Saitoh, M.; Kunitomo, J.; Kimura, E.; Iwashita, H.; Uno, Y.;
[
Onishi, T.; Uchiyama, N.; Kawamoto, T.; Tanaka, T.; Mol, C. D.;
Dougan, D. R.; Textor, G. P.; Snell, G. P.; Takizawa, M.; Itoh, F.;
Kori, M. J Med Chem 2009, 52, 6270.
[40] Mishra, K. B.; Tiwari, V. K. Chemistry Select 2016, 1, 3693.
[41] Kumar, D.; Mishra, A.; Mishra, B. B.; Tiwari, V. K. J Org
Chem 2013, 78, 899.
[
18] Gosselin, F.; Britton, R. A.; Davies, I. W.; Dolman, S. J.;
[42] Mishra, K. B.; Mishra, B. B.; Tiwari, V. K. Carbohydr Res
2014, 399, 2.
Gauvreau, D.; Hoerrner, R. S.; Hughes, G.; Janey, J.; Lau, S.; Molinaro, C.;
Nadeau, C.; O’Shea, P. D.; Palucki, M.; Sidler, R. J Org Chem 2010, 75, 4154.
[43] Mishra, K. B.; Shashi, S.; Tiwari, V. K. RSC Adv 2015, 5,
86840.
[19] Ohmoto, K.;Yamamoto, T.;Okuma,M.;Horiuchi,T.;Imanishi,
H.;Odagaki,Y.;Kawabata,K.;Sekioka,T.;Hirota,Y.;Matsuoka,S.;Nakai,
H.; Toda, M. J Med Chem 2001, 44, 1268.
[44] Mishra, A.; Mishra, B. B.; Tiwari, V. K. RSC Adv 2015, 5,
41520.
[20] Pardridge, W. M. Adv Drug Deliv Rev 1995, 15, 5.
[45] Mishra, K. B.; Mishra, R. C.; Tiwari, V. K. RSC Adv 2015, 5,
51779.
[21] Wong, C. H. Carbohydrate-based Drug Discovery;
Wiley-VCH: New York, 2003.
22] Tiwari, V. K.; Mishra, R. C.; Sharma, A.; Tripathi, R. P.
Mini-Rev Med Chem 2012, 12, 1497.
[46] Brady, R. F. Jr. Carbohydr Res 1970, 15, 35.
[47] Schmidt, O. T. Methods Carbohydr Chem 1963, 2, 318.
[48] Roy, B.; Mukhopadhyay, B. Tetrahedron Lett 2007, 48, 3783.
[
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet