Synthesis of novel glycosyl 1,3,4-oxadiazole derivatives

Article abstract of DOI:10.1515/hc-2014-0166

A convenient and practical protocol was developed to synthesize glycosyl 1,3,4-oxadiazoles from d-glucosamine with good to excellent yields. The key step involved p-TsCl/pyridine-mediated cyclization under mild conditions. Subsequent removal of the acetyl groups in the last step, conducted using the system of NaOMe/MeOH, gave the desired N-acetyl-d-glucosamine 1,3,4-oxadiazole derivatives.

Full text of DOI:10.1515/hc-2014-0166

Heterocycl. Commun. 2014; 20(6): 333–338
Weiwei Liu*, Quxiang Li*, Fengchang Cheng, Dahua Shi and Zhiling Cao
Synthesis of novel glycosyl 1,3,4-oxadiazole
derivatives
Abstract: A convenient and practical protocol was devel- proteoglycans, glycosphingolipids, lipopolysaccha-
oped to synthesize glycosyl 1,3,4-oxadiazoles from d-glu- rides, and chitin/chitosan [7–11]. Recent studies have
cosamine with good to excellent yields. The key step demonstrated that they show a broad range of biologi-
involved p-TsCl/pyridine-mediated cyclization under cal activities like antibacterial, antitumor, antiviral,
mild conditions. Subsequent removal of the acetyl groups anticancer, antioxidant, and anti-inflammatory proper-
in the last step, conducted using the system of NaOMe/ ties [12–15]. Meanwhile, 1,3,4-oxadiazoles are commonly
MeOH, gave the desired N-acetyl-d-glucosamine 1,3,4-oxa- utilized pharmacophores due to their metabolic profile
diazole derivatives.
and ability to engage in hydrogen bonding, which has
attracted considerable interest in medicinal chemistry, as
Keywords: cyclization; derivatives; d-Glucosamine; they are associated with versatile effects, including anti-
1,3,4-oxadiazole.
fungal, antimicrobial, antihypertensive, antitubercular,
immunosuppressive, analgesic, and sedative properties
[16–19]. In particular, marketed antihypertensive agents
such as tiodazosin and nesapidil as well as antibiotics
such as furamizole all contain the oxadiazole system
[20–22]. 1,3,4-Oxadiazole-containing compounds are also
used as HIV integrase inhibitors and angiogenesis inhibi-
tors [23, 24].
Synthesis of the 7-nitrobenz-2,1,3-oxadiazole deriva-
tives via the base-catalyzed reaction of the corresponding
halide (either chloride a or fluoride b, Figure 1) with d-glu-
cosamine to produce the highly fluorescent product c [25]
has been reported. Another report describes the synthesis
of 1,3,4-oxadiazole-linked derivatives of d-glucose d by
acylation with propiolic acid-DCC or chloroacetyl chloride
to give novel inhibitors of glycogen phosphorylase [26].
Chemical modifications of d-glucosamine at the gly-
coside hydroxy group mainly rely on glycosylation [27, 28],
alkylation [29, 30], arylation [31, 32], and phospholipid
formation [33, 34]. Synthesis of compounds containing
both 1,3,4-oxadiazole and d-glucosamine have not been
investigated via the links of the nitrogen glycoside. Herein
we report a mild and efficient protocol for synthesis of
glycosyl 1,3,4-oxadiazole derivatives via p-TsCl/pyridine
mediated cyclization. The p-TsCl reagent replaces some
DOI 10.1515/hc-2014-0166
Received October 16, 2014; accepted November 6, 2014
Introduction
The synthesis of novel molecular scaffolds with unique
structural and biological properties is an increasingly
active area of current chemical research [1]. Glycobiology
and carbohydrate chemistry have been paid enormous
attention over the past few years owing to the remarkable
role played in many biological events [2–4]. d-Glucosa-
mine, a natural amino monosaccharide, widely exists in
marine organisms’ shell [5] and is an indispensable sub-
stance in pharmacology [6]. Moreover, d-glucosamine
and its derivatives are found in numerous biologically
active molecules such as cell surface N-glycoproteins,
*Corresponding authors: Weiwei Liu, School of Chemical Engineering,
Huaihai Institute of Technology, Lianyungang 222005, P.R. China;
School of Chemical Engineering, China University of Mining and
Technology, XuZhou 221116, P.R. China; and Jiangsu Marine Resources
Development Research Institute, Lianyungang 222005, P.R. China,
e-mail: liuww2007ly@aliyun.com; and Quxiang Li, School of Chemical
Engineering, China University of Mining and Technology, XuZhou
221116, P.R. China, e-mail: liquxiang@163.com
Fengchang Cheng: School of Chemical Engineering, China
University of Mining and Technology, XuZhou 221116, P.R. China
Dahua Shi and Zhiling Cao: School of Chemical Engineering,
Huaihai Institute of Technology, Lianyungang 222005, P.R. China;
and Jiangsu Marine Resources Development Research Institute,
Lianyungang 222005, P.R. China
HO
NO2
HO
O
N
N
N
N
O
OH
N
HO
HO
R
HO
HO
O
O
NH
OH
X
O
N
a X = Cl (NBD-Cl)
b X = F (NBD-F)
d
c
NO2
Figure 1ꢀ1,3,4-Oxadiazole derivatives a–d.
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ꢀW. Liu et al.: Glycosyl 1,3,4-oxadiazole derivatives
AcO
HO
HO
O
O
O
i
iii
ii
AcO
AcO
HO
HO
HO
HO
OH
OH
NH2·HCl
NH
NHAc
Cl
O
2
3
1
AcO
OAc
AcO
Ph
O
O
H
N
H
N
O
v
iv
O
AcO
AcO
AcO
NCS
AcO
AcO
N
R
N
S
AcO
NHAc
H
O
NHAc
NHAc
S
N
N
4
6
7
N
R
R
H
v
HO
AcO
O
O
H
H
vi
AcO
AcO
HO
HO
N
N
O
O
NHAc
NHAc
R
N
N
N
8
9
6a, 7a, 8a, 9a: R = CH3
6b, 7b, 8b, 9b: R = C6H5
6c, 7c, 8c, 9c: R = 4-CH3C6H4
6g, 7g, 8g, 9g: R = 4-IC6H4
6h, 7h, 8h, 9h: R = 4-NO2C6H4
6i, 7i, 8i, 9i: R = 4-OHC6H4
6d,7d, 8d, 9d: R = 3-CH3OC6H4
6e, 7e, 8e, 9e: R = 4-FC6H4
6f, 7f, 8f, 9f: R = 4-ClC6H4
6j, 7j, 8j, 9j: R = 4-[(CH3)2N]C6H4
6k, 7k, 8k, 9k: R = 2-pyridyl
6l, 7l, 8l, 9l: R = 2-thienyl
Scheme 1ꢀ(i) Ac2O, TEA, MeOH, 0°C; (ii) CH3COCl, rt; (iii) KSCN, (n-C4H9)4NHSO4, CH3CN, 4-Å molecular sieves; (iv) RCONHNH2 (5), EtOH,
reflux; (v) p-TsCl, pyridine, THF, 65°C, or 2-bromoacetophenone, TEA (see text); (vi) NaOMe, MeOH, 23°C.
Ts
S
O
S
O
R
S
O
Pyridine
Pyridine
Glu
Glu
Glu
P-TsCl
Glu
N
N
N
R
N
N
N
R
N
N
N
R
H
H
H
H
H
H
H
H
Ts
N
O
S
O
Glu
N
N
N
N
R
N
H
Scheme 2ꢀProposed mechanism of cyclization of 6 by the system p-TsCl/pyridine in tetrahydrofuran.
sensitive reagents such as POCl3, DCC, concentrated H2SO4, attempted cyclization did not yield the desired glycosylth-
among others. Importantly, different substituted deriva- iazole 7a. Fortunately, this treatment produced the glyco-
tives of glycosyl-1,3,4-oxadiazole can also be obtained syl-1,3,4-oxadiazole 8a. Encouraged by this result, other
using the present method.
substituted acylthiosemicarbazides were investigated to
examine the generality of this reaction. To our disappoint-
ment, the expected products were obtained in low yield
and the procedure was time consuming.
Results and discussion
It was thought that acylthiosemicarbazides could be
activated toward cyclization of 6 by the reaction with tosyl
First, N-acetylglucosamine 2 [35] was prepared from glu- chloride in the presence of pyridine [38]. Gratifyingly,
cosamine hydrochloride 1. By treatment of 1 with acetic the desired glycosyl-1,3,4-oxadiazoles 8 were obtained
anhydride in the presence of triethylamine (Scheme 1). in high yields of up to 90% using this approach. It was
Compound 4 was synthesized according to the literature found substrates 6 with both electron-withdrawing and
protocol [36] using the reaction of glycosyl chloride 3 electron-donating groups can be smoothly converted
[37] with potassium thiocyanate in acetonitrile and then to the desired products 8. Furthermore, it is noteworthy
treated with various hydrazides 5 in ethanol to yield the that acylthiosemicarbazides carrying heterocyclic groups
key acylthiosemicarbazide intermediates 6. Initially, com- such as pyridyl and thienyl also readily participate in the
pound 6a (Rꢀ= ꢀCH3) was selected as substrate to be directly reaction. The proposed mechanism is shown in Scheme 2.
cyclized by treatment with 2-bromoacetophenone in the The acetyl derivatives 8 were efficiently deprotected to the
presence of a catalytic amount of triethylamine but this hydroxyl derivatives 9 as shown in Scheme 1.
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ꢀ335
removed on a rotary evaporator. The residue was crystallized from
aqueous ethanol to obtain the desired product. Characterization of
the representative compound 6b is presented below.
Conclusions
The synthesis of a novel class of d-glucosamine-based
1,3,4-oxadiazole derivatives is described. The most note-
worthy aspect of this research is the development of a mild
and convenient route to the synthesis of glycosyl-1,3,4-oxa-
diazoles by cyclization of the hydrazides using a system of
p-TsCl/pyridine. d-Glucosamine and its derivatives play
an important role in biomedical research.
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-
N′-5-benzoyl thiosemicarbazide (6b):ꢀWhite solid; yield 87%; mp
1
202–203°C; IR: v 3274, 2931, 2931, 1751, 1668, 1239, 1043, 910 cm-1; H
NMR (DMSO-d6): δ 10.29 (br s, 1H), 10.11 (br s, 1H), 8.21 (d, J ꢀ= ꢀ 9 Hz,
1H), 8.03 (s, 1H), 7.81 (m, 2H), 7.46 (m, 3H), 5.44(t, J ꢀ= ꢀ 9 Hz, 1H), 5.13 (d,
J ꢀ= ꢀ 10 Hz, 1H), 4.82 (d, J ꢀ= ꢀ 9 Hz, 1H), 4.18 (s, 1H), 3.94 (d, J ꢀ= ꢀ 11 Hz, 2H),
3.81(s, 1H), 1.95–1.73 (4s, 12H). HRMS (ESI). Calcd for C22H28N4O9SNa
(M+Na)+: m/z 547.1469. Found: m/z 547.1478.
Experimental
General procedure for the preparation of glycosyl
1,3,4-oxadiazoles 8a–l
All chemicals were purchased from commercial sources and used
without further purification. Melting points were determined on a
Yanaco melting point apparatus and are uncorrected. IR spectra were
Tosyl chloride (0.21 g, 1.1 mmol) was added to a stirred solution of
acylthiosemicarbazide 6 (1 mmol) and pyridine (0.16 mL, 2.0 mmol) in
5 mL THF. The solution was stirred at 65°C for 6 h and then extracted
with dichloromethane (DCM, 20 mL) and distilled water (15 mL). The
aqueous layer was re-extracted three times with DCM. The combined
organic phases were dried over MgSO4 and concentrated to obtain
the crude product, which was purified by column chromatography
on silica gel (MeOH/DCM).
1
recorded on a Bruker Tensor 27 spectrometer using KBr pellets. H
NMR spectra were recorded on a Bruker Avance 400 M Hz instrument
using DMSO-d6 or D2O. HRMS (ESI) analysis was performed on an
Agilent 6230 mass spectrometer. The purity of the compounds was
checked by TLC on plates precoated with silica gel GF254. Flash col-
umn chromatography was performed on silica 200–300 mesh.
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-
glucopyranosyl isothiocyanate (4)
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-
5-methyl-1,3,4-oxadiazole-2-amine (8a):ꢀWhite solid; yield 84%;
1
mp 148–149°C; IR: v 3326, 2928, 1749, 1663, 1243, 1041, 913 cm-1; H
NMR (DMSO-d6): δ 8.33 (d, J ꢀ= ꢀ 9 Hz, 1H), 8.06 (d, J ꢀ= ꢀ 9 Hz, 1H), 5.18
(m, 2H), 4.85 (t, J ꢀ= ꢀ 10 Hz, 1H), 4.20 (dd, J ꢀ= ꢀ 12 and 4 Hz, 1H), 3.93 (dd,
J ꢀ= ꢀ 20 and 10 Hz, 3H), 1.98–1.74 (4s, 12H), 1.24 (s, 3H). HRMS (ESI).
Calcd for C17H24N4O9Na (M+Na)+: m/z 451.1435. Found: m/z 451.1477.
This compound was obtained using the following modification of
the previously published procedure [36]. A mixture of glucosamine
hydrochloride (1, 10 g, 46.37 mmol), acetic anhydride (6.13 mL, 55.64
mmol), and triethylamine (6.46 mL, 46.37 mmol) in methanol (25 mL)
was stirred in an ice bath for 4 h. The mixture was filtered, and the
solid product 2 was dried and dissolved in acetyl chloride (30 mL).
The solution was stirred for 16 h at room temperature and then
extracted with chloroform. The extract was washed with saturated
sodium bicarbonate solution, dried over MgSO4, and concentrated,
and the residue was crystallized from ether to give 3. A mixture of
KSCN (0.58 g, 6 mmol), tetrabutylammonium hydrogen sulfate (0.34 g,
1 mmol), and molecular sieves (4 Å, 3.0 g) in anhydrous acetonitrile
(30 mL) was stirred at room temperature for 2.5 h and then treated
with compound 3 (1.1 g, 3 mmol). The mixture was heated under
reflux until the reaction was completed, as judged by TLC analysis.
The resultant suspension was filtered, and the filtrate was concen-
trated. The residue was purified by column chromatography (silica
gel, EtOAc/hexanes) to afford 4 (0.87 g, 75%) as a white solid; mp
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-
5-phenyl-1,3,4-oxadiazole-2-amine (8b):ꢀWhite solid; yield 90%;
mp 231–232°C; IR: v 3220, 2966, 1749, 1663, 1616, 1228, 1049, 917 cm-1;
1H NMR (DMSO-d6): δ 8.86 (d, J ꢀ= ꢀ 10 Hz, 1H), 8.08 (d, J ꢀ= ꢀ 9 Hz, 1H),
7.85 (dd, J ꢀ= ꢀ 7 and 4 Hz, 2H), 7.55 (m, 3H), 5.21(m, 2H), 4.87 (t, J ꢀ= ꢀ 10
Hz, 1H), 4.20 (dd, J ꢀ= ꢀ 12 and 4 Hz, 1H), 3.99 (q, J ꢀ= ꢀ 9 Hz, 3H), 1.98–1.74
(4s, 12H). HRMS (ESI). Calcd for C22H26N4O9Na (M+Na)+: m/z 513.1592.
Found: m/z 513.1594.
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-
5-(4-methylphenyl)-1,3,4-oxadiazole-2-amine (8c):ꢀWhite solid;
yield 92%; mp 194–195°C; IR: v 3315, 2926, 1749, 1667, 1621, 1227, 1043,
916 cm-1; 1H NMR (DMSO-d6): δ 8.79 (d, J ꢀ= ꢀ 9 Hz, 1H), 8.06 (d, J ꢀ= ꢀ 9 Hz,
1H), 7.73 (d, J ꢀ= ꢀ 8 Hz, 2H), 7.36 (d, J ꢀ= ꢀ 8 Hz, 2H), 5.20 (td, J ꢀ= ꢀ 10 and 5 Hz,
2H), 4.87 (t, J ꢀ= ꢀ 10 Hz, 1H), 4.19 (m, 1H), 3.97 (t, J ꢀ= ꢀ 10 Hz, 3H), 2.37 (s,
3H), 1.96–1.74 (4s, 12H). HRMS (ESI). Calcd for C23H28N4O9Na (M+Na)+:
m/z 527.1748. Found: m/z 527.1750.
1
158–159°C; H NMR (DMSO-d6): δ 8.25 (d, J ꢀ= ꢀ 9 Hz, 1H), 5.36 (d, J ꢀ= ꢀ 9
Hz, 1H), 5.11 (t, J ꢀ= ꢀ 9 Hz, 1H), 4.9 (t, J ꢀ= ꢀ 9 Hz, 1H), 4.12–4.05(m, 4H),
2.03–1.82 (4s, 12H). HRMS (ESI). Calcd for C15H20N2O8SNa (M+Na)+:
m/z 411.0833. Found: m/z 411.0844.
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-
5-(3-methoxyphenyl)-1,3,4-oxadiazole-2-amine (8d):ꢀWhite solid;
yield 88%; mp193–194°C; IR: v 3316, 2946, 1746, 1666, 1622, 1242, 1044,
General procedure for the preparation of glycosyl
acylthiosemicarbazides 6a–l
1
917 cm-1; H NMR (DMSO-d6): δ 8.84 (d, J ꢀ= ꢀ 10 Hz, 1H), 8.05 (d, J ꢀ= ꢀ 9
Hz, 1H), 7.43 (m, 2H), 7.31 (s, 1H), 7.10 (d, J ꢀ= ꢀ 8 Hz, 1H), 5.18 (td, J ꢀ= ꢀ 10
and 4 Hz, 2H), 4.86 (t, J ꢀ= ꢀ 10 Hz, 1H), 4.18 (dd, J ꢀ= ꢀ 12 and 4 Hz, 1H),
3.97 (m, 3H), 3.81 (s, 3 H), 1.94–1.72 (4s, 12H). HRMS (ESI). Calcd for
C23H28N4O10Na (M+Na)+: m/z 543.1698. Found: m/z 543.1703.
Glycosyl isothiocyanate 4 (0.39 g, 1 mmol) was added in one portion
to a stirred solution of hydrazide 5 (1 mmol) in 10 mL ethanol. The
mixture was heated under reflux for 1.5 h, and then the solvent was
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N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)- (dd, J ꢀ= ꢀ 12 and 7 Hz, 1H), 4.01 (dd, J ꢀ= ꢀ 12 and 4 Hz, 1H), 3.98 (m, 3H),
5-(4-fluorophenyl)-1,3,4-oxadiazole-2-amine (8e):ꢀWhite solid; 1.99–1.74 (4s, 12H). HRMS (ESI). Calcd for C21H25N5O9Na (M+Na)+: m/z
yield 82%; mp 210–211°C; IR: v 3383, 2957, 1749, 1668, 1624, 1227, 1045, 514.1544. Found: m/z 514.1548.
917 cm-1; 1H NMR (DMSO-d6): δ 8.83 (d, J ꢀ= ꢀ 10 Hz, 1H), 8.06 (d, J ꢀ= ꢀ 9 Hz,
1H), 7.90 (dd, J ꢀ= ꢀ 9 and 5 Hz, 2H), 7.41 (t, J ꢀ= ꢀ 9 Hz, 2H), 5.20 (td, J ꢀ= ꢀ 10 N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-
and 6 Hz, 2H), 4.87 (t, J ꢀ= ꢀ 10 Hz, 1H), 4.19 (dd, J ꢀ= ꢀ 12 and 5 Hz, 1H), 5-(2-thienyl)-1,3,4-oxadiazole-2-amine (8l):ꢀWhite solid; yield
3.98 (m, 3H), 1.96–1.74 (4s, 12H). HRMS (ESI). Calcd for C22H26FN4O9 81%; mp 204–206°C; IR: v 3406, 2964, 1749, 1662, 1623, 1240, 1038,
1
(M+H)+: m/z 509.1678. Found: m/z 509.1692.
905 cm-1; H NMR (DMSO-d6): δ 8.85 (d, J ꢀ= ꢀ 10 Hz, 1H), 8.04 (d, J ꢀ= ꢀ 9
Hz, 1H), 8.04 (d, J ꢀ= ꢀ 9 Hz, 1H), 7.81 (d, J ꢀ= ꢀ 5 Hz, 1H), 7.59 (d, J ꢀ= ꢀ 3 Hz,
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)- 1H), 7.23 (dd, J ꢀ= ꢀ 5 and 3 Hz, 1H), 5.18 (dt, J ꢀ= ꢀ 14 and 10 Hz, 2H), 4.86
5-(2-chlorophenyl)-1,3,4-oxadiazole-2-amine (8f):ꢀWhite solid; (t, J ꢀ= ꢀ 10 Hz, 1H), 4.20 (dd, J ꢀ= ꢀ 12 and 5 Hz, 1H), 4.00 (m, 3H), 1.98–1.74
yield 64%; mp 189–190°C; IR: v 3321, 2952, 1743, 1666, 1617, 1245, 1041, (4s, 12H). HRMS (ESI). Calcd for C20H24N4O9SNa (M+Na)+: m/z 519.1156.
916 cm-1; 1H NMR (DMSO-d6): δ 8.97 (d, J ꢀ= ꢀ 10 Hz, 1H), 8.08 (d, J ꢀ= ꢀ 9 Hz, Found: m/z 519.1163.
1H), 7.86 (dd, J ꢀ= ꢀ 8 and 2 Hz, 1H), 7.67 (d, J ꢀ= ꢀ 8 Hz, 1H), 7.54 (td, J ꢀ= ꢀ 8
and 6 Hz, 2H), 5.20 (td, J ꢀ= ꢀ 10 and 6 Hz, 2H), 4.87 (t, J ꢀ= ꢀ 10 Hz, 1H),
4.20 (dd, J ꢀ= ꢀ 12 and 4 Hz, 1H), 3.97 (m, 3H), 1.96–1.75 (4s, 12H). HRMS
General procedure for deprotection of O-acetyl-
(ESI). Calcd for C22H25ClN4O9Na (M+Na)+: m/z 547.1202. Found: m/z
substituted compounds 8 to hydroxy derivatives 9
547.1212.
A solution of compound 8 (0.5 mmol) in methanol (5 mL) was treated
with sodium methoxide (1 M in methanol, 0.2 mL). The mixture was
stirred at ambient temperature for 2 h and then neutralized with
Amberlite IR 120 H+ resin and filtered. The filtrate was concentrated
to afford the deprotected product 9. Selected products 9c,d,g,j are
characterized below.
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-
5-(4-iodophenyl)-1,3,4-oxadiazole-2-amine (8g):ꢀWhite solid;
yield 78%; mp 224–225°C; IR: v 3421, 2924, 1747, 1662, 1624, 1224, 1045,
1
915 cm-1; H NMR (DMSO-d6): δ 8.89 (d, J ꢀ= ꢀ 10 Hz, 1H), 8.06 (d, J ꢀ= ꢀ 9
Hz, 1H), 7.93 (d, J ꢀ= ꢀ 9 Hz, 2H), 7.61 (d, J ꢀ= ꢀ 9 Hz, 2H), 5.20 (td, J ꢀ= ꢀ 10
and 4 Hz, 2H), 4.87 (t, J ꢀ= ꢀ 10 Hz, 1H), 4.19 (dd, J ꢀ= ꢀ 12 and 4 Hz, 1H),
3.98 (m, 3H), 1.98–1.74 (4s, 12 H). HRMS (ESI). Calcd for C22H25IN4O9Na
(M+Na)+: m/z 639.0558. Found: m/z 639.0547.
N-(2-Acetamido -2- deoxy-β-d - glucopyr anosyl)-5-(4-
methylphenyl)-1,3,4-oxadiazole-2-amine (9c):ꢀWhite solid; yield
95%; mp 197–198°C; IR: v 3419, 1629, 1579, 1413, 1316, 1052, 820 cm-1; 1H
NMR (D2O): δ 7.72 (d, J ꢀ= ꢀ 8 Hz, 2H), 7.35 (d, J ꢀ= ꢀ 8 Hz, 2H), 4.79 (t, J ꢀ= ꢀ 9
Hz, 1H), 3.66–3.15 (m, 6H), 2.34 (s, 3H), 1.81(s, 3H). HRMS (ESI). Calcd
for C17H22N4O6Na (M+Na)+: m/z 401.1432. Found: m/z 401.1439.
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-
5-(4-nitrophenyl)-1,3,4-oxadiazole-2-amine (8h):ꢀYellow solid;
yield 75%; mp 205–206°C; IR: v 3334, 2956, 1746, 1665, 1617, 1225,
1046, 917 cm-1; 1H NMR (DMSO-d6): δ 9.13 (d, J ꢀ= ꢀ 10 Hz, 1H), 8.39 (d, J ꢀ= ꢀ
9 Hz, 2H), 8.09 (d, J ꢀ= ꢀ 9 Hz, 3H), 5.23 (m, 2H), 4.87 (t, J ꢀ= ꢀ 10 Hz, 1H),
4.20 (m, 1H), 4.00 (m, 3H), 1.97–1.74 (4s, 12H). HRMS (ESI). Calcd for
C22H26N5O11 (M+H)+: m/z 536.1623. Found: m/z 536.1621.
N-(2-Acetamido -2- deox y-β-d - glucopyr anosyl)-5-( 3-
methoxyphenyl)-1,3,4-oxadiazole-2-amine (9d):ꢀWhite solid;
yield 92%; mp 172–173°C; IR: v 3416, 1629, 1581, 1424, 1287, 1042, 853
1
cm-1; H NMR (D2O): δ 7.46 (d, J ꢀ= ꢀ 8 Hz, 1H), 7.32 (dd, J ꢀ= ꢀ 3 and 2 Hz,
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-
5-(4-hydroxyphenyl)-1,3,4-oxadiazole-2-amine (8i):ꢀWhite solid;
yield 80%; mp 182–184°C; IR: v 3392, 3054, 1752, 1630, 1611, 1238,
1H), 7.11 (m, 1H), 4.78 (t, J ꢀ= ꢀ 9 Hz, 1H), 3.83 (s, 3H), 3.65–3.12 (m, 6H),
1.79 (s, 3H). HRMS (ESI). Calcd for C17H22N4O7K (M+K)+: m/z 433.1120.
Found: m/z 433.1120.
1
1045, 916 cm-1; H NMR (DMSO-d6): δ 10.12 (s, 1H), 8.65 (d, J ꢀ= ꢀ 10 Hz,
1H), 8.04 (d, J ꢀ= ꢀ 9 Hz, 1H), 7.67 (d, J ꢀ= ꢀ 9 Hz, 2H), 6.90 (d, J ꢀ= ꢀ 9 Hz, 2H),
5.18 (dt, J ꢀ= ꢀ 14 and 10 Hz, 2H), 4.86 (t, J ꢀ= ꢀ 10 Hz, 1H), 4.19 (dd, J ꢀ= ꢀ 12
and 4 Hz, 1H), 3.96 (m, 3H), 1.98–1.74 (4s, 12H). HRMS (ESI). Calcd for
C22H26N4O10Na (M+Na)+: m/z 529.1541. Found: m/z 529.1537.
N-(2-Acetamido-2-deoxy-β-d-glucopyranosyl)-5-(4-iodophenyl)-
1,3,4-oxadiazole-2-amine (9g):ꢀWhite solid; yield 84%; m.p168–
169°C; IR: v 3388, 2923, 1626, 1530, 1386, 1067, 892 cm-1; 1H NMR (D2O):
δ 7.92 (m, 2H), 7.68 (m, 2H), 4.90 (t, J ꢀ= ꢀ 10 Hz, 1H), 3.90–3.39 (m,
6H), 1.99 (s, 1H). HRMS (ESI). Calcd for C16H19IN4O6Na (M+Na)+: m/z
513.0241. Found: m/z 513.0246.
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-
5-(4-N,N-dimethylphenyl-1,3,4-oxadiazole-2-amine (8j):ꢀWhite
solid; yield 87%; mp 222–223°C; IR: v 3421, 2924, 1747, 1662, 1624, 1224,
1045, 915 cm-1; 1H NMR (DMSO-d6): δ 8.58 (d, J ꢀ= ꢀ 10 Hz, 1H), 8.05 (d, J ꢀ= ꢀ
9 Hz, 1H), 7.63 (d, J ꢀ= ꢀ 9 Hz, 2H), 6.80 (d, J ꢀ= ꢀ 9 Hz, 2H), 5.18 (dt, J ꢀ= ꢀ 17
and 10 Hz, 2H), 4.86 (t, J ꢀ= ꢀ 10 Hz, 1H), 4.20 (dd, J ꢀ= ꢀ 12 and 4 Hz, 1H),
3.96 (m, 3H), 2.99 (s, 6H), 1.99–1.75 (4s, 12H). HRMS (ESI). Calcd for
C24H31N5O9Na (M+Na)+: m/z 556.2014. Found: m/z 556.2015.
N-(2-Acetamido-2-deoxy-β-d-glucopyranosyl)-5-(4-N,N-
dimehylphenyl-1,3,4-oxadiazole-2-amine (9j):ꢀWhite solid; yield
89%; mp179–180°C; IR: v 3447, 2914, 1626, 1578, 1439, 1082, 814 cm-1;
1H NMR (D2O): δ 7.71 (d, J ꢀ= ꢀ 9 Hz, 2H), 6.85 (d, J ꢀ= ꢀ 9 Hz, 2H), 4.84 (t, J ꢀ= ꢀ
10 Hz, 1H), 372 (dd, J ꢀ= ꢀ 16 and 10 Hz, 2H), 3.54 (dd, J ꢀ= ꢀ 12 and 5 Hz,
1H), 3.48 (t, J ꢀ= ꢀ 9 Hz, 1H), 3.34 (m, 1H), 3.24 (t, J ꢀ= ꢀ 9 Hz, 1H), 3.02 (s,
6H), 1.90 (s, 3H). HRMS (ESI). Calcd for C18H25N5O6Na (M+Na)+: m/z
430.1697. Found: m/z 430.1695.
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-
5-(2-pyridyl)-1,3,4-oxadiazole-2-amine (8k):ꢀYellow solid; yield
79%; mp182–184°C; IR: v 3393, 2926, 1750, 1665, 1618, 1227, 1049, 916
cm-1; 1H NMR (DMSO-d6): δ 9.03 (d, J ꢀ= ꢀ 2 Hz, 1H), 8.95 (d, J ꢀ= ꢀ 10 Hz, 1H),
8.72 (d, J ꢀ= ꢀ 4 Hz, 1H), 8.21 (dt, J ꢀ= ꢀ 8.0 and 2 Hz, 1H), 8.05 (d, J ꢀ= ꢀ 9 Hz,
1H), 7.59 (dd, J ꢀ= ꢀ 8 and 5 Hz, 1H), 5.21 (dt, J ꢀ= ꢀ 10 and 2 Hz, 2H), 4.89
Acknowledgments: We are grateful to the Major Project
of Natural Science Research in Colleges and Universities
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