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

Article abstract of DOI:10.3184/174751916X14738636315471

A convenient and mild protocol for the synthesis of glycosyl 1,3,4-Thiadiazole derivatives was developed, which involved the reaction of glycosyl isothiocyanate, hydrazine hydrate, and various aldehydes followed by oxidative cyclisation with ferric ammonium sulfate in methanol. 13 examples of different glycosyl 1,3,4-Thiadiazole derivatives were prepared. Good yields (70-87%) have been achieved. The glycosyl 1,3,4-Thiadiazole derivatives may find applications in medicinal chemistry and pharmaceutical industry.

Full text of DOI:10.3184/174751916X14738636315471

614 RESEARCH PAPER
VOL. 40 OCTOBER, 614–619
JOURNAL OF CHEMICAL RESEARCH 2016
Synthesis of novel glycosyl 1,3,4-thiadiazole derivatives
b
a
a
a,c,d
a,c
a,c
Feng-Chang Cheng , Long Yin , Xiu-Jian Liu , Wei-Wei Liu *, Zhi-Ling Cao , Da-Hua Shi
a
and Lei Wang
a
College of Pharmaceutical Sciences, Huaihai Institute of Technology, Lianyungang 222005, P.R. China
China University of Mining and Technology, Xuzhou 221116, P.R. China
Jiangsu Institute of Marine Resources, Lianyungang 222005, P.R. China
Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Huaihai Institute of Technology, Lianyungang 222005, P.R. China
b
c
d
A convenient and mild protocol for the synthesis of glycosyl 1,3,4-thiadiazole derivatives was developed, which involved the reaction
of glycosyl isothiocyanate, hydrazine hydrate, and various aldehydes followed by oxidative cyclisation with ferric ammonium sulfate in
methanol. 13 examples of different glycosyl 1,3,4-thiadiazole derivatives were prepared. Good yields (70–87%) have been achieved. The
glycosyl 1,3,4-thiadiazole derivatives may find applications in medicinal chemistry and pharmaceutical industry.
Keywords: D-glucosamine, 1,3,4-thiadiazole, glycosyl isothiocyanate
The research of monosaccharides has been highly valued in
areas of chemistry and biology due to the unique structures and
glucosamine derivatives containing 1,3,4-thiadiazole attached
to the C(2)-amino group.
1,2
various biological activities of carbohydrates. D-Glucosamine
is a naturally occurring compound, present within animal bones,
the shells of shellfish and bone marrow. It is the biochemical
precursor of all nitrogen-containing sugars, synthesised
A large number of methods have been reported to synthesise
1,3,4-thiadiazoles. Generally, preparation of 1,3,4-thiadiazole
involves the use of acidic reagents such as POCl , H PO ,
3
3
4
HClO , and some strong mineral acid. However, the harsh
4
3
in vivo as glucosamine-6-phosphate. Recent studies have
reaction conditions, limited substrate scope and environmental
pollution restricts the use of these methods. What is more,
the glycosyl 1,3,4-thiadiazole unit cannot be prepared in
such strong acids. Recently, some milder methods have been
reported for the synthesis of 1,3,4-thiadiazoles using trimethyl
demonstrated that D-glucosamine showed a broad range of
4
–6
biological activities. In particular, D-glucosamine can be used
as a single pharmacological agent to relieve arthritic complaints
and arthritis symptoms in clinics because of its beneficial
7
18
19
20
effects in joint tissues. Advantages of drugs containing
chlorosilane, Lawesson’s reagent and tosyl chloride.
glucosamine are the treatment of arthritis without causing side
effects. Furthermore, D-glucosamine possesses other biological
activities such as antioxidant, anti-inflammatory, antibacterial
But these synthetic methods need high temperature, a long
time, and require difficult separations. The target compound
1,3,4-thiadiazoles have been synthesised by multi-step
procedures in most of the synthetic methods. There is a need to
synthesise 1,3,4-thiadiazoles from mild starting materials using
mild general and convenient procedures.
Herein, we report a facile, high-yielding synthesis of novel
glycosyl 1,3,4-thiadiazole derivatives from a reagent based
cyclisation of ferric ammonium sulfate (FAS). The use of the
FAS will not suffer from serious environmental and operational
issues. This protocol can provide various substituent derivatives
of glycosyl 1,3,4-thiadiazole.
8
–10
and antitumour. In recent years, the use of hybrid molecules
11
for new drug discovery has increased. Recent efforts have been
focused on the chemical synthesis of hybrid molecules where
other active groups are connected to the glucosamine unit via
1
2,13
linkers.
Carroll et al. reported the synthesis of a number
18
of F labelled glucosamine derivatives and evaluation of their
tumour uptake and normal tissue distribution in vivo in a mouse
model of cancer by positron emission tomography imaging.
Rosso et al. have synthesised glucosamine-functionalised poly
(
ε-caprolactone) (PCL), where the poly (ε-caprolactone) (PCL)
Results and discussion
linked with the amino group of the glucosamine, thus showing
enhanced cell density and spreading over the non-functionalised
samples. Ngoje et al. prepared a series of tolyl 2-azido-2-
deoxy-thio-glucoside donors with different combinations of
protecting groups, which can be used in glycosylation reactions
to test the correlations between the stereoselectivity and the
pattern of the protecting groups. Although the modifications
of D-glucosamine have been studied, reports on the synthesis
of amino of D-glucosamine linked to a heterocycle are rare,
especially the link to 1,3,4-thiadiazoles, which are commonly
utilised pharmacophores according to their broad spectrum
of biological activities and their lower toxicity and higher
In this procedure, glycosyl isothiocyanate is an important
intermediate. Our strategy began with the synthesis of glycosyl
isothiocyanate without protection of hydroxyl groups of
D-glucosamine hydrochloride 1 in different ways. But to our
disappointment, the glycosyl isothiocyanate was not obtained.
We speculated that the hydroxyl groups of the D-glucosamine
required protection. The benzyl group was selected to protect
the hydroxy groups. Gratifyingly, 2-isothiocyanate-1,3,4,6-
14
15
21
tetra-O-benzyl-2-deoxy-β-D-glucopyranose 6 , an important
intermediate, can be synthesised from 1,3,4,6-tetra-O-
benzyl-β-D-glucosamine hydrochloride 4 in high yields
2
2,23
16,17
stability in vivo. They have received much attention as useful
intermediates and they have a variety of biological activities such
as antitumour, antiviral, analgesic, antioxidant and anticancer.
In particular, the marketed antiglaucoma drugs acetazolamide
and the carbonic anhydrase inhibitor methazolamide contain
the thiadiazole nucleus and have showed therapeutic potential.
Taking into account the important role of 1,3,4-thiadiazoles in
various biological phenomena, we synthesised a series of novel
(Scheme 1). To obtain the 1,3,4,6-tetra-O-benzyl-β-D-
glucosaminehydrochloride4,theaminogroupofD-glucosamine
hydrochloride 1 was protected by using p-methoxybenzaldehyde
to provide Schiff’s base 2 initially. Then benzylation of the four
hydroxyl groups with NaH and BnBr in DMF at a temperature
ranging from 0 °C to room temperature for 12 h afforded 3
and was followed by the preparation of 2-amino-1,3,4,6-tetra-
O-benzyl-2-deoxy-β-D-glucopyranose hydrochloride
4 by
*
Correspondent. E-mail: liuww323@aliyun.com

JOURNAL OF CHEMICAL RESEARCH 2016 615
the hydrolysis of 3 with hydrochloric acid. By protection of
the hydroxyl groups, the amino group of D-glucosamine can
be converted to the isothiocyanate 6 efficiently. To a solution
of 4 in acetonitrile was added triethylamine at 0 °C, followed
by the addition of carbon disulfide dropwise into the reaction
mixture using a syringe pump. The mixture was stirred for 2 h
to give the dithiocarbamic acid salts 5. Tosyl chloride (TsCl)
was then added to the reaction mixture. After a further 0.5 h,
glycosyl isothiocyanate 6 was obtained by solvent removal and
recrystallisation from ethanol in high yield.
have designed a three-component one-pot synthesis of glycosyl
1,3,4-thiadiazole derivatives which involves the reaction of
aldehydes 8, hydrazine hydrate 7 and glycosyl isothiocyanate 6
(Scheme 2). The procedure was divided into two stages. In the
first phase, treatment of the glycosyl isothiocyanate 6, hydrazine
hydrate 7 and various aldehydes 8a–m in methanol at 65 °C for
2 h afforded the important intermediate thiosemicarbazones 9a–
m. Upon completion of the reaction, as indicated by TLC, the
next phase was initiated.
2
4
In the second phase, we commenced our study with
benzaldehyde 8a, 6 and hydrazine hydrate 7 as model substrates
to select the optimal reaction conditions. Various catalysts,
As 2-isothiocyanate-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-
glucopyranose can now be obtained in an efficient manner, we
OH
OBn
O
OH
O
N
i
HO
HO
ii
BnO
BnO
O
OH
OBn
HO
HO
N
OH
·
NH HCl
2
O
O
1
2
3
OBn
OBn
S
v
iii
iv
OBn
O
O
BnO
BnO
BnO
BnO
O
OBn
OBn
·
2
BnO
BnO
NH HCl
NH
OBn
NCS
S Et NH
3
6
4
5
Reagents and conditions: (i) NaOH, p-methoxybenzaldehyde, H O, r.t., yield 81%; (ii) NaH, BnBr, DMF, 0 °C – r.t., yield 75%;
2
(
iii) 5 M HCl, acetone, reflux, 85%; (iv) Et N, CS , 0 °C, 1.5 h; (v) TsCl, 0.5 h, yield 90%.
3 2
Scheme 1 Synthesis of 2-isothiocyanate-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose 6.
OBn
O
OBn
BnO
BnO
OBn
i
ii
O
NH
NH
ꢀ
OBn
NH
2
NH
2
ꢁH
2
O ꢀ RCHO
BnO
BnO
S
NCS
N
R
6
7
8a−m
9a−m
OBn
O
BnO
BnO
OBn
NH
N
S
N
R
10a−m
a: R ꢂ C H
e: R ꢂ 3-NO C H
i: R ꢂ ꢃ-FC H
6
ꢃ
m: R ꢂ C
8
H
17
6
5
2
6
ꢃ
b: R ꢂ ꢃ-CH C H
ꢃ
f: R ꢂ ꢃ-OHC H
j: R ꢂ 2,3-di-ClC H
3
6
6
ꢃ
6 3
c: R ꢂ ꢃ-CH
d: R ꢂ 2-CH OC H
3
OC
6
H
ꢃ
g: R ꢂ ꢃ-BrC H
k: R ꢂ 2,ꢃ-di-ClC
l: R ꢂ C H
6 3
H
6
ꢃ
h: R ꢂ ꢃ-ClC H
6
3
6
ꢃ
ꢃ
10
7
Reagents and conditions: (i) MeOH, 65 °C. (ii) see table 1
Scheme 2 Synthesis of glycosyl 1,3,4-thiadiazole derivatives 10.

616 JOURNAL OF CHEMICAL RESEARCH 2016
solvents, temperatures were screened and the results are
summarised in Table 1. Two oxidative cyclisation agents were
involved to prepare 10a in our initial efforts: ferric ammonium
sulfate and ferric trichloride. When the precursor was treated
with ferric chloride as the oxidative cyclisation agent in
methanol at 65 °C for 2 h, the product 10a was not obtained
or obtained in very low yield (entries 1–3). Ferric ammonium
sulfate (FAS) was then examined as the oxidative cyclisation
agent, 1 mmol of the FAS was added to the system and furnished
research, these novel compounds may find applications in a
number of fields.
Experimental
All chemicals were purchased from commercial sources and used
without further purification unless otherwise stated. Melting
points were determined on a Yanaco melting point apparatus and
were uncorrected. IR spectra were recorded on a Bruker Tensor 27
1
spectrometer with KBr pellets. H NMR spectra were recorded on a
Bruker Avance 400 MHz at ambient temperature using DMSO-d6
3
0% of the desired product 10a after 2 h of reaction. Raising
the amount of FAS to 2 mmol further enhanced the yield to
5%, and when the amount of FAS was raised to 3 mmol, the
as solvent and TMS as an internal standard. Chemical shifts were
reported in ppm. 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.
Synthesis of 2-amino-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-gluco-
pyranose hydrochloride (4): To a solution of 1 (30 g, 139.1 mmol) in water
6
best result was obtained (entries 4–7). The protic solvents such
as ethanol, methanol and the polar solvents like acetonitrile,
N,N-diethylformamide were tested and the desired product 10a
was obtained with the best yields in the protic solvent methanol
(150 mL) at room temperature with stirring NaOH (5.6 g, 0.14 mmol) was
(entries 6, 8–10). We also investigated the effect of different
added, and 15 min later, p-methoxybezaldehyde (17.1 mL, 0.14 mmol) was
added dropwise. The reaction mixture was stirred at ambient temperature
for an additional 24 h, after which the resulting white solid was filtered
and washed with water (500 mL) to afford 2-(4-methoxy benzylidene)-2-
deoxy-β-D-glucopyranose (33.3 g, 81%). To a mixture of 2-(4-methoxy
benzylidene)-2-deoxy-β-D-glucopyranose (6.6 g, 22.2 mmol) and benzyl
bromide (14 mL, 117.9 mmol) in DMF (50 mL) at 0 °C, NaH (60%, 5 g,
temperatures and times on the reaction (entries 6, 11–14). As
shown in Table 1, the best reaction conditions for synthesis
of 10 were as follows: ferric ammonium sulfate as oxidative
cyclisation agent, methanol as solvent at 65 °C for 2 h.
From a mixture of glycosyl isothiocyanate 6 (1 mmol),
hydrazine hydrate 7 (1 mmol), benzaldehyde 8a (1 mmol) and
ferric ammonium sulfate (3 mmol), N-(1,3,4,6-tetra-O-benzyl-
125 mmol) was added portionwise. The reaction mixture was allowed
2
-deoxy-β-D-glucopyranosyl)-5-phenyl-1,3,4-thiadiazole-2-
to attain room temperature and stirred for 12 h. After the completion of
reaction, the solution was diluted by a large amount of water and extracted
with CH Cl (3 × 50 mL). The solvent was removed under reduced
amine 10a was isolated in 87% yield. The reaction was carried
out in MeOH for 4 h at 65 °C. Subsequently, we examined
whether the same system can be applied to various aldehydes.
Experimental study indicates that the reaction of glycosyl
isothiocyanate 6 with hydrazine hydrate 7 and various aromatic
aldehydes and aliphatic aldehydes could be smoothly converted
to the desired products as shown in Table 2 in good yields
2
2
pressure to give a yellow viscous liquid. The solution of the yellow liquid
in acetone (100 mL) was treated with hydrochloric acid (7 mL, 5 N) to
afford a white solid after heating at reflux for 1 h. The mixture was filtered
and washed with acetone to give 4: Yield 7.5 g, 59%, (overall yield 50%);
–1
m.p. 138––140 °C; IR (ν /cm ) KBr: 3438, 3027, 2925, 1502, 1455,
max
1
(
70–87%). Attempted debenzylation of 10a was carried out
1066, 738, 696; H NMR (300 MHz, DMSO-d ): δ 8.38 (s, 3H, NH HCl),
6
2
2
5
7.50–7.23 (m, 18H, ArH), 7.15 (dd, J = 6.6, 2.9 Hz, 2H, ArH), 4.81 (dd,
by hydrogenolysis using palladium on activated charcoal.
J = 16.7, 9.8 Hz, 4H, PhCH , HGlu), 4.73–4.62 (m, 2H, PhCH ), 4.61–4.48
However, the target product was not found, possibly because of
the presence of sulfur in the product.
In summary, we have developed a versatile, easy and
expeditious one-pot synthesis of 2-glycosylamino-5-aryl-
2
2
(
m, 3H, PhCH ), 3.85 (dd, J = 10.0, 8.6 Hz, 1H, HGlu), 3.76–3.56 (m, 4H,
2
HGlu), 3.06 (dd, J = 9.8, 8.8 Hz, 1H, HGlu).
Synthesis of 2-isothiocyanate-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-gluco-
pyranose (6): To a solution of 1,3,4,6-tetra-O-benzyl-β-D-glucosamine
hydrochloride 4 (1 mmol, 1 equiv.) in acetonitrile (15 mL) was added
triethylamine (3 mmol) and then cooled in an ice bath. Carbon disulfide
1,3,4-thiadiazole which involves the reaction of glycosyl
isothiocyanate 6, hydrazine hydrate 7, and various aldehydes 8
followed by oxidative cyclisation with ferric ammonium sulfate
(1 mmol) was then added dropwise into the reaction mixture via syringe
(
FAS). As D-glucosamine plays an important role in biomedical
pump. The mixture was stirred for 2 h followed by the addition of tosyl
chloride (TsCl) (1 mmol) and the mixture stirred for another 0.5 h. The
crude product was recrystallised from ethanol to give 6: White amorphous
Table 1 Optimising the conditions for the synthesis of 10a in the second
stage
–1
powder; yield 90%; m.p. 55–56 °C; IR (ν /cm ) KBr: 3433, 3030, 2873,
max
1
2
078, 1454, 1359, 1313, 1068; H NMR (400 MHz, DMSO-d ): δ 7.45–7.25
6
b
Entry Reagent
Solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
ACN
DMF
MeOH
MeOH
MeOH
MeOH
Time/h Temp./°C 10a yield /%
(m, 18H), 7.24–7.17 (dd, J = 7.3, 1.9 Hz, 2H), 4.81 (dd, J = 16.7, 9.8 Hz,
4H), 4.73–4.62 (m, 2H), 4.61–4.48 (m, 3H), 3.95–3.87 (m, 2H), 3.67 (ddd,
J = 14.3, 11.7, 6.9 Hz, 3H), 3.54 (dd, J = 11.7, 6.9 Hz, 1H); HRMS (ESI)
1
2
3
4
5
6
7
8
9
FeCl (10%)
2
2
2
2
2
2
2
2
2
2
1
3
2
2
65
65
65
65
65
65
65
65
65
65
65
65
r.t.
40
10
0
0
3
FeCl (3 mmol)
3
+
calcd for C H NO SNa [M + Na] : m/z 604.2128; found: m/z 604.2130.
ZnCl (3 mmol)
35 35
5
2
FAS (1 mmol)
FAS (2 mmol)
FAS (3 mmol)
FAS (4 mmol)
FAS (3 mmol)
FAS (3 mmol)
FAS (3 mmol)
FAS (3 mmol)
FAS (3 mmol)
FAS (3 mmol)
FAS (3 mmol)
30
56
87
87
75
55
64
75
85
0
Synthesis of N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-
5-substituted-1,3,4-thiadiazole-2-amine (10a–m); general procedure
To a 50 mL round-bottom flask fitted with a magnetic mixer and
containing glycosyl isothiocyanate 6 (1.0 mmol, 1 equiv.), hydrazine
hydrate 7 (1.0 mmol, 1 equiv.), and aldehydes 8 (1.0 mmol, 1 equiv.),
methanol (15 mL) was injected and the reaction mixture was stirred
for 2–3 h at 65 °C. The progress of the reaction was monitored by
TLC. Upon completion of the reaction, 3 equiv. of FAS was added
to the reaction, which was heated at 65 °C for a further 2–3 h. After
the reaction, the resulting mixture was filtered to obtain the filtrate.
The filtrate was concentrated, and the crude product was purified by
column chromatography on silica gel using a gradient mixture of ethyl
acetate and petroleum ether as an eluent to give products 10a–m.
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-phenyl-
1,3,4-thiadiazole-2-amine (10a): Following the general procedure,
1
0
1
1
1
2
1
3
14
30
a
Reaction condition: 10a was synthesised from 1 mmol glycosyl isothiocyanate 6, 1 mmol
hydrazine hydrate 7, and 1 mmol benzaldehyde 8a, solvent, 15 mL.
b
Isolated yield.

JOURNAL OF CHEMICAL RESEARCH 2016 617
Table 2 Synthesis of the desired product 10
Entry
Compound 8
Compound 10
Yield/%
85
Entry
2
Compound 8
Compound 10
Yield/%
87
OBn
OBn
CHO
O
CHO
O
BnO
BnO
BnO
BnO
OBn
OBn
NH
N
NH
N
S
S
1
N
N
8
a
8
b
1
0a
1
0b
OBn
OBn
CHO
O
CHO
O
BnO
BnO
BnO
BnO
OBn
OBn
NH
N
O
NH
N
S
S
3
5
80
74
4
6
76
81
N
N
O
O
8
d
O
8
c
10c
1
0d
OBn
O
OBn
C
HO
BnO
BnO
CHO
OBn
O
BnO
NH
N
BnO
OBn
S
NH
N
S
N
N
NO2
OH
HO
8
e
NO
2
8f
1
0f
1
0e
OBn
OBn
CHO
CHO
O
O
BnO
BnO
BnO
BnO
OBn
OBn
NH
N
NH
N
S
S
7
9
80
76
8
78
70
N
N
Br
Cl
Cl
Br
8
g
8h
10h
1
OBn
0g
OBn
CHO
O
O
BnO
BnO
BnO
BnO
CHO
OBn
OBn
NH
N
NH
N
Cl
Cl
S
S
10
N
N
Cl
F
F
8j
Cl
8
i
10i
1
0j
OBn
OBn
CHO
O
O
BnO
BnO
BnO
BnO
CHO
OBn
Cl
OBn
NH
N
NH
N
S
S
C
11
73
85
12
N
86
N
Cl
l
8l
Cl
8
k
1
0k
OBn
S
1
0l
O
BnO
BnO
C H CHO
OBn
8
16
NH
N
13
8
m
N
1
0m
the reaction of glycosyl isothiocyanate 6 (0.58 g), hydrazine hydrate
(0.1 mL), and benzaldehyde 8a (0.106 mL) afforded 10a: White
amorphous powder; yield 0.59 g, 85%; m.p. 141–142 °C; IR (νmax /cm )
1H, H-1), 4.77–4.65 (m, 4H, CH Ph), 4.64–4.51 (m, 4H, CH Ph), 3.86
2 2
7
(t, J = 8 Hz, 1H, H-4), 3.80–3.36 (m, 5H, H-6 , H-6 , H-3, H-5, H-2),
a b
–1
+
2.36 (s, 3H); HRMS (ESI) calcd for C H N O SNa [M + Na] : m/z
43 43 3 5
KBr: 3421, 3176, 3030, 2922, 2868, 1573, 1519, 1497, 1359, 1120, 1068;
736.2816; found: m/z 736.2823.
1
H NMR (400 MHz, DMSO-d ): δ 8.34 (d, J = 8.0 Hz, 1H, NH), 7.75 (t,
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4-
methoxyphenyl)-1,3,4-thiadiazole-2-amine (10c): Following the
general procedure, the reaction of glycosyl isothiocyanate 6 (0.58
g), hydrazine hydrate 7 (0.1 mL), and p-methoxybenzaldehyde 8c
(0.12 mL) afforded 10c: Yellow amorphous powder; yield 0.58 g, 80%;
6
J = 7.7 Hz, 2H, ArH), 7.52–7.43 (m, 3H, ArH), 7.41–7.27 (m, 8H, ArH),
7.26–7.11 (m, 12H, ArH), 4.82 (d, J = 12.0 Hz, 1H, H-1), 4.71 (m, 4H,
CH Ph), 4.58 (m, 4H, CH Ph), 3.87 (t, J = 8 Hz, 1H, H-4), 3.78–3.68
2
2
(
m, 2H, H-6 , H-6 ), 3.62–3.52 (m, 3H, H-3, H-5, H-2); HRMS (ESI)
a b
+
–1
calcd for C H N O SNa [M + Na] : m/z 722.2659; found: m/z
m.p. 105–106 °C; IR (ν /cm ) KBr: 3421, 3029, 2928, 1607, 1577,
42
41
3
5
max
1
7
22.2666.
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-
4-methylphenyl)-1,3,4-thiadiazole-2-amine (10b): Following the
1521, 1453, 1253, 1069; H NMR (400 MHz, DMSO-d ): δ 8.24 (d,
6
J = 9.0 Hz, 1H, NH), 7.71–7.67 (m, 2H, ArH), 7.39–7.27 (m, 8H, ArH),
7.25–7.13 (m, 12H, ArH), 7.06–7.01 (m, 2H, ArH), 4.82 (d, J = 12.5 Hz,
1H, NH), 4.75–4.67 (m, 4H, CH Ph), 4.63–4.52 (m, 4H, CH Ph),
(
general procedure, the reaction of glycosyl isothiocyanate 6 (0.58 g),
hydrazine hydrate 7 (0.1 mL), and 4-methyl benzaldehyde 8b (0.1 mL)
afforded 10b: White amorphous powder; yield 0.62 g, 87%; m.p. 52 °C;
2
2
3.85 (t, J = 9.5 Hz, 1H, H-4), 3.81 (s, 3H, OCH ), 3.77–3.67 (m, 2H,
3
H-6 , H-6 ), 3.60–3.55 (m, 3H, H-3, H-5, H-2); HRMS (ESI) calcd for
a
b
–1
+
IR (ν /cm ) KBr: 3440, 3029, 2866, 1623, 1453, 1360, 1210, 1062;
C H N O SNa [M + Na] : m/z 752.2765; found: m/z 752.2767.
max
43 43 3 6
1
H NMR (400 MHz, DMSO-d ): δ 8.34 (d, J = 8.0 Hz, 1H, NH), 7.66
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-
(2-methoxyphenyl)-1,3,4-thiadiazole-2-amine (10d): Following
6
(d, J = 8.0 Hz, 2H, ArH), 7.43–7.12 (m, 22H, ArH), 4.83 (d, J = 12.0 Hz,

618 JOURNAL OF CHEMICAL RESEARCH 2016
1
the general procedure, the reaction of glycosyl isothiocyanate 6
0.58 g), hydrazine hydrate 7 (0.1 mL), and 2-methoxybenzaldehyde
d (0.12 mL) afforded 10d: Yellow amorphous powder; yield 0.55
H NMR (400 MHz, DMSO-d ): δ 8.34 (d, J = 9.0 Hz, 1H, NH), 7.81
6
(
8
(dd, J = 8.8, 5.4 Hz, 2H, ArH), 7.41–7.27 (m, 10H, ArH), 7.26–7.12 (m,
12H, ArH), 4.82 (d, J = 12.5 Hz, 1H, H-1), 4.77–4.67 (m, 4H, CH Ph),
4.57 (m, 4H, CH Ph), 3.87 (t, J = 8.0 Hz, 1H, H-4), 3.78–3.67 (m, 2H,
H-6 , H-6 ), 3.64–3.53 (m, 3H, H-5, H-3, H-2); HRMS (ESI) calcd for
2
–1
g, 76%; m.p. 73–74 °C; IR (ν /cm ) KBr: 3442, 3029, 3922, 1599,
max
2
1
1
497, 1453, 1360, 1257, 1065; H NMR (400 MHz, DMSO-d ): δ 8.35
6
a
b
+
(
(
(
d, J = 7.2 Hz, 1H, NH), 8.12 (dd, J = 7.8, 1.6 Hz, 1H, ArH), 7.50–7.43
m, 1H, ArH), 7.41–7.28 (m, 8H, ArH), 7.25–7.07 (m, 14H, ArH), 4.83
d, J = 12.0 Hz, 1H, H-1), 4.76–4.67 (m, 4H, CH Ph), 4.62–4.52 (m,
C H ClN O SNa [M + Na] : m/z 740.2565; found: m/z 740.2570.
42 40 3 5
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(2,3-
dichlorophenyl)-1,3,4-thiadiazole-2-amine (10j): Following the
general procedure, the reaction of glycosyl isothiocyanate 6 (0.58
g), hydrazine hydrate 7 (0.1 mL), and 2,3-dichlorobenzaldehyde 8j
(0.175 g) afforded 10j: White amorphous powder; yield 0.53 g, 70%;
m.p. 137–138 °C; IR (νmax /cm ) KBr: 3441, 3028, 2916, 1572, 1496,
1453, 1396, 1357, 1216, 1068. H NMR (400 MHz, DMSO-d ): δ 8.44
(d, J = 9.1 Hz, 1H, NH), 7.93 (dd, J = 7.9, 1.3 Hz, 1H, ArH), 7.78 (dd,
J = 8.0, 1.4 Hz, 1H, ArH), 7.51 (t, J = 8.0 Hz, 1H, ArH), 7.40–7.28 (m,
8H, ArH), 7.26–7.12 (m, 12H, ArH), 4.84 (d, J = 12.4 Hz, 1H, H-1),
4.77–4.67 (m, 4H, CH Ph), 4.64–4.51 (m, 4H, CH Ph), 3.84 (t, J = 8.0
Hz, 1H, H-4), 3.79–3.67 (m, 2H, H-6 , H-6 ), 3.64–3.56 (m, 3H, H-5,
H-3, H-2); HRMS (ESI) calcd for C H Cl N O SNa [M + Na] : m/z
2
4
H, CH Ph), 3.94 (s, 3H), 3.87 (t, J = 8 Hz, 1H, H-4), 3.79–3.68 (m,
2
2
H, H-6 , H-6 ), 3.58 (m, 3H, H-5, H-3, H-2); HRMS (ESI) calcd for
a
b
+
C H N O SNa [M + Na] : m/z 752.2765; found: m/z 752.2776.
43
43
3
6
–1
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4-
nitrophenyl)-1,3,4-thiadiazole-2-amine (10e): Following the general
procedure, the reaction of glycosyl isothiocyanate 6 (0.58 g), hydrazine
hydrate 7 (0.1 mL), and 3-nitrobenzaldehyde 8e (0.15 g) afforded 10e:
Yellow amorphous powder; yield 0.55 g, 74%; m.p. 140–141 °C; IR
1
6
–
1
(
νmax /cm ) KBr: 3441, 3030, 2917, 1585, 1531, 1453, 1350, 1216, 1064;
2
2
1
H NMR (400 MHz, DMSO-d ): δ 8.55 (d, J = 9.1 Hz, 1H, NH), 8.50
s, 1H), 8.31–8.25 (d, J = 8.0 Hz, 1H, ArH), 8.16 (d, J = 8.0 Hz, 1H,
6
a b
(
+
42
39
2
3
5
ArH), 7.78 (t, J = 8.0 Hz, 1H, ArH), 7.41–7.28 (m, 8H, ArH), 7.26–7.13
7
90.1880; found: m/z 790.1882.
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(2,4-
(
m, 12H, ArH), 4.83 (d, J = 12.4 Hz, 1H, H-1), 4.71 (m, 4H, CH Ph),
2
4.64–4.52 (m, 4H, CH Ph), 3.87 (t, J = 8.0 Hz, 1H, H-1), 3.79–3.67 (m,
2
dichlorophenyl)-1,3,4-thiadiazole-2-amine (10k): Following the general
procedure, the reaction of glycosyl isothiocyanate 6 (0.58 g), hydrazine
hydrate 7 (0.1 mL), and 2,4-dichlorobenzaldehyde 8k (0.175 g) afforded
2
H, H-6 , H-6 ), 3.65–3.55 (m, 3H, H-5, H-3, H-2); HRMS (ESI) calcd
a
b
+
for C H N O SNa [M + Na] : m/z 767.2510; found: m/z 757.2502.
42
40
4
7
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4-
hydroxylphenyl)-1,3,4-thiadiazole-2-amine (10f): Following the
general procedure, the reaction of glycosyl isothiocyanate 6 (0.58 g),
hydrazine hydrate 7 (0.1 mL), and p-hydroxybenzaldehyde 8f (0.12 g)
afforded 10f: White amorphous powder; yield 0.58 g, 81%; m.p.
1
0k: White amorphous powder; yield 0.56 g, 73%; m.p. 115–117 °C;
–1
IR (ν /cm ) KBr: 3433, 3204, 3025, 1549, 1482, 1355, 1309, 1059;
max
1
H NMR (400 MHz, DMSO-d ): δ 8.43 (d, J = 9.1 Hz, 1H, NH), 8.04
6
(d, J = 8.6 Hz, 1H, ArH), 7.81 (d, J = 2.1 Hz, 1H, ArH), 7.58 (dd, J =
8.6, 2.1 Hz, 1H, ArH), 7.40–7.27 (m, 8H, ArH), 7.25–7.12 (m, 12H,
–1
8
2–84 °C; IR (ν /cm ) KBr: 3421, 2922, 1607, 1453, 1361, 1283,
max
ArH), 4.83 (d, J = 12.4 Hz, 1H, H-1), 4.72 (m, 4H, CH Ph), 4.64–4.51
(m, 4H, CH Ph), 3.84 (t, J = 8.1 Hz, 1H, H-4), 3.79–3.68 (m, 2H, H-6 ,
H-6 ), 3.64–3.54 (m, 3H, 3H, H-5, H-3, H-2); HRMS (ESI) calcd for
C H Cl N O SNa [M + Na] : m/z 790.1880; found: m/z 790.1857.
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-
naphthyl-1,3,4-thiadiazole-2-amine (10l): Following the general
procedure, the reaction of glycosyl isothiocyanate 6 (0.58 g), hydrazine
hydrate 7 (0.1 mL), and 1-naphthaldehyde 8l (0.156 g) afforded 10l:
2
1
1052; H NMR (400 MHz, DMSO-d ): δ 9.97 (s, 1H, OH), 8.23 (d,
6
2
a
J = 8.4 Hz, 1H, NH), 7.58 (d, J = 8.7 Hz, 2H, ArH), 7.41–7.28 (m, 9H,
b
ArH), 7.26–7.14 (m, 11H, ArH), 6.85 (d, J = 8.7 Hz, 2H, ArH), 4.82 (d,
+
42
39
2
3
5
J = 12.4 Hz, 1H, H-1), 4.77–4.66 (m, 4H, CH Ph), 4.62–4.52 (m, 4H,
2
CH Ph), 3.87 (t, J = 8.0 Hz, 1H, H-4), 3.77–3.67 (m, 2H, H-6 , H-6 ),
2
a
b
3
.58 (m, 3H, H-5, H-3, H-2); HRMS (ESI) calcd for C H N O SNa
42 41 3 6
+
[
M + Na] : m/z 738.2608; found: m/z 738.2607.
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-
4-bromophenyl)-1,3,4-thiadiazole-2-amine (10g): Following the
Yellow amorphous powder; yield 0.64 g, 86%); m.p. 161–163 °C; IR
(
–1
(
νmax /cm ) KBr: 3432, 3172, 3028, 2917, 1562, 1512, 1357, 1215, 1070;
general procedure, the reaction of glycosyl isothiocyanate 6 (0.58 g),
hydrazine hydrate 7 (0.1 mL), and 4-bromobenzaldehyde 8g (0.185 g)
afforded 10g: White amorphous powder; yield 0.62 g, 80%; m.p.
1
H NMR (400 MHz, DMSO-d ): δ 8.74–8.65 (m, 1H, ArH), 8.39 (d,
6
J = 9.1 Hz, 1H, NH), 8.05 (t, J = 7.7 Hz, 2H, ArH), 7.71 (d, J = 7.0 Hz,
1H, ArH), 7.67–7.56 (m, 3H, ArH), 7.41–7.15 (m, 20H, ArH), 4.86
–
1
1
1
1
42–143 °C; IR (νmax /cm ) KBr: 3439, 3030, 2924, 1564, 1497, 1453,
(d, J = 12.4 Hz, 1H, H-1), 4.80–4.70 (m, 4H, CH Ph), 4.67–4.50 (m,
4H, CH Ph), 3.90 (t, J = 8.0 Hz, 1H, H-4), 3.80–3.68 (m, 2H, H-6 ,
H-6 ), 3.69–3.57 (m, 3H, H-5, H-3, H-2); HRMS (ESI) calcd for
C H N O SNa [M + Na] : m/z 772.2816; found: m/z 772.2818.
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-octyl-
1,3,4-thiadiazole-2-amine (10m): Following the general procedure,
the reaction of glycosyl isothiocyanate 6 (0.58 g), hydrazine hydrate
1
2
362, 1066; H NMR (400 MHz, DMSO-d ): δ 8.40 (d, J = 9.0 Hz,
H, NH), 7.73–7.65 (m, 4H, ArH), 7.40–7.28 (m, 8H, ArH), 7.25–7.12
6
2
a
b
(
m, 12H, ArH), 4.82 (d, J = 12.5 Hz, 1H, H-1), 4.71 (m, 4H, CH Ph),
+
2
4
6
43
3
5
4
.57 (m, 4H, CH Ph), 3.86 (t, J = 8.0 Hz, 1H, H-4), 3.78–3.67 (m, 2H,
2
H-6 , H-6 ), 3.63–3.53 (m, 3H, H-5, H-3, H-2); HRMS (ESI) calcd for
a
b
+
C H BrN O SNa [M + Na] : m/z 800.1764; found: m/z 800.1767.
42
40
3
5
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4-
chlorophenyl)-1,3,4-thiadiazole-2-amine (10h): Following the general
procedure, the reaction of glycosyl isothiocyanate 6 (0.58 g), hydrazine
hydrate 7 (0.1 mL), and p-chlorobenzaldehyde 8h (0.14 g) afforded
7
(0.1 mL), and nonanal 8m (0.18 mL) afforded 10m: Yellow
–1
amorphous powder; yield 0.62 g, 85%; m.p. 68–69 °C; IR (ν /cm )
KBr: 3322, 3029, 2922, 1533, 1497, 1452, 1307, 1060; H NMR (400
MHz, DMSO-d ): δ 8.02 (d, J = 8.5 Hz, 1H, NH), 7.40–7.13 (m, 20H,
ArH), 4.81 (d, J = 12.4 Hz, 1H, H-1), 4.74–4.63 (m, 4H, CH Ph), 4.56
max
1
6
1
0h: White amorphous powder; yield 0.57 g, 78%; m.p. 128–129
–1
2
°
C; IR (νmax /cm ) KBr: 3441, 3030, 2924, 1585, 1497, 1398, 1065;
(m, 4H, CH Ph), 3.81 (t, J = 8.0 Hz, 1H, H-4), 3.77–3.66 (m, 2H, H-6 ,
1
2
a
H NMR (400 MHz, DMSO-d ): δ 8.40 (d, J = 9.0 Hz, 1H, NH), 7.78
6
H-6 ), 3.59–3.48 (m, 3H, H-5, H-3, H-2), 1.61 (m, 2H, CH ), 1.25
b
2
(d, J = 8.6 Hz, 2H, ArH), 7.55 (d, J = 8.6 Hz, 2H, ArH), 7.41–7.28 (m,
(m, 12H, CH ), 0.85 (t, J = 6.8 Hz, 3H, CH ); HRMS (ESI) calcd for
2
3
8H, ArH), 7.25–7.12 (m, 12H, ArH), 4.82 (d, J = 12.5 Hz, 1H, H-1),
+
C H N O SNa [M + Na] : m/z 758.3598; found: m/z 758.3609.
4
4
53
3
5
4
.76–4.66 (m, 4H, CH Ph), 4.63–4.52 (m, 4H, CH Ph), 3.86 (t, J = 8.0
2
2
Hz, 1H, H-4), 3.79–3.67 (m, 2H, H-6 , H-6 ), 3.63–3.52 (m, 3H, H-5,
a
b
Acknowledgments
+
H-3, H-2); HRMS (ESI) calcd for C H ClN O SNa [M + Na] : m/z
42
40
3
5
This work was supported by the Project Fund by the Priority
Academic Development Program of Jiangsu Higher Education
Institutions, Natural Science Foundation of Jiangsu Province
7
56.2269; found: m/z 756.2278.
N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-5-(4-
fluorophenyl)-1,3,4-thiadiazole-2-amine (10i): Following the general
procedure, the reaction of glycosyl isothiocyanate 6 (0.58 g), hydrazine
hydrate 7 (0.1 mL), and p-fluorobenzaldehyde 8i (0.107 mL) afforded
(
BK20151281), Open-end Funds of Jiangsu Key Laboratory
of Marine Biotechnology (HS2014007), the Science and
Technology Project of Lianyungang (CG1415) and Public Science
and Technology Research Funds Projects of Ocean (201505023).
10i: Pink amorphous powder; yield 0.54 g, 76%; m.p. 142–143 °C; IR
–1
(νmax /cm ) KBr: 3431, 3030, 2919, 1601, 1586, 1517, 1363, 1228, 1068;

JOURNAL OF CHEMICAL RESEARCH 2016 619
Electronic Supplementary Information
11 R.A. Jones, Synthesis of carbohydrate-drug conjugates: Potential NSAID
pro-drugs. Abstracts of Papers of the American Chemical Society, 2014,
The ESI [1H NMR and HRMS (ESI) spectral data Fig. S1–S28]
is available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
2
48, http://acselb-529643017.us-west-2.elb.amazonaws.com/chem/248nm/
program/view.php?obj_id=267559&terms= [accessed 14 September 2016].
12 R.A. Jones, Y. Thillier, S.S. Panda, N.R. Rosario, C.D. Hall and A.R.
Katritzky, Org. Biomol. Chem., 2014.12, 8325.
13
I. Tworowska, E. Delpassand and M. Schultz, Radiolabeled,
glycoconjugates targeting metastatic melanoma cells, Abstracts of Papers
of the American Chemical Society, 2014, 248, http://acselb-529643017.
us-west-2.elb.amazonaws.com/chem/248nm/program/view.php?obj_
id=279407&terms= [accessed 14 September 2016].
Received 4 June 2016; accepted 12 August 2016
Paper 1604128 doi: 10.3184/174751916X14738636315471
Published online: 23 September 2016
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