Expedient synthesis of novel glycosyl thiazole derivatives

Article abstract of DOI:10.3987/COM-15-13310

An efficient protocol for the synthesis of novel glycosyl thiazole derivatives starting from the commercially available D-glucosamine hydrochloride was described by reaction of 1-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranos-2-yl)thiourea 8 with each of substituted α-bromoacetophenone in ethanol. 1-(1,3,4,6-Tetra-O-benzyl-2-deoxy-β-D-glucopyranos-2-yl)thiourea was an important intermediate, and its synthetic methods were discussed by comparing two different synthetic routes. Moreover, 2-isothiocyanate-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose was obtained in a new and convenient way. Finally, a series of novel glycosyl incorporated with thiazole moiety was synthesized in good purities and overall yields.

Full text of DOI:10.3987/COM-15-13310

HETEROCYCLES, Vol. 91, No. 11, 2015
2113
HETEROCYCLES, Vol. 91, No. 11, 2015, pp. 2113 - 2125. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 27th August, 2015, Accepted, 2nd October, 2015, Published online, 8th October, 2015
DOI: 10.3987/COM-15-13310
EXPEDIENT SYNTHESIS OF NOVEL GLYCOSYL THIAZOLE
DERIVATIVES
Feng-chang Cheng,1,2 Long Yin, Wei-wei Liu, * Qu-xiang Li, Li-juan
1
1,2,3,
2
1,3
1,3
1,3
Tang, Da-hua Shi, and Zhi-ling Cao
1School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang
2
2
22005, P.R. of China. E-mail: liuww323@aliyun.com; School of Chemical
Engineering, China University of Mining and Technology, XuZhou 221116, P.R.
of China; 3Jiangsu Marine Resources Development Research Institute,
Lianyungang 222005, P.R. of China
Abstract – An efficient protocol for the synthesis of novel glycosyl thiazole
derivatives starting from the commercially available D-glucosamine
hydrochloride
was
described
by
reaction
of
1-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranos-2-yl)thiourea 8 with each of
substituted
α-bromoacetophenone
in
ethanol.
1
-(1,3,4,6-Tetra-O-benzyl-2-deoxy-β-D-glucopyranos-2-yl)thiourea
important intermediate, and its synthetic methods were discussed by comparing
two different synthetic routes. Moreover,
-isothiocyanate-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose was obtained
was
an
2
in a new and convenient way. Finally, a series of novel glycosyl incorporated with
thiazole moiety was synthesized in good purities and overall yields.
INTRODUCTION
The numerous carbohydrates, which play an important role in living systems, are underscored by their
1
high abundance and molecular diversity. Sugars are not only regarded as structural support and energy
storage molecules, but also vital potential drug in physiological and pathophysiological processes.2,3
Among these sugars, glucosamine has been paid great attention amongst synthetic chemists over the years,
because of their diverse biological activities demonstrated. Glucosamine, a naturally occurring amino
sugar, is a key component in a variety of biologically important glycoconjugates. It is found in several
4
5
natural products such as tunicamycins and neomycin, which are used as antibiotics, and bacillithiol,

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HETEROCYCLES, Vol. 91, No. 11, 2015
which is used as bacterial antioxidants. Aside from the natural products, it is found in gastrointestinal
mucosal membranes and the cartilage tissues. Thus, glucosamine plays a crucial role on cell recognition,
adhesion6,7 and migration, cell-cell interaction and communication. It is well known as an alternative
8
9
10
therapy for the treatment of osteoarthritis (OA), which is a joint disease characterized by cartilage
1
1
degeneration, joint paint and variable degrees of joint inflammation. Furthermore, D-glucosamine has
been reported to exert anti-inflammatory acitivity12,13 and suppress tumer growth,14,15 and it could be
1
6
effectively employed as an additive in health or functional food to alleviate oxidative stress. Recently it
is found that glucosamine derivatives have been utilized as an efficient inhibitor for the Alzheimer’s
disease.17
One of the successful and effective approaches in the search for new bioactive agents from natural
products is to synthesize novel compounds by simple chemical modifications of naturally occurring lead
1
8
compounds. In order to obtain potential biological lead compounds, the modifications of D-glucosamine
have gained great attention. The hydroxyl groups are the active sites for phosphorylation and
glycosylation when the C(2)-amino is protected, and the 4-hydroxy group of N-acetylglucosamine
1
9
derivatives nevertheless is a very poor nucleophile in glycosylation reactions. Masuko et al. reported the
synthesis of N-acetylglucosamine-1-phosphate and tested for their recognition by the GlmU
uridyltransferase enzyme.20 Serpi et al. reported a novel series of O-4/O-3 N-acetyl-D-glucosamine
phosphoramidates, which were able to significantly decrease the loss of glycosaminoglycan at
2
1
noncytotoxic concentrations. Although the modifications of hydroxyl groups are common, reports on
the functionalization of amino are rare, especially a heterocycle linked to the aminothiazole, one of the
most important scaffolds in heterocyclic chemistry and drug design and discovery, plays vital roles in
2
2
23
many biologically active compounds such as tiazofurin (antineoplastic agents) and ritonavir (anti-HIV
drug). Thiazole containing compounds have reported to exhibit versatile biological activities such as
2
4
25
26
27
antimicrobial, anti-inflammatory, antiviral and antiparasitic, antihistaminic properties, antiallergic.
The recent reports have been declared that the presence of thiazole ring as a part of drug structure could
be determinant for its physicochemical and pharmacokinetic properties. Taking into account the important
role of thiazoles in various biological phenomena, we synthesized a series of novel glucosamine
derivatives containing thiazole attached to the C(2)-amino group.
Various methods have been reported for the synthesis of thiazole derivatives such as Hantzsch synthesis,
solid supported and solution phase. Recently, various catalysts are employed to synthesize thiazole
derivatives like iodine,28 silyl chloride,29 PEG,30 NaICl
31
and ammonium chloride.32 But Hantzsch
2
synthesis is most commonly used among these methods, which involves reaction of α-halo carbonyl
3
3
compounds with thiourea or thioamides. Herein, a convenient and mild protocol for the synthesis of
glycosyl thiazole derivatives was developed, which involved the reaction of glycosyl thiourea and

HETEROCYCLES, Vol. 91, No. 11, 2015
2115
substituted α-bromoacetophenone via Hantzsch synthesis. It is the first time to introduce thiazole ring to
the glucosamine in a convenient way.
RESULTS AND DISCUSSION
In the last few years, the thiourea is of interest as synthetic intermediate. The preparation of thiourea was
achieved by the reaction of primary amine with thiocyanate directly. Our first attempt aimed at
synthesizing
the
glycosyl
thiourea
by
the
reaction
of
thiocyanate
with
2-amino-2-deoxy-β-D-glucopyranose. To our disappointment, the desired product was not obtained
employing this method. We had to design a devious way in which the hydroxyl groups were protected at
the beginning.
To accomplish the reaction on amino, the four hydroxyl groups should be under protection during the
process. The benzyl group was selected to protect the hydroxy groups from a large number of the
protection methods for the hydroxy group due to its versatile and stabilized for protecting hydroxyl
groups in carbohydrate chemistry. The experiment steps are as follows: Firstly, the amino was protected
by using p-methoxybenzaldehyde to get Shiff base, then followed by the benzylation of the four hydroxyl
groups with NaH and BnBr in DMF ranging from 0 °C to room temperature for 12 h, and at last the
2-amino-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose hydrochloride 3 was prepared after the
hydrolysis of 2 by hydrochloric acid (Scheme 1).
Scheme 1. Synthesis of 2-amino-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose hydrochloride.
Reagents and conditions: (i) 1, NaOH, p-methoxybenzaldehyde, H
°C - rt, yield: 75%. (ii) 5 mol/L HCl, acetone, 35 °C, yield: 60%.
2
O, rt, yield: 81%. 2, NaH, BnBr, DMF,
0
To develop a simple way to the synthesis of compounds containing D-glucosamine and thiazole, glycosyl
thiourea was an important intermediate in this reaction. Through long time probing, we have formed
diversified studying methods about the synthesis of glycosyl thiourea. At the onset of the experiments, we
envisaged that glycosyl thiourea could be obtained by amide bond cleavage of glycosyl acylthiourea
under alkaline conditions. In this way, glycosyl acylthiourea must be synthesized at first. At the beginning
of experiment, benzoyl chloride reacted with KSCN to afford benzoyl isothiocyanate using a few drops of
PEG-400
as
catalyst
in
the
mixture
of
dichloromethane
and
acetone.
Then

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HETEROCYCLES, Vol. 91, No. 11, 2015
1-benzoyl-3-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranos-2-yl)thiourea 6 was synthesized from
benzoyl isothiocyanate and 2-amino-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose hydrochloride 3.
To our delight, 6 was converted to 8 successfully by treatment with potassium carbonate in methanol
under refluxing (Scheme 2). And 8 is a novel intermediate prepared for the first time.
Scheme 2. Synthesis of 1-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranos-2-yl)thiourea. Reagents and
conditions: (i) KSCN, PEG-400, DCM, acetone, rt, yield: 95%. (ii) 3, Et
CO , MeOH, refluxing, yield: 93%.
3
N, DCM, rt, yield: 92%. (iii)
K
2
3
However, 1-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranos-2-yl)thiourea was synthesized by
multi-step in low yield, the most important was that this method needed long time and difficult separation.
Therefore, it is still highly expected to synthesis of 8 from readily available starting materials by
convenient procedures in higher yield.
In a further experiment, the amino group of 2-amino-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose
hydrochloride was expected to converted into thiourea directly by simple steps. And in this way we tried
to find a facile way to synthesis of 8 in high yield. According to this idea, we tried to turn the amino of 3
into isothiocyanates to improve reactivity. Isothiocyanates, a reactive functional group in chemical
synthesis, which can be converted to thiourea easily, has higher reactivity compared with amino group.
Numerous synthetic methods have been reported to convert readily available amines into the
isothiocyanate analogue,34-36 but the employed reagents are often harsh, such as thiophosgene, which has
high toxicity and incompatability with many functional groups, and there are very few reports available in
which glycosyl isothiocyanate can be generated using a convenient and mild method. Herein, a facile
protocol for the preparation of isothiocyanates from amine of D-glucosamine is reported. To a solution of
3
in acetonitrile was added triethylamine at 0 °C, followed by addition of carbon disulfide dropwise into
the reaction mixture via bysyringe pump. The mixture was stirred for 2 h. Then tosyl chloride (TsCl) was
added to the reaction mixture. For another 0.5 h, glycosyl isothiocyanate was provided in 90% yield from
4
. It is the first time that the conversion between the amine of D-glucosamine and isothiocyanates has
been studied by using this method. Treatment of 7 in methylene chloride at room temperature with
ammonia, provided 6 in 95% yield from 7. The method have some advantages such as gentle reaction
conditions, high yield and simple operation.

HETEROCYCLES, Vol. 91, No. 11, 2015
2117
Scheme 3. Synthesis of 1-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranos-2-yl)thiourea. Reagents and
conditions: (i) 1, Et N, CS , 0 °C, 1.5 h. 2, TsCl, 0.5 h, yield: 90%. (ii) ammonia, DCM, 2 h, 40 °C, yield:
3
2
95%.
9
was brominated by CuBr under refluxing ethyl acetate and chloroform, and it was quite evident that the
2
dark solvent changed into light green one with white CuBr after the reaction completed. The filtrate was
extracted by water until the organic layer was transparent and without other dispose, 8 was put into the
filtrate to afford 11 under refluxing for 15 min, which was a quite simple and convenient method to give
1
1
1 (Scheme 3). H NMR of 11 exhibited the signal for the anomeric proton at δ 3.88 with coupling
constant of 9.4 Hz assigned as the β-anomer.
Scheme 4. Synthesis of the desired product 11. Reagents and conditions: (i) CuBr
yield: 95%. (ii) 8, EtOH, reflux, yield: 92%.
2
, EtOAc, CHCl , reflux,
3
Table 1. Synthesis of the desired product 11
Entry
Comp. 10
Comp. 11 Yield (%)
Entry
6
Comp. 10
Comp. 11
Yield (%)
87
9
2
1
10a
10f
11a
11f
2
93
7
90
10b
10g
1
1g
11b

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HETEROCYCLES, Vol. 91, No. 11, 2015
3
88
8
9
89
90
1
0h
1
0c
11c
11d
1
1h
4
5
90
89
1
0d
10j
1
1i
10e
11e
In conclusion, a series of novel glycosyl thiazole have been synthesized starting from D-glucosamine.
Synthesis methods of glycosyl thiourea have been discussed by comparing two different synthesis routes.
Although
glycosyl
thiourea
was
obtained
by
the
hydrolysis
CO
of
1-benzoyl-3-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose-2-yl)thiourea by employing K
2
3
, this
route was time consuming and involved several complicated procedures. A new and effective approach
for preparing glycosyl thiourea was introduced, which has characteristics of quickness, simpleness and
high efficiency. In this route, glycosyl isothiocyanate, as an important intermediates, was synthesized
using method of mild conditions, convenient operation and low toxicity. The target compounds have been
prepared directly in good yields with glycosyl thiourea in hand.
EXPERIMENTAL
All chemicals were purchased from commercial sources and used without further purification unless
otherwise stated. All reactions were monitored by TLC. TLC plates were detected with 254 nm UV light.
Melting points were determined on a Yanaco melting point apparatus and were uncorrected. IR spectra
1
were recorded on a Bruker Tensor 27 spectrometer with KBr pellets. H NMR were recorded with Bruker
Avance at 300 Hz using TMS as an internal standard and DMSO-d as a solvent. HRMS(ESI) analysis
6
was performed on a Agilent 6500 mass spectrometer. Flash column chromatography was performed on
silica 200-300 mes.
Preparation of 2-amino-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose hydrochloride (3)
To a solution of 1 (30 g, 139.1 mmol) in water (150 mL) at room temperature with stirring NaOH (5.6 g,

HETEROCYCLES, Vol. 91, No. 11, 2015
2119
0.14 mmol) was added, and 15 min later, p-methoxybenzaldehyde (17.1 mL, 0.14 mmol) was added
dropwise. The reaction mixture was stirred at ambient temperature for additional 24 h, after which the
resulting white solid was filtrated and washed by 500 mL water to afford 2-(4-methoxy-
benzylidene)-2-deoxy-β-D-glucopyranose (33.3 g, 81%). To
benzylidene)-2-deoxy-β-D-glucopyranose (6.6 g, 22.2 mmol) and BnBr (14 mL, 117.9 mmol) in DMF
50 mL) at 0 °C, NaH (60%, 5 g, 125 mmol) was added portion wise. The reaction mixture was allowed
to 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 eliminated under reduced
a
mixture of 2-(4-methoxy-
(
2
2
pressure to give a kind of 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 under refluxing for 1 h. The
mixture was filtrated and wash with acetone to give 3 (7.5 g, 59%, overall yield 50%).
Synthesis of 1-benzoyl-3-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose-2-yl)thiourea (6)
To a solution of benzoyl chloride (0.23 mL, 2 mmol) in CH
0.2 g, 2 mmol) was added at room temperature utilizing a few drops of PEG-400 as catalyst and the
reaction mixture was stirred for additional 2 h. The mixture was filtrated and the filtrate was evaporated
under reduced pressure to give benzoyl isothiocyanate (5). To a solution of 3 (1.2 g, 2 mmol) in CH Cl ,
2
Cl (15 mL) and acetone (15 mL), KSCN
2
(
2
2
triethylamine was added dropwise until the solution was clarified, and 6 was prepared by treating the
solution with benzoyl isothiocyanate at room temperature. The solvent was eliminated under reduced
pressure to afford a crude product which was purified by column chromatography using EtOAc and
petroleum ether as the eluent.
-1
Data for 6: yield = 92%, 1.3 g, white powder; mp 82-84 °C; IR (KBr) v (cm ): 3322 (N-H), 3029 (C-H,
Ph), 2921 (CH -Ph), 1685 (C=O), 1542 (C=S), 1455 (C=C, Ph), 1073 (C-O-C), 744 (C=CH, Ph), 697
2
1
(
(
C=CH, Ph); H NMR (300 MHz, DMSO): δ 11.36 (s, 1H, NH), 10.99 (d, 1H, J = 9.3 Hz, NH), 8.00-7.87
m, 2H, Ph), 7.63 (t, 1H, J = 7.4 Hz, Ph), 7.51 (t, 2H, J = 7.6 Hz, Ph), 7.33 (t, 5H, J = 5.0 Hz, Ph),
.31-7.22 (m, 9H, Ph), 7.22-7.15 (m, 6H, Ph), 4.84 (d, 2H, J = 6.1 Hz, PhCH -), 4.78 (d, 1H, J = 7.6 Hz,
7
2
PhCH
2
-), 4.70 (d, 2H, J = 10.7 Hz, PhCH
2
-), 4.63 (d, 1H, J = 3.0 Hz, PhCH
2
-), 4.60-4.51 (m, 4H, PhCH -,
2
Glu
Glu
Glu
-
CH
2
-), 4.01 (t, 1H, J = 9.1 Hz, H ), 3.71 (t, 2H, J = 9.4 Hz, H ), 3.60-3.53 (m, 2H, H ). ESI-HRMS:
+
Calcd for C42
H
42
N
2
O
6
S [M+Na] 725.2656. Found 725.2643.
Synthesis of 2-isothiocyanate-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose (7)
Triethylamine (3 mmol) was added to a solution of 3 (1 mmol, 1 equiv.) in MeCN (15 mL) in the
condition of ice bath. Carbon disulfide (1 mmol) was added by dropwise into the reaction mixture via by
syringe pump. The mixture was stirred for 2 h. Then tosyl chloride (TsCl) (1 mmol) was added to the
mixture. The mixture was stirred for another 0.5 h. The crude product was recrystallized from EtOH to

2120
HETEROCYCLES, Vol. 91, No. 11, 2015
give product 7.
Data for 7: yield = 90%, white amorphous powder; mp 55-56 °C; IR (KBr) v (cm ): 3433, 3030 (C-H,
Ph), 2873 (CH -Ph), 2078 (-N=C=S), 1454 (C=C, Ph), 1359 (C=C, Ph), 1313 (C=C, Ph), 1068 (C-O-C).
-1
2
1H NMR (300 MHz, DMSO), δ: 7.45-7.25 (m, 18H, Ph), 7.24-7.17 (dd, 2H, J = 7.3, 1.9 Hz, Ph),
Glu
4
3
.88-4.75 (m, 4H, Ph-CH
2
), 4.73-4.62 (m, 2H, Ph-CH
2
), 4.54 (dt, 3H, J=12.4, 10.5 Hz, Ph-CH
2
, H ),
Glu
Glu
Glu
.95-3.87 (m, 2H, H ), 3.67 (ddd, 3H, J=12.3, 11.7, 6.9 Hz, H ), 3.54 (dd, 1H, J=11.7, 6.9 Hz, H ).
+
ESI-HRMS: Calcd for C35
H35NO
5
S [M+Na] 604.2128. Found 604.2130.
Synthesis of 1-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose-2-yl)thiourea (8)
Route (1) Potassium carbonate (0.28 g, 2 mmol) was added to a solution of 5 (0.7 g, 1 mmol) in MeOH
(25 mL). The reaction mixture was stirred under refluxing and monitored by TLC. After the reaction was
over, MeOH was removed under reduced pressure. The product obtained was dissolved in CH Cl and
2
2
washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under
reduced pressure. The desired compound was purified by column chromatography using EtOAc and
petroleum ether as the eluent.
Route (2) 7 (0.58 g, 1 mmol) was dissolved in CH
2
Cl
2
(20 mL), then ammonia was passed though the
Cl was removed to give the product
CH Cl solution in room temperature for 2 h. After the reaction, CH
2
2
2
2
8
.
-1
Data for 8: (1) yield = 90%, (2) yield = 95%, white solid; mp 149-150 °C; IR (KBr) v (cm ): 3431 (N-H),
3
7
2
219 (N-H), 3036 (C-H, Ph), 2868 (CH -Ph), 1627 (C=S), 1537 (N-H), 1497 (C=C, Ph), 1081 (C-O-C),
2
1
49 (C=CH, Ph), 698 (C=CH, Ph); H NMR (300 MHz, DMSO): δ 7.94 (d, 1H, J = 9.0 Hz, NH), 7.32 (m,
0H, Ph), 7.20 (d, 2H, J = 5.7 Hz, NH
2
), 4.81 (d, 1H, J = 12.1 Hz, PhCH
2
-), 4.71 (d, 2H, J = 10.8 Hz,
-), 3.69-3.48 (dd,
-, H ), 3.59-3.48 (m, 2H, H ). ESI-HRMS: Calcd for C35
M+Na] 621.2394. Found 621.2383.
PhCH
2
-), 4.62 (dd, 2H, J = 11.2, 5.4 Hz, PhCH
2
-), 4.51 (dd, 4H, J = 11.6, 7.8 Hz, PhCH
2
Glu
Glu
4H, J = 17.1, 9.7 Hz, -CH
2
H N
38 2
5
O S
+
[
General procedure for the synthesis of 2-(4-arylthiazol-2-yl)-1,3,4,6-tetra-O-benzyl-2-deoxy-β-
D-glucopyranose (11a-11i)
Cupric bromide (0.5 g, 2.2 mmol) was added to a solution of 9 (1 mmol) in EtOAc (15 mL) and CHCl
3
(15 mL). The reaction mixture was stirred and monitored by TLC. After completion of reaction, the
mixture was filtrated and the solvent was washed by water until it was colorless. The solvent was
eliminated under reduced pressure to give 10. Without any purification, 10 was used in the next process. 8
was added to the solution of 10 in EtOH (25 mL). The mixture was completed in 15 min under refluxing
followed by the elimination of EtOH. The crude product was added into Et O and broken by ultrasonic
2
wave. Filtrating the mixture to afford pure desired compound 11.

HETEROCYCLES, Vol. 91, No. 11, 2015
2121
2-(4-Phenylthiazol-2-yl)-1,3,4,6-tetra-O-benzyl-2-deoxy -β-D-glucopyranose (11a)
Following the general procedure, the reaction of 8 (0.3 g, 0.5 mmol) and 10a (0.1 g, 0.5 mmol) afforded
-1
1
1a (0.32 g, 92%); claybank solid; mp 46-47 °C; IR (KBr) v (cm ): 3420 (N-H), 3030 (C-H, Ph), 2922
CH -Ph), 2868 (CH -Ph), 1627 (C=N), 1550 (C=C-S), 1496 (N-H), 1453 (C=C, Ph), 1069 (C-O-C), 736
C=CH, Ph), 697 (C=CH, Ph) cm ; H NMR (300 MHz, DMSO): δ 7.99 (d, 1H, J = 7.8 Hz, NH), 7.83 (d,
(
(
2
2
-1 1
2
4
3
6
H, J = 7.3 Hz, Ph), 7.47-7.11 (m, 23H, Ph), 7.08 (s, 1H, C=CH), 4.83 (d, 1H, J = 12.6 Hz, PhCH
2
-),
.77-4.69 (m, 3H, PhCH -), 4.57 (dd, 4H, J = 16.7, 12.0 Hz, PhCH -), 3.88 (d, 1H, J = 9.1 Hz, H-1),
2
2
.72-3.60 (m, 6H, H-2, H-3, H-4, H-5, H-6a, H-6b); ESI-HRMS: Calcd for C43
99.2887. Found 699.2900.
H
42
N
2
O
S [M+H]+
5
2-(4-(4-Methylphenyl)thiazol-2-yl)-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose (11b)
Following the general procedure, the reaction of 8 (0.3 g, 0.5 mmol) and 10b (0.16 g, 0.5 mmol) afforded
-1
1
1b (0.33 g, 93%); yellow solid; mp 63-64 °C; IR (KBr) v (cm ): 3420 (N-H), 3029 (C-H, Ph), 2920
CH -Ph), 2865 (CH -Ph), 1628 (C=N), 1550 (C=C-S), 1496 (N-H), 1453 (C=C, Ph), 1059 (C-O-C), 736
C=CH, Ph), 697 (C=CH, Ph) cm ; H NMR (300 MHz, DMSO): δ 7.93 (d, 1H, J = 8.7 Hz, NH), 7.72 (d,
(
(
2
2
-1 1
2H, J = 8.1 Hz, Ph), 7.38-7.27 (m, 9H, Ph), 7.24-7.15 (m, 11H, Ph), 6.99 (s, 1H, C=CH), 4.83 (d, 1H, J =
Glu
1
2.5 Hz, PhCH
2
-), 4.77-4.65 (m, 4H, PhCH
2
-, H ), 4.57 (dd, 4H, J = 16.7, 12.1 Hz, PhCH -), 3.83 (d,1H,
2
Glu
Glu
Glu
J = 8.9 Hz, H ), 3.73 (dd, 2H, J = 11.6, 7.0 Hz, H ), 3.68-3.54 (m, 3H, H ); ESI-HRMS: Calcd for
+
C
44
H
44
N
2
O
5
S [M+H] 713.3044. Found 713.3042.
2-(4-(4-Methoxylphenyl)thiazol-2-yl)-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose (11c)
Following the general procedure, the reaction of 8 (0.3 g, 0.5 mmol) and 10c (0.12 g, 0.5 mmol) afforded
-1
1
1c (0.32 g, 88%); white solid; mp 139-141 °C; IR (KBr) v (cm ): 3431 (N-H), 3028 (C-H, Ph), 2870
(CH
2
-Ph), 1612 (C=N), 1511 (C=C-S), 1496 (N-H), 1453 (C=C, Ph), 1064 (C-O-C), 748 (C=CH, Ph),
1
6
97 (C=CH, Ph); H NMR (300 MHz, DMSO): δ 7.92 (d, 1H, J = 8.9 Hz, NH), 7.74 (d, 2H, J = 8.7 Hz,
Ph), 7.35-7.15 (m, 20H, Ph), 6.91 (d, 2H, J = 8.8 Hz, Ph), 6.88 (s, 1H, C=CH), 4.81 (d, 1H, J = 12.5 Hz,
Glu
-), 3.84 (d, 1H, J = 7.6 Hz,HGlu),
PhCH
2
-), 4.74-4.64 (m, 4H, PhCH
2
-, H ), 4.53 (t, 4H, J = 7.9 Hz, PhCH
2
Glu
Glu
3
.74 (s, 3H, CH
3
), 3.69 (dd, 2H, J = 11.1, 7.5 Hz, H ), 3.59-3.52 (m, 3H, H ); ESI-HRMS: Calcd for
+
C
44
H
44
N
2
O
6
S [M+H] 729.2993. Found 729.2992.
2-(4-(3-Methoxylphenyl)thiazol-2-yl)-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose (11d)
Following the general procedure, the reaction of 8 (0.3 g, mmol) and 10d (0.12 g, 0.5 mmol) afforded 11d
-
1
(
(
(
0.35 g, 90%); white solid; mp 147-149 °C; IR (KBr) v (cm ): 3446 (N-H), 3028 (C-H, Ph), 2932
CH
2
-Ph), 2873 (CH
2
-Ph), 1615 (C=N), 1527 (C=C-S), 1495 (N-H), 1453 (C=C, Ph), 1054 (C-O-C), 748
1
C=CH, Ph), 700 (C=CH, Ph); H NMR (300 MHz, DMSO): δ 7.41-7.15 (m, 24H, Ph), 7.13 (s, 1H,

2122
HETEROCYCLES, Vol. 91, No. 11, 2015
C=CH), 6.88 (d, 1H, J = 7.7 Hz, NH), 4.84 (d, 1H, J = 12.5 Hz, PhCH -), 4.73 (d, 4H, J = 10.2 Hz,
2
Glu
Glu
PhCH
2
-), 4.62-4.52 (m, 4H, PhCH
2
-, H ), 3.85 (d, 1H, J = 8.9 Hz, H ), 3.77 (s, 3H, OCH
3
), 3.72 (dd,
S [M+H]+
Glu
Glu
2
H, J = 10.9, 9.2 Hz, H ), 3.64-3.56 (m, 3H, H ); ESI-HRMS: Calcd for C44
H
44
N
2
O
6
7
29.2993. Found 729.3016.
-(4-(4-Fluorophenyl)thiazol-2-yl)-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose (11e)
2
Following the general procedure, the reaction of 8 (0.3 g, mmol) and 10e (0.11 g, 0.5 mmol) afforded 11e
-
1
(
(
(
(
0.32 g, 89%); yellow solid; mp 116-118 °C; IR (KBr) v (cm ): 3420 (N-H), 3029 (C-H, Ph), 2922
CH
2
-Ph), 2853 (CH
2
-Ph), 1640 (C=N), 1553 (C=C-S), 1496 (N-H), 1453 (C=C, Ph), 1061 (C-O-C), 734
1
C=CH, Ph), 696 (C=CH, Ph); H NMR (300 MHz, DMSO): δ 8.00 (d, 1H, J = 9.6 Hz, NH), 7.90-7.76
m, 2H, Ph), 7.37-7.16 (m, 24H, Ph), 7.06 (s, 1H, C=CH), 4.82 (d, 1H, J = 12.5 Hz, PhCH
2
-), 4.72 (m, 4H,
Glu
J = 11.1 Hz, PhCH
2
-, H ), 4.63 (d, 1H, J = 8.4 Hz, PhCH
2
-), 4.58-4.52 (m, 3H, PhCH
2
-) , 3.86 (d, 1H, J
Glu
Glu
Glu
=
7.2 Hz, H ), 3.73 (dd, 3H, J = 11.5, 7.0 Hz, H ), 3.57 (d, 2H, J = 6.4 Hz, H ); ESI-HRMS: Calcd
+
for C43
H41FN
2
O S [M+H] 717.2793. Found 717.2794.
5
2-(4-(4-Chlorophenyl)thiazol-2-yl)-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose (11f)
Following the general procedure, the reaction of 8 (0.3 g, mmol) and 10f (0.12 g, 0.5 mmol) afforded 11f
-
1
(
(
(
0.32 g, 87%); yellow solid; mp 136-138 °C; IR (KBr) v (cm ): 3368 (N-H), 3029 (C-H, Ph), 2911
CH
2
-Ph), 2857 (CH
2
-Ph), 1558 (C=N), 1495 (C=C-S), 1476 (N-H), 1453 (C=C, Ph), 1073 (C-O-C), 729
1
C=CH, Ph), 696 (C=CH, Ph); H NMR (300 MHz, DMSO): δ 8.01 (d, 1H, J = 8.8 Hz, NH), 7.84 (d, 2H,
J = 8.5 Hz, Ph), 7.46-7.15 (m, 22H, Ph), 7.14 (s, 1H, C=CH), 4.82 (d, 1H, J = 12.6 Hz, PhCH
2
-),
-), 3.83 (d, 1H, J = 8.1 Hz, H ), 3.73 (dd, 3H,
S [M+H]+
Glu
Glu
4
.78-4.64 (m, 4H, PhCH
2
-, H ), 4.63-4.50 (m, 4H, PhCH
2
Glu
Glu
J = 11.7, 6.8 Hz, H ), 3.57 (d, 2H, J = 6.1 Hz, H ); ESI-HRMS: Calcd for C43
H41ClN
2
O
5
7
33.2497. Found 733.2513.
-(4-(4-Bromophenyl)thiazol-2-yl)-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose (11g)
2
Following the general procedure, the reaction of 8 (0.3 g, mmol) and 10g (0.14 g, 0.5 mmol) afforded 11g
-
1
(
(
(
0.35 g, 90%); white solid; mp 147-148 °C; IR (KBr) v (cm ): 3421 (N-H), 3061 (C-H, Ph), 2938
CH
2
-Ph), 2873 (CH
2
-Ph), 1615 (C=N), 1526 (C=C-S), 1493 (N-H), 1452 (C=C, Ph), 1072 (C-O-C), 744
1
C=CH, Ph), 699 (C=CH, Ph); H NMR (300 MHz, DMSO): δ 8.24 (s, 1H, C=CH), 7.76 (d, 2H, J = 8.1
Hz, NH), 7.58 (d, 2H, J = 8.5 Hz, Ph), 7.40-7.26 (m, 10H, Ph), 7.22-7.16 (m, 11H, Ph), 4.83 (d, 1H, J =
Glu
1
2.5 Hz, PhCH
2
-), 4.79-4.65 (m, 4H, PhCH
2
-, H ), 4.62-4.52 (m, 4H, PhCH
2
-), 3.84 (d, 1H, J = 7.3 Hz,
S [M+H]+
Glu
Glu
Glu
H ), 3.78-3.68 (m, 3H, H ), 3.63-3.55 (m, 2H, H ); ESI-HRMS: Calcd for C43
H
41ClN
2
O
5
7
77.1992. Found 777.1972.
2-(4-(3-Nitrophenyl)thiazol-2-yl)-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose (11h)

HETEROCYCLES, Vol. 91, No. 11, 2015
2123
Following the general procedure, the reaction of 8 (0.3 g, mmol) and 10h (0.13 g, 0.5 mmol) afforded 11h
-1
(
0.33 g, 89%); white solid; mp 130-132 °C; IR (KBr) v (cm ): 3420 (N-H), 3028 (C-H, Ph), 2868
(CH
2
-Ph), 1615 (C=N), 1531 (C=C-S), 1495 (N-H), 1453 (C=C, Ph), 1065 (C-O-C), 744 (C=CH, Ph),
1
6
8
98 (C=CH, Ph); H NMR (300 MHz, DMSO): δ 8.64-8.58 (m, 1H, Ph), 8.26 (d, 2H, J = 7.9 Hz, Ph),
.13 (dd, 1H, J = 8.2, 1.5 Hz, NH), 7.69 (t, 1H, J = 8.0 Hz, Ph), 7.42 (s, 1H, C=CH), 7.38-7.14 (m, 20H,
Glu
Ph), 4.89-4.80 (m, 1H, PhCH
2
-), 4.79-4.66 (m, 4H, PhCH
2
-, H ), 4.63-4.53 (m, 4H, PhCH -), 3.82 (d,
2
Glu
Glu
Glu
1
H, J = 7.5 Hz, H ), 3.74 (dd, 3H, J = 11.3, 6.9 Hz, H ), 3.63-3.58 (m, 2H, H ); ESI-HRMS: Calcd
+
for C43
H
41
N
3
O S [M+Na] 744.2557. Found 744.2553.
7
2
-((1,1’-Biphenyl-4-yl)thiazol-2-yl)-1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranose (11i)
Following the general procedure, the reaction of 8 (0.3 g, mmol) and 10i (0.14 g, 0.5 mmol) afforded 11i
-
1
(
(
(
0.35 g, 90%); yellow solid; mp 130-132 °C; IR (KBr) v (cm ): 3420 (N-H), 3028 (C-H, Ph), 2921
CH
2
-Ph), 2861 (CH
2
-Ph), 1640 (C=N), 1550 (C=C-S), 1496 (N-H), 1453 (C=C, Ph), 1057 (C-O-C), 734
1
C=CH, Ph), 695 (C=CH, Ph); H NMR (300 MHz, DMSO): δ 8.02 (d, 1H, J = 9.2 Hz, NH), 7.93 (d, 1H,
J = 8.4 Hz, Ph), 7.81 (d, 1H, J = 6.7 Hz, Ph), 7.73-7.67 (m, 3H, Ph), 7.56-7.44 (m, 3H, Ph), 7.38-7.35 (m,
4
H, Ph), 7.34-7.28 (m, 5H, Ph), 7.25-7.17 (m, 12H, Ph), 7.15 (s, 1H, C=CH), 4.84 (d, 1H, J = 12.5 Hz,
Glu
-), 3.86 (d, 1H, J = 9.6 Hz, HGlu),
S [M+H]+
PhCH
2
-), 4.78-4.65 (m, 4H, PhCH
2
-, H ), 4.62-4.51 (m, 4H, PhCH
2
Glu
Glu
3
.76-3.67 (m, 2H, H ), 3.57 (t, 3H, J = 8.8 Hz, H ); ESI-HRMS: Calcd for C49
H
46
N
2
O
5
7
75.3200. Found 775.3188.
ACKNOWLEDGEMENTS
This work was supported by the Project Funded by the Priority Academic Program Development of
Jiangsu Higher Education Institutions, Natural Science Foundation of Jiangsu Province (BK20151281),
Open-end Funds of Jiangsu Key Laboratory of Marine Biotechnology, Huaihai Institute of Technology
(HS2014007, 2013HS004), The Science and Technology Project of Lianyungang (CG1415).
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