Synthesis of novel thioglycoside derivatives containing quinazolinone

Article abstract of DOI:10.1002/jccs.200900062

Aseries of novel thioglycoside derivatives containing 4(3H)-quinazolinone was designed and synthesized from 2-chloromethyl-quinazolin-4(3H)-ones and 1-thioglycose. Several 2-chloromethyl-quinazolin-4(3H)-ones were synthesized on refluxing with 2-(chloroacetylamino)-benzoic acid and arylamines in acetonitrile. All of the novel compounds were characterized by IR, 1H NMR spectra and elemental analysis. The structures of compounds 7b, 8b and 8c have been determined by X-ray diffraction analysis.

Full text of DOI:10.1002/jccs.200900062

Journal of the Chinese Chemical Society, 2009, 56, 419-424
419
Synthesis of Novel Thioglycoside Derivatives Containing Quinazolinone
Hui Huanga (
Duo-Zhi Wanga (
Shu-Bao Zhoua (
), Jian-Fang Gaoa (
), Jian-Bin Zhangb (
) and Yu-Qiang Zhoua (
), Ling-Hua Caoa,* (
),
),
)
aCollege of Chemistry and Chemical Engineering, Xinjiang University,
Urumqi Xinjiang 830046, P. R. China
bPhysics and Chemistry Test Center of Xinjiang University, Urumqi 830046, P. R. China
Aseries of novel thioglycoside derivatives containing 4(3H)-quinazolinone was designed and synthe-
sized from 2-chloromethyl-quinazolin-4(3H)-ones and 1-thioglycose. Several 2-chloromethyl-quin-
azolin-4(3H)-ones were synthesized on refluxing with 2-(chloroacetylamino)-benzoic acid and aryla-
mines in acetonitrile. All of the novel compounds were characterized by IR, 1H NMR spectra and elemen-
tal analysis. The structures of compounds 7b, 8b and 8c have been determined by X-ray diffraction analy-
sis.
Keywords: 4(3H)-Quinazolinone; Thioglycoside; 1-Thioglycose; X-ray diffraction.
INTRODUCTION
RESULTS AND DISCUSSION
Thioglycosides have received considerable attention
in carbohydrate chemistry and carbohydrate biology, be-
cause they are widely employed as biological inhibitors, in-
ducers and ligands for affinity chromatography of carbohy-
drate-processing enzymes and proteins.1,2 Among glycosyl
donors, thioglycosides are widely used owing to their high
degree of stability in many reaction conditions.3
The synthetic route of 2,3-disubstituted quinazolin-
4(3H)-ones is summarized in Scheme I. The anthranilic
acid 3 was linked with chloroaectyl chloride generating 4,
which underwent cyclization by treatment with boiling
acetic anhydride to form the intermediate benzoxazin-4-
one 5. In our experiment, the benzoxazinone by treatment
with arylamines 6a-6d yielded the benzamide derivatives
7a-7d. But the benzoxazinone reacted with o-toluidine (6e)
produced the quinazolinone 8e directly. The IR spectra of
Quinazoline compounds are reported to have physio-
logical and pharmacological activities and applications in
the treatment of several diseases such as leprosy and mental
disorders and also exhibit a wide range of activities, such as
antileukemic, anticonvulsant, antitumor, antimicrobial,
and anti-inflammatory activities.4~9 A well known meth-
aquolone10-containing quinazoline group are sedative and
hypnotic drugs and have been reported to possess anticon-
vulsant activity. Recently, several scientists elucidated that
a quinazoline nucleus possesses variable sites at positions 2
and 3 which can be suitably modified by the introduction of
some active groups to yield the quinazolinone compounds
in possession of higher activity.11
1
7a-7d showed a band at about 3300 cm-1 and H NMR
spectra showed a peak about d 11.10, exhibiting that a N-H
band existed in 7a-7d. Moreover a single crystal of 7b was
obtained; fortunately, furthermore, X-ray diffraction con-
firmed the structure of O-benzamidobenzanilide. Errede
reported12 O-benzamidobenzanilide at a fusion tempera-
ture of about 250 °C for conversion to the corresponding
quinazolones; in order to avoid the various products from
competing reactions, we chose the reagents Ac2O/H2SO4
for our investigations, and the expected product quinazo-
lones have been obtained successfully. The benzamide de-
rivatives 7a-7d were converted to quinazolinone products
8a-8d by heating in acetic acid and concentrated sulfuric
acid (9:1) at 100 °C for 3 hours. In addition, the cyclization
of anthranilic acid 4 with arylamine 6a-6e led to quinazo-
lone 8a-8e in 3 equiv of PCl3/CH3CN at 70 °C. Some re-
Thus, 2-chloromethyl-quinazolin-4(3H)-one was
linked with 1-thioglycose generating novel thioglycosides
derivatives containing quinazolinone which may possess
higher biological activity. The synthetic route of these com-
pounds is shown in Scheme I.
* Corresponding author. E-mail: clhxj@xju.edu.cn

420 J. Chin. Chem. Soc., Vol. 56, No. 2, 2009
Huang et al.
Scheme I
O
O
N
CNHR
amines 6a-6d
Ac2O
O
benzene
CH2Cl
NHCCH2Cl
5
COOH
NH2
COOH
O
7a-7d
ClCOCH2Cl
amine 6e
NHCCH2Cl
O
H2SO4 / HAc
O
R
4
3
amines 6a-6e
N
PCl3 / CH3CN
N
CH2Cl
8a-8d, 8e
O
N
R
NH2
.
NH2CSNH2
Me2CO
8a-8e
K2CO3 acetone
N
gly Br
gly SH
gly
S
HBr
NH
1, 2
S
gly
CH2
9a-9e,10a-10e
R: a C6H5; b p-C6H4CH3; c p-C6H4OCH3; d p-C6H4Cl; e o-C6H4CH3
gly: 1, 9 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl; 2, 10: 2,3,4-tri-O-acetyl-b-D-xylopyranosyl
searchers have reported that benzooxazinones refluxing
with amines in toluene gave a mixture of uncyclized di-
amides and quinazolinones,13 and when benzooxazinone
reacted with primary amine, there were two competitive re-
actions; at temperatures below 150 °C the major product
was O-benzamidobenzanilide.12
The intermediates 1 and 2 are easily prepared from
their corresponding glycosyl bromides, followed by reac-
tion with 8 in the system of K2CO3/acetone at room temper-
Fig. 1a. Molecular stereo configuration for compound
ature, and the target compounds 9, 10 were smoothly af-
forded in mild conditions.
8b.
Crystals of the compounds 7b, 8b and 8c suitable for
single crystal X-ray analysis were obtained from slow
evaporation of an ethanol solution at room temperature.
The structures of all the complexes were determined by di-
rect method procedures in SHELXS-97. The structures of
7b, 8b and 8c are shown in Figs. 1~3.
In Fig. 3a, there were intramolecular hydrogen bonds
and intermolecular hydrogen bonds in the compound 7b
because of having an N-H bond.
EXPERIMENTAL
Melting points were determined on a Yanaco MP-S3
micro melting point apparatus and are corrected. The IR
spectra were recorded as KBr pellets on a Bruker FT-IR
1
Fig. 1b. A view of the crystal packing down an axis for
Equinox 55 instrument. The H NMR spectra were re-
compound 8b.
corded on an Inova 400 (using TMS as the internal stan-

Synthesis of Quinazolinone Thioglycoside Derivatives
J. Chin. Chem. Soc., Vol. 56, No. 2, 2009 421
dard, with chemical shifts expressed in d-units in CDCl3 as
solvent). Elemental analyses were performed on a Thermo
Flash EA-1112 elemental analyzer. Analytical thin-layer
chromatography (TLC) was performed on silica gel GF254
(Qingdao, China) with ethyl acetate and light petroleum
(fraction boiling in the range of 60~90 ºC) and detection by
UV light or iodine vapor. All reagents were commercial
products of analytical grade and were used directly without
processing unless otherwise specified. X-ray single-crystal
diffraction was recorded on a R-AXIS SPIDER X-ray
diffractometer.
2: yield: 43%, m.p. 131~133 °C.
1.2 Compound 4 was prepared according to a re-
ported method15
4: yield 87%, m.p. 183~185 ºC, lit16 m.p. 186~188 ºC.
1.3 Compound 5 was prepared according to a re-
ported method16
5: yield 93%, m.p. 93~94 ºC, lit16 m.p. 95 ºC.
2. General procedure for the preparation of 2-(cholo-
methyl)-3-aryl-4(3H)-quinazolinone
Method 1
Mixtures of the benzoxazinone 5 (5 mmol), aryla-
mines 6a-6d (5.05 mmol) and dry benzene (30 mL) were
stirred for 0.5~4 h at room temperature. Then, the mixtures
were refluxed for 0.5~4 h in an apparatus equipped with a
water separator. The clear solution obtained in the series
was evaporated to dryness at reduced pressure. The residue
was crystallized from ethanol.
1. Synthesis of intermediates
1.1 Synthesis of per-O-acetyl-thioglycoses 1~2 accord-
ing to a reported method14
1: yield: 54%, m.p. 113~114 °C, lit14 m.p. 114~115
°C.
Fig. 2a. Molecular stereo configuration for compound
8c.
Fig. 3a. Molecular stereo configuration for compound
7b.
Fig. 3b. A view of the crystal packing down an axis for
Fig. 2b. A view of the crystal packing down an axis for
compound 7b.
compound 8c.

422 J. Chin. Chem. Soc., Vol. 56, No. 2, 2009
Huang et al.
7a: colourless acicular crystal, yield: 54%, m.p. 187~
189 ºC;
3. Synthesis of thioglycosides derivatives 9a~9e and
10a~10e
To a well-stirred suspension of K2CO3 (0.2 g) in ace-
7b: colourless block crystal, yield: 50%, m.p. 168~
170 ºC;
tone (20 mL) were added sequentially 1-thio-glycose (1
mmol), quinazolinone derivatives (1 mmol) and H2O (0.1
mL). The resultant mixture was stirred at r.t for 3~4 h, di-
luted with CH2Cl2 (20 mL), filtered, and the solution was
evaporated. The expected compound was isolated by crys-
tallization from EtOH/H2O.
9a: syrup, yield: 75%, Rf = 0.43, 1H NMR (400 MHz,
CDCl3): d: 1.97, 1.99, 2.00, 2.03 (3s, 12H, 4 × COCH3),
3.52~3.56 (m, 1H, sugar ring-H-5), 3.57 (d, J = 14 Hz, 1H,
SCHa), 3.68 (d×d, J6,6¢ = 12.4 Hz, J6,5 = 1.2 Hz, 1H, H-6),
3.74 (d, J = 14 Hz, 1H, SCHb), 3.98 (d×d, J6¢,6 = 12.4 Hz,
J6¢,5 = 4.8 Hz, 1H, H-6¢), 4.80~5.07 (m, 3H, sugar ring-H),
5.18 (t, J = 9.2 Hz, 1H, C1-H), 7.00~7.45 (m, 5H, ArH),
7.50~8.28 (m, 4H, quinazolinon-H). Anal. calcd for
C29H30N2O10S; C, 58.19; H, 5.05; N, 4.68; found C, 58.29;
H, 5.03; N, 4.70.
7c: colourless acicular crystal, yield: 43%, m.p. 212~
214 ºC;
7d: colourless acicular crystal, yield: 38%, m.p. 182~
183 ºC.
To a solution of compounds 7a~7d in ethanol was
added acetic acid and concentrated sulfuric acid (9:1), and
the resultant mixture was heated at 100°C for 15 min. The
mixture was cooled to room temperature and diluted with
ice water. 100 mL CHCl3 was added. The organic layer was
separated, washed with saturated aqueous NaHCO3 solu-
tion, and evaporated under vacuum to give oily products,
which crystallized on standing. The crude products 8a~8d
were recrystallized from ethanol.
Method 2
To a solution of the acetylanthranilic acid (5 mmol) in
CH3CN (15 mL) was added a solution of the aniline (5
mmol) in CH3CN (15 mL) at room temperature to give a
white suspension. 15 mmol PCl3 was added, and the resul-
tant mixture was heated to 70 °C for 5 h. The mixture was
cooled to room temperature and diluted with ice water. 100
mL CHCl3 was added. The organic layer was separated,
washed with saturated aqueous NaHCO3 solution, and
evaporated under vacuum to give an oil, which crystallized
on standing. The crude products were recrystallized from
ethanol.17
1
9b: white solid, yield: 87%, m.p. 170~171 °C; H
NMR (400 MHz, CDCl3): d: 1.96, 1.98, 2.00, 2.02 (3s,
12H, 4 × COCH3), 2.43 (s, 3H, CH3), 3.51~3.58 (m, 1H,
sugar ring-H-5), 3.54 (d, J = 14 Hz, SCHa), 3.65 (d×d, J6,6¢
= 12.4 Hz, J6,5 = 1.2 Hz, 1H, H-6), 3.75 (d, J = 14 Hz, 1H,
SCHb), 3.94 (d×d, J6¢,6 = 12.4 Hz, J6¢,5 = 4.8 Hz, 1H, H-6¢),
4.80~5.07 (m, 3H, sugar ring-H), 5.19 (t, J = 9.2 Hz, 1H,
C1-H), 7.05~7.32 (m, 4H, ArH), 7.51~8.28 (m, 4H, quin-
azolinon-H). Anal. calcd for C30H32N2O10S: C, 58.81; H,
5.26; N, 4.57; found C, 58.70; H, 5.24; N, 4.59.
1
8a: yield: 60%, m.p. 155~156 °C, lit18 m.p. 152~154
9c: white solid, yield: 67%, m.p. 182~183 °C; H
ºC, colourless block crystal.
NMR (400 MHz, CDCl3): d: 1.98, 1.98, 1.99, 2.02 (3s,
8b: yield: 40%, m.p. 173~175 °C, colourless block
crystal. 1H NMR (400 MHz, CDCl3), 7.23~8.30 (m, 8H),
4.29 (s, 2H, CH2Cl2), 2.26 (s, 3H, CH3). Anal. calcd for
C16H13ClN2O: C, 67.49; H, 4.60; N, 9.84; found C, 67.63;
H, 4.57; N, 9.87.
12H, 4 × COCH3), 3.53~3.57 (m, 1H, sugar ring-H-5), 3.58
(d, J = 14 Hz, 1H, SCHa), 3.66 (d×d, J6,6 = 12.4 Hz, J6,5
=
1.2 Hz, 1H, H-6), 3.73 (d, J = 14 Hz, 1H, SCHb), 3.88 (s,
3H, OCH3), 3.96 (d×d, J6¢,6 = 12.4 Hz, J6¢,5 = 4.8 Hz, 1H,
H-6¢), 4.81~5.05 (m, 3H, sugar ring-H), 5.17 (t, J = 9.2 Hz,
1H, C1-H), 7.02~7.28 (m, 4H, ArH), 7.52~8.29 (m, 4H,
quinazolinon-H). Anal. calcd for C30H32N2O11S: C, 57.32;
H, 5.13; N, 4.46; found C, 57.43; H, 5.11; N, 4.68.
8c: yield: 43%, m.p. 138~140 °C, colourless block
crystal. 1H NMR (400 MHz, CDCl3), 7.10~8.30 (m, 8H),
4.29 (s, 2H, CH2Cl2), 3.89 (s, 3H, CH3). Anal. calcd for
C16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31; found C, 64.01;
H, 4.38; N, 9.34.
1
9d: white solid, yield: 48%, m.p. 184~186 °C; H
NMR (400 MHz, CDCl3): d: 1.97, 1.99, 2.01, 2.04 (3s,
8d: yield: 41%, m.p. 178~180 °C, colourless crystal.
1H NMR (400 MHz, CDCl3), 7.12~8.30 (m, 8H), 4.32 (s,
2H, CH2Cl2). Anal. calcd for C15H10Cl2N2O: C, 59.04; H,
3.30; N, 9.18; found C, 59.16; H, 3.29; N, 9.22.
8e: yield: 61%, m.p. 107~108 °C, lit18 m.p. 103~105
ºC, colourless acicular crystal.
12H, 4 × COCH3), 3.50~3.56 (m, 1H, sugar ring-H-5), 3.57
(d, J = 14.0 Hz, 1H, SCHa), 3.67 (d×d, J6,6¢ = 12.4 Hz, J6,5
=
1.2 Hz, 1H, H-6), 3.74 (d, J = 14.0 Hz, 1H, SCHb), 3.94
(d×d, J6¢,6 = 12.4 Hz, J6¢,5 = 4.8 Hz, 1H, H-6¢), 4.80~5.07
(m, 3H, sugar ring-H), 5.16 (t, J = 9.2 Hz, 1H, C1-H),
7.21~7.47 (m, 4H, ArH), 7.50~8.27 (m, 4H, quinazo-

Synthesis of Quinazolinone Thioglycoside Derivatives
J. Chin. Chem. Soc., Vol. 56, No. 2, 2009 423
linon-H). Anal. calcd for C29H29ClN2O10S: C, 55.02; H,
4.62; N, 4.43; found C, 55.13; H, 4.64; N, 4.45.
55.55; H, 5.01; N, 5.00.
1
10e: white solid, yield: 46%, m.p. 148~150 °C. H
9e: white solid, yield: 79%, m.p. 84~86 °C; 1H NMR
(400 MHz, CDCl3): d: 1.97, 1.99, 2.02, 2.04 (3s, 12H, 4 ×
COCH3), 2.38 (s, 3H, CH3), 3.51~3.55 (m, 1H, sugar ring-
NMR (400 MHz, CDCl3): d: 1.97, 2.00, 2.03 (3s, 9H, 3 ×
COCH3), 2.44 (s, 3H, CH3), 3.53~3.58 (m, 1H, sugar
ring-H-5), 3.60 (d, J = 14.0 Hz, 1H, SCHa), 3.73 (d, J =
14.0 Hz, 1H, SCHb), 4.01 (d×d, 1H, sugar ring-H-5¢),
4.75~4.90 (m, 3H, sugar ring-H), 5.14 (t, J = 8.0 Hz, 1H,
C1-H), 7.14~7.36 (m, 4H, ArH), 7.49~8.30 (m, 4H, quin-
azolinon-H). Anal. calcd for C27H28N2O8S: C, 59.99; H,
5.22; N, 5.18; found C, 59.87; H, 5.20; N, 5.16.
H-5), 3.59 (d, J = 14.0 Hz, 1H, SCHa), 3.67 (d×d, J6,6¢
=
12.4 Hz, J6,5 = 1.2 Hz, 1H, H-6), 3.72 (d, J = 14.0 Hz, 1H,
SCHb), 3.95 (d×d, J6¢,6 = 12.4 Hz, J6¢,5 = 4.8 Hz, 1H, H-6¢),
4.80~5.07 (m, 3H, sugar ring-H), 5.16 (t, J = 9.2 Hz, 1H,
C1-H), 7.03~7.31 (m, 4H, ArH), 7.49~8.28 (m, 4H, quin-
azolinon-H). Anal. calcd for C30H32N2O10S: C, 58.81; H,
5.26; N, 4.57; found C, 58.70; H, 5.28; N, 4.55.
ACKNOWLEDGEMENT
10a: white solid, yield: 60%, m.p. 194~195 °C; 1H
NMR (400 MHz, CDCl3): d: 1.98, 2.01, 2.02 (3s, 9H, 3 ×
COCH3), 3.50~3.58 (t, 1H, sugar ring-H-5), 3.60 (d, J =
14.0 Hz, 1H, SCHa), 3.74 (d, J = 14.0 Hz, 1H, SCHb), 3.98
(d×d, 1H, sugar ring-H-5¢), 4.78~4.90 (m, 3H, sugar ring-
H), 5.18 (t, J = 8.0 Hz, 1H, C1-H), 7.16~7.36 (m, 5H, ArH),
7.50~8.29 (m, 4H, quinazolinon-H). Anal. calcd for
C26H26N2O8S: C, 59.31; H, 4.98; N, 5.32; found C, 59.43;
H, 5.00; N, 4.30.
10b: white solid, yield: 49%, m.p. 158~159 °C; 1H
NMR (400 MHz, CDCl3): d: 2.00, 2.02, 2.03 (3s, 9H, 3 ×
COCH3), 2.45 (s, 3H, CH3), 3.53~3.57 (t, 1H, sugar
ring-H-5), 3.59 (d, J = 14.0 Hz, 1H, SCHa), 3.73 (d, J =
14.0 Hz, 1H, SCHb), 4.00 (d×d, 1H, sugar ring-H-5¢),
4.80~4.91 (m, 3H, sugar ring-H), 5.12 (t, J = 8.0 Hz, 1H,
C1-H), 7.17~7.35 (m, 4H, ArH), 7.51~8.28 (m, 4H, quin-
azolinon-H). Anal. calcd for C27H28N2O8S: C, 59.99; H,
5.22; N, 5.18; found C, 59.87; H, 5.24; N, 5.16.
This work was supported by the National Natural Sci-
ence Foundation of China (Grant No. 20462006) and Xin-
jiang Key Laboratory of Plant Resources & Natural Prod-
ucts Chemistry.
SUPPLEMENTARY DATA
Complete crystallographic data for the structural
analysis of compounds 7b, 8b and 8c have been deposited
with the Cambridge Crystallographic Data Centre, CCDC
numbers 689057, 693620, and 693621, respectively. Cop-
ies of this information may be obtained free of charge from
the Director, Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge, CB2 1EZ, UK. (telephone: +44-
01223-762910, facsimile: +44-01223-336033, e-mail: de-
posit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk). Sup-
plementary data (tables containing selected bond lengths
and bond angles for compound 1) associated with this arti-
cle can be found in the online version, at http://www.ccdc.
cam.ac. uk /deposit.
1
10c: white solid, yield: 61%, m.p. 191~192 °C; H
NMR (400 MHz, CDCl3) d: 2.00, 2.01, 2.04 (3s, 9H, 3 ×
COCH3), 3.53~3.57 (t, 1H, sugar ring-H-5), 3.60 (d, J =
14.0 Hz, H, SCHa), 3.74 (d, J = 14.0 Hz, H, SCHb), 3.78 (s,
3H, OCH3), 4.01 (d×d, 1H, sugar ring-H-5¢), 4.83~4.91 (m,
3H, sugar ring-H), 5.10 (t, J = 8.0 Hz, 1H, C1-H), 7.16~
7.37 (m, 4H, ArH), 7.50~8.30 (m, 4H, quinazolinon-H).
Anal. calcd for C27H28N2O9S: C, 58.26; H, 5.07; N, 5.03;
found C, 58.14; H, 5.09; N, 5.05.
10d: white solid, yield: 57%, m.p. 149~150 °C; 1H
NMR (400 MHz, CDCl3): d: 1.99, 2.01, 2.04 (3s, 9H, 3 ×
COCH3), 3.50~3.56 (m, 1H, sugar ring-H-5), 3.57 (d, J =
14.0 Hz, 1H, SCHa), 3.74 (d, J = 14.0 Hz, 1H, SCHb), 4.02
(d×d, 1H, sugar ring-H-5¢), 4.81~5.07 (m, 3H, sugar ring-
H), 5.16 (t, J = 8.0 Hz, 1H, C1-H), 7.21~7.47 (m, 4H, ArH),
7.50~8.27 (m, 4H, quinazolinon-H). Anal. calcd for
C26H25ClN2O8S: C, 55.66; H, 4.49; N, 4.99; found C,
Received November 14, 2008.
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