A direct synthetic approach to uracil anhydrothionucleoside derivatives

Article abstract of DOI:10.1016/j.carres.2009.09.006

Direct conversion of peracylated N¹-(β-d-glucopyranosyl)-2-thiouracil derivatives into the corresponding anhydrothionucleosides has been studied under various conditions including: gas-phase pyrolysis, heating without a solvent, and by heating

Full text of DOI:10.1016/j.carres.2009.09.006

Carbohydrate Research 344 (2009) 2322–2328
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
A direct synthetic approach to uracil anhydrothionucleoside derivatives
*
Nouria A. Al-Awadi, Yehia A. Ibrahim , Maher R. Ibrahim
Chemistry Department, Faculty of Science, Kuwait University, PO Box 5969, Safat 13060, Kuwait
a r t i c l e i n f o
a b s t r a c t
Direct conversion of peracylated N1-(b-
D-glucopyranosyl)-2-thiouracil derivatives into the corresponding
anhydrothionucleosides has been studied under various conditions including: gas-phase pyrolysis, heat-
ing without a solvent, and by heating in a solvent of high boiling point (DPE) in the presence of a base
(DABCO) and reaction in a microwave reactor. Heating at 210–220 °C was found to give the best yield
Article history:
Received 16 May 2009
Received in revised form 5 September 2009
Accepted 9 September 2009
Available online 16 September 2009
of
a single isomer. The structures of the new anhydrothionucleosides were confirmed by NMR
techniques.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Pyrolysis
Microwave
Nucleosides
Anhydronucleosides
Pyrimidine
1. Introduction
2. Results and discussion
Much attention has been directed toward the synthesis of 2,20-
and 2,30-anhydronucleosides due to the possibility that these com-
pounds can be attacked by nucleophiles at the C-20 or C-30 posi-
tions affording compounds with anti-AIDS activity.1 Despite the
extensive reported synthesis of anhydronucleosides,1–5 little is re-
ported about the synthesis of anhydrothionucleosides.6,7
In the present work we report our attempts to apply this meth-
odology to the synthesis of anhydrothioglycosides of 2-thiouracil
derivatives.
The starting 1-(tetra-O-acetyl-b-D-glucopyranosyl)-2-thiouracil
derivatives 5a–e required in this study were prepared as outlined
in Scheme 2 from 6-aryl-5-cyano-2-thiouracils 4a–e following
methods reported in the literature11 with slight modifications. This
Recently we reported a novel synthetic approach toward anhy-
drothionucleosides via a gas-phase thermal intramolecular substi-
includes either treatment with tetra-O-acetyl-a-D-glucopyranosyl
tution reaction that led to the conversion of the N-(2-b-
N-(2-b- -galactosyl), and N-(2-b- -ribosyl) derivatives of 3-thioxo-
2,3-dihydro-1,2,4-triazin-5(4H)-ones 1 (X = C@O) into their corre-
sponding 3,20-anhydro-b- -mannosyl, 3,20-anhydro-b-
-talosyl
and 3,20-anhydro-b-
-arabinosyl derivatives 3 (X = C@O) (Scheme
D
-glucosyl),
bromide and triethylamine in DMF or KOH in an acetone–water
mixture. This method yielded in addition to 5a–e the diglycosyl
derivatives 6a–e. Alternatively, first converting 4a–e into their sily-
lated derivatives by treatment with hexamethyldisilazane (HMDS),
D
D
D
D
D
followed by reaction with tetra-O-acetyl-a-D-glucopyranosyl bro-
1).8 The proposed mechanism for the thermal conversion of these
acylated glycosyls into their anhydro derivatives is illustrated in
Scheme 1. This involves the intramolecular SN2 (5-exo-tet) attack
by the sulfur on C-20 of the glycosyl moiety, followed by the elim-
ination of acetate (CH3COOꢀ) and H+, which ultimately produce
acetic acid.9 This synthesis of anhydrothioglycosyls has been im-
proved by studying the reaction under various reaction conditions
including gas-phase pyrolysis and heating the reactants in a sol-
vent of high boiling point in the presence of different bases includ-
ing triethylamine, DABCO, and DBU. The reactions have also been
conducted in a microwave reactor.9 This synthetic approach has
also been successfully extended to the synthesis of anhydrothio-
glycosides of 1,2,4-triazoles 3 (X = 1,2,4-triazole derivatives).10
mide in dry acetonitrile in the presence of SnCl4 as Lewis acid cat-
alyst gave a better yield of 5a–d. In the present investigation the
latter method was used to obtain pure 5a–e, and the former meth-
od was optimized to synthesize 6a–e (cf. Section 4).
In a preliminary experiment we found that compound 5d could
be readily converted to the anhydro derivative 7d in 23% upon
heating in static pyrolyzer at 230 °C for 30 min; however, under
these conditions the isomeric product 8d was also obtained in 9%
yield, which makes purification very difficult. Decreasing the tem-
perature to 210–220 °C gave complete conversion after 1 h with
the sole formation of 7d in 25% (condition B, entry 2), which could
be easily purified by crystallization. Reactions in a microwave
(MW) reactor were also investigated as a possible way to convert
5d into 7d. Thus, when a solution of 5d in xylene was heated in
the MW reactor at 190 °C for 10 min, complete conversion took
place with the formation of 7d (27%) and 8d (9%) along with other
* Corresponding author. Fax: +965 4816482.
E-mail address: yehiaai@kuc01.kuniv.edu.kw (Y.A. Ibrahim).
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.09.006

N. A. Al-Awadi et al. / Carbohydrate Research 344 (2009) 2322–2328
2323
H
R
R
X
X
H
R
X
N
O
N
O
N
O
N
N
N
N
S
N
S
N
S
5-exo-tet
CH3COOH
+
AcO
H
AcO
OAc
AcO
OAc
1
2
3
X = C=O (1,2,4-triazine derivatives),
X = - (1,2,4-triazole derivatives)
Scheme 1. Synthesis and mechanism of anhydrothionucleosides of 1,2,4-triazines.
O
O
N
CN
HN
CN
Ar
N
AcO
AcO
Br
S
N
Ar
S
O
AcO
AcO
O
OAc
O
AcO
O
+
O
OAc
OAc
CN
Ar
OAc
HN
AcO
AcO
AcO
AcO
AcO
AcO
S
N
H
4a-e
AcO
A) TEA/DMF
or B) Acetone/H2O, KOH
5a-e
6a-e
1. HMDS/CH3CN
2. Glucose pentaacetate/SnCl4
a, Ar = C6H5
Ar
Ar
Ar
b,
c,
d,
= C6H4CH3-p
= C H Cl-p
= C6H4OCH3-p
6
4
e, Ar = 3-pyridyl
Scheme 2. Synthesis of peracylated N1-(b-
D-glucopyranosyl)-2-thiouracil derivatives 5a–e.
decomposition products (Table 1, entry 3). Running the reaction in
diphenyl ether (DPE) at 200–210 °C gave also a mixture of the two
isomers 7d and 8d in addition to the starting material 5d (Table 1,
entry 4). Refluxing 5d in xylene in the presence of DABCO for 24 h
also gave the product 7d; however, 7d was obtained in a low yield
along with the starting material and other decomposition prod-
ucts. From these experiments it is clear that the best method to ob-
tain compound 7d is by heating at 210–220 °C for 1 h. Although the
MW reaction gave a better yield of 7d, separation of isomer 8d that
also formed was a serious problem (see Scheme 3).
Application of conditions A–D in Table 1 to the conversion of
other derivatives 5a–c, e to their corresponding anhydro deriva-
tives 7a–c, e was then studied, and the results are shown in Table
2. In all the cases heating of each of the compounds 5a–e at 210–
220 °C without a solvent or a base (condition B) gave the best yield
with the formation of the corresponding single isomeric anhydro-
thionucleosides 7a–e (Tables 1 and 2). The other conditions always
led to other decomposition products and the formation of the iso-
meric anhydrothionucleosides 8a–e. The latter were only identi-
fied by their LC–MS and 1H NMR spectra.
Formation of isomeric anhydrothionucleosides 8a–e results
from the initial thermal rearrangement of 5a–e into their isomeric
3-glucosyl derivatives 9a–e, followed by elimination of acetic acid.
Thermal isomerization of glucosyl derivatives were also recently
reported.10
We also investigated the thermal behavior of the diglucosyl
derivatives 6a–e and found that they gave the same product mix-
ture of anhydrothionucleosides 7a–e and 8a–e obtained under the
same reaction conditions (cf. Table 2).
The structure of the starting compound 5a–e was confirmed as
the 1-glucosyl derivatives based on the presence of an NOE effect
of the anomeric proton upon irradiation of the aromatic-H at d

2324
N. A. Al-Awadi et al. / Carbohydrate Research 344 (2009) 2322–2328
Ar
N
CN
ACO
O
O
ACO
N
S
ACO
Conditions A-F (Table 1)
7a-e
5a-e
-CH3CO2H
O
N
CN
ACO
ACO
O
Ar
Ar
N
N
CN
O
S
ACO
HN
S
8a-e
AcO
AcO
O
OAc
AcO
9a-e
Scheme 3. Conversion of peracylated N1-(b-
D-glucopyranosyl)-2-thiouracil derivatives 5a–e into the corresponding anhydrothionucleosides 7a–e.
Table 1
Table 2
Conditions for converting 5d to the corresponding anhydro derivative 7d
Products and % yields of anhydro derivatives from 5a–c, e, and 6a–e under different
conditions
Entry
Reaction conditionsa
Reaction products %
Entry
Substrate
Reaction conditions
Products (yield %)
8a (10)
7d
8d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
5a
5a
5a
5a
5b
5b
5b
5b
5c
5c
5c
5c
5e
5e
5e
5e
6a
6b
6c
6d
6e
A
B
C
D
A
B
C
D
A
B
C
D
A
B
C
D
A
A
A
A
A
7a (23)
7a (18)
7a (23)
7a (22)
7b (22)
7b (20)
7b (20)
7b (16)
7c (15)
7c (16)
7c (16)
7c (14)
7e (14)
7e (18)
7e (18)
7e (16)
7a (18)
7b (17)
7c (17)
7d (16)
7d (16)
1a
A
B
C
D
E
F
23
25
27
20
5
9
—
9
5
—
—
2a
8a (9)
8a (5)
8b (9)
3b
4a
5b,c
6b,c
11
8b(5)
8b (4)
8c (10)
a
Reaction conditions: (A) static pyrolysis at 230 °C for 30 min, (B) static oil bath
at 210–220 °C for 1 h, (C) MW 190 °C for 10 min, (D) oil bath, DPE, 200–210 °C, 1 h,
(E) xylene, 140 °C, 24 h, and (F) xylene, DABCO, 140 °C, 24 h.
Recovered 2d in runs 3 (9%), 5 (25%), and 6 (12%).
Other unidentified decomposition products are produced, and extending the
reaction time to 48 h gave only decomposition products.
b
8c (5)
8c (7)
8e (12)
c
8e (12)
8e (17)
8a (8)
8b (8)
8c (7)
8d (7)
8d (7)
8.16 as reported.11 Additional evidence comes from the HMBC
experiment for compound 5d which gives the H–C correlations
shown in Figure 1. In this correlation H-8 correlates with the
pyrimidine C-6, and the anomeric proton H-10 correlates with the
C@S in the pyrimidine ring. The structure was further confirmed
by alkylating compound 5d with iodomethane to give a mixture
of the SCH3 and NCH3 10d from which a pure sample of the latter
could be crystallized. In the HMBC experiment compound 10d
showed a similar correlation of the anomeric H-10 with C@S,
whereas the CH3 protons showed correlations with both the C@S
and the C@O carbons. Similarly the HMBC of compound 7d showed
the correlation indicated in Figure 1. The anomeric proton H-10 cor-
relates with the C@S in the pyrimidine ring. Moreover, 15N NMR
(HMBC) of 10d gave two nitrogen signals. One at d 167.5 correlated
with the methyl protons at d 3.58, and the other at d 231.7 corre-
lated with the anomeric H-10 signal at d 5.82. On the other hand,
15N NMR (HMBC) of 5d gave one signal at d 235.5 that correlated
with the anomeric H-10 signal at d 5.80. Full proton and carbon
assignments of compounds 5d, 7d, and 10d and the 15N NMR spec-
(A) Static pyrolysis at 230 °C for 30 min, (B) static oil bath at 210–220 °C for 1 h, (C)
MW 190 °C for 10 min, and (D) oil bath, DPE, 200–210 °C, 1 h.
tral data for 5d and 10d are shown in Figure 1. These assignments
were based on H,H-COSY, HMQC, and HMBC NMR experiments.
Also, the important HMBCs are indicated.
3. Conclusions
The present study extends our recently discovered direct syn-
thesis of anhydrothionucleosides to pyrimidine derivatives, thus
offering direct access to a novel class of compounds that can be
used as starting materials for the synthesis of new modified
nucleosides with the potential for biological activity.

N. A. Al-Awadi et al. / Carbohydrate Research 344 (2009) 2322–2328
2325
55.6
3.94
114.3
O
11
O
163.4
CH3
10
1
131.4
126.7
7.07
76.6
9
62.0
H
8.16
H
167.4
CN
81.4
8
6'
7
CN
115.0
5.80
ACO
ACO
ACO
5'
4'
O
93.0
O
5
O
1'
6
N
235.5
N
O
2
ACO
3
H
2'
4
N
H
H
N
H
H
H
S
3'
S
ACO
OAc
67.8
73.5
OAc
ACO
161.0
68.8
5.16
Important HMBC H-C, C-N correlations
162.5
5d
55.6
3.92
11
114.2
CH3
10
1
O
163.4
O
131.5
7.02
8.13
9
126.4
84.0
65.0
H
H
61.4
8
115.2
6'
7
168.1
CN
CN
ACO
5'
4'
5
92.7
O
1'
2'
ACO
6.36
6
O
N
O
2
3
N
N
ACO
O
4
H
ACO
H
S
N
3'
S
H
ACO
H
ACO
73.0
69.7
157.8
Important HMBC H-C correlations
166.5
O
4.88
49.0
7d
55.6
3.93
114.3
11
O
CH3
10
1
163.1
7.06
130.9
126.9
82.3
9
76.8
H
62.1
H
8
8.11
6'
164.7
7
115.4
CN
CN
ACO
ACO
5.83
5'
4'
5
O
1'
ACO
92.4
6
2
O
4
160.2
N
O
N
231.7
3
N
2'
O
H
H
ACO
H
N
167.5
3'
S
H
CH3
3.58
OAc
S
ACO
CH3
31.0
ACO
OAc
5.32
67.9
73.6
162.2
Important HMBC H-C correlations
68.4
10d
Figure 1. 1H and 13C NMR spectroscopy assignments of 5d, 10d, 7d, and 15N of 5d and 10d measured by an HMBC experiment. The important HMBCs are indicated by arrows
on each structure on the right-hand side.
1H and 13C 15N NMR spectra were recorded on a Bruker DPX 400,
4. Experimental
and AvanceII 600 spectrometers. Mass spectra were measured on
a VG Autospec-Q (high-resolution, high-performance, tri-sector
GC/MS/MS) and with LC–MS using an Agilent 1100 series LC/
All melting points are uncorrected. IR spectra were recorded in
KBr disks on a Perkin–Elmer System 2000 FTIR spectrophotometer.

2326
N. A. Al-Awadi et al. / Carbohydrate Research 344 (2009) 2322–2328
MSD in the API-ES/APCI ionization mode. Microanalyses were per-
formed on a LECO CH NS-932 instrument. The microwave oven
used was a single mode cavity Explorer Microwave Synthesizer
(CEM Corporation, NC, USA).
115.0, 126.7, 131.4, 161.0, 162.5, 163.4, 167.4, 169.3 (2C), 170.1,
170.7. LC–MS: m/z 590. MS: m/z 589 (M+, 10%), 529 (80%), 284
(45%), 98 (100%). HRMS: m/z 589.1362 (C25H27N3O11S requires m/
z 589.1366). Anal. Calcd for C26H27N3O11S (589.6): C, 52.97; H,
4.62; N, 7.13; S, 5.40. Found: C, 53.00; H, 4.63; N, 7.40; S, 5.19.
4.1. 6-Aryl-5-cyano-1-(2,3,4,6-tetra-O-acetyl-b-D-
glucopyranosyl)-2-thiouracils 5a–e. General procedures
4.1.5. 5-Cyano-6-(3-pyridyl)-1-(2,3,4,6-tetra-O-acetyl-b-D-
glucopyranosyl)-2-thiouracil (5e)
A mixture of each of 2-thiouracil 4a–e (10 mmol), HMDS
(60 mL), and (NH4)2SO4 (125 mg) was heated under reflux for
6 h. The excess HMDS was removed under reduced pressure. The
solution of the resultant silyl intermediate in anhyd CH3CN
(20 mL) was stirred and treated with a solution of 2,3,4,6-tetra-
Yellow plates, yield 64%, mp 208–210 °C. IR: 3446, 3077, 2940,
2213, 1752, 1659, 1522, 1522, 1469, 1371, 1244, 1230, 1107, 1038.
1H NMR (DMSO-d): d 1.96, 2.00, 2.03, 2.06 (4s, 12H, 4CH3CO), 4.25
(m, 2H), 4.45 (m, 1H), 5.43 (t, 1H, J 9.6), 5.59 (m, 2H), 6.47 (d, 1H, J
9.4), 8.43 (dd, 1H, J 6.4, 1.6), 9.11 (dd, 1H, J 6.4, 1.2), 9.46 (d, 1H, J
6.4), 9.63 (s, 1H), 12.1 (br, 1H, NH). 13C NMR (DMSO-d): d 20.0,
20.2, 20.4, 20.5, 61.9, 67.0, 70.9, 71.4, 74.7, 83,6, 91.8, 128.3,
142.9, 143.1, 147.6, 143.2, 147.6, 161.5, 162.1, 169.8, 169.9,
170.0, 170.5, 170.6. MS: m/z 560 (M+, 10%), 500 (40%), 331 (25%),
169 (100%). Anal. Calcd for C24H24N4O10S (560.5): C, 51.43; H,
4.32; N, 10.00; S, 5.72. Found: C, 51.40; H, 4.23; N, 10.00; S, 5.59.
O-acetyl-a-D-glucopyranosyl bromide (9 mmol) in anhyd CH3CN
(20 mL). The mixture was cooled to 5 °C, and then anhyd SnCl4
(1.6 mL) was added. The mixture was stirred at rt for 24 h and then
diluted with CHCl3 (150 mL), washed with satd aq NaHCO3
(150 mL) and water (2 ꢁ 25 mL), and then dried over anhyd
Na2SO4. The solvent was then evaporated in vacuo, and the
remaining material was crystallized from EtOH.
4.1.6. 6-Aryl-5-cyano-1-(2,3,4,6-tetra-O-acetyl-b-
D-
4.1.1. 5-Cyano-6-phenyl-1-(2,3,4,6-tetra-O-acetyl-b-
D-
glucopyranosyl)-2-(2,3,4,6-tetra-O-acetyl-b-
D-
glucopyranosyl)-2-thiouracil (5a)
glucopyranosylthio)-2-pyrimidin-4(1H)-ones 6a–e. General
procedures
To a mixture of 2-thiouracil 4a–e (10 mmol) in DMF (10 mL)
and TEA (1 mL) or in 1:1 acetone–water mixture (20 mL) in the
Colorless needles, yield 4.6 g (82%), mp 213–215 °C (lit.11 mp
214–215 °C). IR: 3441, 3144, 3028, 2939, 2225, 1752, 1676, 1544,
1378, 1227, 1060, 1046, 914. 1H NMR (CDCl3): d 1.99, 2.05, 2.08,
2.09 (4s, 12H, 4CH3CO), 3.95 (m, 1H), 4.19 (m, 2H), 5.15 (t, 1H, J
9.6), 5.29 (t, 1H J 9.6), 5.38 (t, 1H, J 9.6), 5.78 (d, 1H, J 9.6), 7.58
(t, 2H, J 7.4), 7.64 (t, 1H, J 7.6), 8.07 (d, 2H, J 7.8). LC–MS: m/z
560 (M+1).
presence of KOH (0.56 g) was added 2,3,4,6-tetra-O-acetyl-a-D-glu-
copyranosyl bromide (12 mmol). The mixture was stirred at rt for
24 h. The solid that precipitated after dilution with ice water
(50 mL) was collected and crystallized from EtOH to yield 6a–e.
Acidification of the aqueous filtrate with few drops of concd HCl
precipitated a white solid, which collected and crystallized from
EtOH yielded compounds 5a–e.
4.1.2. 5-Cyano-1-(2,3,4,6-tetra-O-acetyl-b-
p-tolyl-2-thiouracil (5b)
D-glucopyranosyl)-6-
Yellow plates, yield 4.8 g (77%), mp 190–192 °C (lit.11 mp 189–
190 °C). IR: 3414, 3144, 3047, 2945, 2227, 1752, 1680, 1548, 1376,
1224, 1058, 1041. 1H NMR (CDCl3): d 1.99, 2.05, 2.07, 2.08 (4s,
4CH3CO), 2.48 (s, 3H, CH3), 3.95 (m, 1H), 4.19 (m, 2H), 5.15 (t,
1H, J 9.7), 5.27 (t, 1H, J 9.8), 5.38 (t, 1H, J 9.8), 5.77 (d, 1H, J 9.6),
7.37 (d, 2H, J 8.2), 8.01 (d, 2H, J 8.2), 12.41 (br, 1H, NH). 13C NMR
(CDCl3): d 20.62, 20.65 (2C), 20.67, 21.7, 62.0, 67.8, 68.7, 73.5,
76.6, 81.4, 94.2, 114.7, 129.2, 129.7, 131.7, 143.8, 161.5, 162.5,
168.4, 169.40, 169.42, 170.2, 170.8. LC–MS: m/z 574 (M+1).
4.1.7. 5-Cyano-6-phenyl-1-(2,3,4,6-tetra-O-acetyl-b-
glucopyranosyl)-2-(2,3,4,6-tetra-O-acetyl-b-
glucopyranosylthio)-2-pyrimidin-4(1H)-one (6a)
D-
D
-
Colorless plates, yield 4.4 g (49%), mp 115–117 °C (lit.11 mp 114–
116 °C). IR: 2951, 2228, 1754, 1558, 1524, 1368, 1226, 1059, 1037,
914. 1H NMR (CDCl3): d 1.94, 2.05, 2.06, 2.07, 2.08, 2.09, 2.13 (7s,
3H, 3H, 6H, 3H, 3H, 3H, 3H, 8CH3CO), 3.92 (m, 1H), 4.01 (m, 1H),
4.13 (dd, 1H, J 12.4, 2.0 Hz), 4.21 (m, 1H), 4.30 (dd, 1H, J 12.0,
4.8 Hz), 5.13 (t, 1H, J 9.6), 5.27 (m, 2H), 5.38 (m, 3H), 5.77 (d, 1H, J
9.8), 6.18 (d, 1H, J 7.6), 7.58 (t, 2H, J 7.4), 7.64 (t, 1H, J 7.0), 8.06 (d,
2H, J 7.8). 13C NMR (CDCl3): d 20.54, 20.56, 20.58, 20.60 (2C), 20.61
(2C), 20.74, 61.6, 62.4, 67.8, 68.4, 68.7, 70.2, 72.3, 72.7, 73.7, 76.3,
81.9, 89.9, 94.5, 113.0, 129.0, 129.02, 132.5, 134.5, 168.4, 168.8,
169.3, 169.34, 169.39, 169.44, 170.15, 170.22, 170.6, 170.7, 171.6.
MS: m/z 890 (M+, 10%), 499 (55%), 331 (30%), 229 (85%).
4.1.3. 6-p-Chlorophenyl-5-cyano-1-(2,3,4,6-tetra-O-acetyl-b-D-
glucopyranosyl)-2-thiouracil (5c)
Colorless needles, yield (4.8 g) 81%, mp 188–190 °C. IR: 3410,
3170, 3032, 2945, 2227, 1756, 1698, 1545, 1374, 1241, 1227,
1091, 1062, 1039. 1H NMR (CDCl3): d 2.03, 2.06, 2.09, 2.10 (4s,
12H, 4CH3CO), 3.96 (m, 1H), 4.16 (dd, 2H, J 12.4, 1.6), 4.23 (dd,
1H, J 12.4, 5.2), 5.15 (t, 1H, J 9.8), 5.28 (t, 1H, J 9.8), 5.39 (t, 1H, J
9.6), 5.73 (d, 1H, J 9.4), 7.57 (d, 2H, J 8.8), 8.04 (d, 2H, J 8.8). 13C
NMR (CDCl3): d 20.57 (2C), 20.6, 20.7, 62.0, 67.8, 68.8, 73.3, 76.3,
81.5, 95.0, 114.3, 129.3, 130.4, 132.8, 139.2, 161.6, 162.1, 167.2,
169.3, 169.4, 170.1, 170.7. MS: m/z 593 (M+, 10%), 533 (40%), 331
(25%). Anal. Calcd for C25H24ClN3O10S (593.99): C, 50.55; H, 4.07;
N, 7.07; S, 5.40. Found: C, 50.40; H, 4.00; N, 7.05; S, 5.28.
4.1.8. 5-Cyano-1-(2,3,4,6-tetra-O-acetyl-b-
(2,3,4,6-tetra-O-acetyl-b- -glucopyranosylthio)-6-p-tolyl-2-
pyrimidin-4(1H)-one (6b)
D-glucopyranosyl)-2-
D
Colorless plates, yield 4.2 g (46%), mp 120–122 °C (lit.11 mp
118–120 °C). IR: 2948, 2228, 1756, 1556, 1508, 1369, 1227, 1059,
1037. 1H NMR (CDCl3): d 1.95, 2.06, 2.69, 2.07, 2.08, 2.09, 2.11
(7s, 3H, 3H, 6H, 3H, 3H, 3H, 3H, 8CH3CO), 2.48 (s, 3H, CH3), 3.90
(m, 1H), 4.01 (m, 1H), 4.14 (dd, 1H, J 12.4, 2.0 Hz), 4.21 (m, 2H),
4.30 (dd, 1H, J 12.4, 4.8 Hz), 5.13 (t, 1H, J 9.6), 5.23 (m, 2H), 5.38
(m, 3H), 5.76 (d, 1H, J 9.8), 6.18 (d, 1H, J 7.6), 7.38 (d, 2H, J 8.4),
8.00 (d, 2H, J 8.4). 13C NMR (CDCl3): d 20.53, 20.56, 20.58, 20.60
(2C), 20.61 (2C), 20.7, 21.6, 61.6, 62.4, 67.8, 68.4, 68.7, 70.2, 72.3,
72.7, 73.7, 76.3, 81.9, 89.4, 94.5, 113.2, 129.00, 129.4, 131.7,
143.4, 168.5, 168.8, 169.30, 169.32, 169.34, 169.39, 170.15,
170.22, 170.62, 170.65, 171.4. MS: m/z 903 (M+, 30%), 844 (30%),
513 (40%), 331 (30%), 268 (55%), 169 (100%).
4.1.4. 5-Cyano-6-p-methoxyphenyl-1-(2,3,4,6-tetra-O-acetyl-b-
D-glucopyranosyl)-2-thiouracil (5d)
Colorless plates, yield 5.0 g (85%), mp 208–210 °C. MS: IR: 3438,
3136, 3019, 2946, 1753, 1661, 1542, 1380, 1242, 1042, 1178, 1062,
1042. 1H NMR (CDCl3): d 2.0, 2.06, 2.08, 2.09 (4s, 12H, 4CH3CO),
3.94 (s, 3H, OCH3), 3.98 (m, 1H), 4.20 (m, 2H), 5.16 (t, 1H, J 9.6),
5.28 (t, 1H, J 9.6), 5.40 (t, 1H, J 9.6), 5.79 (d, 1H, J 9.8), 7.07 (d,
2H, J 8.8), 8.16 (d, 2H, J 8.8). 13C NMR (CDCl3): d 20.57 (2C),
20.60, 20.64, 55.6, 62.0, 67.8, 68.8, 73.5, 76.6, 81.4, 93.0, 114.3,

N. A. Al-Awadi et al. / Carbohydrate Research 344 (2009) 2322–2328
2327
4.1.9. 6-p-Chlorophenyl-5-cyano-1-(2,3,4,6-tetra-O-acetyl-b-
glucopyranosyl)-2-(2,3,4,6-tetra-O-acetyl-b-
glycopyranosylthio)-2-pyrimidin-4(1H)-one (6c)
D
-
62.1, 67.9, 68.4, 73.6, 76.8, 82.3, 92.4, 114.3, 115.4, 126.9, 130.9,
160.2, 162.2, 163.1, 164.7, 169.3, 169.4, 170.1, 170.5. MS: m/z
603 (M+, 10%), 544 (10%), 331 (30%), 169 (100%). Anal. Calcd for
C27H29N3O11S (603.6): C, 53.74; H, 4.80; N, 6.96; S, 5.30. Found:
C, 53.70; H, 4.66; N, 6.79; S, 5.42.
D-
Yield 4.7 g (51%), mp 142–144 °C. Colorless plates from EtOH.
IR: 2949, 2228, 1756, 1578, 1555, 1523, 1369, 1224, 1037, 912.
1H NMR (CDCl3): d 1.97, 2.05, 2.06, 2.07, 2.08, 2.12 (6s, 3H, 3H,
6H, 6H, 3H, 3H, 8CH3CO), 3.90 (m, 1H), 4.00 (m, 1H), 4.11 (dd,
1H, J 12.4, 2.4), 4.18 (dd, 2H, J 12.4. 2.0 Hz), 4.27 (m, 2H), 5.13 (t,
1H, J 9.8), 5.24 (m, 2H), 5.38 (m, 3H), 5.72 (d, 1H, J 9.8), 6.18 (d,
1H, J 7.2), 7.55 (d, 2H, J 8.4), 8.05 (d, 2H, J 8.4). 13C NMR (CDCl3):
d 20.57, 20.64 (6C), 20.77, 61.6, 62.5, 67.8, 68.4, 68.7, 70.2, 72.2,
72.7, 73.6, 76.2, 81.9, 89.7, 94.6, 112.9, 129.4, 130.4, 132.8, 139.1,
168.2, 168.4, 168.8, 169.36 (2C), 169.42, 170.2, 170.3, 170.6,
170.7, 171.9. MS: m/z 925 (M+2, 5%), 923 (M+, 10%), 864 (20%),
4.2. 2,20-Anhydro-6-aryl-2-mercapto-1-(3,4,6-tri-O-acetyl-b-
mannopyranosyl)pyrimidin-5(2H)-ones (7a–e). General
procedures
D-
(A) A mixture of each of the appropriate derivatives 5a–e, 6a–e
(1 mmol) was introduced in the reaction tube (1.5 ꢁ 12 cm
Pyrex), cooled in liquid nitrogen, sealed under vacuum
(0.06 mbar), and placed in the pyrolyser heated at 230 °C
(static pyrolyzer) for 30 min. The contents of the tube were
then dissolved in CDCl3, and the yield (Tables 1 and 2) was
determined by 1H NMR spectroscopy.
533 (30%), 288 (75%), 169 (80%). Anal. Calcd for C39H42ClN3O19
(924.3): C, 50.68; H, 4.58; N, 4.55; S, 3.47. Found: C, 50.59; H,
4.55; N, 4.56; S, 3.43.
S
4.1.10. 5-Cyano-6-p-methoxyphenyl-1-(2,3,4,6-tetra-O-acetyl-
(B) A mixture of each of the appropriate derivatives 5a–e
(1 mmol) was heated at 210–220 °C (oil bath) for 1 h. The
contents of the tube were washed with petroleum ether,
and the precipitate that was collected was purified by boil-
ing with CH2Cl2. The precipitate was recrystallized from
EtOH. The yield (Tables 1 and 2) was determined by 1H
NMR spectroscopy.
(C) A mixture of each of the appropriate derivatives 5a–e
(1 mmol) in xylene (2 mL) was introduced in the microwave
reaction tube for 10 min at 190 °C. The contents of the tube
were then dissolved in CDCl3, and the yield was determined
by 1H NMR spectroscopy.
(D) A mixture of each of the appropriate derivatives 5a–e
(1 mmol) and DPE (0.5 mL) was heated at 200–210 °C (oil
bath) for 1 h. The contents of the tube were then dissolved
in CDCl3 and the yield was determined by 1H NMR
spectroscopy.
b-D-glucopyranosyl)-2-(2,3,4,6-tetra-O-acetyl-b-D-
glycopyranosylthio)-2-pyrimidin-4(1H)-one (6d)
Colorless plates, yield 4.6 g (50%), mp 144–146 °C. IR: 2943,
2226, 1756, 1607, 1556, 1508, 1370, 1227, 1037. 1H NMR (CDCl3):
d 1.95, 2.05, 2.06, 2.065, 2.07, 2.08, 2.12 (7s, 3H, 3H, 3H, 3H, 3H, 6H,
3H, 8CH3CO), 3.90 (m, 1H), 3.92 (s, 3H, °CH3), 3.99 (m, 1H), 4.14
(dd, 1H, J 12.4, 2.4), 4.20 (m, 2H), 4.28 (dd, 1H, J 12.4, 4.8), 5.14
(t, 1H, J 9.8), 5.21 (t, 1H, J 9.8), 5.27 (t, 1H, J 9.6), 5.38 (m, 3H),
5.76 (d, 1H, J 9.6), 6.17 (d, 1H, 7.6), 7.07 (d, 2H, J 8.8), 8.14 (d,
2H, J 8.8). 13C NMR (CDCl3): d 20.58, 20.63 (3C), 20.66 (3C),
20.78, 55.6, 61.7, 62.4, 67.8, 68.4, 68.8, 70.2, 72.3, 72.4, 73.7,
76.3, 81.9, 88.5, 94.4, 113.5, 114.4, 126.8, 131.0, 163.2, 168.4,
168.6, 168.8, 169.32, 169.34, 169.4, 170.2, 170.23, 170.6, 170.7,
171.1. MS: m/z 919 (M+, 40%), 860 (50%), 529 (80%), 284 (45%),
169 (100%). Anal. Calcd for C40H45N3O20S (919.9): C, 52.23; H,
4.93; N, 4.57; S, 3.49. Found: C, 52.20; H, 4.99; N, 4.92; S, 3.49.
4.1.11. 5-Cyano-6-(3-pyridyl)-1-(2,3,4,6-tetra-O-acetyl-b-
glucopyranosyl)-2-(2,3,4,6-tetra-O-acetyl-b-
glycopyranosylthio)-2-pyrimidin-4(1H)-one (6e)
D-
D-
4.2.1. 2,20-Anhydro-2-mercapto-6-phenyl-1-(3,4,6-tri-O-acetyl-
b-D
-mannopyranosyl)pyrimidin-5(2H)-one (7a)
Colorless plates, yield 5 g (53%), mp 156–158 °C. IR: 2945, 2231,
1757, 1578, 1557, 1528, 1370, 1225, 1044. 1H NMR (CDCl3): d 2.01,
2.06, 2.07, 2.08, 2.09, 2.13 (6s, 3H, 3H, 3H, 6H, 6H, 3H, 8CH3CO),
3.97 (m, 1H), 4.02 (m, 1H), 4.11 (dd, 1H J 12.4, 2.4), 4.21–4.33
(m, 3H), 5.14 (t, 1H, J 9.8), 5.24 (m, 2H), 5.39 (m, 3H), 5.76 (d,
1H, J 10.4), 6.21 (d, 1H, 7.6), 7.54 (m, 1H), 8.42 (m, 1H), 8.86 (dd,
1H, J 4.8, 1.6), 9.29 (d, 1H, J 1.6). 13C NMR (CDCl3): d 20.58, 20.61,
20.64 (5C), 20.78, 61.6, 62.5, 67.8, 68.3, 68.7, 70.2, 72.2, 72.8,
73.6, 76.3, 81.9, 90.4, 94.6, 112.5, 123.5, 130.5, 136.1, 149.9,
152.9, 167.0, 168.3, 168.8, 169.35, 169.38, 169.43, 170.1, 170.3,
170.60, 170.7, 172.4. MS: m/z 890 (M+, 10%), 500 (10%), 331
(20%), 169 (100%). Anal. Calcd for C38H42N4O19S (890.8): C, 51.24;
H, 4.75; N, 6.29; S, 3.60. Found: C, 51.17; H, 4.66; N, 6.25; S, 3.42.
Colorless needles, mp 224–226 °C. IR: 3060, 2938, 2225, 1746,
1687, 1548, 1506, 1484, 1370, 1220, 1045, 911, 730. 1H NMR
(CDCl3): d 2.09, 2.10, 2.14 (3s, 9H, 3CH3CO), 3.91 (ddd, 1H, J 9.8,
4.5, 2.0), 4.13 (dd, 1H, J 12.6, 2.0), 4.40 (dd, 1H, J 12.6, 4.5), 4.75
(dd, 1H, J 5.6, 3.6), 5.42 (t, 1H, J 9.6), 5.56 (dd, 1H, J 9.6, 5.6), 6.39
(d, 1H, J 3.6), 7.53 (t, 2H, J 7.6), 7.62 (t, 1H, J 7.4), 8.03 (d, 2H, J
7.8). 13C NMR (CDCl3): d 20.5, 20.6, 20.7, 49.1, 61.4, 64.9, 69.6,
73.4, 84.0, 94.3, 114.5, 128.8, 129.2, 129.8, 132.7, 157.4, 167.2,
169.3, 169.4, 169.6, 170.6. LC–MS: m/z 500 (M+1). MS: m/z 499
(M+, 60%), 254 (100%). HRMS: calcd for C23H21N3O8S, m/z
499.1043; found, m/z 499.1050.
4.2.2. 2,20-Anhydro-2-mercapto-6-p-tolyl-1-(3,4,6-tri-O-acetyl-
4.1.12. 5-Cyano-6-p-methoxyphenyl-3-methyl-1-(2,3,4,6-tetra-
O-acetyl-b-D-glucopyranosyl)-2-thiouracil (10d)
b-D
-mannopyranosyl)pyrimidin-5(2H)-one (7b)
Colorless plates, mp 239–240 °C. IR: 3062, 2959, 2930, 2860,
To a mixture of compound 5d (589 mg, 1 mmol) in DMF (10 mL)
and TEA (1 mL), CH3I (0.13 g, 2 mmol) was added. The mixture was
stirred at rt for 24 h. and then, diluted with ice water (50 mL). The
solid precipitate was filtered and crystallized from EtOH to give
colorless plates: yield 0.4 g (66%), mp 223–225 °C. IR: 2983,
2220, 1751, 1681, 1545, 1521, 1377, 1261, 1226, 1063. 1H NMR
(CDCl3): d 1.97, 2.06, 2.08, 2.09 (4s, 12H, 4CH3CO), 3.58 (s, 3H,
NCH3), 3.88 (m, 1H), 3.93 (s, 3H, °CH3), 4.13 (dd, 1H J 12.8, 2.0),
4.21 (dd, 1H J 12.8, 5.6), 5.14 (t, 1H, J 9.8), 5.32 (t, 1H, J 9.4), 5.39
(t, 1H, J 9.2), 5.83 (d, 1H, J 10.4), 7.06 (d, 2H, J 8.8), 8.11 (d, 2H, J
8.8). 13C NMR (CDCl3): d 20.54, 20.57, 20.58, 20.60, 31.0, 55.6,
2224, 1751, 1690, 1547, 1487, 1370, 1221, 1041, 911, 733. 1H
NMR (CDCl3): d 2.07, 2.10, 2.14 (3s, 9H, 3CH3CO), 2.46 (s, 3H,
CH3), 3.90 (ddd, 1H, J 9.9, 4.6, 1.6), 4.13 (dd, 1H, J 12.5, 1.6), 4.41
(dd, 1H, J 12.5, 4.6), 4.73 (dd, 1H, J 5.6, 3.6), 5.42 (t, 1H, J 9.7),
5.55 (dd, 1H, J 9.5, 5.6), 6.36 (d, 1H, J 3.6), 7.33 (d, 2H, J 8.0), 7.98
(d, 2H, J 8.0). 13C NMR (CDCl3): d 21.1, 21.2, 21.3, 22.3, 49.6, 61.9,
65.5, 70.2, 73.6, 84.6, 94.6, 115.4, 129.8, 130.1, 132.0, 144.3,
158.2, 167.5, 169.7, 170.0, 170.2, 171.2: MS: m/z 513 (M+, 80%),
268 (100%), 149 (100%). HRMS: calcd for C24H23N3O8S, m/z
513.1200; found, m/z 513.1206.

2328
N. A. Al-Awadi et al. / Carbohydrate Research 344 (2009) 2322–2328
4.2.3. 2,20-Anhydro-6-p-chlorophenyl-2-mercapto-1-(3,4,6-tri-
O-acetyl-b- -mannopyranosyl)-pyrimidine-5(2H)-one (7c)
1H), 8.42 (m, 1H), 8.82 (dd, 1H, J 4.8, 1.4), 9.24 (s, 1H). MS: m/z
500 (M+, 20%), 230 (70%), 214 (90%), 105 (100). HRMS: calcd for
C22H20N4O8S, m/z 500.0998; found, m/z 500.1003.
D
Colorless needles, mp 236–238 °C. IR: 3028, 2959, 2224, 1750,
1692, 1546, 1505, 1482, 1369, 1221, 1092, 1043, 912, 732. 1H
NMR (CDCl3): d 2.10, 2.14 (2s, 6H, 3H, 3CH3CO), 3.91 (ddd, 1H, J
9.6, 4.8, 2.0), 4.12 (dd, 1H, J 12.8, 2.0), 4.41 (dd, 1H, J 12.8, 4.8),
4.74 (dd, 1H, J 5.6, 3.6), 5.42 (t, 1H, J 9.6), 5.56 (dd, 1H, J 9.6, 5.6),
6.37 (d, 1H, J 3.6), 7.52 (d, 2H, J 8.4), 8.01 (d, 2H, J 8.4). 13C NMR
(CDCl3): d 20.5, 20.7, 20.9, 49.1, 61.4, 64.9, 69.6, 73.1, 84.0, 94.7,
114.4, 129.2, 130.6, 132.6, 139.2, 157.2, 167.4, 167.9, 169.4,
169.7, 170.3. LC–MS: m/z 534 (M+1), 535 (M+2). MS: m/z 533
(M+, 60%), 288 (100%). HRMS: calcd for C23H20N3O8S, m/z
533.0653; found, m/z 533.0656.
Acknowledgments
The support of Kuwait University received through research
Grant No. SC 08/04 and the facilities of Analab/SAF (Grants No.
GS01/01, GS02/01, GS03/01) and the financial support from the
college of graduate studies are gratefully acknowledged. The preli-
minary results obtained by Dr. M. Patel in the present work are also
acknowledged.
References
4.2.4. 2,20-Anhydro-2-mercapto-6-p-methoxyphenyl-1-(3,4,6-
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tri-O-acetyl-b-D-mannopyranosyl)-pyrimidin-5(2H)-one (7d)
Colorless plates, mp 243–245 °C. IR: 3085, 2916, 1752, 1687,
1604, 1547, 1370, 1220, 1061, 910, 732. 1H NMR (CDCl3): d 2.10,
2.14 (2s, 6H, 3H, 3CH3CO), 3.91 (s, 3H, °CH3), 3.93 (m, 1H), 4.13
(dd, 1H, J 12.8, 1.6), 4.40 (dd, 1H, J 12.8, 4.8), 4.73 (dd, 1H, J 5.6,
3.6), 5.42 (t, 1H, J 9.6), 5.56 (dd, 1H, J 9.6, 5.6), 6.37 (d, 1H, J 3.6),
7.02 (d, 2H, J 8.8), 8.12 (d, 2H, J 8.8). 13C NMR (CDCl3): d 20.5,
20.6, 20.7, 49.0, 55.6, 61.4, 65.0, 69.7, 73.0, 84.0, 92.7, 114.2,
115.2, 126.4, 131.5, 157.8, 163.4, 166.5, 168.1, 169.4, 169.6,
170.6. LC–MS: m/z 530 (M+1). MS: m/z 529 (M+, 100%), 284
(50%), 149 (100%). HRMS: calcd for C23H21N3O8S, m/z 529.1148;
found, m/z 529.1150.
7. Fu, Y. L.; Parthasarathy, R.; Bobek, M. J. Carbohydr. Nucleosides Nucleotides 1978,
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4.2.5. 2,20-Anhydro-2-mercapto-6-(3-pyridyl)-1-(3,4,6-tri-O-
acetyl-b-D-mannopyranosyl)-pyrimidin-5(2H)-one (7e)
Colorless plates, mp 226–228 °C. IR: 3085, 2916, 2228, 1752,
1687, 1614, 1557, 1379, 1226, 1060, 913. 1H NMR (CDCl3): d
2.07, 2.10, 2.14 (3s, 9H, 3CH3CO), 3.93 (m, 1H), 4.13 (dd, 1H, J
12.4, 1.6), 4.39 (dd, 1H, J 12.4, 4.8), 4.75 (dd, 1H, J 5.6, 3.6), 5.45
(t, 1H, J 9.6), 5.58 (dd, 1H, J 9.6, 5.6), 6.36 (d, 1H, J 3.6), 7.51 (m,