A new class of dihydropyridine thioglycosides via piperidinium salts

Article abstract of DOI:10.1081/SCC-120021503

A first reported method for preparation of a new class of thioglycosides via reaction of piperidinium salts of dihydropyridinethiones with 2,3,4,6-tetra-O-acetyl-α-D-gluco- and galactopyranosyl bromides has been studied. Comparison with the products obtained from silylated thiopyridines is made.

Full text of DOI:10.1081/SCC-120021503

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A New Class of Dihydropyridine Thioglycosides via
Piperidinium Salts
Adel M. Attia a & Galal H. Elgemeie b
a Department of Chemistry, Faculty of Education, Kafr El-Sheikh, Egypt
b Department of Chemistry, Faculty of Science, Helwan University, Ain-Helwan, Cairo, Egypt
Version of record first published: 17 Aug 2006.
To cite this article: Adel M. Attia & Galal H. Elgemeie (2003): A New Class of Dihydropyridine Thioglycosides via Piperidinium
Salts, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:13,
2243-2255
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 13, pp. 2243–2255, 2003
A New Class of Dihydropyridine Thioglycosides
via Piperidinium Salts
Adel M. Attia1 and Galal H. Elgemeie2,
*
1Department of Chemistry, Faculty of Education, Kafr
El-Sheikh, Egypt
2Department of Chemistry, Faculty of Science, Helwan
University, Ain-Helwan, Cairo, Egypt
ABSTRACT
A first reported method for preparation of a new class of thioglyco-
sides via reaction of piperidiniumsalts of dihydropyridinethiones with
2,3,4,6-tetra-O-acetyl-a-D-gluco- and galactopyranosyl bromides
has been studied. Comparison with the products obtained from
silylated thiopyridines is made.
*Correspondence: Galal H. Elgemeie, Department of Chemistry, Faculty
of Science, Helwan University, Ain-Helwan, Cairo, Egypt; E-mail:
rughe@rusys.cg.net.
2243
DOI: 10.1081/SCC-120021503
Copyright & 2003 by Marcel Dekker, Inc.
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2244
Attia and Elgemeie
In recent reports fromour laboratory, we described the preparation of
different novel functionalized pyridinethione glycosides, which revealed
antagonistic activity.[1–4] In an ealier brief communication we had already
reported the use of dihydropyridinethione glycosides as a substrates or
inhibitors in the protein glycosylation process.[5] These common features,
encouraged us to develop a new straightforward route for synthesis of
these compounds. In the present report, we describe the synthesis of dihy-
dropyridine thioglycosides through reaction of piperidinuimsalts of dihy-
dropyridinethiolates with a-halogeno sugars. As far as we know this is the
first coupling reaction of this type to be reported for glycoside formation.
Thus, it has been found that cyanothioacetamide 1 reacted with chalcones
2 in ethanol containing equivalent amounts of piperidine at room tem-
perature to give the corresponding piperidinuimsalts of 1,4-dihydropyr-
idine-2-thiones 4. The structure of 4 was established on the basis of their
elemental analysis and spectral data. Compounds 4 reacted with 2,3,4,6-
tetra-O-acetyl-a-D-gluco- and galactopyranosyl bromides 5 in acetone at
0ꢀC to give in a high yields the corresponding S-glucosides 9a–c or
S-galactosides 9d–f, respectively. It was suggested that the cis(a) sugar
reacts by a simple SN2 reaction to give the b-glycoside product. The
structure of the reaction products 9a–f were established and confirmed
by their elemental analyses and spectral data (MS, IR, 1H NMR,
13C NMR). Thus, the analytical data for 9a revealed a molecular formula
1
C32H32N2SO9 (Mþ 620). The H NMR spectrumshowed the anomeric
proton as a doublet at ꢀꢀ 6.26 with spin-spin coupling constant of
10.37 Hz which corresponds to the diaxial orientation of H-10 and H-20
protons indicating the b-configuration, while the other six glucose protons
resonated at ꢀ 4.18–5.72. The four acetyl groups appeared as four singlets
at ꢀ 1.70–2.08. The 13C NMR spectrumof 9a contained a signal at ꢀꢀ 80.7
corresponding to the C-10 atomof the b-configuration. Five signals
appearing at ꢀ 62.1, 68.6, 69.4, 73.5, and 75.5 were assigned to C-60,
C-40, C-20, C-30, and C-50, respectively. After deprotection of compounds
9a–f with a saturated solution of ammonia in methanol at 0ꢀC the final
glycosides 10a–f were obtained in almost quantitative yields, the struc-
tures of which have been established on the basis of elemental analyses
and spectral data. Thus, the analytical data for 10a reveal the molecular
formula C24H24N2SO5 (Mþ 452). The 1H NMR spectrumshows the
anomeric proton as a doublet at ꢀ 5.84 (J 10.22 Hz) indicating the presence
of only the b-D-configuration. The signals of the other six glucose protons
appear as a multiplet at ꢀ 3.18–3.89, while the signals of the four hydroxy
groups of the glucose moiety are observed at ꢀ 4.42–5.20 (exchangeable by
D2O). The 13C NMR spectrumof 10a is characterized by a signal at ꢀ 83.3
corresponding to the C-10 atomof b-D-glucopyranose. Another five

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Dihydropyridine Thioglycosides
2245
signals at ꢀ 60.6, 69.4, 73.3, 77.7, and 81.5 are assigned to C-60, C-40, C-20,
C-30, and C-50, respectively. In another experiment, the glycosides 9a–f
when refluxed in dry ethanol for 3 min, the corresponding aromatized
pyridine thioglucosides 8a–c and thiogalactosides 8d–f were obtained. In
order to investigate the scope of the formation of these glycosides further
we studied the coupling of cyanothioacetamide with 2,3,4,6-tetra-O-
acetyl-a-D-gluco- and galactopyranosyl bromides 5 in acetone at room
temperature. The reaction proceeded to give the corresponding cyano-
acetamidethioglycosides 6. Compounds 6 reacted with chalcones 2 in
dry ethanol containing catalytic amounts of piperidine at 60ꢀC to give
the glycosides 8. The structures of the reaction products 8a–f were estab-
lished and confirmed on the basis of their elemental analyses and spectral
data (MS, IR, UV, 1H NMR, 13C NMR). Although the coupling of piperi-
diniumsalts 4 with the glycosyl bromides could also give the correspond-
ing N-glycosides 7, the formation of the S-glycosides 8 were proved using
the 13C NMR spectroscopy which revealed the absence of the thione
carbon at ꢀ 178 and appearance of C-2 carbon[6,7] at ꢀ 160 of the same
value of the corresponding S-methyl derivative 11. When glycosides 8
were treated with methanolic ammonia at room temperature, the free
glycoside derivatives 16a–f were obtained, the structures of which were
established on the basis of elemental analysis and spectral data. With these
two dihydropyridine and pyridine thioglycosides as models, it was decided
to synthesize these compounds with the silylation method and comparing
the products for stereochemical considerations. Thus, in a simple experi-
mental procedure treatment of the piperidinium salts 4 with dilute
hydrochloric acid at 30ꢀC converted it to the corresponding pyridine-
2(1H )thiones 12. The latter compounds were reacted with hexamethyldi-
silazane in the presence of ammonium sulfate to give the corresponding
2-trimethylsilylthiopyridines 14, which was subsequently treated with per-
acetylated sugars 15 in the presence of redistilled SnCl4 to afford the
S-glycosyl compounds 8, which were shown to be the same as those
obtained fromthe reaction of 6 with 2 or fromoxidation of by their
melting points and spectral data. A suggested mechanism for the forma-
tion of the S-glycosides 8 by condensation of silylated bases 14 with
peracetylated sugars in the presence of Lewis acid catalyst is illustrated
in Chart 3. In summary, we have achieved a novel synthesis of interesting
nonclassical dihydropyridine thioglycosides and their corresponding
aromatized forms by the reaction of the piperidinium salts of dihydropyr-
idinethiones with a-halosugars, the nature of the products depends on
thermodynamic factors. These nucleosides can be utilized as an excellent
starting material for the synthesis of other carbohydrate derivatives and
for further biological evaluation studies.

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2246
Attia and Elgemeie
Chart 1.

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Dihydropyridine Thioglycosides
2247
Chart 2.
EXPERIMENTAL
Melting points are uncorrected. Aluminum-coated silica gel 60 F254
(Merck) sheets were used for thin layer chromatography. IR spectra were
collected in the transmission mode on a pye Unicam Spectra-1000
spectrometer. 1H and 13C NMR spectra were measured in (CD3)2SO
using SiMe4 as internal reference on a Varian 400 MHz spectrometer.
Mass spectra were recorded by EI on a Varian Mat 311A spectrometer
and FAB on a kratos MS 50 spectrometer.

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Attia and Elgemeie
Chart 3.
2,3,4,6-Tetra-O-acetyl-b-D-
glycopyranosylthiocyanoacetamides (6a,b)
To a solution of thiocyanoacetamide 1 (0.01 mol) in aqueous potas-
sium hydroxide [0.56 g (0.01 mol) in 6 mL of distilled water], a solution of
2,3,4,6-tetra-O-acetyl-a-D-gluco or galactopyranosyl bromide 5 (0.11 mol)
in acetone 20 mL was added. The reaction mixture was stirred at room
temperature until completion (TLC, 1 h), using chloroform: ether 9:1 v/v

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Dihydropyridine Thioglycosides
2249
(Rf 0.74–0.76 region), then evaporated under reduced pressure and the
residue was washed with distilled water to remove the formed potassium
bromide. The resulting product was dried and crystallized from
chloroform–petroleum ether 40–60 at 0ꢀC to give the yellow products 6.
6a. Yield 83%, m.p. 147ꢀC. IR 2230 (CN), 1754 (CO ester of glu-
1
cose). H NMR 2.01–2.11(4s, 12H, 4CH3CO), 3.70 (m, 2H, CH2), 4.17
(m, 2H, 2H-60), 4.22 (m, 1H, H-50), 4.79 (t, 1H, H-40), 4.84 (m, 1H, H-30),
5.09 (m, 1H, H-20), 5.22 (d, J1 -2 10.56 Hz, 1H, H-10), 7.26 (s, 1H, imine
NH). m/z 430 (Found: C, 47.70; H, 5.24; N, 6.68. C17H22N2SO9 requires
C, 47.44; H, 5.11; N, 6.51%).
0
0
6b. Yield 85%, m.p. 168ꢀC. IR 2228 (CN), 1755 (CO ester of galac-
1
tose). H NMR 1.99–2.09 (4s, 12H, 4CH3CO), 3.88 (m, 2H, CH2), 4.09
(m, 2H, 2H-60), 4.19 (m, 1H, H-50), 4.55 (t, 1H, H-40), 4.80 (m, 1H, H-30),
5.11 (m, 1H, H-20), 5.27 (d, J1 -2 10.0 Hz, 1H, H-10), 7.20 (s, 1H, imine
NH). m/z 430 (Found: C, 47.62; H, 5.20; N, 6.72. C17H22N2SO9 requires
C, 47.44; H, 5.11; N, 6.51%).
0
0
3-Cyano-2-(20,30,40,60-tetra-O-acetyl-b-D
-glycopyranosylthio)-1,4-dihydropyridines (9a–f )
General coupling procedures. A mixture of 1 (0.01 mol) and 2
(0.01 mol) was dissolved in dry ethanol (5 mL), a (0.01 mol) of piperidine
were then added. The reaction mixture was stirred at 0ꢀC for 1 h. The
solvent was removed at reduced pressure and the resulting hydrogenated
thiopyridines 4 was dissolved in dry acetone (5 mL) and a solution of 2,3,
4,6-tetra-O-acetyl-a-D-gluco- or galactopyranosyl bromide 6 5 (0.011 mol)
in dry acetone (20 mL) was then added at 0ꢀC. The reaction mixture was
stirred until the reaction was judged complete by TLC, using chlorofor-
m:ether 4:1 (Rf 0.66–0.70 region), then evaporated under reduced pres-
sure and the residue was crystallized fromchloroform- petroleumether
40–60 at 0ꢀC to give pale yellow crystals.
9a. Yield 72%, m.p. 215ꢀC. IR 2215 (CN), 1748 (CO) cmꢁ1
.
1H NMR 1.70–2.08 (4s, 12H, 4CH3CO), 4.18 (m, 2H, 2H-60 and 1H,
pyridine H-4), 4.38 (m, 1H, H-50), 5.05 (t, 1H, H-40), 5.26 (t, H, H-30),
5.72 (t, 1H, H-20), 6.26 (d, J1 -2 10.37 Hz, 1H, H-10), 7.62 (m, 5H, Ar-H),
7.78 (m, 3H, Ar-H and 1H, pyridine H-5), 8.04 (s,1H, NH), 8.40 (m, 2H,
Ar-H) ppm. 13C NMR 19.9–20.2 (4CH3), 62.1(C60), 68.6 (C40), 69.4 (C20),
73.5 (C30), 75.5 (C50), 80.7 (C10), 104.2 (C4), 115.1 (C3), 117.2 (CN),
127.8–1158.0 (Ar-C), 159.4 (C2), 169.1–169.6 (4CO) ppm. m/z 620
(Found: C, 62.08; H, 5.22; N, 4.60. C32H32N2SO9 requires C, 61.93; H,
5.16; N, 4.51%).
0
0

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2250
Attia and Elgemeie
9b. Yield 73%, m.p. 235ꢀC. IR 2213 (CN), 1747 (CO) cmꢁ1
.
1H NMR 1.61–2.04 (4s, 12H, 4CH3CO), 4.12 (m, 2H, 2H-60 and 1H,
pyridine H-4), 4.35 (m, 1H, H-50), 5.01(t, 1H, H-40), 5.22 (t, 1H, H-30),
5.72 (t, 1H, H-20), 6.22 (d, J1 -2 10.44 Hz, 1H, H-10), 6.84 (q, 1H, furan
H-4), 7.79 (m, 3H, Ar-H and 1H, pyridine H-5), 7.90 (d, 1H, furan H-3),
8.09 (d, 1H, furan H-5), 8.16 (s, 1H, NH), 8.27 (d, 2H, Ar-H) ppm.
13C NMR 19.9–20.9 (4CH3), 61.8 (C60), 68.2 (C40), 68.8 (C20), 72.9
(C30), 75.1(C50), 80.9 (C10), 97.6 (C4), 113.1 (C3), 115.8 (CN),
127.6–158.2 (Ar-C), 160.1 (C2), 169.2–169.7 (4CO) ppm. m/z 610
(Found: C,59.29; H, 5.04; N, 4.73. C30H30N2SO10 requires C, 59.01; H,
4.91; N, 4.59%).
0
0
9c. Yield 70%, m.p. 244ꢀC. IR 2211(CN), 1746 (CO) cmꢁ1. 1H NMR
1.68–2.05 (4s, 12H, 4CH3CO), 4.15 (m, 2H, 2H-60 and 1H, pyridine H-4),
4.26 (m, 1H, H-50), 5.05 (t, 1H, H-40), 5.28 (t, 1H, H-30), 5.62 (t, 1H,
H-20), 6.18 (d, J1 -2 10.38 Hz, 1H, H-1 ), 7.32 (q, 1H, thiophene H-4), 7.80
(m, 3H, Ar-H and 1H, pyridine H-5), 7.92 (dd, 1H, thiophene H-3), 7.98
(dd, 1H, thiophene H-5), 8.04 (s, 1H, NH), 8.35 (m, 2H, Ar-H) ppm.
13C NMR 19.4–19.8(4CH3), 61.6 (C60), 68.2 (C40), 68.9 (C20), 73.0
(C30), 75.0 (C50), 80.2 (C10), 101.3 (C4), 114.0 (C3), 116.2 (CN),
127.3–158.1 (Ar-C), 159.9 (C2), 168.6–169.1 (4CO) ppm. m/z 626
(Found: C, 57.81; H, 4.97; N, 4.66. C30H30N2S2O9 requires C, 57.50;
H, 4.79; N, 4.47%).
0
0
0
9d. Yield 73%, m.p. 148ꢀC. IR 2203 (CN), 1753 (CO) cmꢁ1
.
1H NMR 1.62–2.04 (4s, 12H, 4CH3CO), 4.16 (m, 2H, 2H-60 and 1H,
pyridine H-4), 4.37 (m, 1H, H-50), 5.04 (t, 1H, H-40), 5.25 (t, 1H, H-30),
5.72 (t, 1H, H-20), 6.28 (d, J1 -2 10.46 Hz, 1H, H-10), 7.62 (m, 5H, Ar-H),
7.76 (m, 3H, Ar-H and 1H, pyridine H-5), 8.02 (s, 1H, NH), 8.40 (m, 2H,
Ar-H) ppm. 13C NMR 19.8–20.3(4CH3), 61.9 (C60), 68.2 (C40), 68.8 (C20),
72.9 (C30), 75.1 (C50), 79.9 (C10), 103.7 (C4), 115.2 (C3), 117.0 (CN),
127.8–158.2 (Ar-C), 160.8 (C2), 169.2–169.6 (4CO) ppm. m/z 620
(Found: C, 62.24; H, 5.30; N, 4.71. C32H32N2SO9 requires C, 61.93; H,
5.16; N, 4.51%).
0
0
9e. Yield 71%, m.p. 209ꢀC. IR 2212 (CN), 1758 (CO) cmꢁ1. m/z 610
(Found: C, 59.29; H, 4.98; N, 4.78. C30H30N2SO10 requires C, 59.01; H,
4.91; N, 4.59%).
9f. Yield 72%, m.p. 181ꢀC. IR 2214 (CN), 1750 (CO) cmꢁ1. 1H NMR
1.68–2.12 (4s, 12H, 4CH3CO), 4.20 (m, 2H, 2H-60 and 1H, pyridine H-4),
4.54 (m, 1H, H-50), 5.28 (t, 1H, H-40), 5.42 (t, 1H, H-30), 5.76 (t, 1H,
0
H-20), 6.24 (d, J1 -2 10.39 Hz, 1H, H-1 ), 7.38 (d, 1H, thiophene H-4), 7.75
(m, 3H, Ar-H and 1H, pyridine H-5), 7.96 (d, 1H, thiophene H-3), 8.00
(d, 1H, thiophene H-5), 8.05(s, 1H, NH), 8.42 (d, 2H, Ar-H) ppm.
13C NMR 19.9–20.4 (4CH3), 61.9 (C60), 66.3 (C40), 67.9 (C20), 70.9
0
0

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Dihydropyridine Thioglycosides
2251
(C30), 74.4 (C50), 80.5 (C10), 101.4 (C4), 114.2 (C3), 116.6 (CN),
127.8–157.3 (Ar-C), 160.1 (C2), 169.3–169.9 (4CO) ppm. m/z 626
(Found: C, 57.81; H, 4.88; N, 4.70. C30H30N2S2O9 requires C, 57.50;
H, 4.79; N, 4.47%).
3-Cyano-2-(b-D-glycopyranosylthio)-1,4-
dihydropyridines (10a–f )
General procedure for nucleoside deacylation. Dry ammonia gas was
passed into a solution of protected glycosides 9 (0.5 g) in 20 mL of dry
methanol at 0ꢀC for 0.5 h. The reaction mixture was stirred until comple-
tion as shown by TLC (10–12 h), using chloroform:Methanol 9:1 (Rf
0.62–0.66 region). The resulting mixture was then concentrated under
reduced pressure to afford a solid residue that was crystallized from
methanol–ether at 0ꢀC to furnish colorless crystals.
10a. Yield 81%, m.p. 173ꢀC. IR 3662–3188 (OH), 2206 (CN) cmꢁ1
.
1H NMR 3.18–3.89 (m, 6H, 2H-60, H-50, H-40, H-30, H-20 and 1H,
pyridine H-4), 4.42 (d, 2H, 20-OH and 30-OH), 4.98 (d, 1H, 40-OH),
5.20 (d, 1H, 60-OH), 5.84 (d, J1 -2 10.22 Hz, 1H, H-10), 7.58 (m, 5H,
Ar-H), 7.80 (m, 3H, Ar-H and 1H, pyridine H-5), 7.91 (s, 1H, NH), 8.28
(m, 2H, Ar-H) ppm. 13C NMR 60.6 (C60), 69.4 (C40), 73.3 (C20), 77.7
(C30), 81.5 (C50), 83.3 (C10), 101.8 (C4), 103.3 (C3), 115.5 (CN),
125.4–158.0 (Ar-C), 161.5 (C2) ppm. m/z 452 (Found: C, 63.92; H,
5.44; N, 6.31. C24H24N2SO5 requires C, 63.71; H, 5.30; N, 6.19%).
0
0
10b. Yield 82%, m.p. 208ꢀC. IR 3680–3220 (OH), 2210 (CN) cmꢁ1
.
m/z 442 (Found: C, 59.89; H, 5.12; N, 6.50. C22H22N2SO6 requires C,
59.72; H, 4.97; N, 6.33%).
10c. Yield 83%, m.p. 230ꢀC. IR 3680–3190 (OH), 2211 (CN) cmꢁ1
.
1H NMR 3.28–3.86 (m, 6H, 2H-60, H-50, H-40, H-30, H-20 and 1H,
pyridine H-4), 4.48 (s, 1H, 20-OH), 5.12 (s, 1H, 30-OH), 5.24 (s, 1H,
40-OH), 5.58 (s, 1H, 60-OH), 5.74 (d, J1 -2 10.39 Hz, 1H, H-10), 7.34 (m,
1H, thiophene H-4), 7.74 (m, 3H, Ar-H and 1H, pyridine H-5), 7.96 (m,
2H, thiophene H-3, H-4 and 1H, NH), 8.26 (m, 2H, Ar-H) ppm.
13C NMR 60.7 (C60), 69.7 (C40), 71.7 (C20), 78.5 (C30), 81.0 (C50), 83.9
(C10), 102.0 (C4), 114.8 (C3), 116.1 (CN), 127.6–158.1 (Ar-C), 162.4
(C2) ppm. m/z 458 (Found: C, 57.95; H, 4.88; N, 6.34. C22H22N2S2O5
requires C, 57.64; H, 4.80; N, 6.11%).
0
0
10d. Yield 80%, m.p. 206ꢀC. IR 3730–3240 (OH), 2213 (CN) cmꢁ1
.
1H NMR 3.20–3.96 (m, 6H, 2H-60, H-50, H-40, H-30, H-20 and 1H,
pyridine H-4), 4.64 (d, 2H, 20-OH and 30-OH), 5.18 (s, 1H, 40-OH),
5.42 (s, 1H, 60-OH), 5.76 (d, J1 -2 10.19 Hz, 1H, H-10), 7.58 (m, 5H,
0
0

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Attia and Elgemeie
Ar-H), 7.78 (m, 3H, Ar-H and 1H, pyridine H-5), 7.96 (s, 1H, NH), 8.35
(d, 2H, Ar-H) ppm. 13C NMR 60.5 (C60), 68.5 (C40), 69.9 (C20), 75.0
(C30), 78.9 (C50), 84.4 (C10), 103.3 (C4), 115.6 (C3), 116.4 (CN),
127.4–152.2 (Ar-C), 161.7 (C2) ppm. m/z 452 (Found: C, 63.93; H,
5.48; N, 6.40. C24H24N2SO5 requires C, 63.71; H, 5.30; N, 6.19%).
10e. Yield 80%, m.p. 200ꢀC. IR 3690–3230 (OH), 2212 (CN) cmꢁ1
.
m/z 442 (Found: C, 60.06; H, 5.12; N, 6.49. C22H22N2SO6 requires C,
59.72; H, 4.97; N, 6.33%).
10f. Yield 83%, m.p. 240ꢀC. IR 3690–3290 (OH), 2210 (CN) cmꢁ1
.
1H NMR 3.38–3.95 (m, 6H, 2H-60, H-50, H-40, H-30, H-20 and 1H, pyr-
idine H-4), 4.60 (d, 1H, 20-OH), 4.72 (t, 1H, 30-OH), 5.20 (d, 1H, 40-OH),
5.42 (d, 1H, 60-OH), 5.76 (d, J1 -2 10.18 Hz, 1H, H-10), 7.34 (t, 1H,
thiophene H-4), 7.73 (m, 3H, Ar-H and 1H, pyridine H-5), 7.92 (m,
2H, thiophene H-3, H-5 and 1H, NH), 8.28 (d, 2H, Ar-H) ppm.
13C NMR 60.5 (C60), 68.5 (C40), 68.9 (C20), 74.9 (C30), 79.9 (C50), 83.8
(C10), 100.8 (C4), 114.8 (C3), 115.9 (CN), 127.6–152.2 (Ar-C), 162.6
(C2) ppm. m/z 458 (Found: C, 57.90; H, 5.02; N, 6.25. C22H22N2S2O5
requires C, 57.64; H, 4.80; N, 6.11%).
0
0
3-Cyano-2-(20,30,40,60-tetra-O-acetyl-b-D-
glycopyranosylthio)-pyridines (8a–f )
General coupling procedures. Method A. The piperidiniumsalt of
dihydropyridinethiones 4 (0.01 mol) was dissolved in dry acetone
(5 mL) and a solution of 2,3,4,6-tetra-O-acetyl-a-D-gluco- or galactopyr-
anosyl bromide (0.11 mol) in dry acetone (20 mL) was then added at
30ꢀC. The reaction mixture was stirred until the reaction was judged
complete by TLC, using chloroform:ether 9:1 v/v (Rf 0.70–0.72 region),
then evaporated under reduced pressure and the residue was crystallized
fromethanol to give the yellow products 10a–f.
Method B. 3-Cyanopyridine-2(1H )-thiones 12 (0.01 mol) were
refluxed by stirring under anhydrous condition for 48 h with hexamethyl-
disilazane 60 mL and (NH4)2SO4 (0.02 g). The clear solution obtained was
cooled and the solvent was removed in vacuo. The resulting trimethyl-
silylated pyridines 14 were dissolved in anhydrous acetonitrile (30 mL),
and a solution of b-D-glycopyranose pentaacetate 15 (0.011 mol) in
acetonitrile (10 mL) was then added with stirring. The mixture
was cooled to 0ꢀC and
a
solution of SnCl4 (1.6 mL) in
acetonitrile (5 mL) was added dropwise and the mixture was stirred
until the reaction was judged complete by TLC (4–6 h), then poured
into saturated NaHCO3 solution, and extracted with CHCl3. The

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Dihydropyridine Thioglycosides
2253
organic layer was dried over MgSO4, filtered and concentrated to give the
crude glycosides that were purified by recrystallization fromethanol.
Method C. 3-Cyano-1,4-dihydropyridine-2-thioglycosides 9 (0.01 mol)
were refluxed in ethanol (30 mL) with stirring under anhydrous condition
for 3 min The resulting products were collected by filtration and recrys-
tallized fromethanol.
10a. Yield 70, m.p. 202ꢀC. IR 2216 (CN), 1748 (CO) cmꢁ1. 1H NMR
1.61–2.06 (4s, 12H, 4CH3CO), 4.06 (d, 2H, 2H-60), 4.42 (m, 1H, H-50),
5.03 (t, 1H, H-40), 5.31(t, 1H, H-30), 5.80 (t, 1H, H-20), 6.22 (d, J1 -2
0
0
10.56 Hz, 1H, H-10), 7.61 (m, 5H, Ar-H), 7.78 (m, 3H, Ar-H), 7.90
(s, 1H, pyridine H-5), 8.44 (m, 2H, Ar-H) ppm. 13C NMR 19.4–22.6
(4CH3), 61.3 (C60), 66.9 (C40), 69.3 (C20), 72.6 (C30), 74.9 (C50), 80.1
(C10), 105.8 (C3), 115.5 (CN), 122.4–154.6 (Ar-C), 161.2 (C2),
168.3–169.4 (4CO) ppm. m/z 618 (Found: C, 62.28; H, 5.09; N, 4.61.
C32H30N2SO9 requires C, 62.13; H, 4.85; N, 4.53%).
10b. Yield 68%, m.p. 212ꢀC. IR 2215 (CN), 1746 (CO) cmꢁ1. m/z 608
(Found: C, 59.45; H, 4.64; N, 4.82. C30H28N2SO10 requires C, 59.21; H,
4.60; N, 4.60%).
10c. Yield 69%, m.p. 219ꢀC. IR 2210 (CN), 1754 (CO) cmꢁ1
.
1H NMR 1.72–2.08 (4s, 12H, 4CH3CO), 4.16 (m, 2H, 2H-60 and 1H,
H-50), 4.80 (t, 1H, H-40), 5.12 (t,1H, H-30), 5.78 (t, 1H, H-20), 6.28 (d,
J1 -2 10.32 Hz, 1H, H-10), 6.98 (dd, 1H, thiophene H-4), 7.46 (m, 3H, Ar-
H), 7.81 (m, 1H, thiophene H-3), 7.96 (m, 1H, thiophene H-5 and 1H,
pyridine H-5), 8.38 (m, 2H, Ar-H) ppm. m/z 624 (Found: C, 57.90; H,
4.62; N, 4.68. C30H28N2S2O9 requires C, 57.69; H, 4.48; N, 4.48%).
0
0
10d. Yield 71%, m.p. 161ꢀC. IR 2214 (CN), 1748 (CO) cmꢁ1
.
1H NMR 1.58–2.12(4s, 12H, 4CH3CO), 4.08 (m, 2H, 2H-60), 4.58 (t,
1H, H-50), 5.26 (t, 1H, H-40), 5.42 (d, 1H, H-30), 5.68 (dd, 1H, H-20),
6.25 (d, J1 -2 10.62 Hz, 1H, H-10), 7.58 (m, 5H, Ar-H), 7.78 (m, 3H,
Ar-H), 7.92 (s, 1H, pyridine H-5), 8.40 (m, 2H, Ar-H) ppm. m/z 618
(Found: C, 62.21; H, 5.14; N, 4.70. C32H30N2SO9 requires C, 62.13; H,
4.85; N, 4.53%).
0
0
10e. Yield 68%, m.p. 213ꢀC. IR 2218 (CN), 1750 (CO) cmꢁ1
.
1H NMR 1.68–2.05 (4s, 12H, 4CH3CO), 4.08 (m, 2H, 2H-60), 4.26 (m,
1H, H-50), 4.92 (t, 1H, H-40), 5.14 (t, 1H, H-30), 5.68 (t, 1H, H-20), 6.18 (d,
0
0
0
J1 -2 9.98 Hz, 1H, H-1 ), 6.88 (d, 1H, furan H-4), 7.26 (m, 3H, Ar-H), 7.62
(d, 1H, furan H-3), 8.02 (m, 1H, furan H-5 and 1H, pyridine H-5), 8.30
(d, 2H, Ar-H) ppm. m/z 608 (Found: C, 59.34; H, 4.78; N, 4.84.
C30H28N2SO10 requires C, 59.21; H, 4.60; N, 4.60%).
10f. Yield 70%, m.p. 198ꢀC. IR 2218 (CN), 1750 (CO) cmꢁ1. m/z 624
(Found: C, 57.88; H, 4.56; N, 4.68. C30H28N2S2O9 requires C, 57.69; H,
4.48; N, 4.48%).

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2254
Attia and Elgemeie
3-Cyano-2-(b-D-glycopyransosylthio)pyridines (16a–f )
General procedure. Dry ammonia gas was passed into a solution of
protected glycosdies 8 (0.5 g) in 20 mL of dry methanol at 0ꢀC for 0.5 h.
The reaction mixture was stirred until completion as shown by TLC
(8–12 h), using chloroform:methanol 9:1, v/v (Rf 0.66–0.68 region). The
resulting mixture was then concentrated under reduced pressure to afford
a solid residue that was crystallized frommethanol to furnish colorless
crystals.
16a. Yield 87%, m.p. 220ꢀC. IR 3600–3180 (OH), 2215 (CN) cmꢁ1
.
m/z 450 (Found: C, 64.24; H, 4.98; N, 6.40. C24H22N2SO5 requires C,
64.00; H, 4.88; N, 6.22%).
16b. Yield 85%, m.p. 238ꢀC. IR 3600–3220 (OH), 2215 (CN) cmꢁ1
.
1H NMR 3.28–3.84 (m, 6H, 2H-60, H-50, H-40, H-30 and H-20), 4.42 (t, 1H,
20-OH), 5.12 (d, 2H, 30-OH and 40-OH), 5.58 (d, 1H, 60-OH), 5.72 (d, J1 -2
0
0
10.12 Hz, 1H, H-10), 6.80 (m, 1H, furan H-4), 7.58 (m, 3H, Ar-H), 7.75 (d,
1H, furan H-3), 8.00 (m, 2H, furan H-5 and pyridine H-5), 8.28 (m, 2H,
Ar-H) ppm. m/z 440 (Found: C, 60.12; H, 4.62; N, 6.60. C22H20N2SO6
requires C, 60.00; H, 4.54; N, 6.36%).
16c. Yield 84%, m.p. 248ꢀC. IR 3660–3200 (OH), 2216 (CN) cmꢁ1
.
1H NMR 3.22–3.74 (m, 6H, 2H-60, H-50, H-40, H-30 and H-20), 4.62
(m, 2H, 20-OH and 30-OH), 4.96 (d, 1H, 40-OH), 5.22 (d, 1H, 60-OH),
5.82 (d, J1 -2 10.08 Hz, 1H, H-10), 6.92 (m, 1H, thiophene H-4), 7.16
(m, 1H, thiophene H-3), 7.50 (m, 3H, Ar-H), 7.92 (m, 2H, thiophene
H-5 and pyridine H-5), 8.30 (m, 2H, Ar-H) ppm. 13C NMR 62.2
(C60), 67.8 (C40), 69.8 (C20), 73.6 (C30), 75.0 (C50), 83.1 (C10), 108.5
(C3), 114.7 (CN), 122.2–156.4 (Ar-C), 161.6 (C2) ppm. m/z 456;
(Found: C, 58.12; H, 4.50; N, 6.38. C22H20N2S2O5 requires C, 57.89;
H, 4.38; N, 6.14%).
0
0
16d. Yield 89%, m.p. 230ꢀC. IR 3680–3200 (OH), 2213 (CN) cmꢁ1
.
1H NMR 3.24–3.68 (m, 6H, 2H-60, H-50, H-40, H-30 and H-20), 4.61 (t, 1H,
20-OH), 5.15 (d, 1H, 30-OH), 5.28 (t, 1H, 40-OH), 5.59 (t, 1H, 60-OH), 5.68
(d, J1 -2 9.38 Hz, 1H, H-10), 7.56 (m, 5H, Ar-H), 7.76 (m, 3H, Ar-H), 7.90
0
0
1
(s, 1H, pyridine H-5), 8.28 (m, 2H, Ar-H) ppm. H NMR 3.24–3.81 (m,
6H, 2H-60, H-50, H-40, H-30 and H-20), 4.60 (d, 1H, 20-OH), 4.69 (t, 1H, 30-
OH), 5.04 (d, 1H, 40-OH), 5.43 (d, 1H, 60-OH), 5.68 (d, J1 -2 10.06 Hz,
1H, H-10), 7.59 (m, 5H, Ar-H), 7.86 (m, 3H, Ar-H and 1H, pyridine H-5),
8.29 (m, 2H, Ar-H) ppm. m/z 450 (Found: C, 64.18; H, 5.02; N, 6.48.
C24H22N2SO5 requires C, 64.00; H, 4.88; N, 6.22%).
0
0
16e. Yield 85%, m.p. 233ꢀC. IR 3650–3190 (OH), 2218 (CN) cmꢁ1
.
m/z 440 (Found: C, 60.29; H, 4.66; N, 6.60. C22H20N2SO6 requires C,
60.00; H, 4.54; N, 6.36%).

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Dihydropyridine Thioglycosides
2255
16f. Yield 87%, m.p. 226ꢀC. IR 3680–3220 (OH), 2212 (CN) cmꢁ1
m/z 456 (Found: C, 58.15; H, 4.44; N, 6.30. C22H20N2S2O5 requires C,
57.89; H, 4.38; N, 6.14%).
.
REFERENCES
1. Elgemeie, G.E.H.; Mansour, O.A.; Metwally, N.H. Synthesis and
anti-HIV activity of different novel nonclassical nucleosides.
Nucleosides & Nucleotides. 1999, 18, 113–123.
2. Attia, A.M.; Elgemeie. G.E.H. Synthesis of some N-hexopyranosyl-
2-pyridones and -2-pyridinethiones. Carbohydr. Res. 1955, 268,
295–300.
3. Elgemeie, G.E.H.; Attia, A.M.; Shehada. L.A. Synthesis of some
novel condensed pyridine-2(1H )-thiones and related glycosides.
Tetrahedron 1997, 53, 17441–17448.
4. Elgemeie, G.E.H.; Attia, A.M.; Hussain, B.A. A synthetic strategy to
a new class of cycloalkane ring-fused pyridine nucleosides as poten-
tial anti-HIV agents. Nucleosides & Nucleotides 1998, 17, 855–868.
5. Scala, S.; Akhmed, N.; Rao, U.S.; Paull, K.; Lan, L.; Dickstein, B.;
Lee, J.; Elgemeie, G.E.H.; Stein, W.D.; Bates, S.E. P-Glycoprotein
substrates and antagonists cluster into two distinct groups. Mol.
Pharmacol. 1977, 51, 1024–1033.
6. Still, I.W.; Plavac, N.; Mackinnon, T.M.; Chauhan, M.S.
Carbon-13 nuclear magnetic resonance spectra of organic sulfur
compounds. Comparison of chemical shifts for carbonyl and
thiocarbonyl compounds in the pyron, thiopyrone, and pyridone
series. Can. J. Chem. 1976, 54, 280–289.
7. Stefaniak, L. Nitrogen-14 and carbon-13 NMR of tautomeric
systems of mercapto- and amino-pyridines. Org. Magn. Reson.
1979, 12, 379–382.
Received in the UK July 2, 2002

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