Synthesis of thiopyridines and their hydrogenated thioglycosides via piperidinium salts

Article abstract of DOI:10.1016/S0040-4020(01)01242-X

The synthesis of several new thiopyridines and their hydrogenated thioglycosides via the reaction of piperidinium salts of dihydropyridinethiones with α-halogeno sugars is described.

Full text of DOI:10.1016/S0040-4020(01)01242-X

TETRAHEDRON
Pergamon
Tetrahedron 58 52002) 1399±1405
Synthesis of thiopyridines and their hydrogenated thioglycosides
via piperidinium salts
Adel M. E. Attiap
Department of Chemistry, Faculty of Education, University of Tanta ꢀKafr El-Sheikh Branch), 33516, Egypt
Received 21 March 2001; revised 20 November 2001; accepted 13 December 2001
AbstractÐThe synthesis ofseveral new thiopyridines and their hydrogenated thioglycosides via the reaction ofpiperidinium salts of
dihydropyridinethiones with a-halogeno sugars is described. q 2002 Published by Elsevier Science Ltd.
As part ofour search for the synthesis ofsome antimetabo-
lites,1,2 we have recently reported different novel func-
tionalised pyridine and pyrimidine nucleosides with HIV
and some oncogenic virus antagonistic activity.3±6 In
conjunction with this, we report here a convenient method
for the synthesis of thiopyridines and their dihydropyridine
thioglycosides through reaction ofpiperidinium salts of
dihydropyridinethiolates with a-bromo sugars. As far as
we know this is the ®rst coupling reaction ofthis type to
be reported for glycoside formation. Thus it has been found
that arylmethylidene-cyanothioacetamides 1 reacted with
both benzoyl acetone and ethyl benzoylacetate 2 in ethanol
containing equivalent amounts ofpiperidine at 0 8C to give
the corresponding piperidinium salts of1,4-dihydropyri-
dinethiones 3 5Scheme 1). Compounds 3 reacted with
2,3,4,6-tetra-O-acetyl-a-d-glucopyranosyl bromide or its
a-d-galactopyranosyl isomer in acetone at 08C to give
the corresponding thioglycosides 6 in high yields. The
structures ofthe reaction products 6 were established by
glucopyranose. In another experiment, the piperidinium
salts 3 were reacted with 5 in dry acetone at 308C to afford
the corresponding aromatised pyridine thioglycosides 8 in
good yields via a Walden inversion. The structures of 8 were
established on the basis ofelemental analyses and spectral
data. Although the coupling of 3 with 5 could also give the
corresponding N-glycosides, the formation of S-glycosides
8 were proven using 13C NMR spectroscopy which revealed
the absence ofC vS at d 179 ppm and appearance of
C±S-sugar at 160 ppm, the same value ofthe corresponding
S-methyl derivatives8 10. Deprotection ofthe hydroxy
groups in the S-glycosides 8 with ammonia in methanol
afforded the corresponding 2-5b-d-glycopyranosylthio)-3-
cyanopyridines 9 in 85±88% yields after chromatographic
puri®cation. With these two dihydropyridine and pyridine
thioglycosides as models, it was decided to synthesize these
compounds using the potassium salt method and comparing
the products for stereochemical considerations. Thus, by a
simple experimental procedure, treatment ofpiperidinium
salts 3 with dilute HCl at 308C converted them to the corre-
sponding 3-cyanopyridine-251H)-thiones 4 5Scheme 2). The
formation of 4 has been proven chemically by the treatment
of 1 and 2 in boiling ethanol containing catalytic amounts of
piperidine, and the mechanism ofthis reaction has been
previously reported by us.9 When compounds 4 were
subjected to the reaction with bromides 5 in the presence
ofaqueous potassium hydroxide, the corresponding pyri-
dine thioglycosides 8 were obtained. In summary, the results
show that the reaction of 3 with 5 can lead either to pyridine
thioglycosides or to the dihydropyridine thioglycosides, the
nature ofthe products depends on thermodynamic afctors.
The nucleosides 7 and 9 can be utilised as starting materials
for the synthesis of other carbohydrate derivatives as deoxy,
amino and azido nucleosides.
1
elemental analyses and spectral data. In the H NMR spec-
trum of 6a the anomeric proton H-10 ofthe glucopyranosyl
moiety gives a doublet at d 6.04 ppm with a coupling
constant J5H10 ±H20) of10.3 Hz for the diaxial interaction.
This large coupling constant is characteristic for a b-gluco-
pyranosyl anomer.7 The 13C NMR spectrum of 6a contained
a signal at d 81.8 ppm for the C-10 of b-d-glucopyranose.
Ammonolysis ofprotected nucleosides 6 with methanolic
ammonia at 08C furnished the corresponding 2-5b-d-glyco-
pyranosylthio)-1,4-dihydro-3-cyanopyridines 7 in yields of
84±86%. TLC ofthe rfee thioglycosides 7 showed that a
single compound was produced. The 1H NMR spectrum of
7a showed the anomeric proton as a doublet at d 5.90 ppm
5Jˆ9.0 Hz) indicating the presence ofonly the b-d-gluco-
pyranose moiety. 13C NMR spectra were characterized by a
signal at d 83.2 ppm corresponding to C-10 atom of b-d-
The compounds 8, 9 were tested for their antiviral activity
against human immunode®ciency virus 5HIV-1) in MT-4
cells and against different types of tumour virus; however,
no activity was observed.
Keywords: 6-phenyl-3-cyano-2-thiopyridines; 2-5b-d-glycopyranosylthio)-
pyridines.
Tel./fax: 120-47-223415; e-mail: attia-a@edu-kaf.edu.eg
p
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020501)01242-X

1400
A. M. E. Attia / Tetrahedron 58 ꢀ2002)1399±1405
Scheme 1.
1. Experimental
1.1. 3-Cyano-4,5-disubstituted-6-phenyl-pyridin-2'1H)-
thiones '4a±d): general procedure
Melting points are uncorrected. TLC was carried out on
aluminium sheet silica gel 60 F254 5Merck) detected by
short UV light. IR spectra were obtained 5KBr) using a
To a mixture ofarylmethylenecyanothioacetamides
1
50.01 mol) and benzoyl acetone 2a or ethyl benzoylacetate
2b 50.01 mol) in ethanol 550 mL) a few drops of piperidine
were then added. The mixture was heated under re¯ux for
6 h, and then allowed to stand overnight. The resulting solid
product was collected by ®ltration and crystallised from
EtOH±DMF to afford the title compounds 4a±d.
1
Pye Unicam spectra 1000. H NMR and 13C NMR spectra
were measured on a Varian 400 MHz spectrometer in
DMSO-d6 using SiMe4 as internal standard. Mass spectra
were recorded by EI on a Varian Mat 311 A spectrometer
and FAB on a Kratos MS spectrometer.
Compounds 1a, 1b were prepared from vanillin and iso-
1.1.1. Compound 4a. Yield 63% as a yellow solid, mp
3068C; IR 3454 5OH and NH), 2210 5CN), 1670
vanillin following literature procedures.10

A. M. E. Attia / Tetrahedron 58 ꢀ2002)1399±1405
1401
Scheme 2.
1
5CO) cm21; H NMR 2.28 5s, 3H, CH3CO), 3.82 5s, 3H,
OCH3), 6.90 5m, 3H, Ar-H), 7.65 5m, 5H, Ar-H), 9.48 5s,
1H, OH), 14.15 5s, br, 1H, NH) ppm; 13C NMR 18.3 5CH3),
55.9 5OCH3), 113.4 5C3), 116.9 5CN), 122.5±155.2 5Ar-C),
178.9 5CS), 194.2 5CO) ppm; m/z 376 5Found: C, 67.31; H,
4.44; N, 7.69 C21H16N2SO3 requires C, 67.02; H, 4.25; N,
7.44%).
56.0 5OCH3), 112.2 5C3), 116.9 5CN), 124.8±155.1 5Ar-C),
179.0 5CS), 194.1 5CO) ppm; m/z 376 5Found: C, 67.41; H,
4.38; N, 7.70 C21H16N2SO3 requires C, 67.02; H, 4.25; N,
7.44%).
1.1.4. Compound 4d. Yield 58% as a yellow solid, mp
2668C; IR 3490 5OH and NH), 2218 5CN), 1726
5CO) cm21
;
1H NMR 1.08 5t, Jˆ7.2 Hz, 3H, CH3CO),
3.88 5m, 3H, OCH3 and 2H, CH2), 6.86 5m, 3H, Ar-H),
7.51 5m, 5H, Ar-H), 9.46 5s, 1H, OH), 14.40 5s, br,1H,
NH); 13C NMR 13.6 5CH3), 56.2 5OCH3), 61.8 5CH2),
112.4±154.8 5Ar-C), 164.9 5CO), 179.5 5CS) ppm; m/z
406 5Found: C, 65.28; H, 4.56; N, 6.98 C22H18N2SO4
requires C, 65.02; H, 4.43; N, 6.89%).
1.1.2. Compound 4b. Yield 59% as a yellow solid, mp
2268C; IR 3478 5OH and NH), 2222 5CN), 1720
1
5CO) cm21; H NMR 1.02 5t, Jˆ6.0 Hz, 3H, CH3), 3.82
5m, 3H, OCH3 and 2H, CH2), 6.88 5m, 3H, Ar-H), 7.50
5m, 5H, Ar-H), 9.64 5s, 1H, OH), 14.22 5s, br, 1H,
NH) ppm; 13C NMR 13.7 5CH3), 56.3 5OCH3), 62.1
5CH2), 112.8 5C3), 116.4 5CN), 121.9±154.6 5Ar-C),
166.6 5CO), 179.8 5CS) ppm; m/z 406 5Found: C, 65.33;
H, 4.60; N, 7.08 C22H18N2SO4 requires C, 65.02; H, 4.43;
N, 6.89%).
1.2. 3-Cyano-2-'20,30,40,60-tetra-O-acetyl-b-d-glyco-
pyranosylthio)-1,4-dihydropyridines '6): general
coupling procedures
1.1.3. Compound 4c. Yield 61% as a yellow solid, mp
2308C; IR 3442 5OH and NH), 2222 5CN), 1670
To a mixture ofarylmethylidenecyanothioacetamides
1
50.01 mol) and 2 50.01 mol) in dry ethanol 55 mL) a
50.01 mol) ofpiperidine were then added. The reaction
mixture was stirred at 08C for 1 h, then evaporated under
reduced pressure and the resulting piperidinium salt 3 was
1
5CO) cm21; H NMR 2.24 5s, 3H, CH3CO), 3.80 5s, 3H,
OCH3), 6.74 5m, 3H, Ar-H), 7.64 5m, 5H, Ar-H), 9.12 5s,
1H, OH), 14.30 5s, br, 1H, NH) ppm; 13C NMR 18.4 5CH3),

1402
A. M. E. Attia / Tetrahedron 58 ꢀ2002)1399±1405
dissolved in dry acetone 55 mL) and a solution of2,3,4,6-
tetra-O-acetyl-a-d-glycopyranosyl bromide 50.011 mol) in
dry acetone 520 mL) was then added at 08C. The mixture
was stirred until the reaction was judged complete by TLC
56±8 h), using chloroform±ether 4:1, v/v 5Rf 0.74±0.76
region), then evaporated under reduced pressure and the
residue was crystallized from chloroform±petroleum ether
40±60 at 08C to give the title compounds 6a±h.
1.3. 3-Cyano-2-'b-d-glycopyranosylthio)-1,4-dihydro-
pyridines '7): general procedure for nucleoside
deacylation
Dry ammonia gas was passed into a solution ofacetylated
glycosides 6 50.5 g) in 10 mL ofdry methanol at 0 8C f or
0.5 h. The reaction mixture was stirred until completion as
shown by TLC 510±12 h), using CHCl3±MeOH 9:1, v:v 5Rf
0.64±0.68 region). The resulting mixture was then concen-
trated under reduced pressure at room temperature to afford
a solid residue that was crystallized from methanol±ether at
08C to furnish the title compounds 7.
1.2.1. Compound 6a. Yield 71% as a white solid, mp
1288C; [a]Dˆ30.2 5c 2, CHCl3); IR 3394 5OH and NH),
1
2210 5CN), 1752 5CO ester) cm21; H NMR 1.88±2.08
54s, 12H, 4CH3CO), 2.22 5s, 3H, CH3), 3.80 5s, 3H,
OCH3), 4.08 5m, 2H, 2H-60), 4.18 5m, 2H, H-50 and pyridine
1.3.1. Compound 7a. Yield 86% as a colourless crystals,
mp 2148C; [a]Dˆ50.2 5c 1.5, MeOH); IR 3320 5OH
H-4), 4.82 5t, Jˆ7.2 Hz, 1H, H-40), 5.08 5m, 1H, H-30), 5.26
1
and NH), 2202 5CN) cm21; H NMR 2.22 5s, 3H, CH3),
0
5t, Jˆ8.7 Hz, 1H, H-20), 6.04 5d, J1 ±2 ˆ10.2 Hz, 1H, H-1 ),
6.98 5m, 3H, Ar-H), 7.64 5m, 5H, Ar-H), 7.88 5s, 1H, NH),
8.92 5s, 1H, OH) ppm; 13C NMR 18.6 5CH3 ofpyridine),
20.4±22.5 54CH3), 55.2 5OCH3), 62.0 5C60), 68.4 5C40),
70.6 5C20), 72.8 5C30), 75.1 5C50), 81.8 5C10), 96.2 5C4),
105.6 5C3), 115.0 5CN), 122.7±157.2 5Ar-C), 159.6 5C2),
169.2±169.8 54CO), 194.0 5CO ofpyridine) ppm; m/z 708
5Found: C, 59.66; H, 5.30; N, 4.28 C35H36N2SO12 requires
C, 59.32; H, 5.08; N, 3.95%).
0
0
3.28±3.98 5m, 6H, 2H-60, H-50, H-40, H-30,H-20 and 3H,
OCH3 and 1H, pyridine H-4), 4.46 5s, 1H, 20-OH), 4.78 5s,
1H, 30-OH), 5.12 5s, 1H, 40-OH), 5.34 5s, 1H, 60-OH),
0
0
0
5.90 5d, J1 ±2 ˆ9.0 Hz, 1H, H-1 ), 7.38 5m, 3H, Ar-H),
7.69 5m, 5H, Ar-H), 7.98 5s, 1H, NH), 9.42 5s, 1H,
OH) ppm; 13C NMR 18.4 5CH3), 55.2 5OCH3), 61.8
5C60), 68.2 5C40), 70.0 5C20), 74.9 5C30), 79.3 5C50),
83.2 5C10), 94.8 5C4), 106.2 5C3), 115.4 5CN), 122.8±
156.6 5Ar-C), 160.2 5C2), 192.8 5CO) ppm; m/z 540
5Found: C, 60.18; H, 5.40; N, 5.48 C27H28N2SO8 requires
C, 60.00; H, 5.18; N, 5.18%).
1.2.2. Compound 6c. Yield 74% as a white solid, mp
1808C; [a]Dˆ23.0 5c 2, CHCl3); IR 3365 5OH and NH),
2206 5CN), 1752 5CO) cm21 1H NMR 1.90±2.12 54s,
;
12H, 4CH3CO), 2.18 5s, 3H, CH3CO), 3.90 5s, 3H,
OCH3), 4.22 5m, 4H, 2H-60, H-50 and pyridine H-4),
4.64 5m, 1H, H-40), 5.06 5t, Jˆ5.8 Hz, 1H, H-30), 5.22
1.3.2. Compound 7c. Yield 85% as a colourless crystals,
mp 2188C; [a]Dˆ22.6 5c 1.5, MeOH); IR 3390 5OH and
1
NH), 2205 5CN) cm21; H NMR 2.24 5s, 3H, CH3), 3.28±
5t, Jˆ7.4 Hz, 1H, H-20), 5.98 5d, J1 ±2 ˆ10.1 Hz, 1H,
H-10), 6.88 5m, 3H, Ar-H), 7.62 5m, 5H, Ar-H), 7.90 5s,
1H, NH), 8.96 5s, 1H, OH) ppm; m/z 708 5Found: C,
59.58; H, 5.22; N, 4.25 C35H36N2SO12 requires C, 59.32;
H, 5.08; N, 3.95%).
4.09 5m, 6H, 2H-60, H-50, H-40, H-30, H-20 and 3H, OCH3
and 1H, pyridine H-4), 4.58 5s, 1H, 20-OH), 4.80 5t,
Jˆ7.2 Hz, 1H, 30-OH), 5.05 5m, 2H, 40-OH and 60-OH),
5.92 5d, Jˆ9.7 Hz, 1H, H-10), 7.31 5m, 3H, Ar-H), 7.82
5m, 5H, Ar-H), 8.03 5s, 1H, NH), 9.12 5s, 1H, OH) ppm;
m/z 540 5Found: C, 60.38; H, 5.40; N, 5.54 C27H28N2SO8
requires C, 60.00; H, 5.18; N, 5.18%).
0
0
1.2.3. Compound 6e. Yield 73% as a white solid, mp
1628C; [a]Dˆ38.3 5c 2, CHCl3); IR 3394 5OH and NH),
2210 5CN), 1752 5CO) cm21 1H NMR 1.80±2.12 54s,
;
1.3.3. Compound 7e. Yield 84% as a colourless crystals,
mp 2068C; [a]Dˆ29.1 5c 1.5, MeOH); IR 3406 5OH and
12H, 4CH3CO), 2.21 5s, 3H, CH3), 3.88 5s, 3H, OCH3),
4.08 5m, 2H, 2H-60), 4.22 5m, 2H, H-50 and pyridine H-4),
1
NH), 2202 5CN) cm21; H NMR 2.20 5s, 3H, CH3), 3.26±
4.68 5m, 1H, H-40), 4.95 5m, 1H, H-30), 5.18 5t, Jˆ8.2 Hz,
4.02 5m, 6H, 2H-60, H-50, H-40, H-30, H-20 and 3H, OCH3
and 1H, pyridine H-4), 4.42 5s, 1H, 20-OH), 4.66 5m, 2H,
30-OH and 40-OH), 5.11 5m, 1H, 60-OH), 5.88 5d, Jˆ8.8 Hz,
1H, H-10), 7.18 5m, 3H, Ar-H), 7.60 5m, 5H, Ar-H), 7.86 5s,
1H, NH), 9.23 5s, 1H, OH) ppm; 13C NMR 18.0 5CH3), 55.6
5OCH3), 62.2 5C60), 67.8 5C40), 71.9 5C20), 74.2 5C30), 79.0
5C50), 83.9 5C10), 96.8 5C4), 105.9 5C3), 114.7 5CN), 122.5±
157.4 5Ar-C), 162.1 5C2), 194.0 5CO) ppm; m/z 540 5Found
C, 60.35; H, 5.26; N, 5.41 C27H28N2SO8 requires C, 60.00;
H, 5.18; N, 5.18%).
0
1H, H-20), 6.06 5d, J1 ±2 ˆ10.1 Hz, 1H, H-1 ), 6.98 5m, 3H,
Ar-H), 7.63 5m, 5H, Ar-H), 7.95 5s, 1H, NH), 8.99 5s, 1H,
OH) ppm; 13C NMR 18.8 5CH3 ofpyridine), 21.2±22.5
54CH3), 55.6 5OCH3), 61.8 5C60), 68.7 5C40), 71.2 5C20),
72.0 5C30), 75.3 5C50), 83.2 5C10), 98.8 5C4), 104.9 5C3),
115.6 5CN), 122.0±156.7 5Ar-C), 160.9 5C2), 169.4±169.9
54CO), 192.3 5CO ofpyridine) ppm; m/z 708 5Found: C,
59.60; H, 5.14; N, 4.28 C35H36N2SO12 requires C, 59.32;
H, 5.08; N, 3.95%).
0
0
1.2.4. Compound 6g. Yield 72% as a white solid, mp
1488C; [a]Dˆ42.8 5c 2, CHCl3); IR 3380 5OH and NH),
2214 5CN), 1750 5CO) cm21 1H NMR 1.86±2.08 54s,
;
1.3.4. Compound 7g. Yield 85% as a colourless crystals,
mp 2138C; [a]Dˆ25.5 5c 1.5, MeOH); IR 3400 5OH and
1
NH), 2215 5CN) cm21; H NMR 2.28 5s, 3H, CH3), 3.30±
4.04 5m, 6H, 2H-60, H-50, H-40, H-30, H-20 and 3H, OCH3
12H, 4CH3CO), 2.26 5s, 3H, CH3CO); 3.88 5s, 3H,
OCH3), 4.18 5m, 4H, 2H-60, H-50 and pyridine H-4), 4.48
and 1H, pyridine H-4), 4.48 5d, Jˆ8.4 Hz, 1H, 20-OH), 4.76
5d, Jˆ4.8 Hz, 1H, H-40), 5.02 5m, 1H, H-30), 5.50 5m, 1H,
5m, 2H, 30-OH and 40-OH), 5.02 5d, Jˆ6.8 Hz, 1H, 60-OH),
0
H-20), 6.08 5d, J1 ±2 ˆ10.0 Hz, 1H, H-1 ), 6.88 5m, 3H,
Ar-H), 7.52 5m, 5H, Ar-H), 8.90 5s, 1H, NH), 9.46 5s, 1H,
OH) ppm; m/z 708 5Found: C, 59.70; H, 5.15; N, 4.33
C35H36N2SO12 requires C, 59.32; H, 5.08; N, 3.95%).
0
0
0
0
0
5.86 5d, J1 ±2 ˆ9.6 Hz, 1H, H-1 ), 7.08 5m, 3H, Ar-H), 7.70
5m, 5H, Ar-H), 8.12 5s, 1H, NH), 9.45 5s, 1H, OH) ppm; m/z
540 5Found: C, 60.28; H, 5.30; N, 5.34 C27H28N2SO8
requires C, 60.00; H, 5.18; N, 5.18%).

A. M. E. Attia / Tetrahedron 58 ꢀ2002)1399±1405
1403
1.4. 3-Cyano-2-'20,30,40,60-tetra-O-acetyl-b-d-glyco-
pyranosylthio) pyridines '8): general coupling
procedures
1H, H-10), 6.80 5m, 3H, Ar-H), 7.48 5m, 5H, Ar-H), 9.32 5s,
br, 1H, OH) ppm; m/z 706 5Found: C, 59.81; H, 4.86; N,
4.08 C35H34N2SO12 requires C, 59.49; H, 4.81; N, 3.96%).
1.4.4. Compound 8d. Yield 70% as a white solid, mp
1488C; [a]Dˆ30.8 5c 2, CHCl3); IR 3442 5OH), 2222
Method A. To a mixture ofarylmethylidenecyanothioaceta-
mides 1 50.01 mol) and 2 50.01 mol) in dry ethanol 55 mL), a
0.01 mol ofpiperidine was added. The reaction mixture was
stirred at 08C for 1 h, then evaporated under reduced
pressure at room temperature and the resulting piperidinium
salt 3 was dissolved in dry acetone 55 mL) and a solution of
2,3,4,6-tetra-O-acetyl-a-d-glycopyranosyl bromide 50.011
mol) in dry acetone 520 mL) was then added at 308C. The
mixture was stirred until the reaction was judged complete
by TLC, using chloroform±ether 4:1, v/v 5Rf 0.70±0.74
region), then evaporated under reduced pressure and the
residue was crystallized from ethanol to give the title
compounds 8a±h.
1
5CN), 1752 5CO ester) cm21; H NMR 0.84 5t, Jˆ7.0 Hz,
3H, CH3), 1.76±2.03 54s, 12H, 4CH3CO), 3.84 5s, 3H,
OCH3), 3.96 5m, 2H, CH2), 4.11 5m, 2H, 2H-60 and 1H,
H-50), 5.02 5t, Jˆ4.6 Hz, 1H, H-40), 5.25 5t, Jˆ5.5 Hz,
1H, H-30), 5.66 5t, Jˆ5.2 Hz, 1H, H-20), 6.16 5d, J1 ±2
ˆ
0
0
10.5 Hz, 1H, H-10), 7.08 5m, 3H, Ar-H), 7.78 5m, 5H,
Ar-H), 9.20 5s, br, 1H, OH) ppm; 13C NMR 13.2 5CH3),
20.2±20.4 54CH3CO), 55.6 5OCH3), 61.6 5CH2), 61.9
5C60), 68.2 5C40), 68.8 5C20), 72.9 5C30), 75.0 5C50), 80.2
5C10), 106.3 5C3), 115.2 5CN), 125.9±157.0 5Ar-C), 159.3
5C2), 166.1 5CO), 169.4±169.8 54COCH3) ppm; m/z 736
5Found: C, 58.90; H, 4.95; N, 4.07 C36H36N2SO13 requires
C, 58.69; H, 4.89; N, 3.80%).
Method B. To a solution of3-cyano-4,5-disubstituted-6-
phenyl-pyridin-251H)thiones
4 50.01 mol) in aqueous
1.4.5. Compound 8e. Yield 72% as a white solid, mp
1478C; [a]Dˆ12.9 5c 2, CHCl3); IR 3454 5OH), 2222
potassium hydroxide [0.56 g 50.01 mol) in 6 mL ofdistilled
water], a solution of2,3,4,6-tetra- O-acetyl-a-d-gluco- or
galacto-pyranosyl bromide 5 50.011 mol) in acetone
530 mL) was added. The reaction mixture was stirred at
room temperature until completion 5TLC, 1±2 h), 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 ethanol to afford the title compounds 8a±h.
5CN), 1752 5CO ester) cm21 1H NMR 1.90±2.14 54s,
;
12H, 4CH3CO), 2.32 5s, 3H, CH3), 3.72 5s, 3H, OCH3),
4.15 5m, 2H, 2H-60 and 1H, H-50), 5.28 5t, Jˆ3.8 Hz, 1H,
H-40), 5.39 5t, Jˆ6.6 Hz, 1H, H-30), 5.51 5t, Jˆ6.8 Hz,
0
1H, H-20), 6.18 5d, J1 ±2 ˆ10.4 Hz, 1H, H-1 ), 6.84 5m,
3H, Ar-H), 7.59 5m, 5H, Ar-H), 9.41 5s, 1H, OH) ppm;
m/z 706 5Found: C, 59.68; H, 5.02; N, 4.20 C35H34N2SO12
requires C, 59.49; H, 4.81; N, 3.96%).
0
0
1.4.1. Compound 8a. Yield 72% as a white solid, mp
1138C; [a]Dˆ21.9 5c 2, CHCl3); IR 3418 5OH), 2222
1.4.6. Compound 8f. Yield 71% as a white solid, mp 1208C;
[a]Dˆ26.7 5c 2, CHCl3); IR 3494 5OH), 2222 5CN), 1748
5CN), 1752 5CO ester) cm21 1H NMR 1.89±2.08 54s,
;
12H, 4CH3CO), 2.26 5s, 3H, CH3), 3.78 5s, 3H, OCH3),
1
5CO ester) cm21; H NMR 0.82 5t, Jˆ7.3 Hz, 3H, CH3),
4.03 5m, 2H, 2H-60 and 1H, H-50), 5.01 5t, Jˆ9.1 Hz, 1H,
1.75±2.14 54s, 12H, 4CH3CO), 3.78 5s, 3H, OCH3), 3.96
5m, 2H, CH2), 4.12 5m, 2H, 2H-60 and 1H, H-50), 4.45 5t,
H-40), 5.19 5t, Jˆ5.6 Hz, 1H, H-30), 5.56 5t, Jˆ6.7 Hz, 1H,
0
0
Jˆ9.2 Hz, 1H, H-40), 5.24 5t, Jˆ5.7 Hz, 1H, H-30), 5.38 5t,
0
H-20), 6.20 5d, J1 ±2 ˆ10.4 Hz, 1H, H-1 ), 6.66 5m, 3H,
Ar-H), 7.44 5m, 5H, Ar-H), 9.44 5s, br, 1H, OH) ppm; 13C
NMR 17.8 5CH3), 20.5±23.2 54CH3), 55.5 5OCH3), 61.3
5C60), 68.3 5C40), 70.4 5C20), 73.3 5C30), 75.2 5C50), 80.3
5C10), 105.5 5C3), 115.5 5CN), 122.3±154.9 5Ar-C), 158.6
5C2), 169.4±169.9 54COCH3), 195.3 5CO) ppm; m/z 706
5Found: C, 59.70; H, 4.84; N, 4.22 C35H34N2SO12 requires
C, 59.49; H, 4.81; N, 3.96%).
0
Jˆ7.2 Hz, 1H, H-20), 6.14 5d, J1 ±2 ˆ10.8 Hz, 1H, H-1 ),
6.86 5m, 3H, Ar-H), 7.55 5m, 5H, Ar-H), 9.40 5s, br, 1H,
OH) ppm; 13C NMR 13.3 5CH3), 20.3±21.1 54CH3CO), 55.9
5OCH3), 61.8 5CH2), 61.9 5C60), 66.2 5C40), 68.5 5C20), 71.8
5C30), 74.2 5C50), 80.4 5C10), 106.3 5C3), 115.8 5CN),
121.6±157.2 5Ar-C), 158.8 5C2), 166.3 5CO), 169.5±170.1
54COCH3) ppm; m/z 736 5Found: C, 58.98; H, 5.13; N, 3.98
C36H36N2SO13 requires C, 58.69; H, 4.89; N, 3.80%).
0
0
1.4.2. Compound 8b. Yield 70% as a white solid, mp
1188C; [a]Dˆ36.4 5c 2, CHCl3); IR 3382 5OH), 2222
1.4.7. Compound 8g. Yield 70% as a white solid, mp
1408C; [a]Dˆ21.9 5c 2, CHCl3); IR 3440 5OH), 2225
1
5CN), 1748 5CO ester) cm21; H NMR 0.82 5t, Jˆ7.9 Hz,
5CN), 1748 5CO ester) cm21 1H NMR 1.80±2.12 54s,
;
12H, 4CH3CO), 2.30 5s, 3H, CH3), 3.78 5s, 3H, OCH3),
3H, CH3), 1.75±2.05 54s, 12H, 4CH3CO), 3.78 5s, 3H,
OCH3), 3.94 5m, 2H, CH2), 4.15 5m, 2H, 2H-60 and 1H,
H-50), 4.99 5t, Jˆ3.8 Hz, 1H, H-40), 5.23 5t, Jˆ5.6 Hz,
4.16 5m, 2H, 2H-60 and 1H, H-50), 4.86 5d, Jˆ5.8 Hz, 1H,
0
0
H-40), 5.29 5m, 2H, H-30 and H-20), 6.12 5d, J1 ±2 ˆ9.6 Hz,
1H, H-10), 6.88 5m, 3H, Ar-H), 7.40 5m, 5H, Ar-H), 9.24 5s,
1H, OH) ppm; m/z 706 5Found: C, 59.80; H, 4.96; N, 4.24
C35H34N2SO12 requires C, 59.49; H, 4.81; N, 3.96%).
1H, H-30), 5.60 5t, Jˆ8.0 Hz, 1H, H-20), 6.15 5d, J1 ±2
ˆ
0
0
10.4 Hz, 1H, H-10), 7.48 5m, 3H, Ar-H), 7.76 5m, 5H,
Ar-H), 9.32 5s, br, 1H, OH) ppm; m/z 736 5Found: C,
58.98; H, 4.94; N, 4.06 C36H36N2SO13 requires C, 58.69;
H, 4.89; N, 3.80%).
1.4.8. Compound 8h. Yield 72% as a white solid, mp
1368C; [a]Dˆ35.1 5c 2, CHCl3); IR 3406 5OH), 2222
1.4.3. Compound 8c. Yield 71% as a white solid, mp
1278C; [a]Dˆ38.0 5c 2, CHCl3); IR 3430 5OH), 2226
1
5CN), 1746 5CO ester) cm21; H NMR 0.88 5t, Jˆ7.7 Hz,
5CN), 1750 5CO ester) cm21 1H NMR 1.85±2.02 54s,
;
12H, 4CH3CO), 2.26 5s, 3H, CH3), 3.68 5s, 3H, OCH3),
3H, CH3), 1.76±2.02 54s, 12H, 4CH3CO), 3.90 5s, 3H,
OCH3), 4.04 5m, 2H, CH2), 4.18 5m, 2H, 2H-60 and 1H,
H-50), 4.70 5t, Jˆ6.3 Hz, 1H, H-40), 5.12 5m, 1H, H-30),
4.28 5m, 2H, 2H-60 and 1H, H-50), 4.93 5m, 2H, H-40 and
0
H-30), 5.11 5t, Jˆ6.2 Hz, 1H, H-20), 6.26 5d, J1 ±2 ˆ8.4 Hz,
0
0
0
0
5.39 5m, 1H, H-20), 6.20 5d, J1 ±2 ˆ9.8 Hz, 1H, H-1 ), 6.95

1404
A. M. E. Attia / Tetrahedron 58 ꢀ2002)1399±1405
1
5m, 3H, Ar-H), 7.66 5m, 5H, Ar-H), 9.22 5s, 1H, OH) ppm;
m/z 736 5Found: C, 58.88; H, 5.13; N, 4.12 C36H36N2SO13
requires C, 58.69; H, 4.89; N, 3.80%).
5CN) cm21; H NMR 2.30 5s, 3H, CH3), 3.20±3.71 5m,
6H, 2H-60, H-50, H-40, H-30 and H-20), 3.87 5s, 3H,
OCH3), 4.44 5t, Jˆ6.1 Hz, 1H, 20-OH), 4.83 5d, Jˆ9.6 Hz,
1H, 30-OH), 5.25 5m, 1H, 400-OH), 5.48 5m, 1H, 60-OH), 5.90
0
0
5d, J1 ±2 ˆ9.5 Hz, 1H, H-1 ), 7.18 5m, 3H, Ar-H), 7.79 5m,
5H, Ar-H), 9.20 5s, 1H, OH) ppm; m/z 538 5Found: C, 60.56;
H, 4.90; N, 5.39 C27H26N2SO8 requires C, 60.22; H, 4.83; N,
5.20%).
1.5. 3-Cyano-2-'b-d-glycopyranosylthio)-pyridines '9):
general procedure
Dry gaseous ammonia was passed through a solution of
protected nucleoside 8 50.5 g) in dry methanol 520 mL) at
08C for 0.5 h. The reaction mixture was stirred till complete
as shown by TLC 510±12 h) using CHCl3±MeOH 9:1, v:v
5Rf 0.66±0.68). The resulting mixture was then concentrated
under reduced pressure to afford a solid residue that was
crystallised from methanol to furnish the title compounds 9.
1.5.6. Compound 9f. Yield 80% as a colourless crystal, mp
1858C; [a]D1ˆ28.4 5c 1.5, MeOH); IR 3370 5OH), 2222
5CN) cm21; H NMR 0.83 5t, Jˆ8.1 Hz, 3H, CH3), 3.39±
3.71 5m, 6H, 2H-60, H-50, H-40, H-30 and H-20), 3.85 5s, 3H,
OCH3), 3.96 5m, 2H, CH2), 4.34 5s, 1H, 20-OH), 4.98 5d,
Jˆ5.9 Hz, 2H, 30-OH and 40-OH), 5.22 5s, 1H, 60-OH), 5.62
0
0
0
5d, J1 ±2 ˆ10.2 Hz, 1H, H-1 ), 6.94 5m, 3H, Ar-H), 7.55 5m,
5H, Ar-H), 9.63 5s, 1H, OH) ppm; m/z 568 5Found: C, 59.41;
H, 4.95; N, 5.05 C28H28N2SO9 requires C, 59.15; H, 4.92; N,
4.92%).
1.5.1. Compound 9a. Yield 83% as a colourless crystal, mp
1988C; [a]Dˆ45.4 5c 1.5, MeOH); IR 3394 5OH), 2210
1
5CN) cm21; H NMR 2.20 5s, 3H, CH3), 3.32±3.93 5m,
6H, 2H-60, H-50, H-40, H-30 and H-20 and 3H, OCH3),
4.65 5s, 1H, 20-OH), 4.82 5s, 1H, 30-OH), 5.06 5s, 1H,
1.5.7. Compound 9g. Yield 81% as a colourless crystal, mp
1908C; [a]Dˆ29.0 5c 1.5, MeOH); IR 3370 5OH), 2222
40-OH), 5.46 5s, 1H, 60-OH), 5.61 5d, J1 ±2 ˆ8.1 Hz, 1H,
H-10), 7.07 5m, 3H, Ar-H), 7.76 5m, 5H, Ar-H), 9.49 5s,
1H, OH) ppm; 13C NMR 17.8 5CH3), 55.7 5s, 3H, OCH3),
61.6 5C60), 68.5 5C40), 68.8 5C20), 74.9 5C30), 80.3 5C50),
84.1 5C10), 105.6 5C3), 115.3 5CN), 124.8±157.0 5Ar-C),
161.8 5C2), 194.0 5CO) ppm; m/z 538 5Found: C, 60.50;
H, 4.97; N, 5.38 C27H26N2SO8 requires C, 60.22; H, 4.83;
N, 5.20%).
0
0
1
5CN) cm21; H NMR 2.32 5s, 3H, CH3), 3.18±3.80 5m,
6H, 2H-60, H-50, H-40, H-30 and H-20), 3.86 5s, 3H,
OCH3), 4.50 5m, 2H, 20-OH and 30-OH), 4.99 5s, 1H,
40-OH), 5.43 5s, 1H, 60-OH), 5.78 5d, J1 ±2 ˆ9.0 Hz, 1H,
H-10), 7.13 5m, 3H, Ar-H), 7.66 5m, 5H, Ar-H), 9.28 5s,
1H, OH) ppm; 13C NMR 18.1 5CH3), 55.2 5OCH3), 60.8
5C60), 68.3 5C40), 69.5 5C20), 73.7 5C30), 79.8 5C50), 83.9
5C10), 105.1 5C3), 114.7 5CN), 123.1±158.4 5Ar-C), 162.5
5C2), 190.6 5CO) ppm; m/z 538 5Found: C, 60.46; H, 4.94;
N, 5.48 C27H26N2SO8 requires C, 60.22; H, 4.83; N, 5.20%).
0
0
1.5.2. Compound 9b. Yield 84% as a colourless crystal, mp
2168C; [a]D1ˆ22.8 5c 1.5, MeOH); IR 3360 5OH), 2210
5CN) cm21; H NMR 0.82 5t, Jˆ7.0 Hz, 3H, CH3), 3.26±
3.68 5m, 6H, 2H-60, H-50, H-40, H-30 and H-20), 3.80 5s, 3H,
OCH3), 3.94 5m, 2H, CH2), 4.72 5s, 1H, 20-OH), 5.09 5s, 1H,
30-OH), 5.24 5s, 1H, 400-OH), 5.50 5s, 1H, 60-OH), 5.58 5d,
1.5.8. Compound 9h. Yield 80% as a colourless crystal, mp
1968C; [a]D1ˆ20.7 5c 1.5, MeOH); IR 3370 5OH), 2210
5CN) cm21; H NMR 0.86 5t, Jˆ7.1 Hz, 3H, CH3), 3.22±
3.75 5m, 6H, 2H-60, H-50, H-40; H-30 and H-20), 3.80 5s, 3H,
OCH3), 3.98 5m, 2H, CH2), 4.48 5s, 1H, 20-OH), 5.04 5s, 1H,
30-OH), 5.55 5d, Jˆ9.6 Hz, 2H, 40-OH and 60-OH), 5.93 5d,
Jˆ8.7 Hz, 1H, H-10), 7.08 5m, 3H, Ar-H), 7.63 5m, 5H,
Ar-H), 9.18 5s, 1H, OH) ppm; m/z 568 5Found: C, 59.60;
H, 5.13; N, 4.98 C28H28N2SO9 requires C, 59.15; H, 4.92; N,
4.92%).
0
0
J1 ±2 ˆ9.9 Hz, 1H, H-1 ), 6.92 5m, 3H, Ar-H), 7.34 5m, 5H,
Ar-H), 9.51 5s, 1H, OH) ppm; m/z 568 5Found: C, 59.44; H,
5.04; N, 4.98 C28H28N2SO9 requires C, 59.15; H, 4.92; N,
4.92%).
1.5.3. Compound 9c. Yield 83% as a colourless crystal, mp
2118C; [a]Dˆ18.2 5c 1.5, MeOH); IR 3394 5OH), 2210
1
5CN) cm21; H NMR 2.28 5s, 3H, CH3), 3.36±3.93 5m,
6H, 2H-60, H-50, H-40, H-30 and H-20 and 3H, OCH3),
4.58 5t, Jˆ6.6 Hz, 2H, 20-OH and 30-OH), 4.82 5s, 1H,
40-OH), 5.32 5s, 1H, 60-OH), 5.78 5d, J1 ±2 ˆ8.8 Hz, 1H,
H-10), 7.13 5m, 3H, Ar-H), 7.81 5m, 5H, Ar-H), 9.16 5s,
1H, OH) ppm; m/z 538 5Found: C, 60.48; H, 5.01; N, 5.51
C27H26N2SO8 requires C, 60.22; H, 4.83; N, 5.20%).
Acknowledgements
0
0
The author is deeply indebted to Dr J. P. Bader, Dr V. L.
Narayanan and Dr M. R. Boyd, AIDS Department and Drug
Synthesis and Chemistry Branch ofHealth and Human
Services, NIH for their valuable in vitro anti-HIV and anti-
tumour activity studies for our samples.
1.5.4. Compound 9d. Yield 82% as a colourless crystal, mp
2038C; [a]D1ˆ16.9 5c 1.5, MeOH); IR 3382 5OH), 2210
5CN) cm21; H NMR 0.84 5t, Jˆ7.7 Hz, 3H, CH3), 3.19±
3.79 5m, 6H, 2H-60, H-50, H-40, H-30 and H-20), 3.85 5s, 3H,
OCH3), 3.94 5m, 2H, CH2), 4.79 5s, 1H, 20-OH), 5.16 5d,
References
Jˆ5.0 Hz, 1H, 30-OH), 5.31 5s, 1H, 40-OH), 5.59 5s, 1H,
0
60-OH), 5.63 5d, J1 ±2 ˆ8.3 Hz, 1H, H-1 ), 7.07 5m, 3H,
Ar-H), 7.76 5m, 5H, Ar-H), 9.50 5s, 1H, OH) ppm; m/z
568 5Found: C, 59.58; H, 5.20; N, 5.08 C28H28N2SO9
requires C, 59.15; H, 4.92; N, 4.92%).
0
0
1. Elgemeie, G. H.; Attia, A. M.; Farag, D. S.; Sherif, S. M.
J. Chem. Soc., Perkin Trans. 1 1994, 1285.
2. Elgemeie, G. H.; Attia, A. M. Phosphorus Sulfur Silicon 1994,
92, 95.
3. Attia, A. M.; Elgemeie, G. H. Carbohydr. Res. 1995, 268, 295.
4. Elgemeie, G. H.; Attia, A. M.; Fathy, N. M. Nucleosides
Nucleotides 1997, 16, 485.
1.5.5. Compound 9e. Yield 80% as a colourless crystal, mp
2038C; [a]Dˆ24.6 5c 1.5, MeOH); IR 3394 5OH), 2210

A. M. E. Attia / Tetrahedron 58 ꢀ2002)1399±1405
1405
5. Attia, A. M.; Sallam, M. A.; Almehdi, A. A.; Abbasi, M. M.
Nucleosides Nucleotides 1999, 18, 2307.
8. Still, I. W.; Plavat, N.; Mackinnon, T. M. J. Can. Chem. 1976,
54, 280.
9. Attia, A. M.; Elgemeie, G. H.; Shahada, L. A. Tetrahedron
1997, 53, 17441.
6. Strekowski, L.; Abdou, I. M.; Attia, A. M.; Patterson, S. E.
Tetrahedron Lett. 2000, 41, 4757.
10. Brunskill Asish De, J. S. J. Chem. Soc., Perkin Trans. 1 1978,
629.
7. Elgemeie, G. H.; Attia, A. M.; Alkabai, S. S. Nucleosides
Nucleotides Nucleic Acid 2000, 19, 723.