Nucleic acid components and their analogs: Design and synthesis of novel cytosine thioglycoside analogs

Article abstract of DOI:10.1080/15257770.2016.1231318

The synthesis of a new category of novel cytosine 4-thioglycoside analogs has been first accomplished. The main step of this strategy is the synthesis of sodium pyrimidine-4-thiolate through the condensation of 2-cyano-N-arylacetamides with sodium cyanocarbonimidodithioate, followed by coupling with α-bromo-sugars to afford the corresponding cytosine 4-thioglycoside analogs. The free thioglycosides were also prepared. Subsequent studies on the application of this strategy for the preparation of other potent pyrimidine thioglycosides are reported.

Full text of DOI:10.1080/15257770.2016.1231318

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: http://www.tandfonline.com/loi/lncn20
Nucleic Acid Components and Their Analogs:
Design and Synthesis of Novel Cytosine
Thioglycoside Analogs
Galal H. Elgemeie, Ali M. Salah, Nermeen S. Abbas, Hoda A. Hussein &
Reham A. Mohamed
To cite this article: Galal H. Elgemeie, Ali M. Salah, Nermeen S. Abbas, Hoda A. Hussein &
Reham A. Mohamed (2017): Nucleic Acid Components and Their Analogs: Design and Synthesis
of Novel Cytosine Thioglycoside Analogs, Nucleosides, Nucleotides and Nucleic Acids, DOI:
10.1080/15257770.2016.1231318
To link to this article: http://dx.doi.org/10.1080/15257770.2016.1231318
Published online: 03 Jan 2017.
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Date: 05 January 2017, At: 05:29

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
, VOL. , NO. , –
http://dx.doi.org/./..
Nucleic Acid Components and Their Analogs: Design and
Synthesis of Novel Cytosine Thioglycoside Analogs
Galal H. Elgemeiea, Ali M. Salaha, Nermeen S. Abbasa,c, Hoda A. Husseinb,
and Reham A. Mohamedb
aChemistry Department, Faculty of Science, Helwan University, Helwan, Cairo, Egypt; bPhotochemistry
Department, National Research Center, Dokki, Cairo, Egypt; cChemistry Department, Faculty of Science,
Taibah University, Saudi Arabia
ABSTRACT
ARTICLE HISTORY
Received  January 
Accepted  August 
The synthesis of a new category of novel cytosine 4-thioglycoside
analogs has been first accomplished. The main step of this
strategy is the synthesis of sodium pyrimidine-4-thiolate through
the condensation of 2-cyano-N-arylacetamides with sodium
cyanocarbonimidodithioate, followed by coupling with α-bromo-
sugars to afford the corresponding cytosine 4-thioglycoside
analogs. The free thioglycosides were also prepared. Subsequent
studies on the application of this strategy for the preparation of
other potent pyrimidine thioglycosides are reported.
KEYWORDS
Pyrimidine thioglycosides;
antimetabolites;
-cyano-N-arylacetamides;
sodium
cyanocarbonimidodithioate
Introduction
Nucleoside analogs have been in clinical use and have become fundamental drugs
for treating viral infections and cancer.[1] Thioglycosides are versatile building
blocks in synthetic carbohydrate chemistry.[2,3] It is worthwhile to note that vari-
ous thioglycosides are considered as glycosyltransferases inhibitors.[4] Pyrimidine
nucleoside analogs are components of solid tumor and hematological malignancy
therapies.[5,6] The antitumor and antiviral potencies of many pyrimidine and purine
nucleosides have been evaluated.[7] During our studies on the design and synthe-
sis of nucleoside derivatives, a method for the synthesis of thioglycosides bearing a
functionalized pyrimidine or pyridine ring was desired.[8–11] That method could
generate various analogs of pyrimidine nucleosides with new hydrogen-bonding
patterns.[12–15] Such compounds might display pharmaceutically pivotal roles and
useful antimetabolite potency.[16] The synthesis of novel substituted pyridine thio-
glycosides which showed antagonistic potency have been described.[17] In addition,
the significant use of dihydropyridine thioglycosides as inhibitors of protein glyco-
sylation were reported.[18] These remarkable bioactivities motivated us to develop
a new strategy for the preparation of pyrimidine thioglycosides. Continuing our
CONTACT Galal H. Elgemeie
University, Helwan, Cairo, Egypt.
elgemeie@yahoo.com
Chemistry Department, Faculty of Science, Helwan
©  Taylor & Francis Group, LLC

2
G. H. ELGEMEIE ET AL.
efforts for the development of cost-effective and simple methodologies, novel syn-
thesis of cytosine thioglycoside analogs are reported. This new efficient strategy has
been applied to various functionalized pyrimidine thioglycosides in high yields.
This is the first approach to be accomplished for the synthesis of this new ring
system.
Results and discussions
Chemistry
Sodium cyanocarbonimidodithioate salt 1 was furnished upon the reaction of
aminomethanenitrile with carbon disulfide in sodium ethoxide. Compound 1 was
reacted with 2-cyano-N-arylacetamides 2a-d in the presence of sodium ethoxide
Scheme . Synthetic pathway for pyrimidine--thioglycosides a-d.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
3
for 3 hours to afford the corresponding sodium 2-amino-1-aryl-4-mercapto-6-
oxo-1,6-dihydro-pyrimidine-4-thiolate analogs 5a-d in a relatively quantitative
yields. Treatment of the latter with hydrochloric acid afforded the corresponding
pyrimidine-4-thiol derivatives 6a-d. The structures of compounds 6a-d were estab-
lished and confirmed on the basis of their spectral data (1H-NMR, IR, 13C-NMR)
and elemental analysis. Compounds 6a-d reacted with halosugars 7 in dimethyl
formamide-KOH at room temperature to yield the corresponding S-glycosides
8a–d as outlined in Scheme 1. Compounds 8a-d can also be prepared through the
coupling of pyrimidine-4-thiolate salts 5 with halosugars 7 in dimethylformamide
at room temperature. It has been proposed that the cis-(α) sugars was reacted
by a straightforward SN2 reaction to afford the β-glycoside derivatives.[19] The
structures of 8a-d were confirmed on the basis of their spectral data (IR, 1H-NMR,
13C-NMR) and elemental analysis. The analytical data for 8a showed a molecular
Scheme . Synthetic pathway for pyrimidine--thioglycosides a,b.

4
G. H. ELGEMEIE ET AL.
formula C25H26N4O10S, its 1H-NMR spectrum showing the anomeric proton as a
doublet at δ 5.85–5.87 ppm with a spin-spin coupling constant of 10.00 Hz for the
β-configuration. The other six glucose protons assigned at δ 4.9–5.3 ppm. When
glycosides 8a-d were treated with methanolic ammonia at 0°C, the deprotected
analogs 9a,b were accessed in good yields (Scheme 2), the structures of which were
confirmed by their spectral data and elemental analysis. The analytical data for 9b
show the molecular formula C18H20N4O6S. The 1H NMR spectrum indicates the
anomeric proton as doublet at δ 4.61–4.81 (J1,2 = 10.00 Hz), showing the existence
of only the β-D-configuration. The other six-glucose protons exist as a multiplet
at δ 3.5–4.12 ppm, while the four hydroxy groups of glucose moiety are assigned
at δ 4.35–4.91 ppm (exchangeable by deuterium oxide). Supported by these results,
reaction of dimethyl N-cyanodithioiminocarbonate 10 with cyanothioacetamide 11
in sodium ethoxide yielded the product 12. When the latter was reacted with com-
pound 7, the S-glycoside derivative 13 is formed. Its 1H-NMR spectrum showed the
anomeric proton as a doublet at δ 5.93–5.95 ppm with a spin-spin coupling constant
of 10.00 Hz and a broad band at δ 7.90 ppm which is assignable for an NH2 group.
Scheme . Synthetic pathway for -methylthiopyrimidine--thioglycoside .

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
5
Treatment of 12 with hydrochloric acid afforded the corresponding compound 14.
Another way to access compound 13 was accomplished by reacting compound 14
with the compound 7 in DMF-KOH at room temperature (Scheme 3).
A novel pyrimidobenzothiazole derivative 16 was synthesized by reacting
S,S-dimethyl N-cyanodithioimidocarbonate 10 with 2-cyanomethylbenzo[1,2-
b]thiazole 15 in a dry dioxane solution containing potassium hydroxide at room
Scheme . Synthetic pathway for pyrido[,-a]benzothiazol--thioglycoside .

6
G. H. ELGEMEIE ET AL.
temperature. The structure of 16 was affirmed by its spectral data (1H-NMR, IR,
13C-NMR) and elemental analysis. The mass spectrum of 16 was consistent with
the molecular formula C12H8N4S2 (M+ = 272). The 1H-NMR spectrum showed a
singlet at δ 2.49 ppm assigned to SCH3 group, multiplet at δ 7.54–8.10 ppm des-
ignated for aromatic protons and a broad band at δ 9.30 ppm assigned for an NH
group. The 13C-NMR spectrum was depicted by a signal at δ 12.86 ppm attributed
to SCH3 carbon and a signal at δ 115.12 ppm attributed to the CN carbon. More-
over, a signal appeared at δ 120.54–127.93 ppm corresponding to the aromatic car-
bons, respectively. Sodium cyanocarbonimidodithioate salt 1 was reacted with one
equivalent of 15 in the presence of sodium ethoxide to give compound 17, and
further reaction of 17 with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide 7
yielded 1-imino-3-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-β-D-glucopyranosylthio)-pyrido[6,1-
a]benzothiazol-4-carbonitrile 18 (Scheme 4). The structure of 18 was affirmed by
1
its spectral data and elemental analysis. The H-NMR spectrum indicated a sin-
glet at δ 2.40 ppm assigned to the methylthio group, a multiplet at δ 7.19–7.33 ppm
assignable for aromatic protons, and a broad band at δ 7.90 ppm assigned for
an NH group. The anomeric proton as doublet was shown at δ 6.01–6.03 (J1,2
= 10.00 Hz), showing the existence of only the β-D-configuration. Treatment of
17 with hydrochloric acid afforded the corresponding compound, 3-(mercapto)-
1-imino-pyrido[6,1-a]benzothiazol-4-carbonitrile 19. We obtained compound 18
also by starting with compound 19 and reacting it with 7 in DMF-KOH at room
temperature to give the corresponding S-glycosides (Scheme 4).
Conclusion
A novel and straightforward approach for the synthesis of the cytosine and pyrimi-
dine thioglycoside analogs has been developed from available starting compounds.
Subsequent studies on this innovative method which would represent a major
advance in the glycoside syntheses are under way.
Experimental
Chemistry
All melting points were measured on a Gallenkamp melting point apparatus. The 1H
NMR and 13C NMR spectra were measured on a Jeol-600 MHz and 500 MHz spec-
trometer for solutions DMSO-d6 using Si(CH3)4 as an internal standard at National
Research Center, Cairo, Egypt. The mass spectra was measured in the Cairo Univer-
sity. Progress for the reactions was monitored by TLC using aluminum sheets coated
with silica gel F254 (Merck). Viewing under a short-wavelength UV lamp effected
detection.
General procedure for the synthesis of a-d
A solution of substituted acetanilide derivatives (0.01 mol) and disodium N-
cyanodithioiminocarbonate (0.01 mol) have been refluxed for 3 h in the presence

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
7
of sodium ethoxide (0.01 mol) in absolute ethanol (30 mL). After cooling the reac-
tion mixture to room temperature, it was poured into cooled water and treated with
hydrochloric acid until the medium became just neutral. The resultant precipitate
was collected by filtration and recrystallized.
-Amino--mercapto--oxo--phenyl-,-dihydro-pyrimidine--carbonitrile (a)
Colorless crystals; (EtOH), yield (90%), mp 160°C; IR (KBr, cm-1) υ 3422 (NH2),
1
=
2208 (CN) and 1701 (C O). H-NMR (500 MHz, DMSO-d6): δ 7.38–7.44 (m, 5H,
C6H5), 9.70 (s, 2H, NH2), 11.10 (s, 1H, SH). Anal.Calcd. For C11H8N4OS (244.27):
C, 54.09; H, 3.30; N, 22.94; S, 13.13. Found: C, 54.07; H, 3.30; N, 22.93; S, 13.12.
-Amino--mercapto--oxo--p-tolyl-,-dihydropyrimidine--carbonitrile (b)
Yellow solid; (EtOH), yield (90%), mp 187°C; IR (KBr, cm-1) υ 3375 and 3306
1
(NH2), H-NMR (500 MHz, DMSO-d6): δ 2.35 (s, 3H, CH3), 7.15–7.53 (m, 4H,
C6H4), 9.70 (s, 2H, NH2), 10.70 (s, 1H, SH). Anal.Calcd. For C12H10N4OS (258.30):
C, 55.80; H, 3.90; N, 21.69; S, 12.41. Found: C, 55.80; H, 3.90; N, 21.67; S, 12.40.
-Amino--(-chloro-phenyl)--mercapto--oxo-,-dihydro-pyrimidine--car
bonitrile (c)
Yellow solid; (EtOH), yield (90%), mp 240°C; IR (KBr, cm-1) υ 3453 and 3299
1
=
(NH2), 2209 (CN) and 1658 (C O). H-NMR (500 MHz, DMSO-d6): δ 7.20–7.58
(m, 4H, C6H4), 9.20 (s, 2H, NH2), 11.00 (s, 1H, SH). Anal.Calcd. For C11H7ClN4OS
(278.72): C, 47.40; H, 2.53; Cl, 12.72; N, 20.10; S, 11.50. Found: C, 47.40; H, 2.51; Cl,
12.71; N, 20.10; S, 11.50.
2-Amino-4-mercapto-1-(naphthalen-1-yl)-6-oxo-1,6-dihydro
pyrimidine-5-carbonitrile (6d)
Brown solid; (EtOH), yield (90%), mp 164°C; IR (KBr, cm-1) υ 3322 and 3200
1
=
(NH2), 2193 (CN) and 1670 (C O). H-NMR (500 MHz, DMSO-d6): δ 7.22–7.79
(m, 7H, C10H7), 9.50 (s, 2H, NH2), 10.80 (s, 1H, SH). Anal.Calcd. For C15H10N4OS
(294.33): C, 61.21; H, 3.42; N, 19.04; S, 10.89. Found: C, 61.20; H, 3.41; N, 19.04; S,
10.88.
General procedure for the synthesis of 8a-d
To a solution of 5 (0.01 mol) in dry DMF (20 mL), a solution of 2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-
acetyl-α-D-gluco or -galactopyranosyl bromide 7 (0.01 mol) in dry DMF (10 mL)
was dropped within 30 min. and the reaction mixture was stirred at room temper-
ature until completion (TLC 24h). Then the reaction mixture was poured onto ice
water. A solid product precipitate was filtered off.

8
G. H. ELGEMEIE ET AL.
2-Amino-5-cyano-1-phenyl-1,6-dihydro-4-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-β-D-glucopy
ranosylthio)-pyrimidin-6-one (8a)
Buff solid; (EtOH), yield (75%), mp 186°C; 1H-NMR (500 MHz, DMSO-d6): δ 1.93–
1.95 (4s, 12H, 4xOAc), 4.90 (m, 3H, 2H-6ꢀ and H-5ꢀ), 5.02 (t, 1H, H-4ꢀ), 5.04 (t, 1H,
H-3ꢀ), 5.2–5.3 (t, 1H, H-2ꢀ), 5.85–5.87 (d, 1H, J1 -2 = 10 Hz, H-1ꢀ), 7.28–7.90 (m,
5H, C6H5), 8.62 (s, 2H, NH2). Anal. Calcd. For C25H26N4O10S (574.56): C, 52.26;
H, 4.56; N, 9.75; S, 5.58. Found: C, 52.26; H, 4.56; N, 9.75; S, 5.58.
ꢀ
ꢀ
2-Amino-5-cyano-6-1-p-tolyl-1,6-dihydro-4-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-β-D-glu
copyranosylthio)-pyrimidin-6-one (8b)
White solid; (EtOH), yield (90%), mp 150°C; IR (KBr, cm−1) υ 3448 (NH2), 2184
1
=
(CN) and 1754 (C O). H-NMR (600 MHz, DMSO-d6): δ 1.88–2.29 (4s, 12H,
4xOAc), 2.35 (s, 3H, CH3), 4.05–4.07 (m, 3H, 2H-6ꢀ and H-5ꢀ), 4.3 (t, 1H, H-4ꢀ), 5.04
(t, 1H, H-3ꢀ), 5.2–5.3 (t, 1H, H-2ꢀ), 5.82–5.84 (d, 1H, J1 -2 = 10 Hz, H-1 ), 6.90–7.30
(m, 5H, C6H5), 8.20 (s, 2H, NH2). 13C NMR: δ 19.71–19.95 (4CH3CO), 61.03 (C-
6ꢀ), 67.38 (C-4ꢀ), 67.80 (C-2ꢀ), 73.14 (C-3ꢀ), 74.13 (C-5ꢀ), 82.60 (C-1ꢀ), 118.5 (CN),
128.51 (Ar-C). Anal. Calcd. For C26H28N4O10S (588.59): C, 53.06; H, 4.79; N, 9.52;
S, 5.45. Found: C, 53.04; H, 4.78; N, 9.51; S, 5.45.
ꢀ
ꢀ
ꢀ
2-Amino-1-(4-chloro-phenyl)-5-cyano-1,6-dihydro-4-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-β-
D-glucopyranosylthio)-pyrimidin-6-one (8c)
Buff solid; (EtOH), yield (26%), mp 170°C; IR (KBr, cm-1) υ 3470 and 3300 (NH2),
1
=
2182 (CN) and 1742 (C O). H-NMR (500 MHz, DMSO-d6): δ 1.9–2.02 (4s, 12H,
4xOAc), 3.98–4.16 (m, 3H, 2H-6ꢀ and H-5ꢀ), 4.8 (t, 1H, H-4ꢀ), 4.94–4.96 (t, 1H, H-
3ꢀ), 5.0–5.1 (t, 1H, H-2ꢀ), 5.10–5.30 (d, 1H, J1 -2 = 10 Hz, H-1ꢀ), 7.28–7.55 (m, 5H,
C6H5), 8.8 (s, 2H, NH2). Anal. Calcd. For C25H25ClN4O10S (609.00): C, 49.30; H,
4.14; Cl, 5.82; N, 9.20; S, 5.27. Found: C, 49.30; H, 4.13; Cl, 5.81; N, 9.20; S, 5.27.
ꢀ
ꢀ
2-Amino-5-cyano-1-naphthalen-1-yl-1,6-dihydro-4-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-β-
D-glucopyranosylthio)-pyrimidin-6-one (8d)
Brown solid; (EtOH), yield (24%), mp 200°C; 1H-NMR (500 MHz, DMSO-d6): δ
1.90–2.40 (4s, 12H, 4xOAc), 3.98–4.13 (m, 3H, 2H-6ꢀ and H-5ꢀ), 4.9–5.1 (t, 1H,
H-4ꢀ), 5.12–5.3 (d, 1H, J1 -2 = 10 Hz, H-1ꢀ), 5.34 (t, 1H, H-3ꢀ), 5.6–5.8 (t, 1H, H-
2ꢀ), 7.35–8.05 (m, 8H, C10H8), 8.5 (s, 2H, NH2). Anal.Calcd. For C29H28N4O10S
(624.62): C, 55.76; H, 4.52; N, 8.97; S, 5.13. Found: C, 55.76; H, 4.52; N, 8.97; S, 5.13.
ꢀ
ꢀ
General procedure for the synthesis of 9a-b
A solution of compounds 8 (0.01 mol) in anhydrous MeOH (10 mL) was added at
0°C to a saturated solution of anhydrous NH3 in anhydrous MeOH (25 mL). Mixture

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
9
was stirred at 0°C for 7 h and then crystallized from EtOH to furnish an analytically
pure compound 9.
2-Amino-5-cyano-1-phenyl-1,6-dihydro-4-(β-D- glucopyranosyl–thio)-pyrimidin-
6-one (9a)
1
White solid; (EtOH), yield (70%), mp 222°C; H-NMR (500 MHz, DMSO-d6): δ
3.44–3.67 (s, 2H, H-5ꢀ, H-6ꢀ), 3.71 (s, 1H, H-4ꢀ), 3.96 (s, 1H, H-3ꢀ), 4.10 (s, 1H, H-2ꢀ),
4.30–4.36 (s, 2H, 2ꢀ-OH, 3ꢀ-OH), 4.58–4.66 (d, 1H, J1 -2 = 10 Hz, H-1ꢀ), 4.87–4.90
(d, 2H, 4ꢀ-OH, 6ꢀ-OH), 6.82 (s, br, 2H, NH2), 7.34–7.56 (m, 5H, C6H5). Anal.Calcd.
For C17H18N4O6S (406.09): C, 50.24; H, 4.46; N, 13.79; S, 7.89. Found: C, 50.24; H,
4.46; N, 13.77; S, 7.87.
ꢀ
ꢀ
2-Amino-5-cyano-6-1-p-tolyl-1,6-dihydro-4-(β-D-glucopyran–osylthio)-
pyrimidin-6-one (9b)
Yellow solid; (EtOH), yield (67%), mp 180°C; 1H-NMR (500 MHz, DMSO-d6): 1H-
NMR (500 MHz, DMSO-d6): δ 2.66 (s, 3H, CH3), 3.51–3.69 (s, 2H, H-5ꢀ, H-6ꢀ), 3.79
(s, 1H, H-4ꢀ), 3.91 (s, 1H, H-3ꢀ), 4.12 (s, 1H, H-2ꢀ), 4.35–4.38 (s, 2H, 2ꢀ-OH, 3ꢀ-OH),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
4.61–4.81 (d, 1H, J1 -2 = 10 Hz, H-1 ), 4.91 (d, 2H, 4 -OH, 6 -OH), 6.76 (s, 2H, NH2),
7.34–7.56 (m, 4H, C6H4). Anal.Calcd. For C18H20N4O6S (420.44): C, 51.42; H, 4.79;
N, 13.33; S, 7.63. Found: C, 51.41; H, 4.79; N, 13.33; S, 7.62.
General procedure for the synthesis of 13,14
A solution of cyanothioacetamide (0.01 mol) and dimethyl N-cyanodi
thioiminocarbonate (0.01 mol) was heated (50–60°C) for 1 h in the presence
of sodium ethoxide (0.01 mol) in absolute ethanol. To a solution of 12 in dry DMF
(20 mL), a solution of 2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-α-D-glucopyranosyl bromide 7
(0.01 mol) in dry DMF (10 mL) was dropped within 30 min. and the reaction
mixture was stirred at room temperature until completion (TLC 24h). The reaction
mixture was poured onto ice water. Then a solid product 13 precipitate was filtered
off and crystallized. When the solution of 12 (0.01 mol) was poured onto cold water.
The mixture was treated with hydrochloric acid until just neutral, then the formed
solid 14 was collected by filtration.
2-Amino-6-methylthio-4-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-β-D-glu–copyranosylthio)-py
rimidine-5-carbonitrile (13)
Brown solid; (DMF), yield (20%), mp 200°C; IR (KBr, cm-1) υ 3436 and 3367 (NH2),
1
=
2211 (CN) and 1754 (C O). H-NMR (500 MHz, DMSO-d6): δ 1.9–2.8 (4s, 12H,
4xOAc), 4.01–4.08 (m, 3H, 2H-6ꢀ and H-5ꢀ), 4.9 (t, 1H, H-4ꢀ), 5.02 (t, 1H, H-3ꢀ), 5.6–
5.8 (t, 1H, H-2ꢀ), 5.93–5.95 (d, 1H, J1 -2 = 10 Hz, H-1 ), 7.9 (s, 2H, NH2). Anal.Calcd.
ꢀ
ꢀ
ꢀ

10
G. H. ELGEMEIE ET AL.
For C20H24N4O9S2 (528.56): C, 45.45; H, 4.58; N, 10.60; S, 12.13. Found: C, 45.44;
H, 4.57; N, 10.60; S, 12.11.
2-Amino-4-mercapto-6-(methylthio)-pyrimidine-5-carbo-nitrile (14)
Brown solid; (EtOH), yield (20%), mp 170°C; IR (KBr, cm-1) υ 3470 and 3300
1
=
(NH2), 2182 (CN) and 1742 (C O). H-NMR (500 MHz, DMSO-d6): δ 2.40 (s, 3H,
SCH3), 7.80 (s, 2H, NH2), 9.83 (s, 1H, SH). Anal.Calcd. For C6H6N4S2 (198.27): C,
36.35, H, 3.05; N, 28.26; S, 32.35. Found: C, 36.34; H, 3.04; N, 28.26; S, 32.35.
General procedure for the synthesis of 16–19
Dimethyl N-cyanodithioiminocarbonate (0.01 mol) was added to a stirred solu-
tion of 2-cyanomethylbenzo[1,2-b]thiazole 15 (0.01 mol) in a dry dioxane con-
taining potassium hydroxide (0.01 mol). After stirring 1 h at room temperature,
the product 16 was filtered and recrystallized from the appropriate solvent. Com-
pound 15 (0.01 mol) was refluxed with disodium N-cyanodithioiminocarbonate 1
(0.01 mol) for 3 h in the presence of sodium ethoxide (0.01 mol) in absolute alcohol
(30 mL) to yield 17. To a solution of the latter (0.01 mol) in the presence of dry DMF
(20 mL), a solution of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide 7 in dry
DMF (10 mL) was dropped within 30 min. and the reaction mixture was stirred at
room temperature until completion (TLC 24h). Then the product 18 is extracted
from the reaction mixture by using ethyl acetate. It is worthy to note that by pour-
ing compound 17 (0.01 mol) on cold water and treating it with hydrochloric acid
until the medium became just neutral, compound 19 was formed and collected by
filtration.
3-(Methylthio)-1-imino-pyrido[6,1-a]benzothiazol-4-carbonitrile (16)
Yellow solid; (DMF), yield (97%), mp 230°C; IR (KBr, cm-1) υ 3433 (NH), and
2210 (CN). 1H-NMR (600 MHz, DMSO-d6): δ 2.49 (s, 3H, SCH3), 7.54–8.10 (m,
4H, C6H4), 9.30 (bs, 1H, NH). 13C-NMR (DMSO) δ 12.86 (SCH3), 115.12 (CN),
138.36–164.34 (Hetero-Ar-C), 120.54–127.93 (Ar-C). MS: m/z = 272. Anal.Calcd.
For C12H8N4S2 (272.35): C, 52.92; H, 2.96; N, 20.57; S, 23.55. Found: C, 52.91; H,
2.95; N, 20.57; S, 23.55.
1-Imino-3-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-β-D-glucopyranosylthio)-pyrido[6,1-a]benz
othiazol-4-carbonitrile (18)
Buff solid; (EtOH), yield (10%), mp 128°C; 1H-NMR (500 MHz, DMSO-d6): δ 1.94–
1.96 (4s, 12H, 4xOAc), 2.40 (s, 3H, SCH3), 3.93–4.2 (m, 3H, H-6ꢀ and H-5ꢀ), 4.93
(t, 1H, H-4ꢀ), 5.11 (t, 1H, H-3ꢀ), 5.33 (t, 1H, H-2ꢀ), 6.01–6.03 (d, 1H, J1 -2 = 10 Hz,
ꢀ
ꢀ
H-1ꢀ), 7.19–7.33 (m, 4H, C6H4), 7.9 (s, 1H, NH). Anal.Calcd. For C25H24N4O9S2

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
11
(528.56): C, 51.01; H, 4.11; N, 9.52; S, 10.90. Found: C, 51.00; H, 4.11; N, 9.51; S,
10.90.
3-(Mercapto)-1-imino-pyrido[6,1-a]benzothiazol-4-carbonitrile (19)
Orange solid; (EtOH), yield (90%), mp 120°C; IR (KBr, cm−1) υ 3427 (NH), 2196
=
(CN), 2920 and 1623 (C O). Anal.Calcd. For C11H6N4S2 (258.32): C, 51.14; H, 2.34;
N, 21.69; S, 24.83. Found: C, 51.14; H, 2.34; N, 21.69; S, 24.83.
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