An approach to acyclo-3-deazapyrimidine S-nucleosides via 3,5-dicyano-2(1H)-pyridinethiones

Article abstract of DOI:10.1016/S0040-4020(03)00113-3

A series of different acyclo-3-deazapyrimidine nucleosides have been synthesized. The site of glycosylation was confirmed by ¹³C NMR spectroscopy.

Full text of DOI:10.1016/S0040-4020(03)00113-3

Tetrahedron 59 (2003) 1749–1752
An approach to acyclo-3-deazapyrimidine S-nucleosides
via 3,5-dicyano-2(1H)-pyridinethiones
b
Adel M. E. Attiaa and Abd El-Hamid A. A. Ismail
,
*
aDepartment of Chemistry, Faculty of Education, University of Tanta (Kafr El-Sheikh Branch) 33516, Egypt
bDepartment of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koom, Egypt
Received 19 August 2002; revised 20 December 2002; accepted 16 January 2003
Abstract—A series of different acyclo-3-deazapyrimidine nucleosides have been synthesized. The site of glycosylation was confirmed by
13C NMR spectroscopy. q 2003 Published by Elsevier Science Ltd.
Since the discovery of the utility of 30-azido-30-deoxy-
thymidine (AZT)1 and 20,30-dideoxyinosine (DDI)2 as
antiretroviral agents in spite of their toxic side effects,3,4
the synthesis of other drugs has been desirable. Recently,
a new class of anti-HIV agents has been identified. These
compounds like 1-[(2-hydroxyethoxy)methyl]-6-(phenyl-
thio)-thymine (HEPT)5,6 and 6-benzyl-1-(ethoxymethyl)-
5-isopropyluracil (MKC-442),7,8 show a high selectivity
for the HIV-1 reverse transcriptase. As part of our program
of research on the synthesis of new thiopyrimidine and
thiopyridine cyclic glycosides9–13 with considerable anti-
viral activity, we report here the synthesis of a new class of
acyclo-3-deazapyrimidine S-nucleosides related to HEPT
and MKC-442. As far as we know this is the first coupling
reaction of this type to be reported for pyridinethiones.
1.1 equiv. of sodium hydride in dry dimethylformamide
followed by 1.1 equiv. of the chloromethyl ethyl ether 6.
In all cases the yields were in the range of 75–82%.
The site of attachment of the alkyl substituent to the
heterocyclic bases was concluded from their 13C NMR
spectral comparison with known structurally proven pyri-
dine analogues. Thus, the observed shift of C-2 (163.2 ppm)
in the 13C NMR spectrum of the pyridine derivative 5a
clearly shown glycosidation on a sulfur atom and not on the
nitrogen of 2-thiopyridines when compared with 13C NMR
spectra of S-methylated thiopyridine derivatives.15,16
Deprotection of the hydroxy groups in the nucleosides
5a–d with ammonia in methanol afforded the free acyclic
nucleosides 8a–d in 85–90% yield after crystallization
from methanol. The structure of 8b has been proved by
1H NMR and 13C NMR spectroscopy in DMSO solution.
A strong downfield shift of the C-2 signal (162.8 ppm) is an
unequivocal indication of the position of alkylation as well
Thus it has been found that arylidenemalononitriles and
arylidenecyanoacetates 1a–d reacted with 2-cyanothio-
acetamide 2 in refluxing ethanol containing a catalytic
amount of piperidine to give 3,5-dicycano-2(1H)-pyridine-
thiones 3a–d in good yields after crystallization from
absolute ethanol. The structures of the reaction products
3 were supported by their elemental analysis and spectral
data (see Section 1). Compounds 3 can be coupled with
different classes of acyclo sugars to give a novel series of
acyclonucleosides. For example, 3 reacted with (2-acetoxy-
ethoxy) methyl bromide14 4 in the presence of sodium
hydride in dry dimethylformamide at 08C to yield the
corresponding 3,5-dicyano-2-[(2-acetoxyethoxy) methyl]
pyridines 5a–d after chromatographic purification. For the
synthesis of 3,5-dicyano-2-[(ethoxy) methyl] pyridines
7a–d, compounds 3a–d were likewise treated with
1
as of the disappearance of the acetoxy protons in its H
NMR spectrum (see Section 1).
In summary, the alkylation reactions of 3,5-dicyano-2(1H)-
pyridinethiones with different classes of acyclic sugar
halides provides a novel approach for the synthesis of
precursors of some pyridine S-nucleosides. The obtained
pyridine acyclonucleosides are now under biological
evaluation (Scheme 1).
1. Experimental
1.1. General
Keywords: S-nucleosides; pyridinethiones; acyclonucleoside.
*
Melting points are uncorrected. Aluminum-coated silica
gel60 F254 (Merck) sheets were used for thin layer
Corresponding author. Tel./fax: þ20-47-223415;
e-mail: adelmattia@hotmail.com; attia-a@edu-kaf.edu.eg
0040–4020/03/$ - see front matter q 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4020(03)00113-3

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A. M. E. Attia, A. E.-H. A. A. Ismail / Tetrahedron 59 (2003) 1749–1752
Scheme 1.
chromatography. IR (KBr) spectra were collected in the
transmission mode on a Pye Unicam Spectra-1000 spectro-
meter. 1H and 13C NMR spectra were measured in DMSO-
d6 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.
nitriles 1 (0.01 mol) and 2-cyanothioacetamide 2 (0.01 mol)
in dry ethanol (30 mL), a few drops of piperidine were
added. The reaction mixture was refluxed for a variable
length of time (8–12 h) until the starting material was
exhausted and a solid had been precipitated. It was filtered
off and recrystallized from absolute ethanol to afford the
title compounds 3a–d.
1.1.1. 3,5-Dicyano-4-aryl-2(1H)-pyridinethiones (3).
General procedure. To a suspension of 2-cyanocinnamo-
Compound 3a. Yield 68% as yellow crystals, mp 2328C.
[Found: C, 56.64; H, 3.59; N, 18.95 C14H10N4SO2 requires

A. M. E. Attia, A. E.-H. A. A. Ismail / Tetrahedron 59 (2003) 1749–1752
1751
C, 56.38; H, 3.36; N, 18.79%]; nmax 3450–3180 (OH, NH2
and NH), 2218 (CN) cm21; dH (DMSO-d6) 3.92 (3H, s,
OCH3), 7.67–7.74 (3H, m, Ar-H), 7.87 (1H, s, NH), 8.34
(2H, s, NH2), 9.78 (1H, s, OH); dC (DMSO-d6) 55.6
(OCH3), 101.8 (C5), 112.6 (C3), 115.2 (CN), 116.1 (CN),
121.4–148.2 (Ar-C), 155.7 (C4), 157.3 (C6), 182.4 (C2);
m/z 298.
Compound 5b. Yield 76% as white crystals, mp 1698C.
[Found: C, 55.46; H, 4.57; N, 13.79 C19H18N4SO5 requires
C, 55.07; H, 4.35; N, 13.53%]; nmax 3480–3240 (OH and
NH2), 2215 (CN), 1738 (CO) cm21; dH (DMSO-d6) 2.01
(3H, s, CH3CO), 3.85 (3H, s, OCH3), 4.25 (2H, t, J¼5.0 Hz,
2H-30), 4.84 (2H, t, J¼5.0 Hz, 2H-40), 5.80 (2H, s, 2H-10),
7.05–7.14 (3H, m, Ar-H), 7.98 (2H, s, NH2), 9.44 (1H, s,
OH); dC (DMSO-d6) 20.8 (CH3), 55.5 (OCH3), 62.8 (C40),
67.3 (C30), 81.4 (C10), 102.2 (C5), 111.7 (C3), 115.1 (CN),
116.7 (CN), 119.5–149.6 (Ar-C), 154.4 (C4), 158.3 (C6),
163.5 (C2), 170.9 (CO); m/z 414.
Compound 3b. Yield 70% as yellow crystals, mp 2088C.
[Found: C, 56.71; H, 3.52; N, 19.06 C14H10N4SO2) requires
C, 56.38; H, 3.36; N, 18.79%]; nmax 3470–3200 (OH, NH2
and NH), 2220 (CN) cm21; dH (DMSO-d6) 3.96 (3H, s,
OCH3), 7.62–7.71 (3H, m, Ar-H), 7.86 (1H, s, NH), 8.28
(2H, s, NH2), 9.70 (1H, s, OH); dC (DMSO-d6) 55.5
(OCH3), 101.9 (C5), 112.2 (C3), 115.4 (CN), 116.1 (CN),
121.8–149.2 (Ar-C), 154.8 (C4), 158.0 (C6), 182.1 (C2);
m/z 298.
Compound 5c. Yield 75% as white crystals, mp 1508C.
[Found: C, 55.31; H, 4.36; N, 10.40 C19H17N3SO6 requires
C, 54.94; H, 4.10; N, 10.12%]; nmax 3420–3280 (OH), 2210
(CN), 1740 (CO) cm21; dH (DMSO-d6) 2.04 (3H, s,
CH3CO), 3.86 (3H, s, OCH3), 4.31 (2H, t, J¼4.8 Hz,
2H-30), 4.94 (2H, t, J¼4.8 Hz, 2H-40), 5.70 (2 H, s, 2H-10),
7.09–7.18 (3H, m, Ar-H), 8.68 (1H, s, OH), 9.46 (1H, 0s,
OH); dC (DMSO-d6) 20.5 (CH3), 55.6 (OCH3), 61.9 (C4 ),
64.6 (C30), 87.1 (C10), 94.9 (C5), 111.8 (C3), 115.0 (CN),
115.4 (CN), 119.9–148.4 (Ar-C), 158.1 (C4), 159.7 (C6),
163.1 (C2), 170.2 (CO); m/z 415.
Compound 3c. Yield 66% as yellow crystals, mp 1988C.
[Found: C, 56.61; H, 3.23; N, 14.39 C14H9N3SO3 requires
C, 56.19; H, 3.01; N, 14.05%]; nmax 3450–3190 (OH and
NH), 2215 (CN) cm21; dH (DMSO-d6) 3.88 (3H, s, OCH3),
7.10–7.18 (3H, m, Ar-H), 7.68 (1H, s, NH), 8.48 (1H, s,
OH), 9.14 (1H, s, OH); dC (DMSO-d6) 55.4 (OCH3), 101.7
(C5), 111.6 (C3), 115.2 (CN), 116.3 (CN), 119.4–148.7
(Ar-C), 156.0 (C4), 156.8 (C6), 183.4 (C2); m/z 299.
Compound 5d. Yield 77% as white crystals, mp 1288C.
[Found: C, 55.37, H, 4.29; N, 10.43 C19H17N3SO6 requires
C, 54.94; H, 4.10; N, 10.12%]; nmax 3410–3260 (OH), 2212
(CN) cm21; dH (DMSO-d6) 2.09 (3H, s, CH3CO), 3.82 (3H,
s, OCH3), 4.30 (2H, t, J¼5.2 Hz, 2H-30), 4.98 (2H, t, J¼
5.2 Hz, 2H-40), 5.54 (2H, s, 2H-10), 7.11–7.21 (3H, m,
Ar-H), 8.96 (1H, s, OH), 9.71 (1H, s, OH); dC (DMSO-d6)
20.7 (CH3), 55.7 (OCH3), 61.9 (C40), 68.4 (C30), 83.0 (C10),
98.1 (C5), 112.2 (C3), 115.4 (CN), 115.6 (CN), 121.1–
147.9 (Ar-C), 157.5 (C4), 158.6 (C6), 163.2 (C2), 170.8
(CO); m/z 415.
Compound 3d. Yield 65% as yellow crystals, mp 2208C.
[Found: C, 56.58; H, 3.24; N, 14.37 C14H9N3SO3 requires
C, 56.19; H, 3.01; N, 14.05%]; nmax 3430–3180 (OH and
NH), 2222 (CN) cm21; dH (DMSO-d6) 3.90 (3H, s, OCH3),
7.12–7.21 (3H, m, Ar-H), 7.49 (1H, s, NH), 8.14 (s, 1H,
OH), 9.44 (1H, s, OH); dC (DMSO-d6) 55.6 (OCH3), 101.9
(C5), 112.6 (C3), 115.1 (CN), 116.3 (CN), 121.4–148.1
(Ar-C), 155.9 (C4), 157.1 (C6), 182.5 (C2); m/z 299.
1.1.2. 3,5-Dicyano-4-aryl-2-[(2-acetoxyethoxy)methyl]
pyridines (5). General procedure. To a stirred solution of
pyridinethiones 3 (1 mmol) in dry dimethylformamide
(25 mL) was added (1.1 mmol) of sodium hydride. After
evolution of hydrogen had ceased, the mixture was cooled to
2108C and a solution of (2-acetoxyethoxy) methyl bromide
4 (1.1 mmol) in DMF (5 mL) was added slowly. The stirred
mixture was allowed to warm slowly to room temperature
over a period of 2 h, 0.5 mL of 1 M NaHCO3 (aq) was
added, and volatile materials were evaporated in vacuo.
The residue was applied to a silica gel column and elution
with chloroform–methanol (19:1) afforded the desired
nucleosides as a white solid, which then were recrystallized
from chloroform–petroleum ether 40–60 to give the title
compounds 5a–d.
1.1.3. 3,5-Dicyano-4-aryl-2-[(ethoxy) methyl] pyridines
(7). General procedure. To a stirred solution of pyridine-
thiones 3 (1 mmol) in dry dimethylformamide (25 mL) was
added (1.1 mmol) of sodium hydride. After evolution of
hydrogen had ceased, the mixture was cooled to 08C and a
solution of ethoxymethyl chloride 6 (1.1 mmol) in DMF
(5 mL) was added slowly. The stirred mixture was allowed
to warm slowly to room temperature over a period of 3 h
and then quenched with saturated NaHCO3 (20 mL).
The aqueous phase was extracted with CHCl3 (2£20 mL).
The organic phase was dried (MgSO4) and evaporated under
reduced pressure. The product was purified by silica gel
column chromatography (50% EtOAc–PE) to give the title
compounds 7a–d.
Compound 7a. Yield 82% as white crystals, mp 1468C.
[Found: C, 57.58; H, 4.73; N, 15.99 C17H16N4SO3 requires
C, 57.30; H, 4.49; N, 15.73%], nmax 3450–3230 (OH and
NH2), 2218 (CN) cm21; dH (DMSO-d6) 1.13 (3H, t, J¼
6.8 Hz, CH3), 3.84 (3H, s, OCH3), 4.60 (2H, q, J¼6.8 Hz,
OCH2), 5.52 (2H, s, SCH2), 7.07–7.20 (3H, m, Ar-H), 7.95
(2H, s, NH2), 9.73 (1H, s, OH); m/z 356.
Compound 5a. Yield 78% as white crystals, mp 1598C.
[Found: C, 55.39; H, 4.60; N, 13.88 C19H18N4SO5 requires
C, 55.07; H, 4.35; N, 13.53%]; nmax 3450–3220 (OH and
NH2), 2214 (CN), 1736 (CO) cm21; dH (DMSO-d6) 2.03
(3H, s, CH3CO), 3.88 (3H, s, OCH3), 4.32 (2H, t, J¼4.7 Hz,
2H-30), 4.93 (2H, t, J¼4.7 Hz, 2H-40), 5.67 (2 H, s, 2H-10),
7.08–7.22 (3H, m, Ar-H), 8.02 (2H, s, NH2), 9.66 (1H, s,
OH); dC (DMSO-d6) 20.6 (CH3), 55.8 (OCH3), 61.9 (C40),
64.6 (C30), 79.8 (C10), 94.8 (C5), 112.9 (C3), 115.2 (CN),
115.9 (CN), 121.7–157.5 (Ar-C), 158.1 (C4), 159.7 (C6),
163.2 (C2), 170.1 (CO); m/z 414.
Compound 7b. Yield 80% as white crystals, mp 1238C.
[Found: C, 57.61; H, 4.70; N, 16.05 C17H16N4SO3 requires
C, 57.30; H, 4.49; N, 15.73%]; nmax 3390–3210 (OH and
NH2), 2215 (CN) cm21; dH (DMSO-d6) 1.18 (3H, t,

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A. M. E. Attia, A. E.-H. A. A. Ismail / Tetrahedron 59 (2003) 1749–1752
J¼7.1 Hz, CH3), 3.88 (3H, s, OCH3), 4.54 (2H, q, J¼
7.1 Hz, OCH2), 5.46 (2H, s, SCH2), 7.06–7.15 (3H, m,
Ar-H), 7.90 (2H, s, NH2), 9.48 (1H, s, OH); dC (DMSO-d6)
13.8 (CH3), 55.5 (OCH3), 69.6 (OCH2), 83.8 (SCH2), 94.9
(C5), 111.8 (C3), 115.1 (CN), 115.5 (CN), 120.8–149.1
(Ar-C), 155.3 (C4), 157.0 (C6), 162.9 (C2); m/z 356.
[Found: C, 54.96; H, 4.27; N, 11.55 C17H15N3SO5 requires
C, 54.69; H, 4.02; N, 11.26%]; nmax 3420–3230 (OH), 2212
(CN) cm21; dH (DMSO-d6) 3.68 (2H, t, J¼5.2 Hz, 2H-30),
3.88 (3H, s, OCH3), 4.08 (2H, t, J¼5.2 Hz, 2H-40), 4.56 (1H,
s, OH), 5.82 (2H, s, 2H-10), 7.18–7.25 (3H, m, Ar-H), 8.64
(1H, s, OH), 9.42 (1H, s, OH); m/z 373.
Compound 7c. Yield 80% as white crystals, mp 1528C.
[Found: C, 57.49; H, 4.38; N, 12.03 C17H15N3SO4 requires
C, 57.14; H, 4.20; N, 11.76%]; nmax 3420–3215 (OH), 2220
(CN) cm21; dH (DMSO-d6) 1.17 (3H, t, J¼7.0 Hz, CH3),
3.85 (3H, s, OCH3), 4.62 (2H, q, J¼7.0 Hz, OCH2), 5.53
(2H, s, SCH2), 7.15–7.24 (3H, m, Ar-H), 8.64 (1H, s, OH),
9.71 (1H, s, OH); m/z 357.
Compound 8d. Yield 88% as white crystals, mp 1888C.
[Found: C, 55.04; H, 4.20; N, 11.49 C17H15N3SO5 requires
C, 54.69; H, 4.02; N, 11.26%]; nmax 3410–3200 (OH), 2214
(CN) cm21; dH (DMSO-d6) 3.74 (2H, t, J¼5.4 Hz, 2H-30),
3.85 (3H, s, OCH3), 3.98 (2H, t, J¼5.4 Hz, 2H-40), 4.55 (1H,
s, OH), 5.80 (2H, s, 2H-10), 7.23–7.34 (3H, m, Ar-H), 8.72
(1H, s, OH), 9.51 (1H, s, OH); m/z 373.
Compound 7d. Yield 81% as white crystals, mp 1708C.
[Found: C, 57.53; H, 4.42; N, 11.99 C17H15N3SO4 requires
C, 57.14; H, 4.20; N, 11.76%]; nmax 3460–3280 (OH), 2216
(CN) cm21; dH (DMSO-d6) 1.20 (3H, t, J¼6.9 Hz, CH3),
3.80 (3H, s, OCH3), 4.68 (2H, q, J¼6.9 Hz, OCH2), 5.56
(2H, s, SCH2), 7.08–7.17 (3H, m, Ar-H), 8.96 (1H, s, OH),
9.46 (1H, s, OH); dC (DMSO-d6) 13.9 (CH3), 55.7 (OCH3),
68.4 (OCH2), 82.3 (SCH2), 98.4 (C5), 112.6 (C3), 115.4
(CN), 116.1 (CN), 119.9–149.2 (Ar-C), 154.4 (C4), 158.1
(C6), 163.3 (C2); m/z 357.
References
1. Matsuya, H.; Weinhold, K. J.; Furman, P. A.; Clair, M. H.;
Lehrman, S. N.; Gallo, R. C.; Bolognesi, D.; Barry, D. W.;
Broder, S. Proc. Natl Acad. Sci. USA 1985, 82, 7096.
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1.1.4. 3,5-Dicyano-4-aryl-2-[(2-hydroxyethoxy) methyl]
pyridines (8). General procedure. Saturated ammonia in
methanol (20 mL) was added with stirring to a solution of 5
(2 mmol) in methanol (10 mL) at 08C. The mixture was
stirred at 08C for 4 h and then at room temperature for 12 h
(monitored by TLC analysis). Volatile materials were
evaporated in vacuo and the resulting solid was recrystal-
lized from methanol to give analytically pure compounds
8a–d.
5. Miyasaka, T.; Tanaka, H.; Baba, M.; Hayakawa, H.; Walker,
R. T.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1989, 32,
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6. Baba, M.; Tanaka, H.; De Clercq, E.; Pauwels, R.; Balzarini,
J.; Schols, D.; Nakashima, H.; Perno, C. F.; Walker, R. T.;
Miyasaka, T. Biochem. Biophys. Res. Commun. 1989, 165,
1375.
Compound 8a. Yield 88% as white crystals, mp 1998C.
[Found: C, 55.23; H, 4.51; N, 15.39 C17H16N4SO4 requires
C, 54.84; H, 4.30; N, 15.05%]; nmax 3380–3220 (OH and
NH2), 2213 (CN) cm21; dH (DMSO-d6) 3.58 (2H, t, J¼
4.8 Hz, 2H-30), 3.86 (3H, s, OCH3), 4.12 (2H, t, J¼4.8 Hz,
2H-40), 4.60 (1H, s, OH), 5.78 (2H, s, 2H-10), 7.13–7.22
(3H, m, Ar-H), 8.08 (2H, s, NH2), 9.49 (1H, s, OH); m/z 372.
7. Yuasa, S.; Sadakata, Y.; Takashima, H.; Sekiya, K.; Inouye,
N.; Ubasawa, M.; Baba, M. Mol. Pharmacol. 1993, 44, 895.
8. Baba, M.; Shigeta, S.; Yuasa, S.; Takashima, H.; Sehiya, K.;
Ubasawa, M.; Tanaka, H.; Miyasaka, T.; Walker, R. T.; De
Clercq, E. Antimicrob. Agents Chemother. 1994, 38, 688.
9. Strekowski, L.; Abdou, I. M.; Attia, A. M.; Patterson, S. E.
Tetrahedron Lett. 2000, 41, 4757.
Compound 8b. Yield 87% as white crystals, mp 2268C.
[Found: C, 55.19; H, 4.44; N, 15.36 C17H16N4SO4 requires
C, 54.84; H, 4.30; N, 15.05%]; nmax 3400–3210 (OH and
NH2), 2215 (CN) cm21; dH (DMSO-d6) 3.66 (2H, t, J¼
4.9 Hz, 2H-30), 3.90 (3H, s, OCH3), 4.05 (2H, t, J¼4.9 Hz,
2H-40), 4.82 (1H, s, OH), 5.74 (2H, s, 2H-10), 7.19–7.28
(3H, m, Ar-H), 8.12 (2H, s, NH2), 9.40 (1H, s, OH); dC
(DMSO-d6) 55.2 (OCH3), 59.9 (C40), 70.5 (C30), 76.8 (C10),
101.8 (C5), 110.3 (C3), 115.3 (CN), 116.4 (CN), 120.6–
146.8 (Ar-C), 155.4 (C4), 158.0 (C6), 162.8 (C2); m/z 372.
10. Abdou, I. M.; Attia, A. M.; Strekowski, L. Nucleosides,
Nucleotides Nucleic Acids 2002, 21, 15.
11. Attia, A. M. Tetrahedron 2002, 58, 1399.
12. Attia, A. M. Nucleosides, Nucleotides Nucleic Acids 2002, 21,
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13. Attia, A. M.; Elgemeie, G. H. Carbohydr. Chem. 2002, 21,
325.
14. Robins, M. J.; Hatfield, P. W. Can. J. Chem. 1982, 60, 547.
15. Still, W. J.; Plavac, N.; McKinnon, D. M.; Chauhan, M. S.
Can. J. Chem. 1976, 54, 280.
Compound 8c. Yield 89% as white crystals, mp 1908C.
16. Stefaniak, L. Org. Magn. Reson. 1979, 12, 379.