Glucopyranosides derived from 6-aryl-5-cyano-2-(methylthio)pyrimidin-4(3H)ones

Article abstract of DOI:10.1081/NCN-120006527

The reaction of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide with a 6-aryl-5-cyano-2-(methylthio)pyrimidin-4(3H)one in aqueous acetone in the presence of KOH furnishes a 4-(β-D-glucopyranosyloxy)pyrimidine and a 3-(β-D-glucopyranosyl)pyrimidine as the major and minor product, respectively.

Full text of DOI:10.1081/NCN-120006527

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Glucopyranosides Derived From 6-Aryl-5-Cyano-2-
(
Methylthio)Pyrimidin-4(3H)Ones
a a a a
Ibrahim M. Abdou , Adel M. Attia & Lucjan Strekowski
a
Department of Chemistry, Georgia State University, Atlanta, Georgia, 30303, U.S.A.
Version of record first published: 17 Aug 2006
To cite this article: Ibrahim M. Abdou, Adel M. Attia & Lucjan Strekowski (2002): Glucopyranosides Derived From 6-Aryl-5-
Cyano-2-(Methylthio)Pyrimidin-4(3H)Ones, Nucleosides, Nucleotides and Nucleic Acids, 21:1, 15-21
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 21(1), 15–21 (2002)
GLUCOPYRANOSIDES DERIVED FROM
-ARYL-5-CYANO-2-(METHYLTHIO)PYRIMIDIN-
6
4(3H)ONES
y
z
Ibrahim M. Abdou,* Adel M. Attia, and Lucjan Strekowski
Department of Chemistry, Georgia State University,
Atlanta, Georgia 30303, USA
ABSTRACT
The reaction of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide with a
-aryl-5-cyano-2-(methylthio)pyrimidin-4(3H)one in aqueous acetone in
6
the presence of KOH furnishes a 4-(b-D-glucopyranosyloxy)pyrimidine
and a 3-(b-D-glucopyranosyl)pyrimidine as the major and minor product,
respectively.
INTRODUCTION
Synthesis of nucleosides of 6-substituted pyrimidine-4(3H)ones includ-
ing 6-substituted uracils has mostly been conducted under electrophilic
1
conditions. The reactions of multi-centered anions derived from the 6-sub-
stituted pyrimidinone substrates with an activated sugar have received rela-
tively little attention, in spite of the fact that such glycosidation reactions can
be remarkably regioselective. For example, O-peracetyl derivatives of N3-
(
b-D-glucopyranosyl-, N3-(b-D-galactopyranosyl-, and N3-(b-D-xylopyr-
anosyl-6-methyl-2-(methylthio)pyrimidin-4(3H)one have been obtained
*Current address: Chemistry Department, College of Science, UAE University, Al-Ain,
United Arab Emirates.
y
Current address: Chemistry Department, Faculty of Education, Tanta University, Kafr
El-Sheikh, Egypt.
z
Corresponding author. E-mail: Lucjan@gsu.edu
15
Copyright # 2002 by Marcel Dekker, Inc.
www.dekker.com

16
ABDOU, ATTIA, AND STREKOWSKI
by the reaction of 6-methyl-2-(methylthio)pyrimidin-4(3H)one with the
corresponding O-peracetyl-a-bromo sugar under basic conditions. The ana-
logous reactions of 5-bromo-6-methyl-2-(methylthio)pyrimidin-4(3H)one are
2,3
also N3-regioselective. Recently, we have also reported an efficient synthesis
of 6-aryl-5-cyano-1-(b-D-pyranosyl or b-D-furanosyl)-2-thiocytosines by gly-
cosidation of 6-aryl-5-cyano-2-thiouracils (structure 1 in Sch.) followed by
4,5
ammonolysis of the products. Regioselectivity of these glycosidation reac-
tions agreed well with the calculated electron density distribution in both of the
two monoanions derived by deprotonation of either N1-H or N3-H moiety in
4
5
-cyano-6-phenyl-2-thiouracil 1a. In the same report, on the basis of the cal-
culated charge density distribution, it was also suggested that the anion derived
from 6-aryl-5-cyano-2-(methylthio)pyrimidin-4(3H)one (2) should undergo
preferential glycosidation at the position N1. This work pertains to the
experimental testing of the above suggestion. This work was also stimulated by
the current interest in unnatural nucleosides as potential biologically active
agents. The insecticidal activity of the products will be published in due course.
Scheme.

PYRIMIDINE GLUCOPYRANOSIDES
17
RESULTS AND DISCUSSION
In absolute disagreement with the theoretical prediction, the treatment
of pyrimidinones 2a-d with O-peracetyl-a-D-glucopyranosyl bromide under
4
basic conditions furnished O -nucleosides 3a-d and the corresponding N3-
nucleosides 4a,b,d as the major and minor products, respectively. Only the
4
O -nucleoside 3c was obtained in the reaction with a 6-(2-naphthyl)pyr-
4
imidin-4(3H)one 2c, and the exclusive O -coupling was also observed for the
reaction of 2c with O-peracetyl-a-D-galactopyranosyl bromide (not shown).
These results are in striking contrast with the N3-regioselectivity of a similar
reaction of 6-methyl-2-(methylthio)pyrimidin-4(3H)ones (6-Me analogs of 2)
mentioned above. The products 3 and 4 were easily separated by silica gel
chromatography and fully characterized by elemental analysis, high resolu-
1
tion mass spectrometry, H NMR spectroscopy, and IR spectroscopy.
1
0
In particular, in the H NMR spectrum of 3a, the anomeric proton H1
0
0
gives rise to a doublet at d 6.20 with a coupling constant J(H1 -H2 ) of 7.6 Hz.
This relatively large coupling constant is characteristic for a b-glucopyr-
0
0
2, 5
1
anosyl anomer with a diaxial H1 -H2 interaction.
0
Large coupling con-
0
stants J(H1 -H2 ) of 9.6 Æ 2 Hz are obtained in the H NMR spectra of the
4
remaining nucleosides 3b-d as well. The O -substitution in 3a is consistent
with the results of proton NOE experiments in which the irradiation at d 6.20
0
0
0
for H1 gave strong signals at d 5.36 for H3 and d 5.21 for H5 (close diaxial
interactions) and produced no signals for protons of the phenyl and
methylthio groups. In a similar way, the irradiation at either d 2.63 (SMe) or
d 8.04 (o-Ph) gave no NOE enhancements to protons of the sugar moiety,
and similar results were obtained for the remaining compounds 3b-d. All
these structural results were confirmed by analysis of NOESY spectra of
3
a-d.
The IR spectra of starting materials 2a-d show absorption at
235 Æ 5 cm and 1685 Æ 5 cm for a cyano group and a carbonyl moiety,
À 1
À 1
2
respectively. While the former band is retained, the latter absorption is not
observed in the spectra of the products 3a-d, which is fully consistent with
4
the structure of O -nucleosides. The IR spectra of 3a-d are dominated by a
À 1
strong band centered at 1750 cm
for acetyl carbonyls.
By contrast, all three absorption bands for the cyano, pyrimidinone,
and acetyl moieties are present in the IR spectra of 4a,b,d, indicating the N-
nucleoside structure for these minor products. The substitution at the N3
atom was derived from proton NOE experiments which gave an interaction
0
between the anomeric proton H1 and the SMe group and the lack of
enhancement between the anomeric proton and aromatic protons for all
0
0
products 4a,b,d. As with 3, the coupling constant J(H1 -H2 ) of 8.8 Æ 0.4 Hz
is indicative of the b-configuration of 4.
4
Strong structural support for the O -nucleosides 3 was obtained by
HgBr -mediated rearrangement of the selected compound 3a. In addition to
2

18
ABDOU, ATTIA, AND STREKOWSKI
4
a which was identical in every respect to the nucleoside obtained as dis-
cussed above, this reaction furnished its a-anomer 5. The a-configuration
was assigned on the basis of a small coupling constant (J(H1 -H2 ) of 3.0 Hz
in the H NMR spectrum of 5. The proton NOE experiments conducted as
0
0
1
described above strongly indicated the N3-nucleoside. This structural
assignment is consistent with the similarity of IR spectra of 4a and 5
À1
including the absorption band for a pyrimidinone moiety (1670 Æ 10 cm ).
4
The order of calculated electron densities for the anion derived from 2a
4
is N1 ð0:55Þ > O ð0:27Þ > N3ð0:23Þ. Although the N1 atom contains the
greatest charge density, it is also highly sterically hindered by the adjacent
4
aromatic and methylthio groups. Thus, the observed formation of O -
nucleosides can be explained in terms of this steric hindrance. The expected
high polarizability of the ionized molecule 2 may play an additional role for
the observed O -regioselectivity of the glycosidation.
4
EXPERIMENTAL SECTION
1
General. Melting points (pyrex capillary) are not corrected. The H
NMR including NOESY spectra were recorded and single-irradiation NOE
experiments were conducted on a Varian instrument operating at 300 MHz
with TMS as an internal standard. Optical rotations were measured in
chloroform solutions (c ¼ 2:0 mg= mL) at 589 nm on an Autopol polarimeter.
FAB mass spectra were recorded by using a thioglycerol matrix. IR spectra
were recorded in KBr pellets. Microanalyses were obtained on a Perkin-
Elmer elemental analyzer.
2
of the corresponding aldehyde ArCHO with ethyl cyanoacetate and thiourea
-Thiouracils1a-d. Compounds 1a-c were synthesized by condensation
5
in the presence of piperidine in ethanol. In a similar way, the condensation
of furfural gave 2-thiouracil 1d.
ꢀ
1
5
-Cyano-6-(2-furyl)-2-thiouracil (1d): yield 55%; mp > 300 C;
H
NMR (DMSO-d ) d 12.70 (bs, exchangeable with D O, 2H), 8.15 (m, 1H),
6
2
7
2
.85 (m, 1H), 6.85 (m, 1H). Analysis. Calcd for C H N O S: C, 49.31; H,
9 5 3 2
.30; N, 19.17. Found: C, 49.30; H, 2.28; N, 18.96.
Pyrimidinones 2a-d. The synthesis of compounds 2a,b by methylation
of 2-thiouracils 1a,b with MeI in aqueous KOH has been reported pre-
6,7
viously. This procedure was used for the preparation of 2c,d starting with
c,d. All products 2a-d were crystallized from ethanol and dried at
1
7
ꢀ
0 C=1 mmHg.
5
-Cyano-2-methylthio-6-(2-naphthyl)pyrimidin-4(3H)one (2c): yield
ꢀ
1
44%; mp 297–299 C; H NMR (DMSO-d ) d 12.50 (bs, exchangeable with
D O, 1H), 8.23 (s, 1H), 7.96 (m, 4H), 7.61 (m, 2H), 2.63 (s, 3H). Analysis.
6
2
Calcd for C H N OS: C, 65.51; H, 3.78; N, 14.32. Found: C, 65.42; H, 3.62;
11
16
3
N, 14.19.

PYRIMIDINE GLUCOPYRANOSIDES
19
5
-Cyano-6-(2-furyl)-2-(methylthio)pyrimidin-4(3H)one (2d): yield 53%;
1
ꢀ
mp 245–247 C; H NMR (DMSO-d ) d 12.30 (bs, exchangeable with D O, 1H),
6
2
8
C H N O S: C, 51.49; H, 3.02; N, 18.02. Found: C, 51.34; H, 2.91; N, 17.96.
.16 (m, 1H), 7.62 (m, 1H), 6.85 (m, 1H), 2.63 (s, 3H). Analysis. Calcd for
10
7
3 2
Nucleosides 3a-d and 4a,b,d. A solution of 2,3,4,6-tetra-O-acetyl-a-D-
glucopyranosyl bromide (4.5 g, 11 mmol) in acetone (30 mL) was added to a
solution of 2a-d (10 mmol) in aqueous KOH (1.5 M, 7 mL, 10.5 mmol). The
mixture was stirred at 23 C for 6–12 h until a TLC analysis (silica gel,
ꢀ
ether=chloroform, 1:1) showed the absence of 2a-d. Concentration on a
rotary evaporator followed by silica gel chromatography of the residue
eluting with hexanes=ether=chloroform (1:2:2) gave 3a-d, which was eluted
first, and 4a,b,d. Compounds 3 and 4 were crystallized from 95% ethanol
ꢀ
and dried at 50 C=1 mmHg.
4
-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyloxy)-5-cyano-2-methyl-
ꢀ
25
1
thio-6-phenylpyrimidine (3a): yield 60%; mp 145–147 C; [a] 46.2; H
D
NMR (CDCl ) ( 8.04 (m, 2H), 7.50 (m, 3H), 6.20 (d, J ¼ 7.6 Hz, 1H), 5.36 (m,
3
2
1
5
H), 5.21 (m, 1H), 4.24 (m, 2H), 3.99 (m, 1H), 2.63 (s, 3H), 2.04–2.08 (4s,
2H). High resolution FAB-MS. Calcd for C H N O S (M þ 1) m=z
þ
26
28
3
10
74.1495, observed m=z 574.1500. Analysis. Calcd for C H N O SÁH O:
26
27
3
10
2
C, 52.74; H, 4.90; N, 7.09. Found: C, 52.89; H, 4.72; N, 7.07.
4
-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyloxy)-5-cyano-2-methyl-
ꢀ
25
D
1
thio-6-p-tolyl)pyrimidine (3b): yield 55%; mp 138–140 C; ½aꢁ 32.2; H
NMR (CDCl ) d 7.98 (d, J ¼ 8.0 Hz, 2H), 7.33 (d, J ¼ 8.0 Hz, 1H), 6.13 (d,
3
J ¼ 9.6 Hz, 1H), 5.60 (m, 1H), 5.48 (m, 1H), 5.19 (m, 1H), 4.17 (m, 3H), 2.63
(
C, 55.19; H, 4.97; N, 7.15. Found: C, 55.06; H, 4.85; N, 7.11.
s, 3H), 2.29 (s, 3H), 2.04–2.08 (4s, 12H). Analysis. Calcd for C H N O S:
27
29
3
10
4
-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyloxy)-5-cyano-2-methyl-
ꢀ
25
1
thio-6-(2-naphthyl)pyrimidine (3c): yield 55%; mp 135–137 C; ½aꢁ 28.6; H
D
NMR (CDCl ) d 8.57 (s, 1H), 8.08 (m, 4H), 7.65 (m, 2H), 6.61 (d,
3
J ¼ 11.6 Hz, 1H), 5.65 (m, 1H), 5.23 (m, 1H), 5.08 (m, 1H), 4.41 (m, 1H), 4.24
(
C H N O S: C, 57.78; H, 4.69; N, 6.74. Found: C, 57.70; H, 4.56; N, 6.74.
m, 1H), 4.08 (m, 1H), 2.70 (s, 3H), 2.04–2.08 (4s, 12H). Analysis. Calcd for
30
29
3
10
4
-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyloxy)-5-cyano-6-(2-furyl)-
ꢀ
25
1
2
-methylthio)pyrimidine (3d): yield 60%; mp 142–144 C; ½aꢁ 35.9;
H
D
NMR (CDCl ) d 7.75 (m, 1H), 7.63 (m, 1H), 6.62 (m, 1H), 6.17 (d,
3
J ¼ 7.6 Hz, 1H), 5.36 (m, 2H), 5.20 (m, 1H), 4.25 (m, 1H), 4.17 (m, 1H),
3
.95 (m, 1H), 2.60 (s, 3H), 2.04–2.08 (4s, 12H). High resolution FAB-MS.
þ
Calcd for C H N O S (M þ 1) m=z 564.1288, observed m=z 564.1302.
24
26
3 11
Analysis. Calcd for C H N O S: C, 51.15; H, 4.47; N, 7.46. Found: C,
3 11
24
25
5
1.08; H, 4.29; N, 7.47.
3
-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-5-cyano-2-methylthio-
ꢀ
25
1
6
-phenylpyrimidine (4a): yield 10%; mp 230–232 C; ½aꢁ 51.2; H NMR
D
(
CDCl ) d 8.11 (m, 2H), 7.55 (m, 3H), 6.57 (d, J ¼ 9.2 Hz, 1H), 6.18 (m, 1H),
3
5
.42 (m, 1H), 5.26 (m, 1H), 4.25 (m, 2H), 3.97 (m, 1H), 2.73 (s, 3H), 1.96–2.10

20
ABDOU, ATTIA, AND STREKOWSKI
þ
(
5
5
4s, 12H). High resolution FAB-MS. Calcd for C H N O S (M þ 1) m=z
26
28
3
10
74.1495, observed m=z 574.1469. Analysis. Calcd for C H N O S: C,
26 27 3 10
4.44; H, 4.74; N, 7.33. Found: C, 54.15; H, 4.64; N, 7.02.
3
-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-5-cyano-2-methylthio-
ꢀ
25
D
6
-(p-tolyl)pyrimidin-4(3H)one (4b): yield 10%; mp 200–202 C; ½aꢁ 32.2;
1
H NMR (CDCl ) d 8.03 (d, J ¼ 8.0 Hz, 2H), 7.32 (d, J ¼ 8.0 Hz, 2H), 6.58 (d,
3
J ¼ 9.2 Hz, 1H), 6.20 (m, 1H), 5.42 (m, 1H), 5.25 (m, 1H), 4.24 (m, 2H), 3.99
(
m, 1H), 2.73 (s, 3H), 2.42 (s, 3H), 1.96–2.10 (4s, 12H). High resolution FAB-
þ
MS. Calcd for C H N O S (M þ 1) m=z 588.1652, observed m=z
27
30
3
10
5
Found: C, 53.59; H, 4.91; N, 6.85.
88.1665. Analysis. Calcd for C H N O SÁH O: C, 53.55; H, 5.16; N, 6.94.
27
29
3
10
2
3
-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-5-cyano-6-(2-furyl)-2-
ꢀ
25
(
methylthio)pyrimidin-4(3H)one (4d): yield 5%; mp 205–206 C; ½aꢁ 18.6;
D
1
H NMR (CDCl3) d 7.76 (m, 1H), 7.53 (m, 1H), 6.64 (m, 1H), 6.54 (d,
Jd8.4 Hz, 1H), 6.17 (m, 1H), 5.41 (m, 1H), 5.24 (m, 1H), 4.24 (m, 2H), 3.95
m, 1H), 2.72 (s, 3H), 1.95–2.15 (4s, 12H). Analysis. Calcd for
C H N O S: C, 51.15; H, 4.47; N, 7.46. Found: C, 50.98; H, 4.30; N, 7.44.
(
24
25
3
11
Rearrangement of O-Glucoside 3a. A mixture of 3a (0.59 g, 1 mmol),
anhydrous HgBr (0.36 g, 1 mmol), and anhydrous toluene (20 mL) was
heated under reflux for 1 h. After cooling, the solvent was removed on a
rotary evaporator and the residue was extracted with chloroform
2
(
over Na SO , and concentrated. Chromatography on silica gel eluting with
2 ꢂ 25 mL). The extract was washed with an aqueous solution of KI, dried
2
4
hexanes=ether=chloroform (1:1:1) gave, in order of elution, 4a (0.14 g, 25%)
and 5. Compounds 4a and 5 were crystallized from 95% ethanol.
3
-(2,3,4,6-Tetra-O-acetyl-a-D-glucopyranosyl)-5-cyano-2-methylthio-
25
1
6
(
5
-phenylpyrimidin-4(3H)one (5): yield 0.17 g (30%); ½aꢁ 23.2; H NMR
D
CDCl ) d 8.08 (m, 2H), 7.56 (m, 3H), 6.98 (d, J ¼ 3.0 Hz, 1H), 5.65 (m, 1H),
3
.24 (m, 2H), 4.36 (m, 2H), 4.17 (m, 1H), 2.60 (s, 3H), 1.98–2.11 (4s, 12H).
þ
High resolution FAB-MS. Calcd for C H N O S (M þ 1) m=z 574.1495,
26
28
3
10
observed m=z 574.1510. Analysis. Calcd for C H N O SÁ1=2 H O: C,
26
27
3
10
2
5
3.56; H, 4.80; N, 7.20. Found: C, 53.44; H, 5.08; N, 7.05.
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Hassanein, M.; Abbasi, M.M.; Anwar, M.; Sallam, M. Delta J. Sci. 1993, 17
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2), 78–90. Chem. Abstr. 1997, 126, 305735d.
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Accepted November 1, 2001