Synthesis of N 2-Arylisocytidines and N 2-Aryl- 2′-deoxyisocytidines

Article abstract of DOI:10.1007/s00706-007-0671-9

2-(Arylamino)pyrimidin-4-ones were synthesized, silylated, and condensed with l,2,3,5-tetra-O-acetyl-β- d-ribofuranoside to afford the corresponding N ²-aryl protected isocytidines. Deprotection of the acetylated isocytidines using saturated NH

Full text of DOI:10.1007/s00706-007-0671-9

Monatshefte fu¨r Chemie 138, 917–922 (2007)
DOI 10.1007/s00706-007-0671-9
Printed in The Netherlands
Synthesis of N2-Arylisocytidines and N2-Aryl-20-deoxyisocytidines
ꢀ
Omar M. Ali
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
Received February 20, 2007; accepted February 28, 2007; published online June 29, 2007
# Springer-Verlag 2007
Summary. 2-(Arylamino)pyrimidin-4-ones were synthe-
and layered organic materials [11], as a host for guests
sized, silylated, and condensed with l,2,3,5-tetra-O-acetyl-
ꢀ-D-ribofuranoside to afford the corresponding N2-aryl
protected isocytidines. Deprotection of the acetylated
isocytidines using saturated NH3 in MeOH solution gave
1-(ꢀ-D-ribofuranosyl)-2-(arylamino)-4-pyrimidinones. Methyl
2-deoxy-3,5-di-O-toluyl-ꢁ=ꢀ-D-ribofuranoside was prepared
and condensed with the previously silylated bases to afford
the anomeric mixture of protected nucleosides. The pure
ꢀ-anomers were synthesized with better yield by treating the
sodium salts of N2-arylisocytosine derivatives with 2-deoxy-
3,5-di-O-toluyl-ꢁ-D-ribofuranosyl chloride. Deprotection of
the latter anomers afforded the corresponding free hydroxyl
derivatives. The synthesized free nucleosides are under anti-
viral and oligonucleotide investigations.
with suitable H-bonding abilities [12], or as color re-
agents for metal cations [13]. Nucleoside analogues
bearing unnatural hydrogen bonding patterns have
been proposed to expand the number of comple-
mentary nucleoside pairs available in nucleic acids
[14, 15]. Several nucleoside pairs with complemen-
tary H-bonding patterns have been introduced into
oligonucleotides [16–18]. In this paper we present
the synthesis of N2-arylisocytidines and N2-aryl-20-
deoxyisocytidines.
Results and Discussion
Keywords. Cytosine; Isocytosine; Guanine; Isocytidine;
20-Deoxyisocytidine.
2-(Arylamino)pyrimidin-4-ones 2a–2c were synthe-
sized by refluxing 2-methylthiouracil (1) [19] with
arylamines (aniline, N-methylaniline, and 4-chloro-
aniline) in glacial acetic acid. The products were
recrystallized from AcOH=H2O to afford pale yellow
Introduction
Isocytosine (2-amino-4-pyrimidinone) designates the
pyrimidine part of guanine, and even though it is not
involved directly as a carrier of the genetic code, it is
of biological significance and its medical applications
are numerous [1] (Fig. 1). A variety of 2-amino-4-
pyrimidinones display anticancer, antiviral, or anti-
bacterial properties [2–6], or are rendered as valuable
agrochemicals [7–9]; specifically, platinum group
metal complexes of isocytosine and derivatives at-
tracted considerable attention because of their anti-
tumor activity [10]. In addition, the isocytosine ring
system has been explored as a molecular function-
ality for supramolecular assembly of H-bonded rod
1
powders in 75–90% yields. The H NMR spectra
showed H-5 and H-6 as doublet at ꢂ ¼ 6.17–6.37
and 7.55–7.85 ppm. The 13C NMR spectra showed
the signals of C-5 and C-6 at ꢂ ¼ 109.4–109.6 and
158.9–160.2 ppm. Silylation of these bases was car-
ried out according to the Wittenburg method [20] by
treating the 2-(arylamino)pyrimidin-4-ones 2a–2c with
1,1,1,3,3,3-hexamethyldisilizane (HMDS) in pres-
ence of (NH4)2SO4 as a catalyst at reflux temperature.
Condensation of l,2,3,5-tetra-O-acetyl-ꢀ-D-ribofu-
ranoside (3) with silylated bases using the trimethyl-
silyl trifluoromethanesulfonate (TMS-triflate) method
ꢂ
¨
of Vorbruggen et al. [21] in dry MeCN at ꢁ30 C to
ꢀ
Corresponding author. E-mail: omasaf@hotmail.com
room temperature for 2 h, gave the corresponding

918
O. M. Ali
N2-aryl protected isocytidines 4a–4c in 28–35%
1
yields. The H NMR spectra showed three singlets
at ꢂ ¼ 2.04–2.09, 2.10–2.12, and 2.16–2.18 ppm
corresponding to Me of three Ac groups, while the
anomeric proton appears as doublet at ꢂ ¼ 6.25–
6.28 ppm. The 13C NMR spectra showed three sig-
nals at 20.3, 20.9, and 21.2 corresponding to Me of
three Ac groups, while the three carbonyl groups of
Fig. 1. Structures of cytosine, isocytosine, and guanine
Scheme 1
Scheme 2

N2-Arylisocytidines and N2-Aryl-20-deoxyisocytidines
919
General Procedure for the Synthesis of 2-(Arylamino)
Ac appear at ꢂ ¼ 169.3, 169.7, and 170.1 ppm. Depro-
tection of 4a–4c using saturated NH3 in MeOH
solution at room temperature gave 1-(ꢀ-D-ribofura-
nosyl)-2-(arylamino)-4-pyrimidinones 5a–5c in 91–
pyrimidin-4-ones 2a–2c
A mixture of 2.84 g 1 (20 mmol) and arylamines (30mmol) in
60cm3 glacial acetic acid was refluxed for 10h (TLC). The
solvent was removed under reduced pressure and the residue
was recrystallized from AcOH=H2O to afford 2a–2c as pale
yellow powders in 75–90% yield.
1
93% yields. H and 13C NMR spectra showed the
disappearance of the acetyl groups (Scheme 1).
Methyl 2-deoxy-3,5-di-O-toluyl-ꢁ=ꢀ-D-ribofur-
anoside (6) was prepared from 2-deoxy-D-ribose
[22]. Condensation of 6 with silylated bases 2a–2c
as described before afforded the anomeric mixture of
protected nucleosides 7a–7c and 8a–8c. After sep-
aration and purification by silica gel column chroma-
tography using 30% ether in n-hexane, the ꢀ-anomers
7a–7c were obtained as the major products in 18–
24% yields, while the ꢁ-anomers 8a–8c as the minor
products were isolated in 6–8% yields. The 1H NMR
spectra showed the presence of the anomeric proton
of ꢀ-anomers 7a–7c as multiplet in the range ꢂ ¼
6.34–6.49 ppm, while for ꢁ-anomers 8a–8c gave mul-
tiplet in the range ꢂ ¼ 6.14–6.19ppm. The anomeric
protons as well as the rest of sugar protons were iden-
tified in comparison to the previously identified pro-
tons [23]. In order to synthesize the pure ꢀ-anmoers
7a–7c with better yield than the previously mentioned
method we treated the N2-arylisocytosine derivatives
2a–2c with NaH in dry DMF to form the correspond-
ing sodium salts which were treated directly with
2-deoxy-3,5-di-O-toluyl-ꢁ-D-ribofuranosyl chloride
(11) for 2 h to afford 7a–7c in 29–38%. Deprotection
of 7a–7c and 8a–8c was carried out with saturated
NH3 in MeOH solution at room temperature to afford
the corresponding free hydroxyl derivatives 9a–9c
(92–94%) and 10a–10c (92–93%) (Scheme 2). The
synthesized free nucleosides 5a–5c and 9a–9c are
under antiviral and oligonucleotide investigations.
2-(Phenylamino)pyrimidin-4-one (2a, C10H9N3O)
1
Yield 3.20 g (85%); Mp 217–219ꢂC; H NMR (DMSO-d6,
250 MHz): ꢂ ¼ 6.37 (d, J ¼ 3.7 Hz, H-5), 7.19–7.43 (m, Ph-H,
NH), 7.68 (d, J ¼ 6.8 Hz, H-6), 8.55 (br s, NH) ppm; 13C
NMR (DMSO-d6, 62.5MHz): ꢂ ¼ 109.4 (C-5), 122.8, 122.9,
130.2, 147.2 (Ph-C), 152.6 (C-2), 160.0 (C-6), 164.3 (C-4)
ppm; MS: m=z (%) ¼ 188 [(Mþ þ 1), 12.7].
2-[Methyl(phenyl)amino]pyrimidin-4-one (2b, C11H11N3O)
1
Yield 3.01 g (75%); Mp 207–209ꢂC; H NMR (DMSO-d6,
250 MHz): ꢂ ¼ 3.45 (s, CH3), 6.17 (d, J ¼ 3.0 Hz, H-5),
7.34–7.68 (m, Ph-R, NH), 7.85 (d, J ¼ 6.1 Hz, H-6) ppm;
13C NMR (DMSO-d6, 62.5MHz): ꢂ ¼ 31.9 (CH3), 109.6
(C-5), 122.9, 125.9, 129.6, 141.8 (Ph-C), 153.9 (C-2), 158.9
(C-6), 163.8 (C-4) ppm; MS: m=z (%) ¼ 202 [(Mþ þ 1), 13.2].
2-(4-Chlorophenylamino)pyrimidin-4-one (2c, C10H8ClN3O)
1
Yield 3.96 g (90%); Mp 248–250ꢂC; H NMR (DMSO-d6,
250 MHz): ꢂ ¼ 6.35 (d, J ¼ 3.8 Hz, H-5), 7.05–7.55 (m,
Ph-H, H-6, NH), 8.55 (br s, NH) ppm; 13C NMR (DMSO-
d6, 62.5MHz): ꢂ ¼ 109.4 (C-5), 116.5, 125.6, 128.7, 141.5
(Ph-C), 152.6 (C-2), 160.2 (C-6), 164.3 (C-4) ppm; MS:
m=z (%) ¼ 222 [(Mþ þ 1), 12.8].
1-(2,3,5-Tri-O-acetyl-ꢀ-D-ribofuranosyl)-2-(arylamino)-4-
pyrimidinones 4a–4c
A mixture of 3 mmol 2a–2c, 30 cm3 1,1,1,3,3,3-hexamethyl-
disilizane (HMDS), and 40 mg (NH4)2SO4 (0.22 mmol) was
heated under reflux overnight. The solvent was removed
in vacuo to afford the silylated base which was dissolved
in 20 cm3 dry MeCN. 3 (0.95g, 3 mmol) in 20cm3 dry
MeCN were added and the mixture was cooled to ꢁ30ꢂC. A
solution of 0.25 cm3 trimethylsilyl trifluoromethanesulfonate
(1.24 mmol) in 5 cm3 dry MeCN was added dropwise over
25min to the reaction mixture with stirring. The reaction
mixture was stirred at room temperature for 2 h until the total
consuming of sugar (TLC). The solvent was removed under
reduced pressure and the residue was dissolved in 100cm3
CH2Cl2 and washed with 3ꢃ50cm3 saturated aqueous solu-
tion of NaHCO3 and 3ꢃ50cm3 H2O. The organic layer was
dried over Na2SO4 and evaporated in vacuo to give a crude
dark brown product which was purified by silica gel column
chromatography using ether=pet. ether (1=1, v=v).
Experimental
Melting points were determined using a Kofler block instru-
ment. TLC was performed on plastic plates Silica Gel 60 F254
(E. Merck, layer thickness 0.2 mm). The detection was
achieved by treatment with a solution of 15% H2SO4 in
methanol, and heating at 150ꢂC. NMR spectra were recorded
on a Bruker AC 250 FT NMR spectrometer at 250 MHz for
1H NMR and 62.9MHz for 13C NMR with TMS as an internal
standard. MALDI-MS were measured with a KRATOS Ana-
lytical Compact, using 2,5-dihydroxybenzoic acid (DHB) as
matrix. The (Mþ Na)þ ion was peak matched using ions
derived from the 2,5-dihydroxybenzoic acid matrix. The micro-
analyses were performed at the microanalytical unit, Odense
University, Denmark, and were found to agree favourably with
the calculated values.
1-(2,3,5-Tri-O-acetyl-ꢀ-D-ribofuranosyl)-2-(phenylamino)-
4-pyrimidinone (4a, C21H23N3O8)
White foam (0.45 g, 34%); 1H NMR (CDCl3, 250 MHz):
ꢂ ¼ 2.09, 2.12, 2.17 (3s, 3CH3CO), 4.09–4.34 (m, H-50),
4.43 (m, H-40), 5.71 (dd, J ¼ 5.0, 6.0 Hz, H-30), 5.91 (m,
H-20), 5.99 (d, J ¼ 4.0 Hz, H-5), 6.25 (d, J ¼ 6.0 Hz, H-10),

920
O. M. Ali
7.22–7.40 (m, Ph-H), 7.53 (d, J ¼ 6.8Hz, H-6) ppm; 13C
NMR (CDCl3, 250 MHz): ꢂ ¼ 20.3, 20.9, 21.2 (3CH3CO),
63.0 (C-50), 70.6 (C-30), 73.2 (C-20), 80.4 (C-40), 85.4 (C-10),
105.8 (C-5), 121.9, 122.6, 129.9, 144.2 (Ph-C), 131.6 (C-6)
148.3 (C-2), 164.3 (C-4), 169.3, 169.7, 170.1 (3CH3CO) ppm;
MS: m=z (%) ¼ 468 [(Mþ þ Na), 24.6].
H-5), 6.15 (d, J ¼ 5.2Hz, H-l0), 7.28–7.51 (m, Ph-H), 7.58 (d,
J ¼ 6.8Hz, H-6) ppm; 13C NMR (DMSO-d6, 62.5 MHz):
ꢂ ¼ 34.2 (CH3), 62.1 (C-50), 71.9 (C-30), 72.2 (C-20), 86.7
(C-40), 88.4 (C-10), 106.0 (C-5), 124.7, 125.1, 129.5, 144.7
(Ph-C), 133.0 (C-6) 146.7 (C-2), 163.6 (C-4) ppm; MS: m=z
(%) ¼ 334 [(Mþ þ 1), 18.8].
1-(2,3,5-Tri-O-acetyl-ꢀ-D-ribofuranosyl)-2-(methyl(phenyl)
amino)-4-pyrimidinone (4b, C22H25N3O8)
1-(ꢀ-D-Ribofuranosyl)-2-(4-chlorophenylamino)-4-pyrimidi-
none (5c, C15H16ClN3O5)
White foam (0.38 g, 28%); 1H NMR (CDCl3, 250 MHz):
ꢂ ¼ 2.08, 2.12, 2.18, (3s, 3CH3CO), 3.44 (CH3), 4.10–4.32
(m, H-50), 4.42 (m, H-10), 5.74 (dd, J ¼ 4.6, 6.1Hz, H-30),
5.89 (m, H-20), 5.97 (d, J ¼ 4.0 Hz, H-5), 6.28 (d, J ¼ 6.0 Hz,
H-10), 7.20–7.44 (m, Ph-H), 7.58 (d, J ¼ 6.5 Hz, H-6) ppm;
13C NMR (CDCl3, 62.5MHz): ꢂ ¼ 20.3, 20.9, 21.2 (3CH3CO),
34.2 (CH3), 63.1 (C-50), 70.6 (C-30), 73.4 (C-20), 80.5 (C-40),
89.1 (C-10), 106.0 (C-5), 124.7, 125.2, 129.6, 131.5, 142.1
(Ph-C), 131.5 (C-6),147.6 (C-2), 163.5(C-4), 169.3, 169.7,
170.1 (3CH3CO) ppm; MS: m=z (%) ¼ 482 [(Mþ þ Na),
25.9].
White foam (0.19 g, 92.5%); 1H NMR (DMSO-d6, 250 MHz):
3.35–3.60 (m, H-50), 3.86 (m, H-40), 4.24 (m, H-30), 4.56 (m,
H-20), 5.05 (br s, HO-50), 5.16 (br s, HO-30), 5.38 (br s,
HO-20), 5.95 (d, J ¼ 3.6Hz, H-5), 6.10 (d, J ¼ 5.0 Hz, H-10),
7.12–7.34 (dd, J ¼ 4.0, 8.0 Hz, Ph-H), 7.58 (d, J ¼ 6.8 Hz,
H-6) ppm; 13C NMR (DMSO-d6, 62.5MHz): ꢂ ¼ 62.1 (C-
50), 72.0 (C-30), 73.6 (C-20), 84.9 (C-40), 87.3 (C-10), 105.8
(C-5), 118.7, 124.9, 128.6, 144.2 (Ph-C), 133.2 (C-6) 146.4
(C-2), 162.8 (C-4) ppm; MS: m=z (%) ¼ 354 [(Mþ þ 1), 32.9].
1-(2-Deoxy-3,5-di-O,O-(4-methylbenzoyl)-ꢁ=ꢀ-D-ribofura-
nosyl)-2-(arylamino)-4-pyrimidinones 7a–7c and 8a–8c
Method A: The appropriate base 2a–2c (3mmol) was treated
with 30cm3 1,1,1,3,3,3-hexamethyldisilizane (HMDS) and
40mg (NH4)2SO4 (0.22 mmol) at 130ꢂC for 20h. The sily-
lated compound was concentrated and used, without further
purification, for Vorbruggen coupling. The silylated base
was redissolved in 20cm3 MeCN, 1.15 g 6 (3mmol) in
20cm3 dry MeCN were added, and the mixture was cooled
to ꢁ30ꢂC. Trimethylsilyl trifluoromethanesulfonate (0.25 cm3,
1.24mmol) in 5 cm3 dry MeCN was added dropwise over
25min to the reaction mixture with stirring overnight. After
concentration, the residue was diluted with CH2Cl2. It was
extracted with 3ꢃ50cm3 saturated NaHCO3 and 3ꢃ50cm3
H2O. The organic layer was dried over anhydrous Na2SO4
and purified by column chromatography using 30% ether in
n-hexane to give ꢁ- and ꢀ-derivatives.
Method B: A solution of 2a–2c (3mmol) in 30cm DMF
was treated with 127mg NaH (60% in mineral oil, 3.2mmol).
The solution was heated to 80ꢂC for 1 h. After cooling to
room temperature, 1.17g 11 (3 mmol) were added portionwise,
and the reaction was stirred for 2 h. The reaction mixture was
diluted with CH2Cl2 and washed with 3ꢃ50cm3 NaHCO3
and 3ꢃ50cm3 H2O. The organic layer was dried over anhy-
drous Na2SO4 and purified by column chromatography using
50% ether in n-hexane to give the ꢀ-derivative only.
1-(2,3,5-Tri-O-acetyl-ꢀ-D-ribofuranosyl)-2-(4-chlorophenyl-
amino)-4-pyrimidinone (4c, C21H22ClN3O8)
White foam (0.50 g, 35%); 1H NMR (CDCl3, 250 MHz):
ꢂ ¼ 2.04, 2.10, 2.16 (3s, 3CH3CO), 4.11–4.33 (m, H-50),
4.42 (m, H-10), 5.71 (dd, J ¼ 4.3, 5.8 Hz, H-30), 5.94 (m,
H-20), 6.09 (d, J ¼ 3.8Hz, H-5), 6.26 (d, J ¼ 6.0Hz, H-10),
7.22–7.67 (m, Ph-H, H-6) ppm; 13C NMR (CDCl3,
62.5MHz): ꢂ ¼ 20.3, 20.9, 21.2 (3CH3CO), 63.2 (C-50), 70.9
(C-30), 73.2 (C-20), 80.6 (C-40), 85.4 (C-10), 105.9 (C-5),
118.8, 124.9, 128.7, 144.1 (Ph-C), 131.6 (C-6) 146.2 (C-2),
163.3 (C-4), 169.3, 169.7, 170.1 (3CH3CO) ppm; MS: m=z
(%) ¼ 502 [(Mþ þ Na), 24.6].
1-(ꢀ-D-Ribofuranosyl)-2-(arylamino)-4-pyrimidinones 5a–5c
A solution of 4a–4c (0.6mmol) in 30 cm3 saturated NH3=
MeOH was allowed to stir overnight at room temperature.
The mixture was concentrated and purified by column chro-
matography using 12% MeOH in CH2Cl2.
1-(ꢀ-D-Ribofuranosyl)-2-(phenylamino)-4-pyrimidinone
(5a, C15H17N3O5)
1
White foam (0.18 g, 93%); H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 3.45–3.71 (m, H-50), 3.98 (m, H-40), 4.25 (m, H-30), 4.60
(m, H-20), 4.99 (br s, HO-50), 5.18 (br s, HO-30), 5.41 (br s,
HO-20), 6.05 (d, J ¼ 3.5Hz, H-5), 6.12 (d, J ¼ 5.0Hz, H-10),
7.32–7.45 (m, Ph-H), 7.55 (d, J ¼ 7.0Hz, H-6) ppm; 13C
NMR (DMSO-d6, 62.5MHz): ꢂ ¼ 62.1 (C-50), 71.9 (C-30),
73.9 (C-20), 85.8 (C-40), 87.9 (C-10), 105.8 (C-5), 121.6,
122.5, 129.7, 143.4 (Ph-C), 133.2 (C-6) 147.2 (C-2), 164.6
(C-4) ppm; MS: m=z (%) ¼ 320 [(Mþ þ 1), 18.5].
1-(2-Deoxy-3,5-di-O,O-(4-methylbenzoyl)-ꢀ-D-ribofuranosyl)-
2-(phenylamino)-4-pyrimidinone (7a, C31H29N3O6)
White foam (0.39 g, 24%, method A; 0.61 g, 38%, method B);
1H NMR (CDCl3, 250 MHz): ꢂ ¼ 2.38, 2.46 (2s, 2CH3),
2.88–3.14 (m, H-20), 4.48 (m, H-50), 4.53 (m, H-40), 4.71
(m, H-50), 5.67 (m, H-30), 5.94 (d, J ¼ 3.2 Hz, H-5), 6.49
(m, H-10), 7.10–8.04 (m, Ph-H, H-6) ppm; 13C NMR (CDCl3,
62.5MHz): ꢂ ¼ 20.9, 21.5 (2CH3), 39.9 (C-20), 64.1 (C-50),
75.0 (C-30), 81.7 (C-40), 83.6 (C-10), 105.8 (C-5), 121.8,
122.5, 129.8, 130.8, 132.4, 133.6, 135.5, 138.3, 143.5 (Ph-
C, C-6), 146.3 (C-2), 164.82 (C-4), 165.2, 165.8 (2CO)
ppm; MS: m=z (%) ¼ 562 [(Mþ þ Na), 35.6].
1-(ꢀ-D-Ribofuranosyl)-2-[methyl(phenyl)amino]-4-pyrimidi-
none (5b, C16H19N3O5)
1
White foam (0.19 g, 91%); H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 3.34 (m, H-50), 3.49 (s, CH3), 3.51 (m, H-50), 3.88
(m, H-40), 4.45 (m, H-30), 4.64 (m, H-20), 5.09 (br s, HO-
50), 5.16 (br s, HO-30), 5.39 (br s, HO-20), 5.92 (d, J ¼ 3.6 Hz,

N2-Arylisocytidines and N2-Aryl-20-deoxyisocytidines
921
ppm;13CNMR(CDCl3,62.5MHz):ꢂ ¼ 20.9, 21.7(2CH3),39.7
(C-20), 63.8 (C-50), 74.3 (C-30), 86.5 (C-10), 87.8 (C-40), 105.4
(C-5), 119.0, 124.7, 129.1, 132.4, 138.8, 143.4 (Ph-C, C-6),
163.7 (C-4), 165.4, 165.9 (2CO) ppm; MS: m=z (%) ¼ 596
[Mþ þ Na), 35.4].
1-(2-Deoxy-3,5-di-O,O-(4-methylbenzoyl)-ꢀ-D-ribofuranosyl)-
2-[methyl(phenyl)amino]-4-pyrimidinone (7b, C32H31N3O6)
White foam (0.30 g, 18%, method A; 0.48 g, 29%, method B);
1H NMR (CDCl3, 250 MHz): ꢂ ¼ 2.36, 2.44 (2s, 2CH3), 2.86–
3.20 (m, H-20), 3.50 (s, CH3), 4.48 (m, H-50), 4.52 (m, H-40),
4.74 (m, H-50), 5.65 (m, H-30), 5.88 (d, J ¼ 3.2 Hz, H-5), 6.34
(m, H-10), 7.10–7.96 (m, Ph-H, H-6) ppm; 13C NMR (CDCl3,
62.5MHz): ꢂ ¼ 20.9, 21.5 (2CH3), 34.2 (CH3), 39.1 (C-20),
64.0 (C-50), 74.8 (C-30), 81.6 (C-40), 85.1 (C-10), 106.0
(C-5), 124.7, 125.1, 126.1, 129.0, 129.5, 132.1, 143.5 (Ph-C,
C-6), 146.8 (C-2), 165.5 (C-4), 165.3, 165.8 (2CO) ppm; MS:
m=z (%) ¼ 576 [(Mþ þ Na), 36.3].
1-(2-Deoxy-ꢁ=ꢀ-D-ribofuranosyl)-2-(arylamino)-4-pyrimidi-
nones 9a–9c, and 10a–10c
Compounds 7a–7c and 8a–8c (0.2mmol) in 10cm3 saturated
NH3=MeOH were stirred at room temperature for 16 h. The
resulting solution was evaporated till dryness under reduced
pressure. The residue was chromatographed on a silica gel col-
umn with 8% MeOH in CH2Cl2 to give 9a–9c in 92–94% and
10a–10c in 92–93% yields.
1-(2-Deoxy-3,5-di-O,O-(4-methylbenzoyl)-ꢀ-D-ribofuranosyl)-
2-(4-chlorophenylamino)-4-pyrimidinone (7c, C31H28ClN3O6)
White foam (0.32 g, 22%, method A; 0.50 g, 37%, method B);
1H NMR (CDCl3, 250 MHz): ꢂ ¼ 2.39, 2.44 (2s, 2CH3), 2.92–
3.20 (m, H-20), 4.46 (m, H-50), 4.51 (m, H-40), 4.68 (m, H-50),
5.70 (m, H-30), 6.00 (d, J ¼ 3.4 Hz, H-5), 6.44 (m, H-10), 7.00–
7.94 (m, Ph-H, H-6) ppm; 13C NMR (CDCl3, 62.5MHz):
ꢂ ¼ 20.9, 21.5 (2CH3), 39.9 (C-20), 64.2 (C-50), 75.1 (C-30),
81.8 (C-40), 84.4 (C-10), 105.6 (C-5), 118.7, 124.9, 126.8,
128.6, 129.0, 132.2, 138.9, 143.5 (Ph-C, C-6), 146.5 (C-2),
164.7 (C-4), 165.34, 165.9 (2CO) ppm; MS: m=z (%) ¼ 596
[(Mþ þ Na), 35.3].
1-(2-Deoxy-ꢀ-D-ribofuranosyl)-2-(phenylamino)-4-pyrimidi-
none (9a, C15H17N3O4)
1
White foam (0.06 g, 94%); H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 2.55–2.65 (m, H-20), 3.49–3.75 (m, H-50), 4.24 (m, H-40),
4.48 (m, H-30), 5.08, 5.22 (2s, 2OH), 5.98 (d, J ¼ 3.7 Hz, H-5),
6.19 (dd, J ¼ 6.7, 4.7 Hz, H-10), 7.22–7.48 (m, Ph-H), 7.58 (d,
J ¼ 6.8Hz, H-6) ppm; 13C NMR (DMSO-d6, 62.5 MHz):
ꢂ ¼ 39.6 (C-20), 61.6 (C-50), 70.8 (C-30), 84.8 (C-40), 87.6
(C-10), 105.8 (C-5), 121.6, 122.4, 130.1, 132.2, 137.8, 143.5
(Ph-C, C-6), 147.2 (C-2), 163.2 (C-4) ppm; MS: m=z
(%) ¼ 304 [(Mþ þ 1), 17.7].
1-(2-Deoxy-3,5-di-O,O-(4-methylbenzoyl)-ꢁ-D-ribofuranosyl)-
2-(phenylamino)-4-pyrimidinone (8a, C31H29N3O6)
1-(2-Deoxy-ꢀ-D-ribofuranosyl)-2-[methyl(phenyl)amino]-4-
pyrimidinone (9b, C16H19N3O4)
White foam (0.13 g, 8%); 1H NMR (CDCl3, 250 MHz):
ꢂ ¼ 2.30 (m, H-20), 2.40, 2.49 (2s, 2CH3), 2.62 (m, H-20),
3.54–3.76 (m, H-50), 4.50 (m, H-40), 5.26 (m, H-30), 5.95 (d,
J ¼ 3.4 Hz, H-5), 6.18 (m, H-10), 7.14–7.96 (m, Ph-H, H-6)
ppm; 13C NMR (CDCl3, 62.5MHz): ꢂ ¼ 21.1, 21.5 (2CH3),
39.7 (C-20), 63.9 (C-50), 74.3 (C-30), 86.2 (C-10), 88.0 (C-40),
105.7 (C-5), 122.0, 122.8, 129.1, 132.6, 138.4, 143.7 (Ph-C,
C-6), 146.3 (C-2), 163.9 (C-4), 166.1, 166.8 (2CO) ppm; MS:
m=z (%) ¼ 562 [(Mþ þ Na), 35.5].
1
White foam (0.06 g, 92%); H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 2.38–2.54 (m, H-20), 3.48 (s, CH3), 3.49–3.72 (m, H-50),
4.14 (m, H-40), 4.42 (m, H-30), 5.16, 5.25 (2br s, 2OH), 6.08
(d, J ¼ 3.7 Hz, H-5), 6.27 (dd, J ¼ 6.6, 4.5 Hz, H-10), 7.28–
7.53 (m, Ph-H), 7.64 (d, J ¼ 6.4 Hz, H-6) ppm; 13C NMR
(DMSO-d6, 62.5MHz): ꢂ ¼ 34.2 (CH3), 38.8 (C-20), 61.6
(C-50), 70.8 (C-30), 85.6 (C-40), 87.9 (C-10), 106.1 (C-5),
125.6, 129.5, 132.6, 144.8 (Ph-C, C-6), 147.0 (C-2), 164.7
(C-4) ppm; MS: m=z (%) ¼ 318 [(Mþ þ 1), 18.7].
1-(2-Deoxy-3,5-di-O,O-(4-methylbenzoyl)-ꢁ-D-ribofuranosyl)-
2-[methyl(phenyl)amino]-4-pyrimidinone (8b, C32H31N3O6)
White foam (0.10 g, 6%); 1H NMR (CDCl3, 250 MHz):
ꢂ ¼ 2.33 (m, H-20), 2.41, 2.46 (2s, 2CH3), 2.59 (m, H-20),
3.46 (s, CH3), 3.50–3.75 (m, H-50), 4.55 (m, H-40), 5.29
(m, H-30), 5.90 (d, J ¼ 3.1 Hz, H-5), 6.14 (m, H-10), 7.14–
7.90 (m, Ph-H, H-6) ppm; 13C NMR (CDCl3, 62.5MHz):
ꢂ ¼ 20.9, 21.4 (2CH3), 34.3 (CH3), 39.8 (C-20), 64.1 (C-50),
74.3 (C-30), 86.5 (C-10), 87.9 (C-40), 106.1 (C-5), 124.3, 125.4,
127.1, 129.1, 130.4, 133.7, 144.2 (Ph-C, C-6), 146.9 (C-2),
163.5 (C-4), 165.3, 165.8 (2CO) ppm; MS: m=z (%) ¼ 576
[(Mþ þ Na), 36.7].
1-(2-Deoxy-ꢀ-D-ribofuranosyl)-2-(4-chlorophenylamino)-4-
pyrimidinone (9c, C15H16ClN3O4)
1
White foam (0.06 g, 94%); H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 2.52–2.64 (m, H-20), 3.46–3.70 (m, H-50), 4.20 (m, H-40),
4.42 (m, H-30), 5.10, 5.19 (2br s, 2OH), 5.99 (d, J ¼ 3.8 Hz,
H-5), 6.26 (dd, J ¼ 6.4, 4.8Hz, H-10), 7.06–7.51 (dd, J ¼ 8.2,
4.3 Hz, Ph-H), 7.62 (d, J ¼ 7.0 Hz, H-6) ppm; 13C NMR
(DMSO-d6, 62.5MHz): ꢂ ¼ 39.6 (C-20), 62.0 (C-50), 71.1
(C-30), 84.8 (C-40), 87.4 (C-10), 105.8 (C-5), 118.7, 125.1,
128.6, 132.5, 137.8, 143.4 (Ph-C, C-6), 147.4 (C-2), 163.8
(C-4) ppm; MS: m=z (%) ¼ 338 [(Mþ þ 1), 23.1].
1-(2-Deoxy-3,5-di-O,O-(4-methylbenzoyl)-ꢁ-D-ribofuranosyl)-
2-(4-chlorophenylamino)-4-pyrimidinone (8c, C31H28ClN3O6)
White foam (0.10 g, 7%); 1H NMR (CDCl3, 250 MHz):
ꢂ ¼ 2.34 (m, H-20), 2.39, 2.48 (2s, 2CH3), 2.65 (m, H-20),
3.52–3.74 (m, H-50), 4.53 (m, H-40), 5.22 (m, H-30), 6.01 (d,
J ¼ 3.3 Hz, H-5), 6.19 (m, H-10), 7.05–7.96 (m, Ph-H, H-6)
1-(2-Deoxy-ꢁ-D-ribofuranosyl)-2-(phenylamino)-4-pyrimidi-
none (10a, C15H17N3O4)
1
White foam (0.06 g, 93%); H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 2.17, 2.89 (m, H-20), 3.11–3.29 (m, H-50), 3.79 (m, H-40),
4.42 (m, H-30), 5.98 (d, J ¼ 3.5 Hz, H-5), 6.24 (m, H-10), 7.20–
7.49 (m, Ph-H), 7.62 (d, J ¼ 6.7 Hz, H-6) ppm; 13C NMR

922
O. M. Ali: N2-Arylisocytidines and N2-Aryl-20-deoxyisocytidines
(DMSO-d6, 62.5MHz): ꢂ ¼ 40.7 (C-20), 62.8 (C-50), 74.6 (C-
30), 87.8 (C-10), 88.2 (C-40), 105.5 (C-5), 122.9, 131.1, 133.2,
137.2, 143.7 (Ph-C, C-6), 147.3 (C-2), 163.8 (C-4) ppm; MS:
m=z (%) ¼ 304 [(Mþ þ 1), 17.7].
[7] Mager S, Diudea M, Jugrestan F, Cristea I, Panea I
(1981) Romanian Patent 76712, (1983) Chem Abstr 99:
158454e
[8] Panea I, Mager S, Farcasan V, Hopartean I, Paiu F,
Cristea I, Popa V (1981) Romanian Patent 77114
(1985) Chem Abstr 102: 62259z
[9] Taylor EC, Zhou P (1997) Tetrahedron Lett 38: 4339
[10] Yakovlev KL, Stetsenko AI, Tulub AA (1987) 5th Int.
Symp. on Platinum and Other Coordination Compounds
in Cancer Chemotherapy. Padua, p 361
[11] Toledo LM, Musa K, Lauher JW, Fowler FW (1995)
Chem Mater 7: 1639
[12] Buhlman P, Simon W (1993) Tetrahedron 49: 7627
[13] Shiho D, Takabayashi N (1955) Nippon Kagaku Zasshi
76: 877
[14] Rich A (1962) On the Problems of Evolution and
Biochemical Information Transfer. In: Horizons in Bio-
chemistry, Academic Press, New York, p 103
[15] Benner SA, Alleman RK, Ellington AD, Ge L, Glasfeld
A, Leanz GF, Krauch T, MacPherson LJ, Moroney SE,
Piccirilli AJ, Weinhold E (1987) Cold Spring Harb
Symp Quant Biol 52: 53
[16] Switzer C, Moroney SE, Benner SA (1989) J Am Chem
Soc 111: 8322
[17] Piccirilli JA, Krauch T, Moroney SE, Benner SA (1990)
Nature 343: 33
[18] Voegel JJ, Benner SA (1996) Helv Chim Acta 79: 1863
[19] Brown TH, Blakemore RC, Emmett GJ, Robin GC,
Parsons ME, Anthony DA, Walker TF (1988) Eur J
Med Chem 23: 53
[20] Wittenburg EZ (1964) Chemistry 4: 303
[21] Vorbru¨ggen H, Krolikiewicz K, Bennua B (1981) Chem
Ber 114: 1234
1-(2-Deoxy-ꢁ-D-ribofuranosyl)-2-[methyl(phenyl)amino]-4-
pyrimidinone (10b, C16H19N3O4)
1
White foam (0.06 g, 93%); H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 2.24, 2.84 (m, H-20), 3.18–3.36 (m, H-50), 3.52 (s, CH3),
3.84 (m, H-40), 4.39 (m, H-30), 6.04 (d, J ¼ 3.4 Hz, H-5), 6.21
(m, H-10), 7.16–7.46 (m, Ph-H), 7.59 (d, J ¼ 6.6 Hz, H-6)
ppm; 13C NMR (DMSO-d6, 62.5MHz): ꢂ ¼ 34.6 (CH3), 40.6
(C-20), 63.2 (C-50), 74.7 (C-30), 87.5 (C-10), 87.9 (C-40), 106.5
(C-5), 125.7, 128.9, 133.3, 144.4 (Ph-C, C-6), 146.9 (C-2),
163.8 (C-4) ppm; MS: m=z (%) ¼ 318 [(Mþ þ 1), 18.8].
1-(2-Deoxy-ꢁ-D-ribofuranosyl)-2-(4-chlorophenylamino)-4-
pyrimidinone (10c, C15H16ClN3O4)
1
White foam (0.06 g, 92%); H NMR (DMSO-d6, 250 MHz):
ꢂ ¼ 2.26, 2.84 (m, H-20), 3.18–3.30 (m, H-50), 3.82 (m, H-40),
4.39 (m, H-30), 5.95 (d, J ¼ 3.5 Hz, H-5), 6.22 (m, H-10), 7.10–
7.54 (dd, J ¼ 8.3, 4.4 Hz, Ph-H), 7.64 (d, J ¼ 6.8 Hz, H-6)
13
ppm; C NMR (DMSO-d6, 62.5MHz): ꢂ ¼ 40.4 (C-20), 62.6
(C-50), 73.7 (C-30), 87.5 (C-10), 87.9 (C-40), 105.6 (C-5),
119.4, 124.9, 129.1, 133.3, 137.7, 143.8 (Ph-C, C-6), 147.5
(C-2), 163.9 (C-4) ppm; MS: m=z (%) ¼ 338 [(Mþ þ 1), 32.1].
References
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CV, Mckinney DC, Silverman SK (2005) J Org Chem
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Tetrahedron 63: 312
¨
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¨
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