Synthesis of N4-β-D-glycoside cytosines and sugar N 4-acetylcytosin-1-ylmethylhydrazones as antiviral agents

Article abstract of DOI:10.3184/030823407X215889

Reaction of monosaccharide aldoses with cytosine (1) gave stereoselectively β-N-glycosides 2a-d, which were treated with acetic anhydride in pyridine to afford the corresponding acetylated derivatives 3a-d. N⁴- Acetylcytosine (4) was synthesised and treated with ethyl chloroacetatete give 1-(ethoxycarbonylmethy)-N⁴-acetylcytosine (5). Hydrolysis of the latter ester with hydrazine hydrate afforded the hydrazide derivative 6. Condensation of the hydrazide with monosaccharide aldoses gave the corresponding sugar hydrazones 7a-f. Acetylation of the hydrazones afforded the per-O-acetyl derivatives 8a-f. The prepared compounds were tested for antiviral activity against hepatitis B virus (HBV) which showed moderate activities.

Full text of DOI:10.3184/030823407X215889

JOURNAL OF CHEMICAL RESEARCH 2007
MAY, 281–283
RESEARCH PAPER 281
4
Synthesis of N4-b-D-glycoside cytosines and sugar Nꢀ -acetylcytosin-1-
ylmethylhydrazones as antiviral agents
Omar M. Ali, Hamada H. Amer and Adel A.-H. Abdel-Rahman*
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
Reaction of monosaccharide aldoses with cytosine (1) gave stereoselectively b-N-glycosides 2a–d, which were treated
with acetic anhydride in pyridine to afford the corresponding acetylated derivatives 3a–d. N4-Acetylcytosine (4) was
synthesised and treated with ethyl chloroacetate to give 1-(ethoxycarbonylmethyl)-N4-acetylcytosine (5). Hydrolysis
of the latter ester with hydrazine hydrate afforded the hydrazide derivative 6. Condensation of the hydrazide with
monosaccharide aldoses gave the corresponding sugar hydrazones 7a–f. Acetylation of the hydrazones afforded the
per-O-acetyl derivatives 8a–f. The prepared compounds were tested for antiviral activity against hepatitis B virus
(HBV) which showed moderate activities.
Keywords: cytosine, N4-acetylcytosin, N-glycosides, antiviral activity
Glycosyl amines1-6 are important because these occur as
junctures in glycoproteins.7,8 The chemical and structural
nature of the derivatives formed from the reaction of a
monosaccharide and different nitrogen bases depends upon
the reaction conditions and the base used.9 N-Glycosyl
amines have better advantage in binding to metal ions over
their saccharide counter parts, as these compounds provide
additional binding centres. In view of such important aspects
of N-glycosyl amines, herein we report the synthesis and
characterisation of different N-glycosyl amines of simple
saccharides using cytosine as an amine. Recently, the
synthesis of acyclic nucleosides has attracted much attention.10
Consequently, this significance and possible enhancement
of biological activity resulting from the attachment of
carbohydrate moieties to heterocycles and our interest in
the synthesis of heterocyclic derivatives of carbohydrates,11
attracted our attention to synthesise C-nucleosides using
monosaccharide (N4-acetylcytosine-1-yl)acetohydrazides.
The reaction of 2a–d with acetic anhydride in pyridine at
room temperature led to the acetylation of sugar hydroxyl
groups without affecting the NH group to give tri- or
tetraacetoxy-β-d-glycosides 3a–d in 95–98% yields. The IR
spectra of 3a–d are characterised by two absorption bands at
3380–3395 and 1745–1755 cm-1 indicating the presence OAc
1
and NH groups. In addition, the H NMR spectra showed
triplets at low field δ 5.15–5.20 ppm assigned as H-1' with
J(1,2) = 9.0 Hz, which confirm the expected β-configuration of
4C1 (d) conformation.
Refluxing of cytosine in acetic anhydride afforded the
corresponding N4-acetylcytosine (4),13 which was treated with
ethyl chloroacetate in acetone and anhydrous K2CO3 to afford
1-(ethoxycarbonylmethyl)-N4-acetylcytosine (5) in 75% yield.
Hydrazinolysis of the ethyl ester 5 gave (N4-acetylcytosin-1-
yl)acetohydrazide (6) in 89% yield.
Condensation of the hydrazides 6 with L-arabinose,
d-ribose, d-xylose, d-glucose, d-galactose, and d-mannose
gave the corresponding sugar hydrazones 7a–f in 80-88%
yield. The 1H NMR spectra of the hydrazones 7a–f confirmed
the presence of sugar protons in the range δ 3.14–4.27 ppm and
a doublet at δ 7.20–7.30 ppm corresponding to the proton at
C-1 of the sugar. The assignments of NH and OH groups in
these compounds were achieved by D2O exchange.Acetylation
of 7a–f using acetic anhydride in pyridine at room temperature
gave the corresponding acetylated derivatives 8a–f 80–85%
Results and discussion
Condensation of cytosine (1) with
a
number of
monosaccharides (d-glucose, d-galactose, d-ribose, and
d-xylose) in boiling ethanol and in the presence of a catalytic
amount of glacial acetic acid gave stereoselectively 4-(b-d-
glycopyranosylamino)pyrimidin-2(1H)-ones 2a–d in 85-88%
yields. In the 1H NMR spectra of 2a–d, the anomeric protons
appear as doublet in the range δ 7.16–7.20 ppm, in which J(1,2)
= 8.0 Hz. This value is consistent with the β-configuration of
4C1 (d) conformation.12
1
yields. The H NMR spectra of the acetyl derivatives 8a–f
showed the O-acetyl-methyl groups at δ 1.95–2.10 ppm and
the methine proton as doublet at δ 7.25–7.30 ppm.
R3
R3
R5
R5
O
OH
R4
R4
H
+ H2N-Ar
OH
N
R1
R1
Ar
OH
OH
OH
R2
R2
H2O
R3
R3
R5
R5
O
OH
R4
R4
N
R1
R1
H
N
Ar
Ar
OH
OH
R2
R2
Scheme 1
* Correspondent. E-mail: adelnassar63@hotmail.com
PAPER: 07/4564

282 JOURNAL OF CHEMICAL RESEARCH 2007
NH-A c
NH-A c
NH-A c
R3
NH2
NH-Ac
O
R5
N
i
ii
O
N
N
N
N
iii
N
i
R4
H
N
R1
NH
O
N
O
N
O
N
O
O
O
OH
R
R1
O
N
H
1
O
N
H
4
R2
N
N
NHNH2
N
H
N
H
2a-d
6
7a-f
8a-f
a R1 = R4 = OH, R2 = R3 = H, R5 = CH2OH
b R1 = R3 = OH, R2 = R4 = H, R5 = CH2OH
c R2 = R4 = OH, R1 = R3 = R5 = H
iv
OH
OH HO
HO
O H
OH HO
HO
HO
HO
NH-Ac
d R1 = R4 = OH, R2 = R3 = R5 = H
O H HO
O H
OH
R =
OH
OH
OH
OH
N
ii
OH
OH
OH
OH
OH
OH
R3
O H
HO
OH
O
N
O
R5
a
b
c
e
d
O
f
O
N
R4
OA c
OAc AcO
AcO
H
N
OEt
R1
NH
5
O Ac
OAc A cO
AcO
AcO
OAc
R2
O Ac Ac O
O Ac
OA c AcO
OAc
OAc
R1
=
OAc
OAc
v
3a-d
OAc
OAc
OAc
OAc
OA c
OA c
a R1 = R4 = OAc, R2 = R3 = H, R5 = CH2OAc
b R1 = R3 = OAc, R2 = R4 = H, R5 = CH2OAc
c R2 = R4 = OAc, R1 = R3 = R5 = H
NH-Ac
N
O Ac
OAc
AcO
e
a
b
c
d
f
N
(i) Monosaccharide aldoses /EtOH/ AcOH/reflux; (ii) Ac2O/P y/r.t.
d R1 = R4 = OAc, R2 = R3 = R5 = H
O
O
Scheme 3
NHNH2
6
4-(b-d-Ribopyranosylamino)pyrimidin-2(1H)-one (2c): Yield 88%.
(i) Monosaccharide aldoses/EtOH/AcOH/reflux; (ii) Ac2O/Py/r.t.; (iii) Ac2O/reflux;
(iv) ClCH2CO2Et/Acetone/K2CO3/reflux; (v) N2H4.H2O/EtOH/reflux
1
M.p. 167–169°C. H NMR (DMSO-d6) δ: 3.20–3.50 (m, 2H, H-5'),
4.35–4.95 (m, 7H, H-2', H-3', H-4', 4xOH), 7.18 (d, 1H, J = 8.0 Hz,
H-1'), 7.24 (d, 1H, J = 5.5 Hz, H-5), 7.89 (d, 1H, J = 5.5 Hz,
H-6), 9.55 (brs, 1H, NH). MS: m/z (%) = 266 [(M+ + Na), 30]. Anal.
Calcd. for C9H13N3O5: C, 44.44; H, 5.39; N, 17.28. Found: C, 44.17;
H, 5.22; N, 17.14%.
Scheme 2
Preliminary viral screening against hepatitis B virus (HBV)
(Hep G2 2.2.15 cell method)14 indicated that compounds
2a–c, 3a, 3b, 7a–d, 8a and 8b were found to be active
against HBV replication with IC50 80–90 μM and CC50 85–
95 μM. Compounds 2d, 3c, 7e, and 8d showed moderate
viral replication inhibition and moderate cytotoxicity, while
compounds 3d, 7f, 8c, 8e, and 8f showed very low inhibition
and high cytotoxicity.
4-(b-d-Xylopyranosylamino)pyrimidin-2(1H)-one (2d):Yield 86%.
1
M.p. 145–147°C. H NMR (DMSO-d6) δ: 3.10–3.40 (m, 2H, H-5'),
4.45–4.90 (m, 7H, H-2', H-3', H-4', 4xOH), 7.16 (d, 1H, J = 8.0
Hz, H-1'), 7.23 (d, 1H, J = 5.5 Hz, H-5), 7.81 (d, 1H, J = 5.5 Hz,
H-6), 9.52 (brs, 1H, NH). MS: m/z (%) = 266 [(M+ + Na), 27]. Anal.
Calcd. for C9H13N3O5: C, 44.44; H, 5.39; N, 17.28. Found: C, 44.15;
H, 5.24; N, 17.18%.
4-(2,3,4-Tri-O-acetyl)- and 4-(2,3,4,6-Tetra-O-acetyl-b-d-glyco-
pyranosylamino)pyrimidin-2(1H)-ones 3a–d
Experimental
A mixture of 2a–d (0.2 g), dry pyridine (3 ml) and acetic anhydride
(3 ml) was stirred for 15 min at 0°C, then kept overnight at room
temperature with stirring. The mixture was poured onto crushed-
ice (30 g) and the precipitate was collected by filtration, washed
repeatedly with water, dried, and recrystallised from ethanol–water
(2: 8, v/v) to afford 3a–d in 95–98% yields.
4-(2,3,4,6-Tetra-O-acetyl-b-d-glucopyranosylamino)pyrimidin-
2(1H)-one (3a): Yield 98%. M.p. 140–142°C. IR (cm-1): 3390 (NH),
1750 (C=O). 1H NMR (DMSO-d6) δ: 1.95, 1.97, 1.99, 2.09 (4 s, 12H,
4xCH3CO), 3.75–3.90 (m, 2H, H-6'), 4.60–5.00 (m, 4H, H-2', H-3',
H-4', H-5'), 5.15 (d, 1H, J = 9.0 Hz, H-1'), 7.20 (d, 1H, J = 5.5 Hz,
H-5), 7.70 (d, 1H, J = 5.5 Hz, H-6), 9.58 (brs, 1H, NH). MS: m/z
(%) = 464 [(M+ + Na), 25]. Anal. Calcd. for C18H23N3O10: C, 48.98;
H, 5.25; N, 9.52. Found: C, 48.77; H, 5.17; N, 9.46%.
4-(2,3,4,6-Tetra-O-acetyl-b-d-galactopyranosylamino)pyrimidin-
2(1H)-one (3b): Yield 95%. M.p. 129–131°C. IR (cm-1): 3370 (NH),
1745 (C=O). 1H NMR (DMSO-d6) δ: 1.94, 1.96, 1.99, 2.08 (4 s, 12H,
4xCH3CO), 3.95–4.15 (m, 2H, H-6'), 4.70–5.00 (m, 4H, H-2', H-3',
H-4', H-5'), 5.20 (d, 1H, J = 9.0 Hz, H-1'), 7.21 (d, 1H, J = 5.5 Hz,
H-5), 7.73 (d, 1H, J = 5.5 Hz, H-6), 9.58 (brs, 1H, NH). MS: m/z
(%) = 464 [(M+ + Na), 22]. Anal. Calcd. for C18H23N3O10: C, 48.98;
H, 5.25; N, 9.52. Found: C, 48.73; H, 5.11; N, 9.39%.
4-(2,3,4-Tri-O-acetyl-b-d-ribopyranosylamino)pyrimidin-2(1H)-
one (3c): Yield 97%. M.p. 135–137°C. IR (cm-1): 3396 (NH), 1755
(C=O). 1H NMR (DMSO-d6) δ: 1.97, 1.99, 2.05 (3 s, 9H, 3xCH3CO),
3.80–4.00 (m, 2H, H-5'), 4.80–5.08 (m, 3H, H-2', H-3', H-4'), 5.17
(d, 1H, J = 9.0 Hz, H-1'), 7.25 (d, 1H, J = 5.5 Hz, H-5), 7.70 (d, 1H,
J = 5.5 Hz, H-6), 9.60 (brs, 1H, NH). MS: m/z (%) = 392 [(M+ +
Na), 56]. Anal. Calcd. for C15H19N3O8: C, 48.78; H, 5.19; N, 11.38.
Found: C, 48.66; H, 5.05; N, 11.22%.
Melting points were determined using a Kofler block instrument.
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 150°C.
IR spectra were recorded with a Perkin-Elmer model 1720 FTIR
(KBr). 1H NMR spectra were recorded on a Bruker AC 250 FT NMR
spectrometer, 250 MHz with TMS as an internal standard. MALDI-
MS were measured with a KRATOS Analytical Compact, using 2,5-
dihydroxybenzoic acid (DHB) as matrix. The (M + Na)+ ion was
peak matched using ions derived from the 2,5-dihydroxybenzoic
acid matrix. All commercially available reagents were used without
further purification. Pyridine was distilled from CaH2 and stored
over molecular sieves. The microanalyses were performed at the
microanalytical unit, Universität Konstanz, Germany. Viral screening
against HBV was conducted at the National Liver Institute, Menoufia
University, Shebin El Koam, Egypt.
4-(b-d-Glycopyranosylamino)pyrimidin-2(1H)-ones 2a–d
Asolution of the respective sugar (5 mmol) in ethanol (5 ml) was treated
with 1 (0.55 g, 5 mmol) in ethanol (40 ml), and glacial acetic acid (0.1
ml). The mixture was heated under reflux for 2 h (TLC). The solid,
which separated out on cooling, was filtered, washed with ethanol, and
crystallised from ethanol to afford 2a–d in 85–88% yields.
4-(b-d-Glucopyranosylamino)pyrimidin-2(1H)-one (2a): Yield
87%.M.p.202–204°C.1HNMR(DMSO-d6)δ:3.25–3.60(m,2H,H-6'),
4.30–4.90 (m, 8H, H-2', H-3', H-4', H-5', 4xOH), 7.20 (d, 1H,
J = 8.0 Hz, H-1'), 7.25 (d, 1H, J = 5.5 Hz, H-5), 7.72 (d, 1H, J = 5.5 Hz,
H-6), 9.52 (brs, 1H, NH). MS: m/z (%) = 296 [(M+ + Na), 39]. Anal.
Calcd. for C10H15N3O6: C, 43.96; H, 5.53; N, 15.38. Found: C, 43.88;
H, 5.23; N, 15.19%.
4-(b-d-Galactopyranosylamino)pyrimidin-2(1H)-one (2b): Yield
85%. M.p. 181–183°C. H NMR (DMSO-d6) δ: 3.25–3.60 (m, 2H,
H-6'), 4.30–4.80 (m, 8H, H-2', H-3', H-4', H-5', 4xOH), 7.19 (d, 1H,
J = 8.0 Hz, H-1'), 7.26 (d, 1H, J = 5.5 Hz, H-5), 7.88 (d, 1H, J = 5.5 Hz,
H-6), 9.59 (brs, 1H, NH). MS: m/z (%) = 296 [(M+ + Na), 44]. Anal.
Calcd. for C10H15N3O6: C, 43.96; H, 5.53; N, 15.38. Found: C, 43.75;
H, 5.29; N, 15.21%.
4-(2,3,4-Tri-O-acetyl-b-d-xylopyranosylamino)pyrimidin-2(1H)-
one (3d): Yield 96%. M.p. 120–122°C; IR (cm-1): 3395 (NH), 1755
(C=O). 1H NMR (DMSO-d6) δ: 1.96, 1.98, 2.11 (3 s, 9H, 3xCH3CO),
3.78–4.05 (m, 2H, H-5'), 4.75–4.95 (ms, 3H, H-2', H-3', H-4'), 5.18
(d, 1H, J = 9.0 Hz, H-1'), 7.20 (d, 1H, J = 5.5 Hz, H-5), 7.72 (d, 1H,
J = 5.5 Hz, H-6), 9.61 (brs, 1H, NH). MS: m/z (%) = 392 [(M+ +
Na), 49]. Anal. Calcd. for C15H19N3O8: C, 48.78; H, 5.19; N, 11.38.
Found: C, 48.70; H, 5.03; N, 11.20%.
1
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JOURNAL OF CHEMICAL RESEARCH 2007 283
1-(Ethoxycarbonylmethyl)-N4-acetylcytosine (5)
5xCH3CO), 4.17 (m, 2H, H-5'), 4.25 (m, 1H, H-4'), 4.50 (s, 2H, CH2),
5.60 (m, 1H, H-3'), 5.75 (m, 1H, H-2'), 7.15 (d, 1H, J = 5.5 Hz, H-5),
7.25 (d, 1H, J = 2.5 Hz, H-1¢), 8.05 (d, 1H, J = 5.5 Hz, H-6), 10.10
(brs, 1H, NH). MS: m/z (%) = 548 [(M+ + Na), 22]. Anal. Calcd. for
C21H27N5O11: C, 48.00; H, 5.18; N, 13.33. Found: C, 47.80; H, 5.00;
N, 13.21%.
2,3,4,5-Tetra-O-acetyl-d-(–)-ribose2-[4-acetamido-2-oxopyrimidin-
1(2H)-yl]acetylhydrazone (8b): Yield 80%. M.p. 140–142°C.
1H NMR (DMSO-d6) δ: 1.95, 2.03, 2.11, 2.13, 2.15 (5 s, 15H,
5xCH3CO), 4.19 (m, 2H, H-5'), 4.33 (m, 1H, H-4), 4.53 (s, 2H, CH2),
5.69 (m, 1H, H-3), 5.77 (m, 1H, H-2), 7.13 (d, 1H, J = 5.5 Hz, H-5),
7.27 (d, 1H, J = 2.5 Hz, H-1¢), 8.00 (d, 1H, J = 5.5 Hz, H-6), 10.07
(brs, 1H, NH). MS: m/z (%) = 548 [(M+ + Na), 31]. Anal. Calcd. for
C21H27N5O11: C, 48.00; H, 5.18; N, 13.33. Found: C, 47.88; H, 5.07;
N, 13.23%.
2,3,4,5-Tetra-O-acetyl-d-(+)-xylose 2-[4-acetamido-2-oxopyrimidin-
1(2H)-yl]acetylhydrazone (8c): Yield 87%. M.p. 169–171°C.
1H NMR (DMSO-d6) δ: 1.95, 2.03, 2.11, 2.12, 2.15 (5 s, 15H,
5xCH3CO), 4.29 (m, 2H, H-5), 4.39 (m, 1H, H-4), 4.58 (s, 2H, CH2),
5.74 (m, 1H, H-3), 5.88 (m, 1H, H-2), 7.12 (d, 1H, J = 5.5 Hz, H-5),
7.30 (d, 1H, J = 2.5 Hz, H-1¢), 8.03 (d, 1H, J = 5.5 Hz, H-6), 10.00
(brs, 1H, NH). MS: m/z (%) = 548 [(M+ + Na), 19]. Anal. Calcd. for
C21H27N5O11: C, 48.00; H, 5.18; N, 13.33. Found: C, 47.77; H, 5.04;
N, 13.19%.
2,3,4,5,6-Penta-O-acetyl-d-(+)-glucose 2-[4-acetamido-2-oxopyrimidin-
1(2H)-yl]acetylhydrazone (8d): Yield 85%. M.p. 122–123°C. 1H
NMR (DMSO-d6) δ: 1.95, 2.00, 2.04, 2.10, 2.13, 2.15 (6 s, 18H,
6xCH3CO), 4.00–4.11 (m, 2H, H-6), 4.50 (m, 1H, H-5¢), 4.60 (s, 2H,
CH2), 4.70 (m, 1H, H-4), 5.15 (m, 1H, H-3), 5.45 (m, 1H, H-2), 7.12
(d, 1H, J = 5.5 Hz, H-5), 7.27 (d, 1H, J = 2.5 Hz, H-1¢), 8.03 (d, 1H,
J = 5.5 Hz, H-6), 10.00 (brs, 1H, NH). MS: m/z (%) = 620 [(M+ +
Na), 17]. Anal. Calcd. for C24H31N5O13: C, 48.24; H, 5.23; N, 11.72.
Found: C, 48.09; H, 5.11; N, 11.53%.
A solution of 413 (1.53 g, 10 mmol), dry acetone (100 ml), K2CO3
(1.38 g, 10 mmol) and ethyl chloroacetate (1.23 g, 10 mmol)
was refluxed for 5 h (TLC) and then cooled to room temperature.
The resulting precipitate was filtered and the filtrate was evaporated
under reduced pressure. The residue was recrystallised from
ethanol to give 1.79 g (75%) as yellow crystals. M.p. 180–181°C.
1H NMR (DMSO-d6) δ: 1.20 (t, 3H, J = 8.1 Hz, CH3CH2), 2.11 (s,
3H, CH3CO), 4.18 (q, 2H, J = 8.1 Hz, CH3CH2), 4.61 (s, 2H, CH2),
7.20 (d, 1H, J = 5.5 Hz, H-5), 8.05 (d, 1H, J = 5.5 Hz, H-6), 10.84
(brs, 1H, NH). Anal. Calcd. for C10H13N3O4: C, 50.21; H, 5.48; N,
17.56. Found: C, 50.04; H, 5.18; N, 17.33%.
(N4-Acetylcytosin-1-yl)acetohydrazide (6)
A solution of 5 (2.39 g, 10 mmol) in ethanol (30 ml) was refluxed
with hydrazine hydrate (1.25 g, 25 mmol) for 4 h. After cooling it to
room temperature, a white solid appeared. This was recerystallised
1
from ethanol to afford 6 (2.0 g, 89%). M.p. 258–260°C. H NMR
(DMSO-d6) δ: 2.15 (s, 3H, CH3CO), 4.20 (brs, 2H, NH2), 4.34
(s, 2H, CH2), 7.20 (d, 1H, J = 5.5 Hz, H-5), 7.62 (d, 1H, J = 5.5 Hz,
H-6), 9.50 (brs, 1H, NH). Anal. Calcd. for C8H11N5O3: C, 42.67; H,
4.92; N, 31.10. Found: C, 42.50; H, 4.81; N, 30.94%.
Sugar 2-[4-acetamido-2-oxopyrimidin-1(2H)-yl]acetylhydrazones 7a–f
A solution of the respective sugar (10 mmol) in water (3 ml) was
treated with a solution of 6 (2.25 g, 10 mmol) in ethanol (100 ml)
and few drops of glacial acetic acid. The mixture was boiled under
reflux for 4–5 h (TLC). The excess of ethanol was removed under
reduced pressure and the residue was triturated with diethyl ether
(15 ml). The product was filtered, washed with ether, and recrystallised
from ethanol to give 7a–f in 80–88% yield.
L-(+)-Arabinose 2-[4-acetamido-2-oxopyrimidin-1(2H)-yl]acetyl-
1
hydrazone (7a): Yield 88%. M.p. 150–151°C. H NMR (DMSO-d6)
2,3,4,5,6-Penta-O-acetyl-d-(+)-galactose 2-[4-acetamido-2-oxo-
pyrimidin-1(2H)-yl]acetylhydrazone (8e): Yield 85%. M.p. 144–
146°C. 1H NMR (DMSO-d6) δ: 1.95, 2.00, 2.04, 2.10, 2.12, 2.15 (6 s,
18H, 6xCH3CO), 4.08-4.22 (m, 2H, H-6), 4.59 (m, 1H, H-5¢), 4.69 (s,
2H, CH2), 4.76 (m, 1H, H-4), 5.18 (m, 1H, H-3), 5.40 (m, 1H, H-2),
7.13 (d, 1H, J = 5.5 Hz, H-5), 7.30 (d, 1H, J = 2.5 Hz, H-1), 8.03 (d,
1H, J = 5.5 Hz, H-6), 10.03 (brs, 1H, NH). MS: m/z (%) = 620 [(M+ +
Na), 19]. Anal. Calcd. for C24H31N5O13: C, 48.24; H, 5.23; N, 11.72.
Found: C, 48.13; H, 5.10; N, 11.59%.
δ: 2.15 (s, 3H, CH3CO), 3.14–3.40 (m, 3H, H-4', H-5'), 3.49 (s, 1H,
H-3'), 3.60–3.65 (m, 1H, H-2'), 4.39–4.51 (m, 6H, CH2, 4xOH), 7.22
(d, 1H, J = 5.5 Hz, H-5), 7.30 (d, 1H, J = 2.8 Hz, H-1'), 8.00 (d,
1H, J = 5.5 Hz, H-6), 9.88 (brs, 1H, NH). MS: m/z (%) = 380 [(M+
+ Na), 12].
D-(–)-Ribose 2-[4-acetamido-2-oxopyrimidin-1(2H)-yl]acetylhydra-
zone (7b): Yield 80%. M.p. 140–142°C. 1H NMR (DMSO-d6) δ: 2.18
(s, 3H, CH3CO), 3.14–3.52 (m, 5H, H-2', H-3', H-4', H-5'), 3.99–4.21
(brs, 4H, 4xOH), 4.37 (s, 2H, CH2), 7.15 (d, 1H, J = 5.5 Hz, H-5),
7.25 (d, 1H, J = 2.8 Hz, H-1'), 8.02 (d, 1H, J = 5.5 Hz, H-6), 9.85
(brs, 1H, NH). MS: m/z (%) = 380 [(M+ + Na), 16].
D-(+)-Xylose 2-[4-acetamido-2-oxopyrimidin-1(2H)-yl]acetylhydra-
zone (7c): Yield 87%. M.p. 169–171°C; 1H NMR (DMSO-d6) δ: 2.14
(s, 3H, CH3CO), 3.41–3.69 (brm, 3H, H-4', H-5'), 3.59–3.61 (m, 2H,
H-2', H-3'), 4.35–4.88 (m, 6H, CH2, 4xOH), 7.20–7.25 (m, 2H, H-5,
H-1'), 8.01 (d, 1H, J = 5.5 Hz, H-6), 9.90 (brs, 1H, NH). MS: m/z (%)
= 380 [(M+ + Na), 34].
D-(+)-Glucose 2-[4-acetamido-2-oxopyrimidin-1(2H)-yl]acetylhydra-
zone (7d): Yield 85%. M.p. 122–123°C. 1H NMR (DMSO-d6) δ: 2.18
(s, 3H, CH3CO), 3.44–3.89 (m, 5H, H-3', H-4', H-5', H-6'), 4.27–4.88
(m, 8H, CH2, H-2', 5xOH), 7.18 (d, 1H, J = 5.5 Hz, H-5), 7.27 (d, 1H,
J = 2.8 Hz, H-1'), 8.07 (d, 1H, J = 5.5 Hz, H-6), 9.89 (brs, 1H, NH).
MS: m/z (%) = 410 [(M+ + Na), 11].
D-(+)-Galactose 2-[4-acetamido-2-oxopyrimidin-1(2H)-yl]acetylhydra-
zone (7e): Yield 85%. M.p. 144–146°C; 1H NMR (DMSO-d6)
δ: 2.13 (s, 3H, CH3CO), 3.34–3.93 (m, 3H, H-5', H-6'), 4.12–4.23 (m,
3H, H-2', H-3', H-4'), 4.33–4.80 (m, 7H, CH2, 5xOH), 7.15 (d, 1H,
J = 5.5 Hz, H-5), 7.23 (d, 1H, J = 2.8 Hz, H-1'), 8.00 (d, 1H, J = 5.5 Hz,
H-6), 9.88 (brs, 1H, NH). MS: m/z (%) = 410 [(M+ + Na), 16].
D-(+)-Mannose 2-[4-acetamido-2-oxopyrimidin-1(2H)-yl]acetylhydra-
zone (7f): Yield 82%. M.p. 166–167°C. 1H NMR (DMSO-d6) δ: 2.16
(s, 3H, CH3CO), 3.44–3.78 (m, 6H, H-2', H-3', H-4', H-5', H-6'),
4.36–4.50 (m, 7H, CH2, 5xOH), 7.17 (d, 1H, J = 5.5 Hz, H-5), 7.25
(d, 1H, J = 2.8 Hz, H-1'), 8.01 (d, 1H, J = 5.5 Hz, H-6), 9.86 (brs, 1H,
NH). MS: m/z (%) = 410 [(M+ + Na), 19].
2,3,4,5,6-Penta-O-acetyl-d-(+)-mannose 2-[4-acetamido-2-oxo-
pyrimidin-1(2H)-yl]acetylhydrazone (8f): Yield 82%. M.p. 166–
1
167°C. H NMR (DMSO-d6) δ: 1.98, 2.02, 2.04, 2.11, 2.13, 2.15
(6 s, 18H, 6xCH3CO), 4.13–4.33 (m, 2H, H-6), 4.57 (m, 1H, H-5¢),
4.70 (s, 2H, CH2), 4.79 (m, 1H, H-4), 5.20 (m, 1H, H-3), 5.47 (m,
1H, H-2), 7.14 (d, 1H, J = 5.5 Hz, H-5), 7.30 (d, 1H, J = 2.5 Hz, H-1),
8.06 (d, 1H, J = 5.5 Hz, H-6), 10.05 (brs, 1H, NH). MS: m/z (%) = 620
[(M+ + Na), 24]. Anal. Calcd. for C24H31N5O13: C, 48.24; H, 5.23;
N, 11.72. Found: C, 48.08; H, 5.14; N, 11.57%.
Received 27 March 2007; accepted 17 May 2007
Paper 07/4564 doi: 10.3184/030823407X215889
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Sugar tetra-O-acetyl- and Sugar penta-O-acetyl-2-[4-acetamido-
2-oxopyrimidin-1(2H)-yl]acetylhydrazones 8a–f
A cold solution of sugar hydrazones 7a–f (1 mmol) in dry pyridine
(3 ml) was treated with acetic anhydride (3 ml). The reaction mixture
was left overnight with stirring, then poured onto crushed ice and
the separated product was filtered off, washed with water, dried,
and crystallised from ethanol-water (2: 8, v/v) to afford 8a–f in 80–
85% yields.
2,3,4,5-Tetra-O-acetyl-l-(+)-arabinose
2-[4-acetamido-2-oxo-
pyrimidin-1(2H)-yl]acetylhydrazone (8a): Yield 88%. M.p. 150–
151°C. 1H NMR (DMSO-d6) δ: 1.95, 2.04, 2.10, 2.13, 2.15 (5 s, 15H,
PAPER: 07/4564