4-alkylated 2-(2,3,5-tri-O-acyl-β-D-ribofuranosyl)- and 2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1,2,4-triazine-3,5-diones

Article abstract of DOI:10.1134/S1070428017040121

The alkylation of 2-(2,3,5-tri-O-acyl-β-D-ribofuranosyl)- and 2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)- 1,2,4-triazine-3,5-diones with benzyl halides afforded the corresponding 4-benzyl derivatives whose structure was determined by spectral methods, including X-ray analysis. Some of the synthesized compounds were tested for antibacterial and antitumor activity.

Full text of DOI:10.1134/S1070428017040121

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 4, pp. 573–576. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © A.A. Harutyunyan, H.A. Panosyan, R.A. Tamazyan, A.G. Aivazyan, G.G. Danagulyan, 2017, published in Zhurnal Organicheskoi
Khimii, 2017, Vol. 53, No. 4, pp. 567–570.
4-Alkylated 2-(2,3,5-Tri-O-acyl-β-D-ribofuranosyl)-
and 2-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-
1,2,4-triazine-3,5-diones
A. A. Harutyunyana, b,* H. A. Panosyana, R. A. Tamazyana,
A. G. Aivazyana, and G. G. Danagulyana, b
a Mndzhoyan Institute of Fine Organic Chemistry, Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
*e-mail: harutyunyan.arthur@yahoo.com
b Russian–Armenian (Slavic) University, ul. Ovsela Emina 123, Yerevan, 0051 Armenia
Received October 21, 2016
Abstract—The alkylation of 2-(2,3,5-tri-O-acyl-β-D-ribofuranosyl)- and 2-(2,3,4,6-tetra-O-acetyl-β-D-gluco-
pyranosyl)-1,2,4-triazine-3,5-diones with benzyl halides afforded the corresponding 4-benzyl derivatives whose
structure was determined by spectral methods, including X-ray analysis. Some of the synthesized compounds
were tested for antibacterial and antitumor activity.
DOI: 10.1134/S1070428017040121
6-Azauracil and its β-D-ribofuranosyl and tri-O-
acetyl-β-D-ribofuranosyl derivatives are active anti-
tumor agents which also exhibit antiviral, immuno-
suppressive, and other biological activities [1–3].
Various 6-azauracil derivatives, nucleosides derived
therefrom, and acyclic nucleoside analogs have been
reported as promising antiviral, antibacterial, and anti-
enzyme compounds [4, 5]. Although 6-azauracil be-
longs to the 1,2,4-triazine series, in terms of bioorganic
and pharmaceutical chemistry it is regarded primarily
as 6-aza analog of uracil acting as pyrimidine ex-
change antimetabolite. Therefore, synthesis of new
6-azauracil derivatives and study of their biological
properties are important problems.
tion of nucleosides 4a, 4b, and 5 with alkyl halides in
DMF in the presence of potassium carbonate afforded
previously unknown 4-alkyl derivatives 6a–6d and
7a–7c (Scheme 1).
The structure of compound 6c was unambiguously
determined by X-ray analysis (see table), which
directly confirmed that the glycosylation of 3,5-bis(tri-
methylsiloxy)-1,2,4-triazine (1) with 1,2,3,5-tetra-O-
acetyl-β-D-ribofuranose in the presence of SnCl4 yields
exclusively anomer 4a with β-configuration of the
anomeric carbon atom. The benzene and triazine rings
in molecule 6c in crystal are almost planar, and devia-
tions of atoms from the mean-square planes do not
exceed 0.0082(1) and 0.0138(2) Å, respectively. The
ribofuranose ring adopts an envelope conformation
with the C16, C17, C19, and O20 atoms lying in one plane
within 0.0199(1) Å and the C18 atom deviating from
that plane by 0.5157(1) Å. The dihedral angles formed
by the ribose envelope plane, on the one hand, and
triazine and benzene rings, on the other, are 83.128(2)
and 69.323(2)°, respectively.
In continuation of our studies on the synthesis and
biological activity of nitrogen heterocycles [6], in this
work we performed glycosylation of 3,5-bis(trimethyl-
siloxy)-1,2,4-triazine (1) with peracylated β-D-ribo-
furanoses 2a and 2b and 1,2,3,4,6-penta-O-acetyl-β-D-
glucopyranose (3) to obtain 2-(2,3,5-tri-O-acyl-β-D-
ribofuranosyl)- and 2-(tetra-O-acetyl-β-D-glucopyra-
nosyl)-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-diones 4a,
4b, and 5 (Scheme 1) [7]. 2-(2,3,5-Tri-O-acetyl-β-D-
ribofuranosyl)-1,2,4-triazine-3,5-dione (4a) was isolat-
ed as a thick oily material which was subjected to al-
kylation without preliminary purification. The alkyla-
The antibacterial activity of compounds 6a, 6b and
7a–7c was assessed against gram-positive Staphylo-
coccus aureus 209p and S. aureus 1 and gram-negative
Shigella flexneri 6858 and Escherichia coli 0-55. Only
glucopyranoside 7b showed a weak antibacterial
573

HARUTYUNYAN et al.
574
Scheme 1.
O
N
O
N
R'
OSiMe3
HN
N
O
O
OAc
N
N
SnCl4
R'X, K2CO3
N
RO
O
O
RO
RO
+
N
N
Me3SiO
RO
OR
O
OR OR
OR OR
1
2a, 2b
4a, 4b
6a–6d
O
O
R'
HN
N
O
AcO
N
N
SnCl4
R'X, K2CO3
O
O
N
O
N
1
+
OAc
AcO
AcO
O
OAc
OAc
OAc
AcO
AcO
AcO
AcO
OAc
OAc
3
5
7a–7c
2, 4, R = Ac (a), Bz (b); 6, R = Ac, R′ = Bu (a); R = Bz, R′ = 4-HO-3-MeOC(O)C6H3CH2 (b); R = Ac, R′ = PhCH2 (c),
3-Br-4-MeOC6H3CH2 (d); 7, R′ = 4-MeO-3-O2NC6H3CH2 (a), 3-Br-4-MeOC6H3CH2 (b), 2-ClC6H4CH2 (c).
activity against the four bacterial strains tested, where-
as the other compounds turned out to be completely
inactive. Nucleosides 6b, 7a, and 7b showed no
antitumor activity against early P388 ascite T-cell
leukosis.
pound 6c were obtained at room temperature with
an Enraf Nonius CAD-4 automated diffractometer
(Mo Kα radiation, graphite monochromator, θ/2θ scan-
ning) [8, 9]. The progress of reactions was monitored
by TLC on Silufol UV-254 plates using 2-methyl-
propan-1-ol as eluent; spots were detected by treat-
ment with iodine vapor.
EXPERIMENTAL
Compounds 6a–6d and 7a–7c. A mixture of
0.01 mol of 2-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-,
2-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-, or
2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-2,3,4,5-
tetrahydro-1,2,4-triazine-3,5-dione 4a, 4b, or 5, 1.38 g
(0.01 mol) of potassium carbonate, and 0.01 mol of the
corresponding alkyl halide in 30 mL of anhydrous
DMF was heated for 4 h at 70‒80°C. The mixture was
poured onto 50 g of ice and kept for 4 h in the cold,
and the precipitate was filtered off, thoroughly washed
with ice water, and recrystallized from ethanol.
The IR spectra were recorded on a Nicolet Avatar
330 spectrometer from samples dispersed in mineral
1
oil. The H and 13C NMR spectra were measured on
a Varian Mercury-300 VX instrument at 300.8 and
75.46 MHz, respectively, using tetramethylsilane as
internal standard. The X-ray diffraction data for com-
C33
C12
C11
O4
C31
C13
C9
O30
C16 C17
O32
C3
C10
N3
4-Butyl-2-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-
2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione (6a).
Yield 50%, mp 81‒82°C, Rf 0.18. IR spectrum, ν,
C15
O26
C14
C18
O24
C29
C19
N2
N1
C27
O28
C6
O20
C21
O7
1
cm–1: 1757, 1720, 1674. H NMR spectrum (CDCl3),
C8
δ, ppm: 0.95 t (3H, CH3CH2, J = 7.3 Hz), 1.31‒1.44 m
(2H, CH3CH2), 1.57‒1.68 m (2H, CH2C2H5); 2.08 s,
2.11 s, and 2.12 s (3H each, COCH3); 3.90 t (2H,
NCH2, J = 7.5 Hz), 4.16 d.d (1H, OCH2, J = 11.5,
5.1 Hz), 4.35‒4.37 d.d.d (1H, 4-H, J = 5.8, 5.2,
C25
C23
O22
Structure of the molecule of 4-benzyl-2-(tri-O-acetyl-β-D-
ribofuranosyl)-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione
(6c) according to the X-ray diffraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 4 2017

4-ALKYLATED 2-(2,3,5-TRI-O-ACYL-β-D-RIBOFURANOSYL)- ...
575
Crystallographic data for 4-benzyl-2-(tri-O-acetyl-β-D-ribo-
furanosyl)-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione (6c)
3.7 Hz), 4.39 d.d (1H, OCH2), 5.43 d.d (1H, 3-H, J =
5.8, 5.6 Hz), 5.64 d.d (1H, 2-H, J = 5.6, 3.4 Hz),
6.31 d.d (1H, 1-H, J = 3.4 Hz), 7.46 s (1H, 6′-H).
13C NMR spectrum (CDCl3), δC, ppm: 13.7 (CH3);
20.1, 20.5, 20.5 (COCH3); 20.8 (CH2), 29.2 (CH2),
40.9 (NCH2), 63.3 (OCH2), 70.7 (C3), 72.9 (C2), 79.5
(C4), 89.3 (C1), 135.8 (NCH), 148.4 (NCO), 155.3
(NCO); 169.5, 169.6, 170.5 (COCH3). Found, %:
C 50.43; H 5.67; N 10.21. C18H25N3O9. Calculated, %:
C 50.58; H 5.90; N 9.83.
Formula
Molecular weight
C21H23N3O9
461.42
Monoclinic
P21
Crystal system
Space group
a, Å
b, Å
c, Å
08.6424(17)
08.4641(17)
15.084(3)
Methyl 2-hydroxy-5-{[2-(2,3,5-tri-O-benzoyl-β-
D-ribofuranosyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-
triazin-4-yl]methyl}benzoate (6b). Yield 58%,
mp 128‒130°C, Rf 0.55. IR spectrum, ν, cm–1: 3190,
1733, 1673, 1601. NMR spectrum 1H (CDCl3), δ, ppm:
3.93 s (3H, OCH3), 4.53 d.d (1H, OCH2, J = 12.0,
4.5 Hz), 4.75 m (1H, 4-H), 4.83 d.d (1H, OCH2, J =
12.0, 3.7 Hz), 4.99 s (2H, NCH2), 5.97 d.d (1H, 3-H,
J = 6.0, 5.5 Hz), 6.08 d.d (1H, 2-H, J = 5.5, 3.4 Hz),
6.60 d (1H, 1-H, J = 3.4 Hz), 6.92 d (1H, 3″-H, J =
8.6 Hz); 7.34‒7.46 m (6H), 7.53‒7.62 m (4H), 7.92‒
7.99 m (5H), and 8.05‒8.09 m (2H) (Harom); 10.79 s
(1H, OH). 13C NMR spectrum (CDCl3), δC, ppm: 43.5
(NCH2), 52.4 (OCH3), 63.5 (OCH2), 71.7 (OCH), 73.7
(OCH), 80.3 (OCH), 89.5 (OCH), 135.9 (N=CH),
148.5 (NC=O), 155.2 (NC=O); 165.2, 165.4, 166.1
(OCO). Found, %: C 63.61; H 3.93; N 6.04.
C38H31N3O12. Calculated, %: C 63.24; H 4.33; N 5.82.
β, deg
V, Å3
94.67(3)
1099.7(4)
2
Z
dcalc, g/cm3
μ(MoKα), mm–1
F(000)
1.393
0.110
484
Crystal size, mm
Temperature, K
Radiation wavelength, Å
θmin/θmax, deg
hkl ranges
0.12×0.24×0.40
293
0.71073
1.4/30.0
000 ≤ h ≤ 12
–11 ≤ k ≤ 11
–21 ≤ l ≤ 21
Total number of reflections
7207
Number of reflections
with I > 2.0σ(I)
3854
6376
4-Benzyl-2-(2,3,5-tri-O-acetyl-β-D-ribofura-
nosyl)-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione
(6c). Yield 62%, mp 138‒139°C, Rf10.58. IR spectrum,
ν, cm–1: 1757, 1737, 1717, 1671. H NMR spectrum
(CDCl3), δ, ppm: 2.07 s, 2.10 s, and 2.10 s (3H each,
OAc); 4.15 d.d (1H, 5-H), 4.33 d.d.d (1H, 4-H),
4.38 d.d (1H, 5-H), 5.07 s (2H, NCH2), 5.43 d.d (1H,
3-H), 5.63 d.d (1H, 2-H), 6.32 d (1H, 1-H), 7.29‒
7.36 m (3H, Ph), 7.44‒7.49 m (2H, Ph), 7.50 s (1H,
6′-H). 13C NMR spectrum (CDCl3), δC, ppm: 20.5,
20.5, 20.7 (COCH3); 44.2 (CH2), 63.3 (C5), 70.7 (C3),
72.8 (C2), 79.6 (C4), 89.2 (C1), 128.4 (Cp), 128.7 and
128.7 (Co, Cm), 135.0 (Ci), 135.9 (N=CH), 148.5
(NC=O), 155.2 (NC=O); 169.5, 169.6, 170.5
(COCH3). Found, %: C 55.25; H 5.36; N 9.41.
C21H23N3O9. Calculated, %: C 54.66; H 5.02; N 9.11.
Number of independent
reflections
Number of variables
357
R
0.0530
0.1077
1.04
wR2
Goodness of fit S
5-H), 4.33 d.d.d (1H, 4-H), 4.38 d.d (1H, 5-H), 4.98 s
(2H, CH2), 5.42 d.d (1H, 3-H), 5.63 d.d (1H, 2-H),
6.32 d (1H, 1-H), 6.84 d (1H, 3-H, J = 8.5 Hz),
7.43 d.d (1H, 4″-H, J = 8.5, 2.2 Hz), 7.50 s (1H, 6′-H),
7.70 d (1H, 6″-H, J = 2.2 Hz). 13C NMR spectrum
(CDCl3), δC, ppm: 20.6, 20.6, 20.8 (CH3CO); 43.2
(CH2), 56.4 (OCH3), 63.3 (C5), 70.7 (C3), 72.9 (C2),
79.6 (C4), 89.2 (C1), 111.8, 112.2, 128.5, 130.3, 134.7,
135.8 (N=CH), 135.8, 148.3 (NC=O), 155.1 (NC=O),
156.0, 169.5 (COCH3), 169.6 (COCH3), 170.4
(COCH3). Found, %: C 46.21; H 3.87; Br 14.24;
N 7.18. C22H24BrN3O10. Calculated, %: C 46.33;
H 4.24; Br 14.01; N 7.37.
4-(3-Bromo-4-methoxybenzyl)-2-(2,3,5-tri-O-
acetyl-β-D-ribofuranosyl)-2,3,4,5-tetrahydro-1,2,4-
triazine-3,5-dione (6d). Yield 62%, mp 111‒113°C,
Rf 0.36. IR spectrum, ν, cm–1: 1753, 1684, 1600.
1H NMR spectrum (CDCl3), δ, ppm: 2.07 s, 2.11 s, and
2.11 s (3H each, OAc); 3.88 s (OCH3), 4.15 d.d (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 4 2017

HARUTYUNYAN et al.
576
4-(4-Methoxy-3-nitrobenzyl)-2-(2,3,4,6-tetra-
4-(2-Chlorobenzyl)-2-(2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosyl)-2,3,4,5-tetrahydro-1,2,4-triazine-
3,5-dione (7c). Yield 67%, mp 154‒156°C, Rf 0.64. IR
O-acetyl-β-D-glucopyranosyl)-2,3,4,5-tetrahydro-
1,2,4-triazine-3,5-dione (7a). Yield 62%, mp 148‒
150°C, Rf 0.33. IR spectrum, ν, cm–1: 1754, 1723,
1
spectrum, ν, cm–1: 1754, 1747, 1678, 1593. H NMR
1
1678, 1619. H NMR spectrum (CDCl3), δ, ppm:
spectrum (DMSO-d6), δ, ppm: 1.91 s, 1.97 s, 2.02 s,
2.03 s (3H each, Ac); 3.97‒4.04 m (1H) and 4.18‒
4.24 m (2H) (5-H, 6-H); 5.01 t (1H, 4-H, J = 9.1 Hz),
5.08 s (2H, NCH2), 5.40–5.51 m (2H, 2-H, 3-H),
6.10 d (1H, 1-H, J = 8.0 Hz); 7.03‒7.08 m, 7.19‒
7.28 m, and 7.36‒7.42 m (4H, C6H4); 7.62 s (1H,
6′-H). Found, %: C 50.45; H 4.45; Cl 6.17; N 7.17.
C24H26ClN3O11. Calculated, %: C 50.76; H 4.61;
Cl 6.24; N 7.40.
1.91 s, 2.02 s, 2.05 s, and 2.07 s (3H each, OAc);
3.91 d.d.d (1H, 5-H, J = 10.1, 4.6, 2.3 Hz), 3.95 s (3H,
OCH3), 4.14 d.d (1H, 6-H, J = 12.5, 2.2 Hz), 4.26 d.d
(1H, 6-H, J = 12.5, 4.8 Hz), 5.04 s (2H, NCH2),
5.17 d.d (1H, 4-H, J = 10.1, 9.5 Hz), 5.35 d.d (1H,
3-H, J = 9.5, 9.5 Hz), 5.64 d.d (1H, 2-H, J = 9.5,
9.2 Hz), 5.88 d (1H, 1-H, J = 9.2 Hz), 7.04 d (1H,
H
H
arom, J = 8.6 Hz), 7.51 s (1H, 6′-H), 7.68 d.d (1H,
arom, J = 8.6, 2.3 Hz), 7.95 d (1H, Harom, J = 2.3 Hz).
This study was performed in the framework of the
Program for the Development of the Russian–
Armenian University.
13C NMR spectrum (CDCl3), δC, ppm: 20.5, 20.6, 20.6,
20.7 (CH3CO), 43.0 (CH2), 56.7 (OCH3), 61.6 (C6),
67.7 (C4), 68.3 (C2), 73.6 (C3), 74.5 (C5), 83.1 (C1),
113.7, 126.8, 127.3, 135.6, 135.6 (N=CH), 148.7
(NC=O), 154.9 (NC=O); 169.0, 169.4, 170.1, 170.6
(COCH3). Found, %: C 49.55; H 4.93; N 9.63.
C25H28N4O14. Calculated, %: C 49.35; H 4.64; N 9.21.
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1
1678, 1619. H NMR spectrum (CDCl3), δ, ppm:
1.90 s, 2.02 s, 2.06 s, and 2.08 s (3H each, OAc);
3.88 s (3H, OCH3), 3.91 d.d.d (1H, 5-H, J = 10.1, 4.8,
2.2 Hz), 4.14 d.d (1H, 6-H, J = 12.5, 2.2 Hz), 4.26 d.d
(1H, 6-H, J = 12.5, 4.8 Hz), 4.98 s (2H, NCH2),
5.17 d.d (1H, 4-H, J = 10.1, 9.5 Hz), 5.35 d.d (1H,
3-H, J = 9.5, 9.3 Hz), 5.62 d.d (1H, 2-H, J = 9.3,
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H
arom, J = 8.5 Hz), 7.41 d.d (1H, Harom, J = 8.5,
2.2 Hz), 7.49 s (1H, 6′-H), 7.66 d (1H, Harom, J =
2.2 Hz). 13C NMR spectrum (CDCl3), δC, ppm: 20.5,
20.6, 20.6, 20.8 (CH3CO); 43.2 (CH2), 56.4 (OCH3),
61.7 (C6), 67.8 (C4), 68.4 (C2), 73.7 (C3), 74.5 (C5),
83.0 (C1), 111.8, 128.6, 130.2, 134.5, 135.7 (N=CH),
148.7 (NC=O), 154.9 (NC=O), 156.1; 169.0, 169.4,
170.2, 170.6 (COCH3). Found, %: C 46.5; H 4.45;
Br 12.24; N 6.90. C25H28BrN3O12. Calculated, %:
C 46.75; H 4.39; Br 12.44; N 6.54.
vol. 40, p. 786.
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Czech Republic, Institute of Physics, 2006.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 4 2017