Nucleosides 515: Synthesis of novel 1,2,4-triazolo[3,4-c]-1,2,4-triazole nucleosides

Article abstract of DOI:10.1080/15257770903368377

Ribosylation of 3-methylthio-5-phenyl-1,2,4-triazole (1) with ribose derivative 2 gave the protected 1,2,4-triazole-nucleoside 3, which reacted with hydrazine hydrate to afford the 3-hydrazino-1,2,4-triazole derivative 5. Reaction of 5 with aromatic aldeh

Full text of DOI:10.1080/15257770903368377

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Nucleosides 515: Synthesis of Novel
1,2,4-Triazolo[3,4-c]-1,2,4-Triazole
Nucleosides
M. A. N. Mosselhi a & R. Neidlein b
a Chemistry Department, Faculty of Science, Cairo University, Giza,
Egypt
b Pharmazeutisch-Chemisches Institut, Heidelberg, Germany
Version of record first published: 24 Nov 2009.
To cite this article: M. A. N. Mosselhi & R. Neidlein (2009): Nucleosides 515: Synthesis of Novel 1,2,4-
Triazolo[3,4-c]-1,2,4-Triazole Nucleosides, Nucleosides, Nucleotides and Nucleic Acids, 28:11-12,
1095-1103
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Nucleosides, Nucleotides and Nucleic Acids, 28:1095–1103, 2009
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770903368377
NUCLEOSIDES 515: SYNTHESIS OF NOVEL
1,2,4-TRIAZOLO[3,4-c]-1,2,4-TRIAZOLE NUCLEOSIDES
M. A. N. Mosselhi1 and R. Neidlein2
1Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
2Pharmazeutisch-Chemisches Institut, Heidelberg, Germany
2
X
N
N
Ph
CH3S
N
N
4 steps
N
N
Ph
N
N
Ph
SCH3
N
H
O
BzO
BzO
N
N
O
HO
HO
OBz
OH
Ribosylation of 3-methylthio-5-phenyl-1,2,4-triazole (1) with ribose derivative 2 gave the
protected 1,2,4-triazole-nucleoside 3, which reacted with hydrazine hydrate to afford the 3-hydrazino-
1,2,4-triazole derivative 5. Reaction of 5 with aromatic aldehydes yielded the corresponding
hydrazones 6, which cyclized under bromination in acetic acid to give 8. Debenzoylation of 8 afforded
novel 1,2,4-triazolo[3,4-c]-1,2,4-triazole nucleosides 9.
Keywords Ribosylation; 3-methylthio-5-phenyl-1,2,4-triazole; 1,2,4-triazole-nucleoside;
1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose; 1,2,4-triazolo[3,4-c]-1,2,4-triazole nucle-
osides
Received 12 May 2009; accepted 6 October 2009.
Present address for M.A.N.M.: Taif University, Faculty of Science, Department of Chemistry Taif,
Saudi Arabia.
The authors thank den Deutschen Forschungsgemeinschaft (DFG) for the financial support. The
authors also thank Prof. Dr. Helmut Duddeck, Institut fuer Organische Chemie, Hannover, Germany for
measuring the NOE-1H NMR spectrum of compound 3.
Address correspondence to M.A.N. Mossehli, Chemistry Department, Faculty of Science, Cairo
University, Giza 12613, Egypt. E-mail: mosselhi2008@hotmail.com
1095

1096
INTRODUCTION
M. A. N. Mosselhi and R. Neidlein
1,2,4-Triazoles represent a class of heterocyclic compounds of sig-
nificant importance in agriculture and medicine.[1,2] Compounds with
1,2,4-triazole moiety also have received considerable attention among
medicinal chemists because molecules with these structural features have
been found to display a wide range of potent biological activities, such
as antihypertensive,[2] antifungal,[3] and antibacterial[4] activities. Appro-
priately functionalized 1,2,4-triazoles, such as 4-[3,5-bis(2-hydroxyphenyl)-
1,2,4-triazole-1-yl]benzoic acid, have been shown to selectively form a com-
plex with iron (III), which is useful in iron overload therapy.[5]
Considering the important biological properties of 1, 2, 4-triazole
compounds, several efficient triazole syntheses have been reported.[6,7,8]
According to these interesting biological activities, and as a part of our
research program on the nucleoside chemistry, we report here a synthesis
of two novel fused 1,2,4-triazole nucleosides. So far in the literature the few
examples of 1,2,4-triazolo-[1,2,4]triazole, include 1,2,4-triazolo[1,2-a],[9]
1,2,4-triazolo[3,4-c],[10–12] and 1,2,4-triazolo[3,4-b] [1,2,4]triazoles.[13]
RESULTS AND DISCUSSION
The starting material, 3-methylthio-5-phenyl-1(2H)[1,2,4]triazole (1),
was prepared according to the literature reported method.[14] The ri-
bosylation of 1 with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (2)
was carried out in two different methods to give the benzoylated nu-
cleoside; 3-methylthio-5-phenyl-2-(2ꢁ,3ꢁ,5ꢁ-tri-O-benzoyl-β-D-ribofuranosyl)-
(2H)-1,2,4-triazole 3 or 3-methylthio-5-phenyl-4-(2ꢁ,3ꢁ,5ꢁ-tri-O-benzoyl-β-D-
ribofuranosyl)-(4H)-1,2,4-triazole 4 (see Scheme 1). The first method was
silylation of 1 by reflux in hexamethyl disilazane (HMDS) with ammonium
sulfate as a catalyst and then stirring of the silylated product with ribose
derivative 2 in dry acetonitrite and TMS-triflate (CF3SO2OSiMe3) at room
temperature for 48 hours. This method afforded a product in 60% yield.
The second method was stirring of the lithium salt of compound 1
with 2 in tetrahydrofurane and TMS-triflate at −78◦C for 5 hours and
followed by stirring at room temperature for 24 hours. This method yielded
a product in 90%. The structure of the latter product was established and
confirmed on the bases of its elemental analyses and spectral data. Thus, the
analytical data for it revealed a molecular formula C35H29N3O7S (m/z 635).
1
Its H NMR spectrum showed a doublet at δ 6.1 assigned to the anomeric
proton of the ribose moiety with a spin-spin coupling constant equal to
4.1 Hz, which corresponds to a diaxial orientation for the 1ꢁ- and 2ꢁ- H
protons; that is, the β-configuration.[15–19] The ultraviolet (UV) spectra of
the above product revealed λmax (ethanol) at 249 nm, which is similar to
that of 5-methyl-4-phenyl-3-(tri-O-acetyl-β-D-xylopyranosylmercapto)-1,2,4-

1,2,4-Triazolo[3,4-c]-1,2,4-triazole Nucleosides
1097
N
N
N
N H
SCH3
Ph
SCH3
Ph
N
H
N
1
/
HMDS (NH4)2SO4
1)
2)
OAc
O
2
OBz
BzO
Triflate
/
OBz
N
N
N
Ph
CH3S
Ph
SCH3
N
N
N
O
BzO
O
4
BzO
BzO
OBz
BzO
OBz
3
NH2NH2/
EtOH
N
N
Ph
N
H
Ph
N
C
X
NH2NH
H
X
CHO
N
N
N
N
BzO
BzO
O
O
BzO
BzO
OBz
OBz
6
5
SCHEME 1 X = a, H, b, CH3.
triazole [λmax (ethanol) 245 nm].[19] Furthermore, the irradiation of
the anomeric proton of 3 gave a clear nuclear Overhauser effect (NOE)
response from the ortho protons of the 5-phenyl group due to spatial neigh-
borhood. These findings confirmed the structure of 3 and the structure 4
was discarded.

1098
M. A. N. Mosselhi and R. Neidlein
The reaction of compound 3 with hydrazine hydrate under reflux
in ethanol afforded 3-hydrazino-2-(2ꢁ,3ꢁ,5ꢁ-tri-O-benzoyl)-β-D-ribo-furanozyl-
5-phenyl-(2H)-1,2,4-triazole (5). Furthermore compound 5 reacted with
aromatic aldehydes in presence of acetic acid to give the corresponding
hydrazones (6) in good yields. Next, we examined the bromination of 6
in acetic acid and anhydrous sodium acetate at room temperature. Thus,
it afforded directly the triazolotriazole nucleosides (8) via in situ formed
hydrazonoyl halide derivatives (7) that were not isolated (see Scheme 2).
However, the debenzoylation of compounds 8 in methanol containing
sodium methoxide was succeeful and gave the free 1,2,4-triazolo[3,4-c]-
1,2,4-triazole nucleosides (9) (Scheme 2). Structural assignments of the
Br
N
N
Ph
N
H
N
X
Ph
N
H
X
C
H
N
N
N
Br2/ AcOH/
NaOAc
N
N
BzO
O
BzO
BzO
O
6
OBz
BzO
OBz
7
X
N
NaOCH3 / CH3OH
N
N
Ph
N
N
BzO
BzO
O
OBz
8
X
N
N
N
Ph
N
N
O
HO
OH
HO
9
X= a, H; b, CH3
SCHEME 2

1,2,4-Triazolo[3,4-c]-1,2,4-triazole Nucleosides
1099
products 8 and 9 isolated were made on the basis of their mass spectrometry
1
(MS), H NMR, 13C NMR, infrared (IR) spectra, and elemental analyses
(see Experimental section). For example, the absence of the methine and
nitrogen protons of hydrazones 6 in the 1H NMR spectra of 8 or 9 confirmed
the structure.
EXPERIMENTAL
All chemicals were supplied by Sigma-Aldrich and Merck (Germany).
IR spectra were recorded for KBr discs on Testscan Shimadzu FTIR 8000
1
Series and Bruker IFS 113V spectrophotometers (Germany), H-NMR and
13C-spectra were recorded on a Bruker Ac 250 MHz and on a Varian Gemini
200 MHz NMR spectrometer (Germany) using trimethylsilane (TMS) as
an internal standard; NOE-diffraction was recorded on a Bruker AM 400
MHz spectrometer (Germany); UV spectra were recorded on a Perkin
Elmer spectrophotometer Lambda 5 (USA); MS spectra were recorded on
Varian Mat 711 spectrometer (electron ion [EI] and fast atom bambard-
ment [FAB] in nitrobenzyl alcohol [NBA]). Thin layer chromatography
(TLC) was performed on silica gel sheets F 1550 LS 254 of Schleicher &
Schull and column chromatography on Merck silica gel 60 (particle size
0.063–0.20 mm). Melting points were measured on Gallenkamp melting
point apparatus (UK) and are uncorrected. Elemental analyses were carried
out at Pharmazeutisch-Chemisches Institut (Heidelberg, Germany) and
at Microanalytical Centre (Cairo University, Egypt). 3-Methylthio-5-phenyl-
1,2,4-triazole[10] was prepared as previously described.
3-Methylthio-5-phenyl-2-(2ꢁ,3ꢁ,5ꢁ-tri-O-benzoyl-β-
D-ribofuranosyl)-(2H)-1,2,4-triazole 3
Method A. A mixture of 1 (20 mmol) and dry hexamethyldisilazane
(100 ml) was heated under reflux for 10 hours with a catalytic amount
of ammonium sulfate (100 mg). After the clear solution was cooled, it
was evaporated to dryness under anhydrous condition to give the silylated
derivative, which directly was dissolved in 50 ml of dry 1,2-dichloroethane.
To this a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (2) (9.6
g, 19.6 mmol) in dry 1,2-dichloroethane (50 ml) was added. The mixture
was cooled in ice bath and a solution of trimethylsilyl trifluoromethanesul-
fonate (4 ml, 20 mmol) in dry 1,2-dichloroethane (20 ml), which was added
dropwise. It was stirred at room temperature for 24 hours, diluted with
chloroform (500 ml), washed with a saturated solution of aqueous sodium
bicarbonate (200 ml) and water (3 × 150 ml), and dried over anhydrous
sodium sulfate. The solvent was removed in vacuo and the residue was
chromatographed on silica gel with chloroform as eluent to afford white

1100
M. A. N. Mosselhi and R. Neidlein
solid, which was crystallized from ethanol to yield colorless crystals of the
corresponding nucleoside derivative 3.
Method B. A mixture of 1 (20 mmol) and sodium hydride (20 mmol)
was dissolved in dry tetrahydrofurane (100 ml) at −70◦C and stirred for
1 hour. To this mixture a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-
ribofuranose (2) (9.6 g, 19.6 mmol) in dry tetrahydrofurane (40 ml) was
then added and the mixture was stirred at −70◦C for 5 hours. The excess
solvent was evaporated and the residue was extracted from chloroform and
purified by chromatography as in the above method to give 3, which is
identical in all physical constants with that obtained from the above method.
Compound 3: Yield (60%, method A and 90% method B); m.p.
158–159◦C; ν (cm−1) (KBr) 1750 (CO); λmax (EtOH) (249 nm); δH (CDCl3):
2.61 (s, 3H, SCH3), 4.6–4.9 (m, 3H, 2 H-5ꢁ, H-4ꢁ), 6.1 (d, 1H, H-1ꢁ, J1 ,2
=
ꢁ
ꢁ
4.1 Hz), 6.25–6.35 (pt, 1H, H-3ꢁ), 6.4–6.5 (pt, 1H, H-2ꢁ), 7.3–8.1 (m, 20H,
Ar-H); δC (CDCl3): 18, 60, 71, 78, 84, 93, 121, 125–140, 151, 159, 168 (CO);
m/z (M+): 635, 445, 323, 201, 105, 77; Anal. Found: C, 65.70; H, 4.60; N,
6.72; S, 4.88% C34H26N2O8S requires; C,66.14; H, 4.57; N, 6.61; S, 5.04%.
3-Hydrazino-5-phenyl-2-(2ꢁ,3ꢁ,5ꢁ-tri-O-benzoyl-β-
D-ribofuranosyl)-(2H)-1,2,4-triazole 5
A mixture of the protected nucleoside 3 (15 mmol), absolute ethanol
(50 ml), and hydrazine hydrate (20 ml) was heated under reflux for 2 hours.
Evaporation of the solvent under vacuum gave a colorless solid, which was
crystallized from ethanol/dioxane to give 5 as colorless crystals.
Compound 5: Yield (75%); m.p. 222–224◦C; υ (cm−1) (KBr) 3310, 3190
(NH2, NH), 1750 (CO); δH (DMSO-d6): 4.65–4.90 (m,3H, 2 H-5ꢁ, H-4ꢁ), 5.9
(s, 2H, NH2), 6.2 (d, 1H, H-1ꢁ, J1 ,2 = 4.1 Hz), 6.30–6.35 (pt, 1H, H-3ꢁ),
6.45–6.50 (pt, 1H, H-2ꢁ), 7.25–8.3 (m, 20H, Ar-H), 9.2 (s, 1H, NH); m/z
(M+): 603, Anal. Found: C, 69.5; H, 4.8; N, 6.6%. C35H29N3O7 requires; C,
69.64; H, 4.84; N, 6.96%.
ꢁ
ꢁ
Benzaldehyde and p-Methylbenzaldehyde-[(5-phenyl-2-(2ꢁ,3ꢁ,5ꢁ-tri-
O-benzoyl-β-D-ribofuranosyl)-(2H)-1,2,4-triazol-3-yl]
Hydrazones 6
General method. A mixture of 5 (0.01 mol) and benzaldehyde or p-
methylbenzaldehyde (5 ml each) in ethanol (50 ml) and acetic acid (0.5 ml)
was heated under reflux for 1 hour. The mixture was evaporated to half and
then cooled. The solid formed was filtered and crystallized from ethanol to
give 6 as colorless crystals.
Compound 6a: Yield (48%); m.p. 192–193◦C, υ (cm−1) (KBr) 3311
(NH), 1755 (CO); δH (DMSO-d6): 4.6–4.7 (m, 1H, 4ꢁ-H), 4.85–4.95 (m, 2H,
5ꢁ,5ꢁꢁ-H; 6.0 (d, 1H, J1 ,2 = 4.0 Hz, 1ꢁ-H), 6.2–6.25 (m, 1H, 3ꢁ-H); 6.35–6.45
ꢁ
ꢁ

1,2,4-Triazolo[3,4-c]-1,2,4-triazole Nucleosides
1101
(m, 1H, 2ꢁ-H); 7.2–8.5 (m, 26H, Ar-H & = CH), 9.3 (s, 1H, NH); m/z (M+):
707; Anal. Found: C, 69.2; H, 4.7; N, 10.1%. C41H33N5O7 requires; C,69.58;
H,4.70; N, 9.90%.
Compound 6b: Yield (50%); m.p. 180–182◦C, υ (cm−1) (KBr) 3315
(NH), 1755 (CO); δH (DMSO-d6): 2.2 (s, 3H, CH3), 4.5–4.6 (m, 1H, 4ꢁ-H);
4.75–4.8 (m, 2H, 5ꢁ,5ꢁꢁ- H); 5.95 (d,1H,J1 ,2 = 4.0 Hz, 1ꢁ-H), 6.1–6.2 (m, 1H,
3ꢁ-H); 6.3–4.4 (m, 1H, 2ꢁ-H); 7.3–8.2 (m, 25H, Ar-H & = CH), 9.1 (s, 1H,
NH); m/z (M+): 721; Anal. Found: C, 69.5; H, 4.5; N, 10.0%. C42H35N5O7
requires; C,69.89; H,4.89; N, 9.70%.
ꢁ
ꢁ
1-(2ꢁ,3ꢁ,5ꢁ-Tri-O-benzoyl-β-D-ribofuranosyl)-
5-aryl-3-phenyl–1,2,4-triazolo[3,4-c]-1,2,4-triazole Nucleosides 8
General method. A suspension of 6 (5 mmol) in acetic acid (10 ml) was
treated with bromine (5 ml) in acetic acid (2 ml) dropwise and the reaction
mixture was stirred for 24 hours. It was then diluted with water and the
product was filtered and crystallized from ethanol/dioxane to give 8.
Compound 8a: Yield (65%); m.p. 220–222◦C, υ (cm−1) (KBr) 1765
(CO); λmax (EtOH) (253 nm); δH (DMSO-d6) 4.6–4.7 (m, 1H, 4ꢁ-H);
4.8–4.85 (m, 2H, 5ꢁ,5ꢁꢁ- H); 6.0 (d,1H, J1 ,2 = 2.0 Hz, 1ꢁ-H), 6.1–6.2 (m, 1H,
3ꢁ-H); 6.3–4.4 (m, 1H, 2ꢁ-H); 7.2–8.3 (m, 25H, Ar-H); δC (DMSO-d6): 65, 73,
75, 82, 90, 123, 128–135, 162, 170 (CO); m/z (M+): 705; Anal. Found: C,
68.0; H, 4.5; N, 9.8%. C41H31N5O7 requires; C,69.78; H,4.43; N, 9.92%.
Compound 8b: Yield (70%); m.p. 212–213◦C, υ (cm−1) (KBr) 1760
(CO); λmax (EtOH) (250 nm); δH (DMSO-d6) 2.1 (s, 3H, CH3), 4.5–4.6
ꢁ
ꢁ
(m, 1H, 4ꢁ-H); 4.75–4.8 (m, 2H, 5ꢁ,5ꢁꢁ- H); 6.0 (d,1H, J1 ,2 = 2.0 Hz, 1ꢁ-H),
6.15–6.25 (m, 1H, 3ꢁ-H); 6.3–4.4 (m, 1H, 2ꢁ-H); 7.2–8.3 (m, 24H, Ar-H); δC
(DMSO-d6) 24, 63, 71, 78, 84, 95, 121, 126–136, 160, 169 (CO); m/z (M+):
719; Anal. Found: C, 69.6; H, 4.4; N, 9.5%. C42H33N5O7 requires; C,70.09;
H,4.62; N, 9.73%.
ꢁ
ꢁ
1-(β-D-ribofuranosyl)-5-aryl-3-phenyl-
1,2,4-triazolo[3,4-c]-1,2,4-triazole Nucleosides 9
General method. A mixture of the protected nucleoside 8 (1 mmol),
absolute methanol (20 ml), and sodium methoxide (60 mg, 1.1 mol)
was stirred at room temperature for 24 hours. Evaporation of the solvent
under vacuum gave a colorless solid, which was dissolved in hot water and
neutralized with acetic acid. The precipitate was filtered off and afforded
upon crystallization from water, the nucleosides 9 as colorless crystals.
Compound 9a: Yield (40%); m.p. 245–246◦C, υ (cm−1) (KBr) 3356
(OH); λmax (EtOH) (265 nm); δH (DMSO-d6) 3.5–3.6 (m, 2H, 5ꢁ,5ꢁꢁ-H);
3.9–4.0 (m, 1H,4ꢁ-H); 4.15–4.2 (m, 1H, 3ꢁ-H); 4.35–4.45 (m, 1H, 2ꢁ-H);
4.7–4.8 (t, 1H, 5ꢁ-OH); 5.1–5.2 (d, 1H, 3ꢁ-OH); 5.4–5.5 (d, 1H, 2ꢁ-OH);

1102
M. A. N. Mosselhi and R. Neidlein
6.1–6.2 (d,1H,J1 ,2 = 2.0 Hz, 1ꢁ-H); 7.2–8.0 (m, 10H, Ar-H); m/z (M+): 393;
Anal. Found: C, 60.0; H, 4.5; N, 17.4%. C20H19N5O4 requires; C, 61.06; H,
4.87; N, 17.8%.
ꢁ
ꢁ
Compound 9b: Yield (45%); m.p. 233–234◦C, υ (cm−1) (KBr) 3360
(OH); λmax (EtOH) (260nm); δH (DMSO-d6) 2.0 (s, 3H, CH3), 3.45–3.55
(m, 2H, 5ꢁ,5ꢁꢁ-H); 3.7–3.9 (m, 1H,4ꢁ-H); 4.15–4.25 (m, 1H, 3ꢁ-H); 4.3–4.4 (m,
1H, 2ꢁ-H); 4.65–4.75 (t, 1H, 5ꢁ-OH); 5.1–5.2 (d, 1H, 3ꢁ-OH); 5.4–5.5 (d, 1H,
2ꢁ-OH); 6.1–6.2 (d,1H,J1 ,2 = 2.0 Hz, 1ꢁ-H); 7.2–7.8 (m, 9 H, Ar-H); m/z
(M+): 407; Anal. Found: C, 62.0; H, 5.4; N, 16.8%. C21H21N5O4 requires; C,
61.91; H, 5.2; N, 17.19%.
ꢁ
ꢁ
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